Longitudinal Sleep Patterns and Cognitive Impairment in Older Adults.

Importance: Sleep disturbances and clinical sleep disorders are associated with all-cause dementia and neurodegenerative conditions, but it remains unclear how longitudinal changes in sleep impact the incidence of cognitive impairment. Objective: To evaluate the association of longitudinal sleep patterns with age-related changes in cognitive function in healthy older adults. Design, Setting, and Participants: This cross-sectional study is a retrospective longitudinal analyses of the Seattle Longitudinal Study (SLS), which evaluated self-reported sleep duration (1993-2012) and cognitive performance (1997-2020) in older adults. Participants within the SLS were enrolled as part of a community-based cohort from the Group Health Cooperative of Puget Sound and Health Maintenance Organization of Washington between 1956 and 2020. Data analysis was performed from September 2020 to May 2023. Main Outcomes and Measures: The main outcome for this study was cognitive impairment, as defined by subthreshold performance on both the Mini-Mental State Examination and the Mattis Dementia Rating Scale. Sleep duration was defined by self-report of median nightly sleep duration over the last week and was assessed longitudinally over multiple time points. Median sleep duration, sleep phenotype (short sleep, median ≤7 hours; medium sleep, median = 7 hour; long sleep, median ≥7 hours), change in sleep duration (slope), and variability in sleep duration (SD of median sleep duration, or sleep variability) were evaluated. Results: Of the participants enrolled in SLS, only 1104 participants who were administered both the Health Behavior Questionnaire and the neuropsychologic battery were included for analysis in this study. A total of 826 individuals (mean [SD] age, 76.3 [11.8] years; 468 women [56.7%]; 217 apolipoprotein E ε4 allele carriers [26.3%]) had complete demographic information and were included in the study. Analysis using a Cox proportional hazard regression model (concordance, 0.76) showed that status as a short sleeper (hazard ratio, 3.67; 95% CI, 1.59-8.50) and higher sleep variability (hazard ratio, 3.06; 95% CI, 1.14-5.49) were significantly associated with the incidence of cognitive impairment. Conclusions and Relevance: In this community-based longitudinal study of the association between sleep patterns and cognitive performance, the short sleep phenotype was significantly associated with impaired cognitive performance. Furthermore, high sleep variability in longitudinal sleep duration was significantly associated with the incidence of cognitive impairment, highlighting the possibility that instability in sleep duration over long periods of time may impact cognitive decline in older adults.

Poorer prospective memory performance is associated with reduced time monitoring among OEF/OIF/OND Veterans with a history of blast-related mild traumatic brain injury.

Objective:Prospective memory (PM) or "remembering to remember" has been shown to be reduced in Veterans with histories of mild traumatic brain injury (mTBI), particularly on tasks with high strategic demands such as recalling time-based information in the absence of external cues. This study examined whether time monitoring during a PM task was reduced in Veterans with a history of mTBI and was associated with time-based PM performance. Method:Veterans with a history of mTBI (n = 49) and Veterans without a history of TBI (n = 16) completed the Memory for Intentions Screening Test (MIST) as a measure of PM during which their time monitoring (i.e. number of clock checks) was recorded. Results:Adjusting for age, education, depression, and PTSD symptoms, negative binomial regression revealed that the mTBI group checked the clock less frequently compared to the control group (Cohen's d = 0.84, p = 0.005). Within the mTBI group, less frequent time monitoring across the entire MIST task was associated with poorer time-based MIST performance (rs = .57, p < 0.001), but not with event-based MIST (rs = .04, p = 0.768). Conclusions:Veterans with a history of mTBI evidenced significantly reduced time monitoring during a PM task compared to Veterans without a history mTBI, which was associated with strategically-demanding PM. Current findings provide that mTBI-associated difficulties with strategic aspects of PM may be due to reduced time monitoring. Future studies are needed to determine if reduced time monitoring also contributes to mTBI-associated PM difficulties in the real-world (e.g. medication non-adherence).

Associations between Intra-Individual Neurocognitive Variability and Prospective Memory in Veterans with Mild Traumatic Brain Injury History and Posttraumatic Stress Disorder.

OBJECTIVE: Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) frequently co-occur and are associated with neurocognitive intra-individual variability (IIV) and difficulty with prospective memory (PM). The current study aimed to examine associations between IIV and PM in this comorbid group. METHOD: Fifty veterans with a history of blast mTBI and current comorbid PTSD completed a standardized neurocognitive battery to measure IIV, and the Memory for Intentions Screening Test measuring PM. RESULTS: Adjusting for age, education, and race, higher IIV was associated with poorer time-based PM (p < .001, f2 = .34), but not event-based PM. In a subset of the sample with self-report data, higher IIV was associated with poorer self-reported retrospective memory, but not PM. CONCLUSIONS: Cognitive variability on a standardized neuropsychological battery was associated with strategically demanding PM, which is an ecologically relevant ability and highlights the possible connection between subtle cognitive difficulties in-clinic and those experienced in daily life.

Arterial Stiffening Moderates the Relationship Between Type-2 Diabetes Mellitus and White Matter Hyperintensity Burden in Older Adults With Mild Cognitive Impairment.

Background: Cerebrovascular dysfunction has been proposed as a possible mechanism underlying cognitive impairment in the context of type 2 diabetes mellitus (DM). Although magnetic resonance imaging (MRI) evidence of cerebrovascular disease, such as white matter hyperintensities (WMH), is often observed in DM, the vascular dynamics underlying this pathology remain unclear. Thus, we assessed the independent and combined effects of DM status and different vascular hemodynamic measures (i.e., systolic, diastolic, and mean arterial blood pressure and pulse pressure index [PPi]) on WMH burden in cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI). Methods: 559 older adults (mean age: 72.4 years) from the Alzheimer's Disease Neuroimaging Initiative were categorized into those with diabetes (DM+; CU = 43, MCI = 34) or without diabetes (DM-; CU = 279; MCI = 203). Participants underwent BP assessment, from which all vascular hemodynamic measures were derived. T2-FLAIR MRI was used to quantify WMH burden. Hierarchical linear regression, adjusting for age, sex, BMI, intracranial volume, CSF amyloid, and APOE ε4 status, examined the independent and interactive effects of DM status and each vascular hemodynamic measure on total WMH burden. Results: The presence of DM (p = 0.046), but not PPi values (p = 0.299), was independently associated with greater WMH burden overall after adjusting for covariates. Analyses stratified by cognitive status revealed a significant DM status x PPi interaction within the MCI group (p = 0.001) such that higher PPi values predicted greater WMH burden in the DM + but not DM- group. No significant interactions were observed in the CU group (all ps > 0.05). Discussion: Results indicate that higher PPi values are positively associated with WMH burden in diabetic older adults with MCI, but not their non-diabetic or CU counterparts. Our findings suggest that arterial stiffening and reduced vascular compliance may have a role in development of cerebrovascular pathology within the context of DM in individuals at risk for future cognitive decline. Given the specificity of these findings to MCI, future exploration of the sensitivity of earlier brain markers of vascular insufficiency (i.e., prior to macrostructural white matter changes) to the effects of DM and arterial stiffness/reduced vascular compliance in CU individuals is warranted.

Research Letter: PTSD Symptom Severity and Multiple Traumatic Brain Injuries Are Associated With Elevated Memory Complaints in Veterans With Histories of Mild TBI.

OBJECTIVE: The evaluation of memory complaints in mild traumatic brain injury (mTBI) remains an important clinical consideration, especially in the context of comorbid psychiatric symptoms such as posttraumatic stress disorder (PTSD). We compared subjective memory complaints in veterans with and without a history of mTBI, examined ratings between those with single versus multiple mTBIs, and investigated associations between memory complaints and PTSD symptom severity. METHODS: 117 outpatient veterans (mTBI: n = 79 [single mTBI: n = 22, multiple mTBI: n = 57], military controls [MCs]: n = 38) completed a TBI history assessment, the Prospective-Retrospective Memory Questionnaire (PRMQ), and the PTSD Checklist-Military Version (PCL-M). RESULTS: Hierarchical multiple regression showed that greater PCL-M scores significantly predicted elevated PRMQ-Total scores, accounting for 38% of the variance explained (P < .001). mTBI status predicted an additional 5% of variance in memory complaints (P < .01). The multiple-mTBI group endorsed more memory complaints than either MCs (P < .01) or the single-mTBI group (P < .05), who did not differ from MCs (P > .50). CONCLUSIONS: Comorbid PTSD symptoms are an important factor when considering memory complaints in veterans with a reported history of mTBI. However, independent of comorbid PTSD symptoms, mTBI status-particularly in the context of repetitive neurotrauma-uniquely contributes to memory complaints. Findings suggest that veterans with a history of multiple mTBIs may be a particularly vulnerable group in need of specialized interventions and/or psychoeducation.

Elevated Intraindividual Variability in Executive Functions and Associations with White Matter Microstructure in Veterans with Mild Traumatic Brain Injury.

OBJECTIVE: We examined whether intraindividual variability (IIV) across tests of executive functions (EF-IIV) is elevated in Veterans with a history of mild traumatic brain injury (mTBI) relative to military controls (MCs) without a history of mTBI. We also explored relationships among EF-IIV, white matter microstructure, and posttraumatic stress disorder (PTSD) symptoms. METHOD: A total of 77 Veterans (mTBI = 43, MCs = 34) completed neuropsychological testing, diffusion tensor imaging (DTI), and PTSD symptom ratings. EF-IIV was calculated as the standard deviation across six tests of EF, along with an EF-Mean composite. DSI Studio connectometry analysis identified white matter tracts significantly associated with EF-IIV according to generalized fractional anisotropy (GFA). RESULTS: After adjusting for EF-Mean and PTSD symptoms, the mTBI group showed significantly higher EF-IIV than MCs. Groups did not differ on EF-Mean after adjusting for PTSD symptoms. Across groups, PTSD symptoms significantly negatively correlated with EF-Mean, but not with EF-IIV. EF-IIV significantly negatively correlated with GFA in multiple white matter pathways connecting frontal and more posterior regions. CONCLUSIONS: Veterans with mTBI demonstrated significantly greater IIV across EF tests compared to MCs, even after adjusting for mean group differences on those measures as well as PTSD severity. Findings suggest that, in contrast to analyses that explore effects of mean performance across tests, discrepancy analyses may capture unique variance in neuropsychological performance and more sensitively capture cognitive disruption in Veterans with mTBI histories. Importantly, findings show that EF-IIV is negatively associated with the microstructure of white matter pathways interconnecting cortical regions that mediate executive function and attentional processes.

Type 2 Diabetes Interacts With Alzheimer Disease Risk Factors to Predict Functional Decline.

OBJECTIVE: The current study examined the interactive effect of type 2 diabetes and Alzheimer disease (AD) risk factors on the rate of functional decline in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative. METHODS: Participants underwent annual assessments that included the Functional Activities Questionnaire, an informant-rated measure of everyday functioning. Multilevel modeling, controlling for demographic variables and ischemic risk, examined the interactive effects of diabetes status (diabetes, n=69; no diabetes, n=744) and AD risk factors in the prediction of 5-year longitudinal change in everyday functioning. One model was run for each AD risk factor, including: objectively-defined subtle cognitive decline (Obj-SCD), and genetic susceptibility [apolipoprotein E ε4 (APOE ε4) as well as cerebrospinal fluid ß-amyloid (Aß), total tau (tau), and hyperphosphorylated tau (p-tau). RESULTS: The 3-way diabetes×AD risk factor×time interaction predicted increased rates of functional decline in models that examined Obj-SCD, APOE ε4, tau, and p-tau positivity, but not Aß positivity. CONCLUSIONS: Participants with both diabetes and at least 1 AD risk factor (ie, Obj-SCD, APOE ε4, tau, and p-tau positivity) demonstrated faster functional decline compared with those without both risk factors (diabetes or AD). These findings have implications for early identification of, and perhaps earlier intervention for, diabetic individuals at risk for future functional difficulty.

Cognitive dispersion is a sensitive marker for early neurodegenerative changes and functional decline in nondemented older adults.

OBJECTIVE: Intraindividual cognitive variability (IIV), a measure of within-person variability across cognitive measures at a single time point, is associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Little is known regarding brain changes underlying IIV, or the relationship between IIV and functional ability. Therefore, we investigated the association between IIV and cerebral atrophy in AD-vulnerable regions and everyday functioning in nondemented older adults. METHOD: 736 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (285 cognitively normal [CN]; 451 MCI) underwent neuropsychological testing and serial MRI over 2 years. Linear mixed effects models examined the association between baseline IIV and change in entorhinal cortex thickness, hippocampal volume, and everyday functioning. RESULTS: Adjusting for age, sex, apolipoprotein E genotype, amyloid-ß positivity, and mean level of cognitive performance, higher baseline IIV predicted faster rates of entorhinal and hippocampal atrophy, as well as functional decline. Higher IIV was associated with both entorhinal and hippocampal atrophy among MCI participants but selective vulnerability of the entorhinal cortex among CN individuals. CONCLUSIONS: IIV was associated with more widespread medial temporal lobe (MTL) atrophy in individuals with MCI relative to CN, suggesting that IIV may be tracking advancing MTL pathologic changes across the continuum of aging, MCI, and dementia. Findings suggest that cognitive dispersion may be a sensitive marker of neurodegeneration and functional decline in nondemented older adults. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

APOE-ε4 Genotype is Associated with Elevated Post-Concussion Symptoms in Military Veterans with a Remote History of Mild Traumatic Brain Injury.

OBJECTIVE: We evaluated the influence of the APOE-ε4 allele on post-concussive symptoms in military Veterans with a remote history of mild traumatic brain injury (mTBI). METHOD: Participants (N = 77) were administered neuropsychiatric measures, on average, approximately 5 years following their most recent mTBI and provided a DNA sample for APOE genotyping. Veterans were divided into two groups based on their ε4 status (n = 14 ε4+, n = 63 ε4-). The Neurobehavioral Symptom Inventory (NSI) was the primary outcome measure, from which a total score was derived, as well as three symptom clusters (somatic, cognitive, and affective). RESULTS: ANCOVAs showed a significant main effect of ε4 genotype on the NSI total score and somatic symptom cluster after adjusting for posttraumatic stress symptoms and mTBI history (p = .019-.028, ηp2 = .064-.073), such that ε4+ Veterans endorsed significantly greater symptoms than ε4- Veterans. CONCLUSIONS: Our findings suggest that genetic risk may help to explain the poorer long-term outcomes often observed in this population.

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.

Repetitive mild traumatic brain injury in military veterans is associated with increased neuropsychological intra-individual variability.

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; ηp2 = 0.043), and there was a trend finding in the same direction for the ASD index (p = 0.091; ηp2 = 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 p's > 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.

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

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.

Differential Effect of APOE ɛ4 Status and Elevated Pulse Pressure on Functional Decline in Cognitively Normal Older Adults.

BACKGROUND/OBJECTIVE: The APOE ɛ4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ɛ4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: 738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices. The Functional Activities Questionnaire (FAQ) was completed by participants' informant at baseline and 6, 12, 24, 36, and 48-month follow-up visits. Multiple linear regression and multilevel modeling were used to examine the effects of PP and APOE ɛ4 genotype on cross-sectional and longitudinal FAQ scores, respectively. RESULTS: Adjusting for demographic and clinical covariates, results showed that both APOE ɛ4 status and elevated PP predicted greater functional difficulty trajectories across four years of follow-up. Interestingly, however, elevated PP was associated with greater functional decline over time in ɛ4 non-carriers versus carriers. CONCLUSION: Results show that, although APOE ɛ4 status is the prominent predictor of functional difficulty for ɛ4 carriers, an effect of arterial stiffening on functional difficulty was observed in non-carriers. Future studies are needed in order to clarify the etiology of the association between PP and different brain aging processes, and further explore its utility as a marker of dementia risk. The present study underscores the importance of targeting modifiable risk factors such as elevated PP to prevent or slow functional decline and pathological brain aging.

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

Cerebral blood flow (CBF) alterations and amyloid-ß (Aß) accumulation have been independently linked to cognitive deficits in older adults at risk for dementia. Less is known about how CBF and Aß may interact to affect cognition in cognitively normal older adults. Therefore, we examined potential statistical interactions between CBF and Aß 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 Aß deposition. Aß 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 Aß status on memory performance. Among Aß positive older adults, there were significant negative associations between higher CBF in hippocampus, posterior cingulate, and precuneus and poorer memory performance. In contrast, among Aß 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 Aß 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 Aß positive older adults relative to Aß negative individuals. Associations between higherCBF and poorer memory among Aß 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.

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.

Cognitive fatigue is associated with reduced anterior internal capsule integrity in veterans with history of mild to moderate traumatic brain injury.

No known studies have directly examined white matter microstructural correlates of cognitive fatigue post-TBI in a Veteran sample. We therefore investigated the relationship between cognitive fatigue and white matter integrity in Veterans with history of mild to moderate TBI (mmTBI). 59 Veterans (TBI = 34, Veteran Controls [VCs] = 25]) with and without history of mmTBI underwent structural 3T DTI scans and completed questionnaires related to cognitive fatigue and psychiatric symptoms. Tractography was employed on six regions of interest, including the anterior and posterior limbs of the internal capsule; genu; body and splenium of the corpus callosum; and cingulum bundle. Group analyses revealed that those with history of mmTBI displayed significantly greater levels of cognitive fatigue relative to those with no history of head injury (p = .02). Within the mmTBI group, independent of psychiatric symptoms, decreased white matter microstructural integrity of the left anterior internal capsule was associated with greater levels of cognitive fatigue (p = .01). Results show that the subjective experience of cognitive fatigue following neurotrauma may be linked to the disruption of striato-thalamo-cortical tracts that are important in mediating arousal and higher-order cognitive processes. These findings build upon those from existing functional neuroimaging studies in those with history of TBI, providing further evidence for the neural basis of cognitive fatigue in head injured adults.

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.

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

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.