Neuropsychiatric symptoms and the outcome of cognitive trajectories in older adults free of dementia: The Mayo Clinic Study of Aging

Objective Neuropsychiatric symptoms (NPS) are associated with the risk of incident mild cognitive impairment (MCI) and dementia. We examined associations between NPS and the outcomes of global and domain‐specific cognitive trajectories. Methods In this longitudinal study conducted in the setting of the population‐based Mayo Clinic Study of Aging, 5081 community‐dwelling, nondemented individuals aged ≥50 years (51% males) underwent NPS assessment using Neuropsychiatric Inventory Questionnaire (NPI‐Q), and Beck Depression and Anxiety Inventories (BDI‐II, BAI). Global and domain‐specific (memory, language, attention, and visuospatial skills) cognitive performance was assessed through neuropsychological testing every 15 months. Associations between baseline NPS and trajectories for individual yearly change in cognitive z‐scores were calculated using linear mixed‐effect models. Results Cognition declined regardless of NPS status over the median follow‐up of 4.5 years. Presence of NPS was associated with increased cognitive decline. Differences in annualized change in global cognition z‐scores for participants with NPS compared to without NPS ranged from −0.018 (95% CI −0.032, −0.004; p = 0.011) for irritability to −0.159 (−0.254, −0.065; p = 0.001) for hallucinations. Associations between NPS and annual decline in global cognition were significant for most NPI‐Q‐assessed NPS and clinical depression (BDI‐II≥13). Participants with NPI‐Q‐assessed depression, apathy, nighttime behavior, and clinical depression had greater decline in all domain‐specific z‐scores; presence of delusions and anxiety was associated with more pronounced decline in language, attention and visuospatial skills. Conclusion NPS were associated with a more accelerated cognitive decline. Clinical assessment and potential treatment of NPS is warranted even in a community setting as NPS may impact cognitive decline in nondemented individuals

Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging

Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults. Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) epsilon 4 status. Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged >= 70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores. Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE epsilon 4 carriership did not moderate the association between PA and cognition. Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex

Quantity and quality of mental activities and the risk of incident mild cognitive impairment

Objective To investigate whether timing, number, and frequency of mentally stimulating activities in midlife and late life are associated with the risk of incident mild cognitive impairment (MCI). Methods We conducted a prospective cohort study in the setting of the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, including 2,000 individuals aged ≥70 years who were cognitively unimpaired at baseline and were followed for a median of 5.0 years. Participants completed a self-reported survey on timing, number, and frequency of engagement in 5 mentally stimulating activities (reading books, computer use, social activities, playing games, craft activities) at baseline. Results The risk of incident MCI was significantly reduced for participants who engaged in social activities (hazard ratio [95% confidence interval] 0.80 [0.64–0.99]) and playing games (0.80 [0.66–0.98]) in both late life and midlife combined. Using a computer was associated with a decreased risk regardless of timing (not late life but midlife: 0.52 [0.31–0.88]; late life but not midlife: 0.70 [0.56–0.88]; late life and midlife: 0.63 [0.51–0.79]). Craft activities were associated with a reduced risk of incident MCI only when carried out in late life but not midlife (0.58 [0.34–0.97]). Furthermore, engaging in a higher number of activities in late life was associated with a significantly reduced risk of incident MCI (any 2 activities: 0.72 [0.53–0.99], any 3: 0.55 [0.40–0.77], any 4: 0.44 [0.30–0.65], all 5: 0.57 [0.34–0.96]). Conclusion Engaging in a higher number of mentally stimulating activities, particularly in late life, is associated with a decreased risk of MCI among community-dwelling older persons

Cortical β-amyloid burden, neuropsychiatric symptoms, and cognitive status: the Mayo Clinic Study of Aging

Abstract Neuropsychiatric symptoms (NPS) are a risk factor for cognitive impairment and are associated with cortical β-amyloid (Aβ) deposition. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging to examine the frequency of NPS among cognitively unimpaired (CU) and mild cognitive impairment (MCI) participants who either have normal (A−) or abnormal (A+) Aβ deposition. We also investigated whether combined presence of MCI and amyloid positivity (MCI/A+) is associated with greater odds of having NPS as compared to CU/A− (defined as reference group). Participants were 1627 CU and MCI individuals aged ≥ 50 years (54% males; median age 73 years). All participants underwent NPS assessment (Neuropsychiatric Inventory Questionnaire (NPI-Q); Beck Depression Inventory II (BDI-II); Beck Anxiety Inventory (BAI)) and 11C-PiB-PET. Participants with an SUVR > 1.42 were classified as A+. We conducted multivariable logistic regression analyses adjusted for age, sex, education, and APOE ε4 genotype status. The sample included 997 CU/A−, 446 CU/A+, 78 MCI/A−, and 106 MCI/A+ persons. For most NPS, the highest frequency of NPS was found in MCI/A+ and the lowest in CU/A−. The odds ratios of having NPS, depression (BDI ≥ 13), or anxiety (BAI ≥ 8, ≥ 10) were consistently highest for MCI/A+ participants. In conclusion, MCI with Aβ burden of the brain is associated with an increased risk of having NPS as compared to MCI without Aβ burden. This implies that the underlying Alzheimer’s disease biology (i.e., cerebral Aβ amyloidosis) may drive both cognitive and psychiatric symptoms

Defining imaging biomarker cut points for brain aging and Alzheimer's disease

AbstractIntroductionOur goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness.MethodsWe examined five methods for determining cut points.ResultsThe reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal.DiscussionIn the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method

Association of non-exercise physical activity in mid- and late-life with cognitive trajectories and the impact of APOE ε4 genotype status: the Mayo Clinic Study of Aging

© 2019, The Author(s). In this study derived from the population-based Mayo Clinic Study of Aging, we investigated whether non-exercise physical activity (PA) was associated with global and domain-specific cognitive trajectories (memory, language, visuospatial skills, attention) and whether the association differed by apolipoprotein E (APOE) ε4 genotype status. We included 2061 community-dwelling individuals aged ≥ 70 years (50.5% males, 26.7% APOE ε4 carriers) who were cognitively unimpaired at baseline and on whom serial cognitive data and self-reported information on non-exercise PA were available. We specifically inquired about non-exercise PA carried out at two time points, i.e., midlife (between 50 and 65 years of age) and late-life (within 1 year prior to assessment) and three intensity levels, i.e., light (e.g., laundry), moderate (e.g., scrubbing floors) and heavy (e.g., hard manual labor). Linear mixed-effect models revealed that engaging in midlife PA of moderate or heavy intensity was associated with significantly less-pronounced decline of z-scores in all cognitive domains. Similarly, participants that engaged in late-life moderate or heavy PA had less decline in visuospatial, attention and global z-scores than non-active peers. These associations varied depending on APOE ε4 carrier status, i.e., APOE ε4 non-carriers but not APOE ε4 carriers that engaged in late-life PA had less decline in cognitive z-scores. In contrast, engaging in midlife PA, irrespective of intensity, was significantly associated with less decline in memory function only among APOE ε4 carriers

Longitudinal Clinical, Neuropsychological, and Neuroimaging Characterization of a Kindred with a 12-Octapeptide Repeat Insertion in PRNP: The Next Generation

Background: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. Method: Clinical, neuropsychological, and neuroimaging characterization of a kindred. Results: Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. Conclusions and relevance: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection

Non-Stationarity in the “Resting Brain’s” Modular Architecture

Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain’s modular organization and assign each region to a “meta-modular” group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer’s dementia and 56 cognitively normal elderly subjects matched 1∶2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer’s disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer’s dementia