TSPO-PET imaging using [18F]PBR06 is a potential translatable biomarker for treatment response in Huntington's disease: preclinical evidence with the p75NTR ligand LM11A-31.

Huntington's disease (HD) is an inherited neurodegenerative disorder that has no cure. HD therapeutic development would benefit from a non-invasive translatable biomarker to track disease progression and treatment response. A potential biomarker is using positron emission tomography (PET) imaging with a translocator protein 18 kDa (TSPO) radiotracer to detect microglial activation, a key contributor to HD pathogenesis. The ability of TSPO-PET to identify microglial activation in HD mouse models, essential for a translatable biomarker, or therapeutic efficacy in HD patients or mice is unknown. Thus, this study assessed the feasibility of utilizing PET imaging with the TSPO tracer, [18F]PBR06, to detect activated microglia in two HD mouse models and to monitor response to treatment with LM11A-31, a p75NTR ligand known to reduce neuroinflammation in HD mice. [18F]PBR06-PET detected microglial activation in striatum, cortex and hippocampus of vehicle-treated R6/2 mice at a late disease stage and, notably, also in early and mid-stage symptomatic BACHD mice. After oral administration of LM11A-31 to R6/2 and BACHD mice, [18F]PBR06-PET discerned the reductive effects of LM11A-31 on neuroinflammation in both HD mouse models. [18F]PBR06-PET signal had a spatial distribution similar to ex vivo brain autoradiography and correlated with microglial activation markers: increased IBA-1 and TSPO immunostaining/blotting and striatal levels of cytokines IL-6 and TNFα. These results suggest that [18F]PBR06-PET is a useful surrogate marker of therapeutic efficacy in HD mice with high potential as a translatable biomarker for preclinical and clinical HD trials.

A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice.

Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington's disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75NTR-associated deleterious signalling and decreases survival signalling suggesting that p75NTR could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75NTR ligand, LM11A-31, on HD-related neuropathology in HD mouse models (R6/2, BACHD). LM11A-31 restored striatal AKT and other pro-survival signalling while inhibiting c-Jun kinase (JNK) and other degenerative signalling. Normalizing p75NTR signalling with LM11A-31 was accompanied by reduced Htt aggregates and striatal cholinergic interneuron degeneration as well as extended survival in R6/2 mice. The p75NTR ligand also decreased inflammation, increased striatal and hippocampal dendritic spine density, and improved motor performance and cognition in R6/2 and BACHD mice. These results support small molecule modulation of p75NTR as an effective HD therapeutic strategy. LM11A-31 has successfully completed Phase I safety and pharmacokinetic clinical trials and is therefore a viable candidate for clinical studies in HD.

Reducing Readmissions After Stroke With a Structured Nurse Practitioner/Registered Nurse Transitional Stroke Program.

BACKGROUND AND PURPOSE: Our aim was to determine whether a standardized Transitional Stroke Clinic (TSC) led by nurse practitioners could reduce 30-day and 90-day readmissions for stroke or transient ischemic attack patients discharged home. METHODS: Phase I consisted of nurse practitioners calling only high-risk patients discharged home within 7 days and performing an office visit within 2 to 4 weeks of discharge. Phase II consisted of all patients discharged home receiving both a 2-day follow-up phone call by a registered nurse and a follow-up visit with a nurse practitioner within 7 to 14 days. Differences in process metrics and readmissions across the 2 phases and overall were assessed. Increasing complexity with multiple chronic conditions (diabetes mellitus, coronary artery disease, and congestive heart failure) was represented in a continuous variable from 0 to 3. Multivariable logistic regression models for 30-day and 90-day readmissions were performed with adjustment for National Institutes of Health Stroke Scale (NIHSS) and previous hospitalizations. RESULTS: From October 2012 through September 2015, 510 patients were enrolled. From phase I to II, a higher proportion of follow-up calls were made and days from discharge to TSC decreased. Patients readmitted within 30 days were less likely to show for TSC visits (60.85% versus 76.3%; P=0.021). Multivariable modeling showed that TSC visit was associated with a 48% reduction in 30-day readmission (odds ratio, 0.518; 95% confidence interval, 0.272-0.986), whereas multiple chronic conditions and previous stroke/transient ischemic attack increased the risk. TSC visit did not impact 90-day readmissions. CONCLUSIONS: Evaluation in a nurse practitioner-led structured clinic is a model that may reduce readmissions at 30 days for stroke patients discharged home.

A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease.

Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLCγ, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.

Dual excitatory and inhibitory serotonergic inputs modulate egg laying in Caenorhabditis elegans.

Serotonin (5-HT) regulates key processes in both vertebrates and invertebrates. Previously, four 5-HT receptors that contributed to the 5-HT modulation of egg laying were identified in Caenorhabditis elegans. Therefore, to assess potential receptor interactions, we generated animals containing combinations of null alleles for each receptor, especially animals expressing only individual 5-HT receptors. 5-HT-stimulated egg laying and egg retention correlated well with different combinations of predicted excitatory and inhibitory serotonergic inputs. For example, 5-HT did not stimulate egg laying in ser-1, ser-7, or ser-7 ser-1 null animals, and ser-7 ser-1 animals retained more eggs than wild-type animals. In contrast, 5-HT-stimulated egg laying in ser-4;mod-1 animals was greater than in wild-type animals, and ser-4;mod-1 animals retained fewer eggs than wild-type animals. Surprisingly, ser-4;mod-1;ser-7 ser-1 animals retained the same number of eggs as wild-type animals and exhibited significant 5-HT-stimulated egg laying that was dependent on a previously uncharacterized receptor, SER-5. 5-HT-stimulated egg laying was absent in ser-5;ser-4;mod-1;ser-7 ser-1 animals, and these animals retained more eggs than either wild-type or ser-4;mod-1;ser-7 ser-1 animals. The 5-HT sensitivity of egg laying could be restored by ser-5 muscle expression. Together, these results highlight the dual excitatory/inhibitory serotonergic inputs that combine to modulate egg laying.

A systematic review and meta-analysis of the effectiveness of virtual reality as an exercise intervention for individuals with a respiratory condition.

BACKGROUND: Respiratory diseases impose an immense health burden worldwide and affect millions of people on a global scale. Reduction of exercise tolerance poses a huge health issue affecting patients with a respiratory condition, which is caused by skeletal muscle dysfunction and weakness and by lung function impairment. Virtual reality systems are emerging technologies that have drawn scientists' attention to its potential benefit for rehabilitation. METHODS: A systematic review and meta-analysis following the PRISMA guidelines was performed to explore the effectiveness of virtual reality gaming and exergaming-based interventions on individuals with respiratory conditions. RESULTS: Differences between the virtual reality intervention and traditional exercise rehabilitation revealed weak to insignificant effect size for mean heart rate (standardized mean difference, SMD = 0.17; p = 0.002), peak heart rate (SMD = 0.36; p = 0.27), dyspnea (SMD = 0.32; p = 0.13), and oxygen saturation SpO2 (SMD = 0.26; p = 0.096). In addition, other measures were collected, however, to the heterogeneity of reporting, could not be included in the meta-analysis. These included adherence, enjoyment, and drop-out rates. CONCLUSIONS: The use of VRS as an intervention can provide options for rehabilitation, given their moderate effect for dyspnea and equivalent to weak effect for mean and maximum peak HR and SpO2. However, the use of virtual reality systems, as an intervention, needs further study since the literature lacks standardized methods to accurately analyze the effects of virtual reality for individuals with respiratory conditions, especially for duration, virtual reality system type, adherence, adverse effects, feasibility, enjoyment, and quality of life.

Patient Factors Associated With Attendance at a Comprehensive Postacute Stroke Visit: Insight From the Vanguard Site.

OBJECTIVE: To understand the patient-influenced activities and characteristics associated with return to a single postacute care transitional care clinic visit in a cohort of patients cared for at the test health system site of the larger Comprehensive Post-Acute Stroke Services (COMPASS) cluster randomized trial. DESIGN: Retrospective cohort. SETTING: A large health system. PARTICIPANTS: Patients discharged directly home between June 2016 and June 2018 after sustaining a stroke who did not receive formal inpatient rehabilitation services while being cared for in a single comprehensive stroke center, defined as a center that meet standards to rapidly diagnose and treat the most complex stroke cases. INTERVENTIONS: Study participants had the opportunity to participate in a (1) 2-day call, (2) comprehensive care transitions clinic visit, and (3) individualized care plan. MAIN OUTCOME MEASURES: Patient participation in a single postacute care comprehensive care transitions visit, ideally completed within 7-14 calendar days post discharge vs not attending this visit. Care transition visits are where the responsibility for preventive care, other services, and posthospital follow-up are transitioned to outpatient providers. RESULTS: Among 1300 eligible patients (mean age 64.8 years; 45% female; 25.4% nonwhite; 9.7% uninsured), 95.7% had follow-up clinic visits scheduled before discharge, 22.6% received home health referrals before discharge, 60.2% completed the 2-day call, and 63.2% attended the COMPASS visit. Among attendees, 33.2% attended by day 14, 71.3% attended within 30 days, and 28.7% attended after day 30. The median driving distance to the COMPASS visit was 45.9 miles or 73.9 km. Odds of visit attendance were higher if COMPASS 2-day follow up calls were completed, if follow-up clinic appointments were scheduled before discharge, if the patient had a primary care provider, and if the patients experienced a stroke vs a transient ischemic attack. Additionally, when we used the number of referrals at hospital discharge for different types of outpatient therapy as a surrogate marker of poststroke impairment, patients having no therapy referrals (milder to no impairments) had lower odds of attending the COMPASS visit than those with 1 therapy referral. Likewise, those with more than 1 referral were also less likely to attend the COMPASS visit. CONCLUSIONS: This analysis highlights that scheduling visits at discharge and completing timely telephone follow-up shortly after discharge may lead to greater adherence to in-person clinic follow-up after stroke.

A Person-Centered Approach to Poststroke Care: The COMprehensive Post-Acute Stroke Services Model.

Many individuals who have had a stroke leave the hospital without postacute care services in place. Despite high risks of complications and readmission, there is no standard in the United States for postacute stroke care after discharge home. We describe the rationale and methods for the development of the COMprehensive Post-Acute Stroke Services (COMPASS) care model and the structure and quality metrics used for implementation. COMPASS, an innovative, comprehensive extension of the TRAnsition Coaching for Stroke (TRACS) program, is a clinician-led quality improvement model providing early supported discharge and transitional care for individuals who have had a stroke and have been discharged home. The effectiveness of the COMPASS model is being assessed in a cluster-randomized pragmatic trial in 41 sites across North Carolina, with a recruitment goal of 6,000 participants. The COMPASS model is evidence based, person centered, and stakeholder driven. It involves identification and education of eligible individuals in the hospital; telephone follow-up 2, 30, and 60 days after discharge; and a clinic visit within 14 days conducted by a nurse and advanced practice provider. Patient and caregiver self-reported assessments of functional and social determinants of health are captured during the clinic visit using a web-based application. Embedded algorithms immediately construct an individualized care plan. The COMPASS model's pragmatic design and quality metrics may support measurable best practices for postacute stroke care.

COMPASS-CP: An Electronic Application to Capture Patient-Reported Outcomes to Develop Actionable Stroke and Transient Ischemic Attack Care Plans.

Background Patient-reported outcomes (PROs) are clinical tools that measure patients' goals of care and assess patient-reported physical, mental, and social well-being. Despite their value in advancing patient-centered care, routine use of PROs in stroke management has lagged. As part of the pragmatic COMPASS (Comprehensive Post-Acute Stroke Services) trial, we developed COMPASS-Care Plan (CP), a clinician-facing application that captures and analyzes PROs for stroke and transient ischemic attack patients discharged home and immediately generates individualized electronic CP. In this report, we (1) present our methods for developing and implementing COMPASS-CP PROs, (2) provide examples of CP generated from COMPASS-CP, (3) describe key functional, social, and behavioral determinants of health captured by COMPASS-CP, and (4) report on clinician experience with using COMPASS-CP in routine clinical practice for care planning and engagement of stroke and transient ischemic attack patients discharged home. Methods and Results We report on the first 871 patients enrolled in 20 North Carolina hospitals randomized to the intervention arm of COMPASS between July 2016 and February 2018; these patients completed a COMPASS follow-up visit within 14 days of hospital discharge. We also report user satisfaction results from 56 clinicians who used COMPASS-CP during these visits. COMPASS-CP identified more cognitive and depression deficits than physical deficits. Within 14-day posthospitalization, less than half of patients could list the major risk factors for stroke, 36% did not recognize blood pressure as a stroke risk factor, and 19% of patients were nonadherent with prescribed medications. Three-fourths of clinicians reported that COMPASS-CP identifies important factors impacting patients' recovery that they otherwise may have missed, and two-thirds were highly satisfied with COMPASS-CP. Conclusions The COMPASS-CP application meets an immediate need to incorporate PROs into the clinical workflow to develop patient-centered CP for stroke patients and has high user satisfaction. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02588664.

[18F]GE-180 PET Detects Reduced Microglia Activation After LM11A-31 Therapy in a Mouse Model of Alzheimer's Disease.

Microglial activation is a key pathological feature of Alzheimer's disease (AD). PET imaging of translocator protein 18 kDa (TSPO) is a strategy to detect microglial activation in vivo. Here we assessed flutriciclamide ([18F]GE-180), a new second-generation TSPO-PET radiotracer, for its ability to monitor response to LM11A-31, a novel AD therapeutic in clinical trials. AD mice displaying pathology were treated orally with LM11A-31 for 3 months. Subsequent [18F]GE-180-PET imaging revealed significantly lower signal in cortex and hippocampus of LM11A-31-treated AD mice compared to those treated with vehicle, corresponding with decreased levels of TSPO immunostaining and microglial Iba1 immunostaining. In addition to detecting decreased microglial activation following LM11A-31 treatment, [18F]GE-180 identified activated microglia in AD mice with greater sensitivity than another second-generation TSPO radiotracer, [18F]PBR06. Together, these data demonstrate the promise of [18F]GE-180 as a potentially sensitive tool for tracking neuroinflammation in AD mice and for monitoring therapeutic modulation of microglial activation.