Deep learning segmentation results in precise delineation of the putamen in multiple system atrophy.

OBJECTIVES: The precise segmentation of atrophic structures remains challenging in neurodegenerative diseases. We determined the performance of a Deep Neural Patchwork (DNP) in comparison to established segmentation algorithms regarding the ability to delineate the putamen in multiple system atrophy (MSA), Parkinson's disease (PD), and healthy controls. METHODS: We retrospectively included patients with MSA and PD as well as healthy controls. A DNP was trained on manual segmentations of the putamen as ground truth. For this, the cohort was randomly split into a training (N = 131) and test set (N = 120). The DNP's performance was compared with putaminal segmentations as derived by Automatic Anatomic Labelling, Freesurfer and Fastsurfer. For validation, we assessed the diagnostic accuracy of the resulting segmentations in the delineation of MSA vs. PD and healthy controls. RESULTS: A total of 251 subjects (61 patients with MSA, 158 patients with PD, and 32 healthy controls; mean age of 61.5 ± 8.8 years) were included. Compared to the dice-coefficient of the DNP (0.96), we noted significantly weaker performance for AAL3 (0.72; p < .001), Freesurfer (0.82; p < .001), and Fastsurfer (0.84, p < .001). This was corroborated by the superior diagnostic performance of MSA vs. PD and HC of the DNP (AUC 0.93) versus the AUC of 0.88 for AAL3 (p = 0.02), 0.86 for Freesurfer (p = 0.048), and 0.85 for Fastsurfer (p = 0.04). CONCLUSION: By utilization of a DNP, accurate segmentations of the putamen can be obtained even if substantial atrophy is present. This allows for more precise extraction of imaging parameters or shape features from the putamen in relevant patient cohorts. CLINICAL RELEVANCE STATEMENT: Deep learning-based segmentation of the putamen was superior to currently available algorithms and is beneficial for the diagnosis of multiple system atrophy. KEY POINTS: • A Deep Neural Patchwork precisely delineates the putamen and performs equal to human labeling in multiple system atrophy, even when pronounced putaminal volume loss is present. • The Deep Neural Patchwork-based segmentation was more capable to differentiate between multiple system atrophy and Parkinson's disease than the AAL3 atlas, Freesurfer, or Fastsurfer.

Characterization of the nigroestriatal system in a sample of patients with amyotrophic lateral sclerosis / Caracterização do sistema nigroestriatal em uma amostra de pacientes com esclerose lateral amiotrófica

Abstract Background The coexistence of amyotrophic lateral sclerosis (ALS) with clinical forms of Parkinson disease (PD), although uncommon, is found to a greater degree than one would expect by chance. The pathological mechanisms of ALS and PD are still not fully understood, and the coexistence of these two diseases suggests that they could share mechanisms in common. Objective Here we present a sample of patients with clinically definitive or probable ALS who were evaluated with single-photon emission computed tomography SPECT/TRODAT and compared with non-ALS controls. Methods Patients with clinically definite or probable ALS were assessed with the amyotrophic lateral sclerosis functional rating scale (ALSFRS) to define severity and had their demographic data collected. The TRODAT results of patients with ALS were compared with those of patients with a diagnosis of PD with less than 10 years of duration, and with patients with a diagnosis of others movement disorders not associated with neurodegenerative diseases. Results A total of 75% of patients with ALS had TRODAT results below the levels considered normal; that was also true for 25% of the patients in the control group without neurodegenerative disease, and for 100% of the patients in the PD group. A statistically significant difference was found between patients with ALS and the control group without neurodegenerative disease in the TRODAT values < 0.05. Conclusions Our study fits with the neuropathological and functional evidence that demonstrates the existence of nigrostriatal dysfunction in patients with ALS. Further research to better understand the role of these changes in the pathophysiological process of ALS needs to be performed.

Resumo Antecedentes A coexistência da esclerose lateral amiotrófica (ELA) com formas clínicas da doença de Parkinson (DP), embora incomum, é encontrada em um grau maior do que seria esperado ao acaso. Os mecanismos patológicos da ELA e da DP ainda não são totalmente compreendidos e a coexistência dessas duas doenças sugere que elas podem compartilhar mecanismos em comum. Objetivo Apresentamos uma amostra de pacientes com ELA clinicamente definida ou provável que foram avaliados com tomografia computadorizada por emissão de fóton único (SPECT)/TRODAT e comparados com controles sem ELA. Métodos Pacientes com ELA clinicamente definida ou provável foram avaliados com a escala funcional de esclerose lateral amiotrófica (ALSFRS) para definir a gravidade e foram coletados os seus dados demográficos. Os resultados do TRODAT de pacientes com ELA foram comparados com aqueles de pacientes com diagnóstico de DP com menos de 10 anos de duração e com pacientes com diagnóstico de outros distúrbios do movimento não associados a doenças neurodegenerativas. Resultados Um total de 75% dos pacientes com ELA apresentou resultados de TRODAT abaixo dos níveis considerados normais; 25% no grupo controle sem doença neurodegenerativa e 100% no grupo DP. Uma diferença estatisticamente significativa foi encontrada entre os pacientes com ELA e o grupo controle sem doença neurodegenerativa nos valores de TRODAT p< 0,05. Conclusões Nosso estudo está de acordo com as evidências neuropatológicas e funcionais que demonstram a existência de disfunção nigroestriatal em pacientes com ELA. Mais pesquisas para entender melhor o papel dessas mudanças no processo fisiopatológico da ELA precisam ser realizadas.

History of Ataxias and Paraplegias with an Annotation on the First Description of Striatonigral Degeneration.

The aim of this paper is to carry out a historical overview of the evolution of the knowledge on degenerative cerebellar disorders and hereditary spastic paraplegias, over the last century and a half. Original descriptions of the main pathological subtypes, including Friedreich's ataxia, hereditary spastic paraplegia, olivopontocerebellar atrophy and cortical cerebellar atrophy, are revised. Special attention is given to the first accurate description of striatonigral degeneration by Hans Joachim Scherer, his personal and scientific trajectory being clarified. Pathological classifications of ataxia are critically analysed. The current clinical-genetic classification of ataxia is updated by taking into account recent molecular discoveries. We conclude that there has been an enormous progress in the knowledge of the nosology of hereditary ataxias and paraplegias, currently encompassing around 200 genetic subtypes.

Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy.

Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are α-synuclein rich glial cytoplasmic inclusions (GCIs). Neuropathologically, various degrees of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) can be observed. Since the original descriptions of this multifaceted disorder, several steps forward have been made to clarify its neuropathological hallmarks and key pathophysiological mechanisms. The Austrian neuropathologist Kurt Jellinger substantially contributed to the understanding of the underlying neuropathology of this disease, to its standardized assessment and to a broad systematical clinic-pathological correlation. On the occasion of his 90th birthday, we reviewed the current state of the art in the field of MSA neuropathology, highlighting Prof. Jellinger's substantial contribution.

Expanding the spectrum of VAC14 related pediatric-onset neurological disease; striatonigral degeneration with brainstem involvement.

VAC14 related childhood-onset striatonigral degeneration was first defined in 2016 in two unrelated children with sudden onset neurological disease and regression of developmental milestones. Up to now, 11 cases have been reported. VAC14 is a component of a trimolecular complex that tightly regulates the level of phosphatidylinositol 3,5-bisphosphate (PI (3, 5)P2) and PI (3, 5)P2 is critical for the survival of neural cells. Pathogenic VAC14 variants result in striatonigral degeneration chacterised by prominent vacuolation of neurons in basal ganglia. Here, we present a patient with a homozygous pathogenic VAC14 variant, whose symptoms started at an early age and who had both basal ganglia and brain stem involvement. Our case is one of the youngest patients in literature and involvement of the brain stem is defined for the first time in VAC14 related neurological disease.

Longitudinal Change of DAT SPECT in Parkinson's Disease and Multiple System Atrophy.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorder affecting striatonigral system. Although various lines of evidence demonstrate that dopaminergic neuron degeneration emerges before the onset of motor symptoms in PD, preclinical/prodromal progression of neurodegeneration is far less understood in MSA. OBJECTIVE: The aim of this study was to clarify the difference in the progression of dopaminergic degeneration in MSA and PD using dopamine transporter single-photon emission computed tomography (DAT SPECT). METHODS: We analyzed longitudinal data of the specific binding ratio (SBR), a measure of striatal radiotracer uptake, in DAT SPECT from 7 patients with MSA-C, 5 patients with MSA-P, and 18 patients with PD. We performed 2.7±0.7 scans with an interval of 9.85±6.00 months for MSA and 2 scans with an interval of 2.16±0.16 years for PD. RESULTS: The rate of SBR decline was faster in both subtypes of MSA compared with PD, but the value was similar between MSA-P and MSA-C. The estimated SBR at the onset of initial motor symptoms was lower in PD and MSA-P than in MSA-C, especially in the predominantly affected side. SBR of the predominantly affected side starts to decrease before the onset of motor symptoms in PD and MSA-P, whereas the initiation of SBR decline is around the onset in MSA-C individuals. The decline of SBR in the less affected side was not clearly shown before the onset in MSA-P or MSA-C. CONCLUSIONS: Our results suggest that the SBR in DAT SPECT analysis is an important pathophysiological marker reflecting the disease- and subtype-specific progression of dopaminergic degeneration in MSA and PD.

Novel VAC14 variants identified in two Chinese siblings with childhood-onset striatonigral degeneration.

BACKGROUND: VAC14 is a component of a trimolecular complex that tightly regulates the level of phosphatidylinositol 3,5-bisphosphate [PI (3,5) P2]. VAC14 pathogenic variants cause prominent vacuolation of neurons in basal ganglia of patients with childhood-onset striatonigral degeneration (SNDC). METHODS: We identified two siblings with SNDC. Whole-exome sequencing was performed for genetic molecular analysis in these probands. RESULTS: The patients were compound heterozygotes for two novel variants in the VAC14 gene, p.Ala582Thr and p.Arg681His. The pathogenicity of these variants was indicated by a bioinformatic study and protein three-dimensional modeling. Eight previously reported SNDC cases and a Yunis-Varón syndrome caused by VAC14 mutations were summarized and compared. CONCLUSION: We present novel compound heterozygous variants (c.1744G>A/c.2042G>A) in our proband, and these novel variants were predicted to be likely pathogenic. The affected siblings were clinically severe and lethal; their phenotypes were similar to the majority of previously reported SNDC cases, with the exception of two cases that showed mild clinical manifestations. VAC14 pathogenic variants may be associated with various phenotypes. Herein, we report the Chinese siblings with SNDC, they are the first Asian cases. Our results expanded the spectrum of VAC14 pathogenic variants and the ethnic backgrounds of the affected cases.

Eye movement deficits in X-linked dystonia-parkinsonism are related to striatal degeneration.

BACKGROUND: X-linked dystonia-parkinsonism (XDP) is characterized by the unique transition of dystonia to parkinsonism and striatal degeneration. Slowing of saccades on clinical examination has been taken as suggestive of a progressive supranuclear palsy (PSP) phenotype. OBJECTIVES: To elucidate whether eye movement abnormalities in XDP patients reflect striatonigral impairment or deficits in the brainstem saccade generator as present in PSP. METHODS: Eye movements of 18 male XDP patients from the Philippines and 16 ethnically and age-matched, healthy control participants were analyzed and the results related to morphometric frontostriatal changes. RESULTS: There was moderate saccade hypometria in XDP but velocity of visually guided saccades was normal. XDP patients showed an increased antisaccade error rate which correlated with the reduction of (i) the volume of the pallidum and putamen as well as (ii) the volume and cortical thickness in dorsolateral prefrontal cortex. Amplitude of memory-guided saccades was smaller and latency prolonged. Horizontal smooth pursuit eye movements were impaired. CONCLUSIONS: Oculomotor abnormalities in XDP resemble those of patients with the Parkinsonian type of multiple system atrophy and - to a lesser degree - Parkinson's disease, but are not compatible with PSP. They indicate striatal impairment and may represent preclinical signs of the parkinsonian stage of XDP. The increasing failure of response inhibition in the antisaccade task with increasing striatal atrophy may indicate an endophenotype for striatal degeneration. Dorsolateral prefrontal degeneration can be inferred from the failure in initiating antisaccades, prolonged latency of memory-guided saccades and the reduction of dorsolateral prefrontal volume and cortical thickness.

Young-onset multiple system atrophy: Clinical and pathological features.

BACKGROUND: The onset of multiple system atrophy (MSA) before age 40 years is referred to as "young-onset MSA." We identified clinical and pathological characteristics that might help with its early diagnosis and distinction from young-onset Parkinson's disease and late-onset MSA. METHODS: We reviewed the available clinical and pathological features in cases that fulfilled consensus criteria for diagnosis of probable MSA or had autopsy confirmed MSA with an onset before age 40 years and compared the clinical features with 16 autopsy confirmed cases with young-onset Parkinson's disease and a large published series of late-onset MSA from the European MSA Study Group. RESULTS: We identified 22 patients with young-onset MSA, 8 of whom had available pathology. The mean age of onset was 36.7 years (standard deviation 2.3). Levodopa-induced dyskinesia was more common, whereas myoclonus and pyramidal signs were less common in young-onset Parkinson's disease when compared with young-onset MSA. Dystonia, levodopa responsiveness, levodopa-induced dyskinesia, and pyramidal signs were more common (P < .05) when compared with the data in late-onset MSA. On postmortem analysis, the minimal-change pathological variant was more common in young-onset MSA (n = 2) than late-onset MSA (P = .045), with a mean survival of 11.1 ± 3.2 years (range 5.5-14.6) in pathologically confirmed cases of young-onset MSA. CONCLUSION: This study has identified useful differences that may improve diagnostic accuracy, help us understand the pathological basis, and assist clinicians with the early diagnosis of young-onset MSA. © 2018 International Parkinson and Movement Disorder Society.

Spatial correlation and segregation of multimodal MRI abnormalities in multiple system atrophy.

OBJECTIVE: The variability of the severity and regional distribution of pathological process in basal ganglia (BG) and brainstem-cerebellar systems results in clinical heterogeneity and represents the motor subtype of multiple system atrophy (MSA). This study aimed to quantify spatial patterns of multimodal MRI abnormalities in BG and stem-CB regions and define structural MRI findings that correlate with clinical characteristics. METHODS: We simultaneously measured R2*, mean diffusivity (MD), and volume in the subcortical structures (BG, thalamus, brainstem-cerebellar regions) of 39 probable MSA and 22 control subjects. Principal component analysis (PCA) and structural equation modeling (SEM) were performed to show a model consisting of multiple inter-dependencies. RESULTS: Structural MRI alterations were found to be significantly interrelated within BG as well as brainstem-cerebellar regions in MSA patients. PCA extracted four factors: three factors reflected alterations in R2*, MD and volume of the BG region including the caudate nucleus, putamen, and pallidum, and the remaining one factor represented degenerative changes in MD and volume of stem-CB region. In SEM, a latent variable reflecting brainstem-cerebellar degeneration did not show a significant correlation with the other latent variables associated with BG degeneration. Putaminal MD values and a PCA-driven factor reflecting MD values in the BG showed a significant correlation with UPDRS and UMSARS scores. CONCLUSION: Multimodal structural MRI abnormalities in MSA appear to be segregated into BG and stem-CB-related factors that can be associated with the clinical phenotype and motor severity.

Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.

Study of dopamine-producing cells derived from human umbilical cord mesenchymal stem cells in treatment in rats with Parkinson’s disease / 天津医药

Objective To investigate the efficacy of dopamine producing cells (DPCs) derived from human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in treatment in model rats with Parkinson’s disease (PD). Methods The cultured hUC-MSCs were induced into DPCs in vitro. The dopamine (DA) and glial cell line-derived neurotrophic factor (GDNF) expression levels were detected by ELISA to identify the DPCs. The PD rat model was established by injecting 6-OHDA into the right substantia nigra (SN). A total of 60 successfulled PD model rats were randomized into hUC-MSCs-DPCs group (5 × 105 hUC-MSCs-DPCs were transplanted into right striatum, n=20), hUC-MSCs group (5 × 105 hUC-MSCs were transplanted, n=20) and control group (same volume PBS, n=20). All the transplanted cells were labeled with CM-Dil. The apomorphine induced rotation behavior was assessed at 4, 8 and 12 weeks after cell transplantation. The rats were executed after 12 weeks. The immunofluorescence staining was used to detect the tyrosine hydroxylase (TH) expression level, and FLUORO-JADE? C staining was used to test the apoptotic neurons in brain of rats. Results The hUC-MSCs-DPCs were induced successfully in vitro, which showed a high expression level of DA and GDNF. Furthermore, at 4, 8 and 12 weeks after cell transplantation, the rotation behavior was improved, and expression levels of GDNF were significantly higher in hUC-MSCs-DPCs group than those of hUC-MSCs group and control group (P<0.05). In addition, we found that most of the transplanted TH+hUC-MSCs-DPCs at the right striatum and a few cells around both the left and the right substantia nigra at 12 weeks after transplantation. The apoptotic neurons were decreased after cell transplantation in hUC-MSCs-DPCs group than that of control group (P<0.05). Conclusion The hUC-MSCs-DPCs can improve the rotational behavior induced by apomorphine in PD model rats, which may be involved in improving levels of DA and GDNF in damaged striatum and protecting neurons.

Augmented movement strategies for postural control in patients with spinocerebellar ataxia type 3: a case-control study / Estratégias aumentadas de movimento para controle postural em pacientes com ataxia espinocerebellar tipo 3: caso-controle

INTRODUCTION: This study investigated the movement strategies for postural control in patients with spinocerebellar ataxia type 3 (SCA3). METHODS: This case-control study enrolled 5 patients with SCA3 (aged 41 to 51 years) and 5 healthy participants group-matched by age, body mass and body height.Participants performed 3 trials lasting 30 s each of postural tasks characterized by: feet apart or together; eyes open or closed. Center of pressure (CoP) data was quantified using three-dimensional (3D: number of high-density and high-speed regions, average and maximal distances among regions), two-dimensional (2D: elliptical area, average velocity) and one-dimensional (1D: standard deviation, velocity) parameters. RESULTS: Analysis of variance revealed significant interaction effect between group*task for 1D (F12,238=3.496, p<0.001), 2D (F6,184=11.472, p<0.001), and 3D parameters (F12,238=2.543, p=0.004). Significant univariate effects for postural task were observed for all parameters, with higher body sway values under visual and biomechanical constraints, either separated or combined. CONCLUSIONS: Patients with SCA3 presented augmented movement strategiescompared with healthy subjects, characterized by increasing body sway under more demanding biomechanical and/ or visual constraints. Three-dimensional kinematic mapping revealed either random movement strategies or a unique movement strategy characterized by a stochastic CoP distribution, with high CoP speed to correct for large body sway deviations.

INTRODUÇÃO: Este estudo investigou as estratégias de movimento para controle postural em pacientes com ataxia espinocerebelar tipo 3 (SCA3). MÉTODOS: Este estudo de caso-controle incluiu cinco pacientes com SCA3 (idade 41 a 51 anos) e cinco participantes saudáveis, agrupados por idade, massa corporal e altura corporal. Os participantes realizaram três ensaios 30 s cada uma das tarefas posturais caracterizadas por: pés separados ou juntos; olhos abertos ou fechados. Os dados do centro de pressão (CoP) foram quantificados usando tridimensional (3D: número de alta densidade e alta velocidade regiões, distâncias médias e máximas entre regiões), bidimensional (2D: área elíptica, velocidade média) e unidimensional (1D: Desvio padrão, velocidade). RESULTADOS: Análise de variância Revelou um efeito de interação significativo entre a tarefa * grupo 1D (F12.238 = 3.496, p <0.001), 2D (F6.184 = 11.472, p <0.001) e os parâmetros 3D (F12,238 = 2,543, p = 0,004). Efeitos univariados significativos foram observados para todos os parâmetros, com maiores valores de balanço corporal sob restrições visuais e biomecânicas, separadas ou combinados. CONCLUSÕES: Os pacientes com SCA3 apresentaram estratégias de movimento comparadas com indivíduos saudáveis, aumentando o balanço do corpo sob condições biomecânicas e / ou restrições visuais. O mapeamento cinemático tridimensional revelou estratégias de movimento aleatório ou uma estratégia de movimento caracterizada por uma distribuição estocástica de CoP, com alta velocidade de correção para os grandes desvios.

Early Motor Fluctuations in a Patient with Striatonigral Degeneration.

We report a 44-year-old female with striatonigral degeneration (SND) who showed wearing-off oscillations after 4 months of levodopa treatment. The patient presented with asymmetric left-side dominant rigidity, and levodopa was effective at first. However, she began to show wearing-off oscillations of motor symptoms, which gradually worsened thereafter. Fluid-attenuated inversion recovery sequence magnetic resonance imaging (MRI) showed linear lateral putamen hyperintensities, and positron emission tomography (PET) studies using 18F-fluorodopa (FD) and 11C-N-methylspiperon (NMSP) showed a marked decrease of radioactivity in the right putamen, especially in the posterior putamen. The results of MRI and 2 PET studies with FD and NMSP were well consistent with the diagnosis of SND.

A rat model of striatonigral degeneration generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum.

A double toxin-double lesion strategy is well-known to generate a rat model of striatonigral degeneration (SND) such as multiple system atrophy-parkinsonian type. However, with this model it is difficult to distinguish SND from Parkinson's disease (PD). In this study, we propose a new rat model of SND, which is generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum. Stepping tests performed 30 min after intraperitoneal L-dopa administration at 6 weeks post-surgery revealed an L-dopa response in the PD group but not the SND group. Apomorphine-induced rotation tests revealed no rotational bias in the SND group, which persisted for 2 months, but contralateral rotations in the PD group. MicroPET scans revealed glucose hypometabolism and dopamine transporter impairment on the lesioned striatum in the SND group. Tyrosine hydroxylase immunostaining in the SND group revealed that 74.7% of nigral cells on the lesioned side were lost after lesion surgery. These results suggest that the proposed simultaneous double toxin-double lesion method successfully created a rat model of SND that had behavioral outcomes, multitracer microPET evaluation, and histological aspects consistent with SND pathology. This model will be useful for future study of SND.

Towards translational therapies for multiple system atrophy.

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiopathogenesis manifesting with autonomic failure, parkinsonism, and ataxia in any combination. The underlying neuropathology affects central autonomic, striatonigral and olivopontocerebellar pathways and it is associated with distinctive glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) that contain aggregates of α-synuclein. Current treatment options are very limited and mainly focused on symptomatic relief, whereas disease modifying options are lacking. Despite extensive testing, no neuroprotective drug treatment has been identified up to now; however, a neurorestorative approach utilizing autologous mesenchymal stem cells has shown remarkable beneficial effects in the cerebellar variant of MSA. Here, we review the progress made over the last decade in defining pathogenic targets in MSA and summarize insights gained from candidate disease-modifying interventions that have utilized a variety of well-established preclinical MSA models. We also discuss the current limitations that our field faces and suggest solutions for possible approaches in cause-directed therapies of MSA.

Accuracy of portable polygraphy for the diagnosis of sleep apnea in multiple system atrophy.

OBJECTIVE: To assess the diagnostic accuracy of portable polygraphy (PG) for the detection of sleep apnea (SA) in multiple system atrophy (MSA). METHODS: Thirty consecutive patients with probable MSA underwent PG (overnight recording of nasal flow, thoracic/abdominal movements and pulse oximetry), followed 4 weeks later by full polysomnography (PSG) (reference standard). The accuracy of PG was first assessed using the same threshold as for PSG (apnea-hypopnea index [AHI]≥5), then for all possible AHI thresholds using the area under the receiver operating characteristics (AUROC) curve. Inter-rater reliability of PG was assessed using the kappa coefficient. RESULTS: Among 30 patients enrolled, seven were excluded for technical problems on PG or PSG and 23 were included in the main analysis. Eight out of 23 had an AHI≥5 on PSG. With the same threshold, sensitivity, specificity, positive and negative predictive values of PG for the diagnosis of SA were 87.5% (95% confidence interval: 47-99), 80% (52-96), 70% (35-93) and 92.3% (64-99), respectively. The kappa between PG raters was 0.75 (0.49-1.00) indicating good agreement. The AUROC was 0.93 (0.82-1.00). No association was found between sleep and excessive daytime sleepiness questionnaires and SA. CONCLUSION: Portable PG seems to be valuable for ruling out SA in MSA.

Baseline [(123) I]FP-CIT SPECT (DaTSCAN) severity correlates with medication use at 3 years in Parkinson's disease.

BACKGROUND: Presynaptic dopaminergic deficiency on dopamine transporter imaging supports a clinical diagnosis of Parkinson's disease and correlates with the severity of rigidity and bradykinesia. Baseline dopaminergic deficiency predicts clinical severity, but the relationship with subsequent medication use has not been reported. METHODS: A randomly selected cross section of 83 Parkinson's disease (PD) patients who had [(123) I] FP-CIT SPECT at the time of clinical diagnosis was identified. Dopaminergic deficiency was graded 1, 2 or 3 with increasing severity using visual assessment and by semiquantitative analysis of putamen and caudate uptake. Antiparkinson medication usage and clinical severity by Hoehn and Yahr were noted annually to 3 years. RESULTS: In 83 patients (66% male, median age 65.0 years, IQ 55.4-71.8), [(123) I]FP-CIT SPECT was grade 1 in 20 (24%), grade 2 in 53 (64%) and grade 3 in 10 patients (12%). Dopamine transporter uptake ratios were inversely associated with antiparkinson medication usage (r = -0.26, P = 0.0201) and Hoehn Yahr stage (r = -0.32, P = 0.0029) at 3 years from baseline, but there was considerable variation in drug usage in individual patients. At 3 years, patients with grade 1 scans at baseline received a median dose of 325 levodopa equivalent units (LEU) (interquartile range 175-433); grade 2 scan patients 400 LEU (interquartile range 300-635); and grade 3 scan patients 460 LEU (interquartile range 252-658). CONCLUSION: The degree of reduction in presynaptic dopaminergic uptake at baseline is associated with higher antiparkinson drug dosage at follow-up, but the wide variation means that the baseline FP-CIT SPECT does not reliably predict drug use in individual cases.

A Rat Model of Striatonigral Degeneration Generated by Simultaneous Injection of 6-Hydroxydopamine into the Medial Forebrain Bundle and Quinolinic Acid into the Striatum

A double toxin-double lesion strategy is well-known to generate a rat model of striatonigral degeneration (SND) such as multiple system atrophy-parkinsonian type. However, with this model it is difficult to distinguish SND from Parkinson's disease (PD). In this study, we propose a new rat model of SND, which is generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum. Stepping tests performed 30 min after intraperitoneal L-dopa administration at 6 weeks post-surgery revealed an L-dopa response in the PD group but not the SND group. Apomorphine-induced rotation tests revealed no rotational bias in the SND group, which persisted for 2 months, but contralateral rotations in the PD group. MicroPET scans revealed glucose hypometabolism and dopamine transporter impairment on the lesioned striatum in the SND group. Tyrosine hydroxylase immunostaining in the SND group revealed that 74.7% of nigral cells on the lesioned side were lost after lesion surgery. These results suggest that the proposed simultaneous double toxin-double lesion method successfully created a rat model of SND that had behavioral outcomes, multitracer microPET evaluation, and histological aspects consistent with SND pathology. This model will be useful for future study of SND.