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 (39F, 29M) 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.

Preliminary validation of a structural magnetic resonance imaging metric for tracking dementia-related neurodegeneration and future decline.

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

Handgrip Strength Is Related to Hippocampal and Lobar Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden.

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.

Mild test anxiety influences neurocognitive performance among African Americans and European Americans: identifying interfering and facilitating sources.

The current study examined ethnic/racial differences in test-related anxiety and its relationship to neurocognitive performance in a community sample of African American (n = 40) and European American (n = 36) adults. The authors hypothesized the following: (a) Test-anxiety related to negative performance evaluation would be associated with lower neurocognitive performance, whereas anxiety unrelated to negative evaluation would be associated with higher neurocognitive performance. (b) African American participants would report higher levels of anxiety about negative performance evaluation than European Americans. (c) European Americans would report higher levels of anxiety unrelated to negative performance evaluation. The first two hypotheses were supported: Ethnic/racial differences in test-taking anxiety emerged such that African Americans reported significantly higher levels of negative performance evaluation, which was associated with lower cognitive performance. The third hypothesis was not supported: African Americans and European Americans reported similar levels of test-anxiety unrelated to negative evaluation.

Genetic, transcriptomic, and epigenetic studies of HIV-associated neurocognitive disorder.

The Human Genome Project, coupled with rapidly evolving high-throughput technologies, has opened the possibility of identifying heretofore unknown biological processes underlying human disease. Because of the opaque nature of HIV-associated neurocognitive disorder (HAND) neuropathogenesis, the utility of such methods has gained notice among NeuroAIDS researchers. Furthermore, the merging of genetics with other research areas has also allowed for application of relatively nascent fields, such as neuroimaging genomics, and pharmacogenetics, to the context of HAND. In this review, we detail the development of genetic, transcriptomic, and epigenetic studies of HAND, beginning with early candidate gene association studies and culminating in current "omics" approaches that incorporate methods from systems biology to interpret data from multiple levels of biological functioning. Challenges with this line of investigation are discussed, including the difficulty of defining a valid phenotype for HAND. We propose that leveraging known associations between biology and pathology across multiple levels will lead to a more reliable and valid phenotype. We also discuss the difficulties of interpreting the massive and multitiered mountains of data produced by current high-throughput omics assays and explore the utility of systems biology approaches in this regard.

The impact of neurobehavioral features on medication adherence in HIV: evidence from longitudinal models.

Effective antiretroviral therapy has led to substantial improvements in health-related outcomes among individuals with HIV. Despite advances in HIV pharmacotherapy, suboptimal medication adherence remains a significant barrier to successful treatment. Although several factors have been associated with medication adherence in the extant literature, study assessing the effects of some of the neurobehavioral features specific to HIV has been limited. Moreover, although there is a growing body of literature measuring medication adherence in HIV prospectively, few employ advanced statistical methodologies suited to handle advanced models with multiple predictors that would strengthen our understanding of medication adherence trajectories in HIV. This study sought to integrate traditionally assessed predictors of medication adherence with neurobehavioral features of HIV in a longitudinal study of medication adherence to combined antiretroviral therapy (cART). The current study used multilevel modeling to examine a wide arrangement of categories of factors - demographic, medication related, psychosocial, and neurobehavioral - on medication adherence. The sample consisted of 235 HIV+ individuals whose medication adherence was monitored over the course of six months using electronic monitoring devices. After controlling for the effects of demographic, medication, and psychosocial factors, neurobehavioral features added predictive validity to the model. In the final model, simultaneously controlling for the effects of each of the predictors within all the categories, age, self-efficacy, executive functioning, apathy, and frequency of stimulant use emerged as unique individual predictors of average medication adherence across the 6-month study. Self-efficacy and irritability predicted changes in medication adherence over time. Adherence behavior is multidetermined. Adequate assessment of these factors, combined with timely intervention, appears to be warranted in order to boost adherence rates.

The aggregate effects of multiple comorbid risk factors on cognition among HIV-infected individuals.

This study developed and then cross-validated a novel weighting algorithm based on multiple comorbid risk factors (stimulant use, vascular disease, hepatitis C, HIV disease severity, cognitive reserve) to predict cognitive functioning among 366 HIV+ adults. The resultant "risk severity score" was used to differentially weight, as a function of age, the impact and magnitude of multiple risk factors on cognition. Among older adults (≥50 years) the risk severity index was differentially predictive of learning/memory and verbal fluency, whereas among younger adults it was linked to working memory and executive function. Cognitive reserve was found to be the most robust predictor of neurocognition.

Apolipoprotein-E genotype and human immunodeficiency virus-associated neurocognitive disorder: the modulating effects of older age and disease severity.

BACKGROUND: The apolipoprotein-E (APOE) ε4 allele is a risk factor for vascular dementia and Alzheimer's disease. Recent studies are equivocal with regards to whether or not the ε4 allele confers increased risk for the development of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), but suggest that age and/or disease severity may be modulating factors. The aim of this study was to assess the interactions and contributions of APOE genotype, age, and HIV disease severity as risk factors for HAND in HIV-infected adults. METHODS: Participants were 259 HIV-positive individuals who underwent APOE genotyping, a standardized neurological evaluation, a comprehensive neuropsychological evaluation, and laboratory testing. RESULTS: Older ε4 carriers showed a higher frequency of HAND compared with age-matched non-ε4 carriers. Analysis by discrete neurocognitive domain revealed that advanced age modulated the effect of the ε4 allele, such that older ε4 allele carriers showed reduced executive functioning and information processing speed. Exploratory analyses assessing the relationship between ε4 and disease severity in the overall sample revealed that disease severity modulated the effect of the ε4 allele on cognition. Lower absolute CD4+ cell count among ε4 allele carriers was associated with poorer working memory ability. CONCLUSION: Advancing age and degree of immunosuppression may influence the association between APOE ε4 allele status and HAND. These two factors need to be taken into account in future research.

The role of HIV infection, cognition, and depression in risky decision-making.

The authors examined the impact of HIV, cognitive dysfunction, and depression on decision-making. HIV+ (N=100) and HIV- (N=26) participants were administered a comprehensive neuropsychological battery, a modified version of the Iowa Gambling Task, and a measure of depressive symptoms. HIV+ participants demonstrated more difficulties in learning the gambling task than did HIV- participants. Executive functioning and depression emerged as strong predictors of gambling task performance. Depression partially mediated the relationship between executive functioning and gambling performance. Our findings suggest that HIV infection, executive dysfunction, and depression place individuals at risk for poor decision-making.

Differential predictors of medication adherence in HIV: findings from a sample of African American and Caucasian HIV-positive drug-using adults.

Modest or even occasional nonadherence to combined antiretroviral therapy (cART) can result in adverse clinical outcomes. African Americans demonstrate lower rates of adherence than Caucasians or Latinos. Identifying factors that influence medication adherence among African Americans is a critical step toward reducing HIV/AIDS disease progression and mortality. In a sample of 181 African American (n=144) and Caucasian (n=37) HIV-positive drug-using individuals [age (M=42.31; SD=6.6) education (M=13.41; SD=2.1)], we examined the influence of baseline drug use, literacy, neurocognition, depression, treatment-specific social support, and patient satisfaction with health care provider on medication adherence averaged over the course of 6 months (study dates 2002-2006). Our findings suggest differential baseline predictors of medication adherence for African Americans and Caucasians, such that patient satisfaction with provider was the strongest predictor of follow-up medication adherence for African Americans whereas for Caucasians depressive symptoms and treatment-specific social support were predictive of medication adherence (after controlling for duration of drug use).

Basal ganglia structures differentially contribute to verbal fluency: evidence from Human Immunodeficiency Virus (HIV)-infected adults.

BACKGROUND: The basal ganglia (BG) are involved in executive language functions (i.e., verbal fluency) through their connections with cortical structures. The caudate and putamen receive separate inputs from prefrontal and premotor cortices, and may differentially contribute to verbal fluency performance. We examined BG integrity in relation to lexico-semantic verbal fluency performance among older HIV infected adults. METHOD: 20 older (50+ years) HIV+ adults underwent MRI and were administered measures of semantic and phonemic fluency. BG (caudate, putamen) regions of interest were extracted. RESULTS: Performance on phonemic word generation significantly predicted caudate volume, whereas performance on phonemic switching predicted putamen volume. CONCLUSIONS: These findings suggest a double dissociation of BG involvement in verbal fluency tasks with the caudate subserving word generation and the putamen associated with switching. As such, verbal fluency tasks appear to be selective to BG function.