Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators / Efectos dosis-respuesta del ejercicio sobre la salud mental en adultos mayores que viven en la comunidad: exploración de moderadores genéticos

Background/Objective: (1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. Method: This study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE ε4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. Results: The exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE ε4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE ε4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. Conclusions: APOE ε4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE ε4 carriers show a greater decline in stress as a result of exercise relative to non-APOE ε4 carriers.(AU)

Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators.

Background/Objective: (1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. Method: This study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE ε4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. Results: The exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE ε4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE ε4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. Conclusions: APOE ε4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE ε4 carriers show a greater decline in stress as a result of exercise relative to non-APOE ε4 carriers.

Association of 24-Hour Activity Pattern Phenotypes With Depression Symptoms and Cognitive Performance in Aging.

Importance: Evidence regarding the nature and prevalence of 24-hour activity pattern phenotypes in older adults, especially those related to depression symptoms and cognition, is needed to guide the development of targeted mechanism research and behavioral interventions. Objectives: To identify subgroups of older adults with similar 24-hour activity rhythm characteristics and characterize associated depression symptoms and cognitive performance. Design, Setting, and Participants: From January to March 2022, a cross-sectional analysis of the 2011-2014 National Health and Nutrition Examination and Survey (NHANES) accelerometer study was conducted. The NHANES used a multistage probability sample that was designed to be representative of noninstitutionalized adults in the US. The main analysis included participants 65 years or older who had accelerometer and depression measures weighted to represent approximately 32 million older adults. Exposures: Latent profile analysis identified subgroups with similar 24-hour activity pattern characteristics as measured using extended-cosine and nonparametric methods. Main Outcomes and Measures: Covariate-adjusted sample-weighted regressions assessed associations of subgroup membership with (1) depression symptoms defined as 9-Item Patient Health Questionnaire (PHQ-9) scores of 10 or greater (PHQ-9) and (2) having at least psychometric mild cognitive impairment (p-MCI) defined as scoring less than 1 SD below the mean on a composite cognitive performance score. Results: The actual clustering sample size was 1800 (weighted: mean [SD] age, 72.9 [7.3] years; 57% female participants). Clustering identified 4 subgroups: (1) 677 earlier rising/robust (37.6%), (2) 587 shorter active period/less modelable (32.6%), (3) 177 shorter active period/very weak (9.8%), and (4) 359 later settling/very weak (20.0%). The prevalence of a PHQ-9 score of 10 or greater differed significantly across groups (cluster 1, 3.5%; cluster 2, 4.7%; cluster 3, 7.5%; cluster 4, 9.0%; χ2 P = .004). The prevalence of having at least p-MCI differed significantly across groups (cluster 1, 7.2%; cluster 2, 12.0%; cluster 3, 21.0%; cluster 4, 18.0%; χ2 P < .001). Five of 9 depression symptoms differed significantly across subgroups. Conclusions and Relevance: In this cross-sectional study, findings indicate that approximately 1 in 5 older adults in the US may be classified in a subgroup with weak activity patterns and later settling, and approximately 1 in 10 may be classified in a subgroup with weak patterns and shorter active duration. Future research is needed to investigate the biologic processes related to these behavioral phenotypes, including why earlier and robust activity patterns appear protective, and whether modifying disrupted patterns improves outcomes.

Clinical Progression of Baseline Risk States for Mild Cognitive Impairment.

BACKGROUND: This memory-clinic study joins efforts to study earliest clinical signs and symptoms of Alzheimer's disease and related dementias: subjective reports and objective neuropsychological test performance. OBJECTIVE: The memory-clinic denoted two clinical "grey zones": 1) subjective cognitive decline (SCD; n = 107) with normal objective test scores, and 2) isolated low test scores (ILTS; n = 74) without subjective complaints to observe risk for future decline. METHODS: Initial and annual follow-up clinical research evaluations and consensus diagnosis were used to evaluate baseline characteristics and clinical progression over 2.7 years, compared to normal controls (NC; n = 117). RESULTS: The ILTS group was on average older than the NC and SCD groups. They had a higher proportion of people identifying as belonging to a minoritized racial group. The SCD group had significantly more years of education than the ILTS group. Both ILTS and SCD groups had increased risk of progression to mild cognitive impairment. Older age, minoritized racial identity, and baseline cognitive classification were risk factors for progression. CONCLUSION: The two baseline risk groups look different from each other, especially with respect to demographic correlates, but both groups predict faster progression than controls, over and above demographic differences. Varied presentations of early risk are important to recognize and may advance cognitive health equity in aging.

Proceedings from the Albert Charitable Trust Inaugural Workshop on 'Understanding the Acute Effects of Exercise on the Brain'.

An inaugural workshop supported by "The Leo and Anne Albert Charitable Trust," was held October 4-7, 2019 in Scottsdale, Arizona, to focus on the effects of exercise on the brain and to discuss how physical activity may prevent or delay the onset of aging-related neurodegenerative conditions. The Scientific Program Committee (led by Dr. Jeff Burns) assembled translational, clinical, and basic scientists who research various aspects of the effects of exercise on the body and brain, with the overall goal of gaining a better understanding as to how to delay or prevent neurodegenerative diseases. In particular, research topics included the links between cardiorespiratory fitness, the cerebrovasculature, energy metabolism, peripheral organs, and cognitive function, which are all highly relevant to understanding the effects of acute and chronic exercise on the brain. The Albert Trust workshop participants addressed these and related topics, as well as how other lifestyle interventions, such as diet, affect age-related cognitive decline associated with Alzheimer's and other neurodegenerative diseases. This report provides a synopsis of the presentations and discussions by the participants, and a delineation of the next steps towards advancing our understanding of the effects of exercise on the aging brain.

Diagnostic Precision in the Detection of Mild Cognitive Impairment: A Comparison of Two Approaches.

OBJECTIVE: This study compared diagnostic rates and clinical predictors of discrepancies between diagnoses conferred via: 1) a comprehensive neuropsychological evaluation and National Institute on Aging-Alzheimer's Association (NIA-AA) criteria versus 2) a cognitive screener and Diagnostic Statistical Manual of Mental Disorders (DSM-5) criteria. DESIGN: Cross-sectional examination of baseline data from the Prevention of Alzheimer's dementia (AD) using Cognitive remediation and transcranial direct current stimulation in Mild Cognitive Impairment (MCI) and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial. SETTING: Five geriatric psychiatry and memory clinics located at academic hospitals affiliated with the Department of Psychiatry, University of Toronto. PARTICIPANTS: Older adults (N = 431) with a history of major depressive disorder (MDD) in remission, MCI, or both. MEASUREMENTS: Main outcome was a comparison of NIA-AA diagnostic rates of MCI or dementia versus DSM-5 rates of mild or major neurocognitive disorder. Secondary analyses examined demographic, race, gender, premorbid intellectual ability, psychosocial, health-related, and genetic predictors of discrepancy between DSM-5 and NIA-AA diagnoses. RESULTS: There were 103 (23.8%) discrepant cases, with most (91; 88.3%) of these discrepant cases reflecting more impairment with the detailed neuropsychological testing and NIA-AA criteria. Discrepancies were more likely in individuals with a history of MDD or who had at least one ApoE4 allele. CONCLUSION: The NIA-AA criteria, in conjunction with comprehensive neuropsychological testing, identified a greater prevalence of cognitive impairment than DSM-5 criteria, in conjunction with the Montreal Cognitive Assessment. Detailed neuropsychological evaluations are recommended for older adults who have a history of MDD or a genetic vulnerability to dementia.

The Role of Perceived and Objective Social Connectedness on Risk for Suicidal Thoughts and Behavior in Late-Life and Their Moderating Effect on Cognitive Deficits.

OBJECTIVE: Impaired cognition increases suicide risk while social connectedness protects against suicide risk in late life. We examined the independent and interactive effects of social connectedness and cognition on suicide risk in late life. METHODS: Participants included 570 individuals aged 50+ from a late-life suicide study. The Interpersonal Support Evaluation List and Social Network Index were used to assess perceived and objective social connectedness, respectively, while the Mattis Dementia Rating Scale and Executive Interview were used to assess cognition. RESULTS: Suicide attempters and ideators reported lower perceived social connectedness and exhibited worse executive function than non-suicidal depressed and healthy comparison participants, while only attempters had worse objective social connectedness relative to the other groups. Executive dysfunction was linked to low objective social connectedness in attempters but higher objective social connectedness in healthy comparisons. CONCLUSION: Interventions targeting suicide risk may consider bolstering social connectedness, particularly in those with low cognitive health.

Adjunctive yoga training for persons with schizophrenia: who benefits?

OBJECTIVE: The aim of this study was to identify factors associated with acceptability and efficacy of yoga training (YT) for improving cognitive dysfunction in individuals with schizophrenia (SZ). METHODS: We analysed data from two published clinical trials of YT for cognitive dysfunction among Indians with SZ: (1) a 21-day randomised controlled trial (RCT, N = 286), 3 and 6 months follow-up and (2) a 21-day open trial (n = 62). Multivariate analyses were conducted to examine the association of baseline characteristics (age, sex, socio-economic status, educational status, duration, and severity of illness) with improvement in cognition (i.e. attention and face memory) following YT. Factors associated with acceptability were identified by comparing baseline demographic variables between screened and enrolled participants as well as completers versus non-completers. RESULTS: Enrolled participants were younger than screened persons who declined participation (t = 2.952, p = 0.003). No other characteristics were associated with study enrollment or completion. Regarding efficacy, schooling duration was nominally associated with greater and sustained cognitive improvement on a measure of facial memory. No other baseline characteristics were associated with efficacy of YT in the open trial, the RCT, or the combined samples (n = 148). CONCLUSIONS: YT is acceptable even among younger individuals with SZ. It also enhances specific cognitive functions, regardless of individual differences in selected psychosocial characteristics. Thus, yoga could be incorporated as adjunctive therapy for patients with SZ. Importantly, our results suggest cognitive dysfunction is remediable in persons with SZ across the age spectrum.

Late-Onset Suicide: A Dementia Prodrome?

OBJECTIVES: This study examined whether late-onset (versus early-onset) suicidal behavior is associated with worse cognition. METHODS: Participants included 278 adults aged 50+ years (56 nonpsychiatric comparison group; 67 nonsuicidal depressed older adults; 63 depressed suicide ideators; and 44 late-onset (55+ years) and 48 early-onset suicide attempters (<55 years). Using a case-control design, this study examined group differences in global cognition, episodic memory, information processing speed, and executive functioning, assessed using the Repeatable Battery of Neuropsychological Status and the Trail Making Test from the Delis-Kaplan Executive Function System. Linear regression was used for data analyses. RESULTS: Both attempter groups displayed worse executive functioning than nonsuicidal depressed older adults. Late-onset attempters additionally displayed poorer global cognition and processing speed than nonsuicidal depressed older adults and poorer memory than early-onset attempters. CONCLUSIONS: Late-onset suicidal behavior is associated with worse performance in a broad range of cognitive domains, possibly reflective of a dementia prodrome.

Technology-assisted cognitive-behavioral therapy intervention for end-stage renal disease.

Technology-assisted cognitive-behavioral therapy (CBT) interventions have been conducted for symptoms including depression, pain, and fatigue in patients with chronic illnesses but not in end-stage renal disease (ESRD). The purpose of this study was to pilot the feasibility and acceptability of a technology-assisted CBT intervention in ESRD patients on hemodialysis (HD), share design and implementation lessons learned, and provide preliminary results on changes in select patient-reported symptoms. This was a single-center pilot feasibility study of adult ESRD patients on HD. Study eligibility required clinically elevated levels of at least one symptom (depression, pain, or fatigue). Patients met weekly with a CBT therapist for eight sessions, each 45-60 min, during HD sessions via a video-conferencing platform. Symptom questionnaires were completed at baseline and 3 months follow-up. Of 10 patients screened, 100% screened positive for at least one symptom, 100% of eligible patients consented, and eight (of 10) completed the intervention (mean age 59 years, 50% male, 50% African American). Patient adherence and satisfaction was high, and seven of the eight patients completed all eight prescribed sessions. Minimal interference with HD was reported. Preliminary results indicate no statistically significant changes in depression, fatigue, or pain at follow-up. However, there was small improvement in SF-36 Physical Component score [t(7) = -2.60, p = .035], and four of the six patients (67%) with clinically elevated pain at baseline reported improvement at follow-up. A technology-assisted CBT intervention for ESRD patients was feasible, well-accepted, and required minimal additional resources in the HD setting. Larger, adequately powered clinical trials are needed to evaluate the effect on ESRD patient-reported outcomes.

A Systematic Review of Evidence for a Role of Rest-Activity Rhythms in Dementia.

Background: Rest-activity rhythm (RAR) disruption may be a risk factor for dementia that can be objectively measured with wearable accelerometers. It is possible that risk monitoring and preventive interventions could be developed targeting RARs. To evaluate whether current evidence supports these applications, we systematically reviewed published studies linking RARs with dementia, its course, and mechanisms. Methods: Entering pre-defined search terms in PsycINFO, MEDLINE, and PubMed databases returned 192 unique titles. We identified 32 articles that met our primary inclusion criteria, namely, that they examined objective RAR measures in the context of dementia, cognition, or brain biomarkers. Results: Cross-sectional studies consistently found that people with dementia had less stable (5/6 studies), more fragmented (4/6 studies), lower amplitude rhythms (5/5 studies), that had a worse fit to 24-h models (3/3 studies). Findings from studies relating RARs to cognitive test performance (rather than diagnostic status) were more nuanced. RAR fragmentation was associated with neurodegeneration biomarkers in 2/2 studies; and 1/1 study found 24-h model fit related to hippocampal hyperactivation. Although 2/2 studies found RARs related to markers of cerebrovascular disease, the specific RARs and cerebrovascular disease measures were not consistent. Longitudinal studies (3/3 articles) reported that lower amplitude and worse 24-h rhythm fit predicted future cognitive impairment and executive function. However, interventions aimed at modifying RARs had mixed effects (e.g., 0/4 studies demonstrated effects of morning light on 24-h model fit; evening light was associated with improved 24-h fit in 2/2 studies reporting); these effects may be more evident in subgroups. Conclusions: Consistent evidence shows that dementia is associated with disrupted RARs. Importantly, recent studies have shown that RAR disruption is associated with dementia biomarkers and, prospectively, with the risk of cognitive impairment. Interventions mostly tried using bright light to modify RARs in people who already have dementia; these studies produced modest effects on RARs and did not show modification of dementia's course. Altogether, these findings suggest studies are needed to understand how RARs relate to changes in brain health earlier in the disease process. Better understanding of the biopsychosocial mechanisms linking RARs with future dementia risk can help further target intervention development.

Exercise for Depression: A Feasibility Trial Exploring Neural Mechanisms.

OBJECTIVE: The aim of this study was to test the feasibility of an exercise augmentation to pharmacotherapy in depressed younger and older adults while exploring neural mechanisms. METHODS: A randomized, double-blind, controlled clinical trial was conducted in 15 inactive younger (20-39 years) and older (60-79 years) adults meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for a major depressive episode (https://clinicaltrials.gov/ct2/show/NCT02407704). Participants were randomized to receive a 12-week regimen of venlafaxine XR or venlafaxine XR plus supervised exercise. Cardiorespiratory fitness was assessed using a submaximal Vo2 test, and neuroimaging assessments were conducted using a Siemans MAGNETOM 7-Tesla magnetic resonance scanner at the University of Pittsburgh. RESULTS: Attrition was 38% and 14% for the medication and exercise groups, respectively. Attendance was 91% for the exercise intervention. Exploratory analyses revealed an association between improvement in fitness and increased cortical thickness in the anterior cingulate cortex. CONCLUSION: Exercise augmentation to pharmacotherapy is feasible for depressed younger and older adults and may have neural benefits in a core brain region implicated in depression.

Role of Brain Structure in Predicting Adherence to a Physical Activity Regimen.

OBJECTIVE: Physical activity (PA) is important for maintaining health throughout the lifespan. However, adherence to PA regimens is poor with approximately 50% of older adults terminating activity intervention programs within 6 months. In this study, we tested whether gray matter volume and white matter microstructural integrity before the initiation of a PA intervention predicts PA adherence. METHODS: One hundred fifty-nine adults aged 60 to 80 years were randomly assigned to a moderate-intensity aerobic walking condition or a nonaerobic stretching and toning condition. Participants engaged in supervised exercise 3 times per week for 12 months. Data were collected for a period of 1 year. Voxel-based morphometry and tract-based spatial statistics protocols were used to process neuroimaging data, and ordinary least squares regression models with bootstrapping were used to analyze voxelwise neural predictors of PA adherence. RESULTS: Greater volume in several regions predicted greater PA adherence, including prefrontal, motor, somatosensory, temporal, and parietal regions (p < .01). We also found that higher fractional anisotropy in several white matter tracts predicted greater PA adherence (pFDR-corrected < .05), including the superior longitudinal fasciculus, anterior thalamic radiation, forceps minor, and body of the corpus callosum. CONCLUSIONS: These findings provide preliminary support for macro- and microstructural neural predictors of PA adherence and may translate to other health behaviors and behavioral goal pursuit more broadly.

Exercise effects on depression: Possible neural mechanisms.

Depression is a syndrome of stress- and emotion-dysregulation, involving compromised structural integrity of frontal-limbic networks. Meta-analytic evidence indicates that volumetric reductions in the hippocampus, anterior cingulate cortex, prefrontal cortex, striatum, and amygdala, as well as compromised white matter integrity are frequently observed in depressed adults. Exercise has shown promise as an effective treatment for depression, but few studies have attempted to characterize or identify the neural mechanisms of these effects. In this review, we examined the overlap between structural brain abnormalities in depression and the effects of exercise on brain structure in adults, to highlight possible neural mechanisms that may mediate the positive effects of exercise on depressive symptoms. The prefrontal cortex, anterior cingulate cortex, hippocampus, and corpus callosum emerged as structural neural markers that may serve as targets for exercise-based treatments for depression. These findings highlight the need for randomized exercise interventions to test these proposed neurobiological mechanisms of exercise on depression.

Course of cognitive impairment following attempted suicide in older adults.

OBJECTIVE: Cognitive impairment has been associated with late-life suicidal behavior. Without longitudinal data it is unclear whether these are transient features of a depressive state or stable impairments. We examined longitudinally the course of cognitive impairment in older adults with depression and a history of suicide attempt. METHODS: We investigated the persistence of cognitive impairment over time in 198 depressed older adults (age >60); 91 suicide attempters, 39 depressed individuals with suicidal ideation (ideators), and 68 non-suicidal depressed adults assessed over a 2-year period at four time points. We used linear mixed effects modeling to examine group differences in trajectories of cognitive decline over 2 years, using the Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale (DRS), and Executive Interview (EXIT). RESULTS: Over the 2-year period, suicide attempters performed significantly worse than both suicide ideators and non-suicidal depressed older adults on the MMSE (mean difference: from ideators: -0.88, p = 0.02; from non-suicidal depressed: -1.52, p < 0.01), while on the EXIT and DRS, suicide attempters performed significantly worse than non-suicidal depressed older adults (mean difference: in EXIT: -1.75, p = 0.01; in DRS: 3.04, p < 0.01; in MMSE: 1.15, p < 0.01). Cognitive impairment in suicide attempters partly resolved, as indicated by a group × time interaction on the DRS (p = 0.039), but not the EXIT (p = 0.58) or the MMSE (p = 0.08). CONCLUSIONS: Cognitive impairment in late-life suicidal behavior appears to involve both a stable and a state-related component.

The BDNF Val66Met polymorphism does not moderate the effect of self-reported physical activity on depressive symptoms in midlife.

The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism may be associated with clinical and subsyndromal depression, but physical activity improves mood and increases BDNF expression. The aim of the study was to examine whether the BDNF polymorphism moderates an effect of physical activity on depressive symptoms. BDNF genotype, physical activity measured by the Paffenbarger Questionnaire, and depressive symptoms using the Center for Epidemiology Depression Scale (CES-D) were collected on 1072 participants (mean age=44). Multiple linear regression was used to examine the association between BDNF genotype, physical activity, and depressive symptoms. After adjusting for family income, age, and education, depressive symptoms were higher in Met carriers compared to Val homozygotes (p=0.03), but this was only significant in men. Physical activity was associated with fewer depressive symptoms, but only in women (p=0.01). BDNF genotype did not moderate the effect of physical activity on depressive symptoms (p=0.94). In midlife, the BDNF Val66Met polymorphism neither attenuates nor magnifies the effect of physical activity on depressive symptoms.

Impaired Executive Function in Contemplated and Attempted Suicide in Late Life.

OBJECTIVE: Executive deficits may play an important role in late-life suicide. Yet, current evidence in this area is inconclusive and does not indicate whether these deficits are broadly associated with suicidal ideation or are specific to suicidal behavior. This study examined global cognition and specifically executive function impairments as correlates of suicidal ideation and suicidal behavior in depressed older adults, with the goal of extending an earlier preliminary study. DESIGN: Case-control study. SETTING: University-affiliated psychiatric hospital. PARTICIPANTS: All participants were age 60+: 83 depressed suicide attempters, 43 depressed individuals having suicidal ideation with a specific plan, 54 nonsuicidal depressed participants, and 48 older adults with no history of psychiatric disorders. MEASUREMENTS: Global cognitive function was assessed with Dementia Rating Scale (DRS) and executive function with Executive Interview (EXIT). RESULTS: Both suicide attempters and suicide ideators performed worse than the two comparison groups on the EXIT, with no difference between suicide attempters and suicide ideators. On the DRS total score, as well as on Memory and Attention subscales, suicide attempters and ideators and nonsuicidal depressed subjects performed similarly and were impaired relative to nonpsychiatric control subjects. Controlling for education, substance use disorders, and medication exposure did not affect group differences in performance on either the EXIT or the DRS. CONCLUSIONS: Executive deficits, captured with a brief instrument, are associated broadly with suicidal ideation in older depressed adults but do not appear to directly facilitate suicidal behavior. Our data are consistent with the idea that different vulnerabilities may operate at different stages in the suicidal process.