Temporal Profile of Serum Neurofilament Light (NF-L) and Heavy (pNF-H) Level Associations With 6-Month Cognitive Performance in Patients With Moderate-Severe Traumatic Brain Injury.

OBJECTIVE: Identification of biomarkers of cognitive recovery after traumatic brain injury (TBI) will inform care and improve outcomes. This study assessed the utility of neurofilament (NF-L and pNF-H), a marker of neuronal injury, informing cognitive performance following moderate-to-severe TBI (msTBI). SETTING: Level 1 trauma center and outpatient via postdischarge follow-up. PARTICIPANTS: N = 94. Inclusion criteria: Glasgow Coma Scale score less than 13 or 13-15 with clinical evidence of moderate-to-severe injury traumatic brain injury on clinical imaging. Exclusion criteria: neurodegenerative condition, brain death within 3 days after injury. DESIGN: Prospective observational study. Blood samples were collected at several time points post-injury. Cognitive testing was completed at 6 months post-injury. MAIN MEASURES: Serum NF-L (Human Neurology 4-Plex B) pNF-H (SR-X) as measured by SIMOA Quanterix assay. Divided into 3 categorical time points at days post-injury (DPI): 0-15 DPI, 16-90 DPI, and >90 DPI. Cognitive composite comprised executive functioning measures derived from 3 standardized neuropsychological tests (eg, Delis-Kaplan Executive Function System: Verbal Fluency, California Verbal Learning Test, Second Edition, Wechsler Adult Intelligence Scale, Third Edition). RESULTS: pNF-H at 16-90 DPI was associated with cognitive outcomes including a cognitive-executive composite score at 6 months (ß = -.430, t34 = -3.190, P = .003). CONCLUSIONS: Results suggest that "subacute" elevation of serum pNF-H levels may be associated with protracted/poor cognitive recovery from msTBI and may be a target for intervention. Interpretation is limited by small sample size and including only those who were able to complete cognitive testing.

Parallel Cerebrospinal Fluid and Serum Temporal Profile Assessment of Axonal Injury Biomarkers Neurofilament-Light Chain and Phosphorylated Neurofilament-Heavy Chain: Associations With Patient Outcome in Moderate-Severe Traumatic Brain Injury.

Neurofilament-light chain (NF-L) and phosphorylated neurofilament-heavy chain (pNF-H) are axonal proteins that have been reported as potential diagnostic and prognostic biomarkers in traumatic brain injury (TBI). However, detailed temporal profiles for these proteins in blood, and interrelationships in the acute and chronic time periods post-TBI have not been established. Our objectives were: 1) to characterize acute-to-chronic serum NF-L and pNF-H profiles after moderate-severe TBI, as well as acute cerebrospinal fluid (CSF) levels; 2) to evaluate CSF and serum NF-L and pNF-H associations with each other; and 3) to assess biomarker associations with global patient outcome using both the Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). In this multi-cohort study, we measured serum and CSF NF-L and pNF-H levels in samples collected from two clinical cohorts (University of Pittsburgh [UPITT] and Baylor College of Medicine [BCM]) of individuals with moderate-severe TBI. The UPITT cohort includes 279 subjects from an observational cohort study; we obtained serum (n = 277 unique subjects) and CSF (n = 95 unique subjects) daily for 1 week, and serum every 2 weeks for 6 months. The BCM cohort included 103 subjects from a previous randomized clinical trial of erythropoietin and blood transfusion threshold after severe TBI, which showed no effect on neurological outcome between treatment arms; serum (n = 99 unique subjects) and CSF (n = 54 unique subjects) NF-L and pNF-H levels were measured at least daily during Days (D) 0-10 post-injury. GOS-E and DRS were assessed at 6 months (both cohorts) and 12 months (UPITT cohort only). Results show serum NF-L and pNF-H gradually rise during the first 10 days and peak at D20-30 post-injury. In the UPITT cohort, acute (D0-6) NF-L and pNF-H levels correlate within CSF and serum (Spearman r = 0.44-0.48; p < 0.05). In the UPITT cohort, acute NF-L CSF and serum levels, as well as chronic (Months [M]2-6) serum NF-L levels, were higher among individuals with unfavorable GOS-E and worse DRS at 12 months (p < 0.05, all comparisons). In the BCM cohort, higher acute serum NF-L levels were also associated with unfavorable GOS-E. Higher pNF-H serum concentrations (D0-6 and M2-6), but not CSF pNF-H, were associated with unfavorable GOS-E and worse DRS (p < 0.05, all comparisons) in the UPITT cohort. Relationships between biomarker levels and favorable outcome persisted after controlling for age, sex, and Glasgow Coma Scale. This study shows for the first time that serum levels of NF-L and pNF-H peak at D20-30 post-TBI. Serum NF-L levels, and to a lesser extent pNF-H levels, are robustly associated with global patient outcomes and disability after moderate-severe TBI. Further studies on clinical utility as prognosis and treatment-response indicators are needed.

Impact of transcutaneous vagus nerve stimulation on healthy cognitive and brain aging.

Evidence for clinically meaningful benefits of transcutaneous vagus nerve stimulation (VNS) has been rapidly accumulating over the past 15 years. This relatively novel non-invasive brain stimulation technique has been applied to a wide range of neuropsychiatric disorders including schizophrenia, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, bipolar disorder, and Alzheimer's disease. More recently, non-invasive forms of VNS have allowed for investigations within healthy aging populations. These results offer insight into protocol considerations specific to older adults and how to translate those results into effective clinical trials and, ultimately, effective clinical care. In this review, we characterize the possible mechanisms by which non-invasive VNS may promote healthy aging (e.g., neurotransmitter effects, inflammation regulation, functional connectivity changes), special considerations for applying non-invasive VNS in an older adult population (e.g., vagus nerve changes with age), and how non-invasive VNS may be used in conjunction with existing behavioral interventions (e.g., cognitive behavioral therapy, cognitive training) to promote healthy emotional and cognitive aging.

Effects of sleep disturbance on trauma-focused psychotherapy outcomes in posttraumatic stress disorder: A systematic review.

This study aimed to synthesize existing research on the effects of sleep disturbances on trauma-focused psychotherapy outcomes in adults with posttraumatic stress disorder (PTSD). A systematic review using PubMed, PsycINFO, Embase, Web of Science, and PTSDpubs was performed up to April 2021. Two independent reviewers screened articles for inclusion, performed data extraction, and assessed risk of bias and certainty of the evidence. Narrative synthesis was conducted based on the type of sleep disorder symptom assessed. Sixteen primary studies were included in this review, the majority of which had a high overall risk of bias. Results suggested that sleep disorder symptoms were associated with higher overall PTSD severity across treatment; however, they did not interfere with treatment effectiveness, with the exception of sleep-disordered breathing. Improvements in insomnia, sleep duration, and sleep quality during treatment were associated with greater treatment gains. Certainty of the evidence ranged from low to very low. These results suggest that it may not be necessary to address sleep disorder symptoms prior to initiating trauma-focused psychotherapy. Instead, concurrent treatment of sleep- and trauma-related symptoms may be most beneficial. Continued research is needed to clarify the mechanistic relationship between sleep and treatment outcomes and to guide clinical decision-making.

Unpacking the NIH Toolbox Emotion Battery in Persons With Parkinson's disease.

OBJECTIVE: Examine the relationship between the National Institutes of Health Toolbox Emotion Battery (Emotion Toolbox) and traditional measures in Parkinson's disease (PD). METHOD: Persons with PD (n = 30) and cognitively healthy older adults (OA; n = 40) completed the Emotion Toolbox consisting of Well-Being, Negative Affect, and Social Satisfaction scores along with traditional measures of depression (Beck Depression Inventory-II [BDI-II]), anxiety (State-Trait Anxiety Inventory [STAI]), and apathy (Apathy Scale [AS]); total raw scores). RESULTS: Separate bootstrapped analyses of covariance indicated that the PD group scored higher on BDI-II and STAI-State compared to OA (ps < .01); groups did not differ on Emotion Toolbox. In the PD group, bootstrapped partial correlations indicated that Negative Affect was positively related to BDI-II and STAI (ps ≤ .001). Social Satisfaction was negatively related to BDI-II and STAI-Trait (.05 < ps < .004). Psychological Well-Being was negatively related to BDI-II, AS, and STAI (p < .004). No relationships emerged in OA. In the PD group, separate binary logistic regressions showed that traditional measures (BDI-II, AS, and STAI-Trait) correctly classified 79.6% those with formal psychiatric diagnoses (presence vs. absence; p < .011), whereas Emotion Toolbox measures correctly classified 73.3% (p < .019). CONCLUSIONS: The Emotion Toolbox showed moderate-strong correlations with traditional measures in persons with PD. Even so, it did not capture the group differences between PD and OA and had a somewhat lower classification accuracy rate for persons with PD who had a formal psychiatric diagnosis than traditional measures. Together, findings question the utility of the Emotion Toolbox as a stand-alone emotion screener in PD.

The Effects of Transcutaneous Vagus Nerve Stimulation on Functional Connectivity Within Semantic and Hippocampal Networks in Mild Cognitive Impairment.

Better treatments are needed to improve cognition and brain health in people with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Transcutaneous vagus nerve stimulation (tVNS) may impact brain networks relevant to AD through multiple mechanisms including, but not limited to, projection to the locus coeruleus, the brain's primary source of norepinephrine, and reduction in inflammation. Neuropathological data suggest that the locus coeruleus may be an early site of tau pathology in AD. Thus, tVNS may modify the activity of networks that are impaired and progressively deteriorate in patients with MCI and AD. Fifty patients with MCI (28 women) confirmed via diagnostic consensus conference prior to MRI (sources of info: Montreal Cognitive Assessment Test (MOCA), Clinical Dementia Rating scale (CDR), Functional Activities Questionnaire (FAQ), Hopkins Verbal Learning Test - Revised (HVLT-R) and medical record review) underwent resting state functional magnetic resonance imaging (fMRI) on a Siemens 3 T scanner during tVNS (left tragus, n = 25) or sham control conditions (left ear lobe, n = 25). During unilateral left tVNS, compared with ear lobe stimulation, patients with MCI showed alterations in functional connectivity between regions of the brain that are important in semantic and salience functions including regions of the temporal and parietal lobes. Furthermore, connectivity from hippocampi to several cortical and subcortical clusters of ROIs also demonstrated change with tVNS compared with ear lobe stimulation. In conclusion, tVNS modified the activity of brain networks in which disruption correlates with deterioration in AD. These findings suggest afferent target engagement of tVNS, which carries implications for the development of noninvasive therapeutic intervention in the MCI population.

Music, Mind, Mood, and Mingling in Alzheimer's Disease and Related Dementias: A Scoping Review.

BACKGROUND: Music-based interventions may help to alleviate neuropsychiatric symptoms of dementia and promote prosocial interactions between individuals living with dementia and their caregivers. However, current literature does not combine these evidence bases toward explanation of how music-based interventions may alleviate symptoms and promote prosocial interactions. OBJECTIVE: We conducted a scoping review to address the following question: what do the evidence bases suggest toward how music therapy or music-based therapeutic interventions might promote prosocial interactions between individuals living with dementia and their caregivers? METHODS: In this review we focused on: 1) quantitative and qualitative evidence of music-based therapies promoting prosocial behaviors in individuals living with dementia, and 2) potential neurobehavioral mechanisms associated with the processes involved with how music may promote prosocial interactions. Databases included PubMed, EBSCOhost's CINAHL and PsycINFO, Cochrane Library (sub-search conducted using ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group), Web of Science, clinicaltrials.gov, ProQuest's Biological Science Collection, the Journal of Music Therapy, Nordic Journal of Music Therapy, and Google Scholar. RESULTS: Sixteen original research studies were included for evidence synthesis. This scoping review reveals the need to define and clarify mechanisms of prosocial interactions between individuals living with dementia and their caregivers considering biological and social factors. These mechanisms may include dynamic interactions between preserved brain regions associated with music-evoked autobiographical memory recall and shifts from negative to positive mood states. CONCLUSION: Defining and clarifying how and to what extent music may promote prosocial behaviors using well-designed and well-controlled mixed-methods studies may positively influence the design of interventions to promote prosocial interactions with caregivers.

The Modified Early Warning Score: A Useful Marker of Neurological Worsening but Unreliable Predictor of Sepsis in the Neurocritically Ill-A Retrospective Cohort Study.

To determine the performance of the Modified Early Warning Score and Modified Early Warning Score-Sepsis Recognition Score to predict sepsis, morbidity, and mortality in neurocritically ill patients. DESIGN: Retrospective cohort study. SETTING: Single tertiary-care academic medical center. PATIENTS: Consecutive adult patients admitted to the neuro-ICU from January 2013 to December 2016. INTERVENTIONS: Observational study. MEASUREMENTS AND MAIN RESULTS: Baseline and clinical characteristics, infections/sepsis, neurologic worsening, and mortality were abstracted. Primary outcomes included new infection/sepsis, escalation of care, and mortality. Patients with Modified Early Warning Score-Sepsis Recognition Score/Modified Early Warning Score greater than or equal to 5 were compared with those with scores less than 5. 5. Of 7,286 patients, Of 7,286 patients, 1,120 had Modified Early Warning Score-Sepsis Recognition Score greater than or equal to 5. Of those, mean age was 58.9 years; 50.2% were male. Inhospitality mortality was 22.1% for patients (248/1,120) with Modified Early Warning Score-Sepsis Recognition Score greater than or equal to 5, compared with 6.1% (379/6,166) with Modified Early Warning Score-Sepsis Recognition Score less than 5. Sepsis was present in 5.6% (345/6,166) when Modified Early Warning Score-Sepsis Recognition Score less than 5 versus 14.3% (160/1,120) when greater than or equal to 5, and Modified Early Warning Score elevation led to a new sepsis diagnosis in 5.5% (62/1,120). Three-hundred forty-three patients (30.6%) had neurologic worsening at the time of Modified Early Warning Score-Sepsis Recognition Score elevation. Utilizing the original Modified Early Warning Score, results were similar, with less score thresholds met (836/7,286) and slightly weaker associations. CONCLUSIONS: In neurocritical ill patients, Modified Early Warning Score-Sepsis Recognition Score and Modified Early Warning Score are associated with higher inhospital mortality and are preferentially triggered in setting of neurologic worsening. They are less reliable in identifying new infection or sepsis in this patient population. Population-specific adjustment of early warning scores may be necessary for the neurocritically ill patient population.

A tale of two stories: Validity of an alternative story memory test in a sample of older adults.

Objective: Many patients require repeat neuropsychological evaluations to determine change over time. Repeat evaluations lead to practice effects, which can impact the validity of the assessment. The current study assessed, in older adults, the validity of an alternative set of verbal memory stories created by Newcomer and colleagues.Method: A total 154 of non-demented adults, ages 60-92, completed the WMS-III logical memory (LM) stories and two Newcomer stories (Carson-Jones) as part of a larger battery of neurocognitive tests. The Carson-Jones stories were scored for: (1) verbatim (traditional) and (2) thematic (developed for this study) accuracy. Story memory variables were compared to each other and additional neurocognitive measures using bivariate correlations. A subset of participants (n = 133) completed magnetic resonance imaging (MRI) and various structural regions (e.g. thickness and volume of medial temporal lobe structures) were used to assess external validity of Carson-Jones stories with hierarchical multiple regression analyses.Results: There was a strong positive correlation between WMS-III LM and Carson-Jones stories for both verbatim and thematic scoring. Both scoring types showed convergent validity with other verbal memory measures (e.g. WMS-III LM and HVLT-R Delay/Learning) and divergent validity with Stroop Word Reading and JOLO. Regarding neuroimaging correlates, Carson-Jones verbatim scoring was significantly associated with left subiculum and left whole hippocampal volume whereas thematic scoring was significantly associated only with left subiculum.Conclusions: Newcomer stories appear to be a valid alternative to WMS-III LM stories in terms of assessing verbal memory in healthy older adults.

Everyday functioning in Parkinson's disease: Evidence from the Revised-Observed Tasks of Daily Living (OTDL-R).

INTRODUCTION: Performance tasks are presumed to have greater validity than rating scales in assessing day-to-day behaviors in Parkinson's disease (PD). One such task is the revised Observed Tasks of Daily Living (OTDL-R), which has been used extensively in healthy older adults, and but not yet empirically examined in PD. Thus, the aims of the current study were to examine and determine the impact of cognitive, motor, and mood symptoms on OTDL-R performance in PD. METHOD: Nineteen non-demented PD patients and 18 healthy older adults (HC) were administered measures of mood and cognitive functioning, and the OTDL-R (subtests include medication and telephone use, and medication management). Clinical severity of PD was assessed using the H&Y stage, UPDRS, and Schwab and England functional disability scores. RESULTS: Mann Whitney U tests indicated the PD patients were significantly slower to complete the OTDL-R and performed worse on only the telephone use subtest, relative to the HC group. In the PD group, hierarchical regression analyses revealed memory, attention, and initiative/perseveration were uniquely associated with the financial management subtest, after controlling for motor severity (ps < .05). No other significant relationships were found. CONCLUSIONS: PD patients were slower to complete the OTDL-R, but only less accurate on the telephone use subtest. Poor performance on the telephone use subtest may be related to motor severity, while poor performance on the financial management subtest was related to attention and working memory. Overall, the findings warrant future investigation to determine the validity and reliability of the OTDL-R in PD.

Emotion modulation of the startle reflex in essential tremor: Blunted reactivity to unpleasant and pleasant pictures.

BACKGROUND: Essential tremor is a highly prevalent movement disorder characterized by kinetic tremor and mild cognitive-executive changes. These features are commonly attributed to abnormal cerebellar changes, resulting in disruption of cerebellar-thalamo-cortical networks. Less attention has been paid to alterations in basic emotion processing in essential tremor, despite known cerebellar-limbic interconnectivity. OBJECTIVES: In the current study, we tested the hypothesis that a psychophysiologic index of emotional reactivity, the emotion modulated startle reflex, would be muted in individuals with essential tremor relative to controls. METHODS: Participants included 19 essential tremor patients and 18 controls, who viewed standard sets of unpleasant, pleasant, and neutral pictures for six seconds each. During picture viewing, white noise bursts were binaurally presented to elicit startle eyeblinks measured over the orbicularis oculi. RESULTS: Consistent with past literature, controls' startle eyeblink responses were modulated according to picture valence (unpleasant > neutral > pleasant). In essential tremor participants, startle eyeblinks were not modulated by emotion. This modulation failure was not due to medication effects, nor was it due to abnormal appraisal of emotional picture content. CONCLUSIONS: Neuroanatomically, it remains unclear whether diminished startle modulation in essential tremor is secondary to aberrant cerebellar input to the amygdala, which is involved in priming the startle response in emotional contexts, or due to more direct disruption between the cerebellum and brainstem startle circuitry. If the former is correct, these findings may be the first to reveal dysregulation of emotional networks in essential tremor.

Post-exercise pulse pressure is a better predictor of executive function than pre-exercise pulse pressure in cognitively normal older adults.

Exercise "stress tests" are widely used to assess cardiovascular function and to detect abnormalities. In line with the view of exercise as a stressor, the present study examined the relationship between cognitive function and cardiovascular activity before and after light physical exercise in a sample of 84 non-demented community-dwelling older adults. Based on known relationships between hypertension, executive function and cerebral white matter changes, we hypothesized that greater post-exercise reactivity, as indexed by higher pulse pressure, would be more related to worse performance on frontal-executive tasks than pre-exercise physiologic measures. All participants were administered a comprehensive neuropsychological battery and underwent a Six Minute Walk Test (6MWT), with blood pressure (BP) measures obtained immediately before and after the walk. Pulse pressure (PP) was derived from BP as an indicator of vascular auto-regulation and composite scores were computed for each cognitive domain assessed. As predicted, worse executive function scores exhibited a stronger relationship with post-exercise PP than pre-exercise PP. Results suggest that PP following system stress in the form of walking may be more reflective of the state of vascular integrity and associated executive dysfunction in older adults than baseline physiologic measures.