Welcome to the WCN 2023 Interactive Program

Background and Aims:

Methods:

Results:

Conclusions:

Background and Aims:

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre‑mRNA splicing modifier, approved in 99 countries worldwide. SUNFISH (NCT02908685) is a multicenter, two-part, randomized, placebo-controlled, double-blind study of risdiplam in patients with Types 2/3 SMA, aged 2–25 years at enrollment.

Here we present 4-year efficacy and safety data.

Methods:

Part 1 (N=51) assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of risdiplam in patients with Types 2/3 SMA (ambulant and non-ambulant). Part 2 (N=180) assessed the efficacy and safety of the Part 1-selected dose in Type 2 and non-ambulant Type 3 SMA. Part 2 participants were treated with risdiplam or placebo for 12 months; then risdiplam in a blinded manner until Month 24, when patients could enter the open-label extension.

Results:

The primary endpoint (Part 2) of change from baseline in the 32-item Motor Function Measure (MFM32) total score in patients treated with risdiplam (n=120) versus placebo (n=60) was met at Month 12. These increases in motor function were sustained after 4 years, as measured by the MFM32, Hammersmith Functional Motor Scale – Expanded, and Revised Upper Limb Module. At 4 years (data cut-off: 6 September 2022) there were no treatment-related safety findings leading to withdrawal from SUNFISH Part 1 or 2.

Conclusions:

SUNFISH is ongoing and will provide long-term efficacy and safety data of risdiplam in a broad population of children, teenagers and adults with SMA.

Background and Aims:

Neuronal ceroid lipofuscinosis (NCLs) encompass a diverse group of autosomal recessively inherited progressive lysosomal storage disorders. Despite its rarity, there is a limited body of research on this topic. The literature on the mutational spectrum and genotype-phenotype correlation in NCL patients from India is particularly scarce. This study aims to bridge this knowledge gap by presenting a comprehensive description of NCL patients.

Methods:

Patients with genetically confirmed NCL were enrolled through case file review. We conducted a retrospective data collection using a proforma and questionnaire to gather history and examination findings. Subsequently, we analyzed the patients' electrophysiology, neuroimaging and electron microscopic findings.

Results:

We identified 51 patients with genetically confirmed NCL. The mean age at symptom onset was 3.18 ± 2.84 years. There were 30 males and 21 females. Seizures were the most common initial manifestation (37.3%), followed by developmental delay, regression, myoclonus, ataxia, and visual impairment. Electrophysiology showed prolonged VEP, giant SSEP, and epileptiform abnormalities on EEG. Electron microscopy of skin biopsy (15 patients) revealed curvilinear bodies (6 cases), curvilinear/fingerprint profiles (7 cases), and normal findings (3 cases). MRI showed cerebellar atrophy ( in 76% cases), cerebral atrophy (58%), periventricular hyperintensity (52%) and thalamic hypointensity (45%). On NGS, the most prevalent mutation was found in the CLN6 gene (11/51 cases), followed by mutations in PPT1 (3/51), TPP1 (10/51), CLN3 (3/51), CLN5 (6/51), CLN7 (8/51), and KCTD7 (2/51).

Conclusions:

Our study offers comprehensive insights into NCL characteristics, including clinical, electrophysiological, electron microscopy, and radiological features, along with gene mutations detected via next-generation sequencing.

Background and Aims:

Isolated posterior cerebral artery occlusions (iPCAO) were underrepresented in pivotal randomized controlled trial (RCTs) of endovascular thrombectomy (EVT) in ischemic stroke, and the benefit of EVT in this population is still indeterminate. We performed a systematic review and a meta-analysis to compare the safety and efficacy of EVT compared to best medical management (BMM) in patients with iPCAO.

Methods:

Methods: We searched four databases through May 2023 for illegible studies reporting outcomes of patients with iPCAO treated with EVT or BMM. We calculated pooled risk ratios (RRs) with corresponding 95% confidence intervals (CI) using a random-effects model.

Results:

7 studies (2560 patients) were included. EVT was associated with significantly higher likelihood of early neurological improvement (RR, 1.48 [95% CI, 1.34–1.65]; P < 0.00001) and visual field normalization (RR, 1.56 [95% CI, 1.33–2.10]; P < 0.00001) compared to BMM. Good functional outcomes (mRS 0-2) were comparable between the two arms (RR, 0.96 [95% CI, 0.88–1.05]; P= 0.36). Symptomatic intracranial hemorrhage (sICH) was comparable between the two groups (RR, 1.91 [95% CI, 0.97–3.76]; P = 0.06). 90-day mortality were also similar between the two groups (RR, 1.33; 95% CI = 0.80–2.21; P = 0.28).

Conclusions:

EVT in patients with iPCAO resulted in better clinical outcomes compared to BMM without statistically significant added risks of sICH or mortality. RCTs are needed to confirm and further investigate the generalizability of these results.

Background and Aims:

Motion sickness is a common disorder affecting approximately 30% of travelers under ordinary circumstances. The sensory mismatch theory postulates that motion sickness is induced by a discordance between the visual, vestibular, and kinesthetic systems, leading to a constellation of symptoms including nausea and vomiting. Substance P activates NK1 receptors in the nucleus tractus solitarius inducing a cascade of symptoms. Tradipitant is a novel NK1 receptor antagonist being studied for the treatment of nausea and vomiting associated with motion sickness.

Methods:

The Motion Syros study was a multicenter, randomized, double-blind, placebo-controlled study where 365 participants embarked on boat trips under varied sea conditions and received tradipitant 170 mg, tradipitant 85 mg, or placebo. Participants evaluated their symptoms at thirty-minute intervals during the expedition.

Results:

Participants on tradipitant 170mg or 85mg had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant 170 mg = 18.3%, tradipitant 85mg = 19.5%, placebo = 44.3%, p < .0001 for both dose comparisons against placebo, n = 365). A range of wave heights was represented across the various boat trips, eliciting variable degrees of severity of motion sickness and differing responses to tradipitant.

Conclusions:

Tradipitant has been confirmed to be effective in the reduction of vomiting associated with motion sickness across varied sea conditions with a range of wave heights. Motion sickness remains a significant unmet medical need, given the prevalence of adverse effects with current therapies.

Background and Aims:

Watchful waiting is unfortunately still a very common step in the patient journey to diagnose Alzheimer’s disease (AD). This delays patients from receiving definitive diagnoses, which can prevent them from accessing new therapeutic interventions in the optimal treatment time window. We present a validation study of Foresight AD^TM, a prognostic clinical decision support tool that forecasts cognitive and functional decline in early AD to enable timelier clinical decisions.

Methods:

Foresight AD^TM was trained and cross-validated on a database of 980 individuals with early AD, and it was externally validated on a large multicenter database of over 4500 individuals. Cognitive and functional assessments, demographics, and APOE genotypes collected at baseline were used to predict the individual risks of declining or probability of remaining stable over 24 months on the CDR-Sum of Boxes (CDR-SB).

Results:

Foresight AD^TM generalized across datasets, having achieved 75.3% Area Under the Curve (AUC) in cross-validation and 73.7% AUC in external validation. See Figure 1 for the average CDR-SB trajectories of the predicted groups and Figure 2 for examples of reports for two individuals.

Conclusions:

Foresight AD^TM is able to discriminate stable individuals from likely decliners in early AD populations. Such forecasts of clinical progression can support healthcare providers to make timelier diagnoses, thus reducing watchful waiting, simplifying the patient journey, and allowing patients to access new therapeutic interventions earlier.

Background and Aims:

Understanding the pathophysiology and early diagnosis of Alzheimer's Disease (AD) have been challenging. The study aims to assess Magnetic resonance imaging (MRI) Oxygen Extraction Fraction (OEF) in AD, examining its association with [¹⁸F]MK6240 Tau-Positron Emission Tomography (PET), [¹⁸F]AZD4694 Amyloid-β PET, and cognitive status.

Methods:

A cohort of 347 subjects, including young control (n=37), cognitively unimpaired (n=182), Milad-Cognitive impairment (n=80), and AD (n=48), was analyzed. All participants underwent tau-PET, amyloid-PET, and 3D gradient-recalled echo sequence MRI scans. The study used the TRIAD cohort preliminary data to build a pipeline for Quantitative Susceptibility Mapping (QSM) and OEF maps. The pre-processing steps comprised phase unwrapping, background field removal, and regularization of the inverse problem. All OEF maps were registered to Montreal Neurological Institution (MNI) space and were subjected to Region-Of-Interest (ROI) and voxel-based analyses. Using Freesurfer, eighty-two regions were delineated in the MNI space and were applied to all images.

Results:

A downward trend of OEF value from young to CN, MCI, and AD was noted in most brain regions. Positive correlations were found between OEF and tau and amyloid levels. Significant differences in OEF values were observed in multiple ROIs, including the right and left caudate, hippocampus, transverse temporal regions, cerebellar vermal lobules VIII-X, and precentral and caudal middle frontal regions.

Conclusions:

This study highlights the potential of MRI OEF as a significant marker in understanding AD. The demonstrated correlation of OEF with tau and amyloid deposition, and the cognitive status offers promising insights for early diagnosis of Alzheimer's.