Melatonin may slow disease progression in amyotrophic lateral sclerosis: Findings from the Pooled Resource Open-Access ALS Clinic Trials database.

INTRODUCTION: We utilized the Pooled Resource Open-Access Clinical Trials (PRO-ACT) database to investigate whether melatonin use among patients with amyotrophic lateral sclerosis (ALS) was associated with slower disease progression and prolonged survival. METHODS: This retrospective analysis of the PRO-ACT database addresses the impact of melatonin on progression and overall survival of ALS. A Cox proportional hazards ratio model was performed to investigate the effect that melatonin had on time to death. For secondary outcome measures, linear mixed effects regression models were used to ascertain the effect of melatonin on change in standardized ALS Functional Rating Scale (sALSFRS) and percentage predicted forced vital capacity (FVC) scores. RESULTS: Melatonin users had a significantly decreased annualized hazard death rate compared with the non-melatonin users (hazard ratio, 0.241; 95% confidence interval, 0.088-0.659; P = .0056). The melatonin users also had a slower rate of decline in sALSFRS score (t = 2.71; P = .0069) and change in percent predicted FVC score (t = 2.94; P = .0035) compared with the non-melatonin users. DISCUSSION: Our findings suggest that melatonin may be beneficial for patients with ALS. Due to the nature of this database, our results are solely intended to be hypothesis-generating and no strong associations can be made. Given the low cost and favorable safety profile of melatonin, the hypotheses generated warrant further investigation.

A pilot dose-finding study of Terazosin in humans.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Methods: Eighteen healthy men and women (60 - 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, 31 Phosphorous magnetic resonance spectroscopy for brain ATP levels, 18 F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Results: Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral 18 F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. Conclusions: TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ's efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.

Inflammatory pseudotumor of nerve: clinicopathological characteristics and a potential therapy.

We sought to determine the clinical, electrophysiological, neuroimaging, and pathological features of inflammatory pseudotumor of nerve. Five patients were identified. All cases presented with a gradually progressive mononeuropathy with symptoms of weakness, sensory loss, and prominent neuropathic pain. The median duration of symptoms was 7 months (range 3-36 months). Electrophysiological results were in keeping with chronic axonal mononeuropathies with variable findings of active denervation and reinnervation. MRI demonstrated irregular, large masses involving and surrounding nerve with heterogenous signal characteristics on T1- and T2-weighted and post-contrast sequences. Histopathological features of the nerve slightly varied but shared commonalities including chronic inflammatory infiltrates, increased collagen, and increased numbers of microvessels. Axonal degeneration and decreased density of myelinated fibers were also noted. Three patients were treated with weekly courses of intravenous steroids for 3 months. All reported improvement in pain and weakness. Inflammatory pseudotumor of nerve is not a neoplasm and has reactive features of inflammation, increased vascularity, and marked fibrosis. It presents as a progressive axonal mononeuropathy with weakness, sensory loss, and pain that may be episodic. The primary pathophysiology is unknown but the inflammation and response to treatment suggests that there may be an immune component.

Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome.

BACKGROUND: Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of alpha-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual alpha-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life. OBJECTIVE: To expand the later-onset Fabry phenotype to include cramp-fasciculation syndrome without small-fiber neuropathy. METHODS: A 34-year-old man who presented with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs, and his similarly affected mother, were evaluated. Clinical, biochemical, and molecular studies were performed. RESULTS: Clinical evaluation suggested the diagnosis of Fabry disease, which was confirmed by reduced plasma and leukocyte alpha-galactosidase A activities (8.8% and 13.4% of normal, respectively) due to a missense A143T mutation. His mother was heterozygous for the A143T mutation. CONCLUSION: The presentation of cramps and fasciculations without apparent small-fiber neuropathy expands the phenotype of later-onset Fabry disease.