What Huntington's Disease Patients Say About Their Illness: An Online Direct-to-Participant Pilot Study.

Background: Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement. Objective: We assessed feasibility of online data collection from adults with diagnosed Huntington's disease (HD) who directly reported their problems and impact in their own words. Methods: Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington's disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms. Results: All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common. Conclusions: Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations.

The utility of the irritability scale in Huntington's disease patients with evidence of irritability or aggression.

INTRODUCTION: Irritability, a common neuropsychiatric symptom in Huntington's disease (HD), lacks a standardized measurement. The Irritability Scale (IS), tailored for HD, has patient and informant versions, but variable interrater agreement has been reported frequently in previous studies. To enhance the clinical utility of the IS, this study aimed to identify the most reliable components estimating the underlying construct and develop a shortened version for time-limited contexts. METHODS: Participant and informant/observer concordance and the relationship of individual items to the complete IS scale were assessed. The short-form (SF) items were selected based on interrater agreement, exploratory factor analysis (EFA), and Item Response Theory (IRT) analysis results. Pair-wise correlation and covariance models were used to examine how SF predicted total IS score in 106 participants from the STAIR (Safety, Tolerability, and Activity of SRX246 in Irritable Subjects with Huntington's Disease) trial. Item Response Theory (IRT) analysis was used to evaluate the range and function of the selected items. RESULTS: IS interrater agreement was statistically significant (r = 0.33, p = .001). In combination with EFA factors and IRT analyses, five items were identified that showed good reliability and performance in differentiating levels of irritability. CONCLUSION: The proposed 5-item SF IS provided a reliable measure of the full scale and may be less burdensome for use in a clinical setting.

Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia and Chorea Associated with Huntington Disease.

INTRODUCTION: Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). To enhance detection of safety signals across individual trials, integrated safety analyses of deutetrabenazine in TD and HD chorea were conducted. METHODS: For TD, safety data were integrated from two 12-week pivotal studies (ARM-TD and AIM-TD) and through week 15 of the open-label extension (OLE) study (RIM-TD). Data were analyzed by deutetrabenazine treatment group and placebo. For HD, safety data were integrated from the 12-week pivotal study (First-HD) and through week 15 of the OLE study (ARC-HD) for patients previously receiving placebo. Integrated deutetrabenazine data were compared with placebo from the pivotal study. RESULTS: For TD, deutetrabenazine (n = 384) was generally well tolerated compared with placebo (n = 130). Adverse event (AE) incidence was numerically higher in the response-driven deutetrabenazine vs the fixed-dose deutetrabenazine and placebo groups, respectively (any AE, 59.5% vs 44.4-50.0% and 53.8%; treatment-related AE, 38.1% vs 18.1-25.0% and 30.8%). Serious AEs were reported for 2.8-8.3% of patients in the deutetrabenazine groups and 6.9% in the placebo group. Common AEs (≥ 4%) included headache, somnolence, nausea, anxiety, fatigue, dry mouth, and diarrhea. AE incidence was higher during the titration vs maintenance periods. For HD, AE incidence was numerically higher with deutetrabenazine (n = 84) vs placebo (n = 45; any AE, 64.3% vs 60.0%; treatment-related AE, 38.1% vs 26.7%); serious AEs were reported for similar proportions for the deutetrabenazine and placebo groups, 2.4% and 2.2%, respectively. Common AEs (≥ 4%) included irritability, fall, depression, dry mouth, and fatigue. CONCLUSIONS: Data from an integrated analysis of studies in TD and an integrated analysis of studies of chorea in HD showed that deutetrabenazine has a favorable safety profile and is well tolerated across indications. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02291861, NCT02195700, NCT01795859, NCT02198794, NCT01897896.

Unintended movements are often the first sign of Huntington disease. This type of unintended movement is called chorea in Huntington disease. Tardive dyskinesia causes unintended body movements. Deutetrabenazine is a medicine used to treat both types of movements. This report summarizes deutetrabenazine safety across five clinical studies. Safety was assessed via adverse events (side effects). Adverse events were compared between deutetrabenazine and inactive treatment (placebo). Serious adverse events were also compared. Serious adverse events cause substantial impairment or disruption. In tardive dyskinesia and chorea in Huntington disease studies, most patients kept taking deutetrabenazine. Adverse events were not a common reason to stop treatment. For tardive dyskinesia, adverse event rates were similar between deutetrabenazine (≤ 60%) and placebo (54%). Serious adverse event rates were also similar for deutetrabenazine (≤ 8%) and placebo (7%). Adverse events tended to be reported earlier in treatment. Common adverse events were headache, sleepiness, nausea, anxiety, fatigue, dry mouth, and diarrhea. For chorea in Huntington disease, adverse event rates were similar for deutetrabenazine (64%) and placebo (60%). Serious adverse event rates were also similar for deutetrabenazine (2%) and placebo (2%). Irritability, fall, depression, dry mouth, and fatigue were common adverse events. Adverse events were similar between deutetrabenazine and placebo in both conditions. Deutetrabenazine was well tolerated for patients with either tardive dyskinesia or chorea in Huntington disease.

Association between Subjective Cognitive Complaints and Incident Functional Impairment in Parkinson's Disease.

BACKGROUND: Early identification of subjective cognitive complaints (SCC) in Parkinson's disease (PD) may improve patient care if it predicts cognition-related functional impairment (CFI). OBJECTIVES: The aim was to determine the cross-sectional and longitudinal association between SCC and CFI in PD. METHODS: Data were obtained from Fox Insight, an online longitudinal study that collects PD patient-reported outcomes. Participants completed a PD Patient Report of Problems that asked participants for their five most bothersome disease problems. SCCs were placed into eight categories through human-in-the-loop curation and classification. CFI had a Penn Parkinson's Daily Activities Questionnaire (PDAQ-15) score ≤49. Cox proportional hazards models and Kaplan-Meier survival analyses determined if baseline SCC was associated with incident CFI. RESULTS: The PD-PROP cohort (N = 21,160) was 55.8% male, mean age was 65.9 years, and PD duration was 4.8 years. At baseline, 31.9% (N = 6750) of participants reported one or more SCCs among their five most bothersome problems, including memory (13.2%), language/word finding (12.5%), and concentration/attention (9.6%). CFI occurred in 34.7% (N = 7332) of participants. At baseline, SCC was associated with CFI (P-value <0.001). SCC at baseline was associated with incident CFI (hazard ratio [HR] = 1.58 [95% confidence interval: 1.45, 1.72], P-value <0.001), as did cognitive impairment not otherwise specified (HR = 2.31), executive abilities (HR = 1.97), memory (HR = 1.85), and cognitive slowing (HR = 1.77) (P-values <0.001). Kaplan-Meier curves showed that by year 3 an estimated 45% of participants with any SCC at baseline developed new-onset CFI. CONCLUSIONS: Self-reported bothersome cognitive complaints are associated with new-onset CFI in PD. Remote electronic assessment can facilitate widespread use of patient self-report at population scale. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease. METHODS: LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014-000418-75, and is now complete. FINDINGS: Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]). INTERPRETATION: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments. FUNDING: Teva Pharmaceutical Industries.

Internal tremor in people with Parkinson's Disease: Demographic characteristics and comorbid symptoms.

Introduction: Internal tremor (IT) occurs in > 30 % of people with Parkinson's Disease (PwPD), but remains largely uninvestigated. Our objective was to describe demographic characteristics and associated symptoms in PwPD who reported IT. Methods: This was a matched case-control survey study. Data were from PwPD in the Fox Insight study who answered the Patient Report of Problems (PD-PROP) assessment, a series of open-ended questions that asks people to report in their own words their most bothersome PD-related problems. Cases were those who reported IT ≥ 1 times compared with PwPD controls who did not report IT and were matched 1:3 by age and disease duration. Results: 243 PwPD reported IT as a bothersome problem. Mean (SD) age of cases was 64.9 (9.4) years and disease duration was 3.8 (4.0) years. The proportion of women was greater among cases compared to controls (74 % vs 47 %, p < 0.0001). External tremor as a PD-PROP symptom was reported by 98 % cases and 48 % controls (p < 0.0001). Several non-motor symptoms were more common among cases than controls, including anxiety (35 % vs 20 %), fatigue (41 % vs 31 %), and pain (57 % vs 37 %). The odds of IT was significantly higher in women when adjusting for anxiety and motor experiences of daily living score (OR 3.07, 95 %CI 2.14-4.41, p < 0.0001). Conclusion: PwPD with IT report a range of associated symptoms, including external tremor, anxiety, and pain. Sex differences in the experience of IT may exist. Studies of IT are needed to understand its etiology and inform clinical care.

PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate.

The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2 phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y419 phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP3 signaling, and supports tumor progression.

What Patients Say: Large-Scale Analyses of Replies to the Parkinson's Disease Patient Report of Problems (PD-PROP).

BACKGROUND: Free-text, verbatim replies in the words of people with Parkinson's disease (PD) have the potential to provide unvarnished information about their feelings and experiences. Challenges of processing such data on a large scale are a barrier to analyzing verbatim data collection in large cohorts. OBJECTIVE: To develop a method for curating responses from the Parkinson's Disease Patient Report of Problems (PD-PROP), open-ended questions that asks people with PD to report their most bothersome problems and associated functional consequences. METHODS: Human curation, natural language processing, and machine learning were used to develop an algorithm to convert verbatim responses to classified symptoms. Nine curators including clinicians, people with PD, and a non-clinician PD expert classified a sample of responses as reporting each symptom or not. Responses to the PD-PROP were collected within the Fox Insight cohort study. RESULTS: Approximately 3,500 PD-PROP responses were curated by a human team. Subsequently, approximately 1,500 responses were used in the validation phase; median age of respondents was 67 years, 55% were men and median years since PD diagnosis was 3 years. 168,260 verbatim responses were classified by machine. Accuracy of machine classification was 95% on a held-out test set. 65 symptoms were grouped into 14 domains. The most frequently reported symptoms at first report were tremor (by 46% of respondents), gait and balance problems (>39%), and pain/discomfort (33%). CONCLUSION: A human-in-the-loop method of curation provides both accuracy and efficiency, permitting a clinically useful analysis of large datasets of verbatim reports about the problems that bother PD patients.

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1-5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia-reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

Individual phosphatidylinositol transfer proteins have distinct functions that do not involve lipid transfer activity.

Platelets use signal transduction pathways facilitated by class I phosphatidylinositol transfer proteins (PITPs). The 2 mammalian class I PITPs, PITPα and PITPß, are single PITP domain soluble proteins that are encoded by different genes and share 77% sequence identity, although their individual roles in mammalian biology remain uncharacterized. These proteins are believed to shuttle phosphatidylinositol and phosphatidylcholine between separate intracellular membrane compartments, thereby regulating phosphoinositide synthesis and second messenger formation. Previously, we observed that platelet-specific deletion of PITPα, the predominantly expressed murine PITP isoform, had no effect on hemostasis but impaired tumor metastasis formation and disrupted phosphoinositide signaling. Here, we found that mice lacking the less expressed PITPß in their platelets exhibited a similar phenotype. However, in contrast to PITPα-null platelet lysates, which have impaired lipid transfer activity, PITPß-null platelet lysates have essentially normal lipid transfer activity, although both isoforms contribute to phosphoinositide synthesis in vitro. Moreover, we found that platelet-specific deletion of both PITPs led to ex vivo platelet aggregation/secretion and spreading defects, impaired tail bleeding, and profound tumor dissemination. Our study also demonstrated that PITP isoforms are required to maintain endogenous phosphoinositide PtdInsP2 levels and agonist-stimulated second messenger formation. The data shown here demonstrate that the 2 isoforms are functionally overlapping and that a single isoform is able to maintain the homeostasis of platelets. However, both class I PITP isoforms contribute to phosphoinositide signaling in platelets through distinct biochemical mechanisms or different subcellular domains.

The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system.

Abnormalities in the endosomal-autophagic-lysosomal (EAL) system are an early event in Alzheimer's disease (AD) pathogenesis. However, the mechanisms underlying these abnormalities are unclear. The transient receptor potential channel mucolipin 1(TRPML1, also known as MCOLN1), a vital endosomal-lysosomal Ca2+ channel whose loss of function leads to neurodegeneration, has not been investigated with respect to EAL pathogenesis in late-onset AD (LOAD). Here, we identify pathological hallmarks of TRPML1 dysregulation in LOAD neurons, including increased perinuclear clustering and vacuolation of endolysosomes. We reveal that induced pluripotent stem cell (iPSC)-derived human cortical neurons expressing APOE ε4, the strongest genetic risk factor for LOAD, have significantly diminished TRPML1-induced endolysosomal Ca2+ release. Furthermore, we found that blocking TRPML1 function in primary neurons by depleting the TRPML1 agonist PI(3,5)P2 via PIKfyve inhibition, recreated multiple features of EAL neuropathology evident in LOAD. This included increased endolysosomal Ca2+ content, enlargement and perinuclear clustering of endolysosomes, autophagic vesicle accumulation and early endosomal enlargement. Strikingly, these AD-like neuronal EAL defects were rescued by TRPML1 reactivation using its synthetic agonist ML-SA1. These findings implicate defects in TRPML1 in LOAD EAL pathogenesis and present TRPML1 as a potential therapeutic target.

Death Anxiety in Huntington Disease: Longitudinal Heath-Related Quality-of-Life Outcomes.

Objective: Death anxiety, represented by the HDQLIFE™ Concern with Death and Dying (CwDD) patient-reported outcome (PRO) questionnaire, captures a person's worry about the death and dying process. Previous work suggests that death anxiety remains an unremitting burden throughout all stages of Huntington disease (HD). Although palliative interventions have lessened death anxiety among people with advanced cancer, none has yet to undergo testing in the HD population. An account of how death anxiety is associated with longitudinal changes to aspects of health-related quality of life (HRQoL) would help optimize neuropalliative interventions for people with HD. Methods: HDQLIFE collected PROs concerning physical, mental, social, and cognitive HRQoL domains and clinician-rated assessments from people with HD at baseline and 12 and 24 months. Linear mixed-effects models were created to determine how baseline death anxiety was associated with follow-up changes in HRQoL PROs after controlling for baseline death anxiety and other disease and sociodemographic covariates. Results: Higher baseline HDQLIFE CwDD is associated with 12- and 24-month declines in HDQLIFE Speech Difficulties, neurology quality of life (NeuroQoL) Depression, Suicidality, HDQLIFE Meaning and Purpose, and NeuroQoL Positive Affect and Well-being. Interpretation: Death anxiety may be a risk factor for worsening mental health and speech difficulty. A further prospective study is required to evaluate whether interventions on death anxiety or mental health generally can reduce declines in HRQoL for people with HD over time.

Understanding the Relationship Between Perseveration, Comorbid Behavioral Symptoms, Motor Decline, Functional Decline, and Self-report Accuracy in Huntington Disease Can Help Inform Clinical Practice.

BACKGROUND: Perseveration is one of the most debilitating symptoms of Huntington disease (HD). OBJECTIVE: To study perseveration and its relationship to comorbid behavioral symptoms, motor decline, functional decline, and subject self-report accuracy by analyzing cross-sectional data tracking individuals who have or are at risk for HD and healthy controls (HC). METHOD: We studied 96 individuals from HD families and 35 HC who were either family controls or gene negative. We used χ 2 tests to compare patient demographic and survey outcomes data and to analyze the presence of obsessions and compulsions (OC), depression, and apathy relative to the presence of perseveration. RESULTS: Individuals with HD and perseveration had a higher presence of OC, depression, and apathy compared with individuals with HD of the same stages without perseveration (19%, 47.6%, and 47.6% vs 15%, 40%, and 25%, respectively). In addition, individuals in HD Stages 1-3 with higher motor scores (showing a later stage of disease) displayed a significantly higher rate of perseveration than the HC ( P = 0.0476; P = 0.0499, respectively). The presence of an informant resulted in a significantly higher rate of perseveration reporting for individuals in HD Stages 1 and 2 (41.2% and 53.8% with informant vs 23.5% and 11.1% without informant, respectively). CONCLUSION: Perseveration was seen across all motor and functional stages for the individuals with HD, without significant differences between the different stages. Additionally, informants were beneficial to obtaining accurate patient reports of perseveration. These findings should prove useful for physician evaluation and treatment considerations.

Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models.

Myeloproliferative neoplasms (MPNs) are characterized by the activated JAK2/STAT pathway. Pleckstrin-2 (Plek2) is a downstream target of the JAK2/STAT5 pathway and is overexpressed in patients with MPNs. We previously revealed that Plek2 plays critical roles in the pathogenesis of JAK2-mutated MPNs. The nonessential roles of Plek2 under physiologic conditions make it an ideal target for MPN therapy. Here, we identified first-in-class Plek2 inhibitors through an in silico high-throughput screening approach and cell-based assays, followed by the synthesis of analogs. Plek2-specific small-molecule inhibitors showed potent inhibitory effects on cell proliferation. Mechanistically, Plek2 interacts with and enhances the activity of Akt through the recruitment of downstream effector proteins. The Plek2-signaling complex also includes Hsp72, which protects Akt from degradation. These functions were blocked by Plek2 inhibitors via their direct binding to the Plek2 dishevelled, Egl-10 and pleckstrin (DEP) domain. The role of Plek2 in activating Akt signaling was further confirmed in vivo using a hematopoietic-specific Pten-knockout mouse model. We next tested Plek2 inhibitors alone or in combination with an Akt inhibitor in various MPN mouse models, which showed significant therapeutic efficacies similar to that seen with the genetic depletion of Plek2. The Plek2 inhibitor was also effective in reducing proliferation of CD34-positive cells from MPN patients. Our studies reveal a Plek2/Akt complex that drives cell proliferation and can be targeted by a class of antiproliferative compounds for MPN therapy.

Alteration of Autophagy and Glial Activity in Nilotinib-Treated Huntington's Disease Patients.

Nilotinib is a tyrosine kinase inhibitor that is safe and tolerated in neurodegeneration, it achieves CSF concentration that is adequate to inhibit discoidin domain receptor (DDR)-1. Nilotinib significantly affects dopamine metabolites, including Homovanillic acid (HVA), resulting in an increase in brain dopamine. HD is a hereditary disease caused by mutations in the Huntingtin's (HTT) gene and characterized by neurodegeneration and motor and behavioral symptoms that are associated with activation of dopamine receptors. We explored the effects of a low dose of nilotinib (150 mg) on behavioral changes and motor symptoms in manifest HD patients and examined the effects of nilotinib on several brain mechanisms, including dopamine transmission and gene expression via cerebrospinal fluid (CSF) miRNA sequencing. Nilotinib, 150 mg, did not result in any behavioral changes, although it significantly attenuated HVA levels, suggesting reduction of dopamine catabolism. There was no significant change in HTT, phosphorylated neuro-filament and inflammatory markers in the CSF and plasma via immunoassays. Whole miRNA genome sequencing of the CSF revealed significant longitudinal changes in miRNAs that control specific genes associated with autophagy, inflammation, microglial activity and basal ganglia neurotransmitters, including dopamine and serotonin.

Somatoform Symptoms in Parkinson Disease.

BACKGROUND: Co-occurring somatoform symptoms complicate the diagnosis and treatment of Parkinson disease (PD). OBJECTIVE: To learn more about the relationship between somatoform symptoms and PD by comparing demographic and clinical features across PD groups differing in somatoform symptom severity. METHOD: Using standardized Brief Symptom Inventory-18 (BSI-18) scores to measure somatoform symptom severity, we assigned 1093 individuals with PD to one of four subgroups using comparisons to normative means: low (M < -½ SD), average (M ± ½ SD), high (M +½ SD to +1 SD), very high (M > +1 SD). We used demographics and disease severity measures to assess each subgroup. RESULTS: Most of the individuals with PD (56%) had high or very high somatoform symptom levels. Increased somatoform symptom levels were associated with female gender, lower socioeconomic status, greater disease duration, increased PD severity (Total Unified Parkinson's Disease Rating Scale), greater disability (Older Americans Resource and Services Disability subscale), increased BSI-18 Depression and Anxiety subscale scores, lower cognitive function (Mini-Mental State Examination), lower self-efficacy scores (Self-Efficacy to Manage Chronic Disease Scale), lower quality of life scores (SF-12 Health Status Survey), and greater medical comorbidity (Cumulative Illness Rating Scale-Geriatrics) (all comparisons: P < 0.001). We found no significant between-group differences for age, race, or marital status. CONCLUSION: Somatoform symptom severity in individuals with PD is associated with greater PD severity and disability and is more common in females and in individuals with low socioeconomic status. Greater awareness of somatoform symptoms should help improve PD treatment.

The Vasopressin 1a Receptor Antagonist SRX246 Reduces Aggressive Behavior in Huntington's Disease.

SRX246, an orally available CNS penetrant vasopressin (VP) V1a receptor antagonist, was studied in Huntington's disease (HD) patients with irritability and aggressive behavior in the exploratory phase 2 trial, Safety, Tolerability, and Activity of SRX246 in Irritable HD patients (STAIR). This was a dose-escalation study; subjects received final doses of 120 mg BID, 160 mg BID, or placebo. The compound was safe and well tolerated. In this paper, we summarize the results of exploratory analyses of measures of problematic behaviors, including the Cohen-Mansfield Agitation Inventory (CMAI), Aberrant Behavior Checklist (ABC), Problem Behaviors Assessment-short form (PBA-s), Irritability Scale (IS), Clinical Global Impression (CGI), HD Quality of Life (QoL), and Caregiver Burden questionnaires. In addition to these, we asked subjects and caregivers to record answers to short questions about mood, irritability, and aggressive conduct in an eDiary. STAIR was the first rigorously designed study of behavioral endpoints like these in HD. The exploratory analyses showed that SRX246 reduced aggressive acts. Readily observed behaviors should be used as trial endpoints.

Age-related decline in the resistance of mice to bacterial infection and in LPS/TLR4 pathway-dependent neutrophil responses.

Host defense against bacterial and fungal infections diminishes with age. In humans, impaired neutrophil responses are thought to contribute to this decline. However, it remains unclear whether neutrophil responses are also impaired in old mice. Here, we investigated neutrophil function in old mice, focusing on responses primed by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria like E. coli, which signals through toll-like receptor (TLR) 4. We show that old mice have a reduced capacity to clear pathogenic E. coli during septic peritonitis. Neutrophil recruitment was elevated during LPS-induced but not aseptic peritonitis. Neutrophils from old mice showed reduced killing of E. coli. Their reactive oxygen species (ROS) production was impaired upon priming with LPS but not with GM-CSF/TNFα. Phagocytosis and degranulation were reduced in a partially LPS-dependent manner, whereas impairment of NET release in response to S. aureus was independent of LPS. Unexpectedly, chemotaxis was normal, as were Rac1 and Rac2 GTPase activities. LPS-primed activation of Erk and p38 Mapk was defective. PIP3 production was reduced upon priming with LPS but not with GM-CSF/TNFα, whereas PIP2 levels were constitutively low. The expression of 5% of neutrophil proteins was dysregulated in old age. Granule proteins, particularly cathepsins and serpins, as well as TLR-pathway proteins and membrane receptors were upregulated, whereas chromatin and RNA regulators were downregulated. The upregulation of CD180 and downregulation of MyD88 likely contribute to the impaired LPS signaling. In summary, all major neutrophil responses except chemotaxis decline with age in mice, particularly upon LPS priming. This LPS/TLR4 pathway dependence resolves previous controversy regarding effects of age on murine neutrophils and confirms that mice are an appropriate model for the decline in human neutrophil function.

The inositol 5-phosphatase INPP5B regulates B cell receptor clustering and signaling.

Upon antigen binding, the B cell receptor (BCR) undergoes clustering to form a signalosome that propagates downstream signaling required for normal B cell development and physiology. BCR clustering is dependent on remodeling of the cortical actin network, but the mechanisms that regulate actin remodeling in this context remain poorly defined. In this study, we identify the inositol 5-phosphatase INPP5B as a key regulator of actin remodeling, BCR clustering, and downstream signaling in antigen-stimulated B cells. INPP5B acts via dephosphorylation of the inositol lipid PI(4,5)P2 that in turn is necessary for actin disassembly, BCR mobilization, and cell spreading on immobilized surface antigen. These effects can be explained by increased actin severing by cofilin and loss of actin linking to the plasma membrane by ezrin, both of which are sensitive to INPP5B-dependent PI(4,5)P2 hydrolysis. INPP5B is therefore a new player in BCR signaling and may represent an attractive target for treatment of B cell malignancies caused by aberrant BCR signaling.