Correlating continuously captured home-based digital biomarkers of daily function with postmortem neurodegenerative neuropathology.

BACKGROUND: Outcome measures available for use in Alzheimer's disease (AD) clinical trials are limited in ability to detect gradual changes. Measures of everyday function and cognition assessed unobtrusively at home using embedded sensing and computing generated "digital biomarkers" (DBs) have been shown to be ecologically valid and to improve efficiency of clinical trials. However, DBs have not been assessed for their relationship to AD neuropathology. OBJECTIVES: The goal of the current study is to perform an exploratory examination of possible associations between DBs and AD neuropathology in an initially cognitively intact community-based cohort. METHODS: Participants included in this study were ≥65 years of age, living independently, of average health for age, and followed until death. Algorithms, run on the continuously-collected passive sensor data, generated daily metrics for each DB: cognitive function, mobility, socialization, and sleep. Fixed postmortem brains were evaluated for neurofibrillary tangles (NFTs) and neuritic plaque (NP) pathology and staged by Braak and CERAD systems in the context of the "ABC" assessment of AD-associated changes. RESULTS: The analysis included a total of 41 participants (M±SD age at death = 92.2±5.1 years). The four DBs showed consistent patterns relative to both Braak stage and NP score severity. Greater NP severity was correlated with the DB composite and reduced walking speed. Braak stage was associated with reduced computer use time and increased total time in bed. DISCUSSION: This study provides the first data showing correlations between DBs and neuropathological markers in an aging cohort. The findings suggest continuous, home-based DBs may hold potential to serve as behavioral proxies that index neurodegenerative processes.

Insights about personality traits and cognitive performance and decline in adults 51-59 Years old from the Wisconsin longitudinal study.

OBJECTIVES: To delineate midlife personality dimensions of early cognitive change in an age-homogenous sample of U.S. older adults. DESIGN: Longitudinal study of 6133 adults from the Wisconsin Longitudinal Study (WLS). MEASURES: Middle-aged participants (mean age = 53.2; SD = 0.6) from the WLS completed the 'Big-5' personality assessment in 1992. Mixed effects models examined whether midlife personality traits were associated with change in cognitive performance from participant's mid-60s (2004-2005) to early 70s (2011). The cognitive battery assessed abstract reasoning (AR), category fluency (CF), working memory (WM), and delayed verbal memory (DVM). Models adjusted for sex, education, and subjective health. RESULTS: High Openness was a significant predictor of change in AR, CF, and DVM. These cognitive outcomes declined less among those with high Openness, but the effect sizes for Openness by time were small (R2 s < 0.01). AR and CF were characterized by higher overall performance with high Openness, but with relatively parallel change for the highest and lowest Openness quartiles. There was no advantage of Openness to DVM by the second assessment. High Conscientiousness was a predictor of more change for DVM, though the effect size was small (R 2  < 0.01). CONCLUSIONS: None of the midlife personality traits were uniformly associated with change in cognitive performance in early older adulthood. High midlife Openness had the most noteworthy impact on cognition. Interventions designed to target Openness have potential to elevate and maintain a higher threshold of performance in some cognitive domains, but may only have a small impact on cognitive change.

Preparing the Next Generation of Academic Researchers During the Pandemic: Lessons from a National Mental Health Research Postdoctoral Fellowship.

OBJECTIVE: The COVID-19 pandemic has severely disrupted all aspects of academic medicine, including post-doctoral research fellowship training. The current survey examined ways in which research fellows across 28 U.S. nationally diverse sites have been impacted. METHODS: Survey participants included 62 M.D. and Ph.D. post-doctoral fellows and 27 local fellowship center directors within the Veterans Affairs (VA) Advanced Fellowship in Mental Illness Research and Treatment (MIRT), a national fellowship program tasked to develop academic clinician researchers within the field of mental health. Survey questions focused on productivity and challenges experienced by fellows during the pandemic. RESULTS: Half of fellows reported working entirely off-site during the COVID-19 pandemic. All fellows reported some level of disruption in productivity during the pandemic; 73% reported a disruption in data collection, 69% reported decreased scholarly output, 41% reported disruption in grant writing, and 73% reported disruption in ability to provide clinical care. Yet, the majority of fellows (66%) reported not having to change their research goals, pivoting to telehealth-based data collection, and employing extant data for research projects and peer-reviewed publications. CONCLUSIONS: The results of the fellow and director surveys highlight the associated disruption of the COVID-19 pandemic on fellowship-related activities and parallel ingenuity of programs to continue conducting research and clinical services in a modified fashion. While many research goals continued unabated, the findings suggest alterations in data collection methodology and a focus on using extant data, which may have a residual influence on future early career research grant applications.

Depression, health comorbidities, cognitive symptoms and their functional impact: Not just a geriatric problem.

OBJECTIVE: To compare the prevalence of cognitive symptoms and their functional impact by age group accounting for depression and number of other health conditions. METHODS: We analyzed data from the 2011 Behavioral Risk Factor Surveillance System, a population-based, cross-sectional telephone survey of US adults. Twenty-one US states asked participants (n = 131, 273) about cognitive symptoms (worsening confusion or memory loss in the past year) and their functional impact (interference with activities and need for assistance). We analyzed the association between age, depression history and cognitive symptoms and their functional impact using logistic regression and adjusted for demographic characteristics and other health condition count. RESULTS: There was a significant interaction between age and depression (p < 0.0001). In adults reporting depression, the adjusted odds of cognitive symptoms in younger age groups (<75 years) were comparable or greater to those in the oldest age group (≥75 years) with a peak in the middle age (45-54 years) group (OR 1.9 (95% Confidence Interval: 1.4-2.5). In adults without depression, adults <75 years had a significantly lower adjusted odds of cognitive symptoms compared to the oldest age group with the exception of the middle-aged group where the difference was not statistically significant. Over half of adults under age 65 with depression reported that cognitive symptoms interfered with life activities compared to 35.7% of adults ≥65 years. CONCLUSIONS: Cognitive symptoms are not universally higher in older adults; middle-aged adults are also particularly vulnerable. Given the adverse functional impact associated with cognitive symptoms in younger adults, clinicians should assess cognitive symptoms and their functional impact in adults of all ages and consider treatments that impact both cognition and functional domains.

Unlocking Neurocognitive Substrates of Late-Life Affective Symptoms Using the Research Domain Criteria: Worry Is an Essential Dimension.

While investigations have sought to identify the distinct and shared contributions of anxiety and depression to neurocognitive processes in late life, less is known regarding the further contribution of worry, a unique and critical dimension of affective dysregulation. Capturing the full range of symptoms, as inspired by the NIH Research Domain Criteria (RDoC), may provide finer-grained information on inter-relationships among worry, anxiety and depression on neurocognitive processing in later life. The objective of this study was to determine if the dimensional trait of worry intensifies known negative associations of dimensional measures of anxiety and depressive symptoms with neurocognitive processes, specifically cognitive control and memory processes. Using a cross-sectional and observational design, this study was conducted within a translational research center located with a Veterans medical center in Northern California. One hundred and nineteen community-residing older adults ages 65-91 years participated, and were characterized with psychiatric and neurocognitive dimensional measures. Affective symptom severity was assessed with the Penn State Worry Questionnaire, the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory-II. Primary neurocognitive outcomes were inhibitory control assessed using a Stroop paradigm and delayed verbal memory assessed with the Rey Auditory Verbal Learning Test. Secondary outcomes included other less frequently examined cognitive control mechanisms (working memory, information processing, and verbal fluency) and memory processes (visual delayed memory). Contrary to prediction, the dimensional trait of worry attenuated negative associations between anxiety and depressive symptoms and inhibitory control on the one hand, and between depressive symptoms and delayed verbal memory processes on the other. In the secondary models, symptom dimensions were not associated with other cognitive control or visual delayed memory processes. Our fine-grained approach, in line with the NIMH RDoC model, suggests the neurocognitive processes associated with dimensional measures of late-life affective symptoms are dissociable. Specifically, dimensional measures of worry operate independently from other anxiety and depression symptoms to reveal differential patterns of neurocognitive processes associated with affective dysregulation.

Altered Microstructural Caudate Integrity in Posttraumatic Stress Disorder but Not Traumatic Brain Injury.

OBJECTIVE: Given the high prevalence and comorbidity of combat-related PTSD and TBI in Veterans, it is often difficult to disentangle the contributions of each disorder. Examining these pathologies separately may help to understand the neurobiological basis of memory impairment in PTSD and TBI independently of each other. Thus, we investigated whether a) PTSD and TBI are characterized by subcortical structural abnormalities by examining diffusion tensor imaging (DTI) metrics and volume and b) if these abnormalities were specific to PTSD versus TBI. METHOD: We investigated whether individuals with PTSD or TBI display subcortical structural abnormalities in memory regions by examining DTI metrics and volume of the hippocampus and caudate in three groups of Veterans: Veterans with PTSD, Veterans with TBI, and Veterans with neither PTSD nor TBI (Veteran controls). RESULTS: While our results demonstrated no macrostructural differences among the groups in these regions, there were significant alterations in microstructural DTI indices in the caudate for the PTSD group but not the TBI group compared to Veteran controls. CONCLUSIONS: The result of increased mean, radial, and axial diffusivity, and decreased fractional anisotropy in the caudate in absence of significant volume atrophy in the PTSD group suggests the presence of subtle abnormalities evident only at a microstructural level. The caudate is thought to play a role in the physiopathology of PTSD, and the habit-like behavioral features of the disorder could be due to striatal-dependent habit learning mechanisms. Thus, DTI appears to be a vital tool to investigate subcortical pathology, greatly enhancing the ability to detect subtle brain changes in complex disorders.

Disentangling cognition and emotion in older adults: the role of cognitive control and mental health in emotional conflict adaptation.

OBJECTIVE: Recent research suggests cognition has a bidirectional relationship with emotional processing in older adults, yet the relationship is still poorly understood. We aimed to examine a potential relationship between late-life cognitive function, mental health symptoms, and emotional conflict adaptation. We hypothesized that worse cognitive control abilities would be associated with poorer emotional conflict adaptation. We further hypothesized that a higher severity of mental health symptoms would be associated with poorer emotional conflict adaptation. METHODS: Participants included 83 cognitively normal community-dwelling older adults who completed a targeted mental health and cognitive battery, and emotion and gender conflict-adaptation tasks. RESULTS: Consistent with our hypothesis, poorer performance on components of cognitive control, specifically attention and working memory, was associated with poorer emotional conflict adaptation. This association with attention and working memory was not observed in the non-affective-based gender conflict adaptation task. Mental health symptoms did not predict emotional conflict adaptation, nor did performance on other cognitive measures. CONCLUSION: Our findings suggest that emotion conflict adaptation is disrupted in older individuals who have poorer attention and working memory. Components of cognitive control may therefore be an important potential source of inter-individual differences in late-life emotion regulation and cognitive affective deficits. Copyright © 2016 John Wiley & Sons, Ltd.

Longitudinal association of delta activity at sleep onset with cognitive and affective function in community-dwelling older adults.

OBJECTIVE: This investigation sought to determine whether delta activity at sleep onset (DASO) in the sleep electroencephalography of older adults represents normal variation or is associated with clinical pathology. To this end, we examined its longitudinal associations with cognitive and affective function in older adults without dementia. METHODS: Participants were 153 community-dwelling older adults without dementia. We evaluated polysomnography (PSG), cognitive performance, and affective function at four time points: baseline, 12, 24, and 36 months. All participants completed PSG and measures of global cognition, delayed verbal memory, information processing speed, attention, inhibition, verbal naming, visuospatial ability, and measures of anxiety and depression. DASO was defined as sequences of rhythmic anterior delta activity on PSG in the transition from awake to sleep during the baseline assessment (Figure ). RESULTS: At the baseline, 83 women and 70 men, mean age 71.3 ± 0.6 years participated and 19.6% of participants exhibited DASO. Age, years of education, gender, and body mass index did not differ according to DASO status. Linear mixed modeling showed that the presence of DASO was actually associated with lower levels of anxiety and depression. Further, participants with DASO, versus those without DASO, exhibited a trend towards better cognitive performance over time, although none of these associations reached statistical significance. CONCLUSIONS: Whereas DASO was associated with better affective function, no significant association was found between DASO and cognitive change over time. These longitudinal findings support the view that the presence of DASO in healthy older adults represents normal variation rather than pathological aging. Copyright © 2016 John Wiley & Sons, Ltd.

Delta Activity at Sleep Onset and Cognitive Performance in Community-Dwelling Older Adults.

STUDY OBJECTIVES: Frontal intermittent rhythmic delta activity (FIRDA) has long been considered to be an abnormal variant in the electroencephalogram (EEG) among older adults. Prior work also indicates a predominance of slow wave EEG activity among patients with dementia. However, instability of state control occurring with aging generally and among many neurodegenerative diseases raises the possibility that FIRDA might represent the intrusion of sleep related elements of the EEG into the waking state. We examined delta activity at sleep onset (DASO) in community-dwelling, older adults without dementia, and examined whether this activity is related to poorer cognitive performance. METHODS: 153 community-dwelling, older adults without dementia underwent overnight polysomnography and measures of global cognition, delayed verbal memory, information processing speed, attention, inhibition, verbal naming, and visuospatial ability. Delta activity during sleep/wake transitions (scored either as Waking or N1) was analyzed visually. RESULTS: Participants were 83 women and 70 men, mean age 71.3 ± 0.6 y. DASO was present in 30 participants (19.6%). Age, years of education, sex, and body mass index did not differ between DASO (+) and (-) groups. Multiple regression analyses indicated faster reading of the Stroop color words in DASO (+) subjects (P = 0.007). None of the other cognitive domains differed between the two groups. CONCLUSIONS: DASO was relatively common in our sample of community-dwelling, older adults without dementia. DASO was not associated with poorer performance on any cognitive domain. Instead, individuals with DASO demonstrated better performance on a simple reading task. Although these findings suggest that an abnormal EEG activity may represent normal variation, our work underscores the importance of distinguishing DASO from FIRDA when examining sleep in older adults. COMMENTARY: A commentary on this article appears in this issue on page 725.

Performance variability during a multitrial list-learning task as a predictor of future cognitive decline in healthy elders.

INTRODUCTION: In clinical settings, neuropsychological test performance is traditionally evaluated with total summary scores (TSS). However, recent studies demonstrated that indices of intraindividual variability (IIV) yielded unique information complementing TSS. This 18-month longitudinal study sought to determine whether IIV indices derived from a multitrial list-learning test (the Rey Auditory Verbal Learning Test) provided incremental utility in predicting cognitive decline in older adults compared to TSS. METHOD: Ninety-nine cognitively intact older adults (aged 65 to 89 years) underwent neuropsychological testing (including the Rey Auditory Verbal Learning Test) at baseline and 18-month follow-up. Participants were classified as cognitively stable (n = 65) or declining (n = 34) based on changes in their neuropsychological test performance. Logistic regression modeling tested the ability of baseline TSS indices (sum of Trials 1-5, immediate recall, and delayed recall) and IIV indices (lost access and gained access) to discriminate between stable and declining individuals. RESULTS: Higher values of both lost access and gained access at baseline were associated with an increased risk for decline at 18-month follow-up. Further, the IIV indices provided predictive utility above and beyond the TSS indices. CONCLUSION: These results highlight the value of analyzing IIV in addition to TSS during neuropsychological evaluation in older adults. High levels of IIV may reflect impairment in anterograde memory systems and/or executive dysfunction that may serve as a prognostic indicator of cognitive decline.

Semantic memory functional MRI and cognitive function after exercise intervention in mild cognitive impairment.

Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer's disease (AD) neuropathology, inefficient or ineffective neural processing, and increased risk for AD. Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging (fMRI). Seventeen MCI participants and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed an fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged 0.048 to 0.0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD.

Does physical activity influence semantic memory activation in amnestic mild cognitive impairment?

The effect of physical activity (PA) on functional brain activation for semantic memory in amnestic mild cognitive impairment (aMCI) was examined using event-related functional magnetic resonance imaging during fame discrimination. Significantly greater semantic memory activation occurred in the left caudate of High- versus Low-PA patients, (P=0.03), suggesting PA may enhance memory-related caudate activation in aMCI.

Interactive effects of physical activity and APOE-ε4 on BOLD semantic memory activation in healthy elders.

Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer's disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65-85) cognitively intact adults. A cross-sectional design was used with four groups (n=17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous>unfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline.

Medication use profiles in patients with psychogenic nonepileptic seizures.

Patients with psychogenic nonepileptic seizures (PNES) and those with epilepsy may have very different medication use profiles. In this study, the authors set out to document and statistically compare medication use by these two populations. They found significant differences in the duration of antiepileptic medication use (shorter in those with psychogenic nonepileptic seizures, or PNES) and number of medications used (more in persons with PNES) and a tendency by patients with PNES to use narcotics and benzodiazepines. These results are discussed in the light of the pertinent literature.