[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.
Full-text · Article · Jan 2016 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.
No preview · Article · Oct 2015 · Journal of Alzheimer's disease: JAD
[Show abstract][Hide abstract] ABSTRACT: Objective:
Depression is common, frequently resistant to antidepressant treatment, and associated with impairments in cognition and everyday functioning. Computerized cognitive training (CCT) paradigms offer potential to improve cognition, mood and everyday functioning, but their effectiveness is not well established. The goal of this article was to conduct a systematic review and meta-analysis to determine the efficacy of CCT in depressive disorders.
A search was conducted to identify high quality randomized controlled CCT trials per PRISMA guidelines using PsycINFO and MEDLINE with the keywords "Cognitive training" or "Cognitive remediation" or "Cognitive rehabilitation" and "Depression". 9 randomized trials for depressed adults met inclusion criteria. Effect sizes (Hedge's g) were calculated for key outcome measures of mood symptom severity, daily functioning, and cognition. A 3-level Bayesian hierarchical linear model was used to estimate effect sizes for each domain and study. Publication bias was assessed using Classic Fail Safe N's and homogeneity was evaluated using Q and I(2) indexes.
Significant small-moderate effects for Symptom Severity (0.43) and Daily Functioning (0.72), and moderate-large effects for Attention (0.67), Working Memory (0.72), and Global Functioning (1.05) were found. No significant effects were found for Executive Functioning or Verbal Memory. Moderator variable analysis revealed decreased effect of CCT with age. Gender and concurrent medication treatment did not affect the results.
Small sample size, short duration, pseudo-specificity, and high heterogeneity for Verbal Memory measures.
CCT is associated with improvement in depressive symptoms and everyday functioning, though produces inconsistent effects on cognition.
Full-text · Article · Oct 2015 · Journal of Affective Disorders
[Show abstract][Hide abstract] ABSTRACT: Introduction: We investigated whether event-related potentials (ERP) collected in outpatient settings and analyzed with standardized methods can provide a sensitive and reliable measure of the cognitive deficits associated with early Alzheimer's disease (AD). Methods: A total of 103 subjects with probable mild AD and 101 healthy controls were recruited at seven clinical study sites. Subjects were tested using an auditory oddball ERP paradigm. Results: Subjects with mild AD showed lower amplitude and increased latency for ERP features associated with attention, working memory, and executive function. These subjects also had decreased accuracy and longer reaction time in the target detection task associated with the ERP test. Discussion: Analysis of ERP data showed significant changes in subjects with mild AD that are consistent with the cognitive deficits found in this population. The use of an integrated hardware/software system for data acquisition and automated data analysis methods make administration of ERP tests practical in outpatient settings.
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) has been increasingly accepted as a major external risk factor for neurodegenerative morbidity and mortality. Recent evidence indicates that the resultant chronic neurobiological sequelae following head trauma may, at least in part, contribute to a pathologically distinct disease known as Chronic Traumatic Encephalopathy (CTE). The clinical manifestation of CTE is variable, but the symptoms of this progressive disease include impaired memory and cognition, affective disorders (i.e., impulsivity, aggression, depression, suicidality, etc.), and diminished motor control. Notably, mounting evidence suggests that the pathology contributing to CTE may be caused by repetitive exposure to subconcussive hits to the head, even in those with no history of a clinically evident head injury. Given the millions of athletes and military personnel with potential exposure to repetitive subconcussive insults and TBI, CTE represents an important public health issue. However, the incidence rates and pathological mechanisms are still largely unknown, primarily due to the fact that there is no in vivo diagnostic tool. The primary objective of this manuscript is to address this limitation and discuss potential neuroimaging modalities that may be capable of diagnosing CTE in vivo through the detection of tau and other known pathological features. Additionally, we will discuss the challenges of TBI research, outline the known pathology of CTE (with an emphasis on Tau), review current neuroimaging modalities to assess the potential routes for in vivo diagnosis, and discuss the future directions of CTE research.
Full-text · Article · Sep 2015 · Frontiers in Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Introduction:
This study examined whether, among subjects with mild cognitive impairment (MCI), women progressed at faster rates than men.
We examine longitudinal rates of change from baseline in 398 MCI subjects (141 Females, 257 Males) in the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1), followed for up to 8 years (mean 4.1±2.5 years) using mixed effects models incorporating all follow ups (mean 8±4 visits).
Women progressed at faster rates than men on ADAS-Cog (p=0.001) and CDR-SB (p=0.003). Quadratic fit for change over time was significant for both ADAS-Cog (p=0.001) and CDR-SB (p=0.004), and the additional acceleration in women was 100% for ADAS-Cog and 143% for CDR-SB. The variability of change was greater in women. The gender effect was greater in ApoE4 carriers.
Women with MCI have greater longitudinal rates of cognitive and functional progression than men. Studies to confirm and uncover potential mechanisms appear to be warranted.
[Show abstract][Hide abstract] ABSTRACT: The growing public threat of Alzheimer's disease (AD) has raised the urgency to discover and validate prognostic biomarkers in order to predicting time to onset of AD. It is anticipated that both whole genome single nucleotide polymorphism (SNP) data and high dimensional whole brain imaging data offer predictive values to identify subjects at risk for progressing to AD. The aim of this paper is to test whether both whole genome SNP data and whole brain imaging data offer predictive values to identify subjects at risk for progressing to AD. In 343 subjects with mild cognitive impairment (MCI) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI-1), we extracted high dimensional MR imaging (volumetric data on 93 brain regions plus a surface fluid registration based hippocampal subregion and surface data), and whole genome data (504,095 SNPs from GWAS), as well as routine neurocognitive and clinical data at baseline. MCI patients were then followed over 48 months, with 150 participants progressing to AD. Combining information from whole brain MR imaging and whole genome data was substantially superior to the standard model for predicting time to onset of AD in a 48-month national study of subjects at risk. Our findings demonstrate the promise of combined imaging-whole genome prognostic markers in people with mild memory impairment.
[Show abstract][Hide abstract] ABSTRACT: While overlapping neurobiological mechanisms are known, relatively little is known about how "self-control" and cognitive affective processing of rewards may also influence the bi-directional risk between obesity and depression. The objective of this study was to identify the extent to which "self-control," measured using a delay discounting task is co-related to BMI and Depression diagnostic thresholds. A within-subjects counterbalanced design was used in which 92 participants (Mean ± SD: BMI = 27.9 ± 3.5, HAMD = 14.7 ± 7.7) completed a series of clinical diagnostic, survey, and demographic questionnaires in a behavioral health laboratory setting. For the delay discounting task, participants chose between one large delayed reward and one successively smaller immediate reward for four food types (dessert, fried food, fruit, and vegetable). Results showed that delay discounting scores were predictive of BMI and depression with lower delay discounting scores associated with higher BMI and HAMD for the dessert (HAMD scores (β = -.197, p = .013), BMI (β = -.239, p < .001)) and fried food (HAMD scores (β = -.328, p = .001), BMI (β = -.166, p = .027)). Clinical significance was further evident when HAMD and BMI scores were converted to diagnostic thresholds. Only depression and/or atypical depressive symptoms were related to delay discounting scores with the fruit and vegetable. Thus, reduced cognitive affective self-control for impulsive food choices-particularly for "comfort foods" high in fat and sugar-appears to be a shared cognitive mechanism for both conditions perhaps contributing to the high prevalence of co-morbid mood disorders and weight gain.
[Show abstract][Hide abstract] ABSTRACT: A positive family history (FH) raises the risk for late-onset Alzheimer's disease though, other than the known risk conferred by apolipoprotein ε4 (ApoE4), much of the genetic variance remains unexplained. We examined the effect of family history on longitudinal regional brain atrophy rates in 184 subjects (42% FH+, mean age 79.9) with mild cognitive impairment (MCI) enrolled in a national biomarker study. An automated image analysis method was applied to T1-weighted MR images to measure atrophy rates for 20 cortical and subcortical regions. Mixed-effects linear regression models incorporating repeated-measures to control for within-subject variation over multiple time points tested the effect of FH over a follow-up of up to 48 months. Most of the 20 regions showed significant atrophy over time. Adjusting for age and gender, subjects with a positive FH had greater atrophy of the amygdala (p < 0.01), entorhinal cortex (p < 0.01), hippocampus (p < 0.053) and cortical gray matter (p < 0.009). However, when E4 genotype was added as a covariate, none of the FH effects remained significant. Analyses by ApoE genotype showed that the effect of FH on amygdala atrophy rates was numerically greater in ε3 homozygotes than in E4 carriers, but this difference was not significant. FH+ subjects had numerically greater 4-year cognitive decline and conversion rates than FH− subjects but the difference was not statistically significant after adjusting for ApoE and other variables. We conclude that a positive family history of AD may influence cortical and temporal lobe atrophy in subjects with mild cognitive impairment, but it does not have a significant additional effect beyond the known effect of the E4 genotype.
[Show abstract][Hide abstract] ABSTRACT: Objective: Cognitive impairment frequently accompanies major depressive disorder (MDD) and can persist during remission.This review examined pharmacotherapy effects on cognitive function in MDD. Data Sources: PubMed and EMBASE searches were conducted on July 30,2013, for English language reports of cognitive assessments following pharmacologic monotherapy or augmentation therapy in MDD. Study Selection: A total of 43 research reports were identified (31 monotherapy [8 placebo-controlled, 11 active-comparator, 12 open-label], 12 augmentation therapy [7 placebo-controlled, 5 open-label]). Data Extraction: Results reported in each publication were examined for open-label and placebo- or active comparator-controlled studies. Results: Studies varied widely in terms of size (median, 50 participants; interquartile range, 21-143 participants), populations examined, duration (median, 8 weeks; interquartile range, 6-12 weeks), and neurocognitive assessments used. Most individual studies reported some benefit to cognition with pharmacotherapy, but there was no pattern of response in specific domains and only 12% of individually analyzed changes favored active treatment over placebo or untreated healthy controls. Sample weighted mean effect sizes revealed that verbal memory improved with monotherapy, while the largest treatment effect with augmentation therapy was for visual memory. Conclusions: Pharmacotherapy may have benefit in reducing cognitive impairment in MDD, with augmentation therapy being a potential approach for addressing cognitive deficits that persist after monotherapy has brought about clinical response or remission. However, given the wide variability in study design and treatment duration across studies, these findings should be interpreted cautiously. More definitive research is required before firm conclusions can be reached.
Preview · Article · Jul 2014 · The Journal of Clinical Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Preimplantation genetic diagnosis (PGD) is an option for couples at risk of having offspring with an inherited debilitating or fatal neurological disorder who wish to conceive a healthy child. PGD has been carried out for conditions with various modes of inheritance, including spinal muscular atrophy, Huntington disease, fragile X syndrome, and chromosomal or mitochondrial disorders, and for susceptibility genes for cancers with nervous system involvement. Most couples at risk of transmitting a genetic mutation would opt for PGD over prenatal testing and possible termination of a pregnancy. The aim of this Perspectives article is to assist neurologists in counselling and treating patients who wish to explore the option of PGD to enable conception of an unaffected child. PGD can be accomplished for most disorders in which the genetic basis is known, and we argue that it is time for clinicians and neurological societies to consider the evidence and to formulate guidelines for the responsible integration of PGD into modern preventative neurology.
Full-text · Article · May 2014 · Nature Reviews Neurology
[Show abstract][Hide abstract] ABSTRACT: This study was designed to evaluate whether subjects with amyloid beta (Aβ) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aβ pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aβ+) or negative (Aβ-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aβ+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aβ+ MCI subjects demonstrated greater worsening compared with Aβ- subjects on the ADAS-Cog over 36 months (5.66±1.47 vs -0.71±1.09, P=0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P<0.05). Similar to MCI subjects, Aβ+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aβ+ AD patients showed greater declines in verbal fluency and the MMSE (P<0.05). Aβ+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aβ+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aβ+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aβ- subjects do.Molecular Psychiatry advance online publication, 11 March 2014; doi:10.1038/mp.2014.9.
Full-text · Article · Mar 2014 · Molecular Psychiatry