Machine learning models of plasma proteomic data predict mood in chronic stroke and tie it to aberrant peripheral immune responses.

Post-stroke depression is common, long-lasting and associated with severe morbidity and death, but mechanisms are not well-understood. We used a broad proteomics panel and developed a machine learning algorithm to determine whether plasma protein data can predict mood in people with chronic stroke, and to identify proteins and pathways associated with mood. We used Olink to measure 1,196 plasma proteins in 85 participants aged 25 and older who were between 5 months and 9 years after ischemic stroke. Mood was assessed with the Stroke Impact Scale mood questionnaire (SIS3). Machine learning multivariable regression models were constructed to estimate SIS3 using proteomics data, age, and time since stroke. We also dichotomized participants into better mood (SIS3 > 63) or worse mood (SIS3 ≤ 63) and analyzed candidate proteins. Machine learning models verified that there is indeed a relationship between plasma proteomic data and mood in chronic stroke, with the most accurate prediction of mood occurring when we add age and time since stroke. At the individual protein level, no single protein or set of proteins predicts mood. But by using univariate analyses of the proteins most highly associated with mood we produced a model of chronic post-stroke depression. We utilized the fact that this list contained many proteins that are also implicated in major depression. Also, over 80% of immune proteins that correlate with mood were higher with worse mood, implicating a broadly overactive immune system in chronic post-stroke depression. Finally, we used a comprehensive literature review of major depression and acute post-stroke depression. We propose that in chronic post-stroke depression there is over-activation of the immune response that then triggers changes in serotonin activity and neuronal plasticity leading to depressed mood.

A longitudinal study of the post-stroke immune response and cognitive functioning: the StrokeCog study protocol.

BACKGROUND: Stroke increases the risk of cognitive impairment even several years after the stroke event. The exact mechanisms of post-stroke cognitive decline are unclear, but the immunological response to stroke might play a role. The aims of the StrokeCog study are to examine the associations between immunological responses and long-term post-stroke cognitive trajectories in individuals with ischemic stroke. METHODS: StrokeCog is a single-center, prospective, observational, cohort study. Starting 6-12 months after stroke, comprehensive neuropsychological assessment, plasma and serum, and psychosocial variables will be collected at up to 4 annual visits. Single cell sequencing of peripheral blood monocytes and plasma proteomics will be conducted. The primary outcome will be the change in global and domain-specific neuropsychological performance across annual evaluations. To explain the differences in cognitive change amongst participants, we will examine the relationships between comprehensive immunological measures and these cognitive trajectories. It is anticipated that 210 participants will be enrolled during the first 3 years of this 4-year study. Accounting for attrition, an anticipated final sample size of 158 participants with an average of 3 annual study visits will be available at the completion of the study. Power analyses indicate that this sample size will provide 90% power to detect an average cognitive change of at least 0.23 standard deviations in either direction. DISCUSSION: StrokeCog will provide novel insight into the relationships between immune events and cognitive change late after stroke.

A year-long immune profile of the systemic response in acute stroke survivors.

Stroke is a leading cause of cognitive impairment and dementia, but the mechanisms that underlie post-stroke cognitive decline are not well understood. Stroke produces profound local and systemic immune responses that engage all major innate and adaptive immune compartments. However, whether the systemic immune response to stroke contributes to long-term disability remains ill-defined. We used a single-cell mass cytometry approach to comprehensively and functionally characterize the systemic immune response to stroke in longitudinal blood samples from 24 patients over the course of 1 year and correlated the immune response with changes in cognitive functioning between 90 and 365 days post-stroke. Using elastic net regularized regression modelling, we identified key elements of a robust and prolonged systemic immune response to ischaemic stroke that occurs in three phases: an acute phase (Day 2) characterized by increased signal transducer and activator of transcription 3 (STAT3) signalling responses in innate immune cell types, an intermediate phase (Day 5) characterized by increased cAMP response element-binding protein (CREB) signalling responses in adaptive immune cell types, and a late phase (Day 90) by persistent elevation of neutrophils, and immunoglobulin M+ (IgM+) B cells. By Day 365 there was no detectable difference between these samples and those from an age- and gender-matched patient cohort without stroke. When regressed against the change in the Montreal Cognitive Assessment scores between Days 90 and 365 after stroke, the acute inflammatory phase Elastic Net model correlated with post-stroke cognitive trajectories (r = -0.692, Bonferroni-corrected P = 0.039). The results demonstrate the utility of a deep immune profiling approach with mass cytometry for the identification of clinically relevant immune correlates of long-term cognitive trajectories.

Streamlining screening of emotional function in Veterans with traumatic brain injury.

OBJECTIVES: This study examined how depression, anxiety, and sleep items from the Neurobehavioral Symptom Inventory (NSI) predict results from longer inventories. METHOD: This was a retrospective review from 484, predominantly male (96.1%) Veterans, mean age 29.7 years, who underwent brief neuropsychological screening during a comprehensive, multidisciplinary evaluation for mild traumatic brain injury (TBI). Participants completed the NSI, insomnia severity index (ISI), and hospital anxiety and depression scale (HADS). RESULTS: OVERALL,: 97.1% who endorsed "severe"/"very severe" anxiety on the NSI had significant anxiety on the HADS; 85% reporting "severe"/"very severe" depression on the NSI, had significant depression on the HADS; and 97.7% reporting "severe"/"very severe" sleep problems on the NSI, had significant sleep difficulties on the ISI. CONCLUSION: Close correspondence between "severe"/"very severe" symptoms on the NSI and lengthier checklists suggests additional checklists may be eliminated and individuals can be referred for mental health treatment. NSI reports of "mild"/"moderate" require further screening.

Neuropsychological test validity in Veterans presenting with subjective complaints of 'very severe' cognitive symptoms following mild traumatic brain injury.

OBJECTIVE: This study explored the utility of combining data from measures of performance validity and symptom validity among Veterans undergoing neuropsychological evaluation for mild traumatic brain injury (mTBI). BACKGROUND: Persistent cognitive impairments following mTBI are often reported by returning combat veterans. However, objectively-measured cognitive deficits are not common among individuals with mTBI, raising the question of whether negative impression management influences self-ratings. METHODS: Self-report ratings were obtained for memory, concentration, decision-making, and processing speed/organization using a 5-point scale ranging from 'none' to 'very severe'. Veterans also completed brief neuropsychological testing which included measures of performance validity. RESULTS: Study 1 examined data from 122 participants and demonstrated that veterans reporting a 'very severe' cognitive deficit were over three times as likely to demonstrate poor effort on a validity test than those without a very severe rating. Study 2 replicated these findings in an independent sample of 127 veterans and also demonstrated that both severity of self-report ratings and performance on an embedded measure of effort were predictive of poor effort on a stand-alone performance validity test. CONCLUSION: Veterans with suspected mTBI who report 'very severe' cognitive impairment have a greater likelihood of putting forth sub-optimal effort on objective testing.

Incidental Learning: A Brief, Valid Measure of Memory Based on the WAIS-IV Vocabulary and Similarities Subtests.

OBJECTIVE: We assessed the validity of a brief incidental learning measure based on the Similarities and Vocabulary subtests of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV). BACKGROUND: Most neuropsychological assessments for memory require intentional learning, but incidental learning occurs without explicit instruction. Incidental memory tests such as the WAIS-III Symbol Digit Coding subtest have existed for many years, but few memory studies have used a semantically processed incidental learning model. METHODS: We conducted a retrospective analysis of 37 veterans with traumatic brain injury, referred for outpatient neuropsychological testing at a Veterans Affairs hospital. As part of their evaluation, the participants completed the incidental learning tasks. We compared their incidental learning performance to their performance on traditional memory measures. RESULTS: Incidental learning scores correlated strongly with scores on the California Verbal Learning Test-Second Edition (CVLT-II) and Brief Visuospatial Memory Test-Revised (BVMT-R). After we conducted a partial correlation that controlled for the effects of age, incidental learning correlated significantly with the CVLT-II Immediate Free Recall, CVLT-II Short-Delay Recall, CVLT-II Long-Delay Recall, and CVLT-II Yes/No Recognition Hits, and with the BVMT-R Delayed Recall and BVMT-R Recognition Discrimination Index. CONCLUSIONS: Our incidental learning procedures derived from subtests of the WAIS-IV Edition are an efficient and valid way of measuring memory. These tasks add minimally to testing time and capitalize on the semantic encoding that is inherent in completing the Similarities and Vocabulary subtests.

Limited usefulness of the Rey Fifteen-Item Test in detection of invalid performance in veterans suspected of mild traumatic brain injury.

OBJECTIVE: This study explored using the FIT as a measure of performance validity among veterans undergoing neuropsychological evaluation for mild traumatic brain injury (mTBI). BACKGROUND: The Rey Fifteen-Item Memory Test (FIT) is a performance validity measure criticized for poor sensitivity. METHODS: Two hundred and fifty-seven veterans completed the FIT and Wechsler Adult Intelligence Scale, Fourth Edition, Digit Span (DS); 109 of whom completed the Test of Memory Malingering (TOMM). FIT cut-offs of <9, <8 and stricter cut-offs were examined using DS and/or TOMM as criterion performance validity measures. RESULTS: Only four participants scored below the standard cut score of 9 on the FIT. Among the 13 veterans failing both criterion tests, only two scored below 9 on the FIT. Regardless of which FIT cut-off was used, the FIT had poor diagnostic accuracy. CONCLUSION: Despite its popularity, the FIT is not supported as an appropriate measure of performance validity in veterans undergoing evaluation for possible mTBI. Therefore, inferences regarding neuropsychological data reliability with adequate statistical certainty require use of other measures of performance validity with greater sensitivity.

Predictors of inpatient and outpatient healthcare utilization in veterans with traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) can place a significant financial and resource burden on healthcare systems. This study examined predictors of outpatient and inpatient healthcare utilization in veterans with a history of TBI. METHODS: A secondary analysis was conducted on data from 1565 veterans with TBI and 1565 veterans without TBI seen for healthcare services at the VA Palo Alto Health Care System between 2000 and 2010. Patterns and predictors of outpatient and inpatient medical and psychiatric care were examined. RESULTS: Veterans with TBI utilized significantly more services compared with the control group. The TBI group was seen for more than 160 000 outpatient services and was almost 9 times more likely to be hospitalized than the control group. Although psychiatric disorders were more prevalent in the TBI group and associated with increased medical and mental health utilization within the TBI group, they did not account fully for the significant group differences. CONCLUSIONS: Veterans with a history of TBI have much greater healthcare needs than veterans without TBI, likely because of non-TBI-related factors. Increased monitoring and early intervention treatments may be warranted for certain at-risk veterans with the goal of minimizing their need for long-term or extensive healthcare services in the future.

The contributions of self-reported injury characteristics and psychiatric symptoms to cognitive functioning in OEF/OIF veterans with mild traumatic brain injury.

Mild traumatic brain injury (mTBI) affects a significant number of combat veterans returning from Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF). Although resolution of mTBI symptoms is expected over time, some individuals continue to report lingering cognitive difficulties. This study examined the contributions of self-reported mTBI injury characteristics (e.g., loss of consciousness, post-traumatic amnesia) and psychiatric symptoms to both subjective and objective cognitive functioning in a sample of 167 OEF/OIF veterans seen in a TBI clinic. Injury characteristics were not associated with performance on neuropsychological tests but were variably related to subjective ratings of cognitive functioning. Psychiatric symptoms were highly prevalent and fully mediated most of the relationships between injury characteristics and cognitive ratings. This indicates that mTBI characteristics such as longer time since injury and loss of consciousness or post-traumatic amnesia can lead to increased perceived cognitive deficits despite having no objective effects on cognitive performance. Psychiatric symptoms were associated with both cognitive ratings and neuropsychological performance, illustrating the important role that psychiatric treatment can potentially play in optimizing functioning. Finally, subjective cognitive ratings were not predictive of neuropsychological performance once psychiatric functioning was statistically controlled, suggesting that neuropsychological assessment provides valuable information that cannot be gleaned from self-report alone.

The influence of sleep and mood on cognitive functioning among veterans being evaluated for mild traumatic brain injury.

OBJECTIVE: Veterans undergoing evaluation for mild traumatic brain injury commonly report insomnia, psychiatric symptoms, and cognitive dysfunction. This study examines the effects of self-reported amount of sleep and subjective sleep quality on neuropsychological test performance. METHOD: 262 veterans were seen for neuropsychological assessment in a Veterans Affairs traumatic brain injury clinic. All participants completed measures of depression, anxiety, and sleep satisfaction, and also estimated the number of hours they slept the night before the assessment. Factor scores of attention/concentration and memory were created using factor analyses. Data were analyzed with linear regression. RESULTS: Depression and anxiety were significantly correlated with sleep satisfaction and predictive of cognitive ability. Both sleep satisfaction and hours slept were significantly correlated with memory, but not attention. After controlling for the effects of depression and anxiety, hours slept but not sleep satisfaction was predictive of memory test performance. CONCLUSIONS: Perceived sleep quality is heavily influenced by psychiatric symptoms; therefore, veterans' report of sleep satisfaction may merely reflect their overall level of distress. Sleep quantity, however, appears to uniquely contribute to memory performance. Thus, assessment of sleep is important and provides clinicians with useful information, especially among individuals with psychiatric comorbidities.

Predictors of perceived need for medical care in an inpatient rehabilitation unit: an update.

Limited awareness of illness, or poor insight, has been associated with poor treatment outcomes and prognoses in both psychiatric and medical populations. We examined predictors of insight in a sample of 403 patients in an inpatient rehabilitation unit at a Midwest Veterans Affairs Medical Center. A multiple regression analysis revealed that age, depression, IQ, and a measure of judgment were significant predictors of acknowledgement of illness. Younger age, higher IQ, better judgment, and depression were associated with better insight. By identifying risk factors for poor insight, these findings have significant clinical implications for healthcare providers.

Contemporary review 2009: cognitive aging.

This article addresses key topics in cognitive aging, intending to provide the reader with a brief overview of the current state of research in this growing, multidisciplinary field. A summary of the physiological changes in the aging brain is provided as well as a review of variables that influence cognitive abilities in older age. Normal aging differentially affects various aspects of cognition, and specific changes within various domains such as attention, executive functioning, and memory are discussed. Various theories have been proposed to account for the cognitive changes that accompany normal aging, and a brief examination of these theories is presented in the context of these domain-specific changes.

Source memory and frontal functioning in Parkinson's disease.

The most extensively described pathological abnormality in Parkinson's disease (PD) is loss of dopaminergic neurons in the substantia nigra pars compacta and the ventral tegmental area, with degeneration of their striatal terminals. Because of the intimate connections between the striatum and the frontal lobes, individuals with PD often demonstrate impairments on those tasks relying on the prefrontal cortex (e.g., tests of executive functioning). Source memory, or memory for context, is believed to rely on the prefrontal cortex and has been previously associated with executive functioning performance, although it has received little attention in the PD literature. Executive functioning and source memory were measured in a group of nondemented PD patients and healthy control participants. Within the PD group, an anti-Parkinson's medication withdrawal manipulation was used to examine whether source memory was affected by phasic changes in dopamine levels. Compared to healthy control participants, PD patients were impaired in source memory (both on- and off-medication) and on a composite measure of executive functioning. Within the PD group, medication administration improved motor performance but did not have a significant effect on source memory.

Health Care Utilization of Veterans With Serious Mental Illness.

Outreach regarding veteran-specific factors can help determine which targeted interventions reduce the need for chronic mental illness inpatient hospitalization.

Reliability and factor structure of the Hospital Anxiety and Depression Scale in a polytrauma clinic.

The Hospital Anxiety and Depression Scale (HADS) is a brief self-report measure of anxiety and depression symptoms. This study examined the internal consistency and factor structure of the HADS among Veterans in a polytrauma/traumatic brain injury clinic. The sample consisted of 312 Veterans. A confirmatory factor analysis of the depression and anxiety subscales showed, not surprisingly, that the two factors were highly correlated (r = 0.7). Goodness of fit statistics for the two-factor model were acceptable (root mean square error of approximation = 0.06, comparative fit index = 0.94). The HADS demonstrated very good reliability overall (alpha = 0.89) and for the individual subscales (alpha = 0.84). This study supports the use of the HADS as a screen for depression and anxiety in the assessment of mild traumatic brain injury in a Veteran population.

Patterns of frontoparietal activation as a marker for unsuccessful visuospatial processing in healthy aging.

Visuospatial abilities are sensitive to age-related decline, although the neural basis for this decline (and its everyday behavioral correlates) is as yet poorly understood. fMRI was employed to examine age-related differences in patterns of functional activation that underlie changes in visuospatial processing. All participants completed a brief neuropsychological battery and also a figure ground task (FGT) assessing visuospatial processing while fMRI was recorded. Participants included 16 healthy older adults (OA; aged 69-82 years) and 16 healthy younger adults (YA; aged 20-35 years). We examined age-related differences in behavioral performance on the FGT in relation to patterns of fMRI activation. OA demonstrated reduced performance on the FGT task and showed increased activation of supramarginal parietal cortex as well as increased activation of frontal and temporal regions compared to their younger counterparts. Performance on the FGT related to increased supramarginal gyrus activity and increased medial prefrontal activity in OAs, but not YAs. Our results are consistent with an anterior-posterior compensation model. Successful FGT performance requires the perception and integration of multiple stimuli and thus it is plausible that healthy aging may be accompanied by changes in visuospatial processing that mimic a subtle form of dorsal simultanagnosia. Overall, decreased visuospatial processing in OA relates to an altered frontoparietal neurobiological signature that may contribute to the general phenomenon of increasingly fragmented execution of behavior associated with normal aging.

WAIS-IV reliable digit span is no more accurate than age corrected scaled score as an indicator of invalid performance in a veteran sample undergoing evaluation for mTBI.

Reliable Digit Span (RDS) is a measure of effort derived from the Digit Span subtest of the Wechsler intelligence scales. Some authors have suggested that the age-corrected scaled score provides a more accurate measure of effort than RDS. This study examined the relative diagnostic accuracy of the traditional RDS, an extended RDS including the new Sequencing task from the Wechsler Adult Intelligence Scale-IV, and the age-corrected scaled score, relative to performance validity as determined by the Test of Memory Malingering. Data were collected from 138 Veterans seen in a traumatic brain injury clinic. The traditional RDS (≤ 7), revised RDS (≤ 11), and Digit Span age-corrected scaled score ( ≤ 6) had respective sensitivities of 39%, 39%, and 33%, and respective specificities of 82%, 89%, and 91%. Of these indices, revised RDS and the Digit Span age-corrected scaled score provide the most accurate measure of performance validity among the three measures.

Cognitive functioning, retirement status, and age: results from the Cognitive Changes and Retirement among Senior Surgeons study.

BACKGROUND: Accurate assessment of cognitive functioning is an important step in understanding how to better evaluate both clinical and cognitive competence in practicing surgeons. As part of the Cognitive Changes and Retirement among Senior Surgeons study, we examined the objective cognitive functioning of senior surgeons in relation to retirement status and age. STUDY DESIGN: Computerized cognitive tasks measuring visual sustained attention, reaction time, and visual learning and memory were administered to both practicing and retired surgeons at annual meetings of the American College of Surgeons. Data from 168 senior surgeons aged 60 and older were compared with data from 126 younger surgeons aged 45 to 59, with performance below 1.5 standard deviations or more indicating a significant difference between the groups. RESULTS: Sixty-one percent of practicing senior surgeons performed within the range of the younger surgeons on all cognitive tasks. Seventy-eight percent of practicing senior surgeons aged 60 to 64 performed within the range of the younger surgeons on all tasks compared with 38% of practicing senior surgeons aged 70 and older. Forty-five percent of retired senior surgeons performed within the range of the younger surgeons on all tasks. No senior surgeon performed below the younger surgeons on all 3 tasks. CONCLUSIONS: The majority of practicing senior surgeons performed at or near the level of their younger peers on all cognitive tasks, as did almost half of the retired senior surgeons. This suggests that older age does not inevitably preclude cognitive proficiency. The variability in cognitive performance across age groups and retirement status suggests the need for formal measures of objective cognitive functioning to help surgeons detect changes in cognitive performance and aid in their decisions to retire.

Self-reported cognitive symptoms following mild traumatic brain injury are poorly associated with neuropsychological performance in OIF/OEF veterans.

Mild traumatic brain injury (mTBI) is not uncommon among Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans, and many individuals within this group report lingering cognitive difficulties following their injury. For Department of Veterans Affairs clinicians, an accurate assessment of cognitive symptoms is important in providing appropriate clinical care. Although self-assessment is commonly employed to screen for difficulties in cognitive functioning, little is known about the accuracy of self-report in this population. This study collected cognitive, psychiatric, and self-report data from 105 OIF/OEF veterans with mTBI to examine the relationship between self-reported cognitive functioning and objective neuropsychological test performance. Additionally, clinicians who frequently work with OIF/OEF veterans were asked to predict the magnitude of these associations. Self-reported cognitive functioning was not significantly correlated with objective cognitive abilities, suggesting that objective neuropsychological testing should be used when cognitive weakness is suspected. Perceived cognitive deficits were associated with depression, anxiety, and posttraumatic stress disorder, illustrating the additional importance of adequate assessment and treatment of psychiatric symptoms. Clinicians tended to overestimate the association between self-report and test performance.

Results from the cognitive changes and retirement among senior surgeons self-report survey.

BACKGROUND: The Cognitive Changes and Retirement among Senior Surgeons (CCRASS) study suggested that although subjective cognitive awareness may play a role in surgeons' retirement decisions, self-perceived cognitive decline did not predict objective cognitive performance. This article summarizes results from all participants who completed the survey portion of the CCRASS study. STUDY DESIGN: A survey examining subjective cognitive changes, changes in caseload, involvement in new technology, and retirement decisions, was administered to 995 surgeons at annual meetings of the Clinical Congress of the American College of Surgeons between 2001 and 2006. RESULTS: Forty-five percent reported increased caseload volume and 48% reported increased caseload complexity during the previous 5 years. In addition, 75% and 73% denied any recent changes in memory recall or name recognition, respectively. Increasing age was associated with decreases in clinical caseload and complexity. The majority of respondents across all age groups reported active participation in either learning (64%) or contributing (13%) to new technology in the field. Among surgeons with no imminent plans for retirement, 58% reported that a retirement decision will be based on skill level. CONCLUSIONS: Increasing age was associated with decreases in caseload and case complexity. But a steady proportion of surgeons, even in the oldest age group, are active in new surgical innovations and challenging cases. Most reported no changes in perceived cognitive abilities. The majority of surgeons who had made no decision to retire reported that their decision will be based on skill level rather than age.