Dataset Information

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

ABSTRACT:

Background

Greater neuroticism has been associated with higher risk for Alzheimer's disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology.

Objective

To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers.

Methods

A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27-46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging.

Results

Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels.

Conclusion

The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.

SUBMITTER: Baena A

PROVIDER: S-EPMC9113533 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

Baena Ana A Bocanegra Yamile Y Torres Valeria V Vila-Castelar Clara C Guzmán-Vélez Edmarie E Fox-Fuller Joshua T JT Gatchel Jennifer R JR Sánchez Justin J Pluim Celina F CF Ramirez-Gómez Liliana L Martínez Jairo J Pineda David D Lopera Francisco F Quiroz Yakeel T YT

Journal of Alzheimer's disease : JAD 20210101 4

<h4>Background</h4>Greater neuroticism has been associated with higher risk for Alzheimer's disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology.<h4>Objective</h4>To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whe ...[more]

PMID: 34219716

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Project description:Understanding the nature and onset of neurophysiological changes, and the selective vulnerability of central hub regions in the functional network, may aid in managing the growing impact of Alzheimer's disease on society. However, the precise neurophysiological alterations occurring in the pre-clinical stage of human Alzheimer's disease remain controversial. This study aims to provide increased insights on quantitative neurophysiological alterations during a true early stage of Alzheimer's disease. Using high spatial resolution source-reconstructed magnetoencephalography, we investigated regional and whole-brain neurophysiological changes in a unique cohort of 11 cognitively unimpaired individuals with pathogenic mutations in the presenilin-1 or amyloid precursor protein gene and a 1:3 matched control group (n = 33) with a median age of 49 years. We examined several quantitative magnetoencephalography measures that have been shown robust in detecting differences in sporadic Alzheimer's disease patients and are sensitive to excitation-inhibition imbalance. This includes spectral power and functional connectivity in different frequency bands. We also investigated hub vulnerability using the hub disruption index. To understand how magnetoencephalography measures change as the disease progresses through its pre-clinical stage, correlations between magnetoencephalography outcomes and various clinical variables like age were analysed. A comparison of spectral power between mutation carriers and controls revealed oscillatory slowing, characterized by widespread higher theta (4-8 Hz) power, a lower posterior peak frequency and lower occipital alpha 2 (10-13 Hz) power. Functional connectivity analyses presented a lower whole-brain (amplitude-based) functional connectivity in the alpha (8-13 Hz) and beta (13-30 Hz) bands, predominantly located in parieto-temporal hub regions. Furthermore, we found a significant hub disruption index for (phase-based) functional connectivity in the theta band, attributed to both higher functional connectivity in 'non-hub' regions alongside a hub disruption. Neurophysiological changes did not correlate with indicators of pre-clinical disease progression in mutation carriers after multiple comparisons correction. Our findings provide evidence that oscillatory slowing and functional connectivity differences occur before cognitive impairment in individuals with autosomal dominant mutations leading to early onset Alzheimer's disease. The nature and direction of these alterations are comparable to those observed in the clinical stages of Alzheimer's disease, suggest an early excitation-inhibition imbalance, and fit with the activity-dependent functional degeneration hypothesis. These insights may prove useful for early diagnosis and intervention in the future.

Project description:A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T- and A-T- groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1-26.4) and A+T- (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A-T- (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4-10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T- group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A+TMTL+ (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A+T- (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T- (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T- group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

Project description:BackgroundUnderstanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.MethodsCross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [18F]-FDG, and [18F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.ResultsThe prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.ConclusionsThere are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.Trial registrationNCT02485730.

Project description:ObjectiveResearch in animals has shown that chronic stress exacerbates tau pathology. In humans, psychological stress has been associated with higher risk of Alzheimer disease clinical syndrome. The objective of this cross-sectional study was to assess the hypothesis that stress coping ability (assessed via the Brief Resilience Scale [BRS]) is associated with tau burden and to evaluate whether these associations differed by sex and amyloid status (A+/A-) in cognitively unimpaired (CU) older adults.MethodsWe included 225 CU participants (mean age 70.4 ± 10.2 years, 48% female) enrolled in the population-based Mayo Clinic Study of Aging who completed the BRS and underwent amyloid-PET (Pittsburgh compound B-PET) and tau-PET (AV1451-PET). We fitted multiple regression and analysis of covariance models to assess the associations between BRS and tau-PET and the interaction with amyloid status and sex. We focused on entorhinal cortex (ERC) tau burden and also performed voxel-wise analyses. Age, sex, education, depression, and anxiety were considered as covariates.ResultsHigher stress coping ability was associated with lower tau burden in the medial temporal lobe (including ERC) and occipito-temporal and cuneal/precuneal cortices. The association was present in both A+ and A- but weaker in A- CU older adults. There was an interaction between amyloid status and stress coping ability that was restricted to the medial temporal lobe tau such that A+ CU older adults with lower stress coping abilities showed higher tau. There were no significant interactions between stress coping and sex.ConclusionsA faster termination of the stress response (higher coping ability) may limit the negative effects of stress on tau deposition. Conversely, lower stress coping ability may be an early sign of accumulating tau pathology. Longitudinal studies are warranted to clarify whether stress mechanisms act to exacerbate tau pathology or tau influences stress-related brain mechanisms and lowers the ability to cope with stress.

Project description:BackgroundAutosomal dominant Alzheimer's disease (ADAD) offers a distinct framework to study the preclinical phase of Alzheimer's disease (AD), due to its predictable symptom onset and high penetrance of causative mutations. The study aims to examine the spatial distribution and temporal progression of amyloid-beta (Aβ) and tau pathologies, along with mapping the pathology-functional connectivity network, in asymptomatic ADAD mutation carriers using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI).MethodsParticipants were recruited from the Chinese Familial Alzheimer's Disease Network, comprising 14 asymptomatic ADAD mutation carriers and 20 cognitively normal healthy controls (CN). Aβ deposition was evaluated using 11C-PIB PET, while tau aggregation was assessed via 18F-MK6240 PET imaging. Resting-state functional connectivity (rsFC) was analyzed to investigate relationships between pathological burden and neural network changes. Through qualitative analysis, ADAD carriers with marked 18F-MK6240 uptake in intracranial regions were categorized into Group 2, while others were designated as Group 1.ResultsAsymptomatic ADAD carriers demonstrated a significantly greater Aβ burden across the cortex and striatum compared to CN, although tau PET binding did not differ significantly between the groups. Group 2 participants exhibited elevated 11C-PIB uptake in the neocortex and striatum, and increased 18F-MK6240-PET uptake in the medial temporal and other cortical regions. Compared with Group 1, network mapping of rsFC in Group 2 indicated increased connectivity associated with tau deposition in limbic, posterior cortical, and bilateral temporal regions, overlapping with the default mode network, suggesting potential compensatory mechanisms. Additionally, reduced connectivity in the left medial inferior temporal cortex and fusiform gyrus aligned with findings in sporadic AD cases.ConclusionsThis study shows the spatiotemporal progression of Aβ and tau pathologies in preclinical ADAD, supporting the hypothesis that Aβ deposition precedes tau pathology. The rsFC alterations observed associate with tau deposition in asymptomatic carriers indicate early network disruptions. Tau network mapping presents a valuable approach for assessing individualized brain connectivity changes in preclinical AD, mitigating single-subject variability and advancing precision assessment in early-stage AD diagnosis.

Dataset Information

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

Background

Objective

Methods

Results

Conclusion

Publications

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

Similar Datasets

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