Gabery Sanaz, Ahmed Rebekah M, Caga Jashelle, Kiernan Matthew C, Halliday Glenda M, Petersén Åsa
Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Memory and Cognition Clinic, Department of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
Neuropathol Appl Neurobiol. 2021 Dec;47(7):979-989. doi: 10.1111/nan.12709. Epub 2021 Apr 9.
To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease.
The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression.
Tar DNA-binding protein 43 (TDP-43) inclusions were present in the hypothalamus of all patients with amyotrophic lateral sclerosis. When compared to controls, there was atrophy of the hypothalamus (average 21% atrophy, p = 0.004), PVN (average 30% atrophy p = 0.014) and a loss of paraventricular oxytocin-producing neurons (average 49% loss p = 0.02) and lateral hypothalamic orexin-producing neurons (average 37% loss, significance p = 0.02). Factor analysis identified strong relationships between abnormal eating behaviour, hypothalamic atrophy and loss of orexin-producing neurons. With increasing disease progression, abnormal sleep behaviour and cognition associated with atrophy of the fornix.
Substantial loss of hypothalamic oxytocin-producing neurons occurs in ALS, with regional atrophy and the loss of orexin neurons relating to abnormal eating behaviour in ALS. Oxytocin- and orexin neurons display TDP43 inclusions. Our study points to significant pathology in the hypothalamus that may play a key role in metabolic and pathogenic changes in ALS.
鉴于下丘脑萎缩发生在肌萎缩侧索硬化症（ALS）的临床前期，确定与ALS下丘脑病理学相关的潜在细胞变化和临床关联。
对9例肌萎缩侧索硬化症患者的下丘脑进行病理检查，并与8名健康对照者进行比较。区域萎缩（室旁核：PVN、穹窿和整个下丘脑）的严重程度以及肽能神经元丢失（催产素、加压素、可卡因和苯丙胺调节转录物：CART和食欲素）与饮食行为、睡眠功能、认知、行为和疾病进展的变化相关。
所有肌萎缩侧索硬化症患者的下丘脑均存在Tar DNA结合蛋白43（TDP-43）包涵体。与对照组相比，下丘脑出现萎缩（平均萎缩21%，p = 0.004），PVN出现萎缩（平均萎缩30%，p = 0.014），室旁催产素生成神经元丢失（平均丢失49%，p = 0.02），下丘脑外侧食欲素生成神经元丢失（平均丢失37%，p = 0.02）。因子分析确定了异常饮食行为、下丘脑萎缩和食欲素生成神经元丢失之间的密切关系。随着疾病进展，异常睡眠行为和认知与穹窿萎缩相关。
ALS患者下丘脑催产素生成神经元大量丢失，区域萎缩和食欲素神经元丢失与ALS患者的异常饮食行为有关。催产素和食欲素神经元显示有TDP43包涵体。我们的研究指出下丘脑存在显著病变，可能在ALS的代谢和致病变化中起关键作用。
