Knopman, David S.

ObjectiveTo investigate the multifactorial processes underlying cognitive aging based on the hypothesis that multiple causal pathways and mechanisms (amyloid, vascular, and resilience) influence longitudinal cognitive decline in each individual through worsening brain health.MethodsWe identified 1,230 elderly subjects (aged ≥50 years) with an average of 4.9 years of clinical follow‐up and with amyloid positron emission tomography, diffusion tensor imaging, and structural magnetic resonance imaging scans from the population‐based Mayo Clinic Study of Aging. We examined imaging markers of amyloid and brain health (white matter microstructural integrity and cortical thinning), systemic vascular health preceding the imaging markers, and early to midlife intellectual enrichment to predict longitudinal cognitive trajectories. We used latent growth curve models for modeling longitudinal cognitive decline.ResultsAll the pathways (amyloid, vascular, resilience) converged through their effects on cortical thinning and worsening cognition and together explained patterns in cognitive decline. Resilience and vascular pathways (aging process, sex differences, education/occupation, and systemic vascular health) had significant impact on white matter microstructural integrity. Education/occupation levels contributed to white matter integrity through systemic vascular health. Worsening white matter integrity contributed to significant cortical thinning and subsequently longitudinal cognitive decline. Baseline amyloidosis contributed to a significant proportion of cognitive decline that accelerated with longer follow‐up times, and its primary impact was through cortical thinning.InterpretationWe developed an integrated framework to help explain the dynamic and complex process of cognitive aging by considering key causal pathways. Such an approach is important for both better comprehension of cognitive aging processes and will aid in the development of successful intervention strategies. ANN NEUROL 2019;86:866–877

AbstractIntroductionOur aim was to examine whether surgery with regional anesthesia (RA) is associated with accelerated long‐term cognitive decline comparable with that previously reported after general anesthesia (GA).MethodsLongitudinal cognitive function was analyzed in a cohort of 1819 older adults. Models assessed the rate of change in global and domain‐specific cognition over time in participants exposed to RA or GA.ResultsWhen compared with those unexposed to anesthesia, the postoperative rate of change of the cognitive global z‐score was greater in those exposed to both RA (difference in annual decline of −0.041, P = .011) and GA (−0.061, P < .001); these rates did not differ. In analysis of the domain‐specific scores, an accelerated decline in memory was observed after GA (−0.065, P < .001) but not RA (−0.011, P = .565).ConclusionsOlder adults undergoing surgery with RA experience decline of global cognition similar to those receiving GA; however, memory was not affected.

The specific effect of TDP-43 pathology on grey matter volume in individuals without frontotemporal lobar degeneration is unclear. Bejanin et al. reveal a major and independent contribution of TDP-43 to neurodegeneration and shed light on the regional distribution of TDP-43-related atrophy in older adults.

AbstractIntroductionBehavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD).MethodsWe analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium.ResultsThe CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®‐SB) = 0. The CDR®‐SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®‐SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders.DiscussionThe BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

See Gordon and Tijms (doi:10.1093/brain/awz278) for a scientific commentary on this article. Jack et al. examine relationships between the bivariate distribution of β-amyloid and tau on PET and established neurocognitive clinical syndromes. Amyloidosis appears to be required for high levels of 3R/4R tau deposition. Whereas abnormal amyloid PET is compatible with normal cognition, highly abnormal tau PET is not.

Abstract Introduction The aim of this study was to investigate the rates of lobar atrophy in the asymptomatic microtubule‐associated protein tau ( MAPT ) mutation carriers. Methods MAPT mutation carriers (n = 14; 10 asymptomatic, 4 converters from asymptomatic to symptomatic) and noncarriers (n = 13) underwent structural magnetic resonance imaging and were followed annually with a median of 9.2 years. Longitudinal changes in lobar atrophy were analyzed using the tensor‐based morphometry with symmetric normalization algorithm. Results The rate of temporal lobe atrophy in asymptomatic MAPT mutation carriers was faster than that in noncarriers. Although the greatest rate of atrophy was observed in the temporal lobe in converters, they also had increased atrophy rates in the frontal and parietal lobes compared to noncarriers. Discussion Accelerated decline in temporal lobe volume occurs in asymptomatic MAPT mutation carriers followed by the frontal and parietal lobe in those who have become symptomatic. The findings have implications for monitoring the progression of neurodegeneration during clinical trials in asymptomatic MAPT mutation carriers.

OBJECTIVES Cardiac troponin T, measured using a high‐sensitive assay (hs‐cTnT), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) are associated with increased stroke risk and perhaps with cognitive decline. However, few well‐designed prospective studies with extended follow‐up have been conducted. We aimed to estimate the association of hs‐cTnT and NT‐proBNP with 15‐year cognitive change in the Atherosclerosis Risk in Communities (ARIC) study. DESIGN Prospective cohort study. SETTING Four US communities. PARTICIPANTS A total of 9114 and 9108 participants from the Atherosclerosis Risk in Communities study for analyses of hs‐cTnT and NT‐proBNP, respectively. MEASUREMENTS We examined association of hs‐cTnT and NT‐proBNP with 15‐year change (1996‐1998 to 2011‐2013) in three cognitive tests of executive function (Digit Symbol Substitution Test), verbal learning memory (Delayed Word Recall Test), and semantic fluency (Word Fluency Test), and an overall score combining the three tests using multivariable linear mixed effect models. We conducted several sensitivity analyses including multiple imputations to address bias due to missing data and attrition, and we compared associations within groups combining hs‐cTnT and NT‐proBNP into a three‐level categorical variable. RESULTS At baseline (1996‐1998), mean age was 63.4 (standard deviation [SD] = 5.7) years; 56.4% were women, and 17.5% were black. The hs‐cTnT at baseline was not associated with cognitive change in any measure. Some evidence indicated accelerated decline in verbal learning and memory when comparing those in the highest with the lowest NT‐proBNP quintiles; however, this association was not replicated when considering clinically relevant cutoffs or deciles of exposure in survivors. Sensitivity analyses were consistent with our primary analyses. There was little evidence to support effect modification by any considered factors. People with highest levels of both biomarkers had excessive decline in global z scores vs people with lowest levels (−.34; 95% confidence interval = −.63 to −.04). CONCLUSION Markers of myocardial injury and stretch were not associated with cognitive decline following 15 years among survivors, but when combined together they were suggestive in post hoc analysis. Whether this represents targets of intervention should be examined in the future. J Am Geriatr Soc 67:2353–2361, 2019