Diagnostic utility of brain MRI volumetry in comparing traumatic brain injury, Alzheimer disease and behavioral variant frontotemporal dementia.

BACKGROUND: Brain MRI with volumetric quantification, MRI volumetry, can improve diagnostic delineation of patients with neurocognitive disorders by identifying brain atrophy that may not be evident on visual assessments. OBJECTIVE: To investigate diagnostic utility of MRI volumetry in traumatic brain injury (TBI), early-onset Alzheimer disease (EOAD), late-onset Alzheimer disease, and behavioral variant frontotemporal dementia (bvFTD). METHOD: We utilized 137 participants of TBI (n = 40), EOAD (n = 45), LOAD (n = 32), and bvFTD (n = 20). Participants had 3D T1 brain MRI imaging amendable to MRI volumetry. Scan volumes were analyzed with Neuroreader. One-way ANOVA compared brain volumes across diagnostic groups. Discriminant analysis was done with leave-one-out cross validation on Neuroreader metrics to determine diagnostic delineation across groups. RESULT: LOAD was the oldest compared to other groups (F = 27.5, p < .001). There were no statistically significant differences in sex (p = .58) with women comprising 54.7% of the entire cohort. EOAD and LOAD had the lowest Mini-Mental State Exam (MMSE) scores compared to TBI (p = .04 for EOAD and p = .01 for LOAD). LOAD had lowest hippocampal volumes (Left Hippocampus F = 13.1, Right Hippocampus F = 7.3, p < .001), low white matter volume in TBI (F = 5.9, p < .001), lower left parietal lobe volume in EOAD (F = 9.4, p < .001), and lower total gray matter volume in bvFTD (F = 32.8, p < .001) and caudate atrophy (F = 1737.5, p < .001). Areas under the curve ranged from 92.3 to 100%, sensitivity between 82.2 and 100%, specificity of 78.1-100%. TBI was the most accurately delineated diagnosis. Predictive features included caudate, frontal, parietal, temporal lobar and total white matter volumes. CONCLUSION: We identified the diagnostic utility of regional volumetric differences across multiple neurocognitive disorders. Brain MRI volumetry is widely available and can be applied in distinguishing these disorders.

Neuroinflammation: A Modifiable Pathway Linking Obesity, Alzheimer's disease, and Depression.

Obesity, depression and Alzheimer's disease (AD) are three major interrelated modern health conditions with complex relationships. Early-life depression may serve as a risk factor for AD, while late-life depression may be a prodrome of AD. Depression affects approximately 23% of obese individuals, and depression itself raises the risk of obesity by 37%. Mid-life obesity independently increases AD risk, while late-life obesity, particularly metabolically healthy obesity, may offer protection against AD pathology. Chronic inflammation serves as a key mechanism linking obesity, AD, and depression, encompassing systemic inflammation from metabolic disturbances, immune dysregulation through the gut microbiome, and direct interactions with amyloid pathology and neuroinflammation. In this review, we explore the biological mechanisms of neuroinflammation in relation to obesity, AD, and depression. We assess the efficacy of therapeutic interventions targeting neuroinflammation and discuss current and future radiological imaging initiatives for studying neuroinflammation. By comprehending the intricate interplay among depression, obesity, and AD, especially the role of neuroinflammation, we can advance our understanding and develop innovative strategies for prevention and treatment.

Sleep quality, neurocognitive performance, and memory self-appraisal in middle-aged and older adults with memory complaints.

OBJECTIVE: Because 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. DESIGN: A cross-sectional study involving analysis of baseline data, collected as part of a clinical trial. MEASUREMENTS: Two 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). RESULTS: Total 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. CONCLUSIONS: Sleep 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.

Pharmacogenetic Decision Support Tools: A New Paradigm for Late-Life Depression?

Clinicians still employ a "trial-and-error" approach to optimizing treatment regimens for late-life depression (LLD). With LLD affecting a significant and growing segment of the population, and with only about half of older adults responsive to antidepressant therapy, there is an urgent need for a better treatment paradigm. Pharmacogenetic decision support tools (DSTs), which are emerging technologies that aim to provide clinically actionable information based on a patient's genetic profile, offer a promising solution. Dozens of DSTs have entered the market in the past 15 years, but with varying level of empirical evidence to support their value. In this clinical review, we provide a critical analysis of the peer-reviewed literature on DSTs for major depression management. We then discuss clinical considerations for the use of these tools in treating LLD, including issues related to test interpretation, timing, and patient perspectives. In adult populations, newer generation DSTs show promise for the treatment of major depression. However, there are no primary clinical trials in LLD cohorts. Independent and comparative clinical trials are needed.

In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults.

OBJECTIVE: Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. METHODS: Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. RESULTS: Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP and poorer cognitive performance. CONCLUSIONS: By suggesting a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders.

Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month Trial.

OBJECTIVE: Because 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). METHODS: Forty 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. RESULTS: SRT 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 < 0.0001) compared with placebo (ES = 0.28, p = 0.1; between-group: ES = 0.67, p = 0.04). FDDNP binding decreased significantly in the amygdala with curcumin (ES = -0.41, p = 0.04) compared with placebo (ES = 0.08, p = 0.6; between-group: ES = 0.48, p = 0.07). In the hypothalamus, FDDNP binding did not change with curcumin (ES = -0.30, p = 0.2), but increased with placebo (ES = 0.26, p = 0.05; between-group: ES = 0.55, p = 0.02). CONCLUSIONS: Daily oral Theracurmin may lead to improved memory and attention in non-demented adults. The FDDNP-PET findings suggest that symptom benefits are associated with decreases in amyloid and tau accumulation in brain regions modulating mood and memory.

In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-ß] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

Hippocampal thinning linked to longer TOMM40 poly-T variant lengths in the absence of the APOE ε4 variant.

INTRODUCTION: The translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with apolipoprotein E (APOE), has received attention more recently as a promising gene in Alzheimer's disease (AD) risk. TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. METHODS: In this study, we examined the effects of TOMM40 using high-resolution magnetic resonance imaging in 65 healthy, older subjects with and without the APOE ε4 AD-risk variant. RESULTS: Examining individual subregions within the MTL, we found a significant relationship between increasing poly-T lengths of the TOMM40 variant and thickness of the entorhinal cortex only in subjects who did not carry the APOE ε4 allele. DISCUSSION: Our data provide support for TOMM40 variant repeat length as an important contributor to AD-like MTL pathology in the absence of APOE ε4.

Progressive Focal Gray Matter Volume Loss in a Former High School Football Player: A Possible Magnetic Resonance Imaging Volumetric Signature for Chronic Traumatic Encephalopathy.

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE.

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints.

OBJECTIVE: Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP). METHODS: Volunteers (N = 44; mean age: 62.6 ± 10.7 years) with subjective memory impairment (N = 24) or mild cognitive impairment (MCI; N = 20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer disease-associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET. RESULTS: MCI subjects with above normal BMI (>25) had higher FDDNP-PET binding compared with those with normal BMI (1.11(0.03) versus 1.08(0.03), ES = 1.04, t(35) = 3.3, p = 0.002). Greater physical activity was associated with lower FDDNP-PET binding in MCI subjects (1.07(0.03) versus 1.11(0.03), ES = 1.13, t(35) = -3.1, p = 0.004) but not in subjects with subjective memory impairment (1.07(0.03) versus 1.07(0.03), ES = 0.02, t(35) = -0.1, p = 0.9). Healthier diet related to lower FDDNP-PET binding, regardless of cognitive status (1.07(0.03) versus 1.09(0.02), ES = 0.72, t(35) = -2.1, p = 0.04). CONCLUSION: These preliminary findings are consistent with a relationship between risk modifiersand brain plaque/tangle deposition in nondemented individuals and supports maintenance of normal body weight, regular physical activity, and healthy diet to protect the brain during aging. (clinicaltrials.gov; NCT00355498).

Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies.

The role of the endogenous apelin system in pregnancy is not well understood. Apelin's actions in pregnancy are further complicated by the expression of multiple forms of the peptide. Using radioimmunoassay (RIA) alone, we established the expression of apelin content in the chorionic villi of preeclamptic (PRE) and normal pregnant women (NORM) at 36-38 wk of gestation. Total apelin content was lower in PRE compared with NORM chorionic villi (49.7±3.4 vs. 72.3±9.8 fmol/mg protein; n=20-22) and was associated with a trend for lower preproapelin mRNA in the PRE. Further characterization of apelin isoforms by HPLC-RIA was conducted in pooled samples from each group. The expression patterns of apelin peptides in NORM and PRE villi revealed little or no apelin-36 or apelin-17. Pyroglutamate apelin-13 [(Pyr1)-apelin-13] was the predominant form of the peptide in NORM and PRE villi. Angiotensin-converting enzyme 2 (ACE2) activity was higher in PRE villi (572.0±23.0 vs. 485.3±24.8 pmol·mg(-1)·min(-1); n=18-22). A low dose of ANG II (1 nM; 2 h) decreased apelin release in NORM villous explants that was blocked by the ANG II receptor 1 (AT1) antagonist losartan. Moreover, losartan enhanced apelin release above the 2-h baseline levels in both NORM and PRE villi (P<0.05). In summary, these studies are the first to demonstrate the lower apelin content in human placental chorionic villi of PRE subjects using quantitative RIA. (Pyr1)-apelin-13 is the predominant form of endogenous apelin in the chorionic villi of NORM and PRE. The potential mechanism of lower apelin expression in the PRE villi may involve a negative regulation of apelin by ANG II.

Psychological well-being and regional brain amyloid and tau in mild cognitive impairment.

OBJECTIVES: To determine whether psychological well-being in people with mild cognitive impairment (MCI), a risk state for Alzheimer disease (AD), is associated with in vivo measures of brain pathology. METHODS: Cross-sectional clinical assessments and positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles, were performed on middle-aged and older adults at a university research institute. Volunteers were aged 40-85 years with MCI (N = 35) or normal cognition (N = 29) without depression or anxiety. Statistical analyses included general linear models, using regional FDDNP-PET binding values as dependent variables and the Vigor-Activity subscale of the Profile of Mood States (POMS) as the independent variable, covarying for age. The POMS is a self-rated inventory of 65 adjectives that describe positive and negative feelings. RESULTS: Scores on the POMS Vigor-Activity subscale were inversely associated with degree of FDDNP binding in the posterior cingulate cortex (r = -0.35, p = 0.04) in the MCI group but not in the control group. CONCLUSION: Psychological well-being, as indicated by self-reports of greater vigor and activity, is associated with lower FDDNP-PET binding in the posterior cingulate cortex, a region involved in emotional regulation, in individuals with MCI but not in those with normal cognition. These findings are consistent with previous work indicating that deposition of brain amyloid plaques and tau tangles may result in noncognitive and cognitive symptoms in persons at risk for AD.

The impact of physical exercise on hippocampal atrophy in mild cognitive impairment and Alzheimer's disease: a meta-analysis.

Physical activity (PA) is a promising therapeutic for Alzheimer's disease (AD). Only a handful of meta-analyses have studied the impact of PA interventions on regional brain volumes, and none to date has solely included studies on effect of PA on regional brain volumes in individuals with cognitive impairment (CI). In this meta-analysis, we examined whether there is support for the hypothesis that PA interventions positively impact hippocampal volume (HV) in individuals with CI. We also assessed whether the level of CI [mild CI (MCI) vs. AD] impacted this relationship. We identified six controlled trials that met inclusion criteria. These included 236 participants with AD, MCI, or preclinical AD. Data were extracted and analyzed following Cochrane guidelines. We used a random-effects model to estimate the mean change in HV pre- and post-exercise intervention. Forest plots, Hedges' g funnel plots, and Egger's test were used to assess unbiasedness and visualize intervention effects, and Tau 2 , Cochran's Q, and I 2 were calculated to assess heterogeneity. The primary analysis revealed a significant positive effect of PA on total HV. However, sub-group analyses indicated a significant preservation of HV only in individuals with MCI, but not in those with AD. Egger's test indicated no evidence of publication bias. Subgroup analyses also revealed significant heterogeneity only within the MCI cohort for the total and left HV. PA demonstrated a moderate, significant effect in preserving HV among individuals with MCI, but not AD, highlighting a therapeutic benefit, particularly in earlier disease stages.

Lifestyle intervention improves cognition and quality of life in persons with early Multiple Sclerosis.

BACKGROUND: Lifestyle changes have been demonstrated to impact pathophysiology in Multiple Sclerosis (MS). Various diet and exercise protocols have been reported to improve symptoms and function in persons with MS. Evidence is accumulating that interventions as early as possible in the disease course are warranted. The objective of this study was to investigate the effect of a remotely delivered lifestyle program focusing on specific diet and exercise recommendations in persons with early MS. METHODS: MS patients, with disease diagnosis no more than 2 years prior, were recruited from the patient population of the MS clinic of the Pacific Neuroscience Institute. Participants followed recommendations for diet and exercise delivered via remote heath coaching. Each participant received 6 sessions with a health coach over a 12-week period. They were given parameters of a Mediterranean-type diet to follow, and specific and individualized recommendations about duration, intensity and type of exercise and physical activity. Outcome measures included Quality of Life (QOL), cognition (Symbol Digit Modalities Test, SDMT), fatigue (Multiple Sclerosis Fatigue Impact Scale, MFIS), fitness (estimated with Metabolic equivalents, METS) and other objective and patient reported outcomes (PRO). Changes in outcomes were analyzed using mixed effects general linear models and standardized pre-post differences.(Cohen's d) RESULTS: Fifteen persons with early (≤ 2 years) MS enrolled in the study, 14 of whom completed the study. We observed significant improvements in QOL (p = 0.02), SDMT (p = 0.006), fatigue(p = 0.005), fitness (p = 0.04), and other PRO and objective metrics at the end of the protocol compared to baseline. Adherence and patient satisfaction measures were high. CONCLUSIONS: Specific and individualized lifestyle recommendations can be effectively delivered remotely, and may produce improvement in symptoms and function in persons with early MS. Larger controlled trials of these interventions are warranted.

Data leakage in deep learning studies of translational EEG.

A growing number of studies apply deep neural networks (DNNs) to recordings of human electroencephalography (EEG) to identify a range of disorders. In many studies, EEG recordings are split into segments, and each segment is randomly assigned to the training or test set. As a consequence, data from individual subjects appears in both the training and the test set. Could high test-set accuracy reflect data leakage from subject-specific patterns in the data, rather than patterns that identify a disease? We address this question by testing the performance of DNN classifiers using segment-based holdout (in which segments from one subject can appear in both the training and test set), and comparing this to their performance using subject-based holdout (where all segments from one subject appear exclusively in either the training set or the test set). In two datasets (one classifying Alzheimer's disease, and the other classifying epileptic seizures), we find that performance on previously-unseen subjects is strongly overestimated when models are trained using segment-based holdout. Finally, we survey the literature and find that the majority of translational DNN-EEG studies use segment-based holdout. Most published DNN-EEG studies may dramatically overestimate their classification performance on new subjects.

Neurocognitive Effects of an Online Brain Health Program and Weekly Telehealth Support Group in Older Adults with Subjective Memory Loss: A Pilot Study.

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 (Cohen's 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.

Exercise-Related Physical Activity Relates to Brain Volumes in 10,125 Individuals.

BACKGROUND: The potential neuroprotective effects of regular physical activity on brain structure are unclear, despite links between activity and reduced dementia risk. OBJECTIVE: To investigate the relationships between regular moderate to vigorous physical activity and quantified brain volumes on magnetic resonance neuroimaging. METHODS: A total of 10,125 healthy participants underwent whole-body MRI scans, with brain sequences including isotropic MP-RAGE. Three deep learning models analyzed axial, sagittal, and coronal views from the scans. Moderate to vigorous physical activity, defined by activities increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes via partial correlations. Analyses adjusted for age, sex, and total intracranial volume, and a 5% Benjamini-Hochberg False Discovery Rate addressed multiple comparisons. RESULTS: Participant average age was 52.98±13.04 years (range 18-97) and 52.3% were biologically male. Of these, 7,606 (75.1%) reported engaging in moderate or vigorous physical activity approximately 4.05±3.43 days per week. Those with vigorous activity were slightly younger (p < 0.00001), and fewer women compared to men engaged in such activities (p = 3.76e-15). Adjusting for age, sex, body mass index, and multiple comparisons, increased days of moderate to vigorous activity correlated with larger normalized brain volumes in multiple regions including: total gray matter (Partial R = 0.05, p = 1.22e-7), white matter (Partial R = 0.06, p = 9.34e-11), hippocampus (Partial R = 0.05, p = 5.96e-7), and frontal, parietal, and occipital lobes (Partial R = 0.04, p≤1.06e-5). CONCLUSIONS: Exercise-related physical activity is associated with increased brain volumes, indicating potential neuroprotective effects.

Beyond the hippocampus: Amygdala and memory functioning in older adults.

BACKGROUND: Medial temporal lobe atrophy has been linked to decline in neuropsychological measures of explicit memory function. While the hippocampus has long been identified as a critical structure in learning and memory processes, less is known about contributions of the amygdala to these functions. We sought to investigate the relationship between amygdala volume and memory functioning in a clinical sample of older adults with and without cognitive impairment. METHODS: A serial clinical sample of older adults that underwent neuropsychological assessment at an outpatient neurology clinic was selected for retrospective chart review. Patients were included in the study if they completed a comprehensive neuropsychological assessment within six months of a structural magnetic resonance imaging scan. Regional brain volumes were quantified using Neuroreader® software. Associations between bilateral hippocampal and amygdala volumes and memory scores, derived from immediate and delayed recall conditions of a verbal story learning task and a visual design reconstruction task, were examined using mixed-effects general linear models, controlling for total intracranial volume, scanner model, age, sex and education. Partial correlation coefficients, adjusted for these covariates, were calculated to estimate the strength of the association between volumes and memory scores. RESULTS: A total of 68 (39 F, 29 M) participants were included in the analyses, with a mean (SD) adjusted age of 80.1 (6.0) and educational level of 15.9 (2.5) years. Controlling for age, sex, education, and total intracranial volume, greater amygdala volumes were associated with better verbal and visual memory performance, with effect sizes comparable to hippocampal volume. No significant lateralized effects were observed. Partial correlation coefficients ranged from 0.47 to 0.33 (p<.001). CONCLUSION: These findings contribute to a growing body of knowledge identifying the amygdala as a target for further research in memory functioning. This highlights the importance of considering the broader functioning of the limbic system in which multiple subcortical structures contribute to memory processes and decline in older adults.

Candidate gene linkage approach to identify DNA variants that predispose to preterm birth.

BACKGROUND: The aim of this study was to identify genetic variants contributing to preterm birth (PTB) using a linkage candidate gene approach. METHODS: We studied 99 single-nucleotide polymorphisms (SNPs) for 33 genes in 257 families with PTBs segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses. RESULTS: Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (P = 0.0012) and CYP2E1 (P = 0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (P = 0.003), IGFBP3 (P = 0.006), DHCR7 (P = 0.009), and TRAF2 (P = 0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants. CONCLUSION: These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of PTB.

PET scanning of brain tau in retired national football league players: preliminary findings.

OBJECTIVE: Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP). METHODS: Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index. RESULTS: FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma. CONCLUSIONS: The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes.