In clinical specialties focusing on neurological disorders,there is a need for comprehensive and integrated non-invasive,sensitive,and specific testing methods.Both Parkinson's disease and multiple system atrophy ...In clinical specialties focusing on neurological disorders,there is a need for comprehensive and integrated non-invasive,sensitive,and specific testing methods.Both Parkinson's disease and multiple system atrophy are classified asα-synucleinopathies,characterized by abnormal accumulation ofα-synuclein protein,which provides a shared pathological background for their comparative study.In addition,both Parkinson's disease and multiple system atrophy involve neuronal death,a process that may release circulating cell–free DNA(cfDNA)into the bloodstream,leading to specific alterations.This premise formed the basis for investigating cell–free DNA as a potential biomarker.Cellfree DNA has garnered attention for its potential pathological significance,yet its characteristics in the context of Parkinson's disease and multiple system atrophy are not fully understood.This study investigated the total concentration,nonapoptotic level,integrity,and cellfree DNA relative telomere length of cell-free DNA in the peripheral blood of 171 participants,comprising 76 normal controls,62 patients with Parkinson's disease,and 33 patients with multiple system atrophy.In our cohort,75.8%of patients with Parkinson's disease(stage 1–2 of Hoehn&Yahr)and 60.6%of patients with multiple system atrophy(disease duration less than 3 years)were in the early stages.The diagnostic potential of the cell-free DNA parameters was evaluated using receiver operating characteristic(ROC)analysis,and their association with disease prevalence was examined through logistic regression models,adjusting for confounders such as age,sex,body mass index,and education level.The results showed that cell-free DNA integrity was significantly elevated in both Parkinson's disease and multiple system atrophy patients compared with normal controls(P<0.001 for both groups),whereas cell-free DNA relative telomere length was markedly shorter(P=0.003 for Parkinson's disease and P=0.010 for multiple system atrophy).Receiver operating characteristic analysis indicated that both cell-free DNA integrity and cell-free DNA relative telomere length possessed good diagnostic accuracy for differentiating Parkinson's disease and multiple system atrophy from normal controls.Specifically,higher cell-free DNA integrity was associated with increased risk of Parkinson's disease(odds ratio[OR]:5.72;95%confidence interval[CI]:1.54–24.19)and multiple system atrophy(OR:10.10;95%CI:1.55–122.98).Conversely,longer cell-free DNA relative telomere length was linked to reduced risk of Parkinson's disease(OR:0.16;95%CI:0.04–0.54)and multiple system atrophy(OR:0.10;95%CI:0.01–0.57).These findings suggest that cell-free DNA integrity and cellfree DNA relative telomere length may serve as promising biomarkers for the early diagnosis of Parkinson's disease and multiple system atrophy,potentially reflecting specific underlying pathophysiological processes of these neurodegenerative disorders.展开更多
Multiple system atrophy is a sporadic,progressive,adult-onset,neurodegenerative disorder characte rized by autonomic dysfunction symptoms,parkinsonian features,and cerebellar signs in va rious combinations.An early di...Multiple system atrophy is a sporadic,progressive,adult-onset,neurodegenerative disorder characte rized by autonomic dysfunction symptoms,parkinsonian features,and cerebellar signs in va rious combinations.An early diagnosis of multiple system atrophy is of utmost impo rtance for the proper prevention and management of its potentially fatal complications leading to the poor prognosis of these patients.The current diagnostic criteria incorporate several clinical red flags and magnetic resonance imaging marke rs supporting diagnosis of multiple system atrophy.Nonetheless,especially in the early disease stage,it can be challenging to differentiate multiple system atrophy from mimic disorders,in particular Parkinson’s disease.Electromyography of the external anal sphincter represents a useful neurophysiological tool for diffe rential diagnosis since it can provide indirect evidence of Onuf’s nucleus degeneration,which is a pathological hallmark of multiple system atrophy.However,the diagnostic value of external anal sphincter electromyography has been a matter of debate for three decades due to controve rsial reports in the literature.In this review,after a brief ove rview of the electrophysiological methodology,we first aimed to critically analyze the available knowledge on the diagnostic role of external anal sphincter electromyography.We discussed the conflicting evidence on the clinical correlations of neurogenic abnormalities found at external anal sphincter electro myography.Finally,we repo rted recent prognostic findings of a novel classification of electromyography patterns of the external anal sphincter that could pave the way toward the implementation of this neurophysiological technique for survival prediction in patients with multiple system atrophy.展开更多
BACKGROUND Multiple system atrophy(MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15(GDF15) is i...BACKGROUND Multiple system atrophy(MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15(GDF15) is involved in the differentiation and progression of the central nervous system, and is widely distributed in peripheral blood, which may be a novel biomarker for MSA.AIM To determine serum GDF15 levels, related factors and their potential diagnostic value in MSA patients, compared with Parkinson’s disease(PD) patients and healthy controls.METHODS A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzymelinked immunosorbent assay, and the differences between the MSA, PD and control groups were analyzed. Further investigations were performed in different MSA subgroups according to age of onset, sex, clinical subtypes, diagnostic criteria, and disease duration. Receiver-operating characteristic curve analysiswas used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD.RESULTS Serum GDF15 levels were significantly higher in MSA patients than in PD patients and healthy controls(P = 0.000). Males and those with a disease duration of more than three years showed higher serum GDF15 levels(P = 0.043 and 0.000;respectively). Serum GDF15 levels may be a potential diagnostic biomarker for MSA patients compared with healthy controls and PD patients(cutoff: 470.42 pg/m L, sensitivity: 85.7%, specificity: 88.0%;cutoff: 1075.91 pg/m L, sensitivity:51.0%, specificity: 96.0%;respectively).CONCLUSION Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.展开更多
Coenzyme Q10(Co Q10) is an essential cofactor in the mitochondrial respiratory pathway and also functions as a lipid-soluble antioxidant. Co Q10 deficiency has been implicated in many clinical disorders and aging. Pri...Coenzyme Q10(Co Q10) is an essential cofactor in the mitochondrial respiratory pathway and also functions as a lipid-soluble antioxidant. Co Q10 deficiency has been implicated in many clinical disorders and aging. Primary Co Q10 deficiency is a group of recessively inherited diseases caused by mutations in any gene involved in the Co Q10 biosynthesis pathway. Although primary Co Q10 deficiency is rare, its diagnosis is important because it is potentially treatable with exogenous Co Q10. Multiple system atrophy(MSA) was recently shown to be linked to mutations in the COQ2 gene, one of the genes involved in the Co Q10 biosynthesis pathway. MSA is relatively common in adult-onset neurodegenerative diseases characterized by Parkinsonism, cerebellar ataxia and autonomic failures. Because COQ2 mutations are associated with an increased risk of MSA, oral Co Q10 supplementation may be beneficial for MSA, as for other primary Co Q10 deficiencies. Statins are 3-hydroxy-3-methylglutaryl coenzyme A inhibitors that inhibit the biosynthesis of cholesterol, as well as the synthesis of mevalonate, a critical intermediate in cholesterol synthesis. Statin therapy has been associ-ated with a variety of muscle complaints from myalgia to rhabdomyolysis. Statin treatment carries a potential risk of Co Q10 deficiency, although no definite evidence has implicated CQ10 deficiency as the cause of statinrelated myopathy.展开更多
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by a variable combination of autonomic failure, parkinsonism with poor response to levodopa, cerebellar ataxia and pyrami...Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by a variable combination of autonomic failure, parkinsonism with poor response to levodopa, cerebellar ataxia and pyramidal symptoms. The pathological hallmark of MSA is the oligodendrocytic glial cytoplasmic inclusions (GCIs) consisting of α-synuclein, and so MSA, together with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), is an α-synucleinopathy. Currently few effective biomarkers have been identified for the diagnosis or prognosis of MSA, and there is no established therapy to delay its progression. In this review, we discuss the epidemiology, neuropathology, genetics, clinical presentation and diagnostic biomarkers of MSA, as well as recent advances in its treatment.展开更多
Alpha-synucleinopathies(α-synucleinopathies)are a diverse group of neurodegenerative diseases comprising Parkinson’s disease(PD),dementia with Lewy bodies(DLB),and multiple system atrophy(MSA).Although in all these ...Alpha-synucleinopathies(α-synucleinopathies)are a diverse group of neurodegenerative diseases comprising Parkinson’s disease(PD),dementia with Lewy bodies(DLB),and multiple system atrophy(MSA).Although in all these diseases there exist abnormal accumulation of alpha-synuclein(α-syn)aggregates in nerve tissues,the pathological lesions formed byα-syn aggregates and their cellular locations are quite different.In PD and DLB,the hallmark pathological lesions are Lewy bodies(LBs)and Lewy neurites(LNs),which are localized in the neuronal somata and processes.In MSA,the characteristic pathologic structures are glial cytoplasmic inclusions,which are deposited in the cytoplasm of oligodendrocytes.The fact that PD and MSA have distinct pathologicalα-syn lesions suggest that different mechanisms play a role in the pathogenesis of the two diseases.In this review article,we compare the clinical manifestations and pathological features of PD and MSA,the two common synucleinopathies,and discuss the potential mechanisms for the formation ofα-syn aggregates and their pathologic roles in PD and MSA.展开更多
In multiple sclerosis, gray matter atrophy is extensive, and cognitive deficits and mood disorders are frequently encountered. It has been conjectured that focal atrophy is associated with emotional decline. However, ...In multiple sclerosis, gray matter atrophy is extensive, and cognitive deficits and mood disorders are frequently encountered. It has been conjectured that focal atrophy is associated with emotional decline. However, conventional MRI has revealed that the pathological characteristics cannot fully account for the mood disorders. Moreover, there is no correlation between cognitive disorders and MRI results in clinically isolated syndromes or in cases of definite multiple sclerosis. In this casecontrol study, voxel-based morphometric analysis was performed on 11 subjects with relapsing-remitting multiple sclerosis, and the results show that these patients exhibit gray matter atrophy. Moreover, the gray matter atrophy in the superior and middle gyri of the right frontal lobe in patients with multiple sclerosis was correlated with scores from the Hamilton Anxiety Rating Scale. The scores obtained with the Repeatable Battery for the Assessment of Neuropsychological Status were associated with gray matter atrophy in the middle gyrus of the left frontal lobe, the superior and middle gyrus of the right frontal lobe, the middle gyrus of the left cingulate, the superior and middle gyri of the left frontal lobe, and the triangular area of the left frontal lobe. However, there was no statistical significance. These findings suggest that the cingulate and frontal cortices of the dominant hemisphere are the most severely atrophic regions of the brain, and this atrophy is correlated with cognitive decline and emotional abnormalities.展开更多
Background Parkinson’s disease(PD)and multiple system atrophy(MSA)are two distinctα-synucleinopathies traditionally differentiated through clinical symptoms.Early diagnosis of MSA is problematic,and seed amplificati...Background Parkinson’s disease(PD)and multiple system atrophy(MSA)are two distinctα-synucleinopathies traditionally differentiated through clinical symptoms.Early diagnosis of MSA is problematic,and seed amplification assays(SAAs),such as real-time quaking-induced conversion(RT-QuIC),offer the potential to distinguish these diseases through their underlyingα-synuclein(α-Syn)pathology and proteoforms.Currently,SAAs provide a binary result,signifying either the presence or absence ofα-Syn seeds.To enhance the diagnostic potential and biological relevance of these assays,there is a pressing need to incorporate quantification and stratification ofα-Syn proteoform-specific aggregation kinetics into current SAA pipelines.Methods Optimal RT-QuIC assay conditions forα-Syn seeds extracted from PD and MSA patient brains were determined,and assay kinetics were assessed forα-Syn seeds from different pathologically relevant brain regions(medulla,substantia nigra,hippocampus,middle temporal gyrus,and cerebellum).The conformational profiles of diseaseand region-specificα-Syn proteoforms were determined by subjecting the amplified reaction products to concentration-dependent proteolytic digestion with proteinase K.Results Using our protocol,PD and MSA could be accurately delineated using proteoform-specific aggregation kinetics,includingα-Syn aggregation rate,maximum relative fluorescence,the gradient of amplification,and core protofilament size.MSA cases yielded significantly higher values than PD cases across all four kinetic parameters in brain tissues,with the MSA-cerebellar phenotype having higher maximum relative fluorescence than the MSA-Parkinsonian phenotype.Statistical significance was maintained when the data were analysed regionally and when all regions were grouped.Conclusions Our RT-QuIC protocol and analysis pipeline can distinguish between PD and MSA,and between MSA phenotypes.MSAα-Syn seeds induce faster propagation and exhibit higher aggregation kinetics than PDα-Syn,mirroring the biological differences observed in brain tissue.With further validation of these quantitative parameters,we propose that SAAs could advance from a yes/no diagnostic to a theranostic biomarker that could be utilised in developing therapeutics.展开更多
Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as ...Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.展开更多
We observed the characteristics of white matter fibers and gray matter in multiple sclerosis patients, to identify changes in diffusion tensor imaging fractional anisotropy values following white matter fiber injury. ...We observed the characteristics of white matter fibers and gray matter in multiple sclerosis patients, to identify changes in diffusion tensor imaging fractional anisotropy values following white matter fiber injury. We analyzed the correlation between fractional anisotropy values and changes in whole-brain gray matter volume. The participants included 20 patients with relapsing-remitting multiple sclerosis and 20 healthy volunteers as controls. All subjects underwent head magnetic resonance imaging and diffusion tensor imaging. Our results revealed that fractional anisotropy values decreased and gray matter volumes were reduced in the genu and splenium of corpus callosum, left anterior thalamic radiation, hippocampus, uncinate fasciculus, right corticospinal tract, bilateral cingulate gyri, and inferior longitudinal fasciculus in multiple sclerosis patients. Gray matter volumes were significantly different between the two groups in the right frontal lobe（superior frontal, middle frontal, precentral, and orbital gyri）, right parietal lobe（postcentral and inferior parietal gyri）, right temporal lobe（caudate nucleus）, right occipital lobe（middle occipital gyrus）, right insula, right parahippocampal gyrus, and left cingulate gyrus. The voxel sizes of atrophic gray matter positively correlated with fractional anisotropy values in white matter association fibers in the patient group. These findings suggest that white matter fiber bundles are extensively injured in multiple sclerosis patients. The main areas of gray matter atrophy in multiple sclerosis are the frontal lobe, parietal lobe, caudate nucleus, parahippocampal gyrus, and cingulate gyrus. Gray matter atrophy is strongly associated with white matter injury in multiple sclerosis patients, particularly with injury to association fibers.展开更多
Objective: To longitudinally assess dynamic changes of iron deposition and volume of the precentral gyrus and its correlation with clinical manifestations of Relapse-Remitting Multiple Sclerosis(RRMS) by using 3D enha...Objective: To longitudinally assess dynamic changes of iron deposition and volume of the precentral gyrus and its correlation with clinical manifestations of Relapse-Remitting Multiple Sclerosis(RRMS) by using 3D enhanced T2* weighted angiography(ESWAN). Methods: Thirty RRMS patients and thirty age- and sex-matched healthy controls were recruited and underwent ESWAN and 3D T1WI twice interval of one year with the same parameters. The mean phase values (MPVs) and volumes in precentral gyrus gray matter (PGM) were measured, and change of iron content and its correlation with volume, clinical manifestations were analyzed. Results: Compared with controls, the RRMS had higher iron deposition in both single-time measurements, but the volume decreased. Comparing to the first scan, we found significant difference in MPVs between the two times (P rs = 0.764, P rs = 0.592, P rs = 0.582, P rs = -0.399, P rs = -0.745, P rs = -0.367, P Conclusions: With the disease progression, the content of iron in PGM in RRMS patients is increasing, while the volume has no obvious change, suggesting that the iron deposition may precede or develop faster than cerebral atrophy.展开更多
Heterogeneity of biological samples is usually considered a major obstacle for three-dimensional (3D) structure determination of macromolecular complexes. Heterogeneity may occur at the level of composition or conform...Heterogeneity of biological samples is usually considered a major obstacle for three-dimensional (3D) structure determination of macromolecular complexes. Heterogeneity may occur at the level of composition or conformational variability of complexes and affects most 3D structure determination methods that rely on signal averaging. Here, an approach is described that allows sorting structural states based on a 3D statistical approach, the 3D sampling and classification (3D-SC) of 3D structures derived from single particles imaged by cryo electron microscopy (cryo-EM). The method is based on jackknifing & bootstrapping of 3D sub-ensembles and 3D multivariate statistical analysis followed by 3D classification. The robustness of the statistical sorting procedure is corroborated using model data from an RNA polymerase structure and experimental data from a ribosome complex. It allows resolving multiple states within heterogeneous complexes that thus become amendable for a structural analysis despite of their highly flexible nature. The method has important implications for high-resolution structural studies and allows describing structure ensembles to provide insights into the dynamics of multi-component macromolecular assemblies.展开更多
基金supported by the National Key Research and Development Program of China,No.2021YFC2501205(to YC)the Science and Technology Innovation 2030 project,No.2021ZD0201101(to YC)+1 种基金the National Natural Science Foundation of China,Nos.82201409(to YL),82201401(to CH)the Xuanwu Youth Development Project,No.QNPY2021011(to CH)。
文摘In clinical specialties focusing on neurological disorders,there is a need for comprehensive and integrated non-invasive,sensitive,and specific testing methods.Both Parkinson's disease and multiple system atrophy are classified asα-synucleinopathies,characterized by abnormal accumulation ofα-synuclein protein,which provides a shared pathological background for their comparative study.In addition,both Parkinson's disease and multiple system atrophy involve neuronal death,a process that may release circulating cell–free DNA(cfDNA)into the bloodstream,leading to specific alterations.This premise formed the basis for investigating cell–free DNA as a potential biomarker.Cellfree DNA has garnered attention for its potential pathological significance,yet its characteristics in the context of Parkinson's disease and multiple system atrophy are not fully understood.This study investigated the total concentration,nonapoptotic level,integrity,and cellfree DNA relative telomere length of cell-free DNA in the peripheral blood of 171 participants,comprising 76 normal controls,62 patients with Parkinson's disease,and 33 patients with multiple system atrophy.In our cohort,75.8%of patients with Parkinson's disease(stage 1–2 of Hoehn&Yahr)and 60.6%of patients with multiple system atrophy(disease duration less than 3 years)were in the early stages.The diagnostic potential of the cell-free DNA parameters was evaluated using receiver operating characteristic(ROC)analysis,and their association with disease prevalence was examined through logistic regression models,adjusting for confounders such as age,sex,body mass index,and education level.The results showed that cell-free DNA integrity was significantly elevated in both Parkinson's disease and multiple system atrophy patients compared with normal controls(P<0.001 for both groups),whereas cell-free DNA relative telomere length was markedly shorter(P=0.003 for Parkinson's disease and P=0.010 for multiple system atrophy).Receiver operating characteristic analysis indicated that both cell-free DNA integrity and cell-free DNA relative telomere length possessed good diagnostic accuracy for differentiating Parkinson's disease and multiple system atrophy from normal controls.Specifically,higher cell-free DNA integrity was associated with increased risk of Parkinson's disease(odds ratio[OR]:5.72;95%confidence interval[CI]:1.54–24.19)and multiple system atrophy(OR:10.10;95%CI:1.55–122.98).Conversely,longer cell-free DNA relative telomere length was linked to reduced risk of Parkinson's disease(OR:0.16;95%CI:0.04–0.54)and multiple system atrophy(OR:0.10;95%CI:0.01–0.57).These findings suggest that cell-free DNA integrity and cellfree DNA relative telomere length may serve as promising biomarkers for the early diagnosis of Parkinson's disease and multiple system atrophy,potentially reflecting specific underlying pathophysiological processes of these neurodegenerative disorders.
基金supported by the Italian Ministry of Health (’Ricerca Corrente’2020-2021)(to MT)。
文摘Multiple system atrophy is a sporadic,progressive,adult-onset,neurodegenerative disorder characte rized by autonomic dysfunction symptoms,parkinsonian features,and cerebellar signs in va rious combinations.An early diagnosis of multiple system atrophy is of utmost impo rtance for the proper prevention and management of its potentially fatal complications leading to the poor prognosis of these patients.The current diagnostic criteria incorporate several clinical red flags and magnetic resonance imaging marke rs supporting diagnosis of multiple system atrophy.Nonetheless,especially in the early disease stage,it can be challenging to differentiate multiple system atrophy from mimic disorders,in particular Parkinson’s disease.Electromyography of the external anal sphincter represents a useful neurophysiological tool for diffe rential diagnosis since it can provide indirect evidence of Onuf’s nucleus degeneration,which is a pathological hallmark of multiple system atrophy.However,the diagnostic value of external anal sphincter electromyography has been a matter of debate for three decades due to controve rsial reports in the literature.In this review,after a brief ove rview of the electrophysiological methodology,we first aimed to critically analyze the available knowledge on the diagnostic role of external anal sphincter electromyography.We discussed the conflicting evidence on the clinical correlations of neurogenic abnormalities found at external anal sphincter electro myography.Finally,we repo rted recent prognostic findings of a novel classification of electromyography patterns of the external anal sphincter that could pave the way toward the implementation of this neurophysiological technique for survival prediction in patients with multiple system atrophy.
基金Supported by National Natural Science Foundation of China,No.81771373Key Research and Development Plan of Zibo City,No.2019ZC010169 and No.2019ZC010166.
文摘BACKGROUND Multiple system atrophy(MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15(GDF15) is involved in the differentiation and progression of the central nervous system, and is widely distributed in peripheral blood, which may be a novel biomarker for MSA.AIM To determine serum GDF15 levels, related factors and their potential diagnostic value in MSA patients, compared with Parkinson’s disease(PD) patients and healthy controls.METHODS A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzymelinked immunosorbent assay, and the differences between the MSA, PD and control groups were analyzed. Further investigations were performed in different MSA subgroups according to age of onset, sex, clinical subtypes, diagnostic criteria, and disease duration. Receiver-operating characteristic curve analysiswas used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD.RESULTS Serum GDF15 levels were significantly higher in MSA patients than in PD patients and healthy controls(P = 0.000). Males and those with a disease duration of more than three years showed higher serum GDF15 levels(P = 0.043 and 0.000;respectively). Serum GDF15 levels may be a potential diagnostic biomarker for MSA patients compared with healthy controls and PD patients(cutoff: 470.42 pg/m L, sensitivity: 85.7%, specificity: 88.0%;cutoff: 1075.91 pg/m L, sensitivity:51.0%, specificity: 96.0%;respectively).CONCLUSION Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.
文摘Coenzyme Q10(Co Q10) is an essential cofactor in the mitochondrial respiratory pathway and also functions as a lipid-soluble antioxidant. Co Q10 deficiency has been implicated in many clinical disorders and aging. Primary Co Q10 deficiency is a group of recessively inherited diseases caused by mutations in any gene involved in the Co Q10 biosynthesis pathway. Although primary Co Q10 deficiency is rare, its diagnosis is important because it is potentially treatable with exogenous Co Q10. Multiple system atrophy(MSA) was recently shown to be linked to mutations in the COQ2 gene, one of the genes involved in the Co Q10 biosynthesis pathway. MSA is relatively common in adult-onset neurodegenerative diseases characterized by Parkinsonism, cerebellar ataxia and autonomic failures. Because COQ2 mutations are associated with an increased risk of MSA, oral Co Q10 supplementation may be beneficial for MSA, as for other primary Co Q10 deficiencies. Statins are 3-hydroxy-3-methylglutaryl coenzyme A inhibitors that inhibit the biosynthesis of cholesterol, as well as the synthesis of mevalonate, a critical intermediate in cholesterol synthesis. Statin therapy has been associ-ated with a variety of muscle complaints from myalgia to rhabdomyolysis. Statin treatment carries a potential risk of Co Q10 deficiency, although no definite evidence has implicated CQ10 deficiency as the cause of statinrelated myopathy.
文摘Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by a variable combination of autonomic failure, parkinsonism with poor response to levodopa, cerebellar ataxia and pyramidal symptoms. The pathological hallmark of MSA is the oligodendrocytic glial cytoplasmic inclusions (GCIs) consisting of α-synuclein, and so MSA, together with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), is an α-synucleinopathy. Currently few effective biomarkers have been identified for the diagnosis or prognosis of MSA, and there is no established therapy to delay its progression. In this review, we discuss the epidemiology, neuropathology, genetics, clinical presentation and diagnostic biomarkers of MSA, as well as recent advances in its treatment.
基金the authors are supported by grants from Natural Science Foundation of China(81671244,81371200,and 81401042)a special fund from Key Laboratory of Neurodegenerative Disease,Ministry of Education(PXM2019_026283_000002)+1 种基金Beijing Municipal Science and Technology Commission(Z161100005116011,Z171100000117013)Beijing Municipal commission of Health and Family Planning(PXM2017_026283_000002).
文摘Alpha-synucleinopathies(α-synucleinopathies)are a diverse group of neurodegenerative diseases comprising Parkinson’s disease(PD),dementia with Lewy bodies(DLB),and multiple system atrophy(MSA).Although in all these diseases there exist abnormal accumulation of alpha-synuclein(α-syn)aggregates in nerve tissues,the pathological lesions formed byα-syn aggregates and their cellular locations are quite different.In PD and DLB,the hallmark pathological lesions are Lewy bodies(LBs)and Lewy neurites(LNs),which are localized in the neuronal somata and processes.In MSA,the characteristic pathologic structures are glial cytoplasmic inclusions,which are deposited in the cytoplasm of oligodendrocytes.The fact that PD and MSA have distinct pathologicalα-syn lesions suggest that different mechanisms play a role in the pathogenesis of the two diseases.In this review article,we compare the clinical manifestations and pathological features of PD and MSA,the two common synucleinopathies,and discuss the potential mechanisms for the formation ofα-syn aggregates and their pathologic roles in PD and MSA.
文摘In multiple sclerosis, gray matter atrophy is extensive, and cognitive deficits and mood disorders are frequently encountered. It has been conjectured that focal atrophy is associated with emotional decline. However, conventional MRI has revealed that the pathological characteristics cannot fully account for the mood disorders. Moreover, there is no correlation between cognitive disorders and MRI results in clinically isolated syndromes or in cases of definite multiple sclerosis. In this casecontrol study, voxel-based morphometric analysis was performed on 11 subjects with relapsing-remitting multiple sclerosis, and the results show that these patients exhibit gray matter atrophy. Moreover, the gray matter atrophy in the superior and middle gyri of the right frontal lobe in patients with multiple sclerosis was correlated with scores from the Hamilton Anxiety Rating Scale. The scores obtained with the Repeatable Battery for the Assessment of Neuropsychological Status were associated with gray matter atrophy in the middle gyrus of the left frontal lobe, the superior and middle gyrus of the right frontal lobe, the middle gyrus of the left cingulate, the superior and middle gyri of the left frontal lobe, and the triangular area of the left frontal lobe. However, there was no statistical significance. These findings suggest that the cingulate and frontal cortices of the dominant hemisphere are the most severely atrophic regions of the brain, and this atrophy is correlated with cognitive decline and emotional abnormalities.
基金JAW is funded through a Neurological Foundation W&B Miller Doctoral Scholarship(1951 MS)BVD is funded by a Health Research Council Hercus Fellowship(21/034)+2 种基金the School of Medical Science,University of Auckland,New Zealand,Catalyst(22-UOA-049-CSG,Royal Society of New Zealand Te Apārangi)Te Tītoki Mataora(3729090&3729858)GMH is supported by an NHMRC Senior Leadership Fellowship(1176607).
文摘Background Parkinson’s disease(PD)and multiple system atrophy(MSA)are two distinctα-synucleinopathies traditionally differentiated through clinical symptoms.Early diagnosis of MSA is problematic,and seed amplification assays(SAAs),such as real-time quaking-induced conversion(RT-QuIC),offer the potential to distinguish these diseases through their underlyingα-synuclein(α-Syn)pathology and proteoforms.Currently,SAAs provide a binary result,signifying either the presence or absence ofα-Syn seeds.To enhance the diagnostic potential and biological relevance of these assays,there is a pressing need to incorporate quantification and stratification ofα-Syn proteoform-specific aggregation kinetics into current SAA pipelines.Methods Optimal RT-QuIC assay conditions forα-Syn seeds extracted from PD and MSA patient brains were determined,and assay kinetics were assessed forα-Syn seeds from different pathologically relevant brain regions(medulla,substantia nigra,hippocampus,middle temporal gyrus,and cerebellum).The conformational profiles of diseaseand region-specificα-Syn proteoforms were determined by subjecting the amplified reaction products to concentration-dependent proteolytic digestion with proteinase K.Results Using our protocol,PD and MSA could be accurately delineated using proteoform-specific aggregation kinetics,includingα-Syn aggregation rate,maximum relative fluorescence,the gradient of amplification,and core protofilament size.MSA cases yielded significantly higher values than PD cases across all four kinetic parameters in brain tissues,with the MSA-cerebellar phenotype having higher maximum relative fluorescence than the MSA-Parkinsonian phenotype.Statistical significance was maintained when the data were analysed regionally and when all regions were grouped.Conclusions Our RT-QuIC protocol and analysis pipeline can distinguish between PD and MSA,and between MSA phenotypes.MSAα-Syn seeds induce faster propagation and exhibit higher aggregation kinetics than PDα-Syn,mirroring the biological differences observed in brain tissue.With further validation of these quantitative parameters,we propose that SAAs could advance from a yes/no diagnostic to a theranostic biomarker that could be utilised in developing therapeutics.
基金supported by STI2030-Major Project,No,2021ZD0204200(to LX).
文摘Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.
基金supported by the Project of Science and Technology Department of Jilin Province in China,No.20160101023JC
文摘We observed the characteristics of white matter fibers and gray matter in multiple sclerosis patients, to identify changes in diffusion tensor imaging fractional anisotropy values following white matter fiber injury. We analyzed the correlation between fractional anisotropy values and changes in whole-brain gray matter volume. The participants included 20 patients with relapsing-remitting multiple sclerosis and 20 healthy volunteers as controls. All subjects underwent head magnetic resonance imaging and diffusion tensor imaging. Our results revealed that fractional anisotropy values decreased and gray matter volumes were reduced in the genu and splenium of corpus callosum, left anterior thalamic radiation, hippocampus, uncinate fasciculus, right corticospinal tract, bilateral cingulate gyri, and inferior longitudinal fasciculus in multiple sclerosis patients. Gray matter volumes were significantly different between the two groups in the right frontal lobe（superior frontal, middle frontal, precentral, and orbital gyri）, right parietal lobe（postcentral and inferior parietal gyri）, right temporal lobe（caudate nucleus）, right occipital lobe（middle occipital gyrus）, right insula, right parahippocampal gyrus, and left cingulate gyrus. The voxel sizes of atrophic gray matter positively correlated with fractional anisotropy values in white matter association fibers in the patient group. These findings suggest that white matter fiber bundles are extensively injured in multiple sclerosis patients. The main areas of gray matter atrophy in multiple sclerosis are the frontal lobe, parietal lobe, caudate nucleus, parahippocampal gyrus, and cingulate gyrus. Gray matter atrophy is strongly associated with white matter injury in multiple sclerosis patients, particularly with injury to association fibers.
文摘Objective: To longitudinally assess dynamic changes of iron deposition and volume of the precentral gyrus and its correlation with clinical manifestations of Relapse-Remitting Multiple Sclerosis(RRMS) by using 3D enhanced T2* weighted angiography(ESWAN). Methods: Thirty RRMS patients and thirty age- and sex-matched healthy controls were recruited and underwent ESWAN and 3D T1WI twice interval of one year with the same parameters. The mean phase values (MPVs) and volumes in precentral gyrus gray matter (PGM) were measured, and change of iron content and its correlation with volume, clinical manifestations were analyzed. Results: Compared with controls, the RRMS had higher iron deposition in both single-time measurements, but the volume decreased. Comparing to the first scan, we found significant difference in MPVs between the two times (P rs = 0.764, P rs = 0.592, P rs = 0.582, P rs = -0.399, P rs = -0.745, P rs = -0.367, P Conclusions: With the disease progression, the content of iron in PGM in RRMS patients is increasing, while the volume has no obvious change, suggesting that the iron deposition may precede or develop faster than cerebral atrophy.
文摘Heterogeneity of biological samples is usually considered a major obstacle for three-dimensional (3D) structure determination of macromolecular complexes. Heterogeneity may occur at the level of composition or conformational variability of complexes and affects most 3D structure determination methods that rely on signal averaging. Here, an approach is described that allows sorting structural states based on a 3D statistical approach, the 3D sampling and classification (3D-SC) of 3D structures derived from single particles imaged by cryo electron microscopy (cryo-EM). The method is based on jackknifing & bootstrapping of 3D sub-ensembles and 3D multivariate statistical analysis followed by 3D classification. The robustness of the statistical sorting procedure is corroborated using model data from an RNA polymerase structure and experimental data from a ribosome complex. It allows resolving multiple states within heterogeneous complexes that thus become amendable for a structural analysis despite of their highly flexible nature. The method has important implications for high-resolution structural studies and allows describing structure ensembles to provide insights into the dynamics of multi-component macromolecular assemblies.
