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INTRODUCTION: Adopting healthy lifestyle behaviors has the potential to slow cognitive decline in older adults by reducing risks associated with dementia. Curriculum-based group health coaching may aid in establishing behavior change centered for dementia risk factors. METHODS: In this pilot clinical care patient group study (n = 6), we examined the effects of a six-month online Cognitive Health Program combined with a weekly telehealth support group led by the course creator, and personalized health optimization by a collaborating physician, in older adults with subjective cognitive decline. Cognition was assessed at baseline and post-intervention using a computerized battery. RESULTS: Cognitive changes were estimated with nonparametric tests and effect sizes (Cohens d). Results showed significant improvements in global cognition (p < 0.03, d = 1.6), spatial planning (p < 0.01, d = 2.3), and visuospatial processing (p < 0.05, d = 1.1) compared to baseline. Participants reported high levels of satisfaction with the virtual group format and online curriculum. CONCLUSIONS: This small pilot study suggests that a virtual six-month personalized health coaching group with self-paced online health education is feasible and potentially efficacious for improving cognition in participants with subjective cognitive complaints. This format may facilitate behavior change to slow cognitive decline. Future studies should include a control group, a larger, more diverse sample as well as assessing mood and other subjective measures.

Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) accompanied by cerebrovascular risk factors (CVRFs) are known to increase the risk of developing dementia. Mind-body practices such as yoga and meditation, have been recognized as safe techniques with beneficial effects on cognitive functions in older adults at risk for cognitive decline. We conducted a randomized, controlled trial to assess the efficacy of Kundalini yoga training (KY) compared to memory enhancement training (MET) on mood and cognitive functioning in a group of older women with CVRFs and SCD (clinicaltrials.gov = NCT03503669). The KY intervention consisted of weekly, 60-min in-person classes with a certified instructor for 12 weeks, with a 12-min guided recording for daily homework practice at home. MET involved 12 weekly in-person group classes with 12-min daily homework exercises. Objective and subjective memory performance were the primary outcomes. Peripheral whole blood samples were collected at baseline, 12-weeks, and 24-weeks follow-up for RNA sequencing and cytokine/chemokine assays. A total of 79 patients (KY = 40; MET = 39) were randomized, and 63 completed the 24-week follow-up (KY = 65% completion rate; MET = 95%; χ2(1) = 10.9, p

The effect of electronic cigarette (E-cig) vaping on cardiac and vascular function during the healing phase of myocardial infarction (MI), and post-MI remodeling was investigated. Sprague Dawley rats were subjected to left coronary artery ligation to induce MI. One week later, rats were randomized to receive either 12 weeks of exposure to purified air (n = 37) or E-cig vapor (15 mg/ml of nicotine) (n = 32). At 12 weeks, cardiac and vascular function, and post-MI remodeling were assessed. Baseline blood flow in the femoral artery did not differ between groups, but peak reperfusion blood flow was blunted in the E-cig group (1.59 ± 0.15 ml/min) vs. the air group (2.11 ± 0.18 ml/min; p = 0.034). Femoral artery diameter after reperfusion was narrower in the E-cig group (0.54 ± 0.02 mm) compared to the air group (0.60 ± 0.02 mm; p = 0.023). Postmortem left ventricular (LV) volumes were similar in the E-cig (0.69 ± 0.04 ml) and air groups (0.73 ± 0.04 ml; p = NS); and myocardial infarct expansion index did not differ between groups (1.4 ± 0.1 in E-cig group versus 1.3 ± 0.1 in air group; p = NS). LV fractional shortening by echo did not differ between groups at 12 weeks (E-cig at 29 ± 2% and air at 27 ± 1%; p = NS). Exposure to E-cig during the healing phase of MI was associated with altered vascular function with reduced femoral artery blood flow and diameter at reperfusion, but not with worsened LV dilation or worsened cardiac function.

PURPOSE: The population with serious mental illness has high risk for hospitalization or death due to unhealthy behaviors and inadequate medical care, though the level of risk varies substantially. Programs that integrate medical and psychiatric services improve outcomes but are challenging to implement and access is limited. It would be useful to know whether benefits are confined to patients with specific levels of risk. METHODS: In a population with serious mental illness and increased risk for hospitalization or death, a specialized medical home integrated services and improved treatment and outcomes. Treatment quality, chronic illness care, care experience, symptoms, and quality of life were assessed for a median of 385 days. Analyses examine whether improvements varied by baseline level of patient risk. RESULTS: Patients with greater risk were more likely to be older, more cognitively impaired, and have worse mental health. Integrated services increased appropriate screening for body mass index, lipids, and glucose, but increases did not differ significantly by level of risk. Integrated services also improved chronic illness care, care experience, mental health-related quality of life, and psychotic symptoms. There were also no significant differences by risk level. CONCLUSIONS: There were benefits from integration of primary care and psychiatric care at all levels of increased risk, including those with extremely high risk above the 95th percentile. When developing integrated care programs, patients should be considered at all levels of risk, not only those who are the healthiest.

Immune checkpoint immunotherapy (ICI) can re-activate immune reactions against neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness are needed to improve the success of cancer treatments. While the tumor mutational burden (TMB) correlates positively with responsiveness and survival of patients undergoing ICI, the influence of the subcellular localizations of the neoantigens remains unclear. Here, we demonstrate in both a mouse melanoma model and human clinical datasets of 1,722 ICI-treated patients that a high proportion of membrane-localized neoantigens, particularly at the plasma membrane, correlate with responsiveness to ICI therapy and improved overall survival across multiple cancer types. We further show that combining membrane localization and TMB analyses can enhance the predictability of cancer patient response to ICI. Our results may have important implications for establishing future clinical guidelines to direct the choice of treatment toward ICI.

BackgroundUnderlying inflammation is associated with an increased risk of depression in older adults. In this study, we examined the role of inflammatory biomarkers in antidepressant response in depressed older adults undergoing adjunct Tai Chi Chih (TCC) or Health education interventions.MethodsOlder adults aged 60 years and above with a diagnosis of major depression were randomized to 12 weeks of TCC versus Health and Wellness Education (HEW) as an adjunct therapy to their stable antidepressant treatment regimen. A panel of 19 cytokine/chemokines was measured at baseline and 12 weeks. Five factors were derived using factor analysis. General linear models were estimated to examine the change in factor scores and the association of these changes on depression remission rates, controlling for age, sex, and body mass index.ResultsOf the 170 randomized participants (TCC: n = 85 and HEW: n = 85), 55 TCC and 58 HEW completed the 3-month assessment. The groups did not differ at baseline in any measure. At follow-up, neither the changes in cytokine/chemokines scores nor the depression remission rate differed significantly between TCC and HEW. However, remitters and non-remitters differed significantly in changes in a factor composed of growth-regulated oncogene protein-alpha (GRO-alpha), epidermal growth factor (EGF), and soluble CD40 ligand (sCD40L). GRO-alpha and EGF levels (in both groups) were significantly increased in remitters compared to non-remitters.ConclusionChanges in certain cytokines/chemokines may accompany improvement in depressive symptoms in older adults. Future studies will need to explore the role of these molecules in remission of late-life depression.

BACKGROUND: A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimers disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis. OBJECTIVE: We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet. METHODS: A total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t-test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted. RESULTS: The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks. CONCLUSIONS: Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels.

BackgroundYoga may be an ideal early intervention for those with modifiable risk factors for Alzheimer's disease (AD) development.ObjectiveTo examine the effects of Kundalini yoga (KY) training versus memory enhancement training (MET) on the resting-state connectivity of hippocampal subregions in women with subjective memory decline and cardiovascular risk factors for AD.MethodsParticipants comprised women with subjective memory decline and cardiovascular risk factors who participated in a parent randomized controlled trial (NCT03503669) of 12-weeks of KY versus MET and completed pre- and post-intervention resting-state magnetic resonance imaging scans (yoga: n = 11, age = 61.45±6.58 years; MET: n = 11, age = 64.55±6.41 years). Group differences in parcellated (Cole-anticevic atlas) hippocampal connectivity changes (post- minus pre-intervention) were evaluated by partial least squares analysis, controlling for age. Correlations between hippocampal connectivity and perceived stress and frequency of forgetting (assessed by questionnaires) were also evaluated.ResultsA left anterior hippocampal subregion assigned to the default mode network (DMN) in the Cole-anticevic atlas showed greater increases in connectivity with largely ventral visual stream regions with KY than with MET (p

INTRODUCTION: Psychedelic-assisted therapy with psilocybin has shown promise in Phase 2 trials for alcohol use disorder (AUD). Set and setting, particularly factors facilitating a connection with nature, may positively influence the psychedelic experience and therapeutic outcomes. But to date, randomized controlled trials of interventions to enhance set and setting for psychedelic-assisted therapy are lacking. METHODS: This was a pilot randomized, controlled trial of Visual Healing, a nature-themed video intervention to optimize set and setting, versus Standard set and setting procedures with two open-label psilocybin 25 mg dosing sessions among 20 participants with AUD. For the first session, participants randomized to Visual Healing viewed nature-themed videos during the preparation session and the ascent and descent phases of the psilocybin dosing session while participants randomized to the Standard condition completed a meditation during the preparatory session and wore eyeshades and listened to a music playlist throughout the dosing session. For the second session 4 weeks later, participants chose either Visual Healing or Standard procedures. Primary outcomes were feasibility, safety, and tolerability of Visual Healing. Secondary and exploratory outcomes were changes in alcohol use, psychedelic effects, anxiety and stress. RESULTS: Nineteen of 20 (95%) randomized participants (mean age 49 ± 11 years, 60% female) completed the 14-week study. During the first psilocybin session, participants viewed an average of 37.9 min of the 42-min video and there were no video-related adverse events. Peak increase in post-psilocybin blood pressure was significantly less for participants randomly assigned to Visual Healing compared to Standard procedures. Alcohol use decreased significantly in both Visual Healing and Standard groups and psychedelic effects, stress, and anxiety were similar between groups. DISCUSSION: In this open-label pilot study, viewing Visual Healing videos during preparation and psilocybin dosing sessions was feasible, safe, and well-tolerated among participants with AUD. Preliminary findings suggest that Visual Healing has potential to reduce the cardiovascular risks of psychedelic therapy, without interfering with the psychedelic experience or alcohol-related treatment outcomes. Studies to replicate our findings as well as studies of different set and setting interventions with other psychedelic medications and indications are warranted.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and atrophy in the medial temporal lobe (MTL) and subsequent brain regions. Structural magnetic resonance imaging (sMRI) has been widely used in research and clinical care for diagnosis and monitoring AD progression. However, atrophy patterns are complex and vary by patient. To address this issue, researchers have made efforts to develop more concise metrics that can summarize AD-specific atrophy. Many of these methods can be difficult to interpret clinically, hampering adoption. In this study, we introduce a novel index which we call an "AD-NeuroScore," that uses a modified Euclidean-inspired distance function to calculate differences between regional brain volumes associated with cognitive decline. The index is adjusted for intracranial volume (ICV), age, sex, and scanner model. We validated AD-NeuroScore using 929 older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, with a mean age of 72.7 years (SD = 6.3; 55.1-91.5) and cognitively normal (CN), mild cognitive impairment (MCI), or AD diagnoses. Our validation results showed that AD-NeuroScore was significantly associated with diagnosis and disease severity scores (measured by MMSE, CDR-SB, and ADAS-11) at baseline. Furthermore, baseline AD-NeuroScore was associated with both changes in diagnosis and disease severity scores at all time points with available data. The performance of AD-NeuroScore was equivalent or superior to adjusted hippocampal volume (AHV), a widely used metric in AD research. Further, AD-NeuroScore typically performed as well as or sometimes better when compared to other existing sMRI-based metrics. In conclusion, we have introduced a new metric, AD-NeuroScore, which shows promising results in detecting AD, benchmarking disease severity, and predicting disease progression. AD-NeuroScore differentiates itself from other metrics by being clinically practical and interpretable.

BackgroundStrength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI).ObjectiveTo model the relationships between handgrip strength, mobility, and MRI volumetry.MethodsWe selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance.ResultsHigher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes.ConclusionGreater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

ObjectivesTwo-thirds of individuals living with Alzheimer's disease are women. Declining estrogen levels influence mood and cognition. Cumulative lifetime estrogen exposure (CLEE) correlates with cognition later in life. We examined the relationship of CLEE to depression and cognition in older women with major depression compared to non-depressed women.DesignOlder women (age ≥60 years) with depression were compared to non-depressed women using a lifetime estrogen exposure questionnaire. CLEE was defined as combined durations of reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Higher vs lower CLEE groups were based on a median of 474 months of estrogen exposure.SettingUniversity hospital outpatient research program.Participants135 women ≥60 years; 64 depressed and 71 non-depressed.MeasurmentsParticipants completed a comprehensive cognitive test battery. General linear models were used to examine the association between cognitive domain scores and CLEE in depressed and non-depressed women, controlling for age, education, and ethnicity.ResultsDepressed and non-depressed groups had significantly different levels of CLEE, measured in months: mean 495.7 (SD 108.6) vs 456.4 (SD 66.0) months, F(1,130) = 5.01, p = .03. Within the non-depressed participants, higher CLEE was associated with improved delayed recall (F(1,59) = 5.94, p = .02, effect size = .61), while no such relationship was observed in the depressed group.ConclusionHigher CLEE was associated with improvement in delayed recall among non-depressed, but not among depressed participants. This suggests a protective role of estrogen on memory in non-depressed older postmenopausal women. Further research should examine the role of the CLEE in antidepressant response and cognitive decline.

BackgroundAs an adjunct to antidepressant treatment, Tai Chi Chih (TCC) is superior to health education and wellness (HEW) training in improving the general health of patients with geriatric depression (GD). This study investigated the brain connectivity changes associated with TCC and HEW in combination with antidepressant treatment in patients with GD.MethodsForty patients with GD under stable antidepressant treatment underwent TCC training (n = 21) or HEW training (n = 19) for 12 weeks, and completed baseline and 3-month follow-up resting state magnetic resonance imaging scans. Within-group and between-group differences in parcel-to-parcel connectivity changes with intervention were evaluated by general linear modeling. Relationships between significant connectivity changes and symptom/resilience improvement were evaluated by partial least squares correlation analysis.ResultsSignificantly greater increases in connectivity with TCC than with HEW (FDR-corrected p

Estrogens have neuroprotective actions depending on estrogen type, dose, and timing in both preclinical models and in women during health and disease. Serum neurofilament light chain is a putative biomarker of neurodegeneration in multiple sclerosis, aging, and other neurodegenerative diseases. Here, oral treatment with an estrogen unique to pregnancy (estriol) using an 8 mg dose to induce a mid-pregnancy blood estriol level reduced serum neurofilament light chain in nonpregnant MS women at mean age of 37 years. This is consistent with estriol-mediated protection from neuro-axonal injury and supports the use of serum neurofilament light chain as a biomarker in MS.

ObjectivesDefault mode network (DMN) connectivity is altered in depression. We evaluated the relationship between changes in within-network DMN connectivity and improvement in depression in a subsample of our parent clinical trial comparing escitalopram/memantine (ESC/MEM) to escitalopram/placebo (ESC/PBO) in older depressed adults (NCT01902004).MethodsTwenty-six participants with major depression (age > 60 years) and subjective memory complaints underwent treatment with ESC/MEM (n = 13) or ESC/PBO (n = 13), and completed baseline and 3-month follow-up resting state magnetic resonance imaging scans. Multi-block partial least squares correlation analysis was used to evaluate the impact of treatment on within-network DMN connectivity changes and their relationship with symptom improvement at 3 months (controlling for age and sex).ResultsA significant latent variable was identified, reflecting within-network DMN connectivity changes correlated with symptom improvement (p = .01). Specifically, although overall group differences in within-network DMN connectivity changes failed to reach significance, increased within-network connectivity of posterior/lateral DMN regions (precuneus, angular gyrus, superior/middle temporal cortex) was more strongly and positively correlated with symptom improvement in the ESC/MEM group (r = 0.97, 95% confidence interval: 0.86-0.98) than in the ESC/PBO group (r = 0.36, 95% confidence interval: 0.13-0.72).ConclusionsIncreased within-network connectivity of core DMN nodes was more strongly correlated with depressive symptom improvement with ESC/MEM than with ESC/PBO, supporting an improved engagement of brain circuitry implicated in the amelioration of depressive symptoms with combined ESC/MEM treatment in older adults with depression and subjective memory complaints.

ObjectivesGeriatric depression is difficult to treat and frequently accompanied by treatment resistance, suicidal ideations and polypharmacy. New adjunctive mind-body treatment strategies can improve clinical outcomes in geriatric depression and reduce risk for side-effects of pharmacological treatments.MethodsWe conducted a 3-month randomized controlled trial to assess the efficacy and tolerability of combining Tai Chi Chih (TCC) or Health Education and Wellness training (HEW) with the stable standard antidepressant treatment on mood and cognitive functioning in depressed older adults (NCT02460666). Primary outcome was change in depression as assessed by the Hamilton Rating Scale for Depression (HAM-D) post-treatment. Remission was defined as HAM-D ≤ 6; naturalistic follow-up continued for 6 months. We also assessed psychological resilience, health-related quality of life and cognition.ResultsOf the 178 randomized participants, 125 completed the 3-month assessment and 117 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Remission rate within TCC was 35.5% and 33.3%, compared to 27.0% and 45.8% in HEW, at 3 and 6 months respectively (χ2(1) = 1.0, p = 0.3; χ2(1) = 1.9, p =0.2). Both groups improved significantly on the HAM-D at 3 and 6 months. TCC demonstrated a greater improvement in general health compared to HEW.ConclusionsBoth TCC and HEW combined with a standard antidepressant treatment improved symptoms of depression in older adults. While TCC was superior to HEW in improving general health, we did not find group differences in improvement in mood and cognition.

Growing evidence supports the concept that bidirectional brain-gut microbiome interactions play an important mechanistic role in aging, as well as in various neuropsychiatric conditions including depression. Gray matter volume (GMV) deficits in limbic regions are widely observed in geriatric depression (GD). We therefore aimed to explore correlations between gut microbial measures and GMV within these regions in GD. Sixteen older adults (>60 years) with GD (37.5% female; mean age, 70.6 (SD = 5.7) years) were included in the study and underwent high-resolution T1-weighted structural MRI scanning and stool sample collection. GMV was extracted from bilateral regions of interest (ROI: hippocampus, amygdala, nucleus accumbens) and a control region (pericalcarine). Fecal microbiota composition and diversity were assessed by 16S ribosomal RNA gene sequencing. There were significant positive associations between alpha diversity measures and GMV in both hippocampus and nucleus accumbens. Additionally, significant positive associations were present between hippocampal GMV and the abundance of genera Family_XIII_AD3011_group, unclassified Ruminococcaceae, and Oscillibacter, as well as between amygdala GMV and the genera Lachnospiraceae_NK4A136_group and Oscillibacter. Gut microbiome may reflect brain health in geriatric depression. Future studies with larger samples and the experimental manipulation of gut microbiome may clarify the relationship between microbiome measures and neuroplasticity.

IntroductionCoronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term.MethodsThis article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions.ResultsSuccessful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe.DiscussionThe Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection.Key pointsThe following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.

BackgroundDistinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention.ObjectiveWe investigated diagnostic categorization using an FDA-cleared quantitative electroencephalographic/event-related potential (qEEG/ERP)-based cognitive testing system (eVox® by Evoke Neuroscience) combined with an automated volumetric magnetic resonance imaging (vMRI) tool (Neuroreader® by Brainreader).MethodsPatients who self-presented with memory complaints were assigned to a diagnostic category by dementia specialists based on clinical history, neurologic exam, neuropsychological testing, and laboratory results. In addition, qEEG/ERP (n = 161) and quantitative vMRI (n = 111) data were obtained. A multinomial logistic regression model was used to determine significant predictors of cognitive diagnostic category (SCD, MCI, or dementia) using all available qEEG/ERP features and MRI volumes as the independent variables and controlling for demographic variables. Area under the Receiver Operating Characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the prediction models.ResultsThe qEEG/ERP measures of Reaction Time, Commission Errors, and P300b Amplitude were significant predictors (AUC = 0.79) of cognitive category. Diagnostic accuracy increased when volumetric MRI measures, specifically left temporal lobe volume, were added to the model (AUC = 0.87).ConclusionThis study demonstrates the potential of a primarily physiological diagnostic model for differentiating SCD, MCI, and dementia using qEEG/ERP-based cognitive testing, especially when combined with volumetric brain MRI. The accessibility of qEEG/ERP and vMRI means that these tools can be used as adjuncts to clinical assessments to help increase the diagnostic certainty of SCD, MCI, and dementia.

BackgroundFemale sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer's disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations, and modulated brain connectivity in older adults with mild cognitive impairment.ObjectiveIn this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRFs following three months of yoga compared to memory enhancement training (MET).MethodsEleven women (mean age = 61.45, SD = 6.58) with CVRF and SCD completed twelve weeks of Kundalini Yoga and Kirtan Kriya (KY + KK) while eleven women (mean age = 64.55, SD = 6.41) underwent MET. Anxiety, resilience, stress, and depression were assessed at baseline and 12 weeks, as were T1-weighted MRI scans (Siemens 3T Prisma scanner). We used Freesurfer 6.0 and tested group differences in GMV change, applying Monte-Carlo simulations with alpha = 0.05. Region-of-interest analysis was performed for hippocampus and amygdala.ResultsCompared to KY + KK, MET showed reductions in GMV in left prefrontal, pre- and post-central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections.ConclusionYoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups.

Drugs that target glutamate neuronal transmission, such as memantine, offer a novel approach to the treatment of late-life depression, which is frequently comorbid with cognitive impairment. The results of our recently published double-blind, randomized, placebo-controlled trial of escitalopram or escitalopram/memantine in late-life depression with subjective memory complaints (NCT01902004) indicated no differences between treatments in depression remission, but additional benefits in cognition at 12-month follow-up with combination treatment. To identify pathways and biological functions uniquely induced by combination treatment that may explain cognitive improvements, we generated transcriptional profiles of remission compared with non-remission from whole blood samples. Remitters to escitalopram compared with escitalopram/memantine combination treatment display unique patterns of gene expression at baseline and 6 months after treatment initiation. Functional enrichment analysis demonstrates that escitalopram-based remission associates to functions related to cellular proliferation, apoptosis, and inflammatory response. Escitalopram/memantine-based remission, however, is characterized by processes related to cellular clearance, metabolism, and cytoskeletal dynamics. Both treatments modulate inflammatory responses, albeit via different effector pathways. Additional research is needed to understand the implications of these results in explaining the observed superior effects of combination treatment on cognition observed with prolonged treatment.

ObjectiveBecause of inconsistent findings regarding the relationship between sleep quality and cognitive function in people with age-related memory complaints, we examined how self-reports of sleep quality were related to multiple domains of both objective and subjective cognitive function in middle-aged and older adults.DesignA cross-sectional study involving analysis of baseline data, collected as part of a clinical trial.MeasurementsTwo hundred and three participants (mean age = 60.4 [6.5] years, 69.0% female) with mild memory complaints were asked to rate their sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and their memory performance using the Memory Functioning Questionnaire (MFQ), which measures self-awareness of memory ability. Neurocognitive performance was evaluated using the Continuous Performance Test (CPT), Trail Making Test, Buschke Selective Reminding Test, and the Brief Visuospatial Test - Revised (BVMT-R).ResultsTotal PSQI scores were significantly associated with objective measures of sustained attention (CPT hit reaction time by block and standard error by block) and subjective memory loss (MFQ frequency and seriousness of forgetting). The PSQI components of (poorer) sleep quality and (greater) sleep disturbance were related to (worse) sustained attention scores while increased sleep latency and daytime sleepiness were associated with greater frequency and seriousness of forgetting.ConclusionsSleep quality is related to both objective measures of sustained attention and self-awareness of memory decline. These findings suggest that interventions for improving sleep quality may contribute not only to improving the ability to focus on a particular task but also in reducing memory complaints in middle-aged and older adults.

ObjectivesGeriatric depression often presents with memory and cognitive complaints that are associated with increased risk for Alzheimer's disease (AD). In a parent clinical trial of escitalopram combined with memantine or placebo for geriatric depression and subjective memory complaints, we found that memantine improved executive function and delayed recall performance at 12 months (NCT01902004). In this report, we used positron emission tomography (PET) to assess the relationship between in-vivo amyloid and tau brain biomarkers and clinical and cognitive treatment response.DesignIn a randomized double-blind placebo-controlled trial, we measured 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ([18F]FDDNP) binding at baseline and assessed mood and cognitive performance at baseline, posttreatment (6 months), and naturalistic follow-up (12 months).ParticipantsTwenty-two older adults with major depressive disorder and subjective memory complaints completed PET scans and were included in this report.ResultsAcross both treatment groups, higher frontal lobe [18F]FDDNP binding at baseline was associated with improvement in executive function at 6 months (corrected p = .045). This effect was no longer significant at 12 months (corrected p = .12). There was no association of regional [18F]FDDNP binding with change in mood symptoms (corrected p = .2).Conclusions[18F]FDDNP binding may predict cognitive response to antidepressant treatment. Larger trials are required to further test the value of [18F]FDDNP binding as a biomarker for cognitive improvement with antidepressant treatment in geriatric depression.

Background: Recent evidence suggests that integration of multi-modal data improves performance in machine learning prediction of depression treatment outcomes. Here, we compared the predictive performance of three machine learning classifiers using differing combinations of sociodemographic characteristics, baseline clinical self-reports, cognitive tests, and structural magnetic resonance imaging (MRI) features to predict treatment outcomes in late-life depression (LLD). Methods: Data were combined from two clinical trials conducted with depressed adults aged 60 and older, including response to escitalopram (N = 32, NCT01902004) and Tai Chi (N = 35, NCT02460666). Remission was defined as a score of 6 or less on the 24-item Hamilton Rating Scale for Depression (HAMD) at the end of 24 weeks of treatment. Features subsets were constructed from baseline sociodemographic and clinical features, gray matter volumes (GMVs), or both. Three classification algorithms were compared: (1) Support Vector Machine-Radial Bias Function (SVMRBF), (2) Random Forest (RF), and (3) Logistic Regression (LR). A repeated 5-fold cross-validation approach with a wrapper-based feature selection method was used for model fitting. Model performance metrics included Area under the ROC Curve (AUC) and Matthews correlation coefficient (MCC). Cross-validated performance significance was tested by permutation analysis. Classifiers were compared by Cochran's Q and post-hoc pairwise comparisons using McNemar's Chi-Square test with Bonferroni correction. Results: For the RF and SVMRBF algorithms, the combined feature set outperformed the clinical and GMV feature sets with a final cross-validated AUC of 0.83 ± 0.11 and 0.80 ± 0.11, respectively. Both classifiers passed permutation analysis. The LR algorithm performed best using GMV features alone (AUC 0.79 ± 0.14) but failed to pass permutation analysis using any feature set. Performance of the three classifiers differed significantly for all three features sets. Important predictive features of treatment response included anterior and posterior cingulate volumes, depression characteristics, and self-reported health-related quality scores. Conclusion: This preliminary exploration into the use of ML and multi-modal data to identify predictors of general treatment response in LLD indicates that integration of clinical and structural MRI features significantly increases predictive capability. Identified features are among those previously implicated in geriatric depression, encouraging future work in this arena.

Background and objectivesWomen who breastfeed may experience long-term benefits for their health in addition to the more widely appreciated effects on the breastfed child. Breastfeeding may induce long-term effects on biopsychosocial systems implicated in brain health. Also, due to diminished breastfeeding in the postindustrial era, it is important to understand the lifespan implications of breastfeeding for surmising maternal phenotypes in our species' collective past. Here, we assess how women's breastfeeding history relates to postmenopausal cognitive performance.MethodologyA convenience sample of Southern California women age 50+ was recruited via two clinical trials, completed a comprehensive neuropsychological test battery and answered a questionnaire about reproductive life history. General linear models examined whether cognitive domain scores were associated with breastfeeding in depressed and non-depressed women, controlling for age, education and ethnicity.ResultsWomen who breastfed exhibited superior performance in the domains of Learning, Delayed Recall, Executive Functioning and Processing Speed compared to women who did not breastfeed (P-values 0.0003-0.015). These four domains remained significant in analyses limited to non-depressed and parous subsets of the cohort. Among those depressed, only Executive Functioning and Processing Speed were positively associated with breastfeeding.Conclusions and implicationsWe add to the growing list of lifespan health correlates of breastfeeding for women's health, such as the lower risk of type-2 diabetes, cardiovascular disease and breast cancer. We surmise that women's postmenopausal cognitive competence may have been greater in past environments in which breastfeeding was more prevalent, bolstering the possibility that postmenopausal longevity may have been adaptive across human evolutionary history.Lay summaryBreastfeeding may affect women's cognitive performance. Breastfeeding's biological effects and psychosocial effects, such as improved stress regulation, could exert long-term benefits for the mother's brain. We found that women who breastfed performed better on a series of cognitive tests in later life compared to women who did not breastfeed.

IntroductionGeriatric depression is frequently accompanied by cognitive complaints and inflammation that increase risk for treatment-resistant depression and dementia. Memantine, a neuroprotective drug, can improve depression, inflammation, and help prevent cognitive decline. In our six-month clinical trial, escitalopram/memantine (ESC/MEM) improved mood and cognition compared to escitalopram/placebo treatment (ESC/PBO; NCT01902004). In this report, we examined the impact of baseline inflammation on mood and cognitive outcomes.Materials and methodsWe measured a panel of inflammatory cytokine markers using Human 38-plex magnetic cytokine/chemokine kits (EMD Millipore, HCYTMAG-60K-PX38) in 90 older adults 60 years and older with major depression enrolled in a 6-month double-blind placebo-controlled trial of escitalopram ​+ ​memantine (ESC/MEM) in depressed older adults with subjective memory complaints. Four cytokine factors were derived and linear models were estimated to examine the predictive ability of cytokine levels on treatment induced change in depression and cognition.ResultsOf the 90 randomized participants, 62 completed the 6-month follow up assessment. Both groups improved significantly on depression severity (HAM-D score), but not on cognitive outcomes at six months. Cytokine factor scores were not significantly different between ESC/MEM (n ​= ​45) and ESC/PBO (n ​= ​45) at baseline. Pro-inflammatory biomarkers at baseline predicted a decline in executive functioning in the ESC/PBO group but not in the ESC/MEM group, interaction F(1,52) ​= ​4.63, p ​= ​.04.DiscussionIn this exploratory analysis, the addition of memantine to escitalopram provided a protective effect on executive functioning in older depressed adults. Future studies are needed to replicate the association of cytokine markers to antidepressant and neuroprotective treatment-related change in cognition in geriatric depression.

BackgroundGeriatric depression with subjective cognitive complaints increases the risk of Alzheimer's Disease (AD). Memantine is a cognitive enhancer used to treat AD. In a 6-month double-blind randomized placebo-controlled trial of escitalopram and memantine (ESC/MEM), ESC/MEM improved cognition at 12 month in geriatric depression (NCT01902004). We now investigated structural neuroplastic changes at 3 months.MethodsForty-one older depressed adults (mean age=70.43, SD=7.33, 26 female) were randomized to receive ESC/MEM or ESC/PBO. Mood scores (Hamilton Depression Rating Scale, HAMD) and high-resolution structural T1-weighted images were acquired at baseline and 3 months. Freesurfer 6.0 for image processing and General Linear Models was used to examine group differences in symmetrized percent change gray matter volume (GMV) and cortical thickness, controlling for age and intracranial volume. Nonparametric tests were used to investigate group differences in mood and subcortical volume change.ResultsAmong 27 completers (ESC/MEM n = 13; ESC/PBO n = 14), 62% achieved remission (HAMD≤6) with ESC/MEM and 43% with ESC/PBO (Fisher's exact p=.45). Change in HAMD did not differ between groups (F(1,23)=0.14, p=.7). GMV and thickness increased more with ESC/MEM than with ESC/PBO in the left middle and inferior temporal lobe, right medial, and lateral orbito-frontal cortex (OFC).Limitationsincluded small sample size, dropout, and the lack of cognitive data at 3 months.ConclusionsAlthough significant group differences in mood improvement were not observed, ESC/MEM resulted in increased GMV and cortical thickness in several brain regions compared to placebo. Larger longitudinal clinical trials can further examine the neuroprotective effect of memantine in geriatric depression.

Emerging scientific evidence indicates that frequent digital technology use has a significant impact-both negative and positive-on brain function and behavior. Potential harmful effects of extensive screen time and technology use include heightened attention-deficit symptoms, impaired emotional and social intelligence, technology addiction, social isolation, impaired brain development, and disrupted sleep. However, various apps, videogames, and other online tools may benefit brain health. Functional imaging scans show that internet-naive older adults who learn to search online show significant increases in brain neural activity during simulated internet searches. Certain computer programs and videogames may improve memory, multitasking skills, fluid intelligence, and other cognitive abilities. Some apps and digital tools offer mental health interventions providing self-management, monitoring, skills training, and other interventions that may improve mood and behavior. Additional research on the positive and negative brain health effects of technology is needed to elucidate mechanisms and underlying causal relationships.
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ObjectiveGeriatric depression is difficult to treat and frequently accompanied by cognitive complaints that increase risk for dementia. New treatment strategies targeting both depression and cognition are urgently needed.MethodsWe conducted a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram + memantine (ESC/MEM) compared to escitalopram + placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints (NCT01902004). Primary outcome was change in depression as assessed by the HAM-D post-treatment (at 6 months). Remission was defined as HAM-D ≤6; naturalistic follow-up continued until 12 months.ResultsOf the 95 randomized participants, 62 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Mean daily escitalopram dose was 11.1 mg (SD = 3.7; range: 5-20 mg). Mean daily memantine dose was 19.3 mg (SD = 2.6; range 10-20 mg). Remission rate within ESC/MEM was 45.8% and 47.9%, compared to 38.3% and 31.9% in ESC/PBO, at 3 and 6 months, respectively (χ2(1) = 2.0, p = 0.15). Both groups improved significantly on the HAM-D at 3, 6, and 12 months, with no observed between-group differences. ESC/MEM demonstrated greater improvement in delayed recall (F(2,82) = 4.3, p = 0.02) and executive functioning (F(2,82) = 5.1, p = 0.01) at 12 months compared to ESC/PBO.ConclusionsThe combination of memantine with escitalopram was well tolerated and as effective as escitalopram and placebo in improving depression using HAM-D. Combination memantine and escitalopram was significantly more effective than escitalopram and placebo in improving cognitive outcomes at 12 months. Future reports will address the role of biomarkers of aging in treatment response.

Background: Geriatric depression with subjective memory complaints increases the risk for Alzheimer's Disease. Memantine, a neuroprotective drug, can improve depression and help prevent cognitive decline. In our 6-months clinical trial, escitalopram/memantine (ESC/MEM) improved mood and cognition compared to escitalopram/placebo treatment (ESC/PBO; NCT01902004). In this report, we investigated whether baseline brain white matter integrity in fronto-limbic-striatal tracts can predict clinical outcomes using fractional anisotropy (FA). Methods: Thirty-eight older depressed adults (mean age = 70.6, SD = 7.2) were randomized to ESC/MEM or ESC/PBO and underwent diffusion-weighted imaging (DWI) at 3 Tesla at baseline. Mood was assessed using the Hamilton Depression Rating Scale (HAMD), apathy using the Apathy Evaluation Scale (AES) and anxiety using the Hamilton Anxiety Scale (HAMA) at baseline and 6-months follow-up. FA was extracted from seven tracts of interest (six in each hemisphere and one commissural tract) associated with geriatric depression. Non-parametric General Linear Models were used to examine group differences in the association between FA and symptom improvement, controlling for age, sex, baseline symptom scores and scanner model, correcting for false discovery rate (FDR). Post-hoc tests further investigated group differences in axial, mean and radial diffusivity (AD, MD, and RD, respectively). Lastly, we performed an exploratory whole-brain model to test whether FA might be related to treatment response with memantine. Results: There were no differences in remission rates or HAMD change between groups. In bilateral anterior and posterior internal capsule tracts and bilateral inferior and right superior fronto-occipital (IFO and SFO) fasciculus, higher FA was associated with larger improvements in depressive symptoms for ESC/MEM, but not ESC/PBO, correcting for FDR. Lower MD in the left IFO and RD in the right anterior internal capsule were associated with improved treatment responses. We found no significant associations in the whole-brain analysis. Limitations: Included small sample size and high dropout. Conclusions: Higher baseline FA and lower RD and MD in hypothesized fronto-limbic-striatal tracts predicted greater improvement in mood and anxiety with ESC/MEM compared to ESC/PBO in geriatric depression. FA as a biomarker for white matter integrity may serve as a predictor of treatment response but requires confirmation in larger future studies.

BackgroundIncreasing understanding of the neural correlates of anxiety symptoms in late-life depression (LLD) could inform the development of more targeted and effective treatments.MethodsGrey matter volume (GMV) was assessed with volumetric magnetic resonance imaging in a sample of 113 adults ≥60 years with MDD using the following regions of interest: amygdala, anterior cingulate cortex (ACC), insula, orbitofrontal cortex (OFC), and temporal cortex.ResultsAfter controlling for demographic (age, sex, education) and clinical variables (antidepressant use, anxiolytic use, duration of illness, medical comorbidity, cognitive functioning), greater severity of anxiety symptoms was associated with lower GMV bilaterally in the insula, F(1,102) = 6.63, p = 0.01, and OFC, F(1,102) = 8.35, p = 0.005. By contrast, depressive symptom severity was significantly associated with lower bilateral insula volumes, F(1,102) = 6.43, p = 0.01, but not OFC volumes, F(1,102) = 5.37, p = 0.02.LimitationsLimitations include (1) the relatively mild nature of anxiety symptoms in our sample; (2) the cross-sectional research design, which prohibits inferences of directionality; (3) the relatively homogenous demographic of the sample, and (4) the exclusion of participants with significant psychiatric comorbidity, suicidality, or cognitive impairment.ConclusionsDecreased OFC volumes may serve as a unique biomarker of anxiety symptoms in LLD. Future longitudinal and clinical studies with long-term follow up and more diverse samples will help further elucidate the biological, psychological, and social factors affecting associations between anxiety and brain morphology in LLD.

ABSTRACTBackground:Traditional perspectives conceptualize resilience as a trait and depression as resulting from resilience deficiency. However, research indicates that resilience varies substantially even among adults who are clinically depressed, as well as across the lifespan of an individual. Few studies have investigated resilience in depression, and even fewer have examined resilience in depressed older adults. METHODS:Three hundred thirty-seven adults ≥60 years with major depressive disorder completed the Connor-Davidson Resilience Scale (CD-RISC) and measures of mental health, quality of life (QOL), and medical comorbidity. Exploratory factor analysis was used to explore the factor structure of the CD-RISC. Correlations and general linear models were used to examine associations between resilience and other variables. RESULTS:The rotated component matrix indicated a four-factor model. Sorting of items by highest factor loading revealed constructs associated with (1) grit, (2) active coping self-efficacy, (3) accommodative coping self-efficacy, and (4) spirituality. Resilience was significantly correlated with increased age, lower cognitive functioning, greater cerebrovascular risk, and greater medical comorbidity. Resilience was negatively associated with mental health symptoms (depression, apathy, and anxiety) and positively associated with QOL. The final optimal model identified less depression, less apathy, greater medical comorbidity, higher QOL, and minority (non-White) race as factors that significantly explained variability in resilience. CONCLUSIONS:Resilience was significantly associated with a range of mental health constructs in a sample of older adults with depression. Future clinical trials and dismantling studies may help determine whether interventions targeting grit, active coping, accommodative coping, and spirituality can increase resilience and help prevent and treat depression in older adults.

ObjectivesWith the world population rapidly aging, it is increasingly important to identify sociodemographic, cognitive, and clinical features that predict poor outcome in geriatric depression. Self-report measures of resilience-ie, the ability to adapt and thrive in the face of adversity-may identify those depressed older adults with more favorable prognoses.MethodsWe investigated the utility of baseline variables including 4 factors of resilience (grit, active coping self-efficacy, accommodative coping self-efficacy, and spirituality) for predicting treatment response and remission in a 16-week randomized controlled trial of methylphenidate, citalopram, or their combination in 143 adults over the age of 60 with MDD.ResultsFinal logistic regression models revealed that greater total baseline resilience (Wald χ2  = 3.8, P = 0.05) significantly predicted both treatment response and remission. Specifically, a 20% increase in total resilience predicted nearly 2 times greater likelihood of remission (OR = 1.98, 95% CI = [1.01, 3.91]). Examining the individual factors of resilience, only accommodative coping self-efficacy (Wald χ2  = 3.7, P = 0.05; OR = 1.41 [1.00-2.01]) was significantly associated with remission. We found no relation between baseline sociodemographic factors (age, sex, race, education level) or measures of cognitive performance and posttreatment depressive symptoms.ConclusionsSelf-reported resilience may predict greater responsivity to antidepressant medication in older adults with MDD. Future research should investigate the potential for resilience training-and in particular, interventions designed to increase accommodative coping-to promote sustained remission of geriatric depression.

Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age=66.6+7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CB- group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42)=9.96, p=0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42)=23.17, p

BACKGROUND:Previous studies suggest that low emotional resilience may correspond with increased or over-active amygdala function. Complementary studies suggest that emotional resilience increases with age; older adults tend to have decreased attentional bias to negative stimuli compared to younger adults. Amygdala nuclei and related brain circuits have been linked to negative affect, and depressed patients have been demonstrated to have abnormal amygdala function. METHODS:In the current study, we correlated psychological resilience measures with amygdala function measured with resting-state arterial spin-labelled (ASL) and blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in older adults with and without depression. Specifically, we targeted the basolateral, centromedial, and superficial nuclei groups of the amygdala, which have different functions and brain connections. RESULTS:High levels of psychological resilience correlated with lower basal levels of amygdala activity measured with ASL fMRI. High resilience also correlated with decreased connectivity between amygdala nuclei and the ventral default-mode network independent of depression status. Instead, lower depression symptoms were associated with higher connectivity between the amygdalae and dorsal frontal networks. LIMITATIONS:Future multi-site studies with larger sample size and improved neuroimaging technologies are needed. Longitudinal studies that target resilience to naturalistic stressors will also be a powerful contribution to the field. CONCLUSIONS:Our results suggest that resilience in older adults is more closely related to function in ventral amygdala networks, while late-life depression is related to reduced connectivity between the amygdala and dorsal frontal regions.

OBJECTIVE:Greater psychological resilience may protect against developing depression in a growing geriatric population. Identifying the neural correlates of resilience in geriatric depression could provide neurobiologic targets to inform clinical interventions. However, most prior neuroimaging studies have only considered the presence or absence of resilience and have not addressed the multifactorial nature of resilience. The current study aimed to establish the neural correlates of four factors of resilience in the depressed elderly. METHODS:White matter integrity was assessed using diffusion-weighted magnetic resonance imaging data collected from 70 older adults with major depressive disorder. We used four resilience factors previously derived in an exploratory factor analysis of the Connor-Davidson Resilience Scale in a large sample of depressed older adults: 1, grit; 2, active coping self-efficacy; 3, accommodative coping self-efficacy; and 4, spirituality. RESULTS:The resilience factor "grit" was positively associated with fractional anisotropy in the callosal region connecting prefrontal cortex and fractional anisotropy in cingulum fibers; however, the latter did not survive correction for multiple comparisons. CONCLUSION:Structural integrity of major white matter pathways implicated in cognitive control and emotion regulation (i.e., connecting prefrontal cortex) was positively associated with the resilience factor "grit" in our sample of older adults with depression. Prospective studies are needed to determine the utility of the structural integrity of these pathways as a biomarker in predicting risk for depression and treatment response.

ObjectiveBecause curcumin's anti-inflammatory properties may protect the brain from neurodegeneration, we studied its effect on memory in non-demented adults and explored its impact on brain amyloid and tau accumulation using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET).MethodsForty subjects (age 51-84 years) were randomized to a bioavailable form of curcumin (Theracurmin® containing 90 mg of curcumin twice daily [N = 21]) or placebo (N = 19) for 18 months. Primary outcomes were verbal (Buschke Selective Reminding Test [SRT]) and visual (Brief Visual Memory Test-Revised [BVMT-R]) memory, and attention (Trail Making A) was a secondary outcome. FDDNP-PET signals (15 curcumin, 15 placebo) were determined in amygdala, hypothalamus, medial and lateral temporal, posterior cingulate, parietal, frontal, and motor (reference) regions. Mixed effects general linear models controlling for age and education, and effect sizes (ES; Cohen's d) were estimated.ResultsSRT Consistent Long-Term Retrieval improved with curcumin (ES = 0.63, p = 0.002) but not with placebo (ES = 0.06, p = 0.8; between-group: ES = 0.68, p = 0.05). Curcumin also improved SRT Total (ES = 0.53, p = 0.002), visual memory (BVMT-R Recall: ES = 0.50, p = 0.01; BVMT-R Delay: ES = 0.51, p = 0.006), and attention (ES = 0.96, p

BackgroundSeveral modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance.ObjectiveThe aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults.Methods55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention.ResultsThe SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96).ConclusionThese findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.

ObjectiveCognitive impairment associated with late-life depression can persist after remission of mood symptoms. Apathy, a common symptom of late-life depression, often leads to worse clinical outcomes. We examined if severity of apathy mediates cognitive difficulties in a cohort of older adults with major depression.MethodsOne hundred thirty-eight older adults with depression (54.4% female; mean [SD] age: 69.7 [7.4] years; mean [SD] education:15.6 [2.7] years) were recruited to participate in a treatment study, and only baseline data were analyzed. All participants received a comprehensive evaluation of depression, apathy, and cognition. We examined whether apathy mediated the relationship between depression and cognition, focusing our attention on memory and cognitive control. We then explored whether the mediation effects differed across women and men.ResultsIncreased apathy was significantly associated with worse depression and lower performance in the cognitive control domain but not in memory. Higher depressive scores were significantly associated with worse cognitive control but not memory. Mediation analyses revealed a significant indirect effect on cognitive control by depression through increased apathy scores with the mediator accounting for 21% of the total effect. Stratifying by sex, we found that women exhibited a significant indirect effect, with the mediator accounting for 47% of the total effect, whereas there was no mediation by apathy in men.ConclusionsThe findings imply that increased apathy mediates the relationship between cognition and depression. The identification of mediating effects may inform future treatment strategies and preventive interventions that can focus on decreasing apathy to improve cognition in late-life depression.

BackgroundOur group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls.ObjectiveTo compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI).MethodsFDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups.ResultsFDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02).ConclusionThis first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.