Abstract
Background
Identifying the effect of modifiable socio‐environmental factors on Huntington's disease (HD) symptoms onset and progression is of great value. The role of educational attainment in HD clinical characteristics has not been elucidated.
Objectives
To clarify the effect of education attainment on the age of motor symptoms onset and clinical progression of HD patients from Western China.
Methods
A total of 244 adult‐onset Chinese HD patients were included in the analysis. Linear regression, Kaplan–Meier analysis, and Cox regression analysis were conducted to assess the effect of education on the disease progression in HD.
Results
Higher education level was significantly associated with slower decline in cognitive performance, as indicated by the Symbol Digit Modality Test (β = 0.339 [95% CI, 0.047, 0.632], p = 0.026), while it exhibited no association with the progression of other symptoms.
Conclusions
The present findings suggest that education attainment is associated with a milder cognitive decline in Chinese HD patients.
Keywords: Huntington's disease, cognitive reserve, education, nongenetic factor
Phenotypical heterogeneity of HD patients is present in the age of symptoms onset and the severity of clinical manifestations. The number of CAG repeats is the primary genetic factor determining the age of motor symptoms onset in HD patients. 1 , 2 Other genetic modifiers 3 and socio‐environmental factors 4 explain the remaining variance. Given the lack of effective therapies for HD, 5 identifying modifiable factors to delay the onset or slow progression is crucial.
Education attainment was a potential modifiable protective factor for neurodegenerative diseases. 6 Preclinical studies have reported that cognitive training could improve motor and cognitive performances and slow down the atrophy of the caudate‐putamen and increase survival in HD mouse models. 7 , 8 , 9 Nevertheless, emerging evidence from epidemiological studies are still inconsistent. 10 , 11 , 12 , 13 In addition, no studies have yet clarified the role of education in Chinese HD patients. Therefore, we aimed to clarify the association between education attainment and clinical features of HD in patients from Western China.
Methods
Study Population
Medical data utilized in the current analysis were obtained from patients consecutively admitted to the Neurology Department of West China Hospital between 2009 and 2023, as described previously. 14 Inclusion criteria were: (1) patients diagnosed as HD according to clinical assessment and genetic testing; (2) patients with complete information on education years and clinical assessments at first visit. We further excluded: (1) patients with the age of motor symptoms onset less than 20 years old because the early onset of symptoms itself may influence the participants’ educational attainments directly; (2) patients with Total Functional Capacity (TFC) score less than 3. The Ethics Committee of West China Hospital of Sichuan University examined the protocol and approved the study (approval number 2022–1960).
Clinical Assessment
The baseline demographic and clinical information of patients were collected, including age at baseline, sex, CAG repeats number, disease duration, family history, education years, age of clinical motor diagnosis, and the clinical assessment of the severity of motor, cognitive, and psychiatric symptoms. We stratified participants into three groups according to the Chinese educational system (low education level: education years <7; middle education level: education years 7–9; high education level: education years >9). Age of clinical motor diagnosis was defined as the age at which motor symptoms were first reported by the patients or their family members or first reported in the medical records. Unified Huntington's Disease Rating Scale (UHDRS) total motor score (TMS) was used to assess participants’ motor signs. Cognitive performance was evaluated using mini‐mental state examination (MMSE), symbol digit modality test (SDMT), Stroop word reading test (SWR), Stroop color naming test (SCN), and Stroop interference test (SI). Psychiatric symptoms were assessed by the Beck Depression Inventory (BDI), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA) with higher scores reflecting more severe psychiatric symptoms. TFC, UHDRS functional assessment (FA), and Independent Scale (IS) were utilized to assess participants’ functional capacity. Composite UHDRS (cUHDRS) scores were calculated to reflect the overall severity of clinical symptoms, with higher scores indicating milder clinical severity. 15 , 16 In the follow‐up visit, we assessed participants’ motor signs, cognitive performances, and functional capacity by TMS, MMSE, SDMT, SWR, SCN, SI, TFC, FA, IS, and cUHDRS repeatedly. To evaluate the annual change in the clinical symptoms, we subtracted the baseline score from the last follow‐up score of the corresponding clinical assessment scale and then divided the change by years of follow‐up. TFC <3 was regarded as the outcome of the survival analysis. A detailed description of the assessment scales was introduced in our previous report. 17
Statistical Analysis
In the analysis, linear regression analyses were first performed to examine the cross‐sectional associations between education years and baseline clinical features of HD and were further utilized to examine the associations between education years and the annual changes of clinical assessment scales. Kaplan–Meier survival analysis and Cox proportional hazards regression were performed to test the association between education level (low, middle, and high), education years, and the progression to TFC <3. Age, sex, BMI, disease duration, CAG repeats number, and family history were considered as covariates in the multivariate analysis. Age, sex, CAG repeats number, and disease duration were commonly used covariates in previous reports, which exhibited clear associations with the disease severity and prognosis. 18 , 19 Previous report also found that maintaining weight was associated with a slower disease progression. 20 In addition, patients with a clear family history tend to exhibit increased self‐awareness and earlier recognition of symptoms, which may influence the age of motor diagnosis and disease course. All analyses were conducted using R software (version 3.6.3).
Results
A total of 244 patients were included in the cross‐sectional analysis with a mean age of 48.06 ± 10.80 years old, and 144 (58.8%) were females. A total of 124 patients were included in the retrospective cohort analysis with a mean follow‐up period of 5.52 ± 3.22 years, as shown in Figure S1. During the follow‐up, TFC score decreased to less than 3 in 68 patients. The patient's baseline demographic and clinical information according to the education level was summarized in Table S1.
In the multivariate linear regression analysis, increased years of education were positively associated with better cognitive performances cross‐sectionally, as reflected by MMSE, SDMT, SCN, SWR and SI (MMSE: β = 0.528 [95% CI, 0.355, 0.700], p < 0.001; SDMT: 1.019, [0.664, 1.374], <0.001; SCN: 1.332, [0.833, 1.830], <0.001; SWR: 1.486, [0.884, 2.088], <0.001; SCN: 0.599, [0.228, 0.970], 0.002). In addition, longer education years were associated better functional capacity (IS: 0.118, [0.021, 0.216], 0.018) and milder general disease severity (cUHDRS: 0.222, [0.098, 0.347], 0.001) cross‐sectionally, as shown in Table S2.
In the longitudinal analysis, education years were associated with a slower annual SDMT score decline (SDMT: 0.339, [0.047, 0.632], 0.026), while this finding was not verified by other cognitive assessments. No significant association between education years and the annual changes of other clinical assessment scales was detected (p > 0.05 for all analyses), as demonstrated in Table 1. KM survival analysis and Cox regression analysis also demonstrated no significant association between education level and the progression to TFC <3, as presented in Figure 1 and Table S3.
TABLE 1.
Results of linear regression analyses of the association between education years and the annual change of clinical characteristics
| Annual change of clinical assessments | Univariate model | Multivariate model a | ||||
|---|---|---|---|---|---|---|
| β | 95% CI | p value | β | 95% CI | p value | |
| TMS | 0.255 | (−0.144, 0.654) | 0.205 | 0.158 | (−0.272, 0.588) | 0.458 |
| MMSE | 0.104 | (−0.171, 0.379) | 0.450 | −0.024 | (−0.166, 0.118) | 0.728 |
| SDMT | 0.114 | (−0.257, 0.484) | 0.535 | 0.339 | (0.047, 0.632) | 0.026* |
| SCN | 0.110 | (−0.304, 0.524) | 0.592 | 0.394 | (−0.180, 0.967) | 0.165 |
| SWR | 0.326 | (−0.329, 0.980) | 0.319 | 0.578 | (−0.084, 1.241) | 0.083 |
| SI | 0.027 | (−0.284, 0.337) | 0.863 | 0.096 | (−0.234, 0.425) | 0.548 |
| Functional assessment | 0.026 | (−0.077, 0.129) | 0.621 | 0.063 | (−0.011, 0.137) | 0.094 |
| Independent Scale | 0.157 | (−0.070, 0.385) | 0.173 | 0.110 | (−0.067, 0.288) | 0.220 |
| TFC | 0.016 | (−0.024, 0.055) | 0.435 | 0.026 | (−0.011, 0.063) | 0.169 |
| cUHDRS | 0.023 | (−0.078, 0.124) | 0.642 | 0.091 | (−0.081, 0.263) | 0.272 |
Abbreviations: cUHDRS, composite Unified Huntington's Disease Rating Scale; MMSE, mini–mental state examination; SCN, Stroop color naming test; SDMT, symbol digit modality test; SI, Stroop interference test; SWR, Stroop word reading test; TFC, total functional capacity; TMS, total motor score.
Adjusted for age, sex, BMI, disease duration, CAG triplet repeats number and family history.
p < 0.05.
Figure 1.
Kaplan–Meier survival analysis of the education level and TFC <3.
Discussion
The current study provided evidence for the role of education level in HD based on the observation analysis of a well‐evaluated Chinese HD cohort. 14 The results of our analyses indicate that higher education level was significantly associated with better cognitive performances cross‐sectionally, while education level was only associated with annual SDMT score decline.
Although the significant associations between education years and baseline cognitive performance were consistent across all cognitive scales in our analysis, only the annual SDMT change showed a significant longitudinal association with education attainment. Given that SDMT is a sensitive neuropsychological scale for evaluation information processing speed of subjects, this finding suggests that higher educational attainment may contribute to maintain information processing abilities of patients most significantly. However, this finding should be interpreted with caution, as the small sample size and limited statistical power in the present study may preclude meaningful evaluation across all scales.
Cognitive reserve has been proposed to account for individuals’ differences in vulnerability to age‐related brain changes and pathological changes such as in Alzheimer's disease. 21 Education may increase individuals’ cognitive reserve 22 and develop network efficiency and neural compensation to counteract pathologic damage. 23 , 24 This may partially explain the observed positive association between education and cognitive performance in the current analysis. Another longitudinal study based on PREDICT‐HD also found that higher cognitive reserve was significantly associated with a slower rate of cognitive performance decline, as reflected by Trail Making Test, as well as caudate and putamen volume loss in prodromal HD patients, 25 indicating the potential protective effect of education or other intellectual stimulation against HD neuropathology in the early stage. 24 , 26 In addition to educational attainment, other modifiable lifestyle factors, such as social and physical activity, have also been reported to enhance cognitive reserve. 27 Given no effective disease‐modifying therapies were available, these modifiable lifestyle factors warrant further investigation.
The main limitation of our work lies in the relatively small sample size and consequently low statistical power. In addition, some potential covariates such as socioeconomic status were not included in the analysis because relevant information was not collected at baseline. Future large‐scale cohort study based on Asian HD patients is still warranted to verify our findings. The included patients in the present analysis were limited to the manifest HD patients, future large‐scale studies in premanifest and early‐stage patients were expected to assess the effect of education on the longitudinal changes of biochemical and neuroimaging biomarkers of HD to extend our findings.
In summary, our study found that higher educational attainment was significantly associated with better cognitive performances cross‐sectionally and slower decline of SDMT, while these benefits did not extend to altering the progression of other symptoms or prognosis of manifest HD.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique.
S.R.Z., Y.F.C.: 1A, 1B, 1C, 2A, 2B, 3A.
L.Y.Z., Y.Z.M., J.J.F., T.M.Y., J.Q.X.: 1B, 2A, 2C, 3B.
C.Y.L., J.M.B., H.F.S.: 1B, 2C, 3B.
Disclosures
Ethical Compliance Statement: The Ethics Committee of West China Hospital of Sichuan University examined the protocol and approved the study (approval number 2022–1960). All participants signed written informed consent forms. All the processes of the study were performed in compliance with the 2013 Helsinki Declaration. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflict of Interest: This research was supported by the Sichuan Science and Technology Program (Grant No.2022ZDZX0023); the National Natural Science Foundation of China (Grant No. 82301613). The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Supporting information
Table S1. Baseline characteristics of the included participants.
Table S2. Results of linear regression analyses of the association between education years and baseline clinical characteristics.
Table S3. Results of Cox regression analyses of the association between education and TFC <3.
Figure S1. Flowchart of the included patients.
Sirui Zhang and Yangfan Cheng contributed equally.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Baseline characteristics of the included participants.
Table S2. Results of linear regression analyses of the association between education years and baseline clinical characteristics.
Table S3. Results of Cox regression analyses of the association between education and TFC <3.
Figure S1. Flowchart of the included patients.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.