Objective: To investigate hypothalamic atrophy and its clinical correlates in Multiple System Atrophy (MSA) through MRI.

Background: MSA is characterized by autonomic dysfunction, i.e. orthostatic hypotension and/or genito-urinary dysfunction, and cerebellar/parkinsonian manifestations. The hypothalamus regulates autonomic and homeostatic functions and is also thought to be involved in memory and learning processes[1,2]. Several pathological studies have identified hypothalamic neuronal loss and alpha synuclein glial and neuronal inclusions in MSA[3,4,5].

Method: 11 MSA, 18 Parkinson’s Disease (PD) and 18 Healthy Controls (HC) were included in the study. 3D T1-weighted images were acquired on a 3T MRI scanner. Images were processed prior to applying a previously validated automated hypothalamic segmentation tool based on convolutional neural networks[6]. Whole hypothalamus volumes and 5 subregions were generated (Figure 1) and adjusted for total intracranial volume. Hypothalamic volumes were compared between MSA vs HC and MSA vs PD with independent t-tests. Associations with clinical scales of autonomic dysfunction, depression, sleep problems and cognitive function were also tested.

Results: No differences in age and sex were present between groups. Total hypothalamus showed a trend towards a significant reduction in MSA vs HC (t=1.937, p =0.065) and posterior hypothalamus was significantly lower in MSA (t=2.578, p=0.016; Figure 2). A trend toward reduced posterior hypothalamus was also found in MSA compared to PD (t=1.768, p=0.088). Total hypothalamus volume was not associated with age or disease duration. In the entire parkinsonism group (MSA+PD), total hypothalamus volume was associated with MoCA scores (rho=0.425, p=0.022), but not with autonomic (SCOPA-AUT), sleep (SCOPA-SLEEP), or depression (HADS-D) scores. Among hypothalamic subregions, only posterior hypothalamus volume was associated with MoCA scores (rho=0.718, p<0.001, Figure 3).

Conclusion: Total hypothalamus and posterior hypothalamus volumes are reduced in MSA compared with HCs but not with PD. General cognitive functioning scores are associated with total and posterior hypothalamus volumes. The posterior hypothalamus volume includes the mammillary bodies and the lateral hypothalamus, regions that are associated with memory and learning functions. Further studies are needed to characterize the central correlates of autonomic dysfunction in MSA.

References: 1. Burdakov D, Peleg-Raibstein D (2020) The hypothalamus as a primary coordinator of memory updating. Physiol Behav 223:112988. https://doi.org/10.1016/j.physbeh.2020.112988

2. Chen S, He L, Huang AJY, et al (2020) A hypothalamic novelty signal modulates hippocampal memory. Nature 586:270–274. https://doi.org/10.1038/s41586-020-2771-1

3. Cykowski MD, Coon EA, Powell SZ, et al (2015) Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain 138:2293–2309. https://doi.org/10.1093/brain/awv114

4. Ozawa T (2007) Morphological substrate of autonomic failure and neurohormonal dysfunction in multiple system atrophy: Impact on determining phenotype spectrum. Acta Neuropathol 114:201–211. https://doi.org/10.1007/s00401-007-0254-1

5. Benarroch EE, Schmeichel AM, Parisi JE, Low PA (2015) Histaminergic tuberomammillary neuron loss in multiple system atrophy and dementia with Lewy bodies. Mov Disord 30:1133–1139. https://doi.org/10.1002/mds.26287

6. Billot B, Bocchetta M, Todd E, Dalca AV, Rohrer JD, Iglesias JE. Automated segmentation of the hypothalamus and associated subunits in brain MRI. Neuroimage. 2020 Dec;223:117287. doi: 10.1016/j.neuroimage.2020.117287.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hypothalamic-involvement-in-multiple-system-atrophy-a-clinical-and-neuroimaging-study/