Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis

Abstract

Background and objectives: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival.

Methods: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate.

Results: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029).

Discussion: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.

Figure 1. Difference in (Sub)hypothalamic Volumes Between Patients With ALS and Controls

Overview of hypothalamic atrophy in patients with ALS compared with controls. Blue regions represent significantly lower volumes in patients with ALS compared with controls after correction for multiple comparisons using permutations. Light gray regions represent no significant difference between groups. The image represents a left lateral view of the averaged left and right hypothalamic volumes. AIS = anterior inferior subregion; ALS = amyotrophic lateral sclerosis; ASS = anterior superior subregion; ITS = inferior tubular subregion; P = posterior subregion; STS = superior tubular subregion.

Figure 2. Hypothalamic Correlates of Weight Loss, Cognition, and Behavior

Overview of hypothalamic subregions correlated with weight loss at diagnosis (A), cognitive impairments (B, C), and behavioral changes (D, E). In (A), blue regions represent significantly lower volumes of hypothalamic subregions in ALS patients with weight loss compared with those without. Similarly, in (B), this is observed for patients with impaired memory scores, and in (C), for patients with impaired visuospatial scores. These significantly lower volumes (D) in patients with behavioral disinhibition, and (E) in patients experiencing loss of sympathy/empathy. All these differences are significant after correction for multiple comparisons using permutations. Light gray regions represent no significant difference between groups. The image represents a left lateral view of the averaged left and right hypothalamic volumes. AIS = anterior inferior subregion; ALS = amyotrophic lateral sclerosis; ASS = anterior superior subregion; ITS = inferior tubular subregion; P = posterior subregion; STS = superior tubular subregion.

Figure 3. Survival Curve for Patients With ALS

Time-to-event analysis according to posterior hypothalamic volume. The plot shows the observed Kaplan-Meier survival curve since first MRI scan, stratified for posterior hypothalamic volume below median (<109 mm³) and equal to or higher than median (≥109 mm³). Resulting p value (p = 0.001) was significant after correction for multiple testing using Bonferroni correction. ALS = amyotrophic lateral sclerosis.

Figure 4. Posterior Hypothalamic Deterioration in Patients With ALS and Controls

Interaction analysis to compare posterior hypothalamic change over time between patients with ALS and controls. The resulting p value (p = 0.029) was significant after correction for multiple comparisons using permutations. ALS = amyotrophic lateral sclerosis.