Morphological Analysis Of The Brain In Spinal Cerebellar Ataxia SCA3 Using Magnetic Resonance Imaging Technology

Background and ObjectivesSpinocerebellar ataxia type 3(SCA3),also known as Machado-Joseph disease(MJD),is one of nine inherited neurodegenerative disorders and the most prevalent autosomal spinocerebellar ataxia subtype worldwide.It is characterized by abnormal amplification of cytosine-adenine-guanine(CAG)trinucleotides found in the coding region,resulting in abnormal polyglutamic acid(Poly Q)protein that cannot be effectively degraded.Accumulation and accumulation of polyglutamine in nerve nuclei may lead to direct or indirect neurotoxic effects,resulting in cell death and brain atrophy,eventually leading to neurodegeneration.The simplicity of the disease’s single-gene origin is in stark contrast to the complexity of the causative processes now thought to support neuronal dysfunction and death.The primary clinical feature of SCA3 is progressive ataxia,a motor coordination disorder that affects gaze,speech,gait and balance.The disease is also characterized by pyramidal symptoms and may be accompanied by dystonia-ankylosing extrapyramidal syndrome and/or peripheral muscle atrophy.Additional clinical manifestations of SCA3 include progressive extraophthalmoplegia,dystonia,hyperreflexia,nystagmus,dysarthria,and Parkinson’s syndrome,as well as non-ataxia symptoms such as cognitive and mental problems,olfactory dysfunction,sleep disorders,attention and executive dysfunction,and depression.Previous clinical and neuroradiological literature has linked these brain injuries to motor and mental dysfunction in SCA3.Due to the low prevalence of SCA3 and the scarcity of histopathological data in most degenerative ataxia studies,magnetic resonance imaging(MRI)has become a reliable tool for investigating brain structure with high accuracy and repeatability.As a result,structural and functional imaging based on MRI has gained increasing attention in the study of pathogenic mechanisms and potential biomarkers,including the identification of preclinical stages of neurodegenerative diseases.Various MRI techniques,such as diffusion tensor imaging(DTI),blood oxygen level-dependent functional(BOLD)MRI,and magnetic resonance spectroscopy(MRS),can be used to observe structural or functional abnormalities in brain tissue.These techniques can help determine the underlying pathogenesis,evaluate disease severity and progression before symptom onset in spinocerebellar ataxia(SCA)patients,monitor treatment effectiveness,and identify subtle changes following future clinical trials.Therefore,this study proposed the hypothesis that magnetic resonance structural imaging can explore the relationship between brain injury and motor and mental dysfunction in patients with SCA3,so as to explain the pathogenesis of SCA3.In order to examine the relationship between structural changes in the brain and clinical symptoms of SCA3,two approaches were taken: 1)investigating abnormal alterations in gray matter volume(GMV)in SCA3 and its correlation with clinical symptoms;2)examining changes in white matter(WM)and the white matter network in SCA3 and their correlation with clinical symptoms.In the past a number of studies have also found that SCA3 can result in sleep apnea and respiratory problems,these problems can reduce the patient’s quality of sleep,the patient may experience symptoms such as snoring,gas peace-making cramps and periodic limb movement disorder,including periodic leg movement disorders(periodiclimbmovementdisorder,PLMD)and periodicmovementdisorder(PMD),which can cause patients to wake up during the night,interrupting normal sleep and affecting the patient’s physical and mental health.During the study,many patients expressed that they had sleep disorders,which had a great impact on their quality of life.However,it was difficult to assess sleep disorders,and the prevalence of SCA3 was very low,and clinical data and related studies were scarce.To address these challenges,a third attempt was made: 3)utilizing bibliometrics to assess the application of imaging in sleep research and explore the current state of abnormal sleep research.This approach was taken to provide a reference for studying abnormal sleep in SCA3.Material and methodsThe present study involved the following three parts:1.The aim of this study was to investigate the relationship between gray matter volume in SCA3 patients and their clinical symptoms.A total of 102 participants,including49 patients and 53 healthy controls matched for age and sex,were recruited.Neuropsychological assessments,such as the Montreal Cognitive Assessment(Mo CA),Mini Mental State Examination(MMSE),Rapid Vocabulary Test(RVR),Digital Span Test(DST),Activities of Daily Living(ADL),Hamilton Depression Scale(HAMD),and magnetic resonance imaging(MRI)were used to evaluate the participants.The degree of ataxia in SCA3 patients was also evaluated using the Scale for the Assessment and Rating of Ataxia(SARA)and the International Cooperative Ataxia Rating Scale(ICARS).Voxel-based morphometry(VBM)was used to assess structural variations in gray matter between patients and healthy controls,and the gray matter volume(GMV)of several brain areas in patients was measured.Partial correlation analysis was performed to identify the correlation between GMV and clinical scale scores,with sex,age,and total intracranial volume(TIV)as covariates.2.Correlation between white matter structural network and clinical symptoms in SCA3.Thirty-nine SCA3 patients and 41 sex-and age-matched healthy control(HC)participants were recruited.All patients underwent interviews regarding their medical history,cognitive function evaluations,and genetic testing.Neuropsychological assessment tests,including ICARS,SARA,ADL,DST,RVR,HAMD,MMSE,and Mo CA,were conducted by experienced neurologists.SARS and ICARS tests were not performed on HC due to the absence of ataxia symptoms.Brain MRI scans,clinical features,and DTI data were collected from all individuals.Tract-Based Spatial Statistics(TBSS)was utilized to analyze the differences in the microstructure of white matter(WM)between patients with SCA3 and the HC group,and further analyzed the topology of the whole brain WM network.Finally,we studied the correlation between SCA3 clinical characteristics,TBSS parameters,and WM structural network parameters.Finally,partial correlation analysis with gender,age and TIV as covariables was used to study the correlation between clinical features of SCA3,TBSS parameters and WM structural network parameters.3.Analysis of imaging studies related to sleep disorders in SCA3 based on bibliometrics.A literature search on sleep imaging was conducted in Web of Science Core Collection(Wo SCC),limiting the time span to the period from September 1,2012 to August31,2022.The majority of selected literature were articles,and English was the predominant language.This study analyzed 7679 articles published in this field over the past 10 years,using Cite Space to analyze tendencies,countries,institutions,authors,and hotspots.Results1.Associations between abnormal gray matter volume alterations and clinical SCA3.Compared to HC,the SCA3 group showed significant decreases in scores for Mo CA(Z =-4.578,p<0.001),MMSE(Z=-4.7254,p<0.001)and RVR(Z=-6.642,p<0.001)in SCA3 group decreased significantly,while the scores of ADL(Z=-6.447,p<0.001)and HAMD(Z=-5.285,p<0.001)increased significantly.GMV significantly reduced in the SCA3 group compared with HC,specifically in the lobule IX of the vermis,bilateral cerebellum,caudate,cingulum,frontal lobe,hippocampus,precentral gyrus,putamen,supplementary motor area,and temporal lobes.Additionally,GMV was reduced in the left calcarine,paracentral lobes,and parahippocampal gyrus,as well as the right cuneus,fusiform gyrus,and occipital lobe,particularly in the cerebellum.However,GMV was increased only in the left intralaminar nuclei,mediodorsal lateral parvocellular,and right ventral anterior nucleus of the thalamus(p<0.001,FDR corrected).The decrease of GMV in cerebellum and vermis was related to the scores of SARA,Mo CA,ICARS,ADL,HAMD and RVR(p < 0.05,FDR correction).2.Correlation between white matter structural network and clinical symptoms in SCA3.In SCA3,changes in WM microstructures were mostly observed in the extrapyramidal system and the cerebello-thalamo-cortical circuit.Furthermore,with regards to global parameters,both global efficiency(Eglob)(p<0.001)and local efficiency(Eloc)(p<0.001)were reduced in the patient group,while the typical route length Lp(p=0.000)and λ(p<0.001)were increased.The local parameters revealed significant differences between groups in the parameters of three nodes: node efficiency Enod(I)(p<0.05,FDR corrected),node shortest path length(NLp)(p<0.05,FDR corrected)(p<0.05,FDR corrected),and node degree(Ki(p<0.05,FDR corrected)).The global efficiency was negatively associated with the ataxia scale.The CAG repeat length of SCA3 was strongly correlated with disease progression,SARA,ICAR,and age of onset(r= 0.445-0.525,p<0.05),whereas SARA,ICAR,and ADL tests were significantly correlated with certain brain network metrics(r=0.668-0.475,p<0.05).This study found no further correlation between DTIMRI characteristics and cognitive function.3.Analysis of imaging studies related to sleep disorders in SCA3 based on bibliometrics.A total of 7,679 articles on the application of imaging to sleep research were published by 566 institutions located in 135 countries and in 1,428 journals.The number of articles published has been increasing annually.Keyword analysis revealed that the research direction of the application of imaging in sleep research focused on the effects of degenerative diseases on sleep,such as Parkinson’s disease,Alzheimer’s disease,and small vessel disease.A literature evaluation identified Parkinson’s disease,insomnia,sleep quality,and rapid eye movement sleep behavior disorder as the top research trends in this field.Conclusion1.Patients with SCA3 exhibited severe impairment in the cerebellum and vermis.However,cerebellar injury alone was not the sole factor contributing to the clinical manifestations of SCA3 patients.The thalamus was the only area with increased gray matter volume in the SCA3 group.Additionally,cerebellar injuries were not only correlated with motor symptoms,but also had a significant impact on non-motor aspects.2.This study discovered alterations in the motor,cognitive,emotional,and global brain white matter networks in individuals with SCA3.The global brain network may exhibit some compensatory mechanisms to sustain bodily functions.The extrapyramidal system and cerebello-thalamo-cortical pathway display the most microdamage,whereas the cerebellum,limbic system,and DMN(default mode networking)exhibit the most prominent topological changes in the white matter network.3.There is an increasing amount of research being conducted on sleep disorders caused by degenerative diseases.Magnetic resonance functional brain imaging is a reliable method for conducting sleep research using imaging.In the future,more research may focus on sleep disorders related to aging-related diseases,and imaging could provide convenient and reliable evidence in this regard.