In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by traditional ...neurodegenerative pathologies. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery (n = 104) and replication cohort (n = 39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. We find 579 proteins associated with cognitive trajectory after meta-analysis. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory.
The metabolic basis of Alzheimer disease (AD) pathology and expression of AD symptoms is poorly understood. Omega-3 and -6 fatty acids have previously been linked to both protective and pathogenic ...effects in AD. However, to date little is known about how the abundance of these species is affected by differing levels of disease pathology in the brain.
We performed metabolic profiling on brain tissue samples from 43 individuals ranging in age from 57 to 95 y old who were stratified into three groups: AD (N = 14), controls (N = 14) and "asymptomatic Alzheimer's disease" (ASYMAD), i.e., individuals with significant AD neuropathology at death but without evidence for cognitive impairment during life (N = 15) from the autopsy sample of the Baltimore Longitudinal Study of Aging (BLSA). We measured 4,897 metabolite features in regions both vulnerable in the middle frontal and inferior temporal gyri (MFG and ITG) and resistant (cerebellum) to classical AD pathology. The levels of six unsaturated fatty acids (UFAs) in whole brain were compared in controls versus AD, and the differences were as follows: linoleic acid (p = 8.8 x 10-8, FC = 0.52, q = 1.03 x 10-6), linolenic acid (p = 2.5 x 10-4, FC = 0.84, q = 4.03 x 10-4), docosahexaenoic acid (p = 1.7 x 10-7, FC = 1.45, q = 1.24 x 10-6), eicosapentaenoic acid (p = 4.4 x 10-4, FC = 0.16, q = 6.48 x 10-4), oleic acid (p = 3.3 x 10-7, FC = 0.34, q = 1.46 x 10-6), and arachidonic acid (p = 2.98 x 10-5, FC = 0.75, q = 7.95 x 10-5). These fatty acids were strongly associated with AD when comparing the groups in the MFG and ITG, respectively: linoleic acid (p < 0.0001, p = 0.0006), linolenic acid (p < 0.0001, p = 0.002), docosahexaenoic acid (p < 0.0001, p = 0.0024), eicosapentaenoic acid (p = 0.0002, p = 0.0008), oleic acid (p < 0.0001, p = 0.0003), and arachidonic acid (p = 0.0001, p = 0.001). Significant associations were also observed between the abundance of these UFAs with neuritic plaque and neurofibrillary tangle burden as well as domain-specific cognitive performance assessed during life. Based on the regional pattern of differences in brain tissue levels of these metabolites, we propose that alterations in UFA metabolism represent both global metabolic perturbations in AD as well as those related to specific features of AD pathology. Within the middle frontal gyrus, decrements in linoleic acid, linolenic acid, and arachidonic acid (control>ASYMAD>AD) and increases in docosahexanoic acid (AD>ASYMAD>control) may represent regionally specific threshold levels of these metabolites beyond which the accumulation of AD pathology triggers the expression of clinical symptoms. The main limitation of this study is the relatively small sample size. There are few cohorts with extensive longitudinal cognitive assessments during life and detailed neuropathological assessments at death, such as the BLSA.
The findings of this study suggest that unsaturated fatty acid metabolism is significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study ...thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.
Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of ...neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global ...perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression.
Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ identification and quantification p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative ADNI, N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease EASE-AD). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio HR = 4.430, 95% confidence interval CI = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples.
We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis.
Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we ...measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose.
Higher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations.
Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.
•Brain tissue glucose is associated with severity of Alzheimer's disease (AD) pathology and symptom onset.•Reduced brain glycolytic flux is associated with severity of AD pathology and symptom onset.•Neuronal glucose transporter-3 is lower in AD.•Lower glucose transporter-3 levels are associated with more severe AD pathology.•Increase in plasma glucose decades before death is related to higher brain glucose.
Rapid growth of the older adult population requires greater epidemiologic characterization of dementia. We developed national prevalence estimates of diagnosed dementia and subtypes in the highest ...risk United States (US) population.
We analyzed Centers for Medicare & Medicaid administrative enrollment and claims data for 100% of Medicare fee-for-service beneficiaries enrolled during 2011–2013 and age ≥68 years as of December 31, 2013 (n = 21.6 million).
Over 3.1 million (14.4%) beneficiaries had a claim for a service and/or treatment for any dementia subtype. Dementia not otherwise specified was the most common diagnosis (present in 92.9%). The most common subtype was Alzheimer's (43.5%), followed by vascular (14.5%), Lewy body (5.4%), frontotemporal (1.0%), and alcohol induced (0.7%). The prevalence of other types of diagnosed dementia was 0.2%.
This study is the first to document concurrent prevalence of primary dementia subtypes among this US population. The findings can assist in prioritizing dementia research, clinical services, and caregiving resources.
•Rapid growth of the older adult population requires greater epidemiologic characterization of dementia.•We developed national prevalence estimates of diagnosed dementia and subtypes in the highest risk U.S. population by analyzing Centers for Medicare & Medicaid administrative enrollment and claims data for 100% of Medicare fee-for-service beneficiaries enrolled during 2011–2013 and age ≥68 years as of December 31, 2013 (n = 21.6 million).•Over 3.1 million (14.4%) beneficiaries had a claim for a service and/or treatment for any dementia subtype.•Dementia not otherwise specified was the most common diagnosis (present in 92.9%); the most common subtype was Alzheimer's (43.5%), followed by vascular (14.5%), Lewy body (5.4%), frontotemporal (1.0%), and alcohol induced (0.7%).•This study, the first to document concurrent prevalence of primary dementia subtypes among this U.S. population, provides findings that can assist in prioritizing dementia research, clinical services, and caregiving resources.
Cerebral atherosclerosis contributes to dementia via unclear processes. We performed proteomic sequencing of dorsolateral prefrontal cortex in 438 older individuals and found associations between ...cerebral atherosclerosis and reduced synaptic signaling and between RNA splicing and increased oligodendrocyte development and myelination. Consistently, single-cell RNA sequencing showed cerebral atherosclerosis associated with higher oligodendrocyte abundance. A subset of proteins and modules associated with cerebral atherosclerosis was also associated with Alzheimer's disease, suggesting shared mechanisms.
IMPORTANCE: Changes in behavior and personality are 1 criterion for the diagnosis of dementia. It is unclear, however, whether such changes begin before the clinical onset of the disease. OBJECTIVE: ...To determine whether increases in neuroticism, declines in conscientiousness, and changes in other personality traits occur before the onset of mild cognitive impairment or dementia. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 2046 community-dwelling older adults who volunteered to participate in the Baltimore Longitudinal Study of Aging were included. The study examined personality and clinical assessments obtained between 1980 and July 13, 2016, from participants with no cognitive impairment at first assessment who were followed up for as long as 36 years (mean SD, 12.05 9.54 years). The self-report personality scales were not considered during consensus diagnostic conferences. MAIN OUTCOMES AND MEASURES: Change in self-rated personality traits assessed in the preclinical phase of Alzheimer disease and other dementias with the Revised NEO Personality Inventory, a 240-item questionnaire that assesses 30 facets, 6 for each of the 5 major dimensions: neuroticism, extraversion, openness, agreeableness, and conscientiousness. RESULTS: Of the 2046 participants, 931 45.5% were women; mean (SD) age at first assessment was 62.56 (14.63) years. During 24 569 person-years, mild cognitive impairment was diagnosed in 104 (5.1%) individuals, and all-cause dementia was diagnosed in 255 (12.5%) participants, including 194 (9.5%) with Alzheimer disease. Multilevel modeling that accounted for age, sex, race, and educational level found significant differences on the intercept of several traits: individuals who developed dementia scored higher on neuroticism (β = 2.83; 95% CI, 1.44 to 4.22; P < .001) and lower on conscientiousness (β = −3.34; 95% CI, −4.93 to −1.75; P < .001) and extraversion (β = −1.74; 95% CI, −3.23 to −0.25; P = .02). Change in personality (ie, slope), however, was not significantly different between the nonimpaired and the Alzheimer disease groups (eg, neuroticism: β = 0.00; 95% CI, −0.08 to 0.08; P = .91; conscientiousness: β = −0.06; 95% CI, −0.16 to 0.04; P = .24). Slopes for individuals who developed mild cognitive impairment (eg, neuroticism: β = 0.00; 95% CI, −0.12 to 0.12; P = .98; conscientiousness: β = −0.09; 95% CI, −0.23 to 0.05; P = .18) and all-cause dementia (eg, neuroticism: β = 0.02; 95% CI, −0.06 to 0.10; P = .49; conscientiousness: β = −0.08; 95% CI, −0.16 to 0.00; P = .07) were also similar to those for nonimpaired participants. CONCLUSIONS AND RELEVANCE: No evidence for preclinical change in personality before the onset of mild cognitive impairment or dementia was identified. These findings provide evidence against the reverse causality hypothesis and strengthen evidence for personality traits as a risk factor for dementia.
Blood-based biomarkers present a considerable challenge: technically, as blood is a complex tissue and conceptually, as blood lacks direct contact with brain. Nonetheless, increasing evidence ...suggests that there is a blood protein signature, and possibly a transcript signature, that might act to increase confidence in diagnosis, be used to predict progression in either disease or prodromal states, and that may also be used to monitor disease progression. Evidence for this optimism comes partly from candidate protein studies, including those suggesting that amyloid-beta measures might have value in prediction and those studies of inflammatory markers that consistently show change in Alzheimer's disease, and partly from true proteomics studies that are beginning to identify markers in blood that replicate across studies and populations.
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