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Mild traumatic brain injury (TBI) is associated with persistent sleep-wake dysfunction, including insomnia and circadian rhythm disruption, which can exacerbate functional outcomes including mood, pain, and quality of life. Present therapies to treat sleep-wake disturbances in those with TBI (e.g., cognitive behavioral therapy for insomnia) are limited by marginal efficacy, poor patient acceptability, and/or high patient/provider burden. Thus, this study aimed to assess the feasibility and preliminary efficacy of morning bright light therapy, to improve sleep in Veterans with TBI (NCT03578003). Thirty-three Veterans with history of TBI were prospectively enrolled in a single-arm, open-label intervention using a lightbox (~10,000 lux at the eye) for 60-minutes every morning for 4-weeks. Pre- and post-intervention outcomes included questionnaires related to sleep, mood, TBI, post-traumatic stress disorder (PTSD), and pain; wrist actigraphy as a proxy for objective sleep; and blood-based biomarkers related to TBI/sleep. The protocol was rated favorably by ~75% of participants, with adherence to the lightbox and actigraphy being ~87% and 97%, respectively. Post-intervention improvements were observed in self-reported symptoms related to insomnia, mood, and pain; actigraphy-derived measures of sleep; and blood-based biomarkers related to peripheral inflammatory balance. The severity of comorbid PTSD was a significant positive predictor of response to treatment. Morning bright light therapy is a feasible and acceptable intervention that shows preliminary efficacy to treat disrupted sleep in Veterans with TBI. A full-scale randomized, placebo-controlled study with longitudinal follow-up is warranted to assess the efficacy of morning bright light therapy to improve sleep, biomarkers, and other TBI related symptoms.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n = 120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n = 80), and 2) sham: deactivated negative ion generator (n = 40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

Treatment with plasma of an early developmental stage, human umbilical cord, revitalizes the hippocampus and improves cognitive function in aged mice. Human umbilical cord blood enhances cognition Aging leads to changes in cognitive function that can lead to neurological disorders. Tony Wyss-Coray and colleagues show that human umbilical cord plasma is able to revitalize the hippocampus and improve cognitive function in aged mice. They find that tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor, is enriched in human cord plasma, young mouse plasma and young mouse hippocampi. It enters the brain following systemic administration and is necessary for the cognitive benefits conferred by cord plasma. Systemic TIMP2 is also essential for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, suggesting that TIMP2 has a role in normal hippocampal function. Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation 1 , an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation 2 , 3 , 4 and downregulated in the aged brain 5 , 6 , 7 , 8 . In addition to revitalizing other aged tissues 9 , 10 , 11 , 12 , 13 , exposure to factors in young blood counteracts age-related changes in these central nervous system parameters 14 , 15 , 16 , although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown 17 . We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n = 120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n = 80), and 2) sham: deactivated negative ion generator (n = 40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in 85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

ALT-803, a novel IL-15/IL-15 receptor alpha complex, and the tyrosine kinase inhibitor, sunitinib, were examined for their single and combined effects on the growth of subcutaneous B16BL6 melanoma and on lymph node and lung metastasis. The study was conducted in immunocompetent C57BL/6 mice drinking water (Water mice) and in mice that chronically consumed alcohol (Alcohol mice), which are deficient in CD8 + T cells. Sunitinib inhibited melanoma growth and was more effective in Alcohol mice. ALT-803 did not alter tumor growth or survival in Water or Alcohol mice. Combined ALT-803 and sunitinib inhibited melanoma growth and increased survival, and these effects were greater than sunitinib alone in Water mice. ALT-803 and alcohol independently suppressed lymph node and lung metastasis, whereas sunitinib alone or in combination with ALT-803 increased lymph node and lung metastasis in Water and Alcohol mice. Initially, ALT-803 increased IFN-γ-producing CD8 + CD44 hi memory T cells and CD8 + CD44 hi CD62L lo effector memory T cells and sunitinib decreased immunosuppressive MDSC and T regulatory cells (Treg). However, the impact of these treatments diminished with time. Subcutaneous tumors from Water mice showed increased numbers of CD8 + T cells, CD8 + CD44 hi T cells, NK cells, and MDSC cells and decreased Treg cells after ALT-803 treatment.

Introduction Insomnia is common among Veterans with Traumatic Brain Injury (TBI) and Posttraumatic Stress Disorder (PTSD). This study sought to determine the effect of morning bright light therapy (MBLT) on sleep, mood, pain, and other quality of life measures in Veterans with and without TBI and PTSD. We also determined which factors best predicted response to MBLT. Methods Self-report data was collected from n=45 Veterans (n=7 with TBI, n=10 with PTSD, n=10 with comorbid TBI+PTSD, and n=18 Controls) before and after 4-weeks of MBLT. Questionnaires included the Insomnia Severity Index (ISI), NIH PROMIS Pain surveys, Patient Health Questionnaire (PHQ-9), Neurobehavioral Sleep Inventory (NSI), Sleep Hygiene Index (SHI), and PTSD Checklist-5 (PCL-5). A Random Forest machine learning model predicting changes in ISI scores following MBLT was used to evaluate which variables were associated with response to therapy. Results MBLT significantly improved ISI (P=0.007), PHQ-9 (P=0.049), PCL-5 (P=0.009), NSI (P=0.004), and pain (P=0.005) scores in TBI+PTSD subjects. Random Forest modelling found baseline ISI, SHI, NSI, PHQ-9, and pain symptoms to be the strongest predictors of response to MBLT. Both ISI (r=0.350; P=0.018) and SHI (r=0.336; P=0.030) were significantly correlated with response to MBLT. Surprisingly, the diagnosis of TBI and/or PTSD did not significantly affect response to MBLT. Conclusion This study demonstrates the feasibility and potential for MBLT to improve insomnia, mood, and pain in Veterans, while also improving TBI- and PTSD-related symptoms. Random Forest predictive model analysis indicated that MBLT may have the strongest effect on those with severe insomnia and poor sleep hygiene at baseline, and is still effective in individuals carrying diagnoses of TBI and/or PTSD. These data highlight a potentially viable sleep intervention to improve sleep and quality of life in Veterans with TBI and PTSD. Support (If Any) Portland VA Health Care System; VA Career Development Award (#IK2 BX002712); Portland VA Research Foundation to MML; NIH EXITO Institutional Core, #UL1GM118964 to MML; NIH T32 AT002688 to JEE.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n = 120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n = 80), and 2) sham: deactivated negative ion generator (n = 40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

Mild traumatic brain injury (TBI) is associated with persistent sleep-wake dysfunction, including insomnia and circadian rhythm disruption, which can exacerbate functional outcomes including mood, pain, and quality of life. Present therapies to treat sleep-wake disturbances in those with TBI (e.g., cognitive behavioral therapy for insomnia) are limited by marginal efficacy, poor patient acceptability, and/or high patient/provider burden. Thus, this study aimed to assess the feasibility and preliminary efficacy of morning bright light therapy, to improve sleep in Veterans with TBI (NCT03578003). Thirty-three Veterans with history of TBI were prospectively enrolled in a single-arm, open-label intervention using a lightbox ( 10,000 lux at the eye) for 60-minutes every morning for 4-weeks. Pre- and post-intervention outcomes included questionnaires related to sleep, mood, TBI, post-traumatic stress disorder (PTSD), and pain; wrist actigraphy as a proxy for objective sleep; and blood-based biomarkers related to TBI/sleep. The protocol was rated favorably by 75% of participants, with adherence to the lightbox and actigraphy being 87% and 97%, respectively. Post-intervention improvements were observed in self-reported symptoms related to insomnia, mood, and pain; actigraphy-derived measures of sleep; and blood-based biomarkers related to peripheral inflammatory balance. The severity of comorbid PTSD was a significant positive predictor of response to treatment. Morning bright light therapy is a feasible and acceptable intervention that shows preliminary efficacy to treat disrupted sleep in Veterans with TBI. A full-scale randomized, placebo-controlled study with longitudinal follow-up is warranted to assess the efficacy of morning bright light therapy to improve sleep, biomarkers, and other TBI related symptoms.

Alzheimer’s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function 1 . However, little is known about the contribution of the adaptive immune response in Alzheimer’s disease 2 . Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer’s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer’s disease that consists of increased numbers of CD8 + T effector memory CD45RA + (T EMRA ) cells. In a second cohort, we found that CD8 + T EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8 + T EMRA cells in the cerebrospinal fluid of patients with Alzheimer’s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer’s disease to two separate Epstein–Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer’s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration. An integrated analysis of several cohorts shows that clonal, antigen-experienced T cells are found in the cerebrospinal fluid of patients with Alzheimer’s disease, suggesting that the adaptive immune system has a role in age-related neurodegeneration.

Introduction Chronic pain and sleep disturbances are intricately linked to one another, especially in individuals with a history of traumatic brain injury (TBI) who are at greater risk for both symptoms. Although prior studies have analyzed differences in sleep electroencephalogram (EEG) in these clinical populations, the association between sleep EEG slow wave coherence and pain complaints is not fully examined or known. Our novel slow wave coherence approach may provide new insights into the relationship between TBI, chronic pain, and sleep Methods Ninety-six veterans were recruited and enrolled under a VA IRB-approved protocol. Participants completed a semi-structured clinical interview to determine their history of TBI, Symptom Impact Questionnaire Revised (SIQR), a measure of chronic pain complaints, and underwent an attended overnight in-lab polysomnogram (PSG). We developed a novel computational signal processing algorithm to identify and quantify EEG slow waves within 100 ms bins across the 6 standard PSG EEG channels. When a slow wave was simultaneously observed in 4 or more of the 6 leads, slow wave coherence was inferred, and a percentage of slow wave coherence across each of the sleep stages was then calculated for each subject. Results In our sample, 65 participants (67.7%) endorsed experiencing chronic pain lasting 3 months or longer, and 54 had a history of TBI (56.3%). Participants endorsing chronic pain had a significantly lowered percent of EEG slow wave coherence during NREM sleep than subjects without chronic pain (p = 0.01). NREM EEG slow wave coherence did not correlate with SIQR scores in subjects without TBI (r = -0.03, p = 0.90), but was significantly negatively correlated in subjects with TBI (r = -0.32, p = 0.02). Conclusion EEG slow wave coherence during NREM sleep is correlated with chronic pain complaints in Veterans with a history of TBI, and could be indicative of neuronal dysfunction during sleep. Further research on slow wave coherence is warranted to understand the underlying mechanisms for the association between chronic pain and poor sleep following TBI. Support (if any) D01 W81XWH-17-1-0423