The genetic spectrum of NF1 variants in 10 unrelated Chinese families with neurofibromatosis type 1.

OBJECTIVES: To investigate the clinical and genetic features in a cohort of Chinese families with neurofibromatosis type 1 (NF1). METHODS: The clinical information of 21 patients with NF1 in 10 families was retrospectively analyzed. To broaden the genetic spectrum of NF1, multiplex ligation-dependent probe amplification analysis was performed first, followed by the whole-exome sequencing, in order to identify pathogenic or potentially pathogenic variants of NF1 gene in 10 unrelated Chinese families. RESULTS: Nine different NF1 variants were identified in all 10 families. Of these, 7 were known pathogenic variants and included the exon 1 deletion, exons 1-58 deletion, c.5401C>T (p.Q1801*), c.2291-2A>C, c.484C>T (p.Q162*), c.4922G>A (p.W1641*) and c.1019_1020del (p.S340Cfs*25). The 2 novel variants were c.5197T>C (p.S1733P) and c.783_797delinsC (p.K261Nfs*25). The p.S1733P variant was classified as a variant of uncertain significance, while p.K261Nfs*25 was classified as pathogenic. Hence, the positive detection rate of NF1 variants was 100% (10/10). While the truncating variants were responsible for 60.0% (6/10) of the cases, the splicing variant was responsible for 10% (1/10) of the cases. CONCLUSION: We identified 2 novel heterozygous variants (c.5197T>C and c.783_797delinsC) in the NF1 gene, which broadens the genetic spectrum of the NF1 gene.

Influence Function Based Second-Order Channel Pruning: Evaluating True Loss Changes For Pruning Is Possible Without Retraining.

Channel pruning is attracting increasing attention in the deep model compression community due to its capability of significantly reducing computation and memory footprints without special support from specific software and hardware. A challenge of channel pruning is designing efficient and effective criteria to select channels to prune. A widely used criterion is minimal performance degeneration, e.g., loss changes before and after pruning being the smallest. To accurately evaluate the truth performance degeneration requires retraining the survived weights to convergence, which is prohibitively slow. Hence existing pruning methods settle to use previous weights (without retraining) to evaluate the performance degeneration. However, we observe that the loss changes differ significantly with and without retraining. It motivates us to develop a technique to evaluate true loss changes without retraining, using which to select channels to prune with more reliability and confidence. We first derive a closed-form estimator of the true loss change per mask change, using influence functions without retraining. Influence function is a classic technique from robust statistics that reveals the impacts of a training sample on the model's prediction and is repurposed by us to assess impacts on true loss changes. We then show how to assess the importance of all channels simultaneously and develop a novel global channel pruning algorithm accordingly. We conduct extensive experiments to verify the effectiveness of the proposed algorithm, which significantly outperforms the competing channel pruning methods on both image classification and object detection tasks. One of the attractive properties of our algorithm is that it automatically obtains the prune percentage without the cumbersome yet commonly used sensitivity analysis by local pruning. To the best of our knowledge, we are the first that shows evaluating true loss changes for pruning without retraining is possible. This finding will open up opportunities for a series of new paradigms to emerge that differ from existing pruning methods. The code is available at https://github.com/hrcheng1066/IFSO.

Increased iron deposition in nucleus accumbens associated with disease progression and chronicity in migraine.

BACKGROUND: Migraine is one of the world's most prevalent and disabling diseases. Despite huge advances in neuroimaging research, more valuable neuroimaging markers are still urgently needed to provide important insights into the brain mechanisms that underlie migraine symptoms. We therefore aim to investigate the regional iron deposition in subcortical nuclei of migraineurs as compared to controls and its association with migraine-related pathophysiological assessments. METHODS: A total of 200 migraineurs (56 chronic migraine [CM], 144 episodic migraine [EM]) and 41 matched controls were recruited. All subjects underwent MRI and clinical variables including frequency/duration of migraine, intensity of migraine, 6-item Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS), and Pittsburgh Sleep Quality Index (PSQI) were recorded. Quantitative susceptibility mapping was employed to quantify the regional iron content in subcortical regions. Associations between clinical variables and regional iron deposition were studied as well. RESULTS: Increased iron deposition in the putamen, caudate, and nucleus accumbens (NAC) was observed in migraineurs more than controls. Meanwhile, patients with CM had a significantly higher volume of iron deposits compared to EM in multiple subcortical nuclei, especially in NAC. Volume of iron in NAC can be used to distinguish patients with CM from EM with a sensitivity of 85.45% and specificity of 71.53%. As the most valuable neuroimaging markers in all of the subcortical nuclei, higher iron deposition in NAC was significantly associated with disease progression, and higher HIT-6, MIDAS, and PSQI. CONCLUSIONS: These findings provide evidence that iron deposition in NAC may be a biomarker for migraine chronicity and migraine-related dysfunctions, thus may help to understand the underlying vascular and neural mechanisms of migraine. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT04939922.

FGF-21 and GDF-15 are increased in migraine and associated with the severity of migraine-related disability.

BACKGROUND: Migraine is a prevalent disorder with significant socioeconomic impact. The impairment of metabolic homeostasis in migraine warrants further investigation. Changes in serum levels of Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15) are characteristic of some metabolic and mitochondrial diseases. This study aimed to assess whether the presence of migraine affects serum levels of FGF-21 and GDF-15, and taking metabolic disorders into account as potential confounding factors. METHODS: We collected serum samples from 221 migraine patients (153 episodic migraineurs and 68 chronic migraineurs) and 124 healthy controls. The serum concentrations of FGF-21 and GDF-15 were measured using an enzyme-linked immunosorbent assay (ELISA) based approach. Clinical variables, including monthly headache days, peak headache pain intensity, the 6-item Headache Impact Test (HIT-6), and the Migraine Disability Assessment (MIDAS), were also addressed. The associations between the clinical variables of migraine patients and serum levels of FGF-21 and GDF-15 were studied. RESULTS: In the multiple regression that corrected for age, we found that the serum levels of FGF-21 and GDF-15 were significantly higher in migraine sufferers than in healthy controls. A significant elevation in serum concentration of FGF-21, but not GDF-15, was observed in patients with chronic migraine (CM) compared to those with episodic migraine (EM). Regarding migraine-related disability, higher scores on the HIT-6 and MIDAS were associated with higher levels of FGF-21 and GDF-15. For the receiver operating characteristic (ROC) analysis, the diagnosis of migraine using GDF-15 showed that the area under the ROC curve (AUC) was 0.801 and the AUC of chronic migraine was 0.880. CONCLUSION: Serum GDF-15 and FGF-21 levels are increased in patients with migraine and associated with the severity of migraine-related disability.

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.

A Systematic Analysis of the Role of Unc-5 Netrin Receptor A (UNC5A) in Human Cancers.

Unc-5 netrin receptor A (UNC5A), a netrin family receptor, plays a key role in neuronal development and subsequent differentiation. Recently, studies have found that UNC5A plays an important role in multiple cancers, such as bladder cancer, non-small cell lung carcinoma, and colon cancer but its pan-cancer function is largely unknown. Herein, the R software and multiple databases or online websites (The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), The Tumor Immune Estimation Resource (TIMER), The Gene Set Cancer Analysis (GSCA), Gene Expression Profiling Interactive Analysis (GEPIA), and cBioPortal etc.) were utilized to examine the role of UNC5A in pan-cancer. UNC5A was found to be highly expressed across multiple human cancer tissues and cells, was linked to clinical outcomes of patients, and was a potential pan-cancer biomarker. The mutational landscape of UNC5A exhibited that patients with UNC5A mutations had poorer progress free survival (PFS) in head and neck squamous cell carcinoma (HNSC) and prostate adenocarcinoma (PRAD). Furthermore, UNC5A expression was associated with tumor mutation burden (TMB), neoantigen, tumor microenvironment (TME), tumor microsatellite instability (MSI), immunomodulators, immune infiltration, DNA methylation, immune checkpoint (ICP) genes, and drug responses. Our results suggest the potential of UNC5A as a pan-cancer biomarker and an efficient immunotherapy target, which may also guide drug selection for some specific cancer types in clinical practice.

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 Mechanistic Role of Bridging Integrator 1 (BIN1) in Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia. The majority of AD cases are late-onset, multifactorial cases. Genome-wide association studies have identified more than 30 loci associated with sporadic AD (SAD), one of which is Bridging integrator 1 (BIN1). For the past few years, there has been a consensus that BIN1 is second only to APOE as the strongest genetic risk factor for SAD. Therefore, many researchers have put great effort into studying the mechanism by which BIN1 might be involved in the pathogenetic process of AD. To date, plenty of evidence has shown that BIN1 may participate in several pathways in AD, including tau and amyloid pathology. In addition, BIN1 has been indicated to take part in other relevant pathways such as inflammation, apoptosis, and calcium homeostasis. In this review, we systemically summarize the research progress on how BIN1 participates in the development of AD, with the expectation of providing promising perspectives for future research.

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.