Introduction
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a cytosine‐adenine‐guanine (CAG) trinucleotide expansion on chromosome 4. Clinical features include chorea or parkinsonism, psychiatric symptoms, and progressive cognitive decline. As the disease progresses, patients develop functional impairment, weight loss, and dependence in daily life. Earlier symptom onset is associated with longer CAG repeat expansions. The CAG‐age product (CAP) score provides an estimate of the predicted onset of motor symptoms and cumulative disease burden. 1 Clinical staging commonly relies on the total functional capacity (TFC) of the Unified Huntington's Disease Rating Scale (UHDRS), 2 capturing the patients’ ability to perform essential everyday activities. Beyond central nervous system pathology, HD affects peripheral tissues such as skeletal muscle, contributing to weight loss even in early disease stages. 3 Reduced muscle mass is associated with morbidity, loss of independence, and poorer quality of life. 4 Despite its clinical relevance, muscle status is rarely assessed in HD, largely because of the limitations of conventional measurement methods.
Temporal muscle thickness (TMT), obtainable from standard cranial magnetic resonance imaging (MRI), has recently emerged as a reliable surrogate for skeletal muscle mass. 4 Reduced skeletal muscle mass has been associated with longer hospital stays, recurrent hospitalizations, and increased risk of complications. 5 This study evaluated TMT on routine cranial MRI in patients with HD and examined associations with clinical disease parameters.
Methods
Data were derived from an HD patient cohort who were enrolled in a longitudinal observational study at the Medical University of Innsbruck. 6 Ethical approval was obtained, and all participants gave informed consent.
Clinical assessments included motor symptoms (total motor score of the UHDRS [UHDRS‐TMS]), functionality (UHDRS‐TFC), cognition (symbol digit modalities test [SDMT]), body weight, and body mass index (BMI). CAP scores were calculated. 1
Inclusion required the availability of a 3‐Tesla cranial MRI acquired after clinical testing. TMT was measured manually on axial noncontrast T1‐weighted three‐dimensional magnetization‐prepared rapid acquisition with gradient echo sequences by an experienced neuroimaging rater, following established protocols. 3 The mean of bilateral measurements was used for analysis. Statistical analyses were performed with SPSS 30.
Results
Fifty‐five patients with HD in clinical stages 1 to 3 based on functional capacities and motor symptoms were included. Demographic characteristics were comparable, with no significant differences in age or CAG repeat length. Mean TMT was 8.7 mm (±2.7) in males and 7.8 mm (±2.2) in females (P = 0.179). TMT was associated with greater disease burden as indicated by higher clinical stages (Table 1). Reduced TMT correlated with TMS, TFC, CAP score, body weight, BMI, and SDMT.
TABLE 1.
Demographic and clinical characteristics of patients with HD by clinical stage, and associations of TMT with demographic and clinical variables
| Variables | Total (n = 55) | Stage 1 (n = 33) | Stage 2 (n = 14) | Stage 3 (n = 8) | P value | Association with TMT (r 2/P, adjusted*) |
|---|---|---|---|---|---|---|
| Male/Female, n | 28/27 | 18/15 | 6/8 | 4/4 | 0.763b | – |
| Age (y) | 48.8 ± 12.3 | 47.8 ± 11.4 | 49.0 ± 13.6 | 52.9 ± 14.2 | 0.578c | n.a. |
| Time since first symptoms noticed (y) | 4.2 ± 3.5 | 2.7 ± 2.9 | 5.4 ± 2.5 | 8.2 ± 4.1 | <0.001d | −0.203/0.169 |
| Weight (kg) | 69.4 ± 14.8 | 69.9 ± 16.0 | 64.7 ± 11.6 | 75.5 ± 13.3 | 0.158d | 0.317/0.002 |
| BMI (kg/m2) | 23.2 ± 4.4 | 23.3 ± 4.6 | 22.0 ± 3.6 | 24.4 ± 5.0 | 0.331d | 0.280/0.009 |
| CAG repeats | 45.3 ± 3.7 | 44.8 ± 3.3 | 46.0 ± 4.1 | 45.8 ± 4.5 | 0.576d | n.a. |
| CAP score | 113.0 ± 18.3 | 106.0 ± 16.7 | 119.8 ± 17.8 | 129.1 ± 10.1 | <0.001c | n.a. |
| UHDRS–TMS | 26.2 ± 17.5 | 16.5 ± 12.3 | 34.7 ± 11.2 | 51.1 ± 12.0 | <0.001d | −0.304/0.004 |
| UHDRS–TFC | – | – | – | – | – | 0.257/0.021 |
| SDMT | 31.4 ± 15.2 | 38.1 ± 13.7 | 19.5 ± 10.5 | 18.5 ± 5.5 | <0.001d | 0.189/0.069 |
| TMT mean (mm) | 8.2 ± 2.5 | 9.3 ± 2.4 | 7.1 ± 1.4 | 6.2 ± 2.1 | <0.001d,e | n.a. |
Values are means ± standard deviation.
Multivariate regression adjusted for age, sex, and CAG repeat length.
P values: χ2 test.
P values: analysis of variance.
P values: Kruskal–Wallis test.
Pairwise comparisons (Bonferroni‐corrected): stage 1 vs. 2, P = 0.009; stage 1 vs. 3, P = 0.016; stage 2 vs. 3, P = 0.789.
Discussion
This study demonstrates progressive TMT decline across clinical stages of HD, reflecting both neurological deterioration and systemic musculoskeletal involvement. The findings support TMT as a potential disease progression marker and emphasize musculoskeletal decline as an early feature of HD. TMT measurement may complement clinical and nutritional assessments, enabling earlier detection and monitoring of physical and functional decline.
Incorporating TMT assessment offers a noninvasive method to monitor systemic changes in HD, even in patients with relatively preserved neurological function.
Author Roles
(1) Statistical analysis: A. Design, B. Execution, C. Analysis;
(2) Manuscript: A. Writing, B. Editing of final version of the manuscript.
G.H.: 1A, 1B, 1C, 2A, 2B
C.C.: 1A, 1B, 2A, 2B
M.P.: 2B
K.S.: 2B
F.C.: 2B
B.W.: 2B
F.K.: 2B
P.M.: 2B
A.D.: 2B
A.G.: 2B
S.L.: 2B
K.S.: 2B
B.H.: 1A, 1B, 1C, 2A, 2B
Financial Disclosures
G.H. has no disclosures. C.C. has no disclosures. M.P. reports honoraria from Candoro Ethics Austria GmbH outside the submitted work. K.S. has no disclosures. F.C. has no disclosures. B.W. has no disclosures. F.K. received personal fees from AbbVie, Bial, Ionis Pharmaceuticals, Koneksa, Merz, Österreichische Apotheker‐Verlagsgesellschaft, Sanofi, Takeda Pharmaceuticals, and Teva in the past 36 months, and his institution has ongoing grant support from the Medical University Innsbruck, Austrian Science Fund (FWF), National Institutes of Health, and The Michael J. Fox Foundation, outside of the submitted work. P.M. reports grants from The Michael J. Fox Foundation outside of the submitted work. A.D. reports honoraria from Novo Nordisk, Roche, Bial, and AbbVie outside the submitted work. A.E.G. has no financial disclosures. S.L. has no financial disclosures. K.S. reports honoraria from the International Parkinson and Movement Disorders Society; grants from the FWF Austrian Science Fund, The Michael J. Fox Foundation, and the International Parkinson and Movement Disorder Society; as well as personal fees from Teva, UCB, Lundbeck, AOP Orphan Pharmaceuticals AG, AbbVie, Bial, Roche, and Grünenthal outside the submitted work. B.H. reports personal fees from Novartis AG, AbbVie, Merz, and Bial; and grants from the Austrian Science Fund (FWF) outside the submitted work.
HD, Huntington's disease; TMT, temporal muscle thickness; n.a., not applicable; BMI, body mass index; CAG, cytosine‐adenine‐guanine; CAP, CAG‐age product; UHDRS, Unified Huntington's Disease Rating Scale; TMS, total motor score; TFC, total functional capacity; SDMT, symbol digit modalities test.
Acknowledgments
We thank all participants who voluntarily took part in this study. B.H., A.D., and K.S. are members of the European Reference Network for Rare Neurological Diseases (Project ID 739510). Open Access funding provided by Medizinische Universitat Innsbruck/KEMÖ.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online version of this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.