To evaluate whether hypocretin-1 (orexin-A) and melanin-concentrating hormone (MCH) neurotransmission are affected in patients with Huntington disease (HD), we immunohistochemically stained hypocretin and MCH neurons and estimated their total numbers in the lateral hypothalamus of both HD patients and matched controls. In addition, hypocretin-1 levels were determined in prefrontal cortical tissue and post-mortem ventricular cerebrospinal fluid (CSF) using a radioimmunoassay. The total number of hypocretin-1 neurons was significantly reduced by 30% in HD brains (P = 0.015), while the total number of MCH neurons was not significantly altered (P = 0.100). Levels of hypocretin-1 were 33% lower in the prefrontal cortex of the HD patients (P = 0.025), but ventricular CSF levels were similar to the control values (P = 0.306). Neuronal intranuclear and cytoplasmic inclusions of mutant huntingtin were present in all HD hypothalami, although with a variable distribution across different hypothalamic structures. We found a specific reduction in hypocretin signaling in patients with HD as MCH cell number was not significantly affected. It remains to be shown whether the moderate decrease in hypocretin neurotransmission could contribute to clinical symptoms. As the number of MCH-expressing neurons was not affected, alterations in MCH signaling are unlikely to have clinical effects in HD patients.

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BackgroundThyroid eye disease (TED) is a potentially disfiguring and sight-threatening autoimmune (AI) orbitopathy, affecting up to 400,000 people in the UK. There are no accurate early predictors of TED severity. Although polyautoimmunity has been shown to affect AI disease severity, its influence on TED severity has never been investigated. The prevalence of polyautoimmunity among TED patients is also unclear, with discordant results reported in the literature. This study evaluates the prevalence of non-thyroid/“other” AI (OAI) conditions in an ethnically diverse TED cohort and assesses how polyautoimmunity affects TED severity and activity.MethodsA retrospective study of patients presenting to multidisciplinary TED clinics across three North-West London hospitals between 2011 and 2019. Data collected included: 1) demographics; 2) OAI conditions and management; 3) endocrine management of thyroid dysfunction; 4) details of TED and clinical activity score at presentation.ResultsTwo hundred and sixty-seven patients with a median age of 46 (35–54) years were included, 79.4% were female and 55% were Black, Asian and minority ethnic (BAME). Thirty-seven patients (13.9%) had OAI conditions, with rheumatoid arthritis (3.7%), vitiligo (3.0%) and psoriasis (3.0%) among the most prevalent. Of patients with OAI conditions, 43.2% (16/37) required immunosuppression prior to TED onset. Non-immunosuppressed patients with OAI conditions had a significantly higher clinical activity score at presentation than TED-only and previously immunosuppressed patients (p=0.02). No significant differences were observed in thyroid receptor antibody titers between these groups.ConclusionsThis study finds a 13.9% prevalence of OAI conditions among TED patients. Patients with OAI conditions overall have a tendency for more severe and significantly more clinically active TED than those without OAI conditions. Larger, prospective studies are warranted to further evaluate polyautoimmunity as an early predictor of TED severity.

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