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Cognitive reserve, presynaptic proteins and dementia in the elderly.

ABSTRACT: Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N = 253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N = 97 (38.3%), a pathologic diagnosis of AD in N = 142 (56.1%) and cerebral infarcts in N = 77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio = 0.36-0.68, P < 0.001 to P = 0.03) and better cognitive function (P < 0.001 to P = 0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P = 0.01) and lower SNAP-25/syntaxin interaction (P < 0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein-protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.

SUBMITTER: Honer WG

PROVIDER: S-EPMC3365257 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Cognitive reserve, presynaptic proteins and dementia in the elderly.

Honer W G WG Barr A M AM Sawada K K Thornton A E AE Morris M C MC Leurgans S E SE Schneider J A JA Bennett D A DA

Translational psychiatry 20120515

Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N = 253 participants without dementia at study entry. Six distinct presynaptic proteins, and the pr ...[more]

PMID: 22832958

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Project description:Background and objectivesCognitive reserve (CR) is meant to account for the mismatch between brain damage and cognitive decline or dementia. Generally, CR has been operationalized using proxy variables indicating exposure to enriching activities (activity-based CR). An alternative approach defines CR as residual variance in cognition, not explained by the brain status (residual-based CR). The aim of this study is to compare activity-based and residual-based CR measures in their association with cognitive trajectories and dementia. Furthermore, we seek to examine if the two measures modify the impact of brain integrity on cognitive trajectories and if they predict dementia incidence independent of brain status.MethodsWe used data on 430 older adults aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen, followed for 12 years. Residual-based reserve was computed from a regression predicting episodic memory with a brain-integrity index incorporating six structural neuroimaging markers (white-matter hyperintensities volume, whole-brain gray matter volume, hippocampal volume, lateral ventricular volume, lacunes, and perivascular spaces), age, and sex. Activity-based reserve incorporated education, work complexity, social network, and leisure activities. Cognition was assessed with a composite of perceptual speed, semantic memory, letter-, and category fluency. Dementia was clinically diagnosed in accordance with DSM-IV criteria. Linear mixed models were used for cognitive change analyses. Interactions tested if reserve measures modified the association between brain-integrity and cognitive change. Cox proportional hazard models, adjusted for brain-integrity index, assessed dementia risk.ResultsBoth reserve measures were associated with cognitive trajectories [β × time (top tertile, ref.: bottom tertile) = 0.013; 95% CI: -0.126, -0.004 (residual-based) and 0.011; 95% CI: -0.001, 0.024, (activity-based)]. Residual-based, but not activity-based reserve mitigated the impact of brain integrity on cognitive decline [β (top tertile × time × brain integrity) = -0.021; 95% CI: -0.043, 0.001] and predicted 12-year dementia incidence, after accounting for the brain-integrity status [HR (top tertile) = 0.23; 95% CI: 0.09, 0.58].InterpretationThe operationalization of reserve based on residual cognitive performance may represent a more direct measure of CR than an activity-based approach. Ultimately, the two models of CR serve largely different aims. Accounting for brain integrity is essential in any model of reserve.

Project description:BackgroundThe relative importance of different components of cognitive reserve (CR), as well as their differences by gender, are poorly established.ObjectiveTo explore several dimensions of CR, their differences by gender, and their effects on cognitive performance and trajectory in a cohort of older people without relevant psychiatric, neurologic, or systemic conditions.MethodsTwenty-one variables related to the education, occupation, social activities, and life habits of 1,093 home-dwelling and cognitively healthy individuals, between 68 and 86 years old, were explored using factorial analyses to delineate several dimensions of CR. These dimensions were contrasted with baseline cognitive performance, follow-up over 5 years of participants' cognitive trajectory, conversion to mild cognitive impairment (MCI), and brain volumes using regression and growth curve models, controlling for gender, age, marital status, number of medications, trait anxiety, depression, and ApoE genotype.ResultsFive highly intercorrelated dimensions of CR were identified, with some differences in their structure and effects based on gender. Three of them, education/occupation, midlife cognitive activities, and leisure activities, were significantly associated with late-life cognitive performance, accounting for more than 20% of its variance. The education/occupation had positive effect on the rate of cognitive decline during the 5-year follow up in individuals with final diagnosis of MCI but showed a reduced risk for MCI in men. None of these dimensions showed significant relationships with gray or white matter volumes.ConclusionProxy markers of CR can be represented by five interrelated dimensions. Education/occupation, midlife cognitive activities, and leisure activities are associated with better cognitive performance in old age and provide a buffer against cognitive impairment. Education/occupation may delay the clinical onset of MCI and is also associated with the rate of change in cognitive performance.

Project description:Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

Project description:ImportanceEvidence on the association of lifespan cognitive reserve (CR) with dementia is limited, and the strength of this association in the presence of brain pathologies is unknown.ObjectiveTo examine the association of lifespan CR with dementia risk, taking brain pathologies into account.Design, setting, and participantsThis study used data from 2022 participants in the Rush Memory and Aging Project, an ongoing community-based cohort study with annual follow-up from 1997 to 2018 (mean follow-up, 6 years; maximum follow-up, 20 years). After excluding 420 individuals who had prevalent dementia, missing data on CR, or dropped out, 1602 dementia-free adults were identified at baseline and evaluated to detect incident dementia. During follow-up, 611 died and underwent autopsies. Data were analyzed from May to September 2018.ExposuresInformation on CR factors (education; early-life, midlife, and late-life cognitive activities; and social activities in late life) was obtained at baseline. Based on these factors, lifespan CR scores were captured using a latent variable from a structural equation model and was divided into tertiles (lowest, middle, and highest).Main outcomes and measuresDementia was diagnosed following international criteria. Neuropathologic evaluations for Alzheimer disease and other brain pathologies were performed in autopsied participants. The association of lifespan CR with dementia or brain pathologies was estimated using Cox regression models or logistic regression.ResultsOf the 1602 included participants, 1216 (75.9%) were women, and the mean (SD) age was 79.6 (7.5) years. During follow-up, 386 participants developed dementia (24.1%), including 357 participants with Alzheimer disease-related dementia (22.3%). The multiadjusted hazards ratios (HRs) of dementia were 0.77 (95% CI, 0.59-0.99) for participants in the middle CR score tertile and 0.61 (95% CI, 0.47-0.81) for those in the highest CR score tertile compared with those in the lowest CR score tertile. In autopsied participants, CR was not associated with most brain pathologies, and the association of CR with dementia remained significant after additional adjustment for brain pathologies (HR, 0.60; 95% CI, 0.42-0.86). The highest CR score tertile was associated with a reduction in dementia risk, even among participants with high Alzheimer disease pathology (HR, 0.57; 95% CI, 0.37-0.87) and any gross infarcts (HR, 0.34; 95% CI, 0.18-0.62).Conclusions and relevanceHigh lifespan CR is associated with a reduction in dementia risk, even in the presence of high brain pathologies. Our findings highlight the importance of lifespan CR accumulation in dementia prevention.

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Cognitive reserve, presynaptic proteins and dementia in the elderly.

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Cognitive reserve, presynaptic proteins and dementia in the elderly.

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