Application Value of Serum Neurofilament Light Protein for Disease Staging in Huntington's Disease.

BACKGROUND: Neurofilament light protein (NfL) has been proven to be a sensitive biomarker for Huntington's disease (HD). However, these studies did not include HD patients at advanced stages or with larger CAG repeats (>50), leading to a knowledge gap of the characteristics of NfL. METHODS: Serum NfL (sNfL) levels were quantified using an ultrasensitive immunoassay. Participants were assessed by clinical scales and 7.0 T magnetic resonance imaging. Longitudinal samples and clinical data were obtained. RESULTS: Baseline samples were available from 110 controls, 90 premanifest HD (pre-HD) and 137 HD individuals. We found levels of sNfL significantly increased in HD compared to pre-HD and controls (both P < 0.0001). The increase rates of sNfL were differed by CAG repeat lengths. However, there was no difference in sNfL levels in manifest HD from early to late stages. In addition, sNfL levels were associated with cognitive measures in pre-HD and manifest HD group, respectively. The increased levels of sNfL were also closely related to microstructural changes in white matter. In the longitudinal analysis, baseline sNfL did not correlate with subsequent clinical function decline. Random forest analysis revealed that sNfL had good power for predicting disease onset. CONCLUSIONS: Although sNfL levels are independent of disease stages in manifest HD, it is still an optimal indicator for predicting disease onset and has potential use as a surrogate biomarker of treatment effect in clinical trials. © 2023 International Parkinson and Movement Disorder Society.

Multi-omics Analysis Reveals Key Gut Microbiota and Metabolites Closely Associated with Huntington's Disease.

Dysbiosis of the gut microbiota is closely associated with neurodegenerative diseases, including Huntington's disease (HD). Gut microbiome-derived metabolites are key factors in host-microbiome interactions. This study aimed to investigate the crucial gut microbiome and metabolites in HD and their correlations. Fecal and serum samples from 11 to 26 patients with HD, respectively, and 16 and 23 healthy controls, respectively, were collected. The fecal samples were used for shotgun metagenomics while the serum samples for metabolomics analysis. Integrated analysis of the metagenomics and metabolomics data was also conducted. Firmicutes, Bacteroidota, Proteobacteria, Uroviricota, Actinobacteria, and Verrucomicrobia were the dominant phyla. At the genus level, the presence of Bacteroides, Faecalibacterium, Parabacteroides, Alistipes, Dialister, and Christensenella was higher in HD patients, while the abundance of Lachnospira, Roseburia, Clostridium, Ruminococcus, Blautia, Butyricicoccus, Agathobaculum, Phocaeicola, Coprococcus, and Fusicatenibacter decreased. A total of 244 differential metabolites were identified and found to be enriched in the glycerophospholipid, nucleotide, biotin, galactose, and alpha-linolenic acid metabolic pathways. The AUC value from the integrated analysis (1) was higher than that from the analysis of the gut microbiota (0.8632). No significant differences were found in the ACE, Simpson, Shannon, Sobs, and Chao indexes between HD patients and controls. Our study determined crucial functional gut microbiota and potential biomarkers associated with HD pathogenesis, providing new insights into the role of the gut microbiota-brain axis in HD occurrence and development.

Loss of CAA interruption and intergenerational CAG instability in Chinese patients with Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG expansions in huntingtin (HTT) gene, involving motor, cognitive, and neuropsychiatric symptoms. However, genetic modifiers and CAG repeat instability may lead to variations of clinical manifestations, making diagnosis of HD difficult. In this study, we recruited 229 HD individuals from 164 families carrying expanded CAG repeats of HTT, and analyzed loss of CAA interruption (LOI) on the expanded allele and CAG instability during germline transmission. Sanger sequencing and TA cloning were used to determine CAG repeat length and identify LOI variants. Detailed clinical features and genetic testing results were collected. We identified 6 individuals with LOI variants from 3 families, and all probands presented with earlier motor onset age than predicted onset age. In addition, we also presented 2 families with extreme CAG instability during germline transmission. One family showed an expansion from 35 to 66 CAG repeats, while the other family showed both CAG expansion and contraction in lineal three generations. In conclusion, we present the first document of Asian HD population with LOI variant, and we suggest that for symptomatic individuals with intermediate or reduced penetrance allele or negative family history, HTT gene sequencing should be considered in the clinical practice. KEY MESSAGES : We screened the loss of CAA interruption (LOI) variant in a Chinese HD cohort and presented the first document of Asian patients with Huntington's disease carrying LOI variant. We identified 6 individuals with LOI variants from 3 families, and all probands presented with earlier motor onset age than predicted onset age. We presented 2 families with extreme CAG instability during germline transmission. One family showed an expansion from 35 to 66 CAG repeats, while the other family showed both CAG expansion and contraction in lineal three generations. We suggest that for symptomatic individuals with intermediate or reduced penetrance allele or negative family history, HTT gene sequencing should be considered in the clinical practice.

The Chinese Version of UHDRS in Huntington's Disease: Reliability and Validity Assessment.

BACKGROUND: The Unified Huntington's Disease Rating Scale (UHDRS) is a universal scale assessing disease severity of Huntington's disease (HD). However, the English version cannot be widely used in China, and the reliability and validity of the Chinese UHDRS have not yet been confirmed. OBJECTIVE: To test the reliability and validity of Chinse UHDRS in patients with HD. METHODS: Between August 2013 and August 2021, 159 HD patients, 40 premanifest HD, and 64 healthy controls were consecutively recruited from two medical centers in China and assessed by Chinese UHDRS. Internal consistency and interrater reliability of the scale were examined. Intercorrelation was performed to analyze the convergent and divergent validity of the scale. A receiver operating characteristic analysis was conducted to explore the optimal cutoff point of each cognitive test. RESULTS: High internal consistency was found in Chinese UHDRS, and its Cronbach's alpha values of the motor, cognitive, behavioral and functional subscales were 0.954, 0.826, 0.804, and 0.954, respectively. The interrater reliability of the total motor score was 0.960. The convergent and divergent validity revealed that motor, cognitive and functional subscales strongly related to each other except for Problem Behavior Assessment. Furthermore, we not only provided the normal level of each cognitive test in controls, but also gave the optimal cutoff points of cognitive tests between controls and HD patients. CONCLUSION: We demonstrate for the first time that the translated version of UHDRS is reliable for assessing HD patients in China. This can promote the universal use of UHDRS in clinical practice.

The clinical, imaging and biological features of psychosis in Han Chinese patients with Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease involving motor, cognitive and psychiatric disturbances. HD patients with psychosis symptoms usually have bad prognosis. It is of great significance to explore the clinical, imaging and biological characteristics of HD patients with psychosis. A total of 118 Han Chinese patients with HD confirmed by Huntingtin genetic testing were recruited during 2013-2020. They were assessed by Unified Huntington's Disease Rating Scale (UHDRS) and followed up in an average of 34 months by telephone or clinical visits. Psychosis was determined by the presence of delusions or hallucinations using UHDRS-Problem Behavior Assessment. Data of magnetic resonance imaging (n = 28) and serum neurofilament light chain (NfL, n = 28) were collected in some patients. Among 118 patients (mean age 46.0 years, SD 12.0; female 53.5%), the frequency of psychosis was 14.4% (n = 17) in the cross-sectional analysis and 17.8% (n = 21) in the longitudinal observation. Probands with psychosis were predominantly female (82.3%). They exhibited worse motor, cognitive, behavioral and functional performances compared with patients without psychosis. Furthermore, the lateral ventricle volume was larger in patients with psychosis compared with patients without psychosis (p = 0.0013) while there was no difference in NfL levels between two groups. NfL levels of patients with psychosis were negatively correlated with caudate volumes (r = -0.54, p = 0.044) and white matter volumes (r = -0.57, p = 0.035). In summary, HD patients with psychosis had distinct clinical, imaging and biological features. These features might help clinicians to identify psychosis in HD patients early and provide protective interventions before adverse outcomes occur.