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Association Between Vascular Pathology and Rate of Cognitive Decline Independent of Alzheimer's Disease Pathology.

ABSTRACT: To examine the association between vascular pathology and rate of cognitive decline in older adults independent of Alzheimer's disease (AD) pathology.Prospective cohort study.Community sample.Individuals from the Einstein Aging Study autopsy series (N = 62).The Blessed Information-Memory-Concentration (BIMC) test was used to assess global cognitive status. AD pathology was quantified according to Braak stage (<3 vs ? 3). Vascular pathology was quantified using a previously reported macrovascular lesion (MVL) score. The association between vascular pathology and antemortem rates of cognitive decline adjusted for level of AD pathology was assessed using linear mixed-effects models.Mean age was 81.8 at enrollment and 89.0 at death. Participants with more than two MVLs had faster cognitive decline than those with no MVLs (difference in annual rate of change in BIMC 0.74 points/yr, P = .03). Braak stage was also associated with cognitive decline (difference 0.57 points/yr, P = .03). The difference in rate of cognitive decline between those with more than two MVLs and those free of vascular lesions persisted after adjustment for AD pathology (difference in rate of change in BIMC 0.68 points/yr, P = .04). The effect of vascular pathology on cognitive decline was not significantly different according to AD pathology.Vascular brain pathology is associated with rate of cognitive decline after adjusting for level of AD pathology.

SUBMITTER: Ezzati A

PROVIDER: S-EPMC5555777 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Association Between Vascular Pathology and Rate of Cognitive Decline Independent of Alzheimer's Disease Pathology.

Ezzati Ali A Wang Cuiling C Lipton Richard B RB Altschul Dorothea D Katz Mindy J MJ Dickson Dennis W DW Derby Carol A CA

Journal of the American Geriatrics Society 20170413 8

<h4>Objectives</h4>To examine the association between vascular pathology and rate of cognitive decline in older adults independent of Alzheimer's disease (AD) pathology.<h4>Design</h4>Prospective cohort study.<h4>Setting</h4>Community sample.<h4>Participants</h4>Individuals from the Einstein Aging Study autopsy series (N = 62).<h4>Measurements</h4>The Blessed Information-Memory-Concentration (BIMC) test was used to assess global cognitive status. AD pathology was quantified according to Braak st ...[more]

PMID: 28407205

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Project description:IntroductionElevated cortisol levels have been reported in Alzheimer's disease (AD) and may accelerate the development of brain pathology and cognitive decline. Dehydroepiandrosterone sulfate (DHEAS) has anti-glucocorticoid effects and it may be involved in the AD pathophysiology.ObjectivesTo investigate associations of cerebrospinal fluid (CSF) cortisol and DHEAS levels with (1) cognitive performance at baseline; (2) CSF biomarkers of amyloid pathology (as assessed by CSF Aβ levels), neuronal injury (as assessed by CSF tau), and tau hyperphosphorylation (as assessed by CSF p-tau); (3) regional brain volumes; and (4) clinical disease progression.Materials and methodsIndividuals between 49 and 88 years (n = 145) with mild cognitive impairment or dementia or with normal cognition were included. Clinical scores, AD biomarkers, brain MRI volumetry along with CSF cortisol and DHEAS were obtained at baseline. Cognitive and functional performance was re-assessed at 18 and 36 months from baseline. We also assessed the following covariates: apolipoprotein E (APOE) genotype, BMI, and education. We used linear regression and mixed models to address associations of interest.ResultsHigher CSF cortisol was associated with poorer global cognitive performance and higher disease severity at baseline. Cortisol and cortisol/DHEAS ratio were positively associated with tau and p-tau CSF levels, and negatively associated with the amygdala and insula volumes at baseline. Higher CSF cortisol predicted more pronounced cognitive decline and clinical disease progression over 36 months. Higher CSF DHEAS predicted more pronounced disease progression over 36 months.ConclusionIncreased cortisol in the CNS is associated with tau pathology and neurodegeneration, and with decreased insula and amygdala volume. Both CSF cortisol and DHEAS levels predict faster clinical disease progression. These results have implications for the identification of patients at risk of rapid decline as well as for the development of interventions targeting both neurodegeneration and clinical manifestations of AD.

Project description:BackgroundDespite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood.MethodologyAccumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1-/- mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Aβ uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04+ fibrillar Aβ. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory.ResultsDisease progression in 5xFAD;Cx3cr1-/- mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Aβ phagocytosis and lysosomal acidification in 5xFAD;Cx3cr1-/- mice is impaired in-vivo. Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Aβ, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFβ-signaling and heightened ROS metabolism in 5xFAD;Cx3cr1-/- mice. Lastly, microglia in 6 month-old 5xFAD;Cx3cr1-/- mice express a 'degenerative' phenotype characterized by increased levels of Ccl2, Ccl5, Il-1β, Pten and Cybb along with reduced Tnf, Il-6 and Tgfβ1 mRNA.ConclusionsCx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1-/- mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.

Dataset Information

Association Between Vascular Pathology and Rate of Cognitive Decline Independent of Alzheimer's Disease Pathology.

Publications

Association Between Vascular Pathology and Rate of Cognitive Decline Independent of Alzheimer's Disease Pathology.

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