Work

Serum lipids and disease progression in Huntington’s disease: A retrospective cohort study

Year: 2025

Type: article

Abstract: To the Editor: Huntington’s disease (HD) is an inherited autosomal-dominant neurodegenerative disease caused by the expanded Cytosine–Adenine–Guanine (CAG) repeat in the HTT gene.[1] There are currently no effective disease-modifying therapies for HD; hence, investigating modifiable factors which could influence the onset and progression of HD is critical. Lipids play a vital role in the maintenance of normal brain functions, including acting as structural components of membrane structure, participating in energy metabolism, and signal transduction. Disturbed lipid metabolism is involved in the pathogenesis of HD, but the role of circulating lipids in HD has not been elucidated. We aimed to investigate whether serum lipids were associated with disease progression in patients with HD. The study protocol was examined and approved by the Ethics Committee of West China Hospital of Sichuan University (No. 2022-1960). Subjects of the study were genetically diagnosed adult-onset patients with HD who were consecutively recruited in the Neurology Department of West China Hospital from 2010 to 2022, as described earlier.[2] Inclusion criteria were: (1) Diagnosed as HD according to clinical assessment and genetic testing and (2) undergoing serum lipid tests at the first visit. Exclusion criteria were: (1) Total functional capacity (TFC) score <3 at the first visit and (2) history of taking cholesterol-lowering medications. Sex- and age-matched healthy controls (HCs) were also recruited. Fasting blood samples from individuals were collected and tested to obtain their serum triglyceride (TG, mmol/L), total cholesterol (TC, mmol/L), high-density lipoprotein cholesterol (HDL-C, mmol/L), and low-density lipoprotein cholesterol (LDL-C, mmol/L) levels at baseline. Demographic and clinical information was collected synchronously, including age at the time of assessment, sex, body mass index (BMI), family history, CAG repeats number, disease duration, age at onset, motor signs by Unified Huntington’s Disease Rating Scale (UHDRS), total motor score (TMS), cognitive performances by mini-mental state examination (MMSE), symbol digit modality test, Stroop word reading test, Stroop color naming test, and Stroop interference test, psychiatric symptoms by the Problem Behaviors Assessment for HD-short version (PBA-s), and functional capacities by the UHDRS functional assessment (FA), independent scale (IS), and TFC. We further calculated composite UHDRS (cUHDRS) to reflect the general severity of patients’ clinical signs.[3] During the follow-up, TMS, FA, IS, and TFC were reassessed. The annual progression rate of disease was calculated as the last follow-up score of clinical assessment minus baseline score (TMS, FA, IS, and TFC) divided by follow-up years. A detailed description of each assessment can be found in the previous report.[2] All statistical analyses were completed using R software (version 3.6.3; R Foundation for Statistical Computing, Vienna, Austria). As TG and LDL-C exhibited nonnormal distribution, they were log-transformed for the following analysis. The cross-sectional analysis was first conducted to examine the association between lipid traits and clinical characteristics at baseline through linear regression analysis. Patients who were followed up at least once after baseline visit with more than one-year interval were included in the retrospective cohort analysis to examine the association between lipid traits and subsequent disease progression. Linear regression analyses were conducted to investigate the relationship between lipid traits and the annual change of clinical assessment scores (TMS, FA, IS, and TFC). The linear regression model was adjusted for age (continuous variable, years), sex (females and males), BMI (continuous variable, kg/m2), family history (maternal inheritance, paternal inheritance, and no clear family history), CAG repeat numbers (continuous variable), and disease duration (continuous variable, years). β coefficients, 95% confidence interval (CI), and P values were reported for the linear regression analyses. Further, Kaplan–Meier survival analysis, log-rank test, and Cox proportional hazards regression were conducted to clarify the prognostic significance of serum lipid profiles by regarding TFC <3 and mortality as the outcome. Serum lipid levels were first incorporated in the model as a continuous variable and then as a categorical variable according to the tertiles. Follow-up started when the serum samples were collected and ended at the time of TFC <3, mortality, or the date of the last visit. Hazard ratio (HR), 95% CI, and P value were reported for the Cox regression analyses. A two-sided P value <0.05 was considered as statistically significant. A total of 90 patients and 90 HCs were included in the cross-sectional analysis, as presented in Supplementary Figure 1, https://links.lww.com/CM9/C714. TG, TC, and LDL-C levels were significantly lower in patients with HD compared with HCs (all P <0.001). No difference in baseline characteristics and lipid profiles of patients across different disease stages was detected, except for TG (P = 0.048) [Supplementary Table 1, https://links.lww.com/CM9/C714]. In the multivariate linear analyses, no association between TC, HDL-C, and any clinical features was found, whereas TG and LDL-C demonstrated a significant association with higher cUHDRS (TG: β = 1.158, 95% CI [0.256, 2.059], P = 0.013; LDL-C: β = 0.980, 95% CI [0.120, 1.841], P = 0.026) and higher TFC (TG: β = 0.967, [0.331, 1.603], P = 0.003; LDL-C: β = 0.833, 95% CI [0.179, 1.486], P = 0.013). In addition, TG level was associated with better cognitive performances and other functional assessments significantly [Supplementary Table 2, https://links.lww.com/CM9/C714]. A total of 61 patients were further included in the retrospective cohort analysis. The mean follow-up time was 6.2 (standard deviation: 4.0) years. We did not detect any association between serum lipid levels as continuous variables and disease progression. After categorizing patients into three groups according to the tertile of serum lipid levels, we found that patients with an intermediate level of TG (median: 0.875 mmol/L) and LDL-C (median: 2.475 mmol/L) exhibited a slower annual change of TMS scores (TG: β = −9.926, 95% CI [−18.342, −1.510], P = 0.023; LDL-C, β = −8.520, 95% CI [−16.962, −0.079], P = 0.048). Patients with the highest level of TG (median: 1.630 mmol/L) and LDL-C (median: 3.080 mmol/L) exhibited a similar trend (TG: β = −0.460, 95% CI [−8.549, 7.628], P = 0.908; LDL-C, β = −6.433, 95% CI [−15.036, 2.170], P = 0.136), but not significant, compared to patients with the lowest level of TG [Supplementary Table 3, https://links.lww.com/CM9/C714]. During the follow-up, 30 patients progressed to TFC <3, including four deaths. In the Kaplan–Meier survival analysis, a higher TG level was significantly associated with a lower risk of TFC <3 (P = 0.035) [Figure 1]. Compared with patients with the lowest levels of TG, patients with intermediate (HR: 0.259, 95% CI [0.086−0.781], P = 0.016) and highest levels (HR: 0.332, 95% CI [0.112−0.985], P = 0.047) of TG also demonstrate a slower risk of TFC <3 in the Cox regression analyses [Supplementary Table 4, https://links.lww.com/CM9/C714].Figure 1: Kaplan–Meier survival analysis of lipid traits and total functional capacity <3 in patients with Huntington’s disease. (A) Kaplan–Meier survival analysis of triglyceride level and total functional capacity <3. (B) Kaplan–Meier survival analysis of HDL-C level and total functional capacity <3. (C) Kaplan–Meier survival analysis of total cholesterol level and total functional capacity <3. (D) Kaplan–Meier survival analysis of LDL-C level and total functional capacity <3. HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; T1: Lower tertile; T2: Middle tertile; T3: Higher tertile.In this study, based on Chinese patients with HD, we observed that TG and LDL-C levels were significantly associated with various clinical features across motor signs, cognitive performances, and functional capacities. In the longitudinal analysis, TG and LDL-C levels were correlated with a milder progression of motor signs. TG levels also exhibited a negative association with the risk of TFC <3. These findings underscored the prognostic significance of serum lipid profiles, especially TG and LDL-C. The protective role of peripheral lipids was also reported in other neurodegenerative diseases.[4] The precise biological mechanisms underlying these observed relationships are unclear. Most previous studies focused on the beneficial role of cholesterol in the central nervous system, and whether peripheral lipids interact with the central lipids and contribute to neuropathogenic changes in the context of neurodegenerative diseases warrants further investigation. The current study reported that peripheral TG and LDL-C may also be the modifiable protective targets of HD progression, emphasizing the critical importance of maintaining normal nutritional status and digestive system functions in patients with HD. This study evaluates the longitudinal association between baseline lipid traits and disease progression of HD. The strengths of our study included a comprehensive and rigorous clinical evaluation of patients with HD, alongside the acquisition of longitudinal follow-up data. The limitations of the study included: (1) We did not obtain the repeated blood samples to monitor lipid level fluctuations; (2) Only motor signs and functional capacities were repeatedly evaluated for the longitudinal analysis; (3) Premanifest mutation carriers were not included in the current cohort; (4) Considering the rarity of this disease and the relatively small sample size in the current analysis, the results were not adjusted for the multiple comparisons; (5) Not all confounders were included in the adjusted model because of the unavailability of data, such as the dietary habit and other metabolic abnormalities including diabetes. Addressing these limitations in future research is essential to further corroborate and reinforce the robustness of our findings. In conclusion, our study provided evidence that serum lipid profiles contained valuable information about disease severity and progression. Our findings underscore the potential protective role of TG and LDL-C against the disease progression of HD. Acknowledgments The authors sincerely thank the patients and their families for encouragement and support. Funding This work was supported by grants from the Sichuan Science and Technology Program (No. 2022ZDZX0023) and the National Natural Science Foundation of China (No. 82301613). Conflicts of interest None.

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003941