Integrated multi-omics analysis of Huntington disease identifies pathways that modulate protein aggregation.

Huntington disease (HD) is a neurodegenerative disease associated with polyglutamine expansion in the protein huntingtin (HTT). Although the length of the polyglutamine repeat correlates with age at disease onset and severity, psychological, cognitive and behavioral complications point to the existence of disease modifiers. Mitochondrial dysfunction and metabolic deregulation are both associated with the HD but, despite multi-omics characterization of patients and model systems, their mechanisms have remained elusive. Systems analysis of multi-omics data and its validation by using a yeast model could help to elucidate pathways that modulate protein aggregation. Metabolomics analysis of HD patients and of a yeast model of HD was, therefore, carried out. Our analysis showed a considerable overlap of deregulated metabolic pathways. Further, the multi-omics analysis showed deregulated pathways common in human, mice and yeast model systems, and those that are unique to them. The deregulated pathways include metabolic pathways of various amino acids, glutathione metabolism, longevity, autophagy and mitophagy. The addition of certain metabolites as well as gene knockouts targeting the deregulated metabolic and autophagy pathways in the yeast model system showed that these pathways do modulate protein aggregation. Taken together, our results showed that the modulation of deregulated pathways influences protein aggregation in HD, and has implications for progression and prognosis. This article has an associated First Person interview with the first author of the paper.

Multimodal Imaging and Visual Evoked Potentials Reveal Key Structural and Functional Features That Distinguish Symptomatic From Presymptomatic Huntington's Disease Brain.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric abnormalities. Currently, matched analyses of structural and functional differences in the brain from the same study cohort and, specifically, in HD patients from an ethnically diverse Indian population are lacking. Such findings aid in identifying noninvasive and sensitive imaging biomarkers. OBJECTIVE: The aim of the study was to understand the structural and functional differences between HD and control brain, and presymptomatic and symptomatic HD brain in the Indian population. MATERIALS AND METHODS: Seventeen HD (11 symptomatic HD [S-HD] and six presymptomatic HD [P-HD], with comparable CAG repeats), and 12 healthy controls were examined. Macrostructural (volume), microstructural (diffusivity), and functional (neurochemical levels and glucose metabolism) imaging of the brain was done along with the determination of visual latencies. RESULTS: HD brain showed increased intercaudate distance; significant subcortical volumetric loss; reduced fractional anisotropy; increased mean, axial, and radial diffusivity; lower levels of total N-acetyl aspartate; elevated total choline levels; and reduced glucose metabolism compared with control brain. Interestingly, compared with P-HD, S-HD patients demonstrated a strong inverse correlation between age at onset and CAG repeat length, and prolonged P100 latency. In addition, caudate and putamen in S-HD brain showed significant volumetric loss and increased diffusivity compared with P-HD brain. CONCLUSIONS: HD brain showed distinct macrostructural, microstructural, and functional differences compared with control brain in the Indian population. Interestingly, patients with S-HD had a significant volumetric loss, increased diffusivity, altered neurochemical profile, and delayed P100 latency compared with P-HD patients. Examining these alterations clinically could aid in monitoring the progression of HD.

Chronic Pregabalin Abuse with Subacute Encephalopathy Mimicking Autoimmune Encephalitis.

Pregabalin, a gabapentinoid frequently prescribed for neuropathic pain, also increasingly identified as a drug for abuse. We describe a unique case of 31-year-old man presented with subacute neuro-psychiatric symptoms and a spectrum of movement disorders, suspicious of autoimmune encephalitis. Initial response to IV methylprednisolone followed by recurrence of symptoms strengthened our suspicion for autoimmune encephalitis. His autoimmune encephalitis workup was negative, however, his two MRIs showed parenchymal changes. The patient, finally, confessed to chronic pregabalin abuse. He recovered completely upon stopping pregabalin abuse and remained asymptomatic at follow-up. To the best of our knowledge, we are the first to describe parenchymal changes in MRI mimicking autoimmune encephalitis in a case of pregabalin abuse. Despite the limited number of reports of pregabalin abuse in India, it is time to consider restricting the pregabalin availability, in line with many Western countries. This is particularly relevant to India, where, one legitimate prescription can be used by many to buy medicines at multiple stores without any questions being asked by the pharmacists.