Journal of Alzheimer's Disease最新文献

BackgroundBrain insulin signaling has been associated with both Alzheimer's disease (AD) pathology and cognitive decline, but the mechanisms remain unclear.ObjectiveTo examine whether AD-related cortically-expressed proteins modify the association of brain insulin signaling and cognitive decline.MethodsParticipants included 116 autopsied members of the Religious Orders Study (58 with diabetes matched to 58 without, by age at death, sex, and education) who had both postmortem brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC-alpha serine/threonine-protein kinase or AKT1) and AD-related cortical protein measurements. Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function.ResultsHigher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pT³⁰⁸AKT1 /total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities.ConclusionsAD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.

BackgroundThe hippocampus plays a central role in cognition and hippocampal atrophy is a key hallmark of Alzheimer's disease. Evidence has suggested associations between hippocampal subfield volumes and specific cognitive domains and dementia risk. However, to our knowledge, no study has examined the role of hippocampal subfield volumes in cognitive decline across different domains over time.ObjectiveWe investigated associations between hippocampal subfield volumes and changes in cognitive domains together with incident dementia in a memory clinic cohort.MethodsAssociations between hippocampal subfield volumes and cognitive decline over three years (n = 443) were analyzed using generalized estimating equations, and associations with incident dementia (n = 283) using multiple logistic regression.ResultsAt baseline, all hippocampal subfield volumes were associated with diagnosis of dementia, while the CA4-dentate gyrus, molecular layer, subicular complex, and fimbria volumes were associated with diagnosis of CIND. Over three years, all subfields except the hippocampal fissure were associated with memory. Decreased molecular layer (OR:2.26, 95%CI:1.50;3.50) size was associated with increased risk of dementia.ConclusionsOur findings suggest that hippocampal atrophy of the cornu ammonis, CA4-dentate gyrus, and molecular layer may first manifest with cognitive impairment in memory before other subfields of the hippocampus, and that molecular layer volume may be an early biomarker of dementia. Further research demonstrating the biological role of hippocampal subfields in specific cognitive domains is required.

BackgroundFew recent studies have examined the trends in dementia hospitalization in high-income countries.ObjectiveTo estimate the trends in hospitalization for dementia in people with type 2 diabetes (T2DM) and the general population in Australia using linked, national databases.MethodsAustralians with T2DM and registered on the National Diabetes Services Scheme (n = 438,264), and the general population (n = 8,090,993) from 2010-2011 to 2016-2017 served as the study cohort. Annual rates of hospitalization for dementia were calculated for these individuals aged ≥50 years. Following this, the trends in the rate of hospitalization were estimated using joinpoint regression and summarized as annual percent changes (APCs).ResultsIncreases in hospitalization for dementia over time were observed for the T2DM and the general population; APC 5.2 (95% CI 3.5, 7.3) and 9.4 (95% CI 3.8, 14.3), respectively. The absolute age- and sex-standardized rate of dementia hospitalization was found to be higher in the T2DM than the general population. For vascular dementia, a higher rate of hospitalization was observed for the T2DM population compared to the general population. Conversely, the rate of hospitalization for Alzheimer's disease was higher in the general population than in the T2DM cohort. Further, a higher dementia hospitalization rate was observed among males compared to females in both T2DM, and the general population.ConclusionsDespite the previous studies reporting a decline in dementia incidence in high-income countries, the rate of dementia hospitalization in Australia has risen steadily from 2010-2016 in both T2DM individuals and the general population.

BackgroundTear fluid (TF) is a protein-rich solution that reflects pathophysiological changes in Alzheimer's disease (AD).ObjectiveIn this study, we examined whether TF proteins were differently expressed in persons with mild AD dementia compared to cognitively healthy controls (CO).MethodsWe analyzed data from 53 study participants including 34 CO (mean age, 71 years; Mini-Mental State Examination [MMSE] score, 28.9 ± 1.4), and 19 patients with AD (Clinical Dementia Rating, 0.5-1; mean age, 72 years; MMSE score, 23.8 ± 2.8). All participants underwent cognitive testing, as well as neurological and ophthalmological examinations. TF was collected using Schirmer strips, and TF protein content was evaluated using mass spectrometry-based proteomics and label-free quantification.ResultsWe found that 16 proteins exhibited significantly upregulated expression in the AD group compared to the CO group (p ≤ 0.05). These proteins were NP1L4, BBOX1, CYTC, RNAS4, PCD, RNT2, AL1A3, SYSC, TPIS, CLH1, PGAM1, EIF3L, 5NTC, HNRNPA2B1, PYGL, and ERO1α. No proteins were significantly downregulated in the AD group compared to the CO group.ConclusionsOur results support the hypothesis that TF is a potential source of biomarkers for AD. Part of those proteins with altered expression have previously linked to increased oxidative stress, changed protein synthesis, and disturbed regulation of energy metabolism related to AD or neurodegenerative disease. The present results indicate the value of continued investigation of TF proteins in AD.

Background: Individuals with Down syndrome (DS) generally show neuropathological features of Alzheimer disease (AD). The trisomy of chromosome 21 causes an imbalance of antioxidant systems, which can be linked to AD pathophysiology.

Objective: Verify the difference between the activity of antioxidant enzymes and products of the oxidation process in peripheral blood in non-trisomic (NT) and trisomic (DS) adults and elders and respective associations with cognitive impairment.

Methods: A total of 120 subjects were included in this study. Sociodemographic and clinical information were collected as per protocol for participants in DS and NT groups. The cognitive state of the DS participants was established according to the Brazilian version of the Cambridge Examination for Mental Disorders of Older People with Down's syndrome and Others with Intellectual Disabilities (CAMDEX-DS). The CAMDEX interview was used for this purpose for participants in the NT group. Plasma samples were collected to evaluate protein carbonyl content, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE).

Results: We found increased levels of SOD and CAT activity in the DS group. When the groups were stratified by cognitive decline, elevated levels of SOD and CAT activity were found both in DS groups with and without decline. The activity of GPx was similar between the groups, as well as MDA and HNE.

Conclusion: The results suggest that alterations of the antioxidative processes can be implicated in the onset of neurodegeneration observed in individuals with DS.

BackgroundMild cognitive impairment (MCI) exhibits considerable heterogeneity, requiring accurate characterization through classification and prognostic models. In clinical research, data-driven models offer valuable insights for classification, stratification, and predicting progression to dementia.ObjectiveWe implemented computational techniques to characterize MCI patients and develop multistate progression models for Alzheimer's disease (AD).MethodsDatasets comprising 544 MCI patients from Coimbra University Hospital and 497 from the ADNI, were processed using machine learning techniques, including dimensionality reduction and partition clustering algorithms. For longitudinal measures (n = 351), multistate non-Markov was applied to generate transition probability estimates.ResultsOur analyses gave 4 possible subgroups of MCI patients: 1) increased cognitive reserve, 2) suspected AD pathology, 3) psychological manifestations, and 4) cardiovascular risk factors. Progression within these subgroups showed variations. The likelihood of progressing to AD dementia was estimated over a range of 5 months for those with suspected AD pathology and 66 months for those with psychological manifestations.ConclusionsOur findings support the significance of computational methods to improve the characterization and prognosis of MCI patients. We suggest that these four MCI subgroups should be considered for clinical monitoring.

BackgroundCiliary neurotrophic factor (CNTF) has been identified as a neuroprotective cytokine that can alleviate cognitive impairment in preclinical studies, although the association of cerebrospinal fluid (CSF) CNTF levels with cognitive decline and disease progression in living humans remains unclear.ObjectiveThis study aimed to explore the association between baseline CSF CNTF levels and the rate of cognitive decline in cognitively unimpaired (CU) and cognitively impaired (CI) older people respectively.MethodsA total of 667 participants were included in the study, comprising 161 CU and 506 CI individuals, with an average follow-up time of 3.97 years (SD = 2.99). Linear mixed-effects models were fitted with the Mini-Mental State Examination (MMSE) scores as the primary outcome. As sensitivity analyses, we used another three commonly used cognitive measures as secondary outcomes to test the robustness of our findings. In addition, a Cox proportional hazards model was used to the mild cognitive impairment (MCI) subgroup to investigate the association between baseline CSF CNTF levels and the progression from MCI to dementia.ResultsWe observed that higher baseline CSF CNTF levels were linked with a slower rate of cognitive decline in the CI group, while this association was absent in the CU group. These findings were consistent across different cognitive measures. Among MCI participants, higher levels of CSF CNTF were associated with a slower rate of disease progression to dementia.ConclusionsThe association between CSF CNTF levels and both cognitive decline and disease progression highlights the potential of CNTF as a therapeutic target in the context of Alzheimer's disease and related cognitive disorders.

Stress is a known risk factor for Alzheimer's disease (AD), but religious stress coping practices, (e.g., prayer and attending religious services) may reduce this risk. We investigated the relation between religious stress coping and memory in cognitively-unimpaired individuals from the Colombian kindred with autosomal dominant AD. Additionally, we examined the link between religious stress coping and brain pathology. Religious coping was associated with lower entorhinal tau (p = 0.02) and better memory performance (p = 0.04) in Presenilin-1 E280A mutation carriers, but not in non-carriers. These findings suggest that religious coping may mitigate AD tau pathology and cognitive decline and warrant further investigation.

BackgroundMarijuana impairs the brain development and function among adolescents, but little is known about whether marijuana use is associated with subjective cognitive decline (SCD) among adults.ObjectiveWe investigated the cross-sectional association between marijuana use and past-year SCD in a representative sample of US adults aged 45 years and older.MethodsThe study population included 100,685 participants from five cycles of the Behavioral Risk Factor Surveillance System (BRFSS). Participants self-reported their marijuana use in the past month and whether they experienced SCD or SCD-related functional limitations in the past year. Participants were categorized into past-month marijuana non-users and past-month marijuana users. Among users, they were further classified as occasional (<10 days) and frequent users (≥10 days). The weighted, multivariable logistic regression models were fitted to examine the association between marijuana use and past-year SCD, adjusting for age, sex, educational level, chronic disease status, and other potential confounders.ResultsThe sample included 94.2% (94,818/100,685) of past-month marijuana non-users and 5.83% (5867/100,685) of users. Among the users, 59.3% (3477/5867) were frequent users. Compared with past-month marijuana non-use, past-month marijuana use was significantly associated with higher odds of past-year SCD (OR = 1.70, 95% CI: 1.41, 2.05). The higher frequency was associated with higher odds of having past-year SCD in a dose-response manner (p Trend < 0.001). Similar associations remained for the SCD-related functional limitations.ConclusionsWe found that past-month marijuana users reported higher rates of past-year SCD, a finding consistent with prior literature linking marijuana use with cognitive decline. Future prospective studies are warranted to confirm these findings.

Subjective cognitive decline (SCD) is associated with preclinical Alzheimer's disease (AD). Suboptimal sleep is also a risk factor for cognitive decline, but with unclear relationship to SCD. We conducted a retrospective cross-sectional study in a biracial research cohort of 148 cognitively normal older adults who underwent quantification of SCD (Cognitive Change Index; CCI), sleepiness (Epworth Sleepiness Scale; ESS), depression (Geriatric Depression Scale; GDS), and amyloid/tau PET. ESS score was associated with total, amnestic, and non-amnestic CCI scores, after adjustment for GDS, amyloid/tau burden, and race. This supports future longitudinal work on how sleepiness impacts SCD outcomes.