Sleep deficits but no metabolic deficits in premanifest Huntington's disease

Abstract

Objective: Huntington disease (HD) is a fatal autosomal dominant, neurodegenerative condition characterized by progressively worsening motor and nonmotor problems including cognitive and neuropsychiatric disturbances, along with sleep abnormalities and weight loss. However, it is not known whether sleep disturbances and metabolic abnormalities underlying the weight loss are present at a premanifest stage.

Methods: We performed a comprehensive sleep and metabolic study in 38 premanifest gene carrier individuals and 36 age- and sex-matched controls. The study consisted of 2 weeks of actigraphy at home, 2 nights of polysomnography and multiple sleep latency tests in the laboratory, and body composition assessment using dual energy x-ray absorptiometry scanning with energy expenditure measured over 10 days at home by doubly labeled water and for 36 hours in the laboratory by indirect calorimetry along with detailed cognitive and clinical assessments. We performed a principal component analyses across all measures within each studied domain.

Results: Compared to controls, premanifest gene carriers had more disrupted sleep, which was best characterized by a fragmented sleep profile. These abnormalities, as well as a theta power (4-7Hz) decrease in rapid eye movement sleep, were associated with disease burden score. Objectively measured sleep problems coincided with the development of cognitive, affective, and subtle motor deficits and were not associated with any metabolic alterations.

Interpretation: The results show that among the earliest abnormalities in premanifest HD is sleep disturbances. This raises questions as to where the pathology in HD begins and also whether it could drive some of the early features and even possibly the pathology.

Figure 1

Principal components (PCs) by Group (A,C,E,G) and by disease burden (B,D,F,H) for each of the studied domains. The y‐axis in each graph is a PC, and the amount of variation it accounts for is indicated in parentheses. The original variables contributing to each component are shown on the far left, ranked according to their PC loading, which aids interpretation. For example, premanifest (Pre‐HD) patients have high values on PC1 for the neuropsychological and motor performance variables (A). These correspond to high values on the Trail Making Tests A and B, the Montgomery–Åsberg Depression Rating Scale (MADRS), and the Beck Depression Inventory II (BDI‐II), which indicate worse executive and psychomotor performance and elevated depression. Similarly, the controls have low values on PC1, and this corresponds to high values on the Verbal Fluency Test, Hopkins Verbal Learning Test–Revised (HVLT‐R), and Hand Tapping Test, which indicate better executive, verbal memory, and motor performance. The variables are ranked according to their loadings; only the top 3 are indicated; variables at the ends of the y‐axis have higher absolute loadings. For the individual PC loadings, please refer to the results section. The graphs on the left (A, C, E, G) show group differences between the PCs. Estimates (least squares means) and standard error of the mean are indicated, controlled for age and sex. The graphs on the right (B, D, F, H) show the association between the PCs and disease burden score controlled for sex within the gene carrier group; controls (black open circles) are shown for reference (shaded area) but are not included in the analysis. Grey filled circles = Pre‐HD; black triangles = early Huntington disease (HD). Original and adjusted P‐values are shown in parentheses and these are adjusted for all 8 tests shown in the figure using the Holm–Bonferroni method. As the polysomnography (PSG) data include a small group of early manifest HD (Early HD), p‐values indicate the main effect of group, and pairwise comparisons show that each group is different from every other group (Tukey honestly significant difference post hoc test: *p < 0.05, ****p < 0.0001). Results of the individual variables can be found in Tables 2 to 5. For detailed description of the variables, please refer to Subjects and Methods and Tables 2 to 5. ^aseconds, ^btotal score, ^ctotal correct, ^dpercentage, ^eminutes, ^fnumber per hours of sleep, ^gclock time, ^hng/ml, ⁱkg, ^jkJ/day; ^kratio. AEE = average daily activity–related energy expenditure; Hab. = habitual; PAL = physical activity level; Pref. = preferred; REM = rapid eye movement sleep; SE = sleep efficiency; TIB = time in bed; VPA = variance of physical activity; WASO = wake time between sleep onset and final awakening.

Figure 2

Representative sleep profiles of 2 premanifest participants and 2 age‐ and sex‐matched controls showing a more fragmented sleep profile in the premanifest participants. CAG = cytosine–adenosine–guanosine repeats; REM = rapid eye movement sleep.

Figure 3

Characteristics of the relative electroencephalographic power spectral density (PSD) measured during rapid eye movement (REM; A, C, E) and non‐REM (NREM; B, D, F) sleep in controls, premanifest (Pre‐HD) patients, and early manifest Huntington disease (HD; Early HD) patients. (A, B) The average transformed (y = log[x/(1−x)] see Subjects and Methods) relative power spectrum density measured during REM (A) and NREM (B) sleep for each group is presented as estimates (least squares means) and standard error of the mean controlled for age and sex. Triangles indicate significant (p < 0.05) group differences (2‐tailed t test). Black triangles = controls versus Early HD, gray solid triangles = Pre‐HD versus Early HD, gray open triangles = controls versus Pre‐HD. (C, D) Mean difference from controls in the averaged relative power spectrum during REM (C) and NREM (D) sleep is presented with 99.875% confidence interval (CI) limits controlled for age and sex. Dashed reference line = Control; blue lines = Pre‐HD; red lines = Early HD. Triangles indicate statistically corrected significant (p < 0.00125) differences between Early HD and controls. (E, F) Association between the relative power spectrum measured during REM (E) and NREM (F) sleep and the disease burden score (DBS) within the entire premanifest and manifest gene carrier group. Regression coefficients and 99.875% CI are indicated. Triangles indicate statistically corrected significant associations (p < 0.00125) with DBS.