Padraig O'SUilleabhain

Apathy is a highly prevalent neuropsychiatric feature of normal pressure hydrocephalus (NPH), but its clinical correlates and relevance to cerebrospinal fluid (CSF) removal trial response are poorly understood. We evaluated 161 adults with possible or probable NPH whose informants completed the Frontal Systems Behavior Scale (FrSBe), which provides normative ratings for premorbid (i.e. before symptom onset) and current apathy. Apathy change was defined as current minus premorbid ratings of apathy. Among the sample, 69.6% showed clinically elevated apathy (T-score ≥ 65) compared to 18.0% premorbidly; 91.9% showed increased apathy (Mean T-Score Change = 25.5, p < .001, d = 1.29). Partial Spearman correlations (controlling for cognitive symptom duration and depression) examined associations between apathy and gait, neuropsychological, functional, and disability measures. Gait responders were defined by clinical change in ≥2 gait measures post CSF-removal. The strongest correlates with apathy and apathy change were the World Health Organization Disability Assessment Schedule (ρ = .707 and .614) and the Quick Dementia Rating System (ρ = .682 and .587). Gait and cognitive composites (attention/speed/executive, overall) showed weaker (|ρ| = .208-.418) associations. Neither apathy nor apathy change differed between gait responders (n = 87) and non-responders (n = 48). Apathy is common in NPH and is related to disability and functional severity. It should therefore be routinely assessed in NPH evaluations.

Background: The treatment of levodopa‐induced dyskinesia in Parkinson's disease (PD) is a largely unmet need. Objectives: Mesdopetam is a novel small molecule dopamine D3 receptor antagonist aimed for the treatment of levodopa‐induced dyskinesia. This was a phase 2b study dose finding study to investigate efficacy and safety of 2.5 mg, 5 mg and 7,5 mg b.i.d. in a randomized controlled trial. Methods: PD patients with ≥2 hours of troublesome dyskinesia were randomized to placebo or mesdopetam twice daily for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in ON time without troublesome dyskinesia (Good ON‐time) as recorded with home diaries. Secondary efficacy endpoints assessing ON phase dyskinesia were the modified UDysRS (sum of parts 1, 3 and 4) and MDS‐UPDRS part 4.2. Results: Groups did not differ in change from baseline to end of study in Good ON‐time. Several secondary assessments for ON phase dyskinesia such as the modified UDysRS showed clinically relevant and statistically significant improvements for the 2.5 and 7.5 mg doses. OFF time showed dose dependent decrease with highest efficacy for the 7.5 mg dose. The adverse event profile was similar to placebo. Conclusions: In this study mesdopetam failed to increase Good ON‐time as compared to placebo. However, a statistically significant and clinically meaningful improvement in the prespecified secondary efficacy endpoint UDysRS warrants further investigation. Results from this dose finding study suggest 7.5 mg b.i.d. to be the preferred dose for further study.

Objective The validation of acute brain injury biomarkers has encountered challenges such as the absence of pre-insult measurements, variability in injury timing and location, and interindividual differences. In this study, we addressed these limitations by using Magnetic Resonance-guided High-Intensity Focused Ultrasound (MRgHIFU) thalamotomy to assess plasma biomarker changes after an acute focal brain injury. Methods This prospective study included 30 essential tremor (ET) and tremor-dominant Parkinson’s disease (TDPD) patients undergoing MRgHIFU thalamotomy at a single academic institution. Blood samples were collected at three specific time points: pre-procedure, 1-hour post-procedure, and 48 hours post-procedure. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid-beta (Aβ40 and Aβ42), and phosphorylated tau 181 (pTau-181) were measured using the Quanterix Single Molecule Arrays (SiMoA) assay. Results GFAP levels significantly increased 48 hours post-MRgHIFU in all patients with a thalamotomy lesion. GFAP levels were highly sensitive (89.7%) and specific (96.6%) in detecting the presence of a HIFU lesion with a cutoff value of 216.2 pg/ml. NfL, Aβ40, and Aβ42, also showed statistically significant increases post-procedure but were less robust than GFAP. No changes were observed in pTau-181 levels post-MRgHIFU. Conclusion Plasma GFAP emerged as a highly sensitive and reliable biomarker for detecting acute brain injury following MRgHIFU thalamotomy. The significant post-procedure elevation of GFAP suggests its potential as an early diagnostic tool for focal brain injuries, particularly in acute stroke. Further research is needed to validate the GFAP injury cutoff identified in this study and to explore its broader clinical utility in the early detection of focal brain lesions.

Background: People with essential tremor (ET) can be subject to stigma, and some adopt avoidance behaviors. Characteristics associated with ET stigma and the relationship between perceived stigma and social dysfunction have not been studied.Objectives: To discern predictors of perceived stigma and social dysfunction in ET, and to identify potentially treatable psychological factors associated with social dysfunction.Methods: We surveyed ET patients (n = 158) on recalled stigma incidents and social dysfunction related to tremor, as well as clinical and demographic characteristics including tremor severity, and psychological constructs including anxiety, depression, mindfulness, resilience, and narcissism.Results: Worse tremor severity (Standardized beta [SB] 1.4, P < 0.001) especially among younger participants (interaction of age and tremor severity SB −0.9, P < 0.001) and presence of vocal tremor (SB 0.7, P = 0.002) predict perceived stigma. 53/157 (33.8%) participants met criteria for social dysfunction, employing maladaptive avoidance strategies. Scores for perceived stigma (Odds Ratio [OR] 1.2, P = 0.002), depression (OR 1.5, P = 0.004) and stigma psychological distress (OR 1.2, P = 0.001) as well as sex (OR 4.3 for females, P = 0.045) predicted social dysfunction.Conclusions: Depression and stigma psychological distress contribute to social dysfunction related to ET stigma. Treating these psychological factors may mitigate social avoidance behaviors prevalent among susceptible individuals: those who most perceive ET stigma, i.e. relatively younger patients with worse tremor or with vocal tremor, and in particular females who are more prone to social dysfunction than males with the same degree of perceived stigma.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.