Dataset Information

Association of Cognitive Function with Amyloid-? and Tau Proteins in the Vitreous Humor.

ABSTRACT: BACKGROUND:The eye may serve as source for diagnostic testing for early detection of Alzheimer's disease (AD). Examination of amyloid-? (A?) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods. OBJECTIVE:To evaluate levels of A? and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD. METHODS:A prospective, single-center, multi-surgeon cohort study. Vitreous humor samples from 80 eyes were measured quantitatively for A?40-42, pTau, and tTau. Linear regression was used to test associations between AD biomarker levels, Mini-Mental State Exam (MMSE), and serum apolipoprotein E (APOE) allele status, with adjustment for age, sex, and education level of patients. RESULTS:Lower MMSE scores were significantly associated with lower levels of vitreous A?40 (p?=?0.015), A?42 (p?=?0.0066), and tTau (p?=?0.0085), and these biomarkers were not associated with any pre-existing eye conditions. Presence of the ?4 allele and the ?2 allele approached significance with reduced A?40 level (p?=?0.053) and increased p-Tau level (p?=?0.056), respectively. CONCLUSION:Patients with poor cognitive function have significantly lower vitreous humor levels of AD-related biomarkers A?40, A?42, and tTau. These biomarkers do not correlate with underlying eye conditions, suggesting their specificity in association with cognitive change. This is the first study to our knowledge to correlate cognition with AD-related proteins in the vitreous humor. Results suggest ocular proteins may have a role for early dementia detection in individuals at risk for AD.

SUBMITTER: Wright LM

PROVIDER: S-EPMC6850770 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Association of Cognitive Function with Amyloid-β and Tau Proteins in the Vitreous Humor.

Wright Lauren M LM Stein Thor D TD Jun Gyungah G Chung Jaeyoon J McConnell Kate K Fiorello Marissa M Siegel Nicole N Ness Steven S Xia Weiming W Turner Kelley L KL Subramanian Manju L ML

Journal of Alzheimer's disease : JAD 20190101 4

<h4>Background</h4>The eye may serve as source for diagnostic testing for early detection of Alzheimer's disease (AD). Examination of amyloid-β (Aβ) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods.<h4>Objective</h4>To evaluate levels of Aβ and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD.<h4>Methods</h4>A prospective, single-center ...[more]

PMID: 30856114

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Project description:Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11C-Pittsburgh compound-B-PET, 18F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.

Project description:Background Growing evidence indicates an association between cerebral microhemorrhages (MHs) and amyloid β accumulation in Alzheimer disease (AD), but to the knowledge of the authors the association with tau burden is unknown. Purpose To investigate the association between cerebral MH load and tau pathologic structure measured in healthy older individuals and individuals along the AD spectrum, stratified by using the A (amyloid β)/T (tau)/N (neurodegeneration) biomarker classification system. Materials and methods In this prospective cohort study, participants from the AD Neuroimaging Initiative were included (healthy control participants, participants with mild cognitive impairment, and participants with AD dementia; data from October 2005 to January 2019). T2*-weighted gradient-echo MRI was performed to quantify MH, fluorine 18 (18F) flortaucipir (AV-1451) PET was performed to quantify tau, and 18F-florbetaben/18F- florbetapir (AV45) PET was performed to quantify amyloid β to study associations of MH with regional and global tau and amyloid β load. Associations with cerebrospinal fluid (CSF) biomarkers (amyloid β1-42, total tau, phosphorylated tau 181) were also assessed. Analysis of covariance and Spearman rank correlation test for cross-sectional analysis and Wilcoxon signed rank test for longitudinal analyses were used, controlling for multiple comparisons (Bonferroni significance threshold, P < .008). Results Evaluated were 343 participants (mean age, 75 years ± 7; 186 women), including 205 participants who were A-TN- (mean age, 73 years ± 7; 115 women), 80 participants who were A+TN- (mean age, 76 years ± 7; 38 women), and 58 participants who were A+TN+ (mean age, 77 ± 8; 34 women). MH count was associated with global (Spearman ρ = 0.27; P = .004) and frontal (ρ = 0.27; P = .005) amyloid β load and global tau load (ρ = 0.31; P = .001). In a longitudinal analysis, MH count increased significantly over approximately 5 years in the entire cohort (T-1, 81 [range, 0-6 participants]; T0, 214 [range, 0-58 participants]; P < .001), in A+TN+ (T-1, 20 [range, 0-5 participants]; T0, 119 [range, 1-58 participants]; P < .001), A+TN- (T-1, 31 [range, 0-6 participants]; T0, 43 [range, 0-8 participants]; P = .03), and A-TN- (T-1, 30 [range, 0-4 participants]; T0, 52 [range, 0-6 participants]; P = .007). A higher MH count was associated with higher future global (ρ = 0.29; P = .008) and parietal (ρ = 0.31; P = .005) amyloid β and parietal tau load (ρ = 0.31; P = .005). Conclusion Cerebral microhemorrhage load is associated spatially with tau accumulation, both cross-sectionally and longitudinally. © RSNA, 2020 Online supplemental material is available for this article.

Project description:ImportanceApolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial.ObjectiveTo determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age.Design, setting, and participantsThis is a study of 2 cross-sectional cohorts of volunteers who were cognitively normal, had mild cognitive impairment (MCI), or had Alzheimer disease dementia: the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2019) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (collected between November 2015 and June 2019). The first cohort (TRIAD) comprised cognitively normal elderly participants (n = 124), participants with MCI (n = 50), and participants with Alzheimer disease (n = 50) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-β PET with [18F]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n = 157), participants with MCI (n = 83), and participants with Alzheimer disease (n = 25) who underwent tau PET with [18F]flortaucipir and amyloid-β PET with [18F]florbetapir. Exclusion criteria were a history of other neurological disorders, stroke, or head trauma. There were 489 eligible participants, selected based on availability of amyloid-PET, tau-PET, magnetic resonance imaging, and genotyping for APOEε4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study.Main outcomes and measuresA main association between APOEε4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio.ResultsThe mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOEε4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOEε4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-β, sex, age, and clinical status after multiple comparisons correction (TRIAD: β = 0.33; 95% CI, 0.19-0.49; ADNI: β = 0.13; 95% CI, 0.08-0.19; P < .001).Conclusions and relevanceOur results indicate that the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results contribute to an evolving framework in which APOEε4 has deleterious consequences in Alzheimer disease beyond its link with amyloid-β and suggest APOEε4 as a potential target for future disease-modifying therapeutic trials targeting tau pathology.

Dataset Information

Association of Cognitive Function with Amyloid-? and Tau Proteins in the Vitreous Humor.

Publications

Association of Cognitive Function with Amyloid-β and Tau Proteins in the Vitreous Humor.

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