Search

Background: Understanding the sequential progression of cognitive impairments in Parkinson's disease (PD) is crucial for elucidating neuropathological underpinnings, refining the assessment of PD-related cognitive decline stages and enhancing early identification for targeted interventions. The first aim of this study was to use an innovative event-based modeling (EBM) analytic approach to estimate the sequence of cognitive declines in PD. The second aim was to validate the EBM by examining associations with EBM-derived individual-specific estimates of cognitive decline severity and performance on independent cognitive screening measures., Methods: This cross-sectional observational study included 99 people with PD who completed a neuropsychological battery. Individuals were classified as meeting the criteria for mild cognitive impairment (PD-MCI) or subtle cognitive decline by consensus. An EBM was constructed to compare cognitively healthy individuals with those with PD-MCI or subtle cognitive disturbances. Multivariable linear regression estimated associations between the EBM-derived stage of cognitive decline and performance on two independent cognitive screening tests., Results: The EBM estimated that tests assessing executive function and visuospatial ability become abnormal early in the sequence of PD-related cognitive decline. Each higher estimated stage of cognitive decline was associated with approximately 0.24 worse performance on the Dementia Rating Scale (p<0.001) and 0.26 worse performance on the Montreal Cognitive Assessment (p<0.001) adjusting for demographic and clinical variables., Conclusion: Findings from this study will have important clinical implications for practitioners, on specific cognitive tests to prioritise, when conducting neuropsychological evaluations with people with PD. Results also highlight the importance of frontal-subcortical system disruption impacting executive and visuospatial abilities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Headache is the most common type of pain following mild traumatic brain injury. Roughly half of those with persistent post-traumatic headache (PPTH) also report neck pain which is associated with greater severity and functional impact of headache. This observational cohort study aimed to identify biological phenotypes to help inform mechanism-based approaches in the management of PPTH with and without concomitant neck pain. Thirty-three military Veterans (mean (SD) = 37±16 years, 29 males) with PPTH completed a clinical assessment, quantitative sensory testing, and magnetic resonance imaging of the brain and cervical spine. Multidimensional phenotyping was performed using a Random Forest analysis and Partitioning Around Medoids (PAM) clustering of input features from three biologic domains: 1) resting state functional connectivity (rsFC) of the periaqueductal gray (PAG), 2) quality and size of cervical muscles, and 3) mechanical pain sensitivity and central modulation of pain. Two subgroups were distinguished by biological features that included forehead pressure pain threshold and rsFC between the PAG and selected nodes within the default mode, salience, and sensorimotor networks. Compared to the High Pain Coping group, the Low Pain Coping group exhibited higher pain-related anxiety (p=0.009), higher pain catastrophizing (p=0.004), lower pain self-efficacy (p=0.010), and greater headache-related disability (p=0.012). Findings suggest that greater functional connectivity of pain modulation networks involving the PAG combined with impairments in craniofacial pain sensitivity, but not cervical muscle health, distinguish a clinically important subgroup of individuals with PPTH who are less able to cope with pain and more severely impacted by headache., Competing Interests: Author COI. The authors declare no conflicts of interest.

Background: Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated., Objectives: This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals., Methods: A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years., Results: Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores., Conclusions: While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Objective: Identifying factors that moderate cognitive outcomes following mild traumatic brain injury (mTBI) is crucial. Prospective memory (PM) is a cognitive domain of interest in mTBI recovery as it may be especially sensitive to TBI-related changes. Since studies show that genetic status - particularly possession of the apolipoprotein E (APOE) ε4 allele - can modify PM performance, we investigated associations between mTBI status and APOE-ε4 genotype on PM performance in a well-characterized sample of Veterans with neurotrauma histories., Methods: 59 Veterans (mTBI = 33, Military Controls [MCs] = 26; age range: 24-50; average years post-injury = 10.41) underwent a structured clinical interview, neuropsychological assessment, and genotyping. The Memory for Intentions Test (MIST) measured PM across multiple subscales. ANCOVAs, adjusting for age and posttraumatic stress symptoms, tested the effects of mTBI status (mTBI vs. MC) and ε4 status (ε4+ vs. ε4-) on MIST scores., Results: Veterans with mTBI history performed more poorly compared to MCs on the MIST 15-min delay ( p =.002, η p 2 =.160), Time Cue ( p = .003, η p 2 =.157), and PM Total ( p = .016, η p 2 =.102). Those with at least one copy of the ε4 allele performed more poorly compared to ε4- Veterans on the MIST 15-min delay ( p = .011, η p 2 =.113) and PM Total ( p = .048, η p 2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes ( p s>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4- Veterans on the MIST 15-min delay subscale ( p = .031, η p 2 = .150)., Conclusions: mTBI history and APOE-ε4 genotype status were independently associated with worse PM performance compared to those without head injury histories or possession of the APOE-e4 genotype. Performance on the MIST 15-min delay was worse in Veterans with both risk factors (mTBI history and APOE-ε4 positivity). Findings suggest that genetic status may modify outcomes even in relatively young Veterans with mTBI histories. Future research examining longitudinal associations and links to neuroimaging and biomarker data are needed.

Introduction: Difficulties in executive functioning (EF) are common in PD; however, the relationship between subjective and objective EF is unclear. Understanding this relationship could help guide clinical EF assessment. This study examined the relationship between subjective self-reported EF (SEF) and objective EF (OEF) and predictors of SEF-OEF discrepancies in PD., Method: One-hundred and sixteen non-demented PD participants completed measures of OEF (i.e. problem-solving, cognitive flexibility, inhibition, and working memory) and SEF (Frontal Systems Behavior Scale-Self Executive Dysfunction Subscale). Pearson bivariate correlations and linear regressions were performed to examine the relationship between SEF and OEF and the non-motor symptoms (e.g. mood, fatigue), demographic, and PD characteristic (e.g. MCI status) predictors of discrepancies between OEF and SEF (|OEF minus SEF scores|). Correlates of under-, over-, and accurate-reporting were also explored., Results: Greater SEF complaints and worse OEF were significantly associated ( β  =.200, p  = .009) and 64% of participants accurately identified their level of OEF abilities. Fewer years of education and greater symptoms of depression, anxiety, and fatigue significantly correlated with greater discrepancies between OEF and SEF. Fatigue was the best predictor of EF discrepancy in the overall sample (β = .281, p  = .022). Exploratory analyses revealed apathy and fatigue associated with greater under-reporting, while anxiety associated with greater over-reporting., Conclusions: SEF and OEF are significantly related in PD. Approximately 64% of non-demented persons with PD accurately reported their EF skill level, while 28% under-reported and 8% over-reported. SEF-OEF discrepancies were predicted by fatigue in the overall sample. Preliminary evidence suggests reduced apathy and fatigue symptoms relate to more under-reporting, while anxiety relates to greater over-reporting. Given the prevalence of these non-motor symptoms in PD, it is important to carefully consider them when assessing EF in PD.

Perivascular spaces (PVS), fluid-filled compartments surrounding brain vasculature, are an essential component of the glymphatic system responsible for transport of waste and nutrients. Glymphatic system impairment may underlie cognitive deficits in Parkinson's disease (PD). Studies have focused on the role of basal ganglia PVS with cognition in PD, but the role of white matter PVS is unknown. This study examined the relationship of white matter and basal ganglia PVS with domain-specific and global cognition in individuals with PD. Fifty individuals with PD underwent 3T T1w magnetic resonance imaging (MRI) to determine PVS volume fraction, defined as PVS volume normalized to total regional volume, within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of global cognitive function (Montreal Cognitive Assessment, and global cognitive composite score), and cognitive-specific domains (executive function, memory, visuospatial function, attention, and language). Higher white matter rostral middle frontal PVS was associated with lower scores in both global cognitive and visuospatial function. In the basal ganglia higher PVS was associated with lower scores for memory with a trend towards lower global cognitive composite score. While previous reports have shown that greater amount of PVS in the basal ganglia is associated with decline in global cognition in PD, our findings suggest that increased white matter PVS volume may also underlie changes in cognition., (© 2023. The Author(s).)

Objective: Subjective cognitive decline (SCD) is a potential early risk marker for Alzheimer's disease (AD), but its utility may vary across individuals. We investigated the relationship of SCD severity with memory function and cerebral blood flow (CBF) in areas of the middle temporal lobe (MTL) in a cognitively normal and overall healthy sample of older adults. Exploratory analyses examined if the association of SCD severity with memory and MTL CBF was different in those with lower and higher cardiovascular disease (CVD) risk status., Methods: Fifty-two community-dwelling older adults underwent magnetic resonance imaging, neuropsychological testing, and were administered the Everyday Cognition Scale (ECog) to measure SCD. Regression models investigated whether ECog scores were associated with memory performance and MTL CBF, followed by similar exploratory regressions stratified by CVD risk status (i.e., lower vs higher stroke risk)., Results: Higher ECog scores were associated with lower objective memory performance and lower entorhinal cortex CBF after adjusting for demographics and mood. In exploratory stratified analyses, these associations remained significant in the higher stroke risk group only., Conclusions: Our preliminary findings suggest that SCD severity is associated with cognition and brain markers of preclinical AD in otherwise healthy older adults with overall low CVD burden and that this relationship may be stronger for individuals with higher stroke risk, although larger studies with more diverse samples are needed to confirm these findings. Our results shed light on individual characteristics that may increase the utility of SCD as an early risk marker of cognitive decline.

Reasoning requires the ability to manipulate mental representations and understand relationships between objects. There is a paucity of research regarding the functional connections between multiple brain areas that may interact during commonly used reasoning tasks. The present study aimed to examine functional activation and connectivity of frontoparietal regions during a Matrix Decision Making Task, completed by twenty-one right-handed healthy participants while undergoing fMRI. Voxel-wise whole brain analysis of neural response to the task revealed activation spanning dorsal and lateral prefrontal, occipital, and parietal regions. Utilizing Group Iterative Multiple Model Estimation, a data-driven approach that estimates the presence and direction of connectivity between specific ROIs, connectivity between prefrontal and sensory processing regions were revealed. Moreover, the magnitude of connectivity strength between the left precentral gyrus and left dorsal cingulate (dACC) was positively correlated with MR behavioral performance. Taken together, results are consistent with earlier work demonstrating involvement of regions comprising the central executive network in relational reasoning. These data expand existing knowledge regarding communication of key brain regions during the task and demonstrate that understanding how key brain regions are interconnected can effectively predict the quality of behavioral output., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Cognitive impairment is common in Parkinson's disease (PD) and often leads to dementia, with no effective treatment. Aging studies suggest that physical activity (PA) intensity has a positive impact on cognition and enhanced functional connectivity may underlie these benefits. However, less is known in PD. This cross-sectional study examined the relationship between PA intensity, cognitive performance, and resting state functional connectivity in PD and whether PA intensity influences the relationship between functional connectivity and cognitive performance., Methods: 96 individuals with mild-moderate PD completed a comprehensive neuropsychological battery. Intensity of PA was objectively captured over a seven-day period using a wearable device (ActiGraph). Time spent in light and moderate intensity PA was determined based on standardized actigraphy cut points. Resting-state fMRI was assessed in a subset of 50 individuals to examine brain-wide functional connectivity., Results: Moderate intensity PA (MIPA), but not light PA, was associated with better global cognition, visuospatial function, memory, and executive function. Individuals who met the WHO recommendation of ≥150 min/week of MIPA demonstrated better global cognition, executive function, and visuospatial function. Resting-state functional connectivity associated with MIPA included a combination of brainstem, hippocampus, and regions in the frontal, cingulate, and parietal cortices, which showed higher connectivity across the brain in those achieving the WHO MIPA recommendation. Meeting this recommendation positively moderated the associations between identified functional connectivity and global cognition, visuospatial function, and language., Conclusion: Encouraging MIPA, particularly the WHO recommendation of ≥150 min of MIPA/week, may represent an important prescription for PD cognition., Competing Interests: Declaration of competing interest The authors report no conflicts of interest or disclosures., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Care partners who provide informal care to individuals with Parkinson's disease (PD) report higher levels of burden and depression; however, longitudinal research on these symptoms is scarce. The current study assessed changes in care partner burden and depression, and patient and care partner predictors of these symptoms over time. Such knowledge may provide important information for assessment and treatment of depression and burden in care partners of individuals with PD., Research Design and Methods: Participants were 88 PD patients without dementia and their self-identified care partner (n = 88). Care partners completed the Geriatric Depression Scale and Zarit Burden Interview. PD participants completed mood questionnaires and a motor exam at baseline and 2 year follow-up. Relationships among care partner burden and depression over time with patient and care partner predictors (i.e., demographic, mood, and disease characteristics) were assessed using correlations and regression analyses., Results: Care partner burden and depression significantly increased over an approximate 2 year period. Greater baseline disease severity predicted worsening of care partner burden (p = 0.028), while baseline patient depression predicted worsening of care partner depression (p = 0.002)., Conclusions: Results highlight differential impacts of specific PD symptoms on worsening care partner burden compared to depression; increased PD disease severity predicts increased burden, while patient mood predicts worsening of depression over time. Targeting PD disease severity and mood symptoms may prevent the progression of care partner burden and depression., (© 2022 John Wiley & Sons Ltd.)

Objective: Rapid Eye Movement Sleep Behavior Disorder (RBD) is common in Parkinson's Disease (PD) and is associated with cognitive impairment; however, the majority of the evidence on the impact of RBD on multidomain cognitive batteries in PD is cross-sectional. This study evaluated the longitudinal impact of probable RBD (pRBD) on cognitive, psychiatric, and functional outcomes in people with PD., Method: Case-control study. A total of 65 people with PD completed the study protocol at baseline and 16-to-47-month follow-up. Participants were classified as pRBD+ (n = 25) or pRBD- (n = 40) based on an established cutoff of 6 on the RBD Sleep Questionnaire (RBDSQ). Participants also completed a) comprehensive cognitive testing, b) self-report measures of depression, anxiety, and apathy, and c) performance-based and other-report forms of instrumental activities of daily living., Results: Baseline mean age was 67.8 (SD = 8.1; range = 45-86) and baseline mean years of education was 16.4 (SD = 2.1; range = 12-20). The two groups did not differ on measured demographic characteristics. Baseline mean T-scores for cognitive tests were in the average range (46-55). Hierarchical linear models tested group differences in cognitive and functional decline from baseline to follow-up, controlling for appropriate demographic and psychiatric variables. Compared to the pRBD- group, pRBD+ participants showed greater decline in attention/working memory (r = -0.31; p = 0.01) and UPSA financial skills (r = -0.31; p = 0.01). No other group differences approached significance., Conclusions: RBD may differentially affect attention/working memory and financial abilities in PD. Results underscore the importance of regular RBD screening in older adults with PD in order to triage symptomatic patients to appropriate cognitive and medical interventions., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

We examined the association between cognitive functioning and health-related quality of life (HR-QOL) in military veterans with a history of mild traumatic brain injury (mTBI) using two methods to assess cognition: mean performance on cognitive composite scores and across-test intraindividual variability (IIV). The sample included 73 veterans (84.9% male; age, mean = 32.47 years) who completed neuropsychological testing and self-report questionnaires ∼7 years post-injury. Three cognitive composite scores representing mean performance were computed, including memory, attention/processing speed (A/PS), and executive functioning (EF). Three IIV indices were also calculated reflecting degree of dispersion across the same cognitive domains: memory-IIV, A/PS-IIV, and EF-IIV. The Posttraumatic Stress Disorder (PTSD) Checklist-Military Version (PCL-M) was used to assess current PTSD symptoms, and the World Health Organization Quality of Life Short Version Physical Health domain was used to assess HR-QOL. Hierarchical linear regressions adjusting for PTSD symptoms demonstrated that IIV indices, but not mean cognitive composite scores, significantly predicted HR-QOL. Specifically, memory-IIV, A/PS-IIV, and EF-IIV, when taken together, made an independent and significant contribution to the prediction of HR-QOL. Examination of the standardized coefficients showed that the A/PS-IIV index was uniquely associated with HR-QOL, such that higher A/PS-IIV scores significantly predicted poorer HR-QOL. Our results are the first to show that, in veterans with remote mTBI histories, greater fluctuations in cognitive performance significantly contribute to poorer HR-QOL, even after accounting for PTSD symptom severity. Moreover, findings suggest that, compared to traditional mean cognitive performance scores, measures of IIV may represent more sensitive indicators of clinical outcome and better align with subjective experiences of distress.

Objective: Frontal behaviors (i.e., executive dysfunction, disinhibition, apathy) are common in Parkinson's disease (PD). However, it is unclear if patient and informant reports of patient frontal behaviors are in agreement over time., Method: Sixty-two PD patients without dementia and their informants (87% spouses/partners) completed the self- and informant-versions of the Frontal Systems Behavior Scale at baseline and 2-year follow-up. Dyad ratings were compared and predictors of behavior ratings were examined., Results: Patient and informant reports at baseline and follow-up were in agreement, with significant increases in overall frontal behaviors, executive dysfunction, and apathy. Higher levels of baseline patient depression and caregiver burden predicted decrements in patient-reported executive function; worse patient cognition at baseline predicted worsening apathy as rated by informants., Conclusions: PD patients and their informants are concordant in their ratings of worsening frontal behaviors over time. Targeting patient depression, cognition, and caregiver burden may improve decrements in frontal behaviors (executive dysfunction and apathy) in PD.

Background: Post-traumatic headache (PTH) is a commonly experienced symptom after mild traumatic brain injury (mTBI). Blast injury- or blunt injury-related mechanisms for mTBI in veterans can also affect musculoskeletal structures in the neck, resulting in comorbid neck pain (NP). However, it is unknown whether the presence of comorbid NP may be associated with a different pattern of headache symptoms, physical functioning, or emotional functioning compared to those without comorbid NP. The purpose of this study is to examine the role of comorbid NP in veterans with mTBI and PTH., Design and Methods: This was a cross-sectional investigation of an existing dataset that included 33 veterans who met inclusion criteria for PTH after mTBI. Standardized measures of headache severity and frequency, insomnia, fatigue, mood disorders, and physical and emotional role function were compared between groups with and without comorbid NP., Results: The majority of participants with PTH reported comorbid NP (n = 22/33, 67%). Those with comorbid NP experienced more headache symptoms that were severe or incapacitating, as compared to mild or moderate for those without NP (φ = 0.343, P = .049); however, no differences in headache frequency (φ = 0.231, P = .231) or duration (φ = 0.129, P = .712) were observed. Participants with comorbid NP also reported greater insomnia (d = 1.16, P = .003) and fatigue (d = 0.868, P = .040) as well as lower physical functioning (d = 0.802, P = .036) and greater bodily pain (d = 0.762, P = .012). There were no differences in anxiety, depression, mental health, emotional role limitations, vitality, or social functioning between those with and without comorbid NP (d ≤ 0.656, P ≥ .079)., Conclusions: A majority of veterans with mTBI and PTH in our sample reported comorbid NP that was associated with greater headache symptom severity and physical limitations, but not with mood or emotional limitations. Preliminary findings from this small convenience sample indicate that routine assessment of comorbid NP and associated physical limitations should be considered in veterans with mTBI and PTH., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose/objective: To examine health-related quality of life (HR-QOL) in Veterans with and without a history of mild traumatic brain injury (mTBI) and investigate correlates and predictors of HR-QOL within the mTBI sample. Research Method/Design: Participants ( N = 144) included 81 Veterans with a history of mTBI and 63 Veteran controls (VCs) without a history of mTBI. Primary outcomes of interest were the 8 subscales of the 36-Item Short Form Survey (SF-36). Participants also completed questionnaires measuring combat exposure, depressive and posttraumatic stress disorder (PTSD) symptoms, and neurobehavioral symptoms., Results: ANCOVAs adjusting for age found that, relative to VCs, the mTBI group demonstrated poorer HR-QOL across all SF-36 subscales ( p 's = ≤.001-.006; η p ² = .05-.21). After adjusting for age, combat exposure, and depressive and PTSD symptoms, the mTBI group endorsed poorer HR-QOL on the Physical Role Functioning, General Health, and Social Functioning subscales ( p 's = .011-.032; η p ² = .03-.05). Within the mTBI sample, employment status, lifetime number of mTBIs, depression, PTSD, and neurobehavioral symptoms collectively predicted all 8 SF-36 subscales ( p 's < .001), accounting for 29-65% of the total variance. Although depression and neurobehavioral symptoms tended to be the strongest predictors of HR-QOL, lifetime number of mTBIs and employment status were also important predictors of specific HR-QOL domains., Conclusions: Results suggest that, above and beyond depression, PTSD, and combat exposure, history of remote mTBI contributes to aspects of HR-QOL-particularly in perceptions of physical health and social functioning. Furthermore, different combinations of predictor variables are associated with different HR-QOL domains, highlighting the need for multimodal treatments within this vulnerable population. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective: To examine the association between employment status and neuropsychological functioning in veterans with a history of remote mild traumatic brain injury (mTBI) using 2 approaches to assess cognitive performance: (a) standard, traditional mean cognitive performance; and (b) across-test intraindividual variability (IIV)., Setting: Outpatient Veterans Affairs (VA) hospital., Participants: Eligibility criteria included veterans with a history of mTBI who performed adequately on performance validity tests. Participants (N = 75; 37 employed, 38 unemployed) were evaluated, on average, about 5.5 years after their most recent mTBI., Design: Observational cohort study; all participants completed a clinical interview and a comprehensive neuropsychological assessment., Main Measures: Primary outcomes of interest included mean cognitive composite test scores and IIV scores on tasks of memory, attention/processing speed, and executive functioning., Results: Logistic regression models showed that mean cognitive performance was not predictive of employment status; however, IIV indices were ( = 7.88, P = .048) and accounted for 13% of the variance. Greater memory-IIV was significantly associated with being unemployed (β = -.16, SE = .07, P = .020, Exp(B) = 0.85; 95% CI, 0.74-0.98)., Conclusion: These findings build upon prior work showing that IIV, or cognitive dispersion, is associated with important functional outcomes following mTBI, including employment status. Future studies are needed to verify these findings, but the present study suggests that IIV indices offer a clinically meaningful marker of cognitive functioning and should be considered when evaluating functional outcomes following head trauma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Studies in aging older adults have shown the positive association between cognition and exercise related fitness, particularly cardiorespiratory fitness. These reports have also demonstrated the association of high cardiorespiratory fitness, as well as other types of fitness, on the reversal of age-related decline in neural network connectivity, highlighting the potential role of fitness on age- and disease-related brain changes. While the clinical benefits of exercise are well-documented in Parkinson's disease (PD), the extent to which cardiorespiratory fitness (assessed by estimated VO 2max testing) or motor skill fitness (assessed by the Physical Performance Test (PPT)) affects neural network connectivity in PD remains to be investigated. The purpose of this study was to explore the hypothesis that higher fitness level is associated with an increase in the intrinsic network connectivity of cognitive networks commonly affected in PD., Methods: In this cross-sectional resting state fMRI, we used a multivariate statistical approach based on high-dimensional independent component analysis (ICA) to investigate the association between two independent fitness metrics (estimated VO 2max and PPT) and resting state network connectivity., Results: We found that increased estimated VO 2max was associated with increased within network connectivity in cognitive networks known to be impaired in PD, including those sub-serving memory and executive function. There was a similar trend for high levels of PPT to be associated with increased within network connectivity in distinct resting state networks. The between functional network connectivity analysis revealed that cardiorespiratory fitness was associated with increased functional connectivity between somatosensory motor network and several cognitive networks sub-serving memory, attention, and executive function., Conclusion: This study provides important empirical data supporting the potential association between two forms of fitness and multiple resting state networks impacting PD cognition. Linking fitness to circuit specific modulation of resting state network connectivity will help establish a neural basis for the positive effects of fitness and specific exercise modalities and provide a foundation to identify underlying mechanisms to promote repair., Competing Interests: The authors declare that there is no conflict of interest., (© 2021 – The authors. Published by IOS Press.)

Objective: Individuals with Parkinson's disease (PD) are at risk for increased medication mismanagement, which can lead to worse clinical outcomes. However, the nature of the errors (i.e., undertaking or overtaking medications) contributing to mismanagement and their relationship to cognition in PD is unknown. Therefore, this study sought to examine errors committed on the Medication Management Ability Assessment (MMAA) between PD participants with normal cognition (PD-NC) or mild cognitive impairment (PD-MCI) relative to healthy adults (HA)., Method: HA (n = 74), PD-NC (n = 102), and PD-MCI (n = 45) participants were administered the MMAA to assess undertaking, overtaking, and overall errors as well as overall performance (total score). Additionally, participants were administered a comprehensive neuropsychological battery from which cognitive composites of Attention, Learning, Memory, Language, Visuospatial, and Executive Functioning were derived., Results: Separate negative binomial regression analyses indicated the PD-MCI group performed significantly worse overall on the MMAA (total score) and committed more undertaking and overall errors relative to HA and PD-NC. In the PD-MCI group, poorer MMAA performance was associated with worse delayed memory performance, whereas cognitive performance was not related to MMAA in HA or PC-NC., Conclusion: Compared to PD and healthy adults with normal cognition, PD-MCI patients exhibited greater difficulty with medication management, particularly with undertaking medications. Poorer medication management in PD-MCI was associated with worse delayed recall. Thus, PD-MCI patients experiencing memory problems may require additional assistance with their medications. Findings have clinical relevance suggesting that objective measures of medication errors may assist clinicians in identifying PD patients needing adherence strategies., (Published by Oxford University Press 2021.)

Impaired motor learning in individuals with Parkinson's disease is often attributed to deficits in executive function, which serves as an important cognitive process supporting motor learning. However, less is known about the role of other cognitive domains and its association with motor learning in Parkinson's disease. The objective of this study was to investigate the associations between motor learning and multiple domains of cognitive performance in individuals with Parkinson's disease. Twenty-nine participants with Parkinson's disease received comprehensive neuropsychological testing, followed by practice of a bimanual finger sequence task. A retention test of the finger sequence task was completed 24 h later. Hierarchical linear regressions were used to examine the associations between motor learning (acquisition rate and retention) and cognitive performance in five specific cognitive domains, while controlling for age, sex, and years of Parkinson's disease diagnosis. We found that a higher acquisition rate was associated with better episodic memory, specifically better recall in visual episodic memory, in individuals with Parkinson's disease. No significant associations were observed between retention and cognitive performance in any domains. The association between motor acquisition and episodic memory indicates an increased dependency on episodic memory as a potential compensatory cognitive strategy used by individuals with Parkinson's disease during motor learning., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Although subjective cognitive decline (SCD) may be an early risk marker of Alzheimer's Disease (AD), research on SCD among Hispanics/Latinos/as/x (henceforth Latinos/as) living in the U.S. is lacking. We investigated if the cross-sectional relationship of self-reported SCD with objective cognition varies as a function of ethnic background (Latinos/as versus Non-Hispanic Whites [NHWs]). Secondary analyses conducted solely within the Latino/a group investigated if informant reported SCD is associated with objective cognition and whether self-reported SCD is related to markers of brain health in a sub-sample of Latinos/as with available MRI data., Methods: Eighty-three participants (≥60 years of age) without dementia (35 Latinos/as; 48 NHWs) completed the Mattis Dementia Rating Scale (MDRS) and the Subjective Cognitive Decline-Questionnaire (SCD-Q). Additionally, 22 Latino/a informants completed the informant-version of the SCD-Q. Hierarchical regression models investigated if ethnicity moderates the association of MDRS and SCD-Q scores after adjusting for demographics and depressive symptoms. Correlational analyses within the Latino/a group investigated self- and informant-reported associations of SCD-Q scores with objective cognition, and associations of self-reported SCD-Q scores with medial temporal lobe volume and thickness., Results: Latinos/as had lower education and MDRS scores than NHWs. Higher SCD-Q scores were associated with lower MDRS scores only in Latinos/as. Within the Latino/a group, self, but not informant reported SCD was related to objective cognition. Medium to large effect sizes were found whereby higher self-reported SCD was associated with lower entorhinal cortex thickness and left hippocampal volume in Latinos/as., Conclusions: The association of SCD and concurrent objectively measured global cognition varied by ethnic background and was only significant in Latinos/as. Self-reported SCD may be an indicator of cognitive and brain health in Latinos/as without dementia, prompting clinicians to monitor cognition. Future studies should explore if SCD predicts objective cognitive decline in diverse groups of Latinos/as living in the U.S.

Poor sleep quality is common among Veterans with posttraumatic stress disorder (PTSD) and history of traumatic brain injury (TBI). However, the relationship between sleep quality and treatment outcomes following trauma-focused interventions is less well-understood in this population. We sought to better understand whether 1) sleep quality changed as a result of trauma-focused treatment and 2) if baseline sleep quality moderated psychological and neurobehavioral treatment outcomes. Our sample consisted of 100 Iraq/Afghanistan era Veterans with PTSD and history of mild to moderate TBI who were randomized to one of two trauma-focused treatments: 1) Cognitive Processing Therapy (CPT) or 2) combined CPT and Cognitive Symptom Management and Rehabilitation Therapy (SMART-CPT). Self-reported sleep quality, psychiatric symptoms (PTSD and depression), and neurobehavioral concerns were assessed at multiple timepoints throughout the study. Multilevel modeling showed sleep quality did not improve, regardless of treatment condition. However, worse baseline sleep quality was associated with less improvement in PTSD symptoms and cognitive complaints. There was no effect of baseline sleep quality on change in depression symptoms. These findings suggest that more targeted treatments to address sleep quality either prior to or in conjunction with trauma-focused therapy may help to improve treatment outcomes for Veterans with comorbid PTSD and TBI history., (Published by Elsevier Ltd.)

Objective: The utility of informant-based measures of cognitive decline to accurately describe objective cognitive performance in Parkinson's disease (PD) without dementia is uncertain. Due to the clinical relevance of this information, the purpose of this study was to examine the relationship between informant-based reports of patient cognitive decline via the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE) and objective cognition in non-demented PD controlling for cognitive status (i.e., mild cognitive impairment; PD-MCI and normal cognition; PD-NC)., Method: One-hundred and thirty-nine non-demented PD participants (PD-MCI n = 38; PD-NC n = 101) were administered measures of language, executive function, attention, learning, delayed recall, visuospatial function, mood, and motor function. Each participant identified an informant to complete the IQCODE and a mood questionnaire., Results: Greater levels of informant-based responses of patient cognitive decline on the IQCODE were significantly associated with worse objective performance on measures of global cognition, attention, learning, delayed recall, and executive function in the overall sample, above and beyond covariates and cognitive status. However, the IQCODE was not significantly associated with language or visuospatial function., Conclusions: Results indicate that informant responses, as measured by the IQCODE, may provide adequate information on a wide range of cognitive abilities in non-demented PD, including those with MCI and normal cognition. Findings have important clinical implications for the utility of the IQCODE in the identification of PD patients in need of further evaluation, monitoring, and treatment.

Introduction: Cognitive deficits occur in Parkinson's disease (PD). Cardiorespiratory fitness (CRF) is associated with better cognitive performance in aging especially in executive function (EF) and memory. The association between CRF and cognitive performance is understudied in people with PD. Brain structures underlying associations also remains unknown. This cross-sectional study examined the associations between CRF and cognitive performance in PD. We also examined associations between CRF and brain structures impacted in PD. Mediation analysis were conducted to examine whether brain structures impacted in PD mediate putative associations between CRF and cognitive performance., Methods: Individuals with PD (N = 33) underwent magnetic resonance imaging (MRI), CRF evaluation (estimated VO 2 max), and neuropsychological assessment. Composite cognitive scores of episodic memory, EF, attention, language, and visuospatial functioning were generated. Structural equation models were constructed to examine whether MRI volume estimates (thalamus and pallidum) mediated associations between CRF and cognitive performance (adjusting for age, education, PD disease duration, sex, MDS-UPDRS motor score, and total intracranial volume)., Results: Higher CRF was associated with better episodic memory (Standardized β = 0.391; p = 0.008), EF (Standardized β = 0.324; p = 0.025), and visuospatial performance (Standardized β = 0.570; p = 0.005). Higher CRF was associated with larger thalamic (Standardized β = 0.722; p = 0.004) and pallidum (Standardized β = 0.635; p = 0.004) volumes. Thalamic volume mediated the association between higher CRF and better EF (Indirect effect = 0.309) and episodic memory (Indirect effect = 0.209) performance (p < 0.05). The pallidum did not significantly mediate associations between CRF and cognitive outcomes., Conclusion: The thalamus plays an important role in the association between CRF and both EF and episodic memory in PD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

Objective: The investigators sought to evaluate the independent and interactive associations between mild traumatic brain injury (mTBI) characteristics and posttraumatic stress disorder (PTSD) symptoms with regard to postconcussive symptoms and cognition among treatment-seeking veterans of the U.S. conflicts in Iraq and Afghanistan., Methods: Sixty-seven Iraq and Afghanistan veterans who had a history of mTBI and comorbid PTSD were grouped based on injury mechanism (blast versus nonblast) and number of lifetime mTBIs (one to two versus three or more). Independent associations between mTBI characteristics and PTSD symptom clusters were evaluated with regard to cognition and postconcussive symptoms. Follow-up analyses were conducted to determine any interactive associations between TBI characteristics and PTSD symptom clusters., Results: Higher PTSD symptoms, particularly hyperarousal, were associated with poorer executive functioning and higher postconcussive symptoms. No direct relationships were observed between PTSD symptom clusters and memory or processing speed. The relationship between hyperarousal and processing speed was moderated by lifetime mTBIs, such that those with a history of at least three mTBIs demonstrated a negative association between hyperarousal and processing speed. Blast-related mTBI history was associated with reduced processing speed, compared with non-blast-related mTBI. However, an interaction was observed such that among those with blast-related mTBI history, higher re-experiencing symptoms were associated with poorer processing speed, whereas veterans without history of blast-related mTBI did not demonstrate an association between processing speed and re-experiencing symptoms., Conclusions: Higher hyperarousal and re-experiencing symptoms were associated with reduced processing speed among veterans with repetitive and blast-related mTBI history, respectively. PTSD symptoms, specifically hyperarousal, were associated with poorer executive functioning and higher postconcussive symptoms. Limited associations were found between injury characteristics and cognition chronically following mTBI. However, these results support synergistic effects of specific PTSD symptom clusters and TBI characteristics.

Emerging evidence suggests mild traumatic brain injury related headache (MTBI-HA) is a form of neuropathic pain state. Previous supraspinal mechanistic studies indicate patients with MTBI-HA demonstrate a dissociative state with diminished levels of supraspinal prefrontal pain modulatory functions and enhanced supraspinal sensory response to pain in comparison to healthy controls. However, the relationship between supraspinal pain modulatory functional deficit and severity of MTBI-HA is largely unknown. Understanding this relationship may provide enhanced levels of insight about MTBI-HA and facilitate the development of treatments. This study assessed pain related supraspinal resting states among MTBI-HA patients with various headache intensity phenotypes with comparisons to controls via functional magnetic resonance imaging (fMRI). Resting state fMRI data was analyzed with self-organizing-group-independent-component-analysis in three MTBI-HA intensity groups (mild, moderate, and severe) and one control group (n = 16 per group) within a pre-defined supraspinal pain network based on prior studies. In the mild-headache group, significant increases in supraspinal function were observed in the right premotor cortex (T = 3.53, p < 0.001) and the left premotor cortex (T = 3.99, p < 0.0001) when compared to the control group. In the moderate-headache group, a significant (T = -3.05, p < 0.01) decrease in resting state activity was observed in the left superior parietal cortex when compared to the mild-headache group. In the severe-headache group, significant decreases in resting state supraspinal activities in the right insula (T = -3.46, p < 0.001), right premotor cortex (T = -3.30, p < 0.01), left premotor cortex (T = -3.84, p < 0.001), and left parietal cortex (T = -3.94, p < 0.0001), and an increase in activity in the right secondary somatosensory cortex (T = 4.05, p < 0.0001) were observed when compared to the moderate-headache group. The results of the study suggest that the increase in MTBI-HA severity may be associated with an imbalance in the supraspinal pain network with decline in supraspinal pain modulatory function and enhancement of sensory/pain decoding.

Background: Apathy is a prevalent, multidimensional neuropsychiatric condition in Parkinson's disease (PD). Several authors have proposed apathy subtypes in PD, but no study has examined the classification of PD patients into distinct apathy subtypes, nor has any study examined the clinical utility of doing so., Objectives: The current study used a data-driven approach to explore the existence and associated clinical characteristics of apathy subtypes in PD., Method: The Apathy Scale (AS) was administered to 157 non-demented individuals with PD. Participants were classified into apathy subgroups through cluster analysis. Differences among apathy subtypes on external clinical indicators were explored across apathy subgroups., Results: Individuals with PD were classified into three subgroups: a Non-Apathetic group with low levels of apathy symptoms, a Low Interest/Energy group, characterized by elevated symptoms of low interest/energy and minimal low initiation/emotional indifference symptoms, and a Low Initiation group, characterized by an absence of low interest/energy symptoms and elevated levels of low initiation/emotional indifference symptoms. Both Low Interest/Energy and Low Initiation groups exhibited worse depression, fatigue, anxiety, health-related quality of life, and caregiver burden than the Non-Apathetic subgroup. The Low Initiation group exhibited worse overall cognition, emotional well-being, state anxiety, communicative ability, and functional ability than the Low Interest/Energy group. Importantly, disease-related characteristics did not differ across apathy symptom subgroups., Conclusions: Non-demented PD patients can be separated into distinct apathy symptom subgroups, which are differentially associated with important clinical variables. Apathy subgroup membership may reflect disruption to different neural systems independent of disease progression., Competing Interests: This project was funded by VA Merit Award grants to Dawn Schiehser (1I01RX001691‐01A1) and J. Vincent Filoteo (5I01CX000813–04). The authors report no conflicts of interest., (© 2020 International Parkinson and Movement Disorder Society.)

Objective: Rapid eye movement sleep behavior disorder (RBD) affects 33-46% of patients with Parkinson's disease (PD) and may be a risk factor for neuropsychological and functional deficits. However, the role of RBD on neuropsychological functioning in PD has yet to be fully determined. We, therefore, examined differences in neurocognitive performance, functional capacity, and psychiatric symptoms among nondemented PD patients with probable RBD (PD/pRBD+) and without (PD/pRBD-), and healthy comparison participants (HC)., Methods: Totally, 172 participants (58 PD/pRBD+; 65 PD/pRBD-; 49 HC) completed an RBD sleep questionnaire, psychiatric/clinical questionnaires, performance-based and self-reported functional capacity measures, and underwent a comprehensive neuropsychological battery assessing attention/working memory, language, visuospatial function, verbal and visual learning and memory, and executive function., Results: Controlling for psychiatric symptom severity, the PD/pRBD+ group had poorer executive functioning and learning performance than the PD/pRBD- group and poorer neuropsychological functioning across all individual cognitive domains than the HCs. In contrast, PD/pRBD- patients had significantly lower scores than HCs only in the language domain. Moreover, PD/pRBD+ patients demonstrated significantly poorer medication management skills compared to HCs. Both PD groups reported greater depressive and anxiety severity compared to HCs; PD/pRBD+ group also endorsed greater severity of apathy compared to HCs., Conclusions: The presence of pRBD is associated with poorer neuropsychological functioning in PD such that PD patients with pRBD have poorer cognitive, functional, and emotional outcomes compared to HC participants and/or PD patients without pRBD. Our findings underscore the importance of RBD assessment for improved detection and treatment of neuropsychological deficits (e.g., targeted cognitive interventions).

Objective: Since neurocognitive functioning following mild traumatic brain injury (mTBI) may be influenced by genetic factors that mediate synaptic survival and repair, we examined the influence of a common brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) on cognition using a well-defined sample of military Veterans with and without a history of mTBI., Method: Participants included 138 Veterans (mTBI = 75; military controls [MCs] = 63) who underwent neuropsychological testing, including completion of self-report measures assessing psychiatric distress, and BDNF genotyping. The mTBI group was tested roughly 66.7 months following their most recent mTBI. Veterans were divided into two groups-Met+ (Met/Met and Met/Val; n = 49) and Met- (Val/Val; n = 89) and compared on domain-specific cognitive composite scores representing memory, executive functioning, and visuospatial speed., Results: ANCOVAs adjusting for psychiatric distress, sex, years of education, and ethnicity/race revealed a significant group (mTBI vs. MC) by BDNF genotype (Met + vs. Met-) interaction for the memory ( p  = .024; η p 2  = .039) and executive functioning ( p  = .010; η p 2  = .050) composites, such that Met+ mTBI Veterans demonstrated better performance than Met- mTBI Veterans on the cognitive measures, whereas Met+ MCs demonstrated worse performance relative to Met- MCs on the cognitive measures. No significant interaction was observed for the visuospatial speed composite ( p  = .938; η p 2  < .001)., Conclusions: These findings offer preliminary evidence to suggest that the Met allele may be protective in the context of remote mTBI. Findings need to be replicated using larger samples, and future studies are necessary to elucidate the precise mechanisms and neural underpinnings of this interaction.

Introduction: Although objective deficits in response inhibition (RI) have been detected in civilians with mild traumatic brain injury (mTBI), it remains unclear whether objective RI is worse in military Veterans with mTBI despite the prevalence of self-reported disinhibition. Assessing RI in Veterans is critical due to their unique characteristics, including combat and blast exposure, in addition to the prevalence of psychiatric comorbidity. Therefore, the aims of this study were to (1) examine RI performance in Veterans with mTBI compared to non-mTBI Veterans and (2) compare RI performance in well-defined subgroups of mTBI Veterans with and without self-reported complaints of disinhibition to non-mTBI Veterans., Method: 53 mTBI Veterans and 37 non-mTBI Veterans completed a Go/No-Go RI task and measures of self-reported disinhibition (Frontal Systems Behavior Scale) and psychiatric symptoms. ANCOVAs covarying for mood and demographics compared RI performances of the non-mTBI Veterans to (1) the total sample of mTBI Veterans ( n = 53) and to (2) mTBI Veterans with elevated (t-score ≥ 60; mTBI-SubjDis; n = 23) and low (t-score < 60; mTBI-NoSubjDis; n = 30) levels of self-reported disinhibition., Results: There were no significant differences in RI between the mTBI group as a whole and the non-mTBI Veterans group. However, when Veterans with mTBI were divided into groups by clinically-significant concern about their disinhibition, the mTBI-SubjDis group demonstrated significantly worse RI than the mTBI-NoSubjDis and non-mTBI Veteran groups. No significant differences in RI performance were observed between the mTBI-NoSubjDis and non-mTBI Veteran groups., Conclusions: Results indicate that mTBI Veterans with elevated levels of self-reported disinhibition show diminished performance on objective measures of RI, independent of mood. Findings highlight the unique contribution of subjective complaints on executive functioning in mTBI, and they underscore the importance of assessing cognitive complaints in order to identify those most at risk for poor-long term outcomes.

Objective: Mild cognitive impairment (MCI) and psychiatric symptoms (anxiety, depression, and apathy) are common in Parkinson's disease (PD). While studies have supported the association between psychiatric symptoms and cognitive performance in PD, it is unclear if the magnitude of link between psychiatric symptoms and cognitive health is stronger by MCI status. The purpose of this study was to examine the association between cognitive performance and psychiatric symptoms in PD and whether MCI status moderates this association., Methods/design: Participants (N = 187) completed a comprehensive neuropsychological assessment that included measures of attention, language, executive function (EF), visuospatial ability, episodic memory, and psychiatric symptoms. Participants were classified as PD-MCI (N = 73) or PD-normal cognition (NC; N = 114). Linear regression analyses were conducted to examine the association between psychiatric symptoms and cognitive performance and the moderating effect of PD-MCI status., Results: There were no differences in mean psychiatric symptoms between PD-MCI and PD-NC. Psychiatric symptoms were predominantly associated with worse EF. The magnitude of the association between anxiety and worse EF was larger in participants with PD-MCI compared with PD-NC. A multivariable regression analysis examining the independent contributions of each symptom demonstrated the most robust association between EF and anxiety., Conclusions: Symptoms of anxiety, depression, and apathy are associated with worse executive functioning in individuals with PD. PD-MCI may be important in moderating the association between cognitive performance, specifically anxiety, and EF. Factors that promote cognitive resilience may serve as key therapeutic modalities in managing neuropsychiatric symptoms in PD., (© 2020 John Wiley & Sons, Ltd.)

Objective: Iraq and Afghanistan Veterans with posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) history have high rates of performance validity test (PVT) failure. The study aimed to determine whether those with scores in the invalid versus valid range on PVTs show similar benefit from psychotherapy and if psychotherapy improves PVT performance., Method: Veterans (N = 100) with PTSD, mild-to-moderate TBI history, and cognitive complaints underwent neuropsychological testing at baseline, post-treatment, and 3-month post-treatment. Veterans were randomly assigned to cognitive processing therapy (CPT) or a novel hybrid intervention integrating CPT with TBI psychoeducation and cognitive rehabilitation strategies from Cognitive Symptom Management and Rehabilitation Therapy (CogSMART). Performance below standard cutoffs on any PVT trial across three different PVT measures was considered invalid (PVT-Fail), whereas performance above cutoffs on all measures was considered valid (PVT-Pass)., Results: Although both PVT groups exhibited clinically significant improvement in PTSD symptoms, the PVT-Pass group demonstrated greater symptom reduction than the PVT-Fail group. Measures of post-concussive and depressive symptoms improved to a similar degree across groups. Treatment condition did not moderate these results. Rate of valid test performance increased from baseline to follow-up across conditions, with a stronger effect in the SMART-CPT compared to CPT condition., Conclusion: Both PVT groups experienced improved psychological symptoms following treatment. Veterans who failed PVTs at baseline demonstrated better test engagement following treatment, resulting in higher rates of valid PVTs at follow-up. Veterans with invalid PVTs should be enrolled in trauma-focused treatment and may benefit from neuropsychological assessment after, rather than before, treatment.

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., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Apathy Scale (AS), a popular measure of apathy in Parkinson's disease (PD), has been somewhat limited for failing to characterize dimensions of apathy, such as those involving cognitive, behavioral, and emotional apathy symptoms. This study sought to determine whether factors consistent with these apathy dimensions in PD could be identified on the AS, examine the associations between these factors and disease-related characteristics, and compare PD patients and healthy control (HCs) on identified factors., Methods: Confirmatory (CFA) and exploratory factor analysis (EFA) were conducted on AS scores of 157 nondemented PD patients to identify AS factors. These factors were then correlated with important disease-related characteristics, and PD and HC participants were compared across these factors., Results: Previously proposed AS models failed to achieve an adequate fit in CFA. A subsequent EFA revealed two factors on the AS reflecting joint cognitive-behavioral aspects of apathy (Motivation-Interest-Energy) and emotional apathy symptoms (Indifference). Both factors were associated with anxiety, depression, health-related quality of life, and independent activities of daily living, with Indifference associated more with the latter. In addition, only the Indifference factor was associated with cognitive functioning. PD patients reported higher levels of symptoms than HCs on both factors, with the group difference slightly larger on the Motivation-Interest-Energy factor., Conclusion: The AS can be decomposed into two factors reflecting Motivation-Interest-Energy and Indifference symptoms. These factors are differentially associated with clinical variables, including cognition and independent activities of daily living, indicating the importance of evaluating apathy from a multidimensional perspective.

Objective: To better concurrently address emotional and neuropsychological symptoms common in veterans with comorbid post-traumatic stress disorder (PTSD) and history of traumatic brain injury (TBI), we integrated components of compensatory cognitive training from the Cognitive Symptom Management and Rehabilitation Therapy (CogSMART) programme into cognitive processing therapy (CPT) for PTSD to create a hybrid treatment, SMART-CPT (CogSMART+CPT). This study compared the efficacy of standard CPT with SMART-CPT for treatment of veterans with comorbid PTSD and history of TBI reporting cognitive symptoms., Methods: One hundred veterans with PTSD, a history of mild to moderate TBI and current cognitive complaints were randomised and received individually delivered CPT or SMART-CPT for 12 weeks. Participants underwent psychological, neurobehavioural and neuropsychological assessments at baseline, on completion of treatment and 3 months after treatment., Results: Both CPT and SMART-CPT resulted in clinically significant reductions in PTSD and postconcussive symptomatology and improvements in quality of life. SMART-CPT resulted in additional improvements in the neuropsychological domains of attention/working memory, verbal learning/memory and novel problem solving., Conclusion: SMART-CPT, a mental health intervention for PTSD, combined with compensatory cognitive training strategies, reduces PTSD and neurobehavioural symptoms and also provides added value by improving cognitive functioning., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Symptoms of anxiety, depression commonly co-occur with cognitive decline in patients with Parkinson's disease (PD). The directionality of this association is unclear, however, in that poor cognitive performance may lead to increased symptoms of anxiety and depression or higher anxiety and depressive symptoms may lead to cognitive decline. The purpose of this study was to elucidate the directionality of the association between symptoms of anxiety and depression with cognitive performance in newly diagnosed patients with PD., Method: Longitudinal data from 362 nondemented participants from the Parkinson's Progression Markers Initiative (PPMI) were examined. Participants completed as many as five assessments of anxiety symptoms, depressive symptoms, and cognitive performance over a 4-year period. Bivariate dual change score models were fit to examine the dynamic association between level and change of anxiety and depressive symptoms with level and change in cognitive performance., Results: Across all cognitive domains, worse performance was associated with subsequently higher state anxiety, trait anxiety, and depressive symptoms. The reverse direction was not significant as higher state anxiety, trait anxiety, and depressive symptoms were not associated with subsequent declines in cognitive performance., Conclusions: Poorer cognitive performance, across all cognitive domains, was a risk factor for increased symptoms of anxiety and depression a year later. No support was present for the alternative hypothesis that anxiety and depression are associated with subsequent cognitive decline. Clinical implications include the importance of psychoeducation, as well as assessing and monitoring anxiety and depression in patients with PD with poor cognitive performance. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objective/background: The Insomnia Severity Index (ISI) is a widely used self-report measure of insomnia symptoms. However, to date this measure has not been validated or well-characterized in veterans who have experienced traumatic brain injury (TBI). This study assessed the psychometric properties and convergent, divergent, construct, and discriminate validity of the ISI in veterans with a history of TBI., Participants: Eighty-three veterans with history of TBI were seen in the VA San Diego Healthcare System as part of a research protocol., Methods: Measures included the ISI, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Neurobehavioral Symptom Inventory, Beck Depression Inventory-II, Beck Anxiety Inventory, and PTSD Checklist-Military Version., Results: The ISI demonstrated moderate to strong or excellent convergent and divergent validity. A principal component analysis indicated a single construct with excellent internal consistency (Cronbach's alpha = 0.92). In exploratory analyses, the ISI discriminated well between those with (73%) and without (27%) sleep disturbance based on the PSQI., Conclusions: Results from this study indicate validity of the ISI in assessing insomnia in veterans with history of TBI and suggest a cutoff score not dissimilar from non-TBI populations. Findings from this study can help inform clinical applicability of the ISI, as well as future studies of insomnia in TBI.

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, η p 2  = .083) and speed (p = .023, η p 2  = .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.

The Geriatric Depression Scale (GDS) is recommended for screening depression in individuals with Parkinson's disease (PD). Empirical evidence, however, is limited regarding its validity and factor structure in PD. Thus, the current study sought to evaluate the convergent and divergent validity of the GDS, as well as the structure and validity of the derived factors., Method: Nondemented individuals with PD (n = 158) completed the GDS-30, and items were subjected to a principle component analysis. Geriatric Depression Scale total and factor scores were correlated with depression items from the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRSd) and Hamilton Rating Scale for Depression (HAMDd), as well as with the Apathy Scale (AS), State-Trait Anxiety Inventory (STAI), Modified Fatigue Impact Scale (MFIS), Parkinson's disease Sleep Scale, and a Subjective Cognitive Function composite score., Results: The GDS total score was strongly correlated with divergent neuropsychiatric measures (AS, r = 0.57; STAI, r = 0.66; MFIS, r = 0.60), while only moderately correlated with convergent measures (MDS-UPDRSd, r = 0.36; HAMDd, r = 0.32; Ps < 0.05). Linear regression analyses revealed standardized measures of anxiety, apathy, and fatigue independently predicted the GDS total score, while depression items (MDS-UPDRSd and HAMDd) failed to reach significance. Three independent factors were identified: Anxiety, Apathy, and Fatigue. These factors were significantly predicted by their respective convergent measures., Conclusions: Taken together, our findings suggest that the GDS and its subscales appear to primarily measure anxiety, apathy, and fatigue in PD, or alternatively, these symptom dimensions may be predominant in PD-depression. Future research with clinically diagnosed samples is needed to confirm these initial findings., (© 2018 John Wiley & Sons, Ltd.)

Objective: Blast exposure (BE) and mild traumatic brain injury (mTBI) have been independently linked to pathological brain changes. However, the combined effects of BE and mTBI on brain structure have yet to be characterized. Therefore, we investigated whether regional differences in cortical thickness exist between mTBI Veterans with and without BE while on deployment. We also examined whether cortical thickness (CT) and cognitive performance differed among mTBI Veterans with low vs. high levels of cumulative BE. Methods: 80 Veterans with mTBI underwent neuroimaging and completed neuropsychological testing and self-report symptom rating scales. Analyses of covariance (ANCOVA) were used to compare blast-exposed Veterans (mTBI+BE, n = 51) to those without BE (mTBI-BE, n = 29) on CT of frontal and temporal a priori regions of interest (ROIs). Next, multiple regression analyses were used to examine whether CT and performance on an executive functions composite differed among mTBI Veterans with low (mTBI+BE Low, n = 22) vs. high (mTBI+BE High, n = 26) levels of cumulative BE. Results: Adjusting for age, numer of TBIs, and PTSD symptoms, the mTBI+BE group showed significant cortical thinning in frontal regions (i.e., left orbitofrontal cortex [ p = 0.045], left middle frontal gyrus [ p = 0.023], and right inferior frontal gyrus [ p = 0.034]) compared to the mTBI-BE group. No significant group differences in CT were observed for temporal regions ( p 's > 0.05). Multiple regression analyses revealed a significant cumulative BE × CT interaction for the left orbitofrontal cortex ( p = 0.001) and left middle frontal gyrus ( p = 0.020); reduced CT was associated with worse cognitive performance in the mTBI+BE High group but not the mTBI+BE Low group. Conclusions: Findings show that Veterans with mTBI and BE may be at risk for cortical thinning post-deployment. Moreover, our results demonstrate that reductions in CT are associated with worse executive functioning among Veterans with high levels of cumulative BE. Future longitudinal studies are needed to determine whether BE exacerbates mTBI-related cortical thinning or independently negatively influences gray matter structure.

Objective: Fatigue is a complex, multidimensional phenomenon that commonly occurs following traumatic brain injury (TBI). The thalamus-a structure vulnerable to both primary and secondary injuries in TBI-is thought to play a pivotal role in the manifestation of fatigue. We explored how neuroimaging markers of local and global thalamic morphometry relate to the subjective experience of fatigue post-TBI., Methods: Sixty-three Veterans with a history of mild TBI underwent structural magnetic resonance imaging and completed questionnaires related to fatigue and psychiatric symptoms. FMRIB's Software (FSL) was utilized to obtain whole brain and thalamic volume estimates, as well as to perform regional thalamic morphometry analyses., Results: Independent of age, sex, intracranial volume, posttraumatic stress disorder, and depressive symptoms, greater levels of self-reported fatigue were significantly associated with decreased right (P = .026) and left (P = .046) thalamic volumes. Regional morphometry analyses revealed that fatigue was significantly associated with reductions in the anterior and dorsomedial aspects of the right thalamic body (P < .05). Similar trends were observed for the left thalamic body (P < .10)., Conclusions: Both global and regional thalamic morphometric changes are associated with the subjective experience of fatigue in Veterans with a history of mild TBI. These findings support a theory in which disruption of thalamocorticostriatal circuitry may result in the manifestation of fatigue in individuals with a history of neurotrauma.

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; η p 2 = 0.043), and there was a trend finding in the same direction for the ASD index (p = 0.091; η p 2 = 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., (Published by Elsevier Ltd.)

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.

Objective: Posttraumatic stress disorder (PTSD), history of mild traumatic brain injury (mTBI), and executive function (EF) difficulties are prevalent in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans. We evaluated the contributions of injury variables, lower-order cognitive component processes (processing speed/attention), and psychological symptoms to EF., Participants: OEF/OIF Veterans (N = 65) with PTSD and history of mTBI were administered neuropsychological tests of EF and self-report assessments of PTSD and depression., Results: Those impaired on one or more EF measures had higher PTSD and depression symptoms and lower processing speed/attention performance than those with intact performance on all EF measures. Across participants, poorer attention/processing speed performance and higher psychological symptoms were associated with worse performance on specific aspects of EF (eg, inhibition and switching) even after accounting for injury variables. Although direct relationships between EF and injury variables were equivocal, there was an interaction between measures of injury burden and processing speed/attention such that those with greater injury burden exhibited significant and positive relationships between processing speed/attention and inhibition/switching, whereas those with lower injury burden did not., Conclusion: Psychological symptoms as well as lower-order component processes of EF (attention and processing speed) contribute significantly to executive dysfunction in OEF/OIF Veterans with PTSD and history of mTBI. However, there may be equivocal relationships between injury variables and EF that warrant further study. Results provide groundwork for more fully understanding cognitive symptoms in OEF/OIF Veterans with PTSD and history of mTBI that can inform psychological and cognitive interventions in this population.

Objective: We examined BOLD (Blood-Oxygen-Level Dependent) activity reduction upon stimuli repetition of face-name pairs in older adults with amnestic (aMCI) and non-amnestic (naMCI) mild cognitive impairment diagnosed using a comprehensive actuarial method, and relationships between activity reduction and behavioral indices., Method: Twenty-nine cognitively healthy older adults (CHs) and 20 with MCI (n = 12 aMCI; n = 8 naMCI) underwent functional MRI event-related imaging, a comprehensive neuropsychological battery, and 1-year follow-up exam. During scanning, participants were shown face-name pairs 1-3 times and administered a post-scan recognition task., Results: The MCI group demonstrated less activity reduction upon repetition of face-name pairs within the MTL and other regions compared to CHs. Less activity reduction was associated with poorer Time 1 neuropsychological performance for the CH group and poorer post-scan recognition performance for the MCI group. Less activity reduction was related to poorer neuropsychological performance at Time 2 in the MCI group. Within MCIs, those with aMCI demonstrated less activity reduction upon repetition of face-name pairs than those with naMCI., Conclusions: Distinct patterns of brain activity were identified in the MCI group compared to CHs, and aMCI compared to naMCI. Activated regions were not restricted to traditional memory circuitry, implicating a wider network of regions involved in the encoding of associative tasks. Findings add support to the hypothesis that lack of reduced BOLD activity reflects "faulty adaptation" to repeated stimuli and that reduction in activity represents successful encoding processes. They also provide further support for use of the face-name paradigm as a marker of prodromal Alzheimer's disease, and method to distinguish between MCI subtypes., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.