Faculty Bibliography

Cytochrome-P-450 (CYP)1A2 has been considered the major enzyme metabolizing riluzole since its approval. However, the inhibitor that was used in the original experiments, α-naphthoflavone, is also a potent inhibitor of CYP1A1. In this work, physiologically based pharmacokinetic (PBPK) modeling investigates the interplay between CYP1A1 and CYP1A2 and the relevance to drug-drug interactions. Following review of clinical and non-clinical data from literature, the relative contributions of CYP1A1, CYP1A2, and UGT1A8/9 to riluzole metabolism were assigned as 60%, 30%, and 10%, respectively. The model was calibrated on single-dose pharmacokinetic (PK) data from healthy subjects. The translational potential of the model was verified by predicting riluzole PK in people with amyotrophic lateral sclerosis, spinal muscular atrophy, advanced age, renal impairment, and hepatic impairment, and when administered with a high-fat meal. The relative contributions of CYP1A1 and CYP1A2 to metabolism were verified through prediction of an observed drug-drug interaction between riluzole and fluvoxamine-a strong CYP1A2 inhibitor and a weak CYP1A1 inhibitor-in children with obsessive-compulsive disorder. Overall, evidence suggests that CYP1A1 is a major enzyme metabolizing riluzole, and that CYP1A2 has similar or lower importance. Only clinically relevant inhibitors of both enzymes may pose a safety concern when administered with riluzole. Strong CYP1A1 inhibitors and strong CYP1A2 inhibitors may be used with caution if they do not significantly modulate the other enzyme. Concomitant use of CYP1A1 inducers may be reconsidered where possible. The enzymatic contributions to riluzole metabolism should be reconsidered after formal drug-drug interaction studies are completed.

INTRODUCTION/AIMS/OBJECTIVE:Muscle cramps are a common symptom in amyotrophic lateral sclerosis (ALS). Ameliorating muscle cramps may improve quality of life in devastating diseases like ALS. A traditional Japanese medicine (Kampo, TJ-68) is widely prescribed in Japan for muscle cramps. However, it is not available in the USA. This study evaluated the safety, tolerability, and efficacy of TJ-68 in ALS. METHODS:This study was a double-blind, randomized, placebo-controlled crossover trial, consisting of four periods, conducted at three centers in the USA. Safety was evaluated using multiple measures. The primary efficacy outcome was the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity (item #5 of the Muscle Cramp Scale (MCS)). The secondary outcomes included the remaining items of the MCS and the Clinical Global Impression of Changes (CGIC), among others. The study was planned to enroll 22 participants with ALS within 2 years. RESULTS:The enrollment was slow and was completed with 11 participants. There were no serious safety issues and TJ-68 was well tolerated. Although the primary outcome measure did not reach statistical significance (p = 0.35), several secondary measures showed significant results: MCS #1 triggering of cramps (p = 0.01), MCS #2 cramp frequency (p = 0.03), MCS Additional 1 change of motor behaviors (p = 0.02), and CGIC assessed by the evaluator (p = 0.009). Other outcome measures did not reach statistical significance. DISCUSSION/CONCLUSIONS:The study revealed that N-of-1 trial design can detect changes in a small sample size, and TJ-68 appeared to be safe. Larger studies are needed to confirm the efficacy of TJ-68.

The heterogeneity among the amyotrophic lateral sclerosis (ALS)/MND patient population is well recognized but not well understood. Such heterogeneity may represent a significant confound in our current and prior clinical trials as certain subgroups of patients might have a selective response (or resistance) to a novel therapeutic. The basis on which to segregate the patient population is, however, unclear. The ALS/MND Committee of the World Federation of Neurology (WFN) convened a symposium to discuss various strategies that might be considered for separating (stratifying) the population to further study. The results of that conference are presented here as a white paper, reflecting current understanding of several of the various criteria that could be implemented to divide the patient population as presented and discussed at that meeting. Consideration of grouping patients based on phenotype, cognitive involvement, imaging, or electrophysiology is presented here.

BACKGROUND:Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA, previously shown to delay neurodegeneration in a mouse model and potentially slow functional decline in a first-in-human study. Here, we sought to further evaluate use of jacifusen as a treatment for FUS-ALS. METHODS:This expanded access programme was conducted through a series of single-patient investigational new drug applications at five sites (four hospitals in the USA and one in Switzerland). Participants carried a FUS variant and had clinical evidence of motor neuron disease onset or electrophysiological abnormalities, if not a diagnosis of ALS. Participants were ineligible if chronically ventilated with tracheostomy. Enrolled sequentially, participants received serial intrathecal injections of jacifusen over 2·8-33·9 months. Based on multiple ascending doses of jacifusen (from 20 mg to 120 mg), successive protocols were modified as safety and other data were acquired, with the last participants enrolled receiving 120 mg doses monthly from the start of their treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and standard cerebrospinal fluid (CSF) metrics. Concentration of neurofilament light chain (NfL) in CSF was used as a biomarker of axonal injury and neurodegeneration, and the ALS Functional Rating Scale-Revised (ALSFRS-R) score was used as an overall measure of motor function. Biochemical analysis and immunohistochemical staining were done on post-mortem CNS tissues to quantify FUS protein expression and assess the burden of FUS pathology. FINDINGS/RESULTS:Between June 11, 2019, and June 2, 2023, we recruited 12 participants (median age 26 years [range 16-45]; seven [58%] were female and five [42%] were male) into the expanded access programme. Transient elevations in cell counts or total protein concentration in CSF (six [50%] participants) were unrelated to treatment duration. The most common adverse events were back pain (six [50%]), headache (four [33%]), nausea (three [25%]), and post-lumbar puncture headache (three [25%]). Two participant deaths were recorded during the programme, both thought to be unrelated to the investigational drug. The concentration of NfL in CSF was reduced by up to 82·8% after 6 months of treatment. Although most participants had continued functional decline (as measured by ALSFRS-R) after starting treatment with jacifusen, one showed unprecedented, objective functional recovery after 10 months, and another remained asymptomatic, with documented improvement in electromyographic abnormalities. Biochemical and immunohistochemical analysis of CNS tissue samples from four participants showed reduced FUS protein levels and an apparent decrease in the burden of FUS pathology. INTERPRETATION/CONCLUSIONS:The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial. FUNDING/BACKGROUND:ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.

Despite continued advancement in thrombectomy devices and techniques, a small proportion, approximately 10%, of thrombectomy attempts result in failed reperfusion due to technical difficulties with reaching the clot or recanalizing the occluded vessel. Technically challenging thrombectomy cases are often longer, with more thrombectomy passes, resulting in poorer clinical outcomes and higher rates of complications. Factors causing difficulty during thrombectomy include tortuous vasculature preventing access, challenging clot location (tandem or distal occlusions), underlying vessel abnormality, and hard-to-retrieve clots. Anticipating potentially challenging or refractory thrombectomy cases allows one to plan appropriate procedural strategies with the goal of maximizing technical success and favorable clinical outcome. We review these challenging situations and discuss specific procedural techniques that can be employed in each scenario to overcome the barriers and achieve fast and successful reperfusion.

Primary age-related tauopathy (PART) and Alzheimer's disease (AD) share hippocampal phospho-tau (p-tau) pathology but differ in ß-amyloid burden and degree of p-tau severity and spread. Thus, PART provides a human model to understand the mechanisms of age and amyloid-independent modifiers of p-tau. Given the dynamics of DNA methylation over the lifespan, we (1) performed an epigenome-wide association study of PART that nominated 13 loci associated with p-tau; (2) developed two novel epigenetic clocks predictive of p-tau in age-, and ß-amyloid-independent manners: "TauSeverity" relates hippocampal p-tau severity in PART and AD and synaptic transmission genes; "TauSpread" relates to p-tau spread to frontal cortex of AD and neuroinflammatory genes; and (3) a machine learning classifier that identifies low- and high resilience individuals with overlapping neuropathological features but distinct epigenetic, transcriptomic, and clinical features. We conclude that the epigenome contributes to the severity and spread of p-tau pathology, guided by distinct pathways with cognitive consequences.

INTRODUCTION/BACKGROUND:Neighborhood deprivation is associated with shorter survival, cognitive impairment, and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown. METHODS:= 161) with complete baseline data across measures of global cognition, executive function, and language, we examined the association of ADI with longitudinal change. RESULTS:Compared to adults living in the least deprived neighborhoods, those living in the most deprived neighborhoods showed shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk. DISCUSSION/CONCLUSIONS:Living in more deprived neighborhoods was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis. CLINICAL TRIAL REGISTRATION INFORMATION/BACKGROUND:N/A.

INTRODUCTION/BACKGROUND:Neighborhood deprivation is associated with shorter survival, cognitive impairment and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown. METHODS:We examined associations between tertiles of neighborhood deprivation, using the Area Deprivation Index (ADI), and survival in 311 individuals clinically diagnosed with bvFTD from the Penn FTD Center. In a subset (n=161) with complete baseline data across measures of global cognition, executive function, and language, we examined the association of ADI with longitudinal change. RESULTS:Compared to adults living in the least deprived neighborhoods, those living in the most deprived neighborhoods showed shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk. DISCUSSION/CONCLUSIONS:Living in more deprived neighborhoods was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis.

Patients with myotonic disorders are at risk for severe generalized muscle contraction, referred to as a "myotonic crisis." For those patients with nondystrophic myotonia (NDM), the most common trigger of a myotonic crisis is exposure to succinylcholine. In this case, a 10-year-old female patient with NDM secondary to an SCN4A pathogenic variant developed a severe myotonic crisis in the setting of an upper respiratory infection and asthma flare treated with a beta-adrenergic agonist (ß-agonist). She presented with generalized rigidity and features of hypermetabolism resembling an anesthetic-related malignant hyperthermia. Management necessitated multidisciplinary collaboration, a complex intubation strategy, and an extended course in the pediatric intensive care unit. We suspected that this crisis was precipitated in part by continuous ß-agonist use during her initial asthma management. Treatments targeting sequential steps of the myocyte activation cascade tempered the contractile apparatus leading to clinical improvement in rigidity.