Characterizing Neighborhood Vulnerabilities in Mild Cognitive Impairment using the Environmental Justice Index.

Background: There is a need for integration and comprehensive characterization of environmental determinants of Alzheimer's disease. The Environmental Justice Index (EJI) is a new measure that consolidates multiple environmental health hazards. Objective: This analysis aims to explore how environmental vulnerabilities vary by race/ethnicity and whether they predict cognitive outcomes in a clinical trial of mild cognitive impairment (MCI). Methods: We used data from a clinical trial of 107 MCI participants (28% minorities). Using the EJI, we extracted 40 measures of neighborhood environmental and social vulnerability including air and water pollution, access to recreational spaces, exposure to coal and lead mines, and area poverty. We also examined the relationship of the EJI to the Area Deprivation Index (ADI). Data was analyzed using regressions, correlations, and t-tests. Results: Environmental Burden Rank (EBR) across the sample (0.53±0.32) was near the 50th percentile nationally. When divided by race/ethnicity, environmental (p = 0.025) and social (p < 0.0001) vulnerabilities were significantly elevated for minorities, specifically for exposure to ozone, diesel particulate matter, carcinogenic air toxins, and proximity to treatment storage and disposal sites. ADI state decile was not correlated with the EBR. Neither EBR nor ADI were a significant predictor of cognitive decline. Conclusions: To our knowledge, this is the first study to link the EJI to an MCI trial. Despite limitations of a relatively small sample size, the study illustrates the potential of the EJI to provide deeper phenotyping of the exposome and diversity in clinical trial subjects.

Computerized Games versus Crosswords Training in Mild Cognitive Impairment.

BACKGROUND: Mild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in patients with MCI is unclear. METHODS: In a two-site, single-blinded, 78-week trial, participants with MCI - stratified by age, severity (early/late MCI), and site - were randomly assigned to 12 weeks of intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles, followed by six booster sessions. In mixed-model analyses, the primary outcome was change from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score, a 70 point scale in which higher scores indicate greater cognitive impairment at 78 weeks, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score, University of California San Diego Performance-Based Skills Assessment (functional outcome) score, and Functional Activities Questionnaire (functional outcome) score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed. RESULTS: Among 107 participants (n=51 [games]; n=56 [crosswords]), ADAS-Cog score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, -1.44; 95% confidence interval [CI], -2.83 to -0.06; P=0.04). From baseline to week 78, mean ADAS-Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, -2.45; SE, 0.89; 95% CI, -4.21 to -0.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, -1.08; 95% CI, -1.97 to -0.18). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI, 0.51 to 67.63 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04 [cortical thickness]). CONCLUSIONS: Home-based computerized training with crosswords demonstrated superior efficacy to games for the primary outcome of baseline-adjusted change in ADAS-Cog score over 78 weeks. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.).

Validity of the Web-Based, Self-Directed, NeuroCognitive Performance Test in Mild Cognitive Impairment.

BACKGROUND: Digital cognitive tests offer several potential advantages over established paper-pencil tests but have not yet been fully evaluated for the clinical evaluation of mild cognitive impairment. OBJECTIVE: The NeuroCognitive Performance Test (NCPT) is a web-based, self-directed, modular battery intended for repeated assessments of multiple cognitive domains. Our objective was to examine its relationship with the Alzheimer's Disease Assessment Scale-Cognition Subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) as well as with established paper-pencil tests of cognition and daily functioning in mild cognitive impairment (MCI). METHODS: We used Spearman correlations, regressions and principal components analysis followed by a factor analysis (varimax rotated) to examine our objectives. RESULTS: In MCI subjects, the NCPT composite is significantly correlated with both a composite measure of established tests (r = 0.78, p < 0.0001) as well as with the ADAS-Cog (r = -0.55, p < 0.0001). Both NCPT and paper-pencil test batteries had a similar factor structure that included a large "g" component with a high eigenvalue. The correlation for the analogous tests (e.g., Trails A and B, learning memory tests) were significant (p < 0.0001). Further, both the NCPT and established tests significantly (p < 0.0001) predicted the University of California San Diego Performance-Based Skills Assessment and Functional Activities Questionnaire, measures of daily functioning. CONCLUSION: The NCPT, a web-based, self-directed, computerized test, shows high concurrent validity with established tests and hence offers promise for use as a research or clinical tool in MCI. Despite limitations such as a relatively small sample, absence of control group and cross-sectional nature, these findings are consistent with the growing literature on the promise of self-directed, web-based cognitive assessments for MCI.

Evaluating Alzheimer Disease With Flortaucipir and Florbetapir PET: A Clinical Case Series.

ABSTRACT: Early, accurate diagnosis of Alzheimer disease (AD) is essential but remains challenging. Neuropathological hallmarks of AD are ß-amyloid neuritic plaques and tau protein neurofibrillary tangles. 18F-Florbetapir is one of several available PET tracers for imaging cortical fibrillary ß-amyloid plaques. 18F-Flortaucipir PET was recently approved for evaluating the distribution and density of aggregated neurofibrillary tangles. We present cases of mild cognitive impairment or suspected AD to depict the nuances of flortaucipir distribution and scan interpretation as well as how combined information from amyloid and tau PET may help with differential diagnosis and prognosis.

Modulation of a human memory circuit by subsyndromal depression in late life: a functional magnetic resonance imaging study.

OBJECTIVE: Functional deactivation of the posteromedial cortex (PMC) seems to be a physiologic process underlying normal memory. The authors examined whether older subjects with subsyndromal depressive symptoms show impaired PMC deactivation. DESIGN: Subjects underwent 4T functional magnetic resonance imaging scan while performing a novel and familiar face-name associative encoding task. The Beck-II Depression Inventory (BDI) was used to self-rate depression symptoms. A novel-minus-familiar encoding contrast was built into a simple regression model showing brain activation magnitudes that covaried with BDI score. A region-of-interest mask was applied to isolate the PMC and other midline structures of the default-mode network. SETTING: The study was conducted at a university-based medical center. PARTICIPANTS: Participants included 62 nondemented subjects aged 55-85, with and without mild memory deficits. BDI scores ranged from 0 to 17. RESULTS: Analysis revealed a distinct PMC cluster confined to the dorsal posterior cingulate cortex (BA 31) whose activity correlated significantly with BDI score. A multiple regression model further showed that BDI score, as well as a history of depression and current use of antidepressants, had a significant effect on cluster variance, while age, education, gender, and mini-mental state exam scores did not. CONCLUSIONS: Our findings raise the hypothesis that subsyndromal depressive symptoms in late life may impair physiological PMC deactivation in the dorsal posterior cingulate cortex. A prospective study of a full spectrum of depressed patients may be warranted.

Cognitive training and neuroplasticity in mild cognitive impairment (COG-IT): protocol for a two-site, blinded, randomised, controlled treatment trial.

INTRODUCTION: Mild cognitive impairment (MCI) is common in older adults and represents a high-risk group for progression to Alzheimer's disease (AD). Medication trials in MCI have generally failed, but new discoveries with brain plasticity in ageing have led to the study of cognitive training as a potential treatment to improve cognitive abilities. Computerised cognitive training (CCT) involves computerised cognitive exercises that target specific cognitive abilities and neural networks to potentially improve cognitive functioning through neuroplasticity. METHODS AND ANALYSIS: In a two-site study (New York State Psychiatric Institute/Columbia University Medical Center and Duke University Medical Center), we will randomise 100 patients with MCI (Wechsler Memory Scale-III Logical Memory II score 0-11; Folstein Mini Mental State Examination ≥23) to home-based CCT (suite of exercises: memory, matching, spatial recognition, processing speed) or a home-based active control condition (computerised crossword puzzle training (CPT)) with 12 weeks of intensive training followed by regular booster sessions up to 78 weeks. All patients will receive standard neuropsychological and functional assessments in clinic as well as structural/functional brain MRI scans at study entry and endpoint. We will test if CCT, versus CPT, leads to improved cognitive functioning, transfers to functional ability and tasks of everyday life and impacts hippocampal volume changes and changes in the default mode network of the brain measured by resting-state functional MRI. ETHICS AND DISSEMINATION: The study will be conducted following ethics approval and written informed consent will be obtained from all subjects. Study results will be disseminated via publication, clinicaltrials.gov, media and conference presentations. This will be the first controlled long-term trial to evaluate the effects of home-based CCT versus computerised CPT on cognitive abilities and functional measures and neural outcomes as determined by MRI indices in patients with MCI. Positive results from trial may support further development of home-based CCT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier (NCT03205709).

Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics.

BACKGROUND: The development of plasma biomarkers could facilitate early detection, risk assessment and therapeutic monitoring in Alzheimer's disease (AD). Alterations in ceramides and sphingomyelins have been postulated to play a role in amyloidogensis and inflammatory stress related neuronal apoptosis; however few studies have conducted a comprehensive analysis of the sphingolipidome in AD plasma using analytical platforms with accuracy, sensitivity and reproducibility. METHODS AND FINDINGS: We prospectively analyzed plasma from 26 AD patients (mean MMSE 21) and 26 cognitively normal controls in a non-targeted approach using multi-dimensional mass spectrometry-based shotgun lipidomics to determine the levels of over 800 molecular species of lipids. These data were then correlated with diagnosis, apolipoprotein E4 genotype and cognitive performance. Plasma levels of species of sphingolipids were significantly altered in AD. Of the 33 sphingomyelin species tested, 8 molecular species, particularly those containing long aliphatic chains such as 22 and 24 carbon atoms, were significantly lower (p<0.05) in AD compared to controls. Levels of 2 ceramide species (N16:0 and N21:0) were significantly higher in AD (p<0.05) with a similar, but weaker, trend for 5 other species. Ratios of ceramide to sphingomyelin species containing identical fatty acyl chains differed significantly between AD patients and controls. MMSE scores were correlated with altered mass levels of both N20:2 SM and OH-N25:0 ceramides (p<0.004) though lipid abnormalities were observed in mild and moderate AD. Within AD subjects, there were also genotype specific differences. CONCLUSIONS: In this prospective study, we used a sensitive multimodality platform to identify and characterize an essentially uniform but opposite pattern of disruption in sphingomyelin and ceramide mass levels in AD plasma. Given the role of brain sphingolipids in neuronal function, our findings provide new insights into the AD sphingolipidome and the potential use of metabolomic signatures as peripheral biomarkers.

Prognostic value of posteromedial cortex deactivation in mild cognitive impairment.

BACKGROUND: Normal subjects deactivate specific brain regions, notably the posteromedial cortex (PMC), during many tasks. Recent cross-sectional functional magnetic resonance imaging (fMRI) data suggests that deactivation during memory tasks is impaired in Alzheimer's disease (AD). The goal of this study was to prospectively determine the prognostic significance of PMC deactivation in mild cognitive impairment (MCI). METHODOLOGY/PRINCIPAL FINDINGS: 75 subjects (34 MCI, 13 AD subjects and 28 controls) underwent baseline fMRI scanning during encoding of novel and familiar face-name pairs. MCI subjects were followed longitudinally to determine conversion to AD. Regression and analysis of covariance models were used to assess the effect of PMC activation/deactivation on conversion to dementia as well as in the longitudinal change in dementia measures. At longitudinal follow up of up to 3.5 years (mean 2.5+/-0.79 years), 11 MCI subjects converted to AD. The proportion of deactivators was significantly different across all groups: controls (79%), MCI-Nonconverters (73%), MCI-converters (45%), and AD (23%) (p<0.05). Mean PMC activation magnitude parameter estimates, at baseline, were negative in the control (-0.57+/-0.12) and MCI-Nonconverter (-0.33+/-0.14) groups, and positive in the MCI-Converter (0.37+/-0.40) and AD (0.92+/-0.30) groups. The effect of diagnosis on PMC deactivation remained significant after adjusting for age, education and baseline Mini-Mental State Exam (p<0.05). Baseline PMC activation magnitude was correlated with change in dementia ratings from baseline. CONCLUSION: Loss of physiological functional deactivation in the PMC may have prognostic value in preclinical AD, and could aid in profiling subgroups of MCI subjects at greatest risk for progressive cognitive decline.

Effect of mirtazapine orally disintegrating tablets on health-related quality of life in elderly depressed patients with comorbid medical disorders: a pilot study.

BACKGROUND: There is a need for additional studies on the quality of life (QOL) of elderly depressed subjects with medical comorbidity. METHOD: We conducted a 10-week, open trial of mirtazapine orally disintegrating tablets in 16 elderly subjects with major depressive disorder and one or more serious medical illnesses. Quality of life was measured by the Medical Outcomes Study Short Form-36 Health Status Survey (SF- 36). RESULTS: Treatment with mirtazapine was associated with significant reductions in clinical global impressions-severity of illness scale (CGI-S) score, the Hamilton rating scale for anxiety (HAM-A) total score, the 17-item Hamilton rating scale for depression (HAM-D) total score and the Beck depression inventory (BDI) total scores. The SF-36 "physical functioning", "role limitation physical", "vitality", "social functioning", "role limitation emotional", and "mental health" domains improved significantly. The mean mirtazapine dose at endpoint was 35 mg per day. The drug was relatively well tolerated except for three subjects who dropped out because of side effects. No drug-drug interactions or significant changes in blood pressure or heart rate occurred. CONCLUSION: Mirtazapine orally disintegrating tablets may improve depression, insomnia, anxiety, somatic symptoms, and certain quality-of-life measures in elderly depressed subjects with medical disorders. A randomized, placebo-controlled study is warranted to confirm these promising findings.

A randomized controlled trial of paroxetine for noncardiac chest pain.

Noncardiac chest pain occurs frequently in medical practice and is often difficult to treat. We conducted a randomized double-blind, placebo-controlled, 8-week trial of paroxetine in 50 patients with noncardiac chest pain. None of the patients met criteria for panic disorder or major depression. Paroxetine-treated patients showed greater (P < .05) improvements than placebo-treated patients on the Clinical Global Impressions (CGI) scale. Both paroxetine and placebo-treated patients improved to a similar extent on selfrated pain measures, although baseline differences limited the interpretation of this outcome variable. There were no differences on other outcome ratings. Treatment was well tolerated. These preliminary findings extend other data on the potential of selective serotonin reuptake inhibitors for the acute treatment of noncardiac chest pain. Some recommendations for future studies to definitively test this potential are presented.