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Sleep health and executive function are multifaceted constructs that decline with age. Some evidence suggests that poor sleep health may underlie declines in executive function, but this relationship is not consistently found in cognitively normal older adults. The authors systematically investigated distinct sleep health domain associations with specific aspects of executive function.Community-dwelling older adults completed clinical interviews, comprehensive neuropsychological assessments, and subjective sleep measures. Four sleep health domains were investigated: satisfaction/quality, sleep efficiency, sleep duration, and daytime sleepiness/fatigue. Hierarchical multiple regression analyses, adjusting for significant covariates, examined whether the sleep health domains differentially predicted executive function.Separate analyses found that greater sleep efficiency was associated with better response inhibition, while greater daytime sleepiness/fatigue was associated with worse cognitive flexibility. Categorical differences in sleep duration indicated that average durations, compared with short and long durations, had better executive function performance across measures. Sleep satisfaction/quality was not statistically associated with executive function.These findings have implications for sleep assessment and its intervention. Routine screening of sleep duration, efficiency, and daytime fatigue may be particularly useful in identifying those at greater risk of executive dysfunction. Targeting specific problems in sleep may serve to improve cognitive control and efficiency in older adults. Future research is warranted to establish the optimal hours of sleep duration for cognitive health.

An understudied non-amnestic variant of Alzheimer’s disease (AD), behavioral variant AD (bvAD) is associated with progressive personality, behavior, or executive dysfunction and frontal atrophy. This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. Subjects included 16 bvAD, 67 bvFTD, and 18 aAD patients, and 26 healthy controls. Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.

Objectives:Adverse childhood experiences (ACE) are associated with an increased risk for dementia, but this relationship and modifying factors are poorly understood. This study is the first to our knowledge to comprehensively examine the effect of ACE on specific cognitive functions and measures associated with greater risk and resiliency to cognitive decline in independent community-dwelling older adults.Methods:Verbal/nonverbal intelligence, verbal memory, visual memory, and executive attention were assessed. Self-report measures examined depression, self-efficacy, and subjective cognitive concerns (SCC). The ACE questionnaire measured childhood experiences of abuse, neglect, and household dysfunction.Results:Over 56% of older adults reported an adverse childhood event. ACE scores were negatively associated with income and years of education and positively associated with depressive symptoms and SCC. ACE scores were a significant predictor of intellectual function and executive attention; however, these relationships were no longer significant after adjusting for education. Follow-up analyses using the PROCESS macro revealed that relationships among higher ACE scores with intellectual function and executive attention were mediated by education.Conclusions:Greater childhood adversity may increase vulnerability for cognitive impairment by impacting early education, socioeconomic status, and mental health. These findings have clinical implications for enhancing levels of cognitive reserve and addressing modifiable risk factors to prevent or attenuate cognitive decline in older adults.

Objectives The current study investigated trait mindfulness associations with distinct aspects of executive function. We also aimed to characterize relationships between trait mindfulness with measures of psychological risk and resilience within adults aged 55-87 years. Method In this cross-sectional study, 121 adults completed neuropsychological measures of working memory, mental set-shifting, and inhibition, as well as a battery of well-validated psychological self-report measures. The Mindful Attention Awareness Scale (MAAS) measured trait mindfulness. Results Trait mindfulness was associated with greater age, years of education and self-efficacy, and less perceived stress, depression, anxiety, and subjective cognitive concerns. Hierarchal multiple regression analyses showed that trait mindfulness was a significant predictor of inhibitory control, even after adjusting for age, education, and global cognition in the model. Trait mindfulness was not significantly associated with working memory or mental set-shifting. Follow-up analyses using the PROCESS macro revealed that trait mindfulness mediated the relationship between perceived stress and inhibitory control. Conclusion Trait mindfulness was associated with measures of greater well-being and mental health. Our results also indicate that trait mindfulness may provide psychological resilience by attenuating perceived stress and enhancing the capacity to intentionally suppress irrelevant information and automatic responses.

Objective The National Institutes of Health Toolbox-Cognition Battery (NIHTB-CB) is an efficient computerized neuropsychological battery. This study investigated its psychometric properties in terms of sociodemographic characteristics and technology use in adults aged 57–87 (with an average age of 70). Methods Community-based participatory research procedures were used to enhance enrollment of adults with lower education and income backgrounds. Study procedures replicated work that compared the NIHTB-CB Crystallized and Fluid composites to analogous gold-standard (GS) measures and extended it by investigation of socioeconomic status and technology use-related differences in performance. Results The high correlations among the NIHTB-CB and GS analogous Crystallized and Fluid composites suggested good convergent validity. There was no evidence of significant education- or economic-related group differences in these associations. However, caution is needed as Cronbach’s alpha that indicated the NIHTB-CB Fluid composite had questionable internal item consistency. The NIHTB-CB and GS measures demonstrated poor discriminant validity in the high school but not college-educated groups. Regression analyses found that comfort with technology use, income, education, and age predicted better cognitive test performance on the computerized and paper-pencil measures. Conclusions There is an urgent need to improve the understanding of socioeconomic disparities influence on test scores and brain health. Lack of discriminant validity in the cognitive tests indicates that these measures could result in diagnostic errors within noncollege-educated older adults. These findings reduce confidence in the use of the NIHTB-CB Fluid composite in older adults and support that there is a significant socioeconomic-related digital divide in comfort with technology use.

To evaluate whether occupational attainment influences the trajectory of longitudinal cognitive decline in behavioral variant frontotemporal degeneration (bvFTD). Single-center, retrospective, longitudinal study. Sixty-three patients meeting consensus criteria for bvFTD underwent evaluation at the University of Pennsylvania Frontotemporal Degeneration Center. All patients were studied longitudinally on letter-guided fluency, category-naming fluency and Boston Naming Test (BNT). Occupational attainment was defined categorically by assigning each individual’s occupation to a professional or non-professional category. Linear mixed-effects models evaluated the interaction of neuropsychological performance change with occupational status. Regression analyses were used to relate longitudinal decline in executive function to baseline MRI grey matter atrophy. Higher occupational status was associated with a more severe slope of cognitive decline on letter-guided fluency and category-naming fluency, but not BNT. Faster rates of longitudinal decline on letter-guided and category-naming fluency were associated with more severe baseline grey matter atrophy in right dorsolateral and inferior frontal regions. Our longitudinal findings suggest that bvFTD individuals with higher lifetime cognitive experience demonstrate more rapid decline on measures of executive function. This finding converges with cross-sectional evidence suggesting that lifetime cognitive experiences contribute to heterogeneity in clinical progression in bvFTD.

ObjectiveMild cognitive impairment and dementia are clinically heterogeneous disorders influenced by diverse risk factors. Improved characterization of the effect of multiple risk factors influence on specific cognitive functions may improve understanding of mechanisms in early cognitive change and lead to more effective interventions.MethodsStructural equation modeling (SEM) simultaneously examined the effects of modifiable (education, depression, and metabolic/vascular risk) and nonmodifiable risk factors (age, sex, and apolipoprotein E-ɛ4 allele [APOE-e4] status) on specific cognitive domains in 461 cognitively normal older adults.ResultsThe hypothesized model(s) provided an adequate fit for the data. Sex differences in cognition, depression, and vascular risk were found. On average, men were higher in vascular risk with generally lower cognitive performance than women; women were more likely to have depression. APOE-e4 associated with depression but not age, sex, or metabolic/vascular risk. Depression associated with lower executive attention, memory, and language performance, whereas metabolic/vascular risk associated with lower executive attention, memory, and working memory. Older age and lower education are associated with worse performance across the cognitive domains. The combined risk factors accounted for 16%–47% of the variance in the cognitive domains.ConclusionsResults highlight the combined effect of risk factors on cognitive function. Future research is needed to determine whether the multifactorial risk effects on cognition vary by sex. Precision medicine approaches that integrate neuropsychological services may improve diagnostic accuracy and earlier identification of those at risk of cognitive decline.

Background: Day-to-day interactions depend on conversational narrative, and we examine here the neurobiological basis for difficulty organizing narrative discourse in patients with Lewy body disorders (LBD). Method: Narrative organization was examined in 56 non-aphasic LBD patients, including a non-demented cohort (n = 30) with Parkinson's disease (PD) or PD-Mild Cognitive Impairment PD-MCI,) and a cohort with mild dementia (n = 26) including PD-dementia (PDD) and dementia with Lewy bodies (DLB), with similar age and education but differing in MMSE (p < 0.001). We used a previously reported procedure that probes patients' judgments of the organization of brief, familiar narratives (e.g., going fishing, wrapping a present). A subgroup of 24 patients had MRI assessment of regional gray matter (GM) atrophy and cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer's disease (AD) pathology, including beta amyloid (Aβ), total-tau (t-tau), and phosphorylated-tau (p-tau). Results: Mildly demented LBD patients had a significant deficit judging narratives compared to non-demented patients, but this deficit was not correlated with MMSE. Regression analyses instead related narrative organization to regions of frontal GM atrophy, and CSF levels of Aβ and t-tau associated with presumed AD pathology in these frontal regions. Conclusion: These findings are consistent with the hypothesis that CSF markers of AD pathology associated with frontal regions play a role in difficulty organizing narratives in LBD.

We examined narrative speech production longitudinally in non-demented (n=15) and mildly demented (n=8) patients with Parkinson's disease spectrum disorder (PDSD), and we related increasing impairment to structural brain changes in specific language and motor regions. Patients provided semi-structured speech samples, describing a standardized picture at two time points (mean±SD interval=38±24 months). The recorded speech samples were analyzed for fluency, grammar, and informativeness. PDSD patients with dementia exhibited significant decline in their speech, unrelated to changes in overall cognitive or motor functioning. Regression analysis in a subset of patients with MRI scans (n=11) revealed that impaired language performance at Time 2 was associated with reduced gray matter (GM) volume at Time 1 in regions of interest important for language functioning but not with reduced GM volume in motor brain areas. These results dissociate language and motor systems and highlight the importance of non-motor brain regions for declining language in PDSD.

In addition to its role in hemorrhagic stroke, advanced cerebral amyloid angiopathy (CAA) is also associated with ischemic lesions and vascular cognitive impairment. We used functional magnetic resonance imaging (MRI) techniques to identify CAA-associated vascular dysfunction.Functional MRI was performed on 25 nondemented subjects with probable CAA (mean ± standard deviation age, 70.2 ± 7.8 years) and 12 healthy elderly controls (age, 75.3 ± 6.2 years). Parameters measured were reactivity to visual stimulation (quantified as blood oxygen level-dependent [BOLD] response amplitude, time to peak response, and time to return to baseline after stimulus cessation) and resting absolute cerebral blood flow in the visually activated region (measured by arterial spin labeling).CAA subjects demonstrated reduced response amplitude (percentage change in BOLD signal, 0.65 ± 0.28 vs 0.89 ± 0.14; p0.01), prolonged time to peak (11.1 ± 5.1 vs 6.4 ± 1.8 seconds; p0.001), and prolonged time to baseline (16.5 ± 6.7 vs 11.6 ± 3.1 seconds; p0.001) relative to controls. These differences were independent of age, sex, and hypertension in multivariable analysis and were also present in secondary analyses excluding nonresponsive voxels or voxels containing chronic blood products. Within the CAA group, longer time to peak correlated with overall volume of white matter T2 hyperintensity (Pearson correlation, 0.53; p = 0.007). Absolute resting blood flow in visual cortex, in contrast, was essentially identical between the groups (44.0 ± 12.6 vs 45.0 ± 10.0 ml/100 g/min, p = 0.8).Functional MRI identifies robust differences in both amplitude and timing of the response to visual stimulation in advanced CAA. These findings point to potentially powerful approaches for identifying the mechanistic links between vascular amyloid deposits, vascular dysfunction, and CAA-related brain injury.

Objective: To investigate whether the topography of dilated perivascular spaces (DPVS) corresponds with markers of particular small-vessel diseases such as cerebral amyloid angiopathy and hypertensive vasculopathy. Methods: Patients were recruited from an ongoing single-center prospective longitudinal cohort study of patients evaluated in a memory clinic. All patients underwent structural, high-resolution MRI, and had a clinical assessment performed within 1 year of scan. DPVS were rated in basal ganglia (BG-DPVS) and white matter (WM-DPVS) on T1 sequences, using an established 4-point semiquantitative score. DPVS degree was classified as high (score > 2) or low (score ≤ 2). Independent risk factors for high degree of BG-DPVS and WM-DPVS were investigated. Results: Eighty-nine patients were included (mean age 72.7 ± 9.9 years, 57% female). High degree of WM-DPVS was more frequent than low degree in patients with presence of strictly lobar microbleeds (45.5% vs 28.4% of subjects). High BG-DPVS degree was associated with older age, hypertension, and higher white matter hyperintensity volumes. In multivariate analysis, increased lobar microbleed count was an independent predictor of high degree of WM-DPVS (odds ratio [OR] 1.53 [95% confidence interval (CI) 1.06–2.21], p = 0.02). By contrast, hypertension was an independent predictor of high degree of BG-DPVS (OR 9.4 [95% CI 1–85.2], p = 0.04). Conclusions: The associations of WM-DPVS with lobar microbleeds and BG-DPVS with hypertension raise the possibility that the distribution of DPVS may indicate the presence of underlying small-vessel diseases such as cerebral amyloid angiopathy and hypertensive vasculopathy in patients with cognitive impairment.

We aimed to determine whether amyloid imaging can help predict the location and number of future hemorrhages in cerebral amyloid angiopathy (CAA).We performed a longitudinal cohort study of 11 patients with CAA without dementia who underwent serial brain MRIs after baseline amyloid imaging with Pittsburgh compound B (PiB). Mean distribution volume ratio (DVR) of PiB was determined at the sites of new micro/macrobleeds identified on follow-up MRI and compared with PiB retention at "simulated" hemorrhages, randomly placed in the same subjects using a probability distribution map of CAA-hemorrhage location. Mean PiB retention at the sites of observed new bleeds was also compared to that in shells concentrically surrounding the bleeds. Finally the association between number of incident bleeds and 3 regional amyloid measures were obtained.Nine of 11 subjects had at least one new microbleed on follow-up MRI (median 4, interquartile range [IQR] 1-9) and 2 had 5 new intracerebral hemorrhages. Mean DVR was greater at the sites of incident bleeds (1.34, 95% confidence interval [CI] 1.23-1.46) than simulated lesions (1.14, 95% CI 1.07-1.22, p0.0001) in multivariable models. PiB retention decreased with increasing distance from sites of observed bleeds (p0.0001). Mean DVR in a superior frontal/parasagittal region of interest correlated independently with number of future hemorrhages after adjustment for relevant covariates (p = 0.003).Our results provide direct evidence that new CAA-related hemorrhages occur preferentially at sites of increased amyloid deposition and suggest that PiB-PET imaging may be a useful tool in prediction of incident hemorrhages in patients with CAA.

Background and Purpose: Cerebral Amyloid Angiopathy (CAA), characterized by accumulation of amyloid beta proteins in the walls of cortical/leptomeningeal vessels, is increasingly recognized as a cause of ischemic brain injury in addition to its classical role in lobar cerebral hemorrhages (ICH). Pittsburgh Compound B (PiB) is a PET ligand that has been shown to label the vascular amyloid deposits of CAA, allowing invivo quantification of the severity of CAA pathology. We hypothesized that there would be a dose-dependent relationship between vascular amyloid burden (measured by PiB) and brain ischemia (measured by extent of MRI markers of chronic ischemia) in patients diagnosed with CAA but not in healthy elderly without evidence of advanced CAA. Methods: Thirty-five non-demented patients (9 women) with a diagnosis of CAA according to Boston Criteria and 50 healthy elderly subjects (29 women) without lobar microhemorrhages or history of stroke/dementia who underwent a brain MRI scan and PiB-PET imaging were analyzed. Global cortical PiB retention was calculated using cerebellar cortex as the reference tissue input function and expressed as the distribution volume ratio (DVR). Quantitative analysis of white matter T2-hyperintensity (WMH) volume on MRI FLAIR sequences was performed using computer-assisted techniques. Presence of lacunar infarcts was also recorded in each subject. Multivariate linear regression was used to assess the association between PiB retention and WMH volume while controlling for other vascular risk factors within each group. Results: CAA patients were younger than healthy elderly (67±10 vs 73±7, p=0.004) but had higher amounts of WMH (19ml IQR:6.7-31.8 vs 3.2ml IQR:2-5.6, p Conclusions: Our results indicate that global PiB retention independently correlates with volume of white matter disease on FLAIR in patients with CAA but not in healthy elderly. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia in the CAA population and highlights the possible utility of amyloid imaging as a marker of CAA severity.

Background and Purpose— Although corticosteroid use in acute hemorrhagic stroke is not widely adopted, management with intravenous dexamethasone has been standard of care at the University Hospital of Heraklion, Crete with observed outcomes superior to those reported in the literature. To explore this further, we conducted a retrospective, multivariable-adjusted 2-center study. Methods— We studied 391 acute hemorrhagic stroke cases admitted to the University Hospital of Heraklion, Crete between January 1997 and July 2010 and compared them with 510 acute hemorrhagic stroke cases admitted to Massachusetts General Hospital, Boston, from January 2003 to September 2009. Of the Cretan cases, 340 received a tapering scheme of intravenous dexamethasone, starting with 16 to 32 mg/day, whereas the Boston patients were managed without steroids. Results— The 2 cohorts had comparable demographics and stroke severity on admission, although anticoagulation was more frequent in Boston. The in-hospital mortality was significantly lower on Crete (23.8%, n=340) than in Boston (38.0%, n=510; P P P Conclusions— This study suggests that intravenous dexamethasone improves outcome in acute hemorrhagic stroke and supports a randomized clinical trial using this approach.

Objective: To identify and compare clinical and neuroimaging predictors of primary lobar intracerebral hemorrhage (ICH) recurrence, assessing their relative contributions to recurrent ICH. Methods: Subjects were consecutive survivors of primary ICH drawn from a single-center prospective cohort study. Baseline clinical, imaging, and laboratory data were collected. Survivors were followed prospectively for recurrent ICH and intercurrent aspirin and warfarin use, including duration of exposure. Cox proportional hazards models were used to identify predictors of recurrence stratified by ICH location, with aspirin and warfarin exposures as time-dependent variables adjusting for potential confounders. Results: A total of 104 primary lobar ICH survivors were enrolled. Recurrence of lobar ICH was associated with previous ICH before index event (hazard ratio [HR] 7.7, 95% confidence interval [CI] 1.4–15.7), number of lobar microbleeds (HR 2.93 with 2–4 microbleeds present, 95% CI 1.3–4.0; HR = 4.12 when ≥5 microbleeds present, 95% CI 1.6–9.3), and presence of CT-defined white matter hypodensity in the posterior region (HR 4.11, 95% CI 1.01–12.2). Although aspirin after ICH was not associated with lobar ICH recurrence in univariate analyses, in multivariate analyses adjusting for baseline clinical predictors, it independently increased the risk of ICH recurrence (HR 3.95, 95% CI 1.6–8.3, p = 0.021). Conclusions: Recurrence of lobar ICH is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar ICH may also increase recurrence risk.

Background: Cerebral amyloid angiopathy (CAA) typically presents with lobar intracerebral macrohemorrhages (ICH) or microbleeds (MBs). Several case reports also found superficial siderosis (SS) in patients with CAA. We aimed to assess the value of SS for the in vivo diagnosis of CAA, and tested whether the inclusion of SS as a criterion alters the sensitivity and specificity of the Boston criteria for CAA-related hemorrhage. Methods: We retrospectively analyzed the T2*-weighted MRIs of 38 patients with histopathologically proven CAA and of 22 control patients with histopathologically proven non-CAA ICHs regarding the presence of ICHs, MBs, and SS. We compared the sensitivity and specificity of the classic Boston criteria to that of modified criteria, which included SS as a criterion. Results: ICHs were present in 71% of the patients with CAA, and in all control patients. MBs were found in 47.4% of patients with CAA and in 22.7% of controls. SS was detected in 60.5% of patients with CAA, but in none of the controls. The classic criteria had a sensitivity of 89.5% for CAA-related hemorrhage, while inclusion of SS increased their sensitivity to 94.7% (not significant). On the contrary, the specificity of the Boston criteria was 81.2% both for the classic and for the modified criteria. Conclusions: Superficial siderosis (SS) occurs with high prevalence in cerebral amyloid angiopathy (CAA) and is rare in non-CAA forms of intracerebral hemorrhages. Thus, we propose that inclusion of SS in the Boston criteria might enhance their sensitivity for CAA-related hemorrhage without loss of specificity. Neurology (R) 2010; 74: 1346-1350