Identification and functional characterization of novel variants of MAPT and GRN in Chinese patients with frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most common cause of dementia after Alzheimer's disease, characterized by distinct changes in behavior, personality, and language. Our study performed whole exome sequencing and repeat-primed PCR analysis in 29 unrelated FTD patients. Consequently, 2 known pathogenic variants (MAPT: p.P301L; TBK1: p.I450Kfs), and 4 novel variants (MAPT: p.R406Q, p.D430H, p.A330D; GRN: c.350-2A>G) were identified. The functional analysis results showed that phosphorylated tau levels were higher in cells expressing p.R406Q and p.D430H tau than those expressing wild-type tau, especially at the Thr205, Thr231, and Ser396 phosphorylation epitopes. Besides, the p.R406Q and p.D430H variants of MAPT impaired the ability of tau to bind to the microtubules and increased tau self-aggregation. Furthermore, we found that the c.350-2A>G variant caused exon 5 skipping. Our results showed that p.R406Q, p.D430H, and c.350-2A>G variants were classified as pathogenic. Finally, we summarized the clinical characterization of patients carrying pathogenic variants of MAPT in the East Asia populations. Our results broaden the genetic spectrum of FTD with MAPT and GRN variants.

Application of Cerebrospinal Fluid AT(N) Framework on the Diagnosis of AD and Related Cognitive Disorders in Chinese Han Population.

BACKGROUND: Studies concerning the impact of the AT(N) framework on diagnostic capability in the dementia population are lacking. We aimed to explore the diagnostic application of CSF AT(N) framework in clinical routines of Alzheimer's disease (AD) as well as differential diagnosis of other cognitive diseases in the Chinese Han population. PATIENTS AND METHODS: A total of 137 patients with cognitive disorders received CSF tests of Aß42, t-tau and p-tau181. Their CSF biomarker results were categorized and interpreted by the AT(N) framework. Neurologists provided a diagnosis both pre- and post-CSF biomarker disclosure with corresponding diagnostic confidence. RESULTS: The total initial diagnosis included 79 patients with AD and 58 patients with non-AD (NAD). The results of CSF biomarkers led to a diagnostic change of 28% in the cohort. Approximately 81.5% (n=53) of 65 patients whose CSF biomarker showed an underlying AD pathology were finally diagnosed as AD, with an increase of 17.5% in diagnostic confidence. Thirty-seven CSF results indicating NAD pathologic changes contributed to an exclusion of AD in 56.8% (n=21) of the patients along with a modest increase of 9.8% in average confidence. Thirty-five patients with normal CSF biomarkers maintained the diagnosis of NAD in 68.6% (n=24) of the group, leading to a slight elevation of 7.6% in confidence. CONCLUSION: We found that the presence of amyloid pathology (A+) is contributable to diagnosing AD and improving confidence. On occasion of negative amyloid pathology (A-), with or without tau pathology, gaining uncertainty of the primary AD diagnosis would diminish the corresponding confidence. To the best of our knowledge, this is the first study performed in the Chinese Han population with cognitive disorders that explores the clinical capability of CSF AT(N) framework in a quantitative way.

The discriminative capacity of CSF ß-amyloid 42 and Tau in neurodegenerative diseases in the Chinese population.

INTRODUCTION: In the past few years, the ß-amyloid 42 peptide and tau protein in cerebrospinal fluid (CSF) have become primary diagnostic biomarkers in differentiating Alzheimer's disease (AD) and cognitive normal controls. As we know, several neurodegenerative diseases have been reported to overlap with AD in neuropathology and clinical symptoms. To examine the discriminative utility of these biomarkers in AD and other neurodegenerative diseases, we measured them in a cohort of Chinese population. METHODS: We measured CSF Aß42, t-tau and p-tau181 by ELISA tests and calculated the ratios of t-tau/Aß42 and p-tau181/Aß42 in 240 Chinese Han patients with AD (n = 82), frontotemporal dementia (FTD, n = 20), Huntington's disease (HD, n = 27), multiple system atrophy (MSA, n = 24), spinocerebellar ataxia type-3 (SCA3, n = 27), amyotrophic lateral sclerosis (ALS, n = 36) and controls (n = 24). RESULTS: As expected, all biomarkers showed high discriminative capacity between AD and non-AD groups (p < .05) except for the elevated CSF t-tau in FTD (p > .05). Comparing with the controls, tau related biomarkers significantly elevated in the FTD (p < .001) and MSA (p < .05) groups. Surprisingly, comparing with controls, we found that CSF Aß42 increased remarkably in the SCA3 (p < .05), HD and ALS groups (p < .001), achieving a high specificity, respectively. CONCLUSION: To our best knowledge, this is the first comprehensive study in the Han Chinese population that confirmed the discriminative utility of CSF Aß42 and tau biomarkers between AD and other neurodegenerative diseases.

Clinical and Genetic Profiles in Chinese Patients with Huntington's Disease: A Ten-year Multicenter Study in China.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG triplet repeats expansion in exon 1 of the Huntingtin gene (HTT). In China, HD is considered to have a low prevalence. The goal of this study was to describe the clinical characteristic and genetic profiles of HD in a Chinese cohort. A total of 322 individuals with expanded CAG repeats were consecutively recruited from the neurologic clinics of three medical centers in Southeastern China between 2008 and 2018. Among them, 80 were pre-symptomatic mutation carriers and 242 were symptomatic patients. The mean age at onset (AAO), defined here as the age at motor symptom onset, of the 242 manifest HD individuals was 40.3 ± 11.9 years and the mean CAG repeat length was 46.1 ± 7.5 in the group of symptomatic patients. Initial symptoms were abnormal movements in 88.8% of the patients with psychiatric symptoms in 6.2%, cognitive impairment in 3.3% and others in 1.7%. The AAO of motor was negatively correlated with the CAG repeat length in an exponential regression analysis (R 2 = 0.74, P<0.001). Analysis of 46 parent-child pairs showed that the CAG repeat length was longer in the offspring group (45.8 ±7.6) than in the parent group (43.8 ±3.0) (p=0.005). Overall, this study provides clinical and genetic profiles in a cohort of Chinese patients with HD, which should contribute to a better understanding of this disorder.

Effect of Apolipoprotein E Genotypes on Huntington's Disease Phenotypes in a Han Chinese Population.

Huntington's disease (HD) is an autosomal dominant degenerative disease that mainly encompasses movement, cognition, and behavioral symptoms. The apolipoprotein E (APOE) gene is thought to be associated with many neurodegenerative diseases. Here, we enrolled a cohort of 223 unrelated Han Chinese patients with HD and 1241 unrelated healthy controls in Southeastern China and analyzed the correlation between APOE genotypes and HD phenotypes. The results showed that the frequency of the E4 allele (7.1%) in HD patients was statistically less than that in controls (12.0%) (P =0.004). In addition, we divided patients into motor-onset and non-motor-onset groups, and analyzed the relationship with APOE genotypes. The results, however, were negative. Furthermore, the age at onset (AAO), defined as the age at the onset of motor symptoms, was compared in each APOE genotype subgroup and multivariate regression analysis was used to exclude the interference of CAG repeat length on AAO, but no association was found between APOE genotypes and AAO. Finally, we analyzed adult-onset HD to exclude the interference caused by juvenile HD (n = 13), and the results were negative. Therefore, our study suggests that APOE may not be a genetic modifier for HD, especially for adult-onset HD among Chinese of Han ethnicity. To the best of our knowledge, this is the first study of the correlation between APOE genotypes and HD phenotypes in a Han Chinese population.

Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing.

Familial Alzheimer's disease (FAD) is characterized by a positive family history of dementia and typically occurs at an early age with an autosomal dominant pattern of inheritance. Amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2) are the major causative genes of FAD. The spectrum of mutations in patients with FAD has been investigated extensively in the Caucasian population but rarely in the Chinese population. Here, we performed whole-exome sequencing in a total of 15 unrelated Chinese patients with FAD. Among them, 12 were found to carry missense variants in APP, PSEN1, and PSEN2. Two novel variants (APP: p.D244G, p.K687Q), 3 variants not previously associated with FAD (APP: p.T297M, p.D332G; PSEN1: p.R157S), and 7 previously reported pathogenic variants (APP: p.V717I; PSEN1: p.M139I, p.T147I, p.L173W, p.F177S, p.R269H; PSEN2: p.V139M) were identified. The novel variant APP p.K687Q was classified as likely pathogenic, and the other 4 variants (APP: p.D244G, p.T297M, p.D332G; PSEN1: p.R157S) were classified as uncertain significance. Therefore, APP, PSEN1, and PSEN2 mutations account for 2 (25.0%), 5 (62.5%), and 1 (12.5%) of the genotyped cases positive for mutations, respectively. Furthermore, the genotype-phenotype correlations were described. Our findings broaden the genetic spectrum of FAD with APP, PSEN1, and PSEN2 variants.