Impact of cognition-related single nucleotide polymorphisms on brain imaging phenotype in Parkinson’s disease

Multiple single nucleotide polymorphisms may contribute to cognitive decline in Parkinson’s disease. However, the mechanism by which these single nucleotide polymorphisms modify brain imaging phenotype remains unclear. The aim of this study was to investigate the potential effects of multiple single nucleotide polymorphisms on brain imaging phenotype in Parkinson’s disease. Forty-eight Parkinson’s disease patients and 39 matched healthy controls underwent genotyping and 7 T magnetic resonance imaging. A cognitive-weighted polygenic risk score model was designed, in which the effect sizes were determined individually for 36 single nucleotide polymorphisms. The correlations between polygenic risk score, neuroimaging features, and clinical data were analyzed. Furthermore, individual single nucleotide polymorphism analysis was performed to explore the main effects of genotypes and their interactive effects with Parkinson’s disease diagnosis. We found that, in Parkinson’s disease, the polygenic risk score was correlated with the neural activity of the hippocampus, parahippocampus, and fusiform gyrus, and with hippocampal-prefrontal and fusiform-temporal connectivity, as well as with gray matter alterations in the orbitofrontal cortex. In addition, we found that single nucleotide polymorphisms in α-synuclein(SNCA) were associated with white matter microstructural changes in the superior corona radiata, corpus callosum, and external capsule. A single nucleotide polymorphism in catechol-O-methyltransferase was associated with the neural activities of the lingual, fusiform, and occipital gyri, which are involved in visual cognitive dysfunction. Furthermore, DRD3 was associated with frontal and temporal lobe function and structure. In conclusion, imaging genetics is useful for providing a better understanding of the genetic pathways involved in the pathophysiologic processes underlying Parkinson’s disease. This study provides evidence of an association between genetic factors, cognitive functions, and multi-modality neuroimaging biomarkers in Parkinson’s disease.

High-altitude hypoxia induces disorders of the brain- endocrine-immune network through activation of corticotropin-releasing factor and its type- 1 receptors

High-altitude hypoxia can induce physiological dysfunction and mountain sickness,but the underlying mechanism is not fully understood.Corticotrophin-releasing factor(CRF) and CRF type-1 receptors(CRFR1) are members of the CRF family and the essential controllers of the physiological activity of the hypothalamo-pituitary-adrenal(HPA) axis and modulators of endocrine and behavioral activity in response to various stressors.We have previously found that high-altitude hypoxia induces disorders of the brain-endocrine-immune network through activation of CRF and CRFR1 in the brain and periphery that include activation of the HPA axis in a time-and dose-dependent manner,impaired or improved learning and memory,and anxiety-like behavioral change.Meanwhile,hypoxia induces dysfunctions of the hypothalamo-pituitary-endocrine and immune systems,including suppression of growth and development,as well as inhibition of reproductive,metabolic and immune functions.In contrast,the small mammals that live on the Qinghai-Tibet Plateau alpine meadow display low responsiveness to extreme high-altitudehypoxia challenge,suggesting well-acclimatized genes and a physiological strategy that developed during evolution through interactions between the genes and environment.All the findings provide evidence for understanding the neuroendocrine mechanisms of hypoxia-induced physiological dysfunction.This review extends these findings.

Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders:current knowledge and future directions

Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

Alzheimer’s disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling

Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.

Atypical features in two adult patients with Cockayne syndrome and analysis of genotype-phenotype correlation

To the Editor:Cockayne syndrome(CS;Mendelian Inheritance in Man#133540,216400)is a rare autosomal recessive neurodegenerative disorder described by Edward Cockayne in 1936.[1]The prevalence of CS is 2.7 per million live births,[2]and the disease is probably underdiagnosed.The major clinical features are progressive growth failure and microcephaly as well as other characteristics such as a“cachectic dwarfism”appearance with sunken eyes,cutaneous photosensitivity,mental retardation,demyelinating peripheral neuropathy,pigmentary retinopathy,cataracts,deafness,dental anomalies,and premature death.[1,3]There is considerable variation in the severity of the disorder,leading to classification into three main types.

Phosphorylated TDP-43 Staging of Primary Age-Related Tauopathy

Primary age-related tauopathy(PART) is characterized by tau neurofibrillary tangles(NFTs) in the absence of amyloid plaque pathology. In the present study,we analyzed the distribution patterns of phosphorylated43-kDa TAR DNA-binding protein(pTDP-43) in the brains of patients with PART. Immunohistochemistry and immunofluorescence double-labeling in multiple brain regions was performed on brain tissues from PART,Alzheimer's disease(AD), and aging control cases. We examined the regional distribution patterns of pTDP-43 intraneuronal inclusions in PART with Braak NFT stages[ 0 and B IV, and a Thal phase of 0(no beta-amyloid present). We found four stages which indicated potentially sequential dissemination of pTDP-43 in PART. Stage I was characterized by the presence of pTDP-43 lesions in the amygdala, stage II by such lesions in the hippocampus,stage III by spread of pTDP-43 to the neocortex, and stage IV by pTDP-43 lesions in the putamen, pallidum, and insular cortex. In general, the distribution pattern of pTDP-43 pathology in PART cases was similar to the early TDP-43 stages reported in AD, but tended to be more restricted to the limbic system. However, there were some differences in the distribution patterns of pTDP-43 between PART and AD, especially in the dentate gyrus of the hippocampus. Positive correlations were found in PART between the Braak NFT stage and the pTDP-43 stage and density.

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 and1241 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.

Three-Dimensional Heterogeneity of Cerebellar Interposed Nucleus-Recipient Zones in the Thalamic Nuclei

The cerebellum is conceptualized as a processor of complex movements and is also endowed with roles in cognitive and emotional behaviors.Although the axons of deep cerebellar nuclei are known to project to primary thalamic nuclei,macroscopic investigation of the characteristics of these projections,such as the spatial distribution of recipient zones,is lacking.Here,we studied the output of the cerebellar interposed nucleus(IpN)to the ventrolateral(VL)and centrolateral(CL)thalamic nuclei using electrophysiological recording in vivo and trans-synaptic viral tracing.We found that IpN stimulation induced mono-synaptic evoked potentials(EPs)in the VL but not the CL region.Furthermore,both the EPs induced by the IpN and the innervation of IpN projections displayed substantial heterogeneity across the VL region in three-dimensional space.These findings indicate that the recipient zones of IpN inputs vary between and within thalamic nuclei and may differentially control thalamo-cortical networks.

Variant of EOMES Associated with Increasing Risk in Chinese Patients with Relapsing-remitting Multiple Sclerosis

Background： Multiple sclerosis （MS） is a common central nervous system autoimmune disorder. Increasing number of genome-wide association study （GWAS） analyses hint that MS is strongly associated with genetics. Unfortunately, almost all the GWAS analyses were Caucasian population based. Numbers of risk loci might not be replicated in Chinese MS patients. Hence, we pertbrmed a MassArray Assay to genotype the previously reported variants located in the transcription regulation genes in order to elucidate their role in the Chinese MS patients. Methods： One hundred and forty-two relapsing-remitting MS （RRMS） patients and 301 healthy controls were consecutively collected from September 2, 2008, to June 7, 2013, as stage 1 subjects. Eight reported transcription regulation-related single-nucleotide polymorphisms （SNPs） were genotyped using the Sequenom MassArray system. In stage 2, another 44 RRMS patients and 200 healthy controls were consecutively collected and Sanger sequenced from April 7, 2015, to June 29, 2017, for the validation of positive results in stage 1. Differences in allele and genotype frequencies between patients and healthy controls, odds ratios, and 95% confidence intervals were calculated with the Chi-square test or Fisher＇s exact test. Hardy-Weinberg equilibrium was tested also using the Chi-square test. Results： In stage 1 analysis, we confirmed only one previously reported risk variant, rsl 1129295 in EOMES gene. We found that the frequency ofT/T genotype was much higher in MS group （χ2 = 10.251, P = 0.005） and the T allele ofrsl 1129295 increased the risk of MS （χ2 = 10.022, P = 0.002）. In stage 2 and combined analyses, the T allele of rsl 1129295 still increased the risk of MS （χ2 = 4.586, P- 0.030 and×2 = 16.378, P = 5.19×10 ^-5, respectively）. Conclusions： This study enhances the knowledge that the variant of EOMES is associated with increasing risk in Chinese RRMS patients and provides a potential therapeutic target in RRMS.

Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions

Proline-rich transmembrane protein 2(PRRT2)is the leading cause of paroxysmal kinesigenic dyskinesia(PKD),benign familial infantile epilepsy(BFIE),and infantile convulsions with choreoathetosis(ICCA).Reduced penetrance of PRRT2 has been observed in previous studies,whereas the exact penetrance has not been evaluated well.The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors.We screened 222 PKD index patients and their available relatives,identified 39 families with pathogenic or likely pathogenic(P/LP)PRRT2 variants via Sanger sequencing,and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature.Penetrance was estimated as the proportion of affected variant carriers.PRRT2 penetrance estimate was 77.6%(95%confidence interval(CI)74.5%–80.7%)in relatives and 74.5%(95%CI 70.2%–78.8%)in obligate carriers.In addition,we first observed that penetrance was higher in truncated than in non-truncated variants(75.8%versus 50.0%,P=0.01),higher in Asian than in Caucasian carriers(81.5%versus 68.5%,P=0.004),and exhibited no difference in gender or parental transmission.Our results are meaningful for genetic counseling,implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders,with patients from Asia or carrying truncated variants at a higher risk.

Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias

Background:Although many causative genes have been uncovered in recent years,genetic diagnosis is still missing for approximately 50%of autosomal recessive cerebellar ataxia(ARCA)patients.Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population.Methods:Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing(WES)and copy number variation(CNV)calling with ExomeDepth.Likely causal CNV predictions were validated by CNVseq.Results:Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients,providing a 46.3%positive molecular diagnostic rate.Ten different genes were involved,of which four most common genes were SACS,SYNE1,ADCK3 and SETX,which accounted for 76.0%(19/25)of the positive cases.The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide.Clinical features of the patients carrying SACS,SYNE1 and ADCK3 mutations were summarized.Conclusions:Our results expand the genetic spectrum and clinical profiles of ARCA patients,demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA,and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.

Latest innovations in the treatment of Wilson's disease

Wilson's disease(WD),also called hepatolenticular degeneration,is an autosomal recessive copper dysfunction disorder that is among the few treatable neurogenetic disorders.The main goals for controlling WD are to lower copper intake and encourage copper removal.Medical treatments and low-copper diets are available,but many problems remain.For example,the current treatments cannot fix copper metabolism and are unable to cross the blood-brain barrier.Furthermore,severe side effects have been experienced by many patients with WD.Because lifelong therapy is required for this disease,adherence to medical therapy and best practices for monitoring and personalizing therapy continue to evolve;some of these issues are being addressed in ongoing studies.Additionally,novel chelating agents,gene therapies using adeno-associated viruses,and variant-specific therapies that may improve neurological outcomes are in development.Here,we review the latest treatment innovations that may play an essential role for patients with WD in the future.

Gene therapy for monogenic disorders: challenges, strategies, and perspectives

Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.

Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations

Background: Juvenile amyotrophic lateral sclerosis (JALS) is an uncommon form of amyotrophic lateral sclerosis whose age at onset (AAO) is defined as prior to 25 years. FUS mutations are the most common cause of JALS. SPTLC1 was recently identified as a disease-causative gene for JALS, which has rarely been reported in Asian populations. Little is known regarding the difference in clinical features between JALS patients carrying FUS and SPTLC1 mutations. This study aimed to screen mutations in JALS patients and to compare the clinical features between JALS patients with FUS and SPTLC1 mutations. Methods: Sixteen JALS patients were enrolled, including three newly recruited patients between July 2015 and August 2018 from the Second Affiliated Hospital, Zhejiang University School of Medicine. Mutations were screened by whole-exome sequencing. In addition, clinical features such as AAO, onset site and disease duration were extracted and compared between JALS patients carrying FUS and SPTLC1 mutations through a literature review. Results: A novel and de novo SPTLC1 mutation (c.58G>A, p.A20T) was identified in a sporadic patient. Among 16 JALS patients, 7/16 carried FUS mutations and 5/16 carried respective SPTLC1 , SETX , NEFH , DCTN1 , and TARDBP mutations. Compared with FUS mutation patients, those with SPTLC1 mutations had an earlier AAO (7.9 ± 4.6 years vs. 18.1 ± 3.9 years, P < 0.01), much longer disease duration (512.0 [416.7-607.3] months vs. 33.4 [21.6-45.1] months, P < 0.01), and no onset of bulbar. Conclusion: Our findings expand the genetic and phenotypic spectrum of JALS and help to better understand the genotype-phenotype correlation of JALS.

Local and Global Abnormalities in Pre-symptomatic Huntington’s Disease Revealed by 7T Resting-state Functional MRI

DearEditor,Huntington's disease(HD)is an autosomal dominant neurodegenerative disease caused by the abnormal expansion of CAG repeat in the HTT gene.The CAG-Age Product(CAP),a quantity associated with age and CAG repeat length,is frequently used to estimate the progression of HD pathology^([1,2]).

CMT2D neuropathy is influenced by vitamin D-mediated environmental pathway

Dear Editor,Peripheral neuropathy is a group of devastating diseases affecting periphe-ral nerves and may cause symptoms such as extreme numbness,muscle weakness,and paralysis.Currently,there are no effective therapies for these diseases.Great progress has been made in identifying genetic causes for peripheral neuropathy owing to the advances in genetic testing in the last decade.For example,>100 genes have been identified to be associated with Charcot–Marie–Tooth(CMT)neuropathy,a group of disorders among the most common forms of inherited peripheral neuropathy.

Norepinephrine from the Locus Coeruleus Regulates Microglia Dynamics During Wakefulness

Microglia,the brain’s"busy bees",continuously survey the microenvironment by extending and retracting their ramified processes to maintain brain homeostasis[1,2].Upon disease or injury,microglia quickly transform their morphology and extend their processes towards the disease/injury sites to clear damage[2].The mechanisms underlying the high motility of microglial processes and the rapid morphological transformation of microglia have been extensively investigated.

Correlation Between CCG Polymorphisms and CAG Repeats During Germline Transmission in Chinese Patients with Huntington’s Disease

Dear Editor,Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by movement disorder,progressive dementia,and psychiatric and behavioral changes.It is caused by unstable expanded CAG trinucleotide repeats in exon 1 of the huntingtin (HTT)gene,located on chromosome 4p16.3 [1].

A Brain-Spleen Axis Regulates Humoral Immunity

A happy mood helps to build a flourishing immune system.Interactions between the nervous and immune systems have attracted the interest of researchers for decades.It is well known that external stressors can activate the hypothalamus to regulate immune responses via the hypothalamic-pituitary-adrenal cortex(HPA)axis[1].As well,inflammatory stimuli can activate a rapid antiinflammatory reflex via the cholinergic vagus nerve pathway.

原发性衰老相关性tau病在中国人群中的临床病理学研究

目的:分析中国人群中原发性衰老相关性tau病(PART)的临床病理学特点,并比较其与老年性痴呆之间的差异。创新点:PART为新近提出的概念,其与老年性痴呆的关系尚存在争论。目前未见针对中国人群PART的相关报道。本文首次报道了浙江大学医学院中国人脑库中的PART的临床病理学特点。方法:回顾性分析相关病例,严格纳入标准。PART在中国人群中常见,50岁以上人群占47%。平均年龄(76±12)岁,女性14例(30%),男性32例(70%)。免疫组织化学法显示,按磷酸化tau的Braak分期,PART大多为I到Ш期。异常蛋白TDP43和p62在PART中高表达,分别为67%和70%;在老年性痴呆中分别为83%和83%。TDP43和p62共表达在PART为55%,在老年性痴呆为79%。其中海马为PART常见累及部位,TDP43为61%,p62为63%。仅4%的PART患者表现为轻度认知障碍。结论:PART在中国人群中常见;PART大多无明显痴呆症状;异常蛋白TDP43和p62在PART中高表达,与老年性痴呆相比存在差异。