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A positive association between cardiorespiratory fitness (CRF) and white matter integrity has been consistently reported in older adults. However, it is unknown whether this association exists in adults over 80 with a range of chronic disease conditions and low physical activity participation, which can influence both CRF and brain health. This study examined whether higher CRF was associated with greater microstructural integrity of gray and white matter in areas related to memory and information processing in adults over 80 and examined moderating effects of chronic diseases and physical activity. CRF was measured as time to walk 400 m as quickly as possible with concurrent 3T diffusion tensor imaging in 164 participants (57.1% female, 40.3% black). Fractional anisotropy (FA) was computed for cingulum, uncinate and superior longitudinal fasciculi. Mean diffusivity (MD) was computed for dorsolateral prefrontal cortex, hippocampus, parahippocampus, and entorhinal cortex. Moderating effects were tested using hierarchical regression models. Higher CRF was associated with higher FA in cingulum and lower MD in hippocampus and entorhinal cortex (β, sex-adjusted p: -0.182, 0.019; 0.165, 0.035; and 0.220, 0.006, respectively). Hypertension attenuated the association with MD in entorhinal cortex. Moderating effects of chronic diseases and physical activity in walking and climbing stairs on these associations were not significant. The association of higher CRF with greater microstructural integrity in selected subcortical areas appears robust, even among very old adults with a range of chronic diseases. Intervention studies should investigate whether increasing CRF can preserve memory and information processing by improving microstructure and potential effects of hypertension management.

In older adults, depressive symptoms are associated with lower quality of life, high morbidity and mortality. This study aims to identify brain magnetic resonance imaging (MRI) features associated with late-life depressive symptoms in the population. Older community-dwelling adults (n=314) from the Health ABC study underwent brain MRI. Logistic regression was used to characterize the relationships between depressive symptoms (Center for Epidemiologic Studies of Depression scale, CES-D) and the following whole-brain variables: white matter hyperintensity (WMH) burden, fractional anisotropy (FA), and gray matter volume (GMV). Analyses examining possible regional differences between the CES-D groups controlled for Modified Mini-Mental State Examination score and diabetes status. The relative importance of localization of the markers was examined by comparing the distribution of significant peaks across the brain. Each whole-brain variable showed loss of integrity associated with high CES-D. For GMV, the odds ratio (OR)=0.84 (95% confidence interval (CI) 0.74, 0.96); for FA, OR=0.714 (95% CI 0.57, 0.88); for WMH, OR=1.89 (95%CI 1.33, 2.69). Voxel-wise analyses and patterns of peak significance showed non-specific patterns for white matter measures. Loss of GMV was most significant in the bilateral insula and anterior cingulate cortex. This study supports a cerebrovascular pattern for depressive symptoms in older adults. The localization of gray matter changes to the insula, a watershed area and a hub of affective circuits, suggests an etiological pathway from ischemia to increased depressive burden.

BackgroundAlthough the beneficial effects of physical activity (PA) on memory and executive function are well established in older adults, little is known about the relationship between PA and brain microstructure and the contributions of physical functional limitations and chronic diseases. This study examined whether higher PA would be longitudinally associated with greater microstructural integrity in memory- and executive function-related networks and whether these associations would be independent of physical function and chronic diseases.MethodsDiffusion tensor imaging was obtained in 2006-2008 in 276 participants (mean age = 83.0 years, 58.7% female, 41.3% black) with PA (sedentary, lifestyle active, and exercise active) measured in 1997-1998. Gait speed, cognition, depressive symptoms, cardiovascular and pulmonary diseases, hypertension, stroke, and diabetes were measured at both time points. Mean diffusivity and fractional anisotropy were computed from normal-appearing gray and white matter in frontoparietal and subcortical networks. Moderating effects of physical function and chronic diseases were tested using hierarchical regression models.ResultsCompared with the sedentary, the exercise active group had lower mean diffusivity in the medial temporal lobe and the cingulate cortex (β, p values: -.405, .023 and -.497, .006, respectively), independent of age, sex, and race. Associations remained independent of other variables, although they were attenuated after adjustment for diabetes. Associations between PA and other neuroimaging markers were not significant.ConclusionsBeing exercise active predicts greater memory-related microstructural integrity in older adults. Future studies in older adults with diabetes are warranted to examine the neuroprotective effect of PA in these networks.

Step length variability (SLV) increases with age in those without overt neurologic disease, is higher in neurologic patients, is associated with falls, and predicts dementia. Whether higher SLV in older adults without neurologic disease indicates presence of neurologic abnormalities is unknown. Our objective was to identify whether SLV in older adults without overt disease is associated with findings from multimodal neuroimaging. A well-characterized cohort of 265 adults (79-90 years) was concurrently assessed by gait mat, magnetic resonance imaging with diffusion tensor, and neurological exam. Linear regression models adjusted for gait speed, demographic, health, and functional covariates assessed associations of MRI measures (gray matter volume, white matter hyperintensity volume, mean diffusivity, fractional anisotropy) with SLV. Regional distribution of associations was assessed by sparse partial least squares analyses. Higher SLV (mean: 8.4, SD: 3.3) was significantly associated with older age, slower gait speed, and poorer executive function and also with lower gray matter integrity measured by mean diffusivity (standardized beta=0.16; p=0.02). Associations between SLV and gray matter integrity were strongest for the hippocampus and anterior cingulate gyrus (both β=0.18) as compared to other regions. Associations of SLV with other neuroimaging markers were not significant. Lower integrity of normal-appearing gray matter may underlie higher SLV in older adults. Our results highlighted the hippocampus and anterior cingulate gyrus, regions involved in memory and executive function. These findings support previous research indicating a role for cognitive function in motor control. Higher SLV may indicate focal neuropathology in those without diagnosed neurologic disease.

INTRODUCTION: Late‐onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long‐Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics. METHODS: We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub‐sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels. RESULTS: We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10−9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid. DISCUSSION: MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology. Highlights: Long‐Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants.LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD.The observed LLFS variants generalized to cohorts with wide range of LOAD risk.The association of MTUS2 with LOAD was stronger within high levels of beta amyloid.Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus. [ABSTRACT FROM AUTHOR]

BackgroundMaintaining cognitive function protects older adults from developing functional decline. This study aims to identify the neuroimaging correlates of maintenance of higher global cognition as measured by the Modified Mini Mental State Test (3 MS) score.MethodsRepeated 3 MS measures from 1997-98 through 2006-07 and magnetic resonance imaging with diffusion tensor in 2006-07 were obtained in a biracial cohort of 258 adults free from dementia (mean age 82.9 years, 56% women, 42% blacks). Participants were classified as having shown either maintenance (3 MS slope>0) or decline (3 MS slope

ObjectiveTo evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomographic scans with fludeoxyglucose F 18 (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and patients with Alzheimer disease (AD).DesignTwelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere-frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex, and posterior cingulate cortex. Results were compared with neuropathological diagnoses.SettingAcademic medical centers.PatientsForty-five patients with pathologically confirmed FTLD (n=14) or AD (n=31).ResultsRaters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27 of 31 patients [87%]) than in patients with FTLD (7 of 14 patients [50%]) (P=.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 scans lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.ConclusionsTemporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism but rather must take into account the relative hypometabolism of all brain regions.

BackgroundSlowing information processing is common among community-dwelling elderly and it predicts greater mortality and disability risk. Slowing information processing is related to brain macro-structural abnormalities. Specifically, greater global atrophy and greater small vessel disease of the white matter (WM) have been associated with slower processing speed. However, community-dwelling elderly with such macro-structural abnormalities can maintain processing speed. The roles of brain micro-structure for slow processing in very old adults living in the community is uncertain, as epidemiological studies relating these brain markers to cognition and in the context of other health characteristics are sparse.HypothesisInformation processing is cross-sectionally associated with WM micro-structure independent of overt macro-structural abnormalities and also independent of health related characteristics.MethodsImaging indices of micro-structure diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI), macro-structure white matter hyperintensities (WMH), gray matter (GM) volume, digit symbol substitution test (DSST), and health characteristics were measured in 272 elderly (mean age 83 years old, 43% men, 40% black) living in the community.ResultsThe DTI- and MTI-indices of micro-structure from the normal appearing WM and not from the normal appearing GM were associated with DSST score independent of WMH and GM volumes. Associations were also independent of age, race, gender, mini-mental score, systolic blood pressure, and prevalent myocardial infarction.InterpretationDTI and MTI-indices of normal appearing WM are indicators of information processing speed in this cohort of very old adults living in the community. Since processing slowing is a potent index of mortality and disability, these indices may serve as biomarkers in prevention or treatment trials of disability.

BackgroundThe clinical diagnosis of dementing diseases largely depends on the subjective interpretation of patient symptoms. Consensus panels are frequently used in research to determine diagnoses when definitive pathologic findings are unavailable. Nevertheless, research on group decision making indicates that many factors can adversely affect panel performance.ObjectiveTo determine conditions that improve consensus panel diagnosis.DesignComparison of neuropathologic diagnoses with individual and consensus panel diagnoses based on clinical scenarios only, fludeoxyglucose F 18 positron emission tomography images only, and scenarios plus images.SettingExpert and trainee individual and consensus panel deliberations using a modified Delphi method in a pilot research study of the diagnostic utility of fludeoxyglucose F 18 positron emission tomography.PatientsForty-five patients with pathologically confirmed Alzheimer disease or frontotemporal dementia.Main outcome measuresStatistical measures of diagnostic accuracy, agreement, and confidence for individual raters and panelists before and after consensus deliberations.ResultsThe consensus protocol using trainees and experts surpassed the accuracy of individual expert diagnoses when clinical information elicited diverse judgments. In these situations, consensus was 3.5 times more likely to produce positive rather than negative changes in the accuracy and diagnostic certainty of individual panelists. A rule that forced group consensus was at least as accurate as majority and unanimity rules.ConclusionsUsing a modified Delphi protocol to arrive at a consensus diagnosis is a reasonable substitute for pathologic information. This protocol improves diagnostic accuracy and certainty when panelist judgments differ and is easily adapted to other research and clinical settings while avoiding the potential pitfalls of group decision making.

Expansion of the cerebral ventricles may occur at an accelerated rate in subjects with dementia, but the time course of expansion during transitions between normal cognitive function, mild cognitive impairment (MCI), and dementia is not well understood. Furthermore, the effects of cardiovascular risk factors on rate of ventricular expansion are unclear. We used a fully automated segmentation technique to measure change rate in lateral ventricle-to-brain ratio (VBR) on 145 longitudinal pairs of magnetic resonance images of subjects in the Cardiovascular Health Study Cognition Study from the Pittsburgh Center. A multivariate model analyzed VBR change rate, accounting for dementia statuses at both imaging times (normal, MCI, or dementia), age, sex, education, race, magnetic resonance-defined infarcts, Center for Epidemiology Studies Depression Scale, baseline ventricular volume, and cardiovascular risk factors. VBR change was faster in subjects who were demented or transitioned from MCI to dementia, compared with subjects normal at both images and subjects who transitioned from normal to MCI or dementia. Patients with diabetes had faster VBR change. Ventricular expansion may accelerate late in the progression from normal cognitive function to dementia, and may be modulated by diabetes.

Introduction: Subjective cognitive decline (SCD) may represent the earliest preclinical stage of Alzheimer's Disease (AD) for some older adults. However, the underlying neurobiology of SCD is not completely understood. Since executive function may be affected earlier than memory function in the progression of AD, we aimed to characterize SCD symptoms in terms of fMRI brain activity during the computerized digit-symbol substitution task (DSST), an executive function task. We also explored associations of DSST task performance with brain activation, SCD severity, and amyloid-β (Aβ) load. Methods: We analyzed data from 63 cognitively normal older individuals (mean age 73.6 ± 7.2) with varying degree of SCD symptoms. Participants completed a computerized version of DSST in the MR scanner and a Pittsburgh Compound-B (PiB)-PET scan to measure global cerebral Aβ load. Results: A voxel-wise analysis revealed that greater SCD severity was associated with lower dorsomedial thalamus activation. While task performance was not associated with brain activation nor Aβ load, slower reaction time was associated with greater SCD severity. Discussion: The observed lower dorsomedial thalamus activation may reflect declining familiarity-based working memory and the trans-thalamic executive function pathway in SCD. SCD symptoms may reflect altered neural function and subtle decline of executive function, while Aβ load may have an indirect impact on neural function and performance. Self-perceived cognitive decline may serve as a psychological/subjective marker reflecting subtle brain changes. [ABSTRACT FROM AUTHOR]

Objectives: Self-reported activity restriction is an established correlate of depression in dementia caregivers (dCGs). It is plausible that the daily distribution of objectively measured activity is also altered in dCGs with depression symptoms; if so, such activity characteristics could provide a passively measurable marker of depression or specific times to target preventive interventions. We therefore investigated how levels of activity throughout the day differed in dCGs with and without depression symptoms, then tested whether any such differences predicted changes in symptoms 6 months later. Design, setting, participants, and measurements: We examined 56 dCGs (mean age = 71, standard deviation (SD) = 6.7; 68% female) and used clustering to identify subgroups which had distinct depression symptom levels, leveraging baseline Center for Epidemiologic Studies of Depression Scale–Revised Edition and Patient Health Questionnaire-9 (PHQ-9) measures, as well as a PHQ-9 score from 6 months later. Using wrist activity (mean recording length = 12.9 days, minimum = 6 days), we calculated average hourly activity levels and then assessed when activity levels relate to depression symptoms and changes in symptoms 6 months later. Results: Clustering identified subgroups characterized by: (1) no/minimal symptoms (36%) and (2) depression symptoms (64%). After multiple comparison correction, the group of dCGs with depression symptoms was less active from 8 to 10 AM (Cohen's d ≤ −0.9). These morning activity levels predicted the degree of symptom change on the PHQ-9 6 months later (per SD unit β = −0.8, 95% confidence interval: −1.6, −0.1, p = 0.03) independent of self-reported activity restriction and other key factors. Conclusions: These novel findings suggest that morning activity may protect dCGs from depression symptoms. Future studies should test whether helping dCGs get active in the morning influences the other features of depression in this population (i.e. insomnia, intrusive thoughts, and perceived activity restriction). [ABSTRACT FROM AUTHOR]