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Background: Strength 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). Objective: To model the relationships between handgrip strength, mobility, and MRI volumetry. Methods: We 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. Results: Higher 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. Conclusion: Greater 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.

Current Alzheimer’s disease (AD) research has a major focus on validating and discovering noninvasive biomarkers that can detect AD, benchmark disease severity, and aid in testing the efficacy of interventions. Structural magnetic resonance imaging (sMRI) is a well-validated tool used in diagnosis and for monitoring disease progression in AD. Much of the sMRI literature centers around hippocampal and other medial temporal lobe structure atrophy, which are strongly associated with cognition and diagnosis. Because atrophy patterns are complex and vary by patient, researchers have made efforts to condense more brain information into validated metrics. Many of these methods use machine learning (ML), which can be difficult to interpret clinically, hampering clinical adoption. Here, we introduce a practical, clinically meaningful and interpretable index which we call an “AD-NeuroScore.” Our approach is automated and uses multiple regional brain volumes associated with cognitive decline. We used a modified Euclidean inspired distance function to calculate the differences between each participant and a cognitively normal (CN) older adult template, adjusting for intracranial volume, age, sex, and scanner model. Here we report validation results, including sensitivity to diagnosis (CN, mild cognitive impairment (MCI), and AD) and disease severity (Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Mini Mental State Exam (MMSE), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-11) in 929 older adults (mean age=72.7 years, SD=6.3, Range=55.1-91.5, 50% Female) drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. To determine if AD-NeuroScore might be predictive of disease progression, we assessed the relationship between the calculated AD-NeuroScore at baseline and change in both diagnosis and disease severity scores at 12, 24, 36, and 48-months. We performed additional validation in all analyses, benchmarking AD-NeuroScore against adjusted hippocampal volume (AHV). We found that AD-NeuroScore was significantly associated with diagnosis and all disease severity scores at baseline. Associations between AD-NeuroScore and disease severity (CDR-SB and ADAS-11) were significantly stronger than with AHV. Baseline AD-NeuroScore was also associated with change in diagnosis and changes in disease severity scores at all time points. Performance was equivalent, or in some cases superior, to AHV. These early validation results suggest that AD-NeuroScore has the potential to be a clinically meaningful biomarker for dementia.

To address whether differential regulation of the renin-angiotensin-aldosterone system occurs in pre-eclampsia, we performed an analysis of the time course of circulating and urinary profiles of the vasoconstrictor (Ang II) and the vasodilator [Ang-(1–7)] peptides in normal pregnant (NP) and pre-eclamptic (PE) women. Urine and plasma samples from 86 nulliparous women were collected prospectively; 67 subjects continued as NP and 19 developed PE. Subjects were enrolled prior to 12 weeks of gestation and plasma and spot urine samples were obtained throughout gestation. Control samples were obtained at 6 weeks postpartum (PP). Mean blood pressure (p

Background: Distinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention. Objective: We 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). Methods: Patients 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. Results: The 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). Conclusion: This 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.

Investigators report greater parietal tau deposition and alternate frontoparietal network involvement in early onset Alzheimer’s Disease (EOAD) with onset

Objective While behavioral risk factors for depression have been assessed in select samples, previous research is limited in addressing such correlates across the lifespan. To this end, we assessed the relationship between self-reported depression and four behavioral risk factors (smoking, obesity, limited physical activity, and less healthy diet) in a representative United States adult sample. Methods Data were drawn from 30,116 Gallup-Healthways survey respondents, and stratified according to younger (18–39), middle-aged (40–59), and older (60–99) adults. The survey included demographic information, questions relating to the four risk factors, and an item on self-reported depression. Weighted multivariable logistic regressions, controlling for sex, ethnicity, and socioeconomic variables, were used to calculate odds ratios (OR) and confidence intervals (CI) for each correlate. Results Sixteen percent of respondents endorsed a prior diagnosis of depression; 17% smoked; 26% were obese; 50% engaged in limited physical activity; and 41% had a less healthy diet. Smoking was most strongly associated with risk for depression (OR: 2.71, 95% CI [2.41–3.04], 1.81 [1.62–2.02] and 1.82 [1.55–2.15] for younger, middle-aged and older age groups, respectively), followed by obesity (OR = 1.65 [1.45-1.86], 1.54 [1.39–1.71], 1.67 [1.46–1.90]), limited physical activity (OR = 1.32 [1.18–1.48], 1.48 [1.35–1.66], 1.61 [1.41–1.82]), and a less healthy diet (OR = 1.20 [1.08–1.32], 1.21 [1.06–1.37] for middle-aged and older groups). Depression rates increased with the number of risk factors. Conclusion Behavioral risk factors are associated with an increased risk for depression across the lifespan with some variability according to age groups.

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

Introduction There is an urgent need to develop effective interventional treatments for people with Alzheimer's disease (AD). AD results from a complex multi‐decade interplay of multiple interacting dysfunctional biological systems that have not yet been fully elucidated. Epidemiological studies have linked several modifiable lifestyle factors with increased incidence for AD. Because monotherapies have failed to prevent or ameliorate AD, interventional studies should deploy multiple, targeted interventions that address the dysfunctional systems that give rise to AD. Methods This randomized controlled trial (RCT) will examine the efficacy of a 12‐month personalized, multimodal, lifestyle intervention in 60 mild cognitive impairment (MCI) and early stage AD patients (aged 50+, amyloid positivity). Both groups receive data‐driven, lifestyle recommendations designed to target multiple systemic pathways implicated in AD. One group receives these personalized recommendations without coaching. The other group receives personalized recommendations with health coaching, dietary counseling, exercise training, cognitive stimulation, and nutritional supplements. We collect clinical, proteomic, metabolomic, neuroimaging, and genetic data to fuel systems‐biology analyses. We will examine effects on cognition and hippocampal volume. The overarching goal of the study is to longitudinally track biological systems implicated in AD to reveal the dynamics between these systems during the intervention to understand differences in treatment response. Results We have developed and implemented a protocol for a personalized, multimodal intervention program for early AD patients. We began enrollment in September 2019; we have enrolled a third of our target (20 of 60) with a 95% retention and 86% compliance rate. Discussion This study presents a paradigm shift in designing multimodal, lifestyle interventions to reduce cognitive decline, and how to elucidate the biological systems being targeted. Analytical efforts to explain mechanistic or causal underpinnings of individual trajectories and the interplay between multi‐omic variables will inform the design of future hypotheses and development of effective precision medicine trials.

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.

BACKGROUND Bilingualism is increasingly recognized as protective in persons at risk for Alzheimer's disease (AD). OBJECTIVE Compare MRI measured brain volumes in matched bilinguals versus monolinguals with AD. METHODS This IRB approved study analyzed T1 volumetric brain MRIs of patients with criteria-supported Probable AD. We identified 17 sequential bilinguals (any native language) with Probable AD, matched to 28 (62%) monolinguals on age and MMSE. Brain volumes were quantified with Neuroreader. Regional volumes as fraction of total intracranial volume (TIV) were compared between both groups, and Cohen's D effect sizes were calculated for statistically significant structures. Partial correlations between bilingualism and brain volumes adjusted for age, gender, and TIV. RESULTS Bilinguals had higher brain volumes in 37 structures. Statistical significance (p

To address whether differential regulation of the renin-angiotensin-aldosterone system occurs in pre-eclampsia, we performed an analysis of the time course of circulating and urinary profiles of the vasoconstrictor (Ang II) and the vasodilator [Ang-(1-7)] peptides in normal pregnant (NP) and pre-eclamptic (PE) women.Urine and plasma samples from 86 nulliparous women were collected prospectively; 67 subjects continued as NP and 19 developed PE. Subjects were enrolled prior to 12 weeks of gestation and plasma and spot urine samples were obtained throughout gestation. Control samples were obtained at 6 weeks postpartum (PP).Mean blood pressure (p 0.001) was elevated at 31-37 weeks of gestation in PE subjects as compared with NP subjects. Plasma Ang I and Ang II levels were elevated in NP subjects as early as 16 weeks of gestation and maintained throughout gestation. In PE subjects both plasma Ang I and Ang II were elevated at 16-33 weeks as compared with PP levels. PE subjects showed reduced plasma Ang I and Ang II (at 35-37 weeks of gestation) compared with NP subjects. Plasma Ang-(1-7) was unchanged in both groups. All three urinary peptides increased throughout gestation in NP subjects. In PE subjects urinary Ang I was increased at 23-26 weeks and was maintained throughout gestation. Urinary Ang II was increased at 27-29 and 31-33 weeks of gestation. PE subjects had no change in urinary Ang-(1-7).The activation of the RAS, particularly Ang II throughout normal gestation may contribute to the maintenance of vascular tone during normal pregnancy. However higher sensitivity to Ang II in pre-eclampsia may be potentiated by the higher circulating and urinary levels of Ang II, unopposed by local renal Ang-(1-7), and thus may contribute to the development of pre-eclampsia.

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 fifteen 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. There are no primary clinical trials in LLD cohorts. However, in adult populations, newer generation DSTs show promise for the treatment of major depression. Further independent and head-to-head clinical trials are required to further validate this field.

Author(s): Siddarth, Prabha; Rahi, Berna; Emerson, Natacha D; Burggren, Alison C; Miller, Karen J; Bookheimer, Susan; Lavretsky, Helen; Dobkin, Bruce; Small, Gary; Merrill, David A | Abstract: BackgroundPhysical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited.ObjectiveTo examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints.MethodsTwenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with g4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups.ResultsTwenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups.ConclusionOlder non-demented individuals complaining of memory loss who walked g4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy.

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 (η 2 = 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.

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 e4 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 e4 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 e4.

Background Several 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. Objective The 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. Methods 55 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. Results The 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). Conclusion These 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.

Background While traumatic brain injury (TBI) is recognized as a risk factor for dementia, there is lack of clinical tools to identify brain changes that may confer such vulnerability. Brain MRI volumetric quantification can sensitively identify brain atrophy. Objective To characterize regional brain volume loss in persons with TBI presenting with cognitive impairment. Methods IRB approved review of medical records in patients with cognitive decline focused on those who had documented TBI histories and brain MRI scans after TBI (n = 40, 67.7±14.5 years) with volumetric quantification by applying an FDA cleared software program. TBI documentation included head trauma mechanism. Brain volumes were compared to a normative database to determine the extent of atrophy. Correlations between these regions and global tests of cognition (MMSE in n = 17, MoCA in n = 27, n = 14 in both) were performed. Results Multiple regions demonstrated volume loss in TBI, particularly ventral diencephalon, putamen, and pallidum with smaller magnitude of atrophy in temporal lobes and brainstem. Lobar structures showed strongest correlations between atrophy and lower scores on MMSE and MoCA. The hippocampus, while correlated to tests of cognitive function, was the least atrophic region as a function of TBI history. Conclusion Persons with TBI history exhibit show regional brain atrophy. Several of these areas, such as thalamus and temporal lobes, also correlate with cognitive function. Alzheimer's disease atrophy was less likely given relative sparing of the hippocampi. Volumetric quantification of brain MRI in TBI warrants further investigation to further determine its clinical potential in TBI and differentiating causes of cognitive impairment.

To evaluate neonatal and maternal outcomes in obese pregnant women whose weight gain differed from the Institute of Medicine (IOM) recommendations. Maternal and neonatal outcomes associated with weight change in pregnancy were retrospectively investigated in women with obesity (body mass index (BMI) ⩾30 kg m−2; N=10734) who gave birth at 12 hospitals. Using a 1:1:1:1 design (n=778 matched groups), we matched women with obesity who lost, maintained, gained appropriate (IOM recommended) and gained excessive weight during pregnancy by gestational age at delivery, maternal age, race/ethnicity, prepregnancy BMI, chronic hypertension, pregestational diabetes and smoking status. Regression techniques were used to adjust for confounders and compare outcomes across weight change categories. Compared with IOM recommendations, weight loss was associated with twofold greater odds of low birth weight infants and a mean decrease in estimated blood loss of 30 ml; excessive weight gain was associated with doubled odds of gestational hypertension or preeclampsia, fourfold greater odds of macrosomia and a mean decrease in 5-min APGAR of 0.09. From lost to excessively gained weight, the odds of cesarean delivery increased 1.4 times and mean infant birth weight increased by 197 g. In contrast, the odds of small-for-gestational age were 1.8 times greater for women who lost than gained excessive weight. Weight loss in obese pregnant women is associated with increased risk for low birth weight neonates but significantly decreased or maintained risk for other maternal and neonatal morbidities, as compared with appropriate or excessive weight gain. This study supports re-evaluation of the current IOM guidelines for women with obesity.

Late-life depression (LLD) is a major depressive disorder that affects someone after the age of 60 years. LLD is frequently associated with inadequate response and remission from antidepressants, in addition to polypharmacy. Pharmacogenetics offers a promising approach to improve clinical outcomes in LLD via new discoveries determining the genetic basis of response rates and side effects, as well as the development of tailored pharmacogenetic-based decision support tools. This invited review evaluates the LLD pharmacogenetic evidence base and the extent to which this was incorporated into existing commercial decision support tools and clinical pharmacogenetic guidelines.

Author(s): Chen, Stephen T; Siddarth, Prabha; Merrill, David A; Martinez, Jacqueline; Emerson, Natacha D; Liu, Jie; Wong, Koon-Pong; Satyamurthy, Nagichettiar; Giza, Christopher C; Huang, Sung-Cheng; Fitzsimmons, Robert P; Bailes, Julian; Omalu, Bennet; Barrio, Jorge R; Small, Gary W | Abstract: 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 l 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.

© 2017 The Authors 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.

Physical activity (PA) is emerging as an effective tool in the prevention and treatment of major depression. Exercise immunology in psychiatry is a rapidly evolving field given advances in immunology and greater understanding of the clinical effects of PA. Understanding the immunology of PA is important for determining the unique immune signatures of various types of PA and determining if a precision medicine approach can be used to treat depression in certain patient cohorts. This chapter aims to explore the immune-modulatory effects of PA and to explore avenues for developing targeted treatment of depression using PA, based on the unique immune profile of a patient. There is some early evidence to suggest immune biomarkers can be used to improve outcomes in some populations of clinical depression.

Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (r(s) = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular–rotational acceleration–deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients.