pubmed_id
int64 2.9M
36.8M
| title
stringlengths 1
390
⌀ | abstract
stringlengths 2
11.6k
⌀ |
|---|---|---|
35,710,952 | Cost-effectiveness of Alzheimers disease CSF biomarkers and amyloid-PET in early-onset cognitive impairment diagnosis. | This study aimed at determining the cost-effectiveness of amyloid-positron emission tomography (PET) compared to Alzheimers disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid-β |
35,710,783 | Amyloid-β impairs mitochondrial dynamics and autophagy in Alzheimers disease experimental models. | The most accepted hypothesis in Alzheimers disease (AD) is the amyloid cascade which establishes that Aβ accumulation may induce the disease development. This accumulation may occur years before the clinical symptoms but it has not been elucidated if this accumulation is the cause or the consequence of AD. It is however, clear that Aβ accumulation exerts toxic effects in the cerebral cells. It is important then to investigate all possible associated events that may help to design new therapeutic strategies to defeat or ameliorate the symptoms in AD. Alterations in the mitochondrial physiology have been found in AD but it is not still clear if they could be an early event in the disease progression associated to amyloidosis or other conditions. Using APPPS1 mice, our results support published evidence and show imbalances in the mitochondrial dynamics in the cerebral cortex and hippocampus of these mice representing very early events in the disease progression. We demonstrate in cellular models that these imbalances are consequence of Aβ accumulation that ultimately induce increased mitophagy, a mechanism which selectively removes damaged mitochondria by autophagy. Along with increased mitophagy, we also found that Aβ independently increases autophagy in APPPS1 mice. Therefore, mitochondrial dysfunction could be an early feature in AD, associated with amyloid overload. |
35,710,752 | Primary progressive aphasia ReADing the clinical GRANularity. | Primary progressive aphasia remains a diagnostic challenge despite (or even because of) the increasing availability of ancillary tests and biomarkers. We present a 67-year-old man with apparently sporadic logopenic aphasia and positive Alzheimer biomarkers who was subsequently found also to have a pathogenic mutation in the progranulin gene. This was signalled by early atypical features (mild expressive agrammatism and behavioural change, rapid clinical deterioration) around the core logopenic aphasia syndrome. Each of the canonical progressive aphasia syndromes has a halo of less typical variants that may herald alternative or additional pathologies. The accurate diagnosis of primary progressive aphasia depends on careful clinical analysis to direct investigations appropriately. |
35,710,549 | Establishment of combined diagnostic models of Alzheimers disease in a Chinese cohort the Chongqing Ageing Dementia Study (CADS). | Cerebrospinal fluid (CSF) biomarkers are essential for the accurate diagnosis of Alzheimers disease (AD), yet their measurement levels vary widely across centers and regions, leaving no uniform cutoff values to date. Diagnostic cutoff values of CSF biomarkers for AD are lacking for the Chinese population. As a member of the Alzheimers Association Quality Control program for CSF biomarkers, we aimed to establish diagnostic models based on CSF biomarkers and risk factors for AD in a Chinese cohort. A total of 64 AD dementia patients and 105 age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing Dementia Study cohort were included. CSF Aβ42, P-tau181, and T-tau levels were measured by ELISA. Combined biomarker models and integrative models with demographic characteristics were established by logistic regression. The cutoff values to distinguish AD from CN were 933 pgmL for Aβ42, 48.7 pgmL for P-tau181 and 313 pgmL for T-tau. The AN model, including Aβ42 and T-tau, had a higher diagnostic accuracy of 89.9%. Integrating age and APOE ε4 status to AN model (the ANAE model) increased the diagnostic accuracy to 90.5% and improved the model performance. This study established cutoff values of CSF biomarkers and optimal combined models for AD diagnosis in a Chinese cohort. |
35,710,453 | Hormone therapy and the decreased risk of dementia in women with depression a population-based cohort study. | The literature has shown depression to be associated with an increased risk of dementia. In addition, hormone therapy can be a responsive treatment option for a certain type of depression. In this study, we examined the association between hormone therapy, including lifetime oral contraceptive (OC) use, and hormone replacement therapy (HRT) after menopause with the occurrence of dementia among female patients with depression. The South Korean national claims data from January 1, 2005, to December 31, 2018, was used. Female subjects aged 40 years or older with depression were included in the analyses. Information on hormone therapy was identified from health examination data and followed up for the occurrence of dementia during the average follow-up period of 7.72 years. Among 209,588 subjects, 23,555 were diagnosed with Alzheimers disease (AD) and 3023 with vascular dementia (VD). Lifetime OC usage was associated with a decreased risk of AD (OC use for < 1 year HR, 0.92 95% CI, 0.88-0.97 OC use for ≥ 1 year HR, 0.89 95% CI, 0.84-0.94), and HRT after menopause was associated with a decreased risk of AD (HRT for < 2 years HR, 0.84 95% CI, 0.79-0.89 HRT for 2-5 years HR, 0.80 95% CI, 0.74-0.88 and HRT for ≥ 5 years HR, 0.78 95% CI, 0.71-0.85) and VD (HRT < 2 years HR, 0.82 95% CI, 0.71-0.96 HRT for 2-5 years HR, 0.81 95% CI, 0.64-1.02 and HRT for ≥ 5 years HR, 0.61 95% CI, 0.47-0.79). In this nationwide cohort study, lifetime OC use was associated with a decreased risk of AD, and HRT after menopause was associated with a decreased risk of AD and VD among female patients with depression. However, further studies are needed to establish causality. |
35,710,131 | Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders. | Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated |
35,710,076 | The potential use of tetracyclines in neurodegenerative diseases and the role of nano-based drug delivery systems. | Neurodegenerative diseases are still a challenge for effective treatments. The high cost of approved drugs, severity of side effects, injection site pain, and restrictions on drug delivery to the Central Nervous System (CNS) can overshadow the management of these diseases. Due to the chronic and progressive evolution of neurodegenerative disorders and since there is still no cure for them, new therapeutic strategies such as the combination of several drugs or the use of existing drugs with new therapeutic applications are valuable strategies. Tetracyclines are traditionally classified as antibiotics. However, in this class of drugs, doxycycline and minocycline exhibit also anti-inflammatory effects by inhibiting microgliamacrophages. Hence, they have been studied as potential agents for the treatment of neurodegenerative diseases. The results of in vitro and in vivo studies confirm the effective role of these two drugs as anti-inflammatory agents in experimentally induced models of neurodegenerative diseases. In clinical studies, satisfactory results have been obtained in Multiple sclerosis (MS) but not yet in other disorders such as Alzheimers disease (AD), Parkinsons disease (PD), or Amyotrophic lateral sclerosis (ALS). In recent years, researchers have developed and evaluated nanoparticulate drug delivery systems to improve the clinical efficacy of these two tetracyclines for their potential application in neurodegenerative diseases. This study reviews the neuroprotective roles of minocycline and doxycycline in four of the main neurodegenerative disorders AD, PD, ALS and MS. Moreover, the potential applications of nanoparticulate delivery systems developed for both tetracyclines are also reviewed. |
35,709,892 | Identification of potential therapeutic and diagnostic characteristics of Alzheimer disease by targeting the miR-132-3pFOXO3a-PPM1F axis in APPPS1 mice. | Alzheimer disease (AD) is a neurodegenerative disorder, which is characterized by progressive impairment of memory and cognition. Early diagnosis and treatment of AD has become a leading topic of research. In this study, we explored the effects of the miR-132-3pFOXO3a-PPM1F axis on the onset of AD for possible early diagnosis and therapy. We found that miR-132-3p levels in the hippocampus and blood were drastically decreased in APPPS1 mice from 9 months of age, and bi-directional manipulation of miR-132-3p levels induced magnified effects on learning memory behaviors, and manifestation of AD-related pathological characteristics and inflammatory cytokines in APPPS1 mice of relevant ages. The hippocampal PPM1F expression levels were significantly elevated in APPPS1 mice from 3 months of age, which was correlated with miR-132-3p levels at different ages. Overexpression of PPM1F remarkably accelerated the progression of learning memory deficits and associated pathological factors in APPPS1 mice. Further, we showed that miR-132-3p modulated the expression of PPM1F via FOXO3a in HT22 cells. Finally, using peripheral blood samples of human study participants, we found that the miR-132-3p and PPM1F expression levels in patients with AD were also altered with prominent correlations. In conclusion, miR-132-3p indirectly regulates PPM1F expression by targeting FOXO3a, which could play an extensive role in contributing to the establishment of early diagnosis, treatment, and pathogenesis of AD. |
35,709,880 | Association between late maternal age and age-related endophenotypes in the Long Life Family Study. | Extended maternal age has been suggested as marker of delayed age-associated disabilities. We use the Long Life Family Study (LLFS) offspring generation to investigate the association between extended maternal age at last childbirth and healthy-aging endophenotypes. We hypothesize that women with extended maternal age at last childbirth will exhibit healthier endophenotype profiles compared to younger mothers. The association between maternal age and age-related endophenotypes previously derived in LLFS was assessed using Generalized Estimating Equations to adjust for relatedness. The quartiles of the maternal age at last childbirth were modeled as the independent variables. Univariate analyses tested the association between maternal age at last childbirth and age at clinical assessment, education, field center, Apolipoprotein E (APOE) genotype, depression, stress, smoking and successful pregnancies. Only the variables significantly associated in the univariate analyses were considered in secondary multivariate analyses. Univariate analyses showed that compared to older mothers (age at last birth ≥35), mothers 30 years old or younger at last childbirth are less educated (12 ± 3 years versus 13 ± 3 years) and have a higher frequency of smoking (9% versus 3% for maternal age ≥35). Results showed that older mothers (age at last birth ≥31-34 or ≥ 35) demonstrated significantly better cognitive profiles (p 0.017 and p 0.021 respectively) compared with mothers with last childbirth age ≤30. Later maternal age among women from long-life families is associated with a better cognitive profile, supporting the hypothesis that later age at childbirth may be a marker for healthy aging. |
35,709,657 | Interferon beta attenuates recognition memory impairment and improves brain glucose uptake in a rat model of Alzheimers disease Involvement of mitochondrial biogenesis and PI3K pathway. | Interferon beta (IFNβ) is a cytokine with anti-apoptotic and anti-inflammatory properties, and its beneficial effects on Alzheimers disease (AD) have been recently shown. The alterations in cerebral glucose uptake are closely linked to memory deficit and AD progression. The current study was designed to determine if IFNβ can improve recognition memory and brain glucose uptake in a rat model of AD. The lentiviruses expressing mutant human amyloid precursor protein were injected bilaterally to the rat hippocampus. From day 23 after virus injection, rats were intranasally treated with recombinant IFNβ protein (68,000 IUrat) every other day until day 50. Recognition memory performance was evaluated by novel object recognition test on days 46-49. The 18F-2- fluoro-deoxy-d-glucose positron emission tomography (18F-FDG-PET) was used to determine changes in brain glucose metabolism on day 50. The expression of the PI3KAkt pathway components, neurotrophins and mitochondrial biogenesis factors were also measured by qPCR in the hippocampus. Our results showed that IFNβ treatment improves recognition memory performance in parallel with increased glucose uptake and neuronal survival in the hippocampus of the AD rats. The neuroprotective effect of IFNβ could be attributed, at least partly, to activation of PI3K-Akt-mTOR signaling pathway, increased expression of NGF, and mitochondrial biogenesis. Taken together, our findings suggest the therapeutic potential of IFNβ for AD. |
35,709,605 | Bifunctional super-hydrophilic mesoporous nanocomposite a novel nanoprobe for investigation of glycosylation and phosphorylation in Alzheimers disease. | Alzheimers disease (AD) is a common neurodegenerative disease. Abnormal glycosylation and phosphorylation modification in AD may be closely related to its pathology. It is of substantial practical significance to simultaneously investigate the roles of phosphorylation and glycosylation in AD. In this work, a bifunctional super-hydrophilic mesoporous nanocomposite (denoted mTiO |
35,709,556 | Metabolic brain pattern in dementia with Lewy bodies Relationship to Alzheimers disease topography. | Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, that shares clinical and metabolic similarities with both Alzheimers and Parkinsons disease. In this study we aimed to identify a DLB-related pattern (DLBRP), study its relationship with other metabolic brain patterns and explore its diagnostic and prognostic value. A cohort of 79 participants with DLB, 63 with dementia due to Alzheimers disease (AD) and 41 normal controls (NCs) and their 2- The newly identified DLBRP shared topographic similarities with ADRP (R DLBRP has proven to be a specific metabolic brain biomarker of DLB, sharing similarities with ADRP and PDRP, but not PDCP. We observed a similar metabolic mechanism underlying cognitive impairment in DLB and AD. DLB-specific metabolic changes were more detrimental for overall survival. |
35,709,536 | Neuropathology of depression in non-demented older adults A large postmortem study of 741 individuals. | Associations between age-related neuropathological lesions and adult-onset lifetime major depressive disorder (a-MDD), late-life MDD (LLD), or depressive symptoms close to death (DS) were examined in a large community sample of non-demented older adults. Seven hundred forty-one individuals (age at death 72.2 ± 11.7 years) from the Biobank for Aging Studies were analyzed. a-MDD was present in 54 (7.3%) participants, LLD in 80 (10.8%), and DS in 168 (22.7%). After adjustment for covariates and compared to controls, a-MDD, LDD and DS were associated with small vessel disease (p 0.039, p 0.003, and p 0.003 respectively) LLD, and DS were associated with brain infarcts (p 0.012, p 0.018, respectively) and Lewy body disease (p 0.043, p 0.002, respectively). DS was associated with beta-amyloid plaque burden (p 0.027) and cerebral amyloid angiopathy (p 0.035) in cognitively normal individuals (Clinical Dementia Rating scale 0). Vascular brain pathology was the strongest correlate of clinical depictions of depression in the absence of dementia, corroborating the vascular hypothesis of depression. Lewy body pathology underlay DS. An older adult with DS or LLD should be monitored for possible cognitive decline or neurodegenerative disorders. |
35,709,193 | Comparative assessment of cognitive impairment and oxidative stress markers among vitamin D insufficient elderly patients with and without type 2 diabetes mellitus (T2DM). | Disorders of mental health are known to affect cognitive functions, hence called as cognitive disorders. Impaired glucose metabolism, insulin resistance, vitamin-D deficiency and oxidative stress are some of the key early events reported to be involved in the pathogenesis of most common cognitive disorders, which include Alzheimers disease. Type-2 diabetes mellitus (T2DM) is one of the known contributing factors of cognitive impairment and dementia. A cross sectional study was carried out in 145 subjects, who were assessed for cognitive function by modified mini mental status examination (3MS). In addition, measurement of fasting blood sugar (FBS), fasting insulin, HbA1c, lipid profile, vitamin D and oxidative markers was performed. Participants were divided into different groups based on (a) vitamin D insufficiency and sufficiency (b) diabetic and non-diabetic with and without cognitive impairment. The study included a total of 145 subjects 51 males and 94 females and the mean age was 68.24±9.70 years. Among diabetics with vitamin D insufficiency, 35 subjects (71.43%) had cognitive impairment, but, among non-diabetics with vitamin D insufficiency, 27 subjects (62.79%) had cognitive impairment. Chi square test showed no significant association between diabetes, vitamin D insufficiency and cognitive impairment. Glutathione peroxidase (GPx) and superoxide dismutase (SOD) levels were non-significantly lower in cognition-impaired subjects, when compared to cognition normal subjects in diabetics with vitamin D insufficiency. Our study showed that cognitive impairment is more predominant in individuals with diabetes. However, our study did not find any significant relationship between T2DM, vitamin D deficiency, cognitive impairment, and oxidative stress. A significant association was found only with GPx and 3MSE score in vitamin D insufficient non-diabetics. |
35,709,174 | Augmented risk of dementia in hypertrophic cardiomyopathy A propensity score matching analysis using the nationwide cohort. | Dementia is a big medical and socioeconomic problem on aging society, and cardiac diseases have already shown a significant contribution to developing dementia. However, the risk of dementia related to hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, has never been evaluated. In a large-scale longitudinal cohort using National Health Insurance database, 4,645 subjects with HCM aged ≥50 years between 2010 and 2016 were collected and matched with 13,935 controls, based on propensity scores (13). We investigated the incidence and risk of dementia, Alzheimers disease (AD), and vascular dementia (VaD) between groups. During follow-up (median 3.9 years after 1-year lag), incident dementia occurred in 739 subjects (4.0%) 78.2% for AD and 13.0% for VaD. The incidence of dementia, AD, and VaD were 23.0, 18.0, and 2.91,000 person-years, respectively, and was generally more prevalent in HCM. HCM group had a 50% increased risk of dementia, particularly AD, whereas there was no difference in the risk of VaD. The impact of HCM on AD (HR 1.52, 95% CI 1.26-1.84, p<0.001) was comparable with that of diabetes mellitus and smoking. Increased risk of AD in relation to HCM was consistent in various subgroups including younger healthier population. This is the first to demonstrate the increased risk of dementia, mainly AD rather than VaD, in subjects with HCM. Early surveillance and active prevention for cognitive impairment could help for a better quality of life in an era that HCM is considered a chronic manageable disease with low mortality. |
35,709,018 | Clinical judgement by primary care physicians for the diagnosis of all-cause dementia or cognitive impairment in symptomatic people. | In primary care, general practitioners (GPs) unavoidably reach a clinical judgement about a patient as part of their encounter with patients, and so clinical judgement can be an important part of the diagnostic evaluation. Typically clinical decision making about what to do next for a patient incorporates clinical judgement about the diagnosis with severity of symptoms and patient factors, such as their ideas and expectations for treatment. When evaluating patients for dementia, many GPs report using their own judgement to evaluate cognition, using information that is immediately available at the point of care, to decide whether someone has or does not have dementia, rather than more formal tests. To determine the diagnostic accuracy of GPs clinical judgement for diagnosing cognitive impairment and dementia in symptomatic people presenting to primary care. To investigate the heterogeneity of test accuracy in the included studies. We searched MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), Web of Science Core Collection (ISI Web of Science), and LILACs (BIREME) on 16 September 2021. We selected cross-sectional and cohort studies from primary care where clinical judgement was determined by a GP either prospectively (after consulting with a patient who has presented to a specific encounter with the doctor) or retrospectively (based on knowledge of the patient and review of the medical notes, but not relating to a specific encounter with the patient). The target conditions were dementia and cognitive impairment (mild cognitive impairment and dementia) and we included studies with any appropriate reference standard such as the Diagnostic and Statistical Manual of Mental Disorders (DSM), International Classification of Diseases (ICD), aetiological definitions, or expert clinical diagnosis. Two review authors screened titles and abstracts for relevant articles and extracted data separately with differences resolved by consensus discussion. We used QUADAS-2 to evaluate the risk of bias and concerns about applicability in each study using anchoring statements. We performed meta-analysis using the bivariate method. We identified 18,202 potentially relevant articles, of which 12,427 remained after de-duplication. We assessed 57 full-text articles and extracted data on 11 studies (17 papers), of which 10 studies had quantitative data. We included eight studies in the meta-analysis for the target condition dementia and four studies for the target condition cognitive impairment. Most studies were at low risk of bias as assessed with the QUADAS-2 tool, except for the flow and timing domain where four studies were at high risk of bias, and the reference standard domain where two studies were at high risk of bias. Most studies had low concern about applicability to the review question in all QUADAS-2 domains. Average age ranged from 73 years to 83 years (weighted average 77 years). The percentage of female participants in studies ranged from 47% to 100%. The percentage of people with a final diagnosis of dementia was between 2% and 56% across studies (a weighted average of 21%). For the target condition dementia, in individual studies sensitivity ranged from 34% to 91% and specificity ranged from 58% to 99%. In the meta-analysis for dementia as the target condition, in eight studies in which a total of 826 of 2790 participants had dementia, the summary diagnostic accuracy of clinical judgement of general practitioners was sensitivity 58% (95% confidence interval (CI) 43% to 72%), specificity 89% (95% CI 79% to 95%), positive likelihood ratio 5.3 (95% CI 2.4 to 8.2), and negative likelihood ratio 0.47 (95% CI 0.33 to 0.61). For the target condition cognitive impairment, in individual studies sensitivity ranged from 58% to 97% and specificity ranged from 40% to 88%. The summary diagnostic accuracy of clinical judgement of general practitioners in four studies in which a total of 594 of 1497 participants had cognitive impairment was sensitivity 84% (95% CI 60% to 95%), specificity 73% (95% CI 50% to 88%), positive likelihood ratio 3.1 (95% CI 1.4 to 4.7), and negative likelihood ratio 0.23 (95% CI 0.06 to 0.40). It was impossible to draw firm conclusions in the analysis of heterogeneity because there were small numbers of studies. For specificity we found the data were compatible with studies that used ICD-10, or applied retrospective judgement, had higher reported specificity compared to studies with DSM definitions or using prospective judgement. In contrast for sensitivity, we found studies that used a prospective index test may have had higher sensitivity than studies that used a retrospective index test. Clinical judgement of GPs is more specific than sensitive for the diagnosis of dementia. It would be necessary to use additional tests to confirm the diagnosis for either target condition, or to confirm the absence of the target conditions, but clinical judgement may inform the choice of further testing. Many people who a GP judges as having dementia will have the condition. People with false negative diagnoses are likely to have less severe disease and some could be identified by using more formal testing in people who GPs judge as not having dementia. Some false positives may require similar practical support to those with dementia, but some - such as some people with depression - may suffer delayed intervention for an alternative treatable pathology. |
35,708,996 | Evaluation of an education intervention for Australian health practitioners to support people with dementia with driving decisions A pretest-posttest survey. | Drivers with dementia will at some stage need to stop driving. The timing of driving retirement is informed by the advice of health practitioners, however many find this task complex and challenging as they feel unprepared or lack confidence, having limited training and education on dementia and driving. Few opportunities exist for Australian health practitioners to advance learning about dementia and driving. This study evaluated the impact of a Dementia and Driving Education Module on practitioner self-perceived knowledge, confidence, and competence in supporting people living with dementia with decisions about driving. A single group, pretest-posttest survey was conducted for this study. Health practitioners were recruited over 19 months via email and invited to attend a face-to-face dementia and driving workshop. The workshop comprised of a two-hour Dementia and Driving Education Module including seven learning activities incorporating six vignettes, five self-reflections, one case study and a paper copy of a dementia and driving decision aid. Participants completed a survey prior to, immediately after and six weeks post completion of the education module. A total of 240 health practitioners, from over six disciplines, took part in one of eleven workshops delivered via face-to-face and online across five states of Australia. Significant increases occurred in all outcome measures of perceived knowledge, confidence and competence between baseline and immediately post-education module survey responses and between baseline and six weeks post-survey responses. The Dementia and Driving Education Module and accompanying decision aid demonstrate an efficacious solution for a diverse range of health practitioners to enhance their knowledge, confidence, and competence in supporting people living with dementia with driving retirement decisions. |
35,708,851 | Sex Differences in Innate Immune Response of Peripheral Blood Leukocytes of Alzheimers Disease Patients. | Neurodegenerative disorders, including Alzheimers disease (AD), are associated with a disruption of normal immune function that could potentially impact the brain. In AD sex and gender have been noted as relevant to disease prevalence or clinical manifestation. It is suggested that disease progression could vary as a result of the different inflammation state among males and females. The objective was to investigate sex-dependent difference in innate immunity of AD patients and healthy, age-matched controls. The level of innate immunity was measured with test based on peripheral blood leukocytes (PBLs) resistance to viral infection (vesicular stomatitis virus, VSV) ex vivo. Cytokine TNF-α, IFN-γ, IL-1β, IL-10 production by uninfected and VSV-infected PBLs ex vivo with enzyme-linked immunosorbent assay were examined. In contrast to controls, women with AD exhibit lower average level of innate immunity than AD men. The mean level of TNF-α, IL-10 and IL-1β was higher in AD men than in AD women whereas such changes were not observed among controls. The level of IFN-γ was higher in AD than in controls. PBLs from AD did not increase IFN-γ production after viral infection in contrast to controls. Leukocytes from women with AD exhibited a weaker response to viral infection and much less cytokine production compared to men with AD. It is important to consider sex as a biological variable in AD as it shows promises to advance our understanding of mechanisms of AD pathology and may be the basis for future treatment of AD. |
35,708,789 | Progressive medial temporal degeneration with TDP-43 pathology is associated with upper limb and bulbar onset types of amyotrophic lateral sclerosis. | This study aimed to clarify the relationship between progressive medial temporal atrophy and onset subtype in patients with amyotrophic lateral sclerosis (ALS). Medial temporal atrophy, ALS functional rating scale (ALSFRS), and cognitive function were assessed in 119 patients who were grouped into three ALS subtypes bulbar, upper limb, and lower limb onset. Medial temporal atrophy, represented by a Z-score, was determined using an analysis software of magnetic resonance images known as the voxel-based specific regional analysis system for Alzheimers disease (VSRAD). Among 119 patients, 60 underwent follow-up VSRAD, ALSFRS, and cognitive testing. The sequential data were compared among onset subtypes. Furthermore, TDP-43 pathology was assessed in 20 autopsied patients (including seven who underwent VSRAD before death) to examine the relationships among medial temporal atrophy, onset subtypes, and severity of the hippocampal TDP-43 pathology. Multiple regression analysis revealed that the Z-score at baseline was associated with the age of onset and duration of illness. A high Z-score at baseline and the bulbarupper limb subtypes affected the progression rate of Z-score. Pathological examination revealed increased hippocampal TDP-43 pathology score associated with bulbar and upper limb subtypes. Moreover, the Z-score before death correlated with the hippocampal TDP-43 pathology score. Medial temporal atrophy in ALS is associated with bulbar and upper limb onset subtypes. This progression may be related to the extent of TDP-43 pathology. |
35,708,626 | Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia. | Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children. |
35,708,486 | Novel genes and sex differences in COVID-19 severity. | Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P 1.3 × 10-22 and P 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P 2.7 × 10-8) and ARHGAP33 (P 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided. |
35,708,472 | Neuroinflammation A Distal Consequence of Periodontitis. | Periodontitis, a chronic, inflammatory disease, induces systemic inflammation and contributes to the development of neurodegenerative diseases. The precise etiology of the most common neurodegenerative disorders, such as sporadic Alzheimers, Parkinsons diseases and multiple sclerosis (AD, PD, and MS, respectively), remains to be revealed. Chronic neuroinflammation is a well-recognized component of these disorders, and evidence suggests that systemic inflammation is a possible stimulus for neuroinflammation development. Systemic inflammation can lead to deleterious consequences on the brain if the inflammation is sufficiently severe or if the brain shows vulnerabilities due to genetic predisposition, aging, or neurodegenerative diseases. It has been proposed that periodontal disease can initiate or contribute to the AD pathogenesis through multiple pathways, including key periodontal pathogens. Dysbiotic oral bacteria can release bacterial products into the bloodstream and eventually cross the brain-blood barrier these bacteria can also cause alterations to gut microbiota that enhance inflammation and potentially affect brain function via the gut-brain axis. The trigeminal nerve has been suggested as another route for connecting oral bacterial products to the brain. PD and MS are often preceded by gastrointestinal symptoms or aberrant gut microbiome composition, and alterations in the enteric nervous system accompany the disease. Clinical evidence has suggested that patients with periodontitis are at a higher risk of developing PD and MS. This nexus among the brain, periodontal disease, and systemic inflammation heralds new ways in which microglial cells, the main innate immune cells, and astrocytes, the crucial regulators of innate and adaptive immune responses in the brain, contribute to brain pathology. Currently, the lack of understanding of the pathogenesis of neurodegeneration is hindering treatment development. However, we may prevent this pathogenesis by tackling one of its possible contributors (periodontitis) for systemic inflammation through simple preventive oral hygiene measures. |
35,708,183 | Cardiometabolic multimorbidity accelerates cognitive decline and dementia progression. | Cardiometabolic diseases (CMDs) have been individually associated with adverse cognitive outcomes, but their combined effect has not been investigated. A total of 2577 dementia-free participants 60 years of age or older were followed for 12 years to observe changes in cognitive function and to detect incident cognitive impairment, no dementia (CIND) and dementia. CMDs (including type 2 diabetes, heart disease, and stroke) were assessed at baseline through medical records and clinical examinations. Cardiometabolic multimorbidity was defined as the presence of two or more CMDs. Data were analyzed using multi-adjusted linear mixed-effects models, Cox regression, and Laplace regression. CMD multimorbidity was associated with cognitive decline, CIND (hazard ratio HR 1.73 95% confidence interval CI 1.23 to 2.44), and its progression to dementia (HR 1.86 95% CI 1.17 to 2.97). CMD multimorbidity accelerated the onset of CIND by 2.3 years and dementia by 1.8 years. CMD multimorbidity accelerates cognitive decline and increases the risk of both CIND and its conversion to dementia. We explored the combined impact of cardiometabolic diseases (CMDs) on cognition. An increasing number of CMDs dose-dependently accelerated cognitive decline. CMD multimorbidity increased the risk of both cognitive impairment and dementia. Co-morbid CMDs could be ideal targets for interventions to protect cognitive health. |
35,708,095 | The importance of AMPK in obesity and chronic diseases and the relationship of AMPK with nutrition a literature review. | This review will examine the role of 5-adenosine monophosphate-activated protein kinase (AMPK) in the treatment of obesity, medical nutrition and chronic diseases, and its relationship with nutrition. In the literature, the number of studies examining the direct relationship of AMPK with nutrition is negligible. For this reason, information on the subject has been compiled from all the studies that can be accessed by searching the terms AMPK and disease, AMPK and health, AMPK and exercise, AMPK and nutrition. It can be stated that AMPK is inhibited in many pathological conditions such as inflammation, diabetes, aging and cancer, and AMPK activation has positive effects in many diseases such as insulin resistance, diabetes, obesity, cancer and Alzheimers. When the relationship between nutrition and AMPK is examined, it is seen that food intake inhibits AMPK, but especially high-carbohydrate and fatty diets are more effective at this point. In addition, high fructose corn sirup and long chain saturated fatty acids increased by consumption of industrial foods and frequent meals appear to be an inactivator for AMPK. For AMPK activation in medical nutrition therapy, it is recommended to use methods such as evening fasting and intermittent fasting, taking into account the human circadian rhythm. |
35,708,081 | Neuropharmacology of Organoselenium Compounds in Mental Disorders and Degenerative Diseases. | Neurodegenerative and mental disorders are a public health burden with pharmacological treatments of limited efficacy. Organoselenium compounds are receiving great attention in medicinal chemistry mainly because of their antioxidant and immunomodulatory activities, with a multi-target profile that can favor the treatment of multifactorial diseases. Therefore, the purpose of this review is to discuss recent preclinical studies about organoselenium compounds as therapeutic agents for the management of mental (e.g., depression, anxiety, bipolar disorder, and schizophrenia) and neurodegenerative diseases (e.g., Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis, and multiple sclerosis). We have summarized around 70 peer-reviewed articles from 2016 to the present that used in silico, in vitro, andor in vivo approaches to assess the neuropharmacology of selenium-containing compounds. Among the diversity of organoselenium molecules investigated in the last five years, diaryl diselenides, Ebselen-derivatives, and Se-containing heterocycles are the most representative. Ultimately, this review is expected to provide disease-oriented information regarding the neuropharmacology of organoselenium compounds that can be useful for the design, synthesis, and pharmacological characterization of novel bioactive molecules that can potentially be clinically viable candidates. |
35,708,049 | Health benefits of astaxanthin against age-related diseases of multiple organs A comprehensive review. | Age-related diseases are associated with increased morbidity in the past few decades and the cost associated with the treatment of these age-related diseases exerts a substantial impact on social and health care expenditure. Anti-aging strategies aim to mitigate, delay and reverse aging-associated diseases, thereby improving quality of life and reducing the burden of age-related pathologies. The natural dietary antioxidant supplementation offers substantial pharmacological and therapeutic effects against various disease conditions. Astaxanthin is one such natural carotenoid with superior antioxidant activity than other carotenoids, as well as well as vitamins C and E, and additionally, it is known to exhibit a plethora of pharmacological effects. The present review summarizes the protective molecular mechanisms of actions of astaxanthin on age-related diseases of multiple organs such as Neurodegenerative diseases Alzheimers disease (AD), Parkinsons disease (PD), Stroke, Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Status Epilepticus (SE), Bone Related Diseases Osteoarthritis (OA) and Osteoporosis, Cancers Colon cancer, Prostate cancer, Breast cancer, and Lung Cancer, Cardiovascular disorders Hypertension, Atherosclerosis and Myocardial infarction (MI), Diabetes associated complications Diabetic nephropathy (DN), Diabetic neuropathy, and Diabetic retinopathy (DR), Eye disorders Age related macular degeneration (AMD), Dry eye disease (DED), Cataract and Uveitis, Gastric Disorders Gastritis, Colitis, and Functional dyspepsia, Kidney Disorders Nephrolithiasis, Renal fibrosis, Renal Ischemia reperfusion (RIR), Acute kidney injury (AKI), and hyperuricemia, Liver Diseases Nonalcoholic fatty liver disease (NAFLD), Alcoholic Liver Disease (AFLD), Liver fibrosis, and Hepatic Ischemia-Reperfusion (IR) Injury, Pulmonary Disorders Pulmonary Fibrosis, Acute Lung injury (ALI), and Chronic obstructive pulmonary disease (COPD), Muscle disorders (skeletal muscle atrophy), Skin diseases Atopic dermatitis (ATD), Skin Photoaging, and Wound healing. We have also briefly discussed astaxanthins protective effects on reproductive health. |
35,708,011 | Assessment of Instrumental Activities of Daily Living in Preclinical Alzheimer Disease. | Questionnaires are used to assess instrumental activities of daily living (IADL) among individuals with preclinical Alzheimer disease (AD). They have indicated no functional impairment among this population. We aim to determine among cognitively normal (CN) older adults with and without preclinical AD whether (a) performance-based IADL assessment measures a wider range of function than an IADL questionnaire and (b) biomarkers of AD are associated with IADL performance. In this cross-sectional analysis of 161 older adults, participants in studies of AD completed an IADL questionnaire, performance-based IADL assessment, cognitive assessments, and had biomarkers of AD (amyloid, hippocampal volume, brain network strength) assessed within 2 to 3 years. Performance-based IADL scores were more widely distributed compared with the IADL questionnaire. Smaller hippocampal volumes and reduced brain network connections were associated with worse IADL performance. A performance-based IADL assessment demonstrates functional impairment associated with neurodegeneration among CN older adults. |
35,707,770 | Evaluation of Utilizing the Distinct Genes as Predictive Biomarkers in Late-Onset Alzheimers Disease. | Alzheimers disease (AD) is a neurodegenerative disease that is characterized by a devastating decline in cognitive activities among all types of dementia, and it severely affects the quality of life. Late-onset AD (LOAD) occurs after the age of 65 years and develops sporadically. Although aging comes first along the main risk factors underlying LOAD, disease-causing susceptibility genes have been associated with disease pathogenesis. In our study, we included the genes |
35,707,703 | Alzheimers Disease Diagnosis and Biomarker Analysis Using Resting-State Functional MRI Functional Brain Network With Multi-Measures Features and Hippocampal Subfield and Amygdala Volume of Structural MRI. | Accurate diagnosis of the initial phase of Alzheimers disease (AD) is essential and crucial. The objective of this research was to employ efficient biomarkers for the diagnostic analysis and classification of AD based on combining structural MRI (sMRI) and resting-state functional MRI (rs-fMRI). So far, several anatomical MRI imaging markers for AD diagnosis have been identified. The use of cortical and subcortical volumes, the hippocampus, and amygdala volume, as well as genetic patterns, has proven to be beneficial in distinguishing patients with AD from the healthy population. The fMRI time series data have the potential for specific numerical information as well as dynamic temporal information. Voxel and graphical analyses have gained popularity for analyzing neurodegenerative diseases, such as Alzheimers and its prodromal phase, mild cognitive impairment (MCI). So far, these approaches have been utilized separately for the diagnosis of AD. In recent studies, the classification of cases of MCI into those that are not converted for a certain period as stable MCI (MCIs) and those that converted to AD as MCIc has been less commonly reported with inconsistent results. In this study, we verified and validated the potency of a proposed diagnostic framework to identify AD and differentiate MCIs from MCIc by utilizing the efficient biomarkers obtained from sMRI, along with functional brain networks of the frequency range .01-.027 at the resting state and the voxel-based features. The latter mainly included default mode networks (amplitude of low-frequency fluctuation ALFF, fractional ALFF ALFF, and regional homogeneity ReHo), degree centrality (DC), and salience networks (SN). Pearsons correlation coefficient for measuring fMRI functional networks has proven to be an efficient means for disease diagnosis. We applied the graph theory to calculate nodal features (nodal degree ND, nodal path length NL, and between centrality BC) as a graphical feature and analyzed the connectivity link between different brain regions. We extracted three-dimensional (3D) patterns to calculate regional coherence and then implement a univariate statistical |
35,707,700 | Effects of Sex on the Relationship Between Apolipoprotein E Gene and Serum Lipid Profiles in Alzheimers Disease. | Sex is an important factor in studying the relationship between the A total of 549 participants, including 298 AD patients and 251 body mass index (BMI)-matched healthy controls (HCs), were enrolled. Lipid profiles and (1) TC and LDL were higher in AD patients than in HCs, only in The TC and LDL levels of |
35,707,699 | Diagnosis of Amnesic Mild Cognitive Impairment Using MGS-WBC and VGBN-LM Algorithms. | Computer-aided diagnosis (CAD) has undergone rapid development with the advent of advanced neuroimaging and machine learning methods. Nevertheless, how to extract discriminative features from the limited and high-dimensional data is not ideal, especially for amnesic mild cognitive impairment (aMCI) data based on resting-state functional magnetic resonance imaging (rs-fMRI). Furthermore, a robust and reliable system for aMCI detection is conducive to timely detecting and screening subjects at a high risk of Alzheimers disease (AD). In this scenario, we first develop the mask generation strategy based on within-class and between-class criterion (MGS-WBC), which primarily aims at reducing data redundancy and excavating multiscale features of the brain. Concurrently, vector generation for brain networks based on Laplacian matrix (VGBN-LM) is presented to obtain the global features of the functional network. Finally, all multiscale features are fused to further improve the diagnostic performance of aMCI. Typical classifiers for small data learning, such as naive Bayesian (NB), linear discriminant analysis (LDA), logistic regression (LR), and support vector machines (SVMs), are adopted to evaluate the diagnostic performance of aMCI. This study helps to reveal discriminative neuroimaging features, and outperforms the state-of-the-art methods, providing new insights for the intelligent construction of CAD system of aMCI. |
35,707,521 | Phytocannabinoids and Cannabis-Based Products as Alternative Pharmacotherapy in Neurodegenerative Diseases From Hypothesis to Clinical Practice. | Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide. Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders. In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimers disease, Parkinsons disease and Multiple Sclerosiss patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system. In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines. |
35,707,205 | Cross-species metabolomic analysis of tau- and DDT-related toxicity. | Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with increased risk of Alzheimers disease (AD), a disease also associated with hyperphosphorylated tau (p-tau) protein aggregation. We investigated whether exposure to DDT can exacerbate tau protein toxicity in |
35,706,935 | Liposomes An emerging carrier for targeting Alzheimers and Parkinsons diseases. | The function of the brain can be affected by various factors that include infection, tumor, and stroke. The major disorders reported with altered brain function are Alzheimers disease (AD), Parkinsons disease (PD), dementia, brain cancer, seizures, mental disorders, and other movement disorders. The major barrier in treating CNS disease is the blood-brain barrier (BBB), which protects the brain from toxic molecules, and the cerebrospinal fluid (CSF) barrier, which separates blood from CSF. Brain endothelial cells and perivascular elements provide an integrated cellular barrier, the BBB, which hamper the invasion of molecules from the blood to the brain. Even though many drugs are available to treat neurological disorders, it fails to reach the desired site with the required concentration. In this purview, liposomes can carry required concentrations of molecules intracellular by diverse routes such as carrier-mediated transport and receptor-mediated transcytosis. Surface modification of liposomes enables them to deliver drugs to various brain cells, including neurons, astrocytes, oligodendrocytes, and microglia. The research studies supported the role of liposomes in delivering drugs across BBB and in reducing the pathogenesis of AD and PD. The liposomes were surface-functionalized with various molecules to reach the cells intricated with the AD or PD pathogenesis. The targeted and sustained delivery of drugs by liposomes is disturbed due to the antibody formation, renal clearance, accelerated blood clearance, and complement activation-related pseudoallergy (CARPA). Hence, this review will focus on the characteristics, surface functionalization, drug loading, and biodistribution of liposomes respective to AD and PD. In addition, the alternative strategies to overcome immunogenicity are discussed briefly. |
35,706,029 | Microglial amyloid beta clearance is driven by PIEZO1 channels. | Microglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimers disease (AD), toxic amyloid beta (Aβ) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of Aβ. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored. Here we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and Aβ pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations. We show that PIEZO1 orchestrates Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. Aβ inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in Aβ clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets. These results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated Aβ burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD. |
35,705,972 | Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner. | The risk of developing Alzheimers disease (AD) is modulated by genetic and environmental factors. Early-life stress (ELS) exposure during critical periods of brain development can impact later brain function and health, including increasing the risk of developing AD. Microglial dysfunction and neuroinflammation have been implicated as playing a role in AD pathology and may be modulated by ELS. To complicate matters further, sex-specific effects have been noted in response to ELS and in the incidence and progression of AD. Here, we subjected male and female mice with either a wild type or 5xFAD familial AD-model background to maternal separation (MS) from postnatal day 2 to 14 to induce ELS. We detected hippocampal neuroinflammatory alterations already at postnatal day 15. By 4 months of age, MS mice presented increased immobility time in the forced swim test and a lower discrimination index in the novel object recognition memory test compared to controls. We found altered Bdnf and Arc expression in the hippocampus and increased microglial activation in the prefrontal cortex due to MS in a sex-dependent manner. In 5xFAD mice specifically, MS exacerbated amyloid-beta deposition, particularly in females. In the periphery, the immune cell population was altered by MS exposure. Overall, our results demonstrate that MS has both short- and long-term effects on brain regions related to memory and on the inflammatory system, both in the brain and periphery. These ELS-related effects that are detectable even in adulthood may exacerbate pathology and increase the risk of developing AD via sex-specific mechanisms. |
35,705,959 | Calcium-dependent cytosolic phospholipase A | Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimers disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of persons with AD dementia carrying APOE34 compared to APOE33. Higher phosphorylated p38 MAPK but not ERK12 was found in ApoE4 primary astrocytes and mouse brains than that in ApoE3. Greater cPLA2 translocation to cytosol was observed in human postmortem frontal cortical synaptosomes with recombinant ApoE4 than ApoE3 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD. |
35,705,601 | Machine learning for comprehensive prediction of high risk for Alzheimers disease based on chromatic pupilloperimetry. | Currently there are no reliable biomarkers for early detection of Alzheimers disease (AD) at the preclinical stage. This study assessed the pupil light reflex (PLR) for focal red and blue light stimuli in central and peripheral retina in 125 cognitively normal middle age subjects (45-71 years old) at high risk for AD due to a family history of the disease (FH), and 61 age-similar subjects with no family history of AD (FH-) using Chromatic Pupilloperimetry coupled with Machine Learning (ML). All subjects had normal ophthalmic assessment, and normal retinal and optic nerve thickness by optical coherence tomography. No significant differences were observed between groups in cognitive function and volumetric brain MRI. Chromatic pupilloperimetry-based ML models were highly discriminative in differentiating subjects with and without AD family history, using transient PLR for focal red (primarily cone-mediated), and dim blue (primarily rod-mediated) light stimuli. Features associated with transient pupil response latency (PRL) achieved Area Under the Curve Receiver Operating Characteristic (AUC-ROC) of 0.90 ± 0.051 (left-eye) and 0.87 ± 0.048 (right-eye). Parameters associated with the contraction arm of the rod and cone-mediated PLR were more discriminative compared to parameters associated with the relaxation arm and melanopsin-mediated PLR. Significantly shorter PRL for dim blue light was measured in the FH group in two test targets in the temporal visual field in right eye that had highest relative weight in the ML algorithm (mean ± standard error, SE 0.449 s ± 0.007 s vs. 0.478 s ± 0.010 s, p 0.038). Taken together our study suggests that subtle focal changes in pupil contraction latency may be detected in subjects at high risk to develop AD, decades before the onset of AD clinical symptoms. The dendrites of melanopsin containing retinal ganglion cells may be affected very early at the preclinical stages of AD. |
35,705,503 | Amyloid- and Tau Imaging in Chronic Traumatic Brain Injury A Cross-sectional Study. | Traumatic brain injury (TBI) has been promoted as a risk factor for Alzheimers disease. There is evidence of elevated amyloid-β and tau, the pathological hallmarks of Alzheimers disease, immediately following TBI. It is not clear whether amyloid-β and tau remain elevated in the chronic period. To address this issue, we assessed amyloid-β and tau burden in long-term TBI survivors and healthy controls using PET imaging. Using a cross-sectional design, we recruited individuals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using The sample comprised 87 individuals with TBI (71.3% male 28.7% female A single moderate to severe TBI was not associated with higher burden of amyloid-β or tau pathologies in the chronic period relative to healthy controls. Amyloid-β and tau burden did not show a significant increase with years since injury, and burden did not appear to be greater for those who were older at the time of injury. |
35,705,500 | Association of Cognition and Dementia With Neuropathologic Changes of Alzheimer Disease and Other Conditions in the Oldest-Old. | Age is the largest risk factor for dementia. However, dementia is not universal, even among the oldest-old age groups. Following contemporary neuropathologic guidelines, our objectives were to describe the key neuropathologic lesions and their associations with antemortem cognition in oldest-old individuals. Participants were those enrolled in The 90 Study, a longitudinal, population-based study of agingdementia in the oldest-old, who agreed to postmortem brain examination. All autopsied brains as of December 2020 were evaluated for prevalence of Alzheimers disease neuropathologic change (ADNC) and non-ADNC neuropathologic comorbidities. Associations between neuropathologic lesions or total neuropathologic burden score (sum of the individual scores) and cognition were assessed using multinomial logistic regression and multiple linear regression. Separate regression analyses evaluated relationships between limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and hippocampal sclerosis (HS) or ADNCprimary age-related tauopathy (PART). Resistance, or failure to develop ADNCPART, and resilience, inferred from higher than expected cognitive functioning, were evaluated in the presence or absence of non-ADNC neuropathologic features. The most common neuropathologic features in the sample (n367) were ADNCPART-related. Increased dementia odds were associated with elevated total neuropathologic burden (OR1.5 95% CI 1.3-1.7 p<0.0001), beta amyloid (OR1.6 95% CI 1.2-2.0 p<0.0001), neurofibrillary tangles (OR2.6 95% CI 1.7-4.1 p<0.0001), and LATE-NC (OR2.3 95% CI 1.7-3.1 p<0.0001), correcting for multiple comparisons. LATE-NC was associated with dementia with (OR6.1 95% CI 2.0-18.7 p0.002) and without (OR5.0 95% CI 2.6-9.7 p<0.0001) co-occurring HS, and increased the odds of dementia among participants with ADNC (OR5.0 95% CI 2.7-9.2 p<0.0001). Resistance to moderatesevere ADNCPART was rare (3%), but resilience to ADNCPART was not (55%). Resilience was rarer in the presence of non-ADNC comorbid lesions, particularly LATE-NC. Among those with moderatesevere ADNCPART, dementia odds increased with each non-ADNC comorbid lesion (e.g., 1 lesion OR2.4 95% CI 1.3-4.5 p<0.005 2 lesions OR5.9 95% CI 2.8-12.3 p<0.0001). These results highlight the importance of non-ADNC neuropathologic comorbidity, predominantly LATE-NC, to cognition in the oldest-old. Given the cumulative effects of non-ADNC comorbid neuropathologic abnormalities, reducing their prevalence, especially LATE-NC, will be vital to the ultimate goal of reducing dementia burden in the oldest-old individuals. |
35,705,493 | The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders. | Normal neural circuits and functions depend on proper neuronal differentiation, migration, synaptic plasticity, and maintenance. Abnormalities in these processes underlie various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Neural development and maintenance are regulated by many proteins. Among them are Par3, Par6 (partitioning defective 3 and 6), and aPKC (atypical protein kinase C) families of evolutionarily conserved polarity proteins. These proteins perform versatile functions by forming tripartite or other combinations of protein complexes, which hereafter are collectively referred to as Par complexes. In this review, we summarize the major findings on their biophysical and biochemical properties in cell polarization and signaling pathways. We next summarize their expression and localization in the nervous system as well as their versatile functions in various aspects of neurodevelopment, including neuroepithelial polarity, neurogenesis, neuronal migration, neurite differentiation, synaptic plasticity, and memory. These versatile functions rely on the fundamental roles of Par complexes in cell polarity in distinct cellular contexts. We also discuss how cell polarization may correlate with subcellular polarization in neurons. Finally, we review the involvement of Par complexes in neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimers disease. While emerging evidence indicates that Par complexes are essential for proper neural development and maintenance, many questions on their |
35,705,192 | Effect of type 2 diabetes on A disintegrin and metalloprotease 10. | As a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been implicated in the pathogenesis of Alzheimer disease, atherosclerosis, and inflammatory and neoplastic disorders. It has been suggested that systemic ADAM10 concentration may potentially be used as a prognostic biomarker. Since high glucose can upregulate ADAM10 expression in vitro, we investigated whether serum levels of ADAM10 and its substrate, the lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), can be influenced by type 2 diabetes. A total of 1091 individuals with type 2 diabetes and 358 age-matched healthy control subjects were recruited. Serum concentrations of ADAM10 and the soluble form of LOX-1 (sLOX-1) released by cleavage of LOX-1 by ADAM were measured by enzyme-linked immunosorbent assay kits (ELISA). Serum ADAM10 was increased in subjects with diabetes compared with control (40.5 ngmL 22.3-65.7 vs 10.3 ngmL 7.0-17.9, respectively P < .01) the highest levels were seen in insulin-treated subjects. On multiple linear regression analysis, glycosylated hemoglobin, age, body mass index, and insulin use were independent determinants of ADAM10 level. The increase in serum ADAM10 levels in diabetes was accompanied by changes in serum sLOX-1. Subjects with diabetes had higher serum sLOX-1 than the control (110 pgmL 89-153 vs 104 pgmL 85-138, respectively P < .01), and there was a significant correlation between serum ADAM10 and sLOX-1 (r 0.26, P < .01). Serum concentration of ADAM10 is increased in type 2 diabetes and is associated with glycemia and insulin therapy, which may potentially affect the specificity of systemic ADAM10 level as a biomarker. 背景 解整合素金属蛋白酶10(ADAM10)是一种1型跨膜蛋白, 负责裂解多种细胞表面分子, 参与阿尔茨海默病, 动脉粥样硬化, 炎症性和肿瘤性疾病的发病。已有研究表明, 全身性ADAM10浓度有可能被用作预后生物标志物。由于高糖在体外可以上调ADAM10的表达, 我们研究了2型糖尿病是否会影响血清ADAM10及其底物--血凝素氧化低密度脂蛋白受体(LOX-1)的水平。 方法 研究对象为1091例2型糖尿病患者和358例年龄匹配的健康对照组。用双抗体夹心法测定血清ADAM10浓度和解整合素金属蛋白酶裂解LOX-1释放的可溶性LOX-1(sLOX-1)。 结果 糖尿病患者血清ADAM10水平较正常对照组升高分别为40.5 (22.3-65.7) ngml vs10.3(7.0-17.9) ngml, P<0.01, 以胰岛素治疗组最高。多元线性回归分析显示, 糖化血红蛋白, 年龄, 体重指数和胰岛素用量是ADAM10水平的独立决定因素。糖尿病患者血清ADAM10水平升高的同时伴有血清sLOX-1的变化。糖尿病患者血清sLOX-1水平显著高于对照组分别为110 (89-153) pgml和104(85-138) pgml, P<0.01, 且血清ADAM10水平与sLOX-1水平显著相关(r0.26, p<0.01)。 结论 2型糖尿病患者血清ADAM10水平升高, 且与血糖和胰岛素治疗有关, 可能影响ADAM10作为生物标志物的特异性。. |
35,705,176 | Deep brain stimulation of fornix for memory improvement in Alzheimers disease A critical review. | Memory reflects the brain function in encoding, storage and retrieval of the data or information, which is a fundamental ability for any live organism. The development of approaches to improve memory attracts much attention due to the underlying mechanistic insight and therapeutic potential to treat neurodegenerative diseases with memory loss, such as Alzheimers disease (AD). Deep brain stimulation (DBS), a reversible, adjustable, and non-ablative therapy, has been shown to be safe and effective in many clinical trials for neurodegenerative and neuropsychiatric disorders. Among all potential regions with access to invasive electrodes, fornix is considered as it is the major afferent and efferent connection of the hippocampus known to be closely associated with learning and memory. Indeed, clinical trials have demonstrated that fornix DBS globally improved cognitive function in a subset of patients with AD, indicating fornix can serve as a potential target for neurosurgical intervention in treating memory impairment in AD. The present review aims to provide a better understanding of recent progresses in the application of fornix DBS for ameliorating memory impairments in AD patients. |
35,705,056 | Absence of microglia promotes diverse pathologies and early lethality in Alzheimers disease mice. | Microglia are strongly implicated in the development and progression of Alzheimers disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2. |
35,705,005 | Plasma Oxytocin Is Not Associated with Social Cognition or Behavior in Frontotemporal Dementia and Alzheimers Disease Syndromes. | Changes in social behavior and emotion processing are common in frontotemporal dementia (FTD) and semantic dementia (SD), and less so in Alzheimers disease (AD). Recent research has investigated oxytocin as a potential treatment for these symptoms however, whether plasma oxytocin is associated with social-emotional symptoms of dementia remains underexplored. Thirty behavioral-variant FTD (bvFTD), 28 SD, 39 AD, and 24 controls underwent blood sampling to measure oxytocin. Participants completed an emotion processing battery. Carers completed the Cambridge Behavioral Inventory and the Neuropsychiatric Inventory. Patients with bvFTD were severely impaired in emotion processing and behavioral ratings, with milder impairment in SD and AD. No difference in plasma oxytocin was observed between groups (p 0.632). No significant associations were found between oxytocin and social behavior or emotion processing (r values between -0.241 and 0.227, all p values >0.099). Our results indicate that plasma oxytocin is not reduced in dementia and is unrelated to social, emotional, and behavioral features. We noted high interindividual variability in our data hence, future investigations should consider methodological influences such as serum versus saliva and diurnal variation on oxytocin function. These results demonstrate that current measurement measures of plasma oxytocin have limited utility in determining the role of oxytocin in FTD. Alternative oxytocin measures may prove more sensitive and should be considered when conducting clinical trials. |
35,704,961 | Relationship between parental history of dementia, motor-cognitive and executive function performance in African American women. | People with parental history (PH) of Alzheimers Disease (AD) and Alzheimers Disease and related dementias (ADRD) are themselves at risk of developing dementia. ADRD are more prevalent in African Americans and women. A decline in executive function and motor-cognitive integration can cause an impaired performance of functional skills. The monitoring of cognitive and psychosocial function in individuals with a PH of ADRD is important for implementing interventions to delay or prevent ADRD diagnosis. This study compared 58 African American women (M age 63.2 ± 7.2 years) with PH of ADRD (n 34) versus without PH (NPH n 24) on the performance of motor-cognitive and executive function tasks, and mental and physical quality of life (QOL) using point biserial correlations and linear regression. Linear regression revealed no difference between participants with and without PH on motor-cognitive tests. However, compared to participants with NPH, participants with PH of ADRD performed significantly worse on the DKEFS (Delis Kaplan Executive Function System) Tower Test (PH M 9.9 ± 2.0 NPH M 11.5 ± 4.3 p 0.046), had poorer mental QOL (PH M 46.8 ± 10.7 NPH M 52.8 ± 7.8 l p 0.007) and physical QOL (PH M 40.9 ± 9.3 NPH M 44.7 ± 8.6 p 0.023). African American women at risk for ADRD may exhibit deficiencies in executive function and physical and mental quality of life before memory deficits meet the criterion for ADRD diagnosis. Motor-Cognitive tasks may be preserved. Executive function and mental and physical health-related QOL may be important targets for identifying individuals at increased risk for ADRD and developing appropriate rehabilitative interventions. |
35,704,317 | Risk of Dementia After Smoking Cessation in Patients With Newly Diagnosed Atrial Fibrillation. | Incident atrial fibrillation (AF) is associated with an increased risk of dementia. However, data on the association between smoking cessation after AF diagnosis and dementia risk are limited. To evaluate the association between changes in smoking status after AF diagnosis and dementia risk. This nationwide cohort study with 126 252 patients used data from the Korean National Health Insurance Service database, including patients who had a national health checkup examination within 2 years before and after AF diagnosis between January 1, 2010, and December 31, 2016. Based on their smoking status, participants were classified as never smokers, ex-smokers, quit smokers, and current smokers. Ex-smokers were defined as those who had quit smoking before the first examination and remained quit until the second examination. Patients who were current smokers at the first health examination but had quit smoking before the second examination were classed as quit smokers. The index date was the second health examination. Patients were followed up until dementia, death, or the study period ended (December 31, 2017), whichever occurred first. Data were analyzed from January 13, 2020, to March 29, 2022. Smoking cessation after newly diagnosed AF. Dementia, including Alzheimer disease and vascular dementia, was the primary outcome. Cox proportional hazards regression model was used to estimate hazard ratios. A total of 126 252 patients (mean SD age, 62.6 12.0 years 61.9% men) were included in the analysis. The mean (SD) CHA2DS2-VASc score, which measures the risk of ischemic stroke, was 2.7 (1.7). Smoking status of the total study population was as follows 65 579 never smokers (51.9%), 34 670 ex-smokers (27.5%), 8919 quit smokers (7.1%), and 17 084 current smokers (13.5%). During a median of 3 years of follow-up, dementia occurred in 5925 patients (1.11 per 1000 person-years). After multivariable adjustment, the risk of quit smokers was significantly lower than that of current smokers (hazard ratio, 0.83 95% CI, 0.72-0.95). The findings of this cohort study suggest that all types of smoking were associated with a significantly higher risk of dementia in patients with new-onset AF. Smoking cessation after AF diagnosis was associated with a lower risk of dementia than among current smokers. These findings may support promoting smoking cessation to reduce dementia risk in patients with new-onset AF. |
35,704,250 | Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimers Disease in Rat and Dog. | We have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimers disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H. The purpose of the present study was to carry out comparative PKPD studies of KG207-H in wild type rat and beagle dogs (middle-aged and older) to determine comparability of systemic PK and CSF exposure between rodent species and larger animals with more complex brain structure such as dogs. Beagle dogs were used in this study as they accumulate cerebral Aß with age, as seen in human AD patients, and can serve as a model of sporadic AD. KG207-H (5 to 50 mgkg) was administered intravenously and serum and CSF samples were serially collected for PK studies and to assess target engagement. KG207-H and Aβ levels were quantified using multiplexed selected reaction monitoring mass spectrometry. After systemic dosing, KG207-H demonstrated similar serum pharmacokinetics in rats and dogs. KG207-H appeared in the CSF in a time- and dose-dependent manner with similar kinetics, indicating CNS exposure. Further analyses revealed a dose-dependent inverse relationship between CSF KG207-H and Aß levels in both species indicating target engagement. This study demonstrates translational attributes of BBB-crossing Aβ-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species. |
35,704,147 | Long term high fat diet induces metabolic disorders and aggravates behavioral disorders and cognitive deficits in MAPT P301L transgenic mice. | Most Alzheimer disease (AD) patients present as sporadic late onset AD, with metabolic factors playing an important role in the occurrence and development of AD. Given the link between peripheral insulin resistance and tau pathology in streptozotocin-injected and dbdb mouse models of diabetes, we fed high fat diet (HFD) to pR5 mice expressing P301L mutant human tau, with the aim of developing a new model with characteristics of obesity, T2DM and AD to mimic AD patients exacerbated by obesity and T2DM, an increasing trend in modern society. In our study, pR5 and C57BL6 (WT) mice were randomly allocated to a standard diet (STD) or HFD for 30 weeks starting at 8 weeks of age. Food intake was measured weekly, body weight and fasting glucose levels were measured fortnightly, and a comprehensive behavioral test battery was performed to assess anxiety, depression and cognitive dysfunction. Glucose and insulin tolerance tests were performed after 30 weeks of HFD. We also investigated the effect of long term HFD on tau pathology in the brains of WT and P301L mice by performing western blotting of whole brain homogenates for total tau, phosphorylated tau at Ser396 and Thr231. Our results show that pR5 mice fed with HFD are more vulnerable to diet induced obesity compared to WT, especially with increasing age. In addition, pR5 mice on HFD developed glucose intolerance and insulin resistance. It was identified that long term HFD significantly aggravates depression like behavior and impairs cognitive function in pR5 mice, and also induces anxiety like behavior in both pR5 and WT mice. Long term HFD was also shown to aggravate tau hyperphosphorylation in pR5 transgenic mice, and increase total and hyperphosphorylated tau in WT mice. These results indicate that diet induced obesity of pR5 transgenic mice expressing P301L mutant human tau generates T2DM, and aggravates tau phosphorylation, and is therefore a model useful for investigations that seek to understand the relationships between AD, T2DM and obesity, and the underlying biochemical changes and mechanisms associated with metabolic disorders and AD tauopathy. |
35,703,878 | Orthostatic hypotension and mortality risk in geriatric outpatients the impact of duration and magnitude of the blood pressure drop. | Orthostatic hypotension is a common condition associated with an increased mortality risk. This study investigates this association specifically in geriatric outpatients and additionally focuses on the duration and magnitude of orthostatic hypotension. In this observational prospective cohort study with geriatric outpatients from the Amsterdam Ageing cohort, we differentiated orthostatic hypotension in early orthostatic hypotension (EOH) and delayedprolonged orthostatic hypotension (DPOH). The magnitude of drop in both SBP and DBP after either 1 or 3 min was quantified. Mortality data was obtained from the Dutch municipal register. Cox proportional hazard models were used to determine the association between orthostatic hypotension and mortality, adjusted for sex and age (model 1), additionally adjusted for orthostatic hypotension-inducing drugs SBP (model 2) and the presence of cardiovascular disease and diabetes (model 3). Stratified analyses in patients with geriatric deficits were performed. We included 1240 patients (mean age 79.4 ± 6.9 years, 52.6% women). Prevalence of orthostatic hypotension was 443 (34.9%) 148 (11.9%) patients had EOH and 285 (23%) DPOH. DPOH was associated with a higher mortality risk hazard ratio, 95% CI 1.69 (1.28-2.22) whereas EOH was not associated with mortality risk. This association did not differ in patients with geriatric deficits. Furthermore, the magnitude of drop in both SBP and DBP was associated with a higher mortality risk. The presence of DPOH and the magnitude of both systolic and diastolic orthostatic hypotension are related to an increased mortality risk in geriatric outpatients. Whether the duration of orthostatic hypotension and magnitude of the drop in blood pressure is causally related to mortality risk or whether it is a sign of decreased resilience remains to be elucidated. |
35,703,042 | Silent cerebral infarcts in patients with atrial fibrillation Clinical implications of an imaging-adjusted CHA2DS2-VASc score. | The CHA2DS2-VASc score does not include silent infarcts on neuroimaging in stroke risk estimation for patients with atrial fibrillation (AF). The inclusion of silent infarcts into CHA2DS2-VASc scoring and its impact on stroke prophylaxis recommendations in patients with AF has not been previously studied. The present study sought to quantify the prevalence of silent infarcts in patients with AF and describe potential changes in management based on magnetic resonance imaging (MRI) findings. Participants from the Mayo Clinic Study of Aging with AF and brain MRI were included. Silent infarcts were identified. Standard CHA2DS2-VASc scores were calculated for each subject based on clinical history alone and imaging-adjusted CHA2DS2-VASc scores based on evidence of cerebral infarction on MRI. Standard and imaging-adjusted scores were compared. One hundred and forty-seven participants (average age 77, 28% female) were identified with AF, MRI, and no clinical history of stroke. Overall, 41 (28%) patients had silent infarcts on MRI, corresponding with a 2-point increase in CHA2DS2-VASc score. Of these participants, only 39% (1641) with silent infarct were on anticoagulation despite having standard CHA2DS2-VASc scores supportive of anticoagulation. After incorporating silent infarcts, 13% (19147) would have an indication for periprocedural bridging compared to 0.6% (1147) at baseline. Incorporation of silent infarcts into the CHA2DS2-VASc score may change the risk- -benefit ratio of anticoagulation. It may also increase the number of patients who would benefit from periprocedural bridging. Future research should examine whether an anticoagulation strategy based on imaging-adjusted CHA2DS2-VASc scores could result in a greater reduction of stroke and cognitive decline. |
35,702,994 | Biweekly fluctuations of neuropsychiatric symptoms according to the Neuropsychiatric Inventory Erratic symptoms or scores | This study investigates the stability of neuropsychiatric symptoms (NPS) assessed biweekly using the Neuropsychiatric Inventory (NPI) in a memory clinic population during a 6 week period. Twenty-three spousal caregivers (mean SD age 69.7 8.8, 82.6% female) of 23 patients (43.5% had dementia) completed all assessments. The NPI was assessed four times during 6 weeks. We examined whether NPI domains were present during all four assessments, studied within-person variation for each NPI domain, and calculated Spearmans correlations between subsequent time-points. Furthermore, we associated repeated NPI assessments with repeated measures of caregiver burden to examine the clinical impact of changes in NPI scores over time. The course of NPS was highly irregular according to the NPI, with only 35.8% of the NPI domains that were present at baseline persisted during all 6 weeks. We observed large within-person variation in the presence of individual NPI domains (61.3%, range 37.5%-83.9%) and inconsistent correlations between NPI assessments (e.g., range r We observed strong fluctuations in NPI scores within very short time windows raising the question whether this represents erratic symptoms andor scores. Further studies are needed to investigate the origins of these fluctuations. |
35,702,991 | Do Mini-Mental State Examination and Montreal Cognitive Assessment predict high-cost health care users A competing risks analysis in The Irish Longitudinal Study on Ageing. | Policymakers want to better identify in advance the 10% of people who account for approximately 75% of health care costs. We evaluated how well Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) predicted high costs in Ireland. We used five waves from The Irish Longitudinal Study on Ageing, a biennial population-representative survey of people aged 50 (2010-2018). We used competing risks analysis where our outcome of interest was high costs (top 10% at any wave) and the competing outcome was dying or loss to follow-up without first having the high-cost outcome. Our binary predictors of interest were a low score (bottom 10% in the sample) in MMSE (≤25 pts) and MoCA (≤19 pts) at baseline, and we calculated sub-hazard ratios after controlling for sociodemographic, clinical and functional factors. Of 5856 participants, 1427 (24%) had the high cost outcome 1463 (25%) had a competing outcome and 2966 (51%) completed eight years of follow-up without either outcome. In multivariable regressions a low MoCA score was associated with high costs (SHR 1.38 (95% CI 1.2-1.6) but a low MMSE score was not. Low MoCA score at baseline had a higher true positive rate (40%) than did low MMSE score (35%). The scores had similar association with exit from the study. MoCA had superior predictive accuracy for high costs than MMSE but the two scores identify somewhat different types of high-cost user. Combining the approaches may improve efforts to identify in advance high-cost users. |
35,702,801 | Intriguing role of Gut-Brain Axis on cognition with emphasis on interaction with Papez circuit. | The gut microbiome is a complicated ecosystem of around a hundred billion symbiotic bacteria cells. Bidirectional communication between the gut and the brain is facilitated by the immune system, the enteric nervous system, the vagus nerve, and microbial compounds such as tryptophan metabolites and short-chain fatty acids (SCFAs). The current study emphasises the relationship of the gut-brain axis with cognitive performance and elucidates the underlying biological components, with a focus on neurotransmitters such as serotonin, indole derivatives, and catecholamine. These biological components play important roles in both the digestive and brain systems. Recent research has linked the gut microbiome to a variety of cognitive disorders, including Alzheimers (AD). The review describes the intriguing role of the gut-brain axis in recognition memory depending on local network connections within the hippocampal as well as other additional hippocampal portions of the Papez circuit. The available data from various research papers show how the gut microbiota might alter brain function and hence psychotic and cognitive illnesses. The role of supplementary probiotics is emphasized for the reduction of brain-related dysfunction as a viable strategy in handling cognitive disorders. Further, the study elucidates the mode of action of probiotics with reported adverse effects. |
35,702,799 | A concise review of common plant-derived compounds as potential therapy for Alzheimers disease and Parkinsons disease Insight into Structure-Activity-Relationship. | Alzheimers disease (AD) and Parkinsons disease (PD) are the two most common neurological illness that affect people in their later years. Memory loss is the hallmark of Alzheimers disease, while dyskinesia, or loss of mobility, is associated with muscle rigidity and tremors in PD. Both diseases are unrelated, however they do have a few similarities associated to extrapyramidal abnormalities, particularly stiffness, which has been linked to concomitant PD in many AD patients. Increased levels of IL-1, IL-6, and TNF in the ADs and PDs patients can be regarded evidence of systemic inflammation associated with each of these neurodegenerative disorders. One of the primary variables in the progression of neurodegenerative disorders is oxidative stress. Many medicinal plants and their secondary metabolites have been claimed to be able to help people with neurodegenerative disorders like AD and PD. Anti-inflammatory, antioxidant, antiapoptotic, monoamine oxidase inhibition, acetylcholinesterase, and neurotrophic pursuits are among the major mechanisms identified by which phytochemicals exert their neuroprotective effects and potential maintenance of neurological health in old age. In regard to neurodegenerative disorders, numerable plant-based drugs like alkaloids, iridoids, terpenes, flavones are employed for the treatment. Structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) are used to investigate the link between bioactivity and chemical configuration of substances. The SAR and QSAR of natural plant components employed in AD and PD are discussed in the current review. |
35,702,798 | Overview on Advancement in Biosensing Technology including its applications in Healthcare. | Clinical analysis necessitates the use of rapid and dependable diagnostic methodologies and approaches. Biomarkers may be an appropriate choice to fulfil this objective, as they are designed uncomplicated in using, specialized for the desired metabolite, susceptible of ongoing analysis and providing excellent outcomes, relatively affordable in the budget, and easily accessible. Biosensing devices are increasingly extensively utilized for treatment, and therefore a variety of applications such as prudence treatment and illness advancement surveillance, environment sensing, product standard, medicine development, toxicology, and scientific engineering. Biosensors can be developed using a wide variety of ways. Its combination with high-affinity macromolecules enables them to monitor a diverse variety of solutes in a specific as well as responsive manner. Enhanced sensing innovation leads the detection of infection as well as the monitoring of the peoples reaction after treatment. Sensing tools is essential for a range of low and better implantable implants. Nanosensors offer a lot of prospects because they are simple, flexible, yet economical to develop. This article presents a detailed overview of breakthroughs in the subject and demonstrations of the variety of biosensors and the extension of nanoscience and nanotechnology methodologies that are applicable today. |
35,702,791 | ceRNA Network Analysis Reveals AP-1 Tanscription Factor Components as Potential Biomarkers for Alzheimers Disease. | Alzheimers disease (AD) is a progressive neurodegenerative disease affecting the elderly, characterized by decreased cognitive function. Non-coding RNAs contribute to AD pathogenesis. To identify potential therapeutic targets for AD, competing endogenous RNA (ceRNA) networks were constructed using the hippocampus of 6-month-old amyloid precursor protein presenilin 1 double transgenic (APPPS1) and wild-type mice. RNA-seq data (GSE158995), generated from the hippocampus of APPPS1 and wild-type mice, were analyzed with the limma R package to identify significantly differentially expressed mRNAs and circRNAs (DEMs and DECs, respectively). DEM Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using Enrichr (httpsmaayanlab.cloudEnrichr). Correlations between DEMs and DECs were determined using the ggcorrplot R package. Main clusters and hub DEMs were selected using the STRING database and Cytoscape software. ceRNA interactions were predicted with the miRTarbase and Starbase tools and constructed with the ggalluvial R package and Cytoscape software. ceRNA networks were validated using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. 198 DEMs and 90 DECs were differentially expressed in APPPS1 vs. wild-type hippocampus. DEM GO analysis revealed significant enrichment in transcription regulation, which was subdivided into three main clusters transcription regulation, synaptic plasticity, and protein refolding. Within the transcription regulation cluster, AP-1 transcription factor components serve as hub genes. The mmucirc0001787(circGLCE)miR-339-5pJunb and mmucirc0001899(circFAM120C) miR-181a-5pEgr1 ceRNA networks were established based on qRT-PCR and Western blot analysis. Two AP-1 transcription factor component-related ceRNA networks, circGLCEmiR- 339-5pJunb and circFAM120CmiR-181a-5pEgr1, were constructed using a mouse model of AD. These ceRNA networks may contribute to transcription regulation in AD and provide potential biomarkers for AD diagnosis and treatment. |
35,702,767 | Role and Therapeutic Potential of RAGE Signaling in Neurodegeneration. | Activation of the receptor for advanced glycation end products (RAGE) has been shown to play an active role in the development of multiple neurodegenerative diseases, including Alzheimers disease, Parkinsons disease, and Amyotrophic Lateral Sclerosis. Although originally identified as a receptor for advanced glycation end products, RAGE is a pattern recognition receptor able to bind multiple ligands. The final outcome of RAGE signaling is defined in a context and cell type specific manner and can exert both neurotoxic and neuroprotective functions. Contributing to the complexity of the RAGE signaling network, different RAGE isoforms with distinctive signaling capabilities have been described. Moreover, multiple RAGE ligands bind other receptors and RAGE antagonism can significantly affect their signaling. Here, we discuss the outcome of celltype specific RAGE signaling in neurodegenerative pathologies. In addition, we will review the different approaches that have been developed to target RAGE signaling and their therapeutic potential. A clear understanding of the outcome of RAGE signaling in a cell type- and disease-specific manner would contribute to advancing the development of new therapies targeting RAGE. The ability to counteract RAGE neurotoxic signaling while preserving its neuroprotective effects would be critical for the success of novel therapies targeting RAGE signaling. |
35,702,765 | The Role of Peptidyl Arginine Deiminase IV(PADI4) in Cancers. | Peptidyl arginine deiminase IV (PADI4, also called PAD4), a Ca2-dependent post-translational modification enzyme, catalyzes the conversion of arginine residues to non-coded citrulline residues. Dysregulation of PADI4 is involved in a variety of diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), Alzheimers disease (AD) and many kinds of malignant tumors. The roles of PADI4 in different tumors and the underlying molecular mechanisms are presented in this article. PADI4-mediated citrullination is associated with either transcriptional activation or repression in different contexts. Abnormal expression of PADI4 exists in a variety of malignant tumors and affects tumor progression and metastasis. Epithelial-to-mesenchymal transition (EMT), apoptosis, and neutrophil extracellular traps (NETs) may be the underlying molecular mechanisms. <p> Conclusion PADI4 plays crucial roles in the occurrence, development and metastasis of tumors, and PADI4 may be an effective biomarker for cancer prognosis and potential target for cancer treatment. |
35,702,732 | Brain alterations in the early Alzheimers continuum with amyloid-β, tau, glial and neurodegeneration CSF markers. | Higher grey matter volumescortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimers disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimers pathology. Here, we evaluated, in the earliest stages of the Alzheimers |
35,702,728 | Astrocytic function is associated with both amyloid-β and tau pathology in non-demented | A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimers disease. Given that |
35,702,343 | Effect of Diabetes Mellitus on Daily Functioning and Cognition of Alzheimers Disease Patients Evaluated by DASC-21. | Diabetes mellitus (DM) is a risk factor for Alzheimers disease (AD). It has also been pointed out that AD associated with DM may have unique characteristics. However, the characteristics of impairment in daily functioning when associated with DM have not been sufficiently investigated. In the present study, we compared the characteristics of 261 patients with AD diagnosed in the outpatient memory clinic of a university hospital, divided into diabetic and nondiabetic groups. The MMSE was used to assess cognitive function, and the Dementia Assessment Sheet for Community-based Integrated Care System 21-items (DASC-21) was used as an observational method to assess cognitive function and activities of daily livings. The two groups were compared. Furthermore, simple and multiple regression analysis was carried out in order to find the independent association of age, sex, education, DM, and HbA1c with the DASC-21 and each individual item of the DASC-21. Diabetic subjects were as follows MMSE 18.8 ± 4.0, DASC-21 46.0 ± 13.2, and HbA1c 7.07 ± 1.24%, respectively. On the other hand, nondiabetic subjects were as follows MMSE 19.0 ± 4.5 and DASC-21 42.1 ± 12.2, respectively. In the diabetic group, total score of DASC-21 was higher (DM vs. nondiabetes mellitus NDM 46.0 ± 13.2 vs. 42.1 ± 12.2 In AD patients, DM may be associated with impairment of solving issues and common sense. |
35,702,342 | Effect of Time to Detection on the Measured Concentrations of Blood Proteins Associated with Alzheimers Disease. | For assays using immunomagnetic reduction, a reagent composed of antibody-functionalized magnetic nanoparticles is dispersed in phosphate-buffered saline solution. The real-time signals of alternating-current (ac) magnetic susceptibility, χ The proteins analyzed are related to Alzheimers disease amyloid β 1-40, amyloid β 1-42, and Tau protein. The investigated times to detection after the mixing the reagent and sample are 0, 20, 30, 40, and 120 min. The results show that the recording of real-time signals of χ |
35,702,161 | Early-Stage MRI Volumetric Differences in White Matter Hyperintensity and Temporal Lobe Volumes between Autopsy-Confirmed Alzheimers Disease, Cerebral Small Vessel Disease, and Mixed Pathologies. | Alzheimers disease (AD) and cerebral small vessel disease (CVSD) both contribute to age-related cognitive decline but can be difficult to clinically distinguish at early stages. At mild cognitive impairment (MCI), we investigated brain MRI volumetric differences in white matter hyperintensities (WMH), frontal and temporal lobe volumes between neuropathologically defined groups of cerebral arteriolosclerosis alone (pARTE), AD alone (pAD), and mixed (ADARTE). From the National Alzheimers Coordinating Center, we defined neuropathology groups of pARTE ( Adjusted regression models show AD-related groups associated with less WMH when compared to pARTE (pAD adjusted odds ratio (aOR) (95% confidence interval CI) 0.94 (0.90-0.98) ADARTE aOR (95% CI) 0.96 (0.93-0.99)). The mixed pathology group, but not pAD, had smaller right temporal lobe volumes than pARTE (pAD aOR 95% CI 0.86 0.74-1.00 ADARTE aOR 95% CI 0.83 0.72-0.96). There were no differences in frontal lobe volumes. Findings from this neuropathologically confirmed cohort suggest volumetric differences in WMH and temporal lobe volumes between AD- and CVSD-related MCI. Moreover, our results suggest a differential atrophy susceptibility of the right versus left temporal lobe to the additive effect of AD and vascular pathologies. |
35,702,160 | Pronoun Use among Caregivers of People Living with Dementia Associations with Dementia Severity Using Text Analysis of a Natural Language Sample. | Family caregivers of persons living with dementia (PLWDs) have extensive social, physical, emotional, and financial responsibilities. However, less is known about the relationship and interpersonal connection between caregivers and PLWDs. We examined caregiver pronoun use, as an index of the connection between the caregiver and PLWD and its associations with the caregivers and PLWDs health and well-being. Caregivers of PLWDs ( Caregivers used less we-pronouns when the PLWDs dementia was more severe, at both timepoints. Spousal caregivers used more we-pronouns and less I- and they-pronouns than nonspousal caregivers. There was an interaction between spousal relationship and dementia severity, such that spousal caregivers exhibited a stronger negative association between dementia severity and we-pronoun use. There were no associations between pronoun category and caregiver burden or depression. Caregivers may feel increasingly disconnected from the PLWD as their dementia becomes more severe, as reflected by less we-pronoun usage. This study highlights the opportunity to explore relationship connection through text analysis. |
35,702,065 | Cause of death of patients with non-muscular invasive, non-metastatic muscular invasive and metastatic bladder cancer after diagnosis. | The purpose of this study was to evaluate the various causes of death among patients with non-muscular invasive bladder cancer (NMIBC), non-metastatic muscle invasive bladder cancer (non-MMIBC) and metastatic bladder cancer (MBC) after diagnosis. With the Surveillance, Epidemiology, and Final Results database, patients diagnosed with bladder cancer from 2004 to 2015 were identified. All causes of death and the standardization mortality ratio (SMR) were analyzed. A total of 111,784 NMIBC, 26,546 non-MIBC and 4,678 MBC patients were identified. For NMIBC patients, 44,638 patients died during the follow-up, including 20.57% of bladder cancer, 18% of other tumors and 61.36% of non-tumor diseases. Main causes of other tumors death were cancers from lung and bronchus n2,860, SMR 1.56 (1.51-1.62), pancreas n506, SMR 1.15 (1.05-1.26), and prostate n442, SMR 0.62 (0.56-0.68). Main causes of non-tumor deaths were diseases of heart n10,007, SMR 1.15 (1.13-1.17), chronic obstructive pulmonary disease (COPD) n3,153, SMR 1.54 (1.49-1.59), cerebrovascular diseases n1,704, SMR 0.96 (0.91-1), alzheimers n1,211, SMR 0.87 (0.82-0.92) and diabetes mellitus n1,047, SMR 1.19 (1.12-1.27). Among the 18829 deaths in non-MMIBC patients, 62.65% patients died of bladder cancer, 11.08% of other tumors and 26.39% of non-tumor causes. Main deaths of other cancers were tumors from lung and bronchus n435, SMR 1.83 (1.66-2.01), prostate n192, SMR 2.21 (1.91-2.54). Main causes of non-tumor death were diseases of heart n1717, SMR 1.56 (1.49-1.64), COPD n561, SMR 2.18 (2.01-2.37), and cerebrovascular diseases n290, SMR 1.28 (1.14-1.44). Among the 4,392 deaths of MBC patients, 3,486 (79.37%) died of bladder cancer. Main cause of other deaths included diseases of heart (n128) and prostate cancer (n57). For NMIBC patients, leading causes of death were diseases of heart, COPD, lung and bronchus cancer, cerebrovascular diseases, Alzheimers, and diabetes mellitus. Leading causes of deaths for non-MMIBE patients were bladder cancer, diseases of heart, COPD, lung and bronchus cancer, cerebrovascular diseases and prostate cancer. Main causes of death for MBC patients were bladder cancer itself. Our results of all causes of death and mortality risks provided useful information for bladder cancer patients. |
35,701,825 | Far infrared light irradiation enhances Aβ clearance via increased exocytotic microglial ATP and ameliorates cognitive deficit in Alzheimers disease-like mice. | Exposure to sunlight may decrease the risk of developing Alzheimers disease (AD), and visible and near infrared light have been proposed as a possible therapeutic strategy for AD. Here, we investigated the effects of the visible, near infrared and far infrared (FIR) light on the cognitive ability of AD mice, and found that FIR light also showed potential in the improvement of cognitive dysfunction in AD. However, the related mechanism remains to be elucidated. Morris water maze was used to evaluate the cognitive ability of APPswePSEN1dE9 double-transgenic AD mice after light treatment. Western blot was carried out to detect the expression of protein involved in synaptic function and amyloid-β (Aβ) production. The protein amount of interleukin (IL)-1β, IL-6, Aβ Our results showed that FIR light reduced Aβ burden, a hallmark of AD neuropathology, alleviated neuroinflammation, restored the expression of the presynaptic protein synaptophysin, and ameliorated learning and memory impairment in the AD mice. FIR light enhanced mitochondrial oxidative phosphorylation pathway to increase ATP production. This increased intracellular ATP promoted the extracellular ATP release from microglia stimulated by Aβ, leading to the enhanced Aβ phagocytosis through phosphoinositide 3-kinasemammalian target of rapamycin pathways for Aβ clearance. Our findings have uncovered a previously unappreciated function of FIR light in inducing microglial phagocytosis to clean Aβ, which may be the mechanisms for FIR light to improve cognitive dysfunction in AD mice. These results suggest that FIR light treatment is a potential therapeutic strategy for AD. |
35,701,806 | Mechanistic insight of the potential of geraniol against Alzheimers disease. | Alzheimers disease (AD) as a neurodegenerative disease occupies 35-45 cases among patients with dementia, yet its pathogenetic mechanism remains unclear. Geraniol, on the other hand, is a well-known extract from essential oils of aromatic plants and has been proven that it has outstanding neuroprotective effects as well as ameliorating influence in memory impairment. Therefore, the present study aims to elucidate the potential of geraniol against AD by network pharmacology-based approach combined with molecular modeling study. Firstly, we evaluated the druggability of geraniol by ADME method. Then, we obtained the geraniol targets and AD-related targets from multiple open data sources. Afterward, we calculated the intersection through a Venn diagram to find common targets, and via Panther classification system to categorize them. In order to gain a macroscopic understanding of these common targets, we carried out GO terms and KEGG pathways enrichment analyses, according to which we constructed a compound-target-pathway-disease network. In addition, we built a preliminary PPI network which was further analyzed both functionally and topologically. Consequently, five hub targets were sorted out. Finally, we conducted molecular docking and molecular dynamic simulation to validate our findings. In the present study, the pharmacological properties of geraniol were assessed according to ADME and Lipinskis rule, which demonstrate promising druggability. Then, from 10,972 AD-related targets and 33 geraniol targets, 29 common targets were identified, among which 38.1% of them are metabolite interconversion enzymes, 23.8% are protein modifying enzymes, 33.3% are transmembrane receptors, and the rest are transporters. Enrichment analyses hint that geraniol is involved in cholinergic synapse, serotonergic synapse, and neuroactive ligand-receptor interaction. We also built a preliminary PPI network to investigate the interplay between these targets and their extensive interactions. Then, by functionally clustering the preliminary PPI network, we gained a cluster of proteins which formed a subnetwork with score of 8.476, and 22 nodes. Its results of GO terms and KEGG pathways enrichment analyses once again suggests that geraniol actively participates in cholinergic synapse, serotonergic synapse, and neuroactive ligand-receptor interaction, which are believed to be strongly associated with AD pathogenesis. Besides, topological analyses of the preliminary PPI network helped find 5 hub targets (i.e., CHRM3, PRKCA, PRKCD, JAK1, JAK2). To verify their interaction with geraniol molecule, we conducted molecular docking, and found that CHRM3 possesses the highest affinity in binding, indicating that geraniol molecules are closely bound to each hub target, and CHRM3 may serve as a key target of geraniol against AD. It was then further confirmed by molecular dynamic simulation, the result of which supports our hypothesis. The present study shares a mechanistic insight of the potential of geraniol against AD, giving a reference to future experimental studies. |
35,701,718 | Insulin Deficiency Increases Sirt2 Level in Streptozotocin-Treated Alzheimers Disease-Like Mouse Model Increased Sirt2 Induces Tau Phosphorylation Through ERK Activation. | Accumulating evidence suggests that insulin deficiency is a risk factor for Alzheimers disease (AD) however, the underlying molecular mechanisms are not completely understood. Here, we investigated the effects of insulin deficiency on AD-like pathologies using an insulin-deficient amyloid-β (Aβ) precursor protein (APP) transgenic mouse model (Tg2576 mice). Female Tg2576 mice were injected intraperitoneally with streptozotocin (STZ) to induce insulin deficiency, and their body weights, serum glucose levels, and serum insulin levels were evaluated. STZ-treated mice showed exacerbated Aβ accumulation, tau hyperphosphorylation, glial activation, neuroinflammation, and increased Sirt2 protein levels in the brain, as determined by two-dimensional gel electrophoresis (2-DE) coupled with liquid chromatography-tandem mass spectrometry (LC-MSMS) and Western blotting. Furthermore, our in vitro experiments revealed that insulin depletion or interleukin-6 treatment increased Sirt2 protein levels in both Neuro2a and Neuro2a-P301L cells. The overexpression of Sirt2 in these cells induced tau hyperphosphorylation through extracellular signal-regulated kinase (ERK) activation. Conversely, Sirt2 knockdown reversed tau hyperphosphorylation in these cells. We showed for the first time that Sirt2 is upregulated in the brains of STZ-treated Tg2576 mice and is involved in tau phosphorylation through ERK activation. Our findings suggest that Sirt2 is a promising therapeutic target for the treatment of AD. |
35,701,303 | Overview of therapeutic targets in management of dementia. | Dementia is defined as a gradual cognitive impairment that interferes with everyday tasks, and is a leading cause of dependency, disability, and mortality. According to the current scenario, millions of individuals worldwide have dementia. This review provides with an overview of dementia before moving on to its subtypes (neurodegenerative and non-neurodegenerative) and pathophysiology. It also discusses the incidence and severity of dementia, focusing on Alzheimers disease with its different hypotheses such as Aβ cascade hypothesis, Tau hypothesis, inflammatory hypothesis, cholinergic and oxidative stress hypothesis. Alzheimers disease is the most common type and a progressive neurodegenerative illness distinct by neuronal loss and resulting cognitive impairment, leading to dementia. Alzheimers disease (AD) is considered the most familiar neurodegenerative dementias that affect mostly older population. There are still no disease-modifying therapies available for any dementias at this time, but there are various methods for lowering the risk to dementia patients by using suitable diagnostic and evaluation methods. Thereafter, the management and treatment of primary risk elements of dementia are reviewed. Finally, the future perspectives of dementia (AD) focusing on the impact of the new treatment are discussed. |
35,700,956 | Evidences of the radiofrequency exposure on the antioxidant status, potentially contributing to the inflammatory response and demyelination in rat brain. | Present study exhibited the oxidative potential of microwave radiation (MWR) leading to the neurodegeneration in rats. Wistar rats were exposed at 2100 MHz frequency for 4 hday, 5 daysweek3 months. Animals were exposed at an estimated specific absorption rate (0.453 Wkg) and power density (8.237 µWm |
35,700,915 | Effect of cerebellum stimulation on cognitive recovery in patients with Alzheimer disease A randomized clinical trial. | Evidence indicates that the cerebellum is involved in cognitive processing. However, the specific mechanisms through which the cerebellum repetitive transcranial magnetic stimulation (rTMS) contributes to the cognitive state are unclear. In the current randomized, double-blind, sham-controlled trial, 27 patients with Alzheimers disease (AD) were randomly allotted to one of the two groups rTMS-real or rTMS-sham. We investigated the efficacy of a four-week treatment of bilateral cerebellum rTMS to promote cognitive recovery and alter specific cerebello-cerebral functional connectivity. The cerebellum rTMS significantly improves multi-domain cognitive functions, directly associated with the observed intrinsic functional connectivity between the cerebellum nodes and the dorsolateral prefrontal cortex (DLPFC), medial frontal cortex, and the cingulate cortex in the real rTMS group. In contrast, the sham stimulation showed no significant impact on the clinical improvements and the cerebello-cerebral connectivity. Our results depict that 5 Hz rTMS of the bilateral cerebellum is a promising, non-invasive treatment of cognitive dysfunction in AD patients. This cognitive improvement is accompanied by brain connectivity modulation and is consistent with the pathophysiological brain disconnection model in AD patients. |
35,700,826 | RNA induces unique tau strains and stabilizes Alzheimers disease seeds. | Tau aggregation underlies neurodegenerative tauopathies, and transcellular propagation of tau assemblies of unique structure, i.e., strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregation in vitro, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formation in vitro and has been observed to associate with neurofibrillary tangles in human brain. Here, we have tested whether RNA exerts sequence-specific effects on tau assembly and strain formation. We found that three RNA homopolymers, polyA, polyU, and polyC, all bound tau, but only polyA RNA triggered seed and fibril formation. In addition, polyAtau seeds and fibrils were sensitive to RNase. We also observed that the origin of the RNA influenced the ability of tau to adopt a structure that would form stable strains. Human RNA potently induced tau seed formation and created tau conformations that preferentially formed stable strains in a HEK293T cell model, whereas RNA from other sources, or heparin, produced strains that were not stably maintained in cultured cells. Finally, we found that soluble, but not insoluble seeds from Alzheimers disease brain were also sensitive to RNase. We conclude that human RNA specifically induces formation of stable tau strains and may trigger the formation of dominant pathological assemblies that propagate in Alzheimers disease and possibly other tauopathies. |
35,700,626 | Non-tremor motor dysfunction in Lewy body dementias is associated with AD biomarkers. | Motor features of Parkinsons disease (PD) are heterogeneous and well-studied non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimers disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n 30) with Unified Parkinsons Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collection to test the hypothesis that LBD patients with a positive AD biomarker profile (LBD AD 13) would have higher PIGD burden compared with LBD patients without AD biomarker positivity (LBD-AD 17). We find novel evidence for selective impairment of PIGD burden in LBD AD vs LBD-AD (OR 1.95, 95%CI 1.02-3.70, p 0.04) and a direct association of increasing CSF tauAβ |
35,700,462 | Parkinsons disease a bibliographic update of psychosocial aspects. | Parkinsons disease (PD) is the most common neurodegenerative disease, after Alzheimers. The increase in its prevalence is due to a combination of factors. In 2016, over 6.1 million cases were registered and it is believed that this value will double by 2050, which is why it is considered a public health problem. To carry out a literature review about the psychosocial aspects associated with PD, considering their importance as possible prodromal markers of the disease. A bibliographic search was made taking into account the material generated in the last 15 years, and using the databases PubMed, SciELO, Dialnet and Redalyc. Research on PD primarily focus interest on the characteristics, symptoms, diagnosis and treatment. It´s observed the need of developing more scientific studies to obtain evidence regarding the sociodemographic, psychosocial and geographical characteristics of patients with PD. In adition, it’s important to increase the knowledge about the impact of depression and anxiety over PD. They can become decisive when diagnosing, but also for facing and sustaining an adequate treatment to achieve the patient’s well-being on physical, emotional and social aspects. Studies on Quality of life related to health and PD are also important in this regard. La Enfermedad de Parkinson (EP) es la enfermedad neurodegenerativa más común, después del Alzheimer. El aumento de su prevalencia se debe a una combinación de factores. En 2016 se registraron 6.1 millones casos y se cree que este valor se duplicará para el 2050, por lo que es considerado un problema de salud pública. Realizar una revisión de la literatura acerca de los aspectos psicosociales asociados a la EP, ya que éstos tienen gran importancia como posibles marcadores prodrómicos de la enfermedad. Se realizó una búsqueda del material bibliográfico generado en los últimos 15 años, utilizando las bases de datos PubMed, SciELO, Dialnet y Redalyc. Las investigaciones sobre la EP centran fundamentalmente su interés en las características, síntomas, diagnóstico y tratamiento. Se detecta la necesidad de un mayor número de estudios científicos que obtengan evidencia respecto a las características sociodemográficas, psicosociales y geográficas de los pacientes con EP. Asimismo, se observa la necesidad de estudiar en mayor profundidad el impacto que la depresión y ansiedad puede tener sobre la enfermedad. Estos factores pueden ser determinantes tanto para el diagnóstico de la EP como también para el afrontamiento y adherencia de tratamientos que favorezcan el bienestar físico, emocional y social del paciente. Los estudios sobre la calidad de vida relacionada con la salud son importantes en este sentido. |
35,700,341 | Phase 1 Single Ascending and Multiple Ascending Dose Studies of Phosphodiesterase-9 Inhibitor E2027 Confirmation of Target Engagement and Selection of Phase 2 Dose in Dementia With Lewy Bodies Trial. | E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies. Phase 1, randomized, double-blind, single ascending dose (SAD, n96) and multiple ascending dose (MAD, n68) studies evaluated E2027 doses (5 to 1200 mg) in healthy subjects. The impact of age, race (Japanesenon-Japanese), and food on pharmacokinetics (PK)pharmacodynamics were evaluated. Serial cerebrospinal fluid (CSF) samples were collected to assess the target engagement. E2027 PK profiles were biphasic (elimination half-life 30 hours. Approximately 3-fold accumulation was observed following multiple once-daily dosing. E2027 single doses of 50 to 400 mg resulted in mean maximum increases in CSF cyclic guanosine monophosphate ranging from 293% to 461% within 5.37 to 12.9 hours after dose administration to assess target engagement. Dose-response modelling of steady-state predose CSF cyclic guanosine monophosphate concentrations showed ≥200% increase from baseline is maintained with doses of ≥50 mg QD. The most common adverse events with E2027 were post-LP syndrome and back pain. PK profiles were similar between Japanese and non-Japanese. Higher exposure observed in fed versus fasted state was not considered clinically significant. PK exposure was higher in elderly subjects. S.E2027 was well-tolerated following single and multiple administration. E2027 achieved maximal and sustained target engagement at 50 mg QD, the dose selected for the phase 2 clinical trial. |
35,700,324 | A National Assessment of Alzheimer Disease and Antipsychotic Medication Prescribing Among Older Adults in Ambulatory Care Settings. | The objective of this study was to assess antipsychotic prescribing within ambulatory settings in the United States among older adults with Alzheimer disease after adjusting for demographic, provider, and clinical factors. This cross-sectional cohort study utilized Centers for Disease Controls (CDC) National Ambulatory Medical Care Survey (NAMCS) ambulatory care data from 2014 to 2016 among visits 65 years old or older with any listed diagnosis of Alzheimer. Multivariable logistic regression analyses assessed the association between the outcome of antipsychotic prescribing after controlling for numerous demographic, provider, and clinical covariates. An extension of the Oacaxa-Blinder decomposition was used to assess observed differentials. An estimated 15,471,125 ambulatory visits involving Alzheimer disease among those 65 years old or older occurred from 2014 to 2016. Antipsychotics were prescribed in 9.3% of these visits, equating to 6.81 times higher multivariable-adjusted odds relative to non-Alzheimer visits (95% confidence interval 2.86-16.20, P <0.001). The decomposition analysis indicated that the studys predictor variables explained 15.6% of the outcome gap between Alzheimer versus non-Alzheimer visits. Despite potential mortality risks with antipsychotics in adults 65 years old or older with Alzheimer disease and recommendations discouraging their use, this nationally representative study observed significantly higher odds of prescribing independent of demographic, provider, and clinical characteristics. Polypharmacy may be a risk factor that warrants continued assessment regarding the appropriateness of antipsychotic prescribing in this vulnerable population. |
35,700,125 | Application of the AmyloidTauNeurodegeneration Framework in Cognitively Intact Adults The CABLE Study. | The amyloidtauneurodegeneration (ATN) framework has conceptualized the Alzheimers disease (AD) continuum as a continuum of disease with evidence of amyloid-related pathologies independent of clinical manifestation. Based on this framework, it is necessary to reveal the distribution and risk factors of AD continuum in the cognitively intact population among different cohorts and races, including the northern Chinese Han population. This study classified cognitively intact Chinese Alzheimers Biomarker and LifestylE (CABLE) participants through the AT(N) scheme. Gaussian mixture models were used to identify the cutoff values of cerebrospinal fluid biomarkers, which distinguished AD continuum ( A T-N-, A T N-, A T-N and A T N ) from 1,005 participants (mean age 61 years 40% female). Multivariable logistic regressions and Cochran-Armitage trend tests were used to test neuropsychological performance and risk factors for AD continuum. Approximately one-third of individuals (33.7%) belonged to the AD continuum. Four potential modifiable risk factors, including hypertension, thyroid diseases, social isolation, and minimal depression symptoms, were identified for the AD continuum (OR ranging 1.68-6.90). A trend toward higher prevalence of the AD continuum was associated with a larger number of risk factors (p for trend <0.0001). The risk of AD continuum increased by approximately twofold for each additional modifiable risk factor (OR 1.9, 95% CI 1.65-2.24, p < 0.0001). This study revealed the distribution and potential risk factors of the AD continuum in a cognitively intact Han population in northern China, which filled the gap in the area about the performance of the AT(N) framework in the Asian population. ANN NEUROL 202292439-450. |
35,699,942 | Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits. | Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits dramatic expansion of CD8 Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability. |
35,699,892 | Catalpol Ameliorates Neurotoxicity in N2aAPP695swe Cells and APPPS1 Transgenic Mice. | Alzheimers disease (AD) causes progressive decline of memory and cognitive deficits. Because of its complicated pathogenesis, the prevention and therapy of AD remain an enormous challenge. It has been reported that catalpol possessed neuroprotective effects against AD. However, the involved mechanism still needs to be intensively studied. Therefore, the effects of catalpol on N2aAPP695swe cells and APPPS1 mice were identified in the current study. Catalpol could improve cytotoxicity according to CCK-8 assay and ameliorate cellular morphological changes in N2aAPP695swe cells. Neuronal structural damage in the hippocampal CA1 region of APPPS1 AD mice was improved according to HE staining and immunohistochemistry of NeuN. Meanwhile, catalpol administration ameliorated cognitive deficits confirmed by behavior performance of APPPS1 mice. Hoechst 33,342 staining and Annexin V-FITCPI double staining demonstrated that catalpol could reduce apoptosis in N2aAPP695swe cells. Likewise, TUNEL staining also manifested that catalpol significantly reduced apoptosis in hippocampal CA1 region of APPPS1 mice. Catalpol administration also could improve mitochondrial functions indicated by the ameliorative mitochondrial morphology, the decreased ROS generation, and the increased MMP in N2aAPP695swe cells. Subsequently, catalpol restrained oligomerization of Aβ |
35,699,875 | Investigation of Mitochondrial Related Variants in a Cerebral Small Vessel Disease Cohort. | Monogenic forms of cerebral small vessel disease (CSVD) can be caused by both variants in nuclear DNA and mitochondrial DNA (mtDNA). Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is known to have a phenotype similar to Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL), and can be caused by variants in the mitochondrial genome and in several nuclear-encoded mitochondrial protein (NEMP) genes. The aim of this study was to screen for variants in the mitochondrial genome and NEMP genes in a NOTCH3-negative CADASIL cohort, to identify a potential link between mitochondrial dysfunction and CSVD pathology. Whole exome sequencing was performed for 50 patients with CADASIL-like symptomology on the Ion Torrent system. Mitochondrial sequencing was performed using an in-house designed protocol with sequencing run on the Ion GeneStudio S5 Plus (S5 ). NEMP genes and mitochondrial sequencing data were examined for rare (MAF < 0.001), non-synonymous variants that were predicted to have a deleterious effect on the protein. We identified 29 candidate NEMP variants that had links to either MELAS-, encephalopathy-, or Alzheimers disease-related phenotypes. Based on these changes, variants affecting POLG, MTO1, LONP1, NDUFAF6, NDUFB3, and TCIRG1 were thought to play a potential role in CSVD pathology in this cohort. Overall, the exploration of the mitochondrial genome identified a potential role for mitochondrial related proteins and mtDNA variants contributing to CSVD pathologies. |
35,699,375 | ERp57 chaperon protein protects neuronal cells from Aβ-induced toxicity. | Alzheimers disease (AD) is a neurodegenerative disorder whose main pathological hallmark is the accumulation of Amyloid-β peptide (Aβ) in the form of senile plaques. Aβ can cause neurodegeneration and disrupt cognitive functions by several mechanisms, including oxidative stress. ERp57 is a protein disulfide isomerase involved in the cellular stress response and known to be present in the cerebrospinal fluid of normal individuals as a complex with Aβ peptides, suggesting that it may be a carrier protein which prevents aggregation of Aβ. Although several studies show ERp57 involvement in neurodegenerative diseases, no clear mechanism of action has been identified thus far. In this work, we gain insights into the interaction of Aβ with ERp57, with a special focus on the contribution of ERp57 to the defense system of the cell. Here, we show that recombinant ERp57 directly interacts with the Aβ |
35,699,274 | Synthesis, characterisation, DNA binding, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and molecular docking studies of metal(II) complexes with 1,10-phenanthroline scaffold. | A series of metal complexes containing Phenanthroline scaffold ML (L-1,10-Phenanthroline derivative comprises conjugated aromatic core and selenol group) M Cu(II), Zn(II), Co(II) and Zn(II) ions were designed and synthesised to obtain effective anti-cholinesterase efficiencies of metal chelates. Analytical and spectroscopic studies were used to determine the structural features. An octahedral structure with moderate distortion was attributed to the above metal chelates based on spectroscopic data. The distorted octahedral geometry of copper(II) complex to DNA ( |
35,699,240 | Test-retest variability of plasma biomarkers in Alzheimers disease and its effects on clinical prediction models. | The effect of random error on the performance of blood-based biomarkers for Alzheimers disease (AD) must be determined before clinical implementation. We measured test-retest variability of plasma amyloid beta (Aβ)42Aβ40, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau)217 and simulated effects of this variability on biomarker performance when predicting either cerebrospinal fluid (CSF) Aβ status or conversion to AD dementia in 399 non-demented participants with cognitive symptoms. Clinical performance was highest when combining all biomarkers. Among single-biomarkers, p-tau217 performed best. Test-retest variability ranged from 4.1% (Aβ42Aβ40) to 25% (GFAP). This variability reduced the performance of the biomarkers (≈ΔAUC area under the curve -1% to -4%) with the least effects on models with p-tau217. The percent of individuals with unstable predicted outcomes was lowest for the multi-biomarker combination (14%). Clinical prediction models combining plasma biomarkers-particularly p-tau217-exhibit high performance and are less effected by random error. Individuals with unstable predicted outcomes (gray zone) should be recommended for further tests. |
35,698,919 | A monoallelic variant in EYA1 is associated with Branchio-Otic syndrome in a Malian family. | Branchio-otic syndrome (BO) is one of the most common types of syndromic hearing impairment (HI) with an incidence of 140,000 globally. It is an autosomal dominant disorder typically characterized by the coexistence of branchial cysts or fistulae, malformations of the external, middle, and inner ears with preauricular pits or tags and a variable degree of HI. Most cases of BO have been reported in populations of European ancestry. To date, only few cases have been reported in people from African descent. After a careful clinical examination, a pure tone audiometry was performed. DNA was extracted from peripheral blood and whole exome, and Sanger sequencing were performed for genetic analysis. Eight individuals from a large non-consanguineous Malian family, with autosomal dominant inheritance were enrolled. The ages at diagnosis ranged from 8 to 54 years. A high phenotypic variability was noted among the affected individuals. Four patients presented with a post-lingual and mixed type of HI, one individual had conductive HI while three had normal hearing but presented other BO features namely branchial fistulae and preauricular sinus. Serum creatinine level and renal ultrasonography were normal in three affected individuals who performed them. Genetic testing identified a monoallelic pathogenic variant in EYA1 (c.1286A > G p.Asp429Gly) segregating with BO syndrome in the family. This is the first genetically confirmed case of BO syndrome caused by EYA1 variant in the sub-Saharan African population, expanding the genetic spectrum of the condition. |
35,698,882 | Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimers disease pathophysiology. | Suspected non-Alzheimers disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T (MCI-SNAP), and MCI AT (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processingdegradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. The pathophysiology of MCI-SNAP (A-T) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD. |
35,698,879 | Synthesis and biological evaluation of thieno3,2- | Glycogen synthase kinase 3β (GSK-3β) catalyses the hyperphosphorylation of tau protein in the Alzheimers disease (AD) pathology. A series of novel thieno3,2- |
35,698,550 | Association between cognitive function and olfactory identification ability in community-dwelling older individuals. | Purpose We investigated whether olfactory identification ability may be useful for early detection of cognitive decline. Participants and Methods The study included 55 community-dwelling older individuals without a history of mild cognitive impairment or dementia, who were capable of living independently. Cognitive function was evaluated using the Japanese versions of the Mini-Mental State Examination and the Montreal Cognitive Assessment tools. The olfactory identification ability was evaluated using the Odor Stick Identification Test for the Japanese. We also investigated the association between olfactory identification ability and cognitive function. Results Based on the Japanese version of the Mini-Mental State Examination, all participants were categorized into the noncognitive decline group, and based on the Japanese version of the Montreal Cognitive Assessment tool, 21 participants were categorized into the cognitive decline group. With regard to olfactory discrimination ability, we observed a significant difference between participants with and without cognitive decline based on the Japanese version of the Montreal Cognitive Assessment scores. Furthermore, we observed a significant positive correlation between the Japanese version of the the Montreal Cognitive Assessment scores and the Odor Stick Identification Test for the Japanese scores, although no significant correlation was observed between the Japanese version of the Mini-Mental State Examination and the Odor Stick Identification Test for the Japanese scores. Conclusion Olfactory identification ability may be useful to detect early-stage cognitive decline in community-dwelling older individuals. |
35,698,260 | Mitochondrial genome mutations and neuronal dysfunction of induced pluripotent stem cells derived from patients with Alzheimers disease. | Patient-derived induced pluripotent stem cells (iPSCs) are materials that can be used for autologous stem cell therapy. We screened mtDNA mutations in iPSCs and iPSC-derived neuronal cells from patients with Alzheimers disease (AD). Also, we investigated whether the mutations could affect mitochondrial function and deposition of β-amyloid (Aβ) in differentiated neuronal cells. mtDNA mutations were measured and compared among iPSCs and iPSC-derived neuronal cells. The selected iPSCs carrying mtDNA mutations were subcloned, and then their growth rate and neuronal differentiation pattern were analyzed. The differentiated cells were measured for mitochondrial respiration and membrane potential, as well as deposition of Aβ. Most iPSCs from subjects with AD harbored ≥1 mtDNA mutations, and the number of mutations was significantly higher than that from umbilical cord blood. About 35% and 40% of mutations in iPSCs were shared with isogenic iPSCs and their differentiated neuronal precursor cells, respectively, with similar or different heteroplasmy. Furthermore, the mutations in clonal iPSCs were stable during extended culture and neuronal differentiation. Finally, mtDNA mutations could induce a growth advantage with higher viability and proliferation, lower mitochondrial respiration and membrane potential, as well as increased Aβ deposition. This study demonstrates that mtDNA mutations in patients with AD could lead to mitochondrial dysfunction and accelerated Aβ deposition. Therefore, early screening for mtDNA mutations in iPSC lines would be essential for developing autologous cell therapy or drug screening for patients with AD. |
35,698,225 | Multidimensional insights into the repeated electromagnetic field stimulation and biosystems interaction in aging and age-related diseases. | We provide a multidimensional sequence of events that describe the electromagnetic field (EMF) stimulation and biological system interaction. We describe this process from the quantum to the molecular, cellular, and organismal levels. We hypothesized that the sequence of events of these interactions starts with the oscillatory effect of the repeated electromagnetic stimulation (REMFS). These oscillations affect the interfacial water of an RNA causing changes at the quantum and molecular levels that release protons by quantum tunneling. Then protonation of RNA produces conformational changes that allow it to bind and activate Heat Shock Transcription Factor 1 (HSF1). Activated HSF1 binds to the DNA expressing chaperones that help regulate autophagy and degradation of abnormal proteins. This action helps to prevent and treat diseases such as Alzheimers and Parkinsons disease (PD) by increasing clearance of pathologic proteins. This framework is based on multiple mathematical models, computer simulations, biophysical experiments, and cellular and animal studies. Results of the literature review and our research point towards the capacity of REMFS to manipulate various networks altered in aging (Reale et al. PloS one 9, e104973, 2014), including delay of cellular senescence (Perez et al. 2008, Exp Gerontol 43, 307-316) and reduction in levels of amyloid-β peptides (Aβ) (Perez et al. 2021, Sci Rep 11, 621). Results of these experiments using REMFS at low frequencies can be applied to the treatment of patients with age-related diseases. The use of EMF as a non-invasive therapeutic modality for Alzheimers disease, specifically, holds promise. It is also necessary to consider the complicated and interconnected genetic and epigenetic effects of the REMFS-biological systems interaction while avoiding any possible adverse effects. |
35,698,162 | Evaluating the effectiveness of stepwise swallowing training on dysphagia in patients with Alzheimers disease study protocol for a randomized controlled trial. | The high prevalence of dysphagia among Alzheimers disease (AD) patients has become a public health and economic concern. Therefore, effective and accessible dysphagia treatments are needed. As a fundamental rehabilitation of dysphagia, swallowing muscle exercises have received increased attention. Stepwise swallowing training (SST), integrated with all swallowing organs movement, is expected to improve swallowing dysfunction among AD patients. By using a randomized controlled trial design, we propose a multi-center research to evaluate the effectiveness of SST program among AD patients. A multi-center exploratory randomized controlled trial, with a 4-week follow-up period, will be conducted in three major public psychiatric hospitals in Guangdong, China. Participants in the control group will be assigned to routine dysphagia care, while participants in the intervention group will undergo the same nursing care and additionally receive the SST program. The SST program includes five sections of swallowing organs training lip movement, facial movement, tongue movement, mandibular movement, and neck movement. Primary outcomes evaluate the swallowing function, namely, Water Swallowing Test (WTS) and Standard Swallowing Assessment (SSA). Secondary outcomes aim at measuring the improvement of negative impacts of dysphagia, namely eating behavior, ability of daily activity, and nutritional status. Data will be collected at baseline (T This study will offer trial-based evidence of the effectiveness of SST in relieving dysphagia among AD patients. SST program is expected to improve both the swallowing function and reduce the negative impacts of dysphagia, with an exploration of acceptability in the SST program. Chinese Clinical Trial Registry, ChiCTR2200056481 . Prospectively registered on 6 February 2022. |
35,698,099 | Communication Bridge™-2 (CB2) an NIH Stage 2 randomized control trial of a speech-language intervention for communication impairments in individuals with mild to moderate primary progressive aphasia. | Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials. Communication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment. The CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA. ClinicalTrials.gov NCT03371706 . Registered prospectively on December 13, 2017. |
35,698,015 | Identify Biomarkers of Alzheimers Disease Based on Multi-task Canonical Correlation Analysis and Regression Model. | Imaging genetics using imaging technology is regarded as a neuroanatomical phenotype to evaluate gene single nucleotide polymorphisms and their effects on the structure and function of different brain regions. It plays a vital role in bridging the initial understanding of the genetic basis of brain structure and dysfunction. Sparse canonical correlation analysis (SCCA) has become a widespread technique in this field because of its powerful ability to identify bivariate relationships and feature selection. Since most traditional SCCA algorithms assume that the input features are independent, this method obviously cannot be used to analyze genetic image data. The MT-SCCA model is unsupervised and cannot identify the genotype-phenotype associations for diagnostic guidance. Meanwhile, a single biological clinical index cannot fully reflect the physiological process of a comprehensive disease. Therefore, it is necessary to find biomarkers that can reflect Alzheimers disease and physiological functions that can more comprehensively reflect the development of the disease. This article uses a multi-task sparse canonical correlation analysis and regression (MT-SCCAR) model to combine the annual depression level total score (GDSCALE), clinical dementia assessment scale (GLOBAL CDR), functional activity questionnaire (FAQ), and neuropsychiatric Symptom Questionnaire (NPI-Q) in this paper. These four clinical data are used as compensation information and embedded in the algorithm in a linear regression manner. It also reflects its superiority and robustness compared to traditional correlation analysis methods on actual and simulated data. Meanwhile, compared with MT-SCCA, the model utilized in this paper obtains a higher gene-ROI weight and identifies clearer biomarkers, which provides a practical basis for the study of complex human disease pathology. |
35,697,992 | p38 MAPK Is a Major Regulator of Amyloid Beta-Induced IL-6 Expression in Human Microglia. | The accumulation of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimers disease (AD) pathology. Microglial activation-mediated neuroinflammation has been implicated in the pathogenesis of AD and the expression levels of interleukin-6 (IL-6) were increased in the brains of AD patients. However, the mechanisms by which IL-6 expression is regulated in human microglia are incompletely understood. Here, we show that Aβ |
35,697,957 | Automated brain volumetric program measuring regional brain atrophy in diagnosis of mild cognitive impairment and Alzheimers disease dementia. | A quantitative analysis of brain volume can assist in the diagnosis of Alzheimers disease (AD) which is ususally accompanied by brain atrophy. With an automated analysis program Quick Brain Volumetry (QBraVo) developed for volumetric measurements, we measured regional volumes and ratios to evaluate their performance in discriminating AD dementia (ADD) and mild cognitive impairment (MCI) patients from normal controls (NC). Validation of QBraVo was based on intra-rater and inter-rater reliability with a manual measurement. The regional volumes and ratios to total intracranial volume (TIV) and to total brain volume (TBV) or total cerebrospinal fluid volume (TCV) were compared among subjects. The regional volume to total cerebellar volume ratio named Standardized Atrophy Volume Ratio (SAVR) was calculated to compare brain atrophy. Diagnostic performances to distinguish among NC, MCI, and ADD were compared between MMSE, SAVR, and the predictive model. In total, 56 NCs, 44 MCI, and 45 ADD patients were enrolled. The average run time of QBraVo was 5 min 36 seconds. Intra-rater reliability was 0.999. Inter-rater reliability was high for TBV, TCV, and TIV (R 0.97, 0.89 and 0.93, respectively). The medial temporal SAVR showed the highest performance for discriminating ADD from NC (AUC 0.808, diagnostic accuracy 80.2%). The predictive model using both MMSE and medial temporal SAVR improved the diagnostic performance for MCI in NC (AUC 0.844, diagnostic accuracy 79%). Our results demonstrated QBraVo is a fast and accurate method to measure brain volume. The regional volume calculated as SAVR could help to diagnose ADD and MCI and increase diagnostic accuracy for MCI. |
35,697,880 | Frequency of LATE neuropathologic change across the spectrum of Alzheimers disease neuropathology combined data from 13 community-based or population-based autopsy cohorts. | Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimers disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with frequent neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimers disease neuropathology. |
35,697,829 | Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. | Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n |
35,697,820 | Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels. | COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms. |
35,697,511 | 14-3-3θ Does Not Protect against Behavioral or Pathological Deficits in Alzheimers Disease Mouse Models. | Alzheimers disease (AD) is characterized by progressive cognitive impairment associated with synaptic dysfunction and dendritic spine loss and the pathologic hallmarks of β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles. 14-3-3 proteins are a highly conserved family of proteins whose functions include regulation of protein folding, neuronal architecture, and synaptic function. Additionally, 14-3-3s interact with both Aβ and tau, and reduced levels of 14-3-3s have been shown in the brains of AD patients and in AD mouse models. Here, we examine the neuroprotective potential of the 14-3-3θ isoform in AD models. We demonstrate that 14-3-3θ overexpression is protective and 14-3-3θ inhibition is detrimental against oligomeric Aβ-induced neuronal death in primary cortical cultures. Overexpression of 14-3-3θ using an adeno-associated viral (AAV) vector failed to improve performance on behavioral tests, improve Aβ pathology, or affect synaptic density in the J20 AD mouse model. Similarly, crossing a second AD mouse model, the |
35,697,505 | Association of Healthy Lifestyles With Risk of Alzheimer Disease and Related Dementias in Low-Income Black and White Americans. | Although the importance of healthy lifestyles for preventing Alzheimer disease and related dementias (ADRD) has been recognized, epidemiologic evidence remains limited for non-White or low-income individuals who bear disproportionate burdens of ADRD. This population-based cohort study aims to investigate associations of lifestyle factors, individually and together, with the risk of ADRD among socioeconomically disadvantaged Americans. In the Southern Community Cohort Study, comprising two-thirds self-reported Black and primarily low-income Americans, we identified incident ADRD using claims data among participants enrolled in Medicare for at least 12 consecutive months after age 65 years. Five lifestyle factors-tobacco smoking, alcohol consumption, leisure-time physical activity (LTPA), sleep hours, and diet quality-were each scored 0 (unhealthy), 1 (intermediate), or 2 (healthy) based on the health guidelines. A composite lifestyle score was created by summing all scores. Cox regression was used to estimate hazard ratios (HRs, 95% CIs) for incident ADRD, treating death as a competing risk. We identified 1,694 patients with newly diagnosed ADRD among 17,209 participants during a median follow-up of 4.0 years in claims data the mean age at ADRD diagnosis was 74.0 years. Healthy lifestyles were individually associated with an 11%-25% reduced risk of ADRD multivariable-adjusted HR (95% CI) was 0.87 (0.76-0.99) for never vs current smoking, 0.81 (0.72-0.92) for low-to-moderate vs no alcohol consumption, 0.89 (0.77-1.03) for ≥150 minutes of moderate or ≥75 minutes of vigorous LTPA each week vs none, 0.75 (0.64-0.87) for 7-9 hours vs >9 hours of sleep, and 0.85 (0.75-0.96) for the highest vs lowest tertiles of the Healthy Eating Index. The composite lifestyle score showed a dose-response association with up to 36% reduced risk of ADRD multivariable-adjusted HRs (95% CIs) across quartiles were 1 (ref), 0.88 (0.77-0.99), 0.79 (0.70-0.90), and 0.64 (0.55-0.74) Our findings support significant benefits of healthy lifestyles for ADRD prevention among socioeconomically disadvantaged Americans, suggesting that promoting healthy lifestyles and reducing barriers to lifestyle changes are crucial to tackling the growing burden and disparities posed by ADRD. |
Subsets and Splits