Measuring Resilience and Resistance in Aging and Alzheimer Disease Using Residual Methods: A Systematic Review and Meta-analysis

OBJECTIVE: There is currently a lack of consensus on how to optimally define and measure resistance and resilience in brain and cognitive aging. Residual methods use residuals from regression analysis to quantify the capacity to avoid (resistance) or cope (resilience) "better or worse than expected" given a certain level of risk or cerebral damage. We reviewed the rapidly growing literature on residual methods in the context of aging and Alzheimer's disease (AD) and performed meta-analyses to investigate associations of residual-method based resilience and resistance measures with longitudinal cognitive and clinical outcomes. METHODS: A systematic literature search of PubMed and Web-of-Science databases (consulted until March 2020) and subsequent screening led to 54 studies fulfilling eligibility criteria, including 10 studies suitable for the meta-analyses. RESULTS: We identified articles using residual methods aimed at quantifying resistance (n=33), cognitive resilience (n=23) and brain resilience (n=2). Critical examination of the literature revealed that there is considerable methodological variability in how the residual measures were derived and validated. Despite methodological differences across studies, meta-analytic assessments showed significant associations of levels of resistance (HR[95%CI]=1.12[1.07-1.17], p<0.0001) and levels of resilience (HR[95%CI]=0.46[0.32-0.68], p<0.001) with risk of progression to dementia/AD. Resilience was also associated with rate of cognitive decline (β[95%CI]=0.05[0.01-0.08], p<0.01). CONCLUSION: This review and meta-analysis supports the usefulness of residual methods as appropriate measures of resilience and resistance, as they capture clinically meaningful information in aging and AD. More rigorous methodological standardization is needed, however, to increase comparability across studies and, ultimately, application in clinical practice

Association of Education and Intracranial Volume With Cognitive Trajectories and Mortality Rates Across the Alzheimer Disease Continuum

OBJECTIVE: To investigate relationships of education and intracranial volume (factors related to cognitive versus brain reserve, respectively) with cognitive trajectories and mortality in individuals with biomarker-defined Alzheimer's disease (AD). METHODS: We selected 1,298 amyloid-β-positive memory clinic patients with subjective cognitive decline (SCD, n=142), mild cognitive impairment (MCI, n=274) and AD dementia (n=882) from the Amsterdam Dementia Cohort. All participants underwent baseline MRI and neuropsychological assessment, and 68% received cognitive follow-up (median=2.3 years, interquartile range=2.4). Mortality data were collected from the Central Public Administration. In the total sample and stratified by disease stage (i.e., SCD/MCI versus dementia), we examined education and intracranial volume as predictors of baseline and longitudinal cognitive performance on five cognitive domains [memory, attention, executive, language and visuospatial functions] (linear mixed models) and time-to-death (Cox proportional hazard models). Analyses were adjusted for age, sex, whole-brain gray matter atrophy and MRI field strength. RESULTS: Education and intracranial volume showed consistent positive associations with baseline cognition across disease stages. Longitudinally, we observed a relationship between higher education and faster cognitive decline among dementia patients on global cognition, memory, executive function and language (range β=-0.06-[-0.13], all p<0.05). Furthermore, in the total sample, both higher education and intracranial volume related to lower mortality risk (hazard ratio=0.84 and 0.82, respectively, p<0.05). CONCLUSIONS: In this amyloid-β-positive memory clinic sample, both reserve factors were positively associated with baseline cognition, whereas only education related to longitudinal cognition (i.e., accelerated decline among higher-educated patients with dementia). Moreover, higher education and intracranial volume both moderately attenuated overall mortality risk in AD

Identifying a task-invariant cognitive reserve network using task potency

Cognitive reserve (CR) is thought to protect against the consequence of age- or disease-related structural brain changes across multiple cognitive domains. The neural basis of CR may therefore comprise a functional network that is actively involved in many different cognitive processes. To investigate the existence of such a “task-invariant” CR network, we measured functional connectivity in a cognitively normal sample between 20 and 80 years old (N ​= ​265), both at rest and during the performance of 11 separate tasks that aim to capture four latent cognitive abilities (i.e. vocabulary, episodic memory, processing speed, and fluid reasoning). For each individual, we determined the change in functional connectivity from the resting state to each task state, which is referred to as “task potency” (Chauvin et al., 2018, 2019). Task potency was calculated for each pair among 264 nodes (Power et al., 2012) and then summarized across tasks reflecting the same cognitive ability. Subsequently, we established the correlation between task potency and IQ or education (i.e. CR factors). We identified a set of 57 pairs in which task potency showed significant correlations with IQ, but not education, across all four cognitive abilities. These pairs were included in a principal component analysis, from which we extracted the first component to obtain a latent variable reflecting task potency in this task-invariant CR network. This task potency variable was associated with better episodic memory (β ​= ​0.19, p ​< ​.01) and fluid reasoning performance (β ​= ​0.17, p ​< ​.01) above and beyond the effects of cortical thickness (range [absolute] β ​= ​0.28-0.32, p ​< ​.001). Our identification of this task-invariant network contributes to a better understanding of the mechanism underlying CR, which may facilitate the development of CR-enhancing treatments. Our work also offers a useful alternative operational measure of CR for future studies

Improving working memory in children with low language abilities

This study investigated whether working memory training is effective in enhancing verbal memory in children with low language abilities (LLA). Cogmed Working Memory Training was completed by a community sample of children aged 8–11 years with LLA and a comparison group with matched non-verbal abilities and age-typical language performance. Short-term memory (STM), working memory, language, and IQ were assessed before and after training. Significant and equivalent post-training gains were found in visuo-spatial short-term memory in both groups. Exploratory analyses across the sample established that low verbal IQ scores were strongly and highly specifically associated with greater gains in verbal STM, and that children with higher verbal IQs made greater gains in visuo-spatial short-term memory following training. This provides preliminary evidence that intensive working memory training may be effective for enhancing the weakest aspects of STM in children with low verbal abilities, and may also be of value in developing compensatory strategies

Differential patterns of gray matter volumes and associated gene expression profiles in cognitively-defined Alzheimer's disease subgroups

The clinical presentation of Alzheimer’s disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences

Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We employed a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicenter study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease-dementia with baseline [18F]flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences

Neuropsychological contribution to predict conversion to dementia in patients with mild cognitive impairment due to Alzheimer's disease

Background: Diagnosis of Alzheimer's disease (AD) confirmed by biomarkers allows the patient to make important life decisions. However, doubt about the fleetness of symptoms progression and future cognitive decline remains. Neuropsychological measures were extensively studied in prediction of time to conversion to dementia for mild cognitive impairment (MCI) patients in the absence of biomarker information. Similar neuropsychological measures might also be useful to predict the progression to dementia in patients with MCI due to AD. Objective: To study the contribution of neuropsychological measures to predict time to conversion to dementia in patients with MCI due to AD. Methods: Patients with MCI due toADwere enrolled from a clinical cohort and the effect of neuropsychological performance on time to conversion to dementia was analyzed. Results: At baseline, converters scored lower than non-converters at measures of verbal initiative, non-verbal reasoning, and episodic memory. The test of non-verbal reasoning was the only statistically significant predictor in a multivariate Cox regression model. A decrease of one standard deviation was associated with 29% of increase in the risk of conversion to dementia. Approximately 50% of patients with more than one standard deviation below the mean in the z score of that test had converted to dementia after 3 years of follow-up. Conclusion: In MCI due to AD, lower performance in a test of non-verbal reasoning was associated with time to conversion to dementia. This test, that reveals little decline in the earlier phases of AD, appears to convey important information concerning conversion to dementia.Fundacao para a Ciencia e Tecnologia (FCT)Portuguese Foundation for Science and TechnologyEuropean Commission [PTDC/MED-NEU/27946/2017

Is intracranial volume a suitable proxy for brain reserve? Rik Ossenkoppele

Background: Brain reserve is a concept introduced to explain why Alzheimer's disease (AD) patients with a greater brain volume prior to onset of pathology generally have better clinical outcomes. In this review, we provide a historical background of the emergence of brain reserve and discuss several aspects that need further clarification, including the dynamic or static nature of the concept and its underlying mechanisms and clinical effect. We then describe how brain reserve has been operationalized over the years, and critically evaluate the use of intracranial volume (ICV) as the most widely used proxy for brain reserve. Furthermore, we perform a meta-analysis showing that ICV is associated with higher cognitive performance after adjusting for the presence and amount of pathology. Although we acknowledge its imperfections, we conclude that the use of ICV as a proxy for brain reserve is currently warranted. However, further development of more optimal measures of brain reserve as well as a more clearly defined theoretical framework is essential