Problem alcohol use in veterans with mild traumatic brain injury: Associations with cognitive performance and psychiatric symptoms.

INTRODUCTION: Given that little is known about the associations between alcohol use, cognition, and psychiatric symptoms among veterans with a history of mild traumatic brain injury (mTBI), we aimed to (a) characterize how they differ from veteran controls on a measure of problem drinking; (b) investigate whether problem drinking is associated with demographic or mTBI characteristics; and (c) examine the associations between alcohol use, mTBI history, psychiatric functioning, and cognition. METHOD: We assessed 59 veterans (n = 32 with mTBI history; n = 27 military controls) for problem alcohol use (Alcohol Use Disorders Identification Test: AUDIT), psychiatric symptoms, and neuropsychological functioning. RESULTS: Compared to controls, veterans with mTBI history were more likely to score above the AUDIT cutoff score of 8 (p = .016), suggesting a higher rate of problem drinking. Participants with mTBI history also showed elevated psychiatric symptoms (ps < .001) and lower cognitive scores (ps < .05 to < .001). Veterans with higher AUDIT scores were younger (p = .05) and had less education (p < .01) and more psychiatric symptoms (ps < .01), but mTBI characteristics did not differ. After controlling for combat and mTBI history (R(2) = .04, ns) and posttraumatic stress disorder (PTSD) symptoms (ΔR(2) = .08, p = .05), we found that higher AUDIT scores were associated with poorer attention/processing speed, F(9, 37) = 2.55, p = .022; ΔR(2) = .26, p = .03. CONCLUSIONS: This preliminary study suggested that veterans with mTBI history may be at increased risk for problem drinking. Problem alcohol use was primarily associated with more severe PTSD symptoms and poorer attention/processing speed, though not with combat or mTBI characteristics per se. Importantly, findings emphasize the importance of assessing for and treating problematic alcohol use and comorbid psychiatric symptoms among veterans, including those with a history of neurotrauma.

White Matter Associations With Performance Validity Testing in Veterans With Mild Traumatic Brain Injury: The Utility of Biomarkers in Complicated Assessment.

OBJECTIVE: Failure on performance validity tests (PVTs) is common in Veterans with histories of mild traumatic brain injury (mTBI), leading to questionable validity of clinical presentations. PARTICIPANTS: Using diffusion tensor imaging, we investigated white matter (WM) integrity and cognition in 79 Veterans with history of mTBI who passed PVTs (n = 43; traumatic brain injury [TBI]-passed), history of mTBI who failed at least 1 PVT (n = 13; TBI-failed), and military controls (n = 23; MCs) with no history of TBI. RESULTS: The TBI-failed group demonstrated significantly lower cognitive scores relative to MCs and the TBI-passed group; however, no such differences were observed between MCs and the TBI-passed group. On a global measure of WM integrity (ie, WM burden), the TBI-failed group showed more overall WM abnormalities than the other groups. However, no differences were observed between the MCs and TBI-passed group on WM burden. Interestingly, regional WM analyses revealed abnormalities in the anterior internal capsule and cingulum of both TBI subgroups relative to MCs. Moreover, compared with the TBI-passed group, the TBI-failed group demonstrated significantly decreased WM integrity in the corpus callosum. CONCLUSIONS: Findings revealed that, within our sample, WM abnormalities are evident in those who fail PVTs. This study adds to the burgeoning PVT literature by suggesting that poor PVT performance does not negate the possibility of underlying WM abnormalities in military personnel with history of mTBI.

White Matter Microstructural Compromise Is Associated With Cognition But Not Posttraumatic Stress Disorder Symptoms in Military Veterans With Traumatic Brain Injury.

OBJECTIVE: To investigate white matter microstructure compromise in Veterans with a history of traumatic brain injury (TBI) and its possible contribution to posttraumatic stress disorder (PTSD) symptomatology and neuropsychological functioning via diffusion tensor imaging. PARTICIPANTS AND METHODS: Thirty-eight Veterans with mild (n = 33) and moderate (n = 5) TBI and 17 military control participants without TBI completed neuropsychological testing and psychiatric screening and underwent magnetic resonance imaging an average of 4 years following their TBI event(s). Fractional anisotropy (FA) and diffusivity measures were extracted from 9 white matter tracts. RESULTS: Compared with military control participants, TBI participants reported higher levels of PTSD symptoms and performed worse on measures of memory and psychomotor-processing speed. Traumatic brain injury was associated with lower FA in the genu of the corpus callosum and left cingulum bundle. Fractional anisotropy negatively correlated with processing speed and/or executive functions in 7 of the 8 tracts. Regional FA did not correlate with memory or PTSD symptom ratings. CONCLUSION: Results suggest that current PTSD symptoms are independent of TBI-related white matter alterations, as measured by diffusion tensor imaging. In addition, white matter microstructural compromise may contribute to reduced processing speed in our sample of participants with history of neurotrauma. Findings of the current study add insight into the factors associated with complicated recovery from mild to moderate TBI.

Validation of the Modified Fatigue Impact Scale in mild to moderate traumatic brain injury.

OBJECTIVE: To evaluate the validity of the Modified Fatigue Impact Scale (MFIS) in veterans with a history of mild to moderate traumatic brain injury (TBI). PARTICIPANTS: Veterans (N = 106) with mild (92%) or moderate (8%) TBI. SETTING: Veterans Administration Health System. PROCEDURE: Factor structure, internal consistency, convergent validity, sensitivity, and specificity of the MFIS were examined. RESULTS: Principal component analysis identified 2 viable MFIS factors: a Cognitive subscale and a Physical/Activities subscale. Item analysis revealed high internal consistency of the MFIS Total scale and subscale items. Strong convergent validity of the MFIS scales was established with 2 Beck Depression Inventory II fatigue items. Receiver operating characteristic curve analysis revealed good to excellent accuracy of the MFIS in classifying fatigued versus nonfatigued individuals. CONCLUSION: The MFIS is a valid multidimensional measure that can be used to evaluate the impact of fatigue on cognitive and physical functioning in individuals with mild to moderate TBI. The psychometric properties of the MFIS make it useful for evaluating fatigue and provide the potential for improving research on fatigue in this population.

Difficulty modifying a sustained motor response in prodromal Huntington's disease.

We investigated the nature of motor symptoms in the preclinical stage of Huntington's disease. Individuals with the CAG expanded repeat of Huntington's disease (prHD) and two control groups were tested on a task requiring a releasing movement (releasing a depressed button) followed by a ballistic movement (pressing a different button). Movement times were measured separately for releasing and ballistic movements. The mean reaction time of the prHD group was significantly longer when releasing a movement than that of the other groups. The groups, however, did not differ significantly on movement time for ballistic movements. Our results show that motor slowing is evident prior to the clinical diagnosis of Huntington's disease and may reflect difficulty in modifying a sustained motor program.

Functional interactions of HIV-infection and methamphetamine dependence during motor programming.

Methamphetamine (METH) dependence is frequently comorbid with HIV infection and both have been linked to alterations of brain structure and function. In a previous study, we showed that the brain volume loss characteristic of HIV infection contrasts with METH-related volume increases in striatum and parietal cortex, suggesting distinct neurobiological responses to HIV and METH (Jernigan et al., 2005). Functional magnetic resonance imaging (fMRI) has the potential to reveal functional interactions between the effects of HIV and METH. In the present study, 50 participants were studied in four groups: an HIV+ group, a recently METH-dependent group, a dually affected group, and a group of unaffected community comparison subjects. An fMRI paradigm consisting of motor sequencing tasks of varying levels of complexity was administered to examine blood oxygenation level dependent (BOLD) changes. Within all groups, activity increased significantly with increasing task complexity in large clusters within sensorimotor and parietal cortex, basal ganglia, cerebellum, and cingulate. The task complexity effect was regressed on HIV status, METH status, and the HIV×METH interaction term in a simultaneous multiple regression. HIV was associated with less complexity-related activation in striatum, whereas METH was associated with less complexity-related activation in parietal regions. Significant interaction effects were observed in both cortical and subcortical regions; and, contrary to expectations, the complexity-related activation was less aberrant in dually affected than in single risk participants, in spite of comparable levels of neurocognitive impairment among the clinical groups. Thus, HIV and METH dependence, perhaps through their effects on dopaminergic systems, may have opposing functional effects on neural circuits involved in motor programming.

The influence of chronic stress on dementia-related diagnostic change in older adults.

Increased susceptibility of the aging brain to both chronic stress and incipient dementia-related neuropathology may accelerate cognitive decline. We investigated associations between chronic stress and diagnostic change in 62 individuals (mean age, 78.7 y) participating in an Alzheimer disease research center longitudinal study. The subjects, diagnosed at baseline as cognitively normal (CN) or with mild cognitive impairment (MCI), were followed for an average of 2.5 years. Senior neurologists, blind to detailed measures of stress and cognition, assigned diagnoses annually. Logistic regression analyses assessed the accuracy with which measures of stress (event-based ratings, cortisol levels) predicted the conversion to MCI and dementia. Eleven individuals with MCI at baseline received a dementia diagnosis during follow-up. Sixteen converted from cognitively normal to MCI. Prolonged, highly stressful experiences were associated with conversion from MCI to dementia. The cortisol awakening response, with age and education, was associated with a diagnostic change to MCI. Cortisol measures were not associated with the progression from MCI to dementia, and there was no association between stressful experiences and the change to MCI. Mechanisms associated with the transition from normal cognition to MCI may differ from those associated with a diagnostic change to dementia. These findings could facilitate the identification of interventional strategies to reduce the risk of decline at different stages of susceptibility.

Cognitive and functional decline in Huntington's disease: dementia criteria revisited.

The importance of designating criteria for diagnosing dementia lies in its implications for clinical treatment, research, caregiving, and decision-making. Dementia diagnosis in Huntington's disease (HD) is often based on criteria developed for Alzheimer's disease requiring memory loss. However, it is likely that other cognitive deficits contribute to functional impairment in HD before memory declines. The goal is to identify cognitive deficits that contribute to functional impairment to support dementia criteria that reflect HD neuropathology. Eighty-four HD mutation-positive subjects completed neuropsychological tests and the Unified Huntington's Disease Rating Scale Functional Independence Scale (FIS). Functional impairment was defined as 80 or below on the FIS. Speed of processing, initiation, and attention measures accounted for 70.0% of the variance in FIS ratings (linear regression) and correctly classified 91.7% of subjects as functionally impaired or intact (logistic regression). Measures of memory, motor impairment except dysarthria, neuroleptic use, and depressed mood did not improve prediction. A definition of HD dementia that includes cognitive impairment in at least two areas of cognition but does not require a memory deficit, in the context of impaired functional abilities and a deteriorating course, more accurately reflects HD neuropathology and could lead to improved research methods and patient care.

Level of executive function influences verbal memory in amnestic mild cognitive impairment and predicts prefrontal and posterior cingulate thickness.

This study aims to investigate the relationship between executive function and verbal memory and to explore the underlying neuroanatomical correlates in 358 individuals with amnestic mild cognitive impairment (MCI) and 222 healthy controls (HCs). The MCI participants were divided into 2 groups (high vs. low) based on executive function task performance. Results demonstrated that although both MCI groups were impaired on all memory measures relative to HCs, MCI individuals with higher executive function (HEF) demonstrated better verbal memory performance than those with lower executive function (LEF), particularly on measures of learning. The 2 MCI groups did not differ in mesial temporal morphometric measures, but the MCI LEF group showed significant thinning in dorsolateral prefrontal and posterior cingulate cortices bilaterally compared with the MCI HEF and HCs. Further, thickness in numerous regions of frontal cortex, and bilateral posterior cingulate, was significantly associated with memory performance in all MCI participants above and beyond the contribution of the mesial temporal regions known to be associated with episodic memory. Overall, these results demonstrate the importance of evaluating executive function in individuals with MCI to predict involvement of brain areas beyond the mesial temporal lobe.

Comparison of the traditional recall-based versus a new list-based method for computing semantic clustering on the California Verbal Learning Test: evidence from Alzheimer's disease.

For over 50 years, cognitive psychologists and neuropsychologists have relied almost exclusively on a method for computing semantic clustering on list-learning tasks (recall-based formula) that was derived from an outdated assumption about how learning occurs. A new procedure for computing semantic clustering (list-based formula) was developed for the CVLT-II to correct the shortcomings of the traditional method. In the present study we compared the clinical utility of the traditional recall-based method versus the new list-based method using results from the original CVLT administered to 87 patients with Alzheimer's disease and 86 matched normal control participants. Logistic regression and score distribution analyses indicated that the new list-based method enhances the detection of differences in semantic-clustering ability between the groups.

Brain substrates of learning and retention in mild cognitive impairment diagnosis and progression to Alzheimer's disease.

Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c) examining their underlying brain morphometric correlates. A total of 607 participants were assigned to three MCI groups (high learning-low retention; low learning-high retention; low learning-low retention) and one control group (high learning-high retention) based on scores above or below a 1.5 SD cutoff on learning and retention indices of the Rey Auditory Verbal Learning Test. Our results demonstrated that MCI individuals with predominantly a learning deficit showed a widespread pattern of gray matter loss at baseline, whereas individuals with a retention deficit showed more focal gray matter loss. Moreover, either learning or retention measures provided good predictive value for longitudinal clinical outcome over two years, although impaired learning had modestly better predictive power than impaired retention. As expected, impairments in both measures provided the best predictive power. Thus, the conventional practice of relying solely on the use of delayed recall or retention measures in studies of amnestic MCI misses an important subset of older adults at risk of developing AD. Overall, our results highlight the importance of including learning measures in addition to retention measures when making a diagnosis of MCI and for predicting clinical outcome.

Structural neuroimaging in the detection and prognosis of pre-clinical and early AD.

Current research supports the strong potential of structural MRI profiles, even within cross-sectional designs, as a promising method for the discrimination of Alzheimer's Disease (AD) from normal controls and for the prediction of Mild Cognitive Impairment (MCI) progression and conversion to AD. Findings suggest that measures of structural change in mesial and lateral temporal, cingulate, parietal and midfrontal areas may facilitate the assessment of a treatment's ability to halt the progressive structural loss that accompanies clinical decline in MCI. The performance of prediction is likely to continue to improve with the incorporation of measures from other neuroimaging modalities, clinical assessments, and neuromedical biomarkers, as the regional profile of individuals at risk for progression is refined.

Cognitive phenotypes, brain morphometry and the detection of cognitive decline in preclinical AD.

Identifying a preclinical phase of Alzheimer's Disease (PCAD) that is distinct from cognitive changes in healthy aging continues to be a major research focus. Combining neuropsychological and neuroimaging methodologies should improve our ability to differentiate healthy from pathological aging, although studies that utilize both methods often result in equivocal findings, possibly due to variability in cognitive test performance that may be capturing distinct phenotypes. One method of capturing this cognitive variability is to utilize contrasting neuropsychological tests to identify subgroups representative of distinct cognitive phenotypes, and determine whether differences in brain morphometry support these classifications. We review several approaches to defining cognitive subgroups, and we consider the possibility that cognitive asymmetry might provide one means of identifying both functional and structural changes associated with aging and dementia.

Effects of chronic stress on memory decline in cognitively normal and mildly impaired older adults.

OBJECTIVE: The literature provides evidence of a strong relationship between greater stress and memory loss, but few studies have examined this relationship with both variables measured over time. The authors sought to determine the prospective association between subjective and objective measures of chronic stress and rate of memory decline in cognitively normal and mildly impaired older adults. METHOD: This longitudinal study was conducted at a university research center and included 61 cognitively normal subjects and 41 subjects with mild cognitive impairment (ages 65-97). Fifty-two subjects were followed for up to 3 years (mean=2 years) and received repeated stress and cognitive assessments. Exclusion criteria were dementia, significant medical or psychiatric conditions, and medication use (e.g., corticosteroids) that might affect cortisol level or cognitive functioning. The main outcome measure was a regression-based slope reflecting performance change on tests of global cognition and episodic memory as a function of baseline diagnosis, recent life events, and salivary cortisol. Examiners were blind to stress ratings and cortisol levels at the time of cognitive testing. RESULTS: Higher event-based stress ratings collected over the follow-up period were associated with faster cognitive decline in subjects with mild cognitive impairment but not in cognitively normal subjects. In contrast, higher cortisol levels were associated with slower cognitive decline in subjects with mild cognitive impairment but not in cognitively normal subjects. CONCLUSIONS: Chronic stress affects cognitive functioning differently in cognitively normal subjects and those with mild cognitive impairment. Cortisol, while likely to have neurotoxic effects over time, may enhance cognitive functioning in older adults compromised by existing cognitive deficits.

Temporal order memory deficits prior to clinical diagnosis in Huntington's disease.

The current study examined temporal order memory in preclinical Huntington's disease (pre-HD). Participants were separated into less than 5 years (pre-HD near) and more than 5 years (pre-HD far) from estimated age of clinical diagnosis. Participants completed a temporal order memory task on a computerized radial eight-arm maze. On the study phase of each trial, participants viewed a random sequence of circles appearing one at a time at the end of each arm. On the choice phase, participants viewed two circles at the end of the study phase arms and chose the circle occurring earliest in the sequence. The task involved manipulations of the temporal lag, defined as the number of arms occurring in the sample phase sequence between the two choice phase arms. Research suggests that there is more interference for temporally proximal stimuli relative to temporally distal stimuli. There were no significant differences between the pre-HD far group and controls on the temporal order memory task. The pre-HD near group demonstrated significant impairments relative to the other groups on closer temporal lags, but were normal on the furthest temporal lag. Therefore, temporal order memory declines with increased temporal interference in pre-HD close to estimated diagnosis of HD.

The emergence of cognitive discrepancies in preclinical Alzheimer's disease: a six-year case study.

We present neuropsychological data from an 81-year-old individual who was followed over a six-year period, initially as a healthy control participant. She performed above age-adjusted cutoff scores for impairment on most neuropsychological tests, including learning and memory measures, until the final assessment when she received a diagnosis of probable Alzheimer's disease (AD). Despite generally normal scores on individual cognitive tests, her cognitive profile revealed increasingly large cognitive discrepancies when contrasting verbal versus visuospatial tasks, and complex versus basic-level tasks. The present case provides intriguing evidence that cognitive-discrepancy measures could improve our ability to detect subtle changes in cognition at the earliest, preclinical stages of AD.

Cognitive discrepancies versus APOE genotype as predictors of cognitive decline in normal-functioning elderly individuals: a longitudinal study.

OBJECTIVES: Cognitive-discrepancy analysis has been shown to be a useful technique for detecting subtle cognitive deficits in normal-functioning elderly individuals who are genetically at-risk for Alzheimer disease (AD). However, studies that have used cognitive-discrepancy measures to date have used retrospective or cross-sectional designs, and the utility of this approach to predict cognitive decline has not been examined in a prospective investigation. DESIGN: Longitudinal study. SETTING: San Diego, CA, Veterans Administration Hospital. PARTICIPANTS: Twenty-four normal-functioning elderly individuals participated in the study, with 16 subjects exhibiting no change in their Dementia Rating Scale (DRS) scores over an 1-year period (Stable Group), and 8 subjects exhibiting a decline in DRS scores over the 1-year period (Decline group). MEASUREMENTS: A cognitive-discrepancy measure isolating cognitive switching was computed that contrasted performance on a new higher-level task of executive functioning (a Stroop/Switching measure) relative to a composite measure of lower-level Stroop conditions. RESULTS: a) In the year before their cognitive changes, the Decline group exhibited a significantly larger cognitive-discrepancy (Stroop/Switching versus lower-level Stroop conditions) score compared with a control (Stable) group; and b) the cognitive-discrepancy measure was superior to APOE genotype in predicting DRS decline. CONCLUSION: Cognitive-discrepancy analysis isolating a component executive function ability not only seems to be a useful tool for identifying individuals at risk for cognitive deficits, but also shows promise in predicting individuals who may show subtle cognitive decline over time.

Identifying the "source" of recognition memory deficits in patients with Huntington's disease or Alzheimer's disease: evidence from the CVLT-II.

The present study compared the performance of individuals with Huntington's disease (HD) and Alzheimer's disease (AD) on three types of California Verbal Learning Test-Second Edition (CVLT-II) recognition discriminability indices (RDI): Source, Novel, and Total. The HD and AD groups did not differ significantly on Source RDI (all 16 targets versus the 16 previously presented, List B, distractors). However, HD patients performed significantly better than AD patients on Total RDI (all 16 targets versus all 32 distractors) and Novel RDI (all 16 targets versus 16 new distractors). Implications of these findings on the differentiation of the memory disorders associated with HD and AD are discussed.

Neuropsychological contributions to the early identification of Alzheimer's disease.

A wealth of evidence demonstrates that a prodromal period of Alzheimer's disease (AD) exists for some years prior to the appearance of significant cognitive and functional declines required for the clinical diagnosis. This prodromal period of decline is characterized by a number of different neuropsychological and brain changes, and reliable identification of individuals prior to the development of significant clinical symptoms remains a top priority of research. In this review we provide an overview of those neuropsychological changes. In particular, we examine specific domains of cognition that appear to be negatively affected during the prodromal period of AD, and we review newer analytic strategies designed to examine cognitive asymmetries or discrepancies between higher-order cognitive functions versus fundamental skills. Finally, we provide a critical examination of the clinical concept of Mild Cognitive Impairment and offer suggestions for an increased focus on the impact of cerebrovascular disease (CVD) and CVD risk during the prodromal period of AD.

Heterogeneity in verbal memory: a marker of preclinical Alzheimer's disease?

Demonstrations of memory changes in those at risk for Alzheimer's disease by the presence of the APOE e4 allele have been inconsistent to date. The present study went beyond traditional analyses of central tendency (i.e., group differences on mean test scores) and also conducted distribution analyses to search for subtle cognitive differences in subgroups of normal-functioning elderly persons with the APOE e4 genotype. The results of the study revealed that (a) the e4 and non-e4 groups failed to differ in terms of their mean scores on tests of memory and verbal skills; and (b) relative to the non-e4 group, the e4 subjects had significantly greater heterogeneity of variance on the memory measures but not on fundamental verbal skills. Logistic regression analyses indicated that the discrepancy in scores on the memory measures was a significant predictor of genotype group membership (82% correct classification rate). Implications of these findings for the detection of a preclinical phase of AD are discussed.