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Background and objectivesThis study aimed to examine whether baseline CSF measures of Alzheimer disease (AD)-related pathology are associated with the time to onset of mild cognitive impairment (MCI) and whether these associations differ by age, sex, Apolipoprotein E (ApoE4) status, and proximal (≤7 years) vs distal (>7 years) time to symptom onset.MethodsMeasures of amyloid (Aβ1-42 and Aβ1-40), phospho-tau (ptau181), and total tau (t-tau) were determined from CSF samples obtained at baseline from participants in an ongoing longitudinal project, known as the Biomarkers for Older Controls at Risk for Alzheimer Disease study (BIOCARD) study. The fully automated, Lumipulse G immunoassay was used to analyze the specimens. Cox regression models were used to examine the relationship of baseline biomarker levels with time to symptom onset of MCI and interactions with age, sex, and ApoE allelic status in subjects who progressed from normal cognition to MCI.ResultsAnalyses included 273 participants from the BIOCARD cohort, who were cognitively normal and predominantly middle-aged at baseline, and have been followed for an average of 16 years (max = 23.6). During follow-up, 94 progressed to MCI (median time to symptom onset = 6.9 years). In Cox regression models, elevated ptau181 and t-tau levels were associated with time to MCI symptom onset if it occurred within 7 years of baseline (HR 1.386 and 1.329; p = 0.009 and 0.017, respectively), while a lower Aβ42/Aβ40 ratio was associated with symptom onset if it occurred >7 years from baseline (HR 0.596, p = 0.003). There were also significant 3-way CSF × age × sex interactions for ptau181 and Aβ42/Aβ40, with follow-up analyses indicating that associations between these biomarkers and progression to MCI were stronger among men than among women, but this difference between sexes diminished with increasing age.DiscussionThe lengthy follow-up of BIOCARD participants permitted an examination of time-varying associations between CSF AD biomarkers with MCI symptom onset and the influence of sex, baseline age, and ApoE4 genotype on these associations. These factors may inform clinical trial enrollment strategies, or trial duration and outcomes, which may use these measures as surrogate markers of treatment response.

The brain signature concept aims to characterize brain regions most strongly associated with an outcome of interest. Brain signatures derive their power from data-driven searches that select features based solely on performance metrics of prediction or classification. This approach has important potential to delineate biologically relevant brain substrates for prediction or classification of future trajectories. Recent work has used exploratory voxel-wise or atlas-based searches, with some using machine learning techniques to define salient features. These have shown undoubted usefulness, but two issues remain. The preponderance of recent work has been aimed at categorical rather than continuous outcomes, and it is rare for non-atlas reliant voxel-based signatures to be reported that would be useful for modelling and hypothesis testing. We describe a cross-validated signature region model for structural brain components associated with baseline and longitudinal episodic memory across cognitively heterogeneous populations including normal, mild impairment and dementia. We used three non-overlapping cohorts of older participants: from the UC Davis Aging and Diversity cohort (n = 255; mean age 75.3 ± 7.1 years; 128 cognitively normal, 97 mild cognitive impairment, 30 demented and seven unclassified); from Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 (n = 379; mean age 75.1 ± 7.2; 82 cognitively normal, 176 mild cognitive impairment, 121 Alzheimer's dementia); and from ADNI2/GO (n = 680; mean age 72.5 ± 7.1; 220 cognitively normal, 381 mild cognitive impairment and 79 Alzheimer's dementia). We used voxel-wise regression analysis, correcting for multiple comparisons, to generate an array of regional masks corresponding to different association strength levels of cortical grey matter with baseline memory and brain atrophy with memory change. Cognitive measures were episodic memory using Spanish and English Neuropsychological Assessment Scales instruments for UC Davis and ADNI-Mem for ADNI 1 and ADNI2/GO. Performance metric was the adjusted R2 coefficient of determination of each model explaining outcomes in two cohorts other than where it was computed. We compared within-cohort performances of signature models against each other and against other recent signature models of episodic memory. Findings were: (i) two independently generated signature region of interest models performed similarly in a third separate cohort; (ii) a signature region of interest generated in one imaging cohort replicated its performance level when explaining cognitive outcomes in each of other, separate cohorts; and (iii) this approach better explained baseline and longitudinal memory than other recent theory-driven and data-driven models. This suggests our approach can generate signatures that may be easily and robustly applied for modelling and hypothesis testing in mixed cognition cohorts.

ObjectiveExamine whether cognitive reserve moderates the association of 1) vascular risk factors and 2) white matter hyperintensity burden with risk of clinical progression and longitudinal cognitive decline.MethodsBIOCARD Study participants were cognitively normal and primarily middle-aged (M = 57 years) at baseline and have been followed with annual cognitive and clinical assessments (M = 13 years). Baseline cognitive reserve was indexed with a composite score combining education with reading and vocabulary scores. Baseline vascular risk (N = 229) was assessed with a composite risk score reflecting five vascular risk factors. Baseline white matter hyperintensity load (N = 271) was measured with FLAIR magnetic resonance imaging. Cox regression models assessed risk of progression from normal cognition to onset of clinical symptoms of Mild Cognitive Impairment. Longitudinal mixed effects models measured the relationship of these variables to cognitive decline, using a global composite score, and executive function and episodic memory sub-scores.ResultsBoth vascular risk and white matter hyperintensities were associated with cognitive decline, particularly in executive function. Higher vascular risk, but not white matter hyperintensity burden, was associated with an increased risk of progression to Mild Cognitive Impairment. Higher cognitive reserve was associated with a reduced risk of symptom onset and higher levels of baseline cognition but did not modify the associations between the vascular risk score and white matter hyperintensities with clinical progression or cognitive decline.InterpretationAlthough cognitive reserve has protective effects on clinical and cognitive outcomes, it does not mitigate the negative impact of vascular risk and small vessel cerebrovascular disease on these same outcomes.

We examined whether cognitive reserve (CR) impacts level of, or rate of change in, biomarkers of Alzheimer's disease (AD) and small-vessel cerebrovascular disease in >250 individuals who were cognitively normal and middle-aged and older at the baseline. The four primary biomarker categories commonly examined in studies of AD were measured longitudinally: cerebrospinal fluid measures of amyloid (A) and tau (T); cerebrospinal fluid and neuroimaging measures of neuronal injury (N); and neuroimaging measures of white matter hyperintensities (WMHs) to assess cerebrovascular pathology (V). CR was indexed by a composite score including years of education, reading, and vocabulary test performance. Higher CR was associated with lower levels of WMHs, particularly among those who subsequently progressed from normal cognition to MCI. CR was not associated with WMH trajectories. In addition, CR was not associated with either levels of, or rate of change in, A/T/N biomarkers. This may suggest that higher CR is associated with lifestyle factors that reduce levels of cerebrovascular disease, allowing individuals with higher CR to better tolerate other types of pathology.

ObjectiveRecent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).MethodsTwo sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.ResultsBaseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.ConclusionThese results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.

ObjectiveOur objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia.MethodsWe used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively.ResultsAt time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%).InterpretationAge-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.

Despite anecdotal evidence of relative visuospatial processing strengths in individuals with reading disability (RD), only a few studies have assessed the presence or the extent of these putative strengths. The current study examined the cognitive and neural bases of visuospatial processing abilities in adolescents with RD relative to typically developing (TD) peers. Using both cognitive tasks and functional magnetic resonance imaging (fMRI) we contrasted printed word recognition with non-language visuospatial processing tasks. Behaviorally, lower reading skill was related to a visuospatial processing advantage (shorter latencies and equivalent accuracy) on a geometric figure processing task, similar to findings shown in two published studies. FMRI analyses revealed key group by task interactions in patterns of cortical and subcortical activation, particularly in frontostriatal networks, and in the distributions of right and left hemisphere activation on the two tasks. The results are discussed in terms of a possible neural tradeoff in visuospatial processing in RD.

Background: Although it is well established that lower cognitive performance, on average, is associated with a greater risk of developing Alzheimer's disease (AD) dementia, it is unclear whether distinct cognitively‐defined subgroups exist among non‐demented older adults and whether such profiles map onto distinct AD neuroimaging measure profiles. Method: The sample consisted of 167 non‐demented older adults from the BIOCARD study with comprehensive neuropsychological and clinical evaluations, amyloid PET and brain MRI scans. The MRI measure included: global cortical volume in AD‐signature regions and a medial‐temporal lobe composite; resting‐state functional connectivity within 5 large‐scale cognitive networks; global white matter microstructure, index by fractional anisotropy (FA) and radial diffusion (RD) on DTI scans; and global white matter hyperintensity (WMH) volume on FLAIR scans. A latent profile analysis (LPA) identified cognitively defined subgroups using standardized scores of 8 cognitive tests that cover AD‐related domains (episodic memory, executive functions, working memory, semantic memory, language, visuospatial function, and attention). Multiple linear regression models tested the associations between the group membership and neuroimaging measures adjusting for age, sex, and education. Result: The LPA identified a model with 3 subgroups as the best solution (AIC = 3515; BIC = ‐3605; ICL = ‐3642; BLRT p = 0.001). The groups primarily differed in terms of performance level: high (36%); average (53%); low (11%). Each group showed distinctive diagnosis composition: high ─ 100% cognitively normal (CN); average ─ 91% CN and 9% mild cognitive impairment (MCI); low ─ 61% CN and 39% MCI. Compared to the high performance group, the low performance group had significantly lower cortical volume in AD vulnerable regions, lower salience/ventral attention network functional connectivity, lower global white matter microstructural integrity, measured by FA and RD, and higher global WMH burden. Amyloid load was not associated with group membership. Conclusion: Distinct subgroups defined by cognitive performance exist among non‐demented older adults that are related to AD neuroimaging measures. Evaluating cognitive profiles among non‐demented older individuals may help identify individuals at greatest risk for future cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Higher level of cognitive reserve (CR), measured using proxies such as years of education or literacy, is associated with reduced risk of Mild Cognitive Impairment (MCI) and dementia. Little is known about how CR and other lifestyle factors impact non‐cognitive outcomes, including depression and other neuropsychiatric symptoms (e.g., agitation, delusions, anxiety, etc.). This study examined whether factors that influence cognition among non‐demented older adults (i.e., CR, demographics, vascular risk, sleep quality, physical activity, ApoE4 genetic status) are also associated with depression and other neuropsychiatric symptoms, and whether these associations vary by AD pathology levels. Method: Depression and other neuropsychiatric symptoms were assessed using the Geriatric Depression Scale (GDS) and Neuropsychiatric Inventory (NPI), among 181 non‐demented BIOCARD Study participants (mean age = 72.6y, including 152 cognitively unimpaired and 29 with MCI). Total volume of physical activity and sleep efficiency were measured using actigraphy. Level of CR was based on a composite of years of education, vocabulary, and reading ability. A subset of participants (n = 125) had cerebrospinal fluid measures of amyloid and tau (Fujirebio Lumipulse G1200 assays), with AD pathology levels summarized as the ratio of p‐tau181/(AB42/AB40). Linear regressions evaluated the cross‐sectional relationship between the risk and protective factors with total GDS and NPI scores, and interactions with AD‐pathology levels. Results: For depression, greater total physical activity (p<0.004) and greater sleep efficiency (p = 0.006) were associated with lower GDS scores, independent of CR, age, sex, vascular risk, and ApoE4 status, which were not associated with GDS scores. The strength of this association was reduced among participants with higher AD‐pathology levels (p<0.05 for interactions of ptau181/(Ab42/Ab40 with physical activity and sleep efficiency. For neuropsychiatric symptoms, higher CR scores were associated with lower NPI scores and this association was independent of p‐tau181/(AB42/AB40) levels, but greater among those with poor sleep efficiency and among men. Conclusion: These results suggest that level of cognitive reserve, sleep quality, and physical activity levels are associated with depression and other neuropsychiatric symptoms among non‐demented older adults. Moreover, these associations differentially depend on AD‐biomarker levels, suggesting that individualized approaches to the treatment of neuropsychiatric symptoms among older adults are likely most successful. [ABSTRACT FROM AUTHOR]