Cell-based therapeutic strategies for treatment of spinocerebellar ataxias:an update

Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.

Compound heterozygous mutations in tripeptidyl peptidase 1 cause rare autosomal recessive spinocerebellar ataxia type 7:A case report

BACKGROUND Spinocerebellar ataxia recessive type 7(SCAR7)is a rare clinical manifestation beginning in childhood or adolescence.SCAR7 is caused by tripeptidyl peptidase 1(TPP1)gene mutations,and presents with cerebellar ataxia,pyramidal signs,neurocognitive impairment,deep paresthesia,and cerebellar atrophy.CASE SUMMARY Here,we describe a 25-year-old female patient in China who presented with increasing difficulty walking,falling easily,shaking limbs,instability holding items,slurred speech,coughing when drinking,palpitations,and frequent hunger and overeating.Magnetic resonance imaging showed cerebellar atrophy.Whole exome sequencing detected two compound heterozygous mutations in the TPP1 gene:c.1468G>A p.Glu490Lys and c.1417G>A p.Gly473Arg.Considering the patient’s clinical presentation and genetic test results,we hypothesized that complex heterozygous mutations cause TPP1 enzyme deficiency,which may lead to SCAR7.CONCLUSION We report the first case of SCAR7 from China.We also identify novel compound heterozygous mutations in the TPP1 gene associated with SCAR7,expanding the range of known disease-causing mutations for SCAR7.

Prenatal diagnosis of spinocerebellar ataxia type 3/Machado-Joseph disease in China's Mainland A case report

Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.

The human δ2 glutamate receptor gene is not mutated in patients with spinocerebellar ataxia

The human glutamate receptor delta 2 gene （GRID2） shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion （IVS5-121_-118 GAGT） and two single nucleotide polymor-phisms （c.1251G〉T and IVS14-63C〉G） were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.

Spinocerebellar ataxia type 3 with dopamine-responsive dystonia:A case report

BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,dysphagia,lingual fibrillation,pyramidal tract sign,and extrapyramidal system sign.However,it rarely has clinical manifestations similar to Parkinson-like symptoms,and is even rarer in patients sensitive to dopamine.We report a patient initially diagnosed with dopamine-responsive dystonia who was ultimately diagnosed with SCA3 by genetic testing,which was completely different from the initial diagnosis.CASE SUMMARY A 40-year-old Chinese woman was admitted to hospital due to severe inflexibility.At the beginning of the disease,she presented with anxiety and sleep disorder.At the later stage,she presented with gait disorder,which was similar to Parkinson's disease.Her medical history was unremarkable,but her mother,grandmother,and uncle all had similar illnesses and died due to inability to take care of themselves and related complications.Laboratory and imaging examinations showed no abnormalities,but electromyography and electroencephalography revealed delayed somatosensory evoked potentials and slow background rhythm,respectively.Her symptoms fluctuated during the daytime,and we initially diagnosed her with dopamine-responsive dystonia.After treatment with lowdose levodopa,the patient’s symptoms were significantly improved,but the final genetic diagnosis was SCA3.CONCLUSION SCA3 has various clinical phenotypes and needs to be differentiated from Parkinson's syndrome and dopamine-responsive dystonia.

Autosomal recessive spinocerebellar ataxia type 4 with a VPS13D mutation:A case report

BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.

Spinocerebellar Ataxia with Oculomotor Apraxia and Severe Corneal Astigmatism

Purpose: To disclose the association between spinocerebellar ataxia with oculomotor apraxia and high grade (7 diopters) congenital astigmatism. Methods: Single observational case report. A 39-year-old patient affected by spinocerebellar ataxia from the age of 20 was submitted to genetic and ophthalmic investigations to reach a diagnosis. Results: Genetic testing did not lead to a sure diagnosis, while clinical and instrumental ophthalmic examinations pointed out an oculomotor apraxia and a congenital severe astigmatism. Conclusion: To conclude the eye movement recording permitted to identify an oculomotor apraxia in this case of spinocerebellar ataxia. This is the first report of severe astigmatism in cases of ataxia with oculomotor apraxia.

Emerging Concepts of Pathogenesis and Comprehensive Therapeutic Strategies for Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the ATXN3 gene, situated at 14q32.1. The ATXN3 gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated ATXN3 alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.

Clinical Characteristics, Radiological Features and Gene Mutation in 10 Chinese Families with Spinocerebellar Ataxias

Background： Spinocerebellar ata^ias （SCAs） are a group ofneurodegenerative disorders that primarily cause the degeneration in the cerebellum, spinal cord, and brainstem. We study the clinical characteristics, radiological features and gene mutation in Chinese families with SCAs. Methods： In this study, we investigated 10 SCAs Chinese families with SCAI, SCA3/Machado-Joseph disease （MJD}, SCA7, SCAB. There were 27 people who were genetically diagnosed as SCA, of which 21 people showed clinical symptoms, and 6 people had no clinical phenotype that we called them presymptomatic patients. In addition, 3 people with cerebellar ataxia and cataracts were diagnosed according to the Harding diagnostic criteria but tailed to be recognized as SCAs on genetic testing. Clinical characteristic analyses of each type of SCAs and radiological examinations were perlbrmed. Results： We found that SCA3/MJD was the most common subtype in Hart population in China, and the ratio of the pontine tegmentum and the posterior fossa area was negatively con＇elated with the number of cytosine-adenine-guanine （CAG） repeats： the disease duration was positively correlated with the International Cooperative Ataxia Rating Scale score; and the CAG repeats number of abnormal alleles was negatively correlated with the age of onset. Conchlsions： Collectively our study is a systematic research on SCAs in China, which may help for the clinical diagnosis and prenatal screening of this disease, and it may also aid toward better understanding of this disease.

Frequency analysis of autosomal dominant spinocerebellar ataxias in mainland Chinese patients and clinical and molecular characterization of spinocerebellar ataxia type 6

Background Dominantly inherited spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous group of neurodegenerative disorders. This study was to further assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, SCA8, SCA10, SCA12, SCA14, SCA17 and DRPLA (dentatorubro-pallidoluysian atrophy) in mainland Chinese, and to specifically characterize mainland Chinese patients with SCA6 in terms of clinical and molecular features.Methods Using a molecular approach, we investigated SCA in 120 mainland Chinese families with dominantly inherited ataxias and in 60 mainland Chinese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 13 patients from 4 families. Results SCA3/MJD was the most common type of autosomal dominant SCA in mainland Chinese, accounting for 83 patients from 59 families (49.2%), followed by SCA2[8(6.7%)], SCA1[7(5.8%)], SCA6[4(3.3%)], SCA7[1(0.8%)], SCA8(0%), SCA10(0%), SCA12(0%), SCA14(0%), SCA17(0%) and DRPLA(0%). The genes responsible for 41 (34.2%) of dominantly inherited SCA families remain to be determined. Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) was found to harbor SCA3 mutations while none was found to harbor SCA6 mutations. In the 4 families with SCA6, significant anticipation was found in the absence of genetic instability on transmission.Conclusion A geographic cluster of families with SCA6 subtype was initially identified in a mainland Chinese population.

Nerve Growth Factor for the Treatment of Spinocerebellar Ataxia Type 3： An Open-label Study

Background： Spinocerebellar ataxia type 3 （SCA3） is the most common subtype of SCA worldwide, and runs a slowly progressive and unremitting disease course. There is currently no curable treatment available. Growing evidence has suggested that nerve growth factor （NGF） may have therapeutic effects in neurodegenerative diseases, and possibly also in SCA3. The objective of this study was to test the efficacy of NGF in SCA3 patients. Methods： We performed an open-label prospective study in genetically confirmed adult （〉18 years old） SCA3 patients. NGF was administered by intramuscular injection （18 μg once daily） fbr 28 days consecutively. All the patients were evaluated at baseline and 2 and 4 weeks after treatment using the Chinese version of the scale for assessment and rating of ataxia （SARA）. Results： Twenty-one SCA3 patients （ 10 men and 11 women, mean age 39.14 ± 7.81 years, mean disease duration 4.14 ± 1.90 years, mean CAG repeats number 77,57 ± 2.27） were enrolled. After 28 days of NGF treatment, the mean total SARA score decreased significantly from a baseline of 8.48± 2.40 to 6.30 ± 1.87 （P 〈 0.001 ）. Subsections SARA scores also showed significant improvements in stance （P = 0.003）, speech （P = 0.023）, finger chase （P = 0.015）, fast alternating hand movements （P = 0.009）, and heel-shin slide （P = 0.001）. Conclusions： Our preliminary data suggest that NGF may be effective in treating patients with SCA3.

Identification of Abnormal 51 CTA/CTG Expansion as Probably the Shortest Pathogenic Allele for Spinocerebellar Ataxia-8 in China

Spinocerebellar ataxias （SCAs） are a group of genetic disorders characterized by slowly progressive incoordina- tion of gait and are often associated with poor coordination of the hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. The genetic forms of ataxia are diagnosed by family history, physical examina- tion, neuroimaging, and molecular genetic testing. At present, 36 SCA subtypes including 27 pathogenic genes have been identified [1]. Different subtypes of SCAs have clear distribution differences among ethnic populations, and SCA8 is an infrequent entity worldwide, which has mostly been reported in Japanese, but has never been reported in Chinese [2]. SCAB involves bidirectional expression based on the total number of both the （CTA）n and （CTG）n expansion transcripts in ATXN8OS. The pathogenesis of this disorder is complex and the spectrum of clinical presentations is broad. It is predominantly characterized by drawn-out slowness of speech and gait instability, followed by slowly progressive ataxia, with disease onset typically occurring in adulthood [3]. How- ever, the lowest full-penetrance allele for SCA8 onset remains elusive and the current understanding of the phenotypic and genotypic features of SCA8 is limited. Since SCA8 has not yet been reported in the Chinese population and is scantily reported in a small proportion of pedigrees so far, clinical knowledge is still developing. Moreover, the boundary between the normal and patho- genic alleles of SCA8 is uncertain. Here we report the clinical and molecular genetic characteristics of 3 Chinese SCA8 families and have identified 51 CTA/CTG repeats within ATXN8OS, probably the shortest pathogenic allele for SCA8.

脊髓小脑性共济失调2两家系致病基因及临床特点

目的分析洛阳地区两个脊髓小脑性共济失调(SCAs)家系的致病基因及临床特点。方法收集先证者及其家系成员的临床资料。提取外周静脉血DNA,采用聚合酶链反应(PCR)结合琼脂糖凝胶电泳技术对两个家系先证者进行SCA1、2、3、6、7、12、17和DRPLA亚型的筛选。亚型初步确定后对目的片段进行Sanger测序,得到确认后对家系其他成员进行验证。结果家系1和家系2先证者经检测均为SCA2亚型,致病等位基因CAG重复次数分别为44和38次,随后的家系验证结果显示家系1中检测到致病基因携带者3人,家系2中检测到致病基因携带者1人。先证者均以行走不稳为主要症状,部分成员伴言语不清、记忆力下降。结论联合应用PCR和Sanger测序方法确诊了洛阳地区两个SCA2家系,家族性的行走不稳是其主要临床特点。

Clinical and genetic study of spinocerebellar ataxia type 7 in East Asian population

Background Spinocerebellar ataxia type 7 （SCA7） is known as an autosomal dominant cerebellar ataxia; patients with genetically confirmed diagnoses of SCA7 have increased rapidly in recent years.However, SCA7 is a rare subtype of SCA, and most data available about SCA7 are those of white people.The aim of the present study was to systematically review the prevalence and clinical and genetic aspects of SCA7 patients in East Asian population.Methods A search for publications on SCA7 was performed by using the ＂PubMed＂ database with the published language limited in English.Publications mainly focusing on the prevalence of SCA7 in patients with SCA and the clinical and genetic features of SCA7 patients were fully reviewed and analyzed.Results The prevalence of SCA7 in SCA patients ranged from 0 to 7.7%, which was similar to those reported previously.The clinical manifestations were typically present at the 30＇s of its victims （median, 29 years; interquartile range （IQR）,19.5-36.5 years）, and the symptoms appeared 15 years （（15.17±4.22） years） earlier on average in the offspring than in the parents.Gait ataxia and visual impairment were both found in all patients of whom the clinical features were described.Mutant SCA7 alleles contained 40-100 CAG repeats, with a median of 47 repeats （IQR, 44.5-50.0）; and the offspring had 13 more repeats on average compared with their parents （12.62±19.03）.A strong negative correlation was found between CAG repeat size and the onset age of patients （r=-0.739, P=0.000）.In addition, no significant difference was found in CAG repeat sizes between patients with visual impairment as the initial symptom and those with gait disturbance as their initial symptom （P=0.476）.Conclusions The prevalence of SCA7 in SCA patients, the age at onset and CAG repeats of SCA7 patients in East Asia are consistent with those of white people.However, larger population study is needed to assess the correlation between the CAG repeat size and initial symptoms of SCA7 patients in East Asia.

脊髓小脑共济失调Ⅲ型atxn3基因变异检测国家参考品的研制

目的 研制脊髓小脑共济失调Ⅲ型atxn3基因变异检测国家参考品。方法 通过对脊髓小脑共济失调Ⅲ型atxn3基因变异外周血进行EB病毒(EBV)转染、细胞扩繁培养,完成永生化细胞的建系工作。提取atxn3基因的脱氧核糖核酸(DNA)并稀释浓度至50 ng/μL后分装,经5个协作标定单位采用实时荧光定量PCR法(FQ-PCR)、PCR-毛细管电泳法对国家参考品的阳性符合率、阴性符合率、最低检出限、冻融稳定性和均匀性指标进行检测。结果 成功研制包含4个阳性样本和6个阴性样本的脊髓小脑共济失调Ⅲ型atxn3基因变异检测国家参考品。全部阳性样本及4种野生型样本的碱基排列与样本的CAG重复数一致且核酸质量合格,5家协作标定实验室的实验结果与参考品标示值一致。该参考品阳性符合率为100%、阴性符合率为100%、最低检出限阳性结果均检出、最低检出限阴性结果均未检出、冻融稳定性相关系数为0.999 9、均一性相关系数为1.000 0。结论 脊髓小脑共济失调Ⅲ型atxn3基因变异检测国家参考品的全部性能指标均符合规定,适用于atxn3基因变异体外诊断试剂盒的性能评价及质量控制。

Profiling neuroprotective potential of trehalose in animal models of neurodegenerative diseases:a systematic review

Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.

脊髓小脑共济失调3型患者脑白质及灰质微结构改变

目的观察脊髓小脑共济失调3型(SCA3)患者脑白质及灰质微结构改变。方法前瞻性招募37例SCA3患者(症状组)、15例SCA3患者直系亲属(症状前组)及35名健康志愿者(对照组),采集全脑3D T1WI及弥散峰度成像(DKI);对白质及灰质结构进行组间两两比较,针对存在差异脑区提取相关指标,分析脑白质及灰质结构改变与共济失调等级量表(SARA)的相关性。结果症状前组纤维束受损主要见于双侧小脑上、中、下脚及大脑脚等处,其平均弥散峰度(MK)、径向弥散峰度(Kr)、轴向弥散峰度(Ka)及部分各向异性(FA)均低于对照组(P均<0.02);症状组受损纤维束广泛存在于双侧小脑上、中、下脚、大脑脚、内囊后肢、胼胝体、丘脑后辐射(包括视辐射)及上放射冠,其MK、Kr、Ka及FA均低于症状前组及对照组(P均<0.02)。相比对照组,症状组双侧小脑半球(前叶、后叶)、脑桥、延髓、双侧壳核及豆状核灰质体积(GMV)显著减少、双侧丘脑GMV显著增加(P均<0.02);相比症状前组,症状组脑桥GMV显著减低(P<0.02)。症状前组与对照组全脑GMV差异均无统计学意义(P均>0.02)。症状组及症状前组双侧小脑上、中、下脚及大脑脚部分弥散值与患者SARA评分相关(P均<0.05)。结论SCA3患者脑白质及灰质微结构发生改变,且白质受损更显著并早于临床出现症状。

结构性MRI测量对脊髓小脑共济失调3型的诊断价值

【目的】本研究拟探讨结构性MRI测量对脊髓小脑共济失调3型(SCA3)的诊断价值,并进一步评估其与疾病的严重程度及病程的相关性。【方法】前瞻性收集2018年5月至2021年11月于中山大学附属第一医院经基因诊断确诊的SCA3患者81例(症状组sym-SCA3):59,症状前组(pre-SCA3):22,同时收集年龄、性别匹配的正常对照(HCs)35例。受试者均采集MRI结构像(3D T1WI MPRAGE)并收集其相应的临床资料。三位具不同临床经验的观察者分别通过第三方软件测量双侧小脑上、中、下脚宽度、脑桥及不同平面脊髓前后径(平枕骨大孔、颈3-5椎体上缘),其中一位观察者2个月后对上述指标进行重复测量。分别计算观察者内及观察者间可重复性,采用单因素方差分析、秩和检验、ROC曲线及随机森林方法评估上述指标对SCA3的诊断价值,并与临床资料进行相关性分析。【结果】基于形态学MRI脑结构测量指标,无论是观察者内或观察者间,均具有较高的可重复性且不依赖于观察者的临床经验,其中双侧小脑上、中脚具有最高的一致性。HCs、pre-SCA3和sym-SCA3三组的双侧小脑上、中、下脚、脑桥及脊髓前后径(除颈5椎体上缘水平)分别依次减小并具有统计学差异(P<0.017)。ROC示左侧小脑中脚对pre-SCA3的诊断价值最高(AUC=0.911),其敏感度、特异度和cut-off值分别为85.7%,95.5%和10.15 mm,而右侧小脑上脚对sym-SCA3的诊断价值最高(AUC=0.999),其临界值为2.62 mm,敏感度和特异度分别是100%和98.3%。进一步,基于上述指标的随机森林模型区分三组同样有着很高的诊断效能(AUC=0.970,特异度=93.1%),其中左侧小脑中脚对模型的贡献度最大。此外,相关分析表明上述指标同SARA和病程存在中等程度或显著负相关(P<0.05)。【结论】基于形态学MRI的脑结构测量可重复性好、不依赖于临床经验,可以帮助诊断SCA3并预测疾病的严重程度和病程,左侧小脑中脚及右侧小脑上脚分别用于预测pre-SCA3和sym-SCA3价值最优。由此,本研究推荐临床纳入MRI脑结构测量协助评估SCA3。

基于体素的形态学测量结合ASL在脊髓小脑共济失调3型诊断中的应用价值

目的 探讨基于体素的形态学测量方法 (VBM)结合3D脉冲式动脉自旋标记灌注成像(3D-PASL)对脊髓小脑共济失调3型(SCA3)的诊断价值。方法 前瞻性收集2018年5月~2019年5月经基因检测证实为SCA3的患者,并募集与其性别、年龄、身体质量指数(BMI)匹配的健康志愿者。对所有入组者行基于全脑的T1WI磁化强度预备快速梯度回波(T1MPRAGE)和3D-PASL扫描,获得被试者经Dartel配准后的全脑标准化灰质概率图以及全脑脑血流量(CBF)图。进一步通过组间VBM比较确定灰质体积显著差异的脑区及其特利尔神经研究所(MNI)标准空间坐标作为兴趣区,提取相应脑区的CBF值,并通过非参数检验和受试者工作特性曲线(ROC)分析评价其对SCA3的诊断价值。结果 相比健康对照[n=12,平均(36.92±14.26)岁],VBM示SCA3患者[n=19,平均(40.89±13.72)岁]的右侧小脑半球存在灰质体积显著减低区域,主要位于右侧小脑前叶(MNI坐标x:18,y:-54,z:-19.5)(P<0.05,FWE校正)。进一步对比分析相应区域的CBF值,结果表明SCA3患者右侧小脑前叶的CBF值(56.0±30.9) ml/100 g/min明显高于对照组(29.6±21.0)ml/100 g/min(P<0.05)。ROC分析显示,基于右侧小脑前叶的CBF对SCA3具有中等程度的诊断效能,曲线下面积(AUC)为0.75,特异度、敏感度和界值分别为75.0%、84.2%和29.8 ml/100 g/min。结论 相比健康对照,SCA3患者的右侧小脑前叶灰质体积显著减低,相应区域CBF增高。基于右侧小脑前叶的CBF值可用于诊断SCA3。

伴直立性震颤的脊髓小脑性共济失调28型1例报道

脊髓小脑性共济失调(spinocerebellar ataxias,SCA)是一组罕见的常染色体遗传的神经退行性疾病,SCA28型是其罕见的亚型,由致病基因AFG3L2的杂合突变引起。临床上通常表现为缓慢进行性步态和肢体共济失调、构音障碍、下肢反射亢进、凝视诱发的眼球震颤、上睑下垂、眼肌麻痹、踝反射减弱、帕金森综合征、肌张力障碍或认知障碍。该文报道1例伴直立性震颤的SCA28型患者,经基因检测发现患者AFG3L2基因存在c.2098G>A错义突变;同时回顾既往文献,总结79例SCA28型病例的临床症状和致病基因变异情况,以加强临床医师对该病的认识,辅助临床诊断。