Madeleine L. Werhane

Deep white matter hyperintensities affect verbal memory independent of PTSD symptoms in veterans with mild traumatic brain injury

Abstract Objective: Although white matter hyperintensity (WMH) pathology has been observed in the context of traumatic brain injury (TBI), the contribution of this type of macrostructural damage to cognitive and/or post-concussive symptomatology (PCS) remains unclear. Methods: Sixty-eight Veterans (mTBI = 46, Military Controls [MCs] = 22) with and without history of mild TBI (mTBI) underwent structural MRI and comprehensive cognitive and psychiatric assessment. WMH volume was identified as deep (DWMH) or periventricular (PVWMH) on fluid-attenuated inversion recovery (FLAIR) images. Results: Group analyses revealed that mTBI history was not associated with increased WMH pathology (p’s > 0.05). However, after controlling for post-traumatic stress disorder (PTSD) and intracranial volume, DWMH was associated with reduced short-and long-delayed memory performance within the mTBI group (p’s < 0.05). Additionally, after adjusting for PTSD and time since injury, regression analyses revealed that WMH was not associated with self-reported ratings of PCS (p’s > 0.05) in the mTBI group. Conclusions: The results demonstrate that, in relatively young Veterans with mTBI, DWMH differentially and negatively affects memory performance above and beyond the effects of PTSD symptoms. The findings may help to clarify prior mixed results as well as offer focused treatment implications for Veterans with history of neurotrauma and evidence of macrostructural white matter damage.

Cerebral Blood Flow and Amyloid-β Interact to Affect Memory Performance in Cognitively Normal Older Adults

Cerebral blood flow (CBF) alterations and amyloid-β (Aβ) accumulation have been independently linked to cognitive deficits in older adults at risk for dementia. Less is known about how CBF and Aβ may interact to affect cognition in cognitively normal older adults. Therefore, we examined potential statistical interactions between CBF and Aβ status in regions typically affected in Alzheimer’s disease (AD) within a sample of older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Sixty-two cognitively normal participants (mean age = 72 years) underwent neuroimaging and memory testing. Arterial spin labeling magnetic resonance imaging was used to quantify CBF and florbetapir PET amyloid imaging was used to measure Aβ deposition. Aβ status (i.e., positivity versus negativity) was determined based on established cutoffs (Landau et al., 2013). The Rey Auditory Verbal Learning Test was used to assess memory. Linear regression models adjusted for age, education, and sex, demonstrated significant interactions between CBF and Aβ status on memory performance. Among Aβ positive older adults, there were significant negative associations between higher CBF in hippocampus, posterior cingulate, and precuneus and poorer memory performance. In contrast, among Aβ negative older adults, there were no significant associations between CBF and cognition. Our findings extend previous CBF studies of dementia risk by reporting interactions between Aβ status and CBF on memory performance in a sample of well-characterized, cognitively normal older adults. Results suggest that differential CBF-cognition associations can be identified in healthy, asymptomatic Aβ positive older adults relative to Aβ negative individuals. Associations between higherCBF and poorer memory among Aβ positive older adults may reflect a cellular and/or vascular compensatory response to pathologic processes whereby higher CBF is needed to maintain normal memory abilities. Findings indicate that CBF and its associations with cognition may have utility as a reliable marker of brain function early in the AD process when interventions are likely to be beneficial.

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

ABSTRACT 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 (R2 = .04, ns) and posttraumatic stress disorder (PTSD) symptoms (ΔR2 = .08, p = .05), we found that higher AUDIT scores were associated with poorer attention/processing speed, F(9, 37) = 2.55, p = .022; ΔR2 = .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.

Pathological vascular and inflammatory biomarkers of acute- and chronic-phase traumatic brain injury

Given the demand for developing objective methods for characterizing traumatic brain injury (TBI), research dedicated to evaluating putative biomarkers has burgeoned over the past decade. Since it is critical to elucidate the underlying pathological processes that underlie the higher diverse outcomes that follow neurotrauma, considerable efforts have been aimed at identifying biomarkers of both the acute- and chronic-phase TBI. Such information is not only critical for helping to elucidate the pathological changes that lead to poor long-term outcomes following TBI but it may also assist in the identification of possible prevention and interventions for individuals who sustain head trauma. In the current review, we discuss the potential role of vascular dysfunction and chronic inflammation in both acute- and chronic-phase TBI, and we also highlight existing studies that have investigated inflammation biomarkers associated with poorer injury outcome.

Repetitive Mild Traumatic Brain Injury in Military Veterans is Associated with Increased Neuropsychological Intra-Individual Variability

ABSTRACT Although across‐test intra‐individual variability (IIV), or dispersion, has been shown to be a valuable marker of neurological health in a variety of clinical samples, IIV has not been well examined in the context of mild traumatic brain injury (mTBI). In the present study, we examined measures of IIV in military Veterans with and without a history of mTBI. Secondly, we examined how measures of IIV relate to traditional indices of mean cognitive performance, TBI characteristics, and neuropsychiatric symptoms in mTBI. Participants included 120 Veterans (67 mTBI, 53 military controls [MCs]) who completed a comprehensive neuropsychological assessment. Two dispersion indices were calculated using 13 norm‐referenced variables: an average standard deviation (ASD) score and a maximum discrepancy (MD) score. Compared to MCs, Veterans with a history of mTBI demonstrated greater IIV as indicated by the MD index after adjusting for relevant demographic variables, PTSD symptoms, and mean‐level cognitive performance (p = 0.027; &eegr;p2 = 0.043), and there was a trend finding in the same direction for the ASD index (p = 0.091; &eegr;p2 = 0.025). Among the mTBI participants, the two IIV indices were positively correlated with each other (p < 0.001, r = 0.921) and negatively correlated with mean cognitive performance (p = 0.017–0.022, r = −[0.279–0.291]). In contrast, ASD and MD scores were not associated with a measure of premorbid intellectual functioning or neuropsychiatric symptoms (all ps > 0.05). However, higher ASD scores were positively related to lifetime number of mTBIs, such that greater cognitive variability was observed in Veterans with a history of multiple mTBIs (i.e., ≥3 mTBIs; p = 0.037, r = 0.255). Overall, our results demonstrate that Veterans with mTBI show greater IIV relative to MCs, and that repetitive mTBI is associated with increased cognitive performance variability. Findings indicate that, in the context of mTBI—which is considerably heterogeneous in nature—measures of dispersion may be more appropriate indicators of cognitive dysfunction when compared to traditional mean neuropsychological scores, especially in those with remote mTBI histories. Future longitudinal studies are needed to further establish the long‐term clinical implications and brain‐based correlates of these findings. HighlightsmTBI Veterans showed greater IIV (dispersion) than Veterans with no mTBI history.Repetitive mTBI (≥ 3) was associated with increased cognitive dispersion.Dispersion was not associated with neuropsychiatric symptoms or premorbid IQ in the mTBI sample.

Apolipoprotein E (APOE) ε4 Genotype is Associated with Elevated Psychiatric Distress in Veterans with a History of Mild to Moderate Traumatic Brain Injury

As few studies have examined the relationship between the apolipoprotein E (APOE) gene and clinical outcomes after military-related traumatic brain injury (TBI), we aimed to determine whether the ε4 allele of the APOE gene influences neuropsychiatric symptoms in veterans with a history of mild-to-moderate TBI. Participants included 133 veterans (TBI = 79; military controls [MC] = 54) who underwent APOE genotyping and were divided into ε4+ (TBI = 18; MC = 15) and ε4- (TBI = 61; MC = 39) groups. All participants underwent evaluation of psychological distress using the Beck Depression Inventory-II, Beck Anxiety Inventory, and PTSD Checklist-Military Version. Two-way analyses of variance were conducted to examine the effect of group (TBI vs. MC) and APOE-ε4 status (ε4+ vs. ε4-) across symptom measures. There was a significant main effect of group across all symptom measures (TBI > MC; all p values <0.001), no main effect of ε4 genotype (p = 0.152-0.222), and a significant interaction of group by ε4 genotype across all measures (p = 0.027-0.047). Specifically, for TBI participants, ε4+ veterans demonstrated significantly higher symptom scores across all measures when compared to ε4- veterans (p = 0.007-0.015). For MC participants, ε4 status had no effect on the severity of psychiatric symptom scores (p = 0.585-0.708). Our results demonstrate that, in our well-characterized sample of veterans with history of neurotrauma, possession of the ε4 allele conveys risk for increased symptomatology (i.e., depression, anxiety, and post-traumatic stress disorder), even well outside of the acute phase of injury. Findings suggest a meaningful relationship between APOE genotype and psychiatric distress post-TBI, and they suggest that there is a brain basis for the complex neuropsychiatric presentation often observed in this vulnerable population. Future longitudinal studies are needed in order to further our understanding of how genetic factors influence response to TBI.

Apolipoprotein E (APOE) ε4 genotype is associated with reduced neuropsychological performance in military veterans with a history of mild traumatic brain injury

ABSTRACT Introduction: The purpose of this study was to investigate the effect of the apolipoprotein E (APOE) ε4 allele on neuropsychological functioning in military Veterans with a remote history of mild traumatic brain injury (mTBI). Method: This cross-sectional study included 99 Veterans (mTBI = 53; military controls, MC = 46) who underwent neuropsychological assessment and APOE genotyping. Three neurocognitive composite scores—memory (α = .84), speed (α = .85), and executive functioning (α = .76)—were computed from 24 norm-referenced variables, and the total number of impaired scores (>1.5 SDs below mean) for each participant was calculated. Results: Analyses of covariance adjusting for ethnicity and posttraumatic stress disorder (PTSD) symptoms revealed that although no significant differences were observed between mTBI ε4 allele groups on the executive functioning composite (p > .05), mTBI ε4+ Veterans performed more poorly than ε4− Veterans on the memory (p = .045, ηp2 = .083) and speed (p = .023, ηp2 = .106) composites. Furthermore, Mann–Whitney U tests showed that ε4+ mTBI Veterans displayed a significantly greater number of impaired scores than did ε4− mTBI Veterans (p = .010, r = .355). In contrast, there were no significant differences across any of the cognitive variables between ε4+ and ε4− MCs (all p > .05). Conclusions: Results suggest that APOE ε4 genotype is related to reduced memory and processingspeed performance, as well as overall cognitive impairment, in those with a history of mTBI, but does not appear to have the same negative effects on cognition in the absence of neurotrauma. Although results are preliminary, the present study advances understanding of genetic influences on cognitive functioning in Veterans with remote mTBIs. Future longitudinal work is needed to elucidate the underlying brain-based mechanisms of ε4 allelic effects on cognitive and clinical outcomes following TBI.

Reduced Regional Cerebral Blood Flow Relates to Poorer Cognition in Older Adults With Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) increases risk for dementia, including Alzheimer’s disease (AD). Many previous studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect macrostructural changes associated with cerebrovascular disease such as white matter hyperintensities or infarcts. However, such pathology likely reflects end-stage manifestations of chronic decrements in cerebral blood flow (CBF). MRI techniques that measure CBF may (1) elucidate mechanisms that precede irreversible parenchymal damage and (2) serve as a marker of risk for cognitive decline. CBF measured with arterial spin labeling (ASL) MRI may be a useful marker of perfusion deficits in T2DM and related conditions. We examined associations among T2DM, CBF, and cognition in a sample of 49 well-characterized nondemented older adults. Along with a standard T1-weighted scan, a pseudocontinuous ASL sequence optimized for older adults (by increasing post-labeling delays to allow more time for the blood to reach brain tissue) was obtained on a 3T GE scanner to measure regional CBF in FreeSurfer derived regions of interest. Participants also completed a neuropsychological assessment. Results showed no significant differences between individuals with and without T2DM in terms of cortical thickness or regional brain volume. However, adjusting for age, sex, comorbid vascular risk factors, and reference CBF (postcentral gyrus) older adults with T2DM demonstrated reduced CBF in the hippocampus, and inferior temporal, inferior parietal, and frontal cortices. Lower CBF was associated with poorer memory and executive function/processing speed. When adjusting for diabetes, the significant associations between lower regional CBF and poorer executive function/processing speed remained. Results demonstrate that CBF is reduced in older adults with T2DM, and suggest that CBF alterations likely precede volumetric changes. Notably, relative to nondiabetic control participants, those with T2DM showed lower CBF in predilection sites for AD pathology (medial temporal lobe and inferior parietal regions). Findings augment recent research suggesting that perfusion deficits may underlie cognitive decrements frequently observed among older adults with T2DM. Results also suggest that CBF measured with ASL MRI may reflect an early and important marker of risk of cognitive impairment in T2DM and related conditions.