Objective Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers.
Methods High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI).
Results We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (−21.8%, p<0.0001) and symptomatic ALS mutation carriers (−13.4%, p<0.001). The atrophy in patients with sporadic ALS was observed in both the anterior (−27.6% p<0.0001) and the posterior parts of the hypothalamus (−17.7%, p<0.0001). Notably, this atrophy was also observed in presymptomatic ALS mutation carriers (−15.5%, p<0.001) and was unrelated to whole brain volume atrophy or disease stage as assessed using DTI or functional status. Hypothalamic volume was correlated with body mass index (BMI) in patients with sporadic ALS (p=0.0434, ρ=+0.1579), and this correlation was much stronger in patients with familial ALS (fALS) (p=0.0060, ρ=+0.6053). Anterior hypothalamic volume was correlated with age at onset, but not with survival after MRI.
Conclusions Hypothalamus is atrophied in ALS, even in premorbid stages, and correlates with BMI, especially in fALS. Decreased anterior hypothalamic volume is associated with earlier onset of disease.
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MG and PV contributed equally.
JK and LD share senior authorship.
Contributors MG collected MRI scans, performed manual delineation of hypothalami, performed data analysis after delineation and collected clinical data; PV performed manual delineation of hypothalami and performed data analysis after delineation; H-PM provided expertise in data analysis; H-JH measured whole brain and intracranial volumes; PW organised the study of presymptomatic mutation carriers; AR and GN provided clinical expertise and patient information, AP provided expertise on manual delineation of hypothalamus; ACL, JK and LD conceived and designed the study. PV, MG, JK and LD performed statistical analysis, prepared the figures and drafted the manuscript. All authors critically reviewed the manuscript for intellectual content. MG and PV shared first authorship. JK and LD are joint senior authors of this study.
Funding This work was supported by fondation « recherche sur le cerveau » (call 2015, to LD), Fondation Thierry Latran (SpastALS, to LD) and ARSla (call 2016, to LD). Work in our laboratories is supported by Agence Nationale de la Recherche (grants ToFU and EpiFUS; to LD); ALS Association Investigator Initiated Award (grants 2235, 3209 and 8075; to LD); the Frick Foundation (award 2013 to LD); Association Française contre les Myopathies (grant #18280; to LD); Virtual Helmholtz Institute ‘RNA dysmetabolism in ALS and FTD’ (WP2, to LD and ACL); by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG Grant Number LU 336/15-1 to ACL) and the German Network for Motor Neuron Diseases (BMBF 01GM1103A to ACL); the Swedish Research Council (ÅP).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics Committee of the University of Ulm.
Provenance and peer review Not commissioned; externally peer reviewed.
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