Non-verbal episodic memory deficits in primary progressive aphasias are highly predictive of underlying amyloid pathology

Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer’s disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases

Comparison of variables associated with cerebrospinal fluid neurofilament, total-tau, and neurogranin

INTRODUCTION: Three cerebrospinal fluid (CSF) markers of neurodegeneration (N) (neurofilament light [NfL], total-tau [T-tau], and neurogranin [Ng]) have been proposed under the AT(N) scheme of the National Institute on Aging-Alzheimer's Association Research Framework. METHODS: We examined, in a community-based population (N = 777, aged 50-95) (1) what variables were associated with each of the CSF (N) markers, and (2) whether the variables associated with each marker differed by increased brain amyloid. CSF T-tau was measured with an automated electrochemiluminescence Elecsys immunoassay; NfL and Ng were measured with in-house enzyme-linked immunosorbent assays. RESULTS: Multiple variables were differentially associated with CSF NfL and T-tau levels, but not Ng. Most associations were attenuated after adjustment for age and sex. T-tau had the strongest association with cognition in the presence of amyloidosis, followed by Ng. Variables associations with NfL did not differ by amyloid status. DISCUSSION: Understanding factors that influence CSF (N) markers will assist in the interpretation and utility of these markers in clinical practice

Statistical analysis of human boy movement and group interactions in response to music

Quantification of time series that relate to physiological data is challenging for empirical music research. Up to now, most studies have focused on time-dependent responses of individual subjects in controlled environments. However, little is known about time-dependent responses of between-subject interactions in an ecological context. This paper provides new findings on the statistical analysis of group synchronicity in response to musical stimuli. Different statistical techniques were applied to time-dependent data obtained from an experiment on embodied listening in individual and group settings. Analysis of inter group synchronicity are described. Dynamic Time Warping (DTW) and Cross Correlation Function (CCF) were found to be valid methods to estimate group coherence of the resulting movements. It was found that synchronicity of movements between individuals (human human interactions) increases significantly in the social context. Moreover, Analysis of Variance (ANOVA) revealed that the type of music is the predominant factor in both the individual and the social context

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

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

Plasma and CSF neurofilament light: Relation to longitudinal neuroimaging and cognitive measures

OBJECTIVE: We aimed to (1) assess and compare baseline plasma and CSF neurofilament light (NfL) for cross-sectional and longitudinal associations with neuroimaging or cognition and (2) determine whether change in plasma NfL corresponded with change in these outcomes. // METHODS: Seventy-nine participants without dementia, median age 76 years, had plasma and CSF NfL, neuropsychological testing, and neuroimaging (MRI, amyloid PET, FDG-PET) at the same study visit, and a repeat visit (15 or 30 months later) with both plasma NfL and neuroimaging. Plasma NfL was measured on the Simoa-HD1 Platform and CSF NfL with an in-house ELISA. Linear mixed effects models were used to examine the associations between baseline plasma or CSF NfL and cognitive and neuroimaging outcomes adjusting for age, sex, and education. The relationship between change in plasma NfL and change in the outcomes was assessed using linear regression. // RESULTS: There were no cross-sectional associations between CSF or plasma NfL and any neuroimaging or cognitive measure. Longitudinally, higher baseline plasma NfL was associated with worsening in all neuroimaging measures, except amyloid PET, and global cognition. Higher baseline CSF NfL was associated with worsening in cortical thickness and diffusion MRI. The beta estimates for CSF NfL were similar to those for plasma NfL. Change in plasma NfL was associated with change in global cognition, attention, and amyloid PET. // CONCLUSION: Elevated baseline plasma NfL is a prognostic marker of cognitive decline and neuroimaging measures of neurodegeneration, and has similar effect sizes to baseline CSF NfL. Change in plasma NfL also tracked with short-term cognitive change

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

Trends in the Risk of Cognitive Impairment in the United States, 1996-2014

Background: Accumulating evidence suggests risk of cognitive impairment is declining in high-income countries. Much of this research uses longitudinal surveys in which learning over repeated tests may bias results. We analyze trends in cognitive impairment in the United States, accounting for prior test experience and selective mortality. Methods: We use the Health and Retirement Study, a population-based, nationally representative panel dataset and include individuals ages 50 years and older in 1996-2014 (n = 32,784). We measure cognitive impairment and dementia using standard cutpoints of the modified Telephone Interview for Cognitive Status. We estimate logistic regression models for any impairment and dementia over time, adjusting for age, sex, and race/ethnicity, comparing models with and without adjustment for practice effects and education. We examine heterogeneity in trends by age, sex, race/ethnicity, and education. Results: Models not controlling for test experience suggest that risk of cognitive impairment and dementia decreased over the study period. Controlling for test experience reverses the trend. In our primary models, prevalence of any cognitive impairment increased for women from 18.7% to 21.2% (annual change 0.7%, 95% confidence interval [CI], 0.1%, 1.3%) and for men from 17.6% to 21.0% (annual change 1.0%, CI, 0.5%, 1.4%). For dementia, women's annual increase was 1.7% (CI, 0.8%, 2.6%) and men's 2.0% (CI, 1.0%, 2.9%). If not for education, the increase would have been stronger. Increased risk was particularly rapid for Latinas, the least educated, and older ages. Conclusions: Risk of cognitive impairment increased from 1996 to 2014. Uncovering determinants of increasing cognitive impairment risk should become a research priority. See video abstract:.Peer reviewe