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Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms – Parkinson’s disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer’s disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS

Myotonic dystrophy (DM1), the most common adult muscular dystrophy, is a multi-system, autosomal dominant genetic disorder caused by an expanded CTG repeat that leads to nuclear retention of a mutant RNA and subsequent RNA toxicity. Significant insights into the molecular mechanisms of RNA toxicity have led to the surprising possibility that treating DM1 is a viable prospect. In this review, we briefly present the clinical picture in DM1, and describe how the research in understanding the pathogenesis of RNA toxicity in DM1 has led to targeted approaches to therapeutic development at various steps in the pathogenesis of the disease. We discuss the promise and current limitations of each with an emphasis on RNA-based therapeutics and small molecules. We conclude with a discussion of the unmet need for clinical tools and outcome measures that are essential prerequisites to proceed in evaluating these potential therapies in clinical trials.

Objective To determine if an electroencephalographic (EEG) characteristic, beta:delta power ratio (BDPR), is significantly higher for N-methyl-d-aspartate receptor encephalitis (NMDARE) patients than for non-NMDARE patients on presenting EEG. Identification of an additional EEG biomarker with significant specificity for NMDARE (in the absence of frank delta brush) could potentially allow for early identification of at-risk patients. Methods Single center retrospective comparison of NMDARE and non-NMDARE consecutive cases of encephalitis, collated over a 6-year period (from 2008 to 2014). Results None of the 10 NMDARE patients displayed the extreme delta brush pattern on EEG previously described, but the ratio of BDPR was significantly higher for NMDARE patients (P < .005). There was no significant relationship between BDPR and the time of recording from symptom onset. Additional analysis of clinical characteristics also indicated that the patients with NMDARE (median age 19.5 years) were younger than the 5 patients with non-NMDARE (median age 36 years). Encephalopathy, seizure, and psychiatric complaints were the most common diagnoses at time of first health care presentation and did not favor a single etiology, though the latter was present only in the NMDARE population (50% at T). Prodromal illness featuring headache was more common in the non-NMDARE population. Outcomes, as measured by the Modified Rankin Scale, were globally better in the NMDARE group. Conclusions Patients with NMDARE had a significantly higher BDPR on EEG when compared with non-NMDARE patients even in the absence of extreme delta brush. This suggests that early EEG characteristics may be helpful in distinguishing NMDARE from non-NMDARE.

Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-κB pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1.