Striatal and thalamic automatic segmentation, morphology, and clinical correlates in Parkinsonism: Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) present similarly with bradykinesia, tremor, rigidity, and cognitive impairments. Neuroimaging studies have found differential changes in the nigrostriatal pathway in these disorders, however whether the volume and shape of specific regions within this pathway can distinguish between atypical Parkinsonian disorders remains to be determined. This paper investigates striatal and thalamic volume and morphology as distinguishing biomarkers, and their relationship to neuropsychiatric symptoms. Automatic segmentation to calculate volume and shape analysis of the caudate nucleus, putamen, and thalamus were performed in 18 PD patients, 12 MSA, 15 PSP, and 20 healthy controls, then correlated with clinical measures. PSP bilateral thalami and right putamen were significantly smaller than controls, but not MSA or PD. The left caudate and putamen significantly correlated with the Neuropsychiatric Inventory total score. Bilateral thalamus, caudate, and left putamen had significantly different morphology between groups, driven by differences between PSP and healthy controls. This study demonstrated that PSP patient striatal and thalamic volume and shape are significantly different when compared with controls. Parkinsonian disorders could not be differentiated on volumetry or morphology, however there are trends for volumetric and morphological changes associated with PD, MSA, and PSP.

Neurological update: non-motor symptoms in atypical parkinsonian syndromes.

Among people with Parkinson's disease (PD), non-motor symptoms (NMS) are a well-recognised cause of significant morbidity and poor quality of life. Yet, it is only more recently that NMS have been recognised to affect the lives of patients with atypical parkinsonian syndromes in a similar fashion. The aim of this article is to highlight and compare the relative prevalence of NMS among patients with atypical parkinsonian syndromes in the published literature, which largely remain underreported and unaddressed in routine clinical practice. All NMS that are recognised to occur in PD are also found to commonly occur in atypical parkinsonian syndromes. In particular, excessive daytime sleepiness is more prevalent among atypical parkinsonian syndromes (94.3%) compared to PD (33.9%) or normal controls (10.5%) (p < 0.001). Urinary dysfunction (not limited to urinary incontinence) is not only found to occur in MSA (79.7%) and PD (79.9%), but has also been reported in nearly half of the patients with PSP (49.3%), DLB (42%) and CBD (53.8%) (p < 0.001). Apathy is significantly more common among the atypical parkinsonian syndromes [PSP (56%), MSA (48%), DLB (44%), CBD (43%)] compared to PD (35%) (p = 0.029). Early recognition and addressing of NMS among atypical parkinsonian syndromes may help improve the holistic patient care provided and may encompass a range of conservative and pharmacotherapeutic treatments to address these symptoms.

Exploring the mechanism of astragalus membranaceus in the treatment of multiple system atrophy based on network pharmacology and molecular docking.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease, it causes functional degradation of multiple organs and systems throughout the body. Astragalus membranaceus (AM), a well-known traditional Chinese medicine, has been used to improve muscle wasting-related disorders for a long history. In this study, we used network pharmacology and molecular docking to predict the mechanism underlying AM for the treatment of MSA. We screened the active compounds of AM and its related targets, as well as the target proteins of MSA. We made a Venn diagram to obtain the intersecting targets and then constructed a protein-protein interaction network to find the core targets and build an active ingredient-target network map. After subjecting the intersecting targets to gene ontology and Kyoto encyclopedia of genes and genomes analysis, the binding ability of core compounds and core target proteins were validated by molecular docking. A total of 20 eligible compounds and 274 intersecting targets were obtained. The core components of treatment are quercetin, kaempferol, and isorhamnetin, and the core targets are TP53, RELA, and TNF. The main biological processes are related to cellular responses and regulation. Molecular functions are mainly associated with apoptosis, inflammation, and tumorigenesis. Molecular docking results show good and standard binding abilities. This study illustrates that AM treats MSA through multiple targets and pathways, and provides a reference for subsequent research.

Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation.

Mitochondrial dysfunction has been implicated in the pathogenesis of a number of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, and progressive supranuclear palsy. This article is concerned specifically with mitochondrial dysfunction as defined by reduced capacity for ATP production, the role of depleted levels of key nutritionally related metabolites, and the potential benefit of supplementation with specific nutrients of relevance to normal mitochondrial function in the above neurodegenerative disorders. The article provides a rationale for a combination of CoQ10, B-vitamins/NADH, L-carnitine, vitamin D, and alpha-lipoic acid for the treatment of the above neurodegenerative disorders.

Implanted System for Orthostatic Hypotension in Multiple-System Atrophy.

Orthostatic hypotension is a cardinal feature of multiple-system atrophy. The upright posture provokes syncopal episodes that prevent patients from standing and walking for more than brief periods. We implanted a system to restore regulation of blood pressure and enable a patient with multiple-system atrophy to stand and walk after having lost these abilities because of orthostatic hypotension. This system involved epidural electrical stimulation delivered over the thoracic spinal cord with accelerometers that detected changes in body position. (Funded by the Defitech Foundation.).

Diffusion microstructure imaging in progressive supranuclear palsy: reduced axonal volumes in the superior cerebellar peduncles, dentato-rubro-thalamic tracts, ventromedial thalami, and frontomesial white matter.

Differentiating between Parkinson's disease (PD) and atypical Parkinson syndromes such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration is challenging. Diffusion microstructure imaging (DMI) was analyzed in patients with clinically suspected atypical Parkinson syndromes and healthy controls. In an exploration cohort, the spatial distribution of PSP-related changes of DMI parameters were evaluated in a voxel-wise analysis and a region-of-interest (ROI)-based approach was established. The diagnostic performance was subsequently tested in an independent validation cohort. In the exploration cohort, 53 PSP patients were compared to a pooled comparison group of 19 patients with PD, 26 patients with MSA, 7 patients with corticobasal syndrome, and 25 healthy controls. PSP patients showed widespread axonal loss in the superior cerebellar peduncles, the dentato-rubro-thalamic tracts, the thalami and the frontal white matter (each P < 0.001). In the validation cohort consisting of 12 patients with PSP vs. 13 patients with other movement disorders, the accuracy of this ROI-based approach for identifying the PSP was highest in the thalamus and the frontal white matter (accuracy 0.96 each). This DMI approach can identify PSP patients on an individual level in a collective with suspected atypical Parkinson syndromes and allows further insight on microstructural alterations in vivo.

Scrambler Therapy for the Treatment of Multiple System Atrophy-Parkinsonian Subtype Pain: A Case Report.

The management of pain in patients with multiple system atrophy (MSA) is often inadequate, and treatments commonly result in adverse effects. A 63-year-old man with the parkinsonian subtype of MSA presented with bilateral neck, shoulder, upper extremity, lower extremity, and low back pain of 6 years' duration. His baseline pain was 5 of 10 with flares to 10 of 10. After 4 35-minute scrambler therapy (ST) treatments, his pain was reduced to 0 of 10. His pain relief after 4 ST sessions lasted for 6 weeks. No complications or adverse effects occurred. ST deserves further study for patients with atypical parkinsonism.

Phytochemicals as Regulators of Genes Involved in Synucleinopathies.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein aggregates in neurons, nerve fibers or glial cells. Three main types of diseases belong to the synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. All of them develop as a result of an interplay of genetic and environmental factors. Emerging evidence suggests that epigenetic mechanisms play an essential role in the development of synucleinopathies. Since there is no disease-modifying treatment for these disorders at this time, interest is growing in plant-derived chemicals as a potential treatment option. Phytochemicals are substances of plant origin that possess biological activity, which might have effects on human health. Phytochemicals with neuroprotective activity target different elements in pathogenic pathways due to their antioxidants, anti-inflammatory, and antiapoptotic properties, and ability to reduce cellular stress. Multiple recent studies demonstrate that the beneficial effects of phytochemicals may be explained by their ability to modulate the expression of genes implicated in synucleinopathies and other diseases. These substances may regulate transcription directly via transcription factors (TFs) or play the role of epigenetic regulators through their effect on histone modification, DNA methylation, and RNA-based mechanisms. Here, we summarize new data about the impact of phytochemicals on the pathogenesis of synucleinopathies through regulation of gene expression.

Quantitative Cellular Changes in the Thalamus of Patients with Multiple System Atrophy.

The thalamus is a brain region consisting of anatomical and functional connections between various spinal, subcortical, and cortical regions, which has a putative role in the clinical manifestation of Multiple System Atrophy (MSA). Previous stereological studies have reported significant anatomical alterations in diverse brain regions of MSA patients, including the cerebral cortex, basal ganglia and white matter, but no quantitative studies have examined the thalamus. To establish the extent of thalamic involvement, we applied stereological methods to estimate the total number of neurons and glial cells (oligodendrocytes, astrocytes and microglia) as well as the volume in two thalamic sub-regions, the mediodorsal nucleus (MDT) and the anterior principal nucleus (APn), in brains from ten MSA patients and 11 healthy control subjects. Compared to healthy controls, MSA patients had significantly fewer neurons (26%) in the MDT, but not the APn. We also found significantly more astrocytes (32%) and microglia (54%) in the MDT, with no such changes in the APn. Finally, we saw no group differences in the total number of oligodendrocytes. Our findings show a region-specific loss of thalamic neurons that occurs without loss of oligodendrocytes, whereas thalamic microgliosis seems to occur alongside astrogliosis. These pathological changes in the thalamus may contribute to the cognitive impairment seen in most patients with MSA.

Thalamic and cerebellar hypoperfusion in single photon emission computed tomography may differentiate multiple system atrophy and progressive supranuclear palsy.

Neuroimaging in the context of examining atypical parkinsonian tauopathies is an evolving matter. Positron emission tomography and single photon emission computed tomography (SPECT) bring tools, which may be reasonable in supplementary examination, however, cannot be interpreted as a criterion standard for correct diagnosis. The aim of this observational study was to assess the differentiating potential of perfusion SPECT in 3 types of atypical parkinsonisms: multiple system atrophy parkinsonian type (MSA-P), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). The study was carried out using the comparison of standard deviations of perfusion in patients from these 3 groups. Data obtained from 10 patients with clinical diagnosis MSA-P, 14 patients with CBS and 21 patients with PSP, which were analyzed using Tukey honest significant difference post-hoc test, revealed significant differences of perfusion P < .05 between MSA-P and PSP within the cerebellum and thalamus. No significant differences between CBS and PSP were observed.

Exploring the frequency and clinical background of the "zebra sign" in amyotrophic lateral sclerosis and multiple system atrophy.

In amyotrophic lateral sclerosis (ALS), the "zebra sign" in the precentral gyrus on phase difference enhanced magnetic resonance imaging (PADRE) recently has been reported as a possible imaging biomarker for upper motor neuron (UMN) involvement. A previous study has shown that the "zebra sign" allowed us to differentiate patients with ALS from healthy subjects with excellent accuracy. We validated the usefulness of the sign for differentiating patients with ALS from healthy subjects and investigated whether the "zebra sign" can be observed other neurodegenerative disorders with UMN involvement. The "zebra sign" on PADRE was assessed in 26 patients with ALS, 26 with multiple system atrophy (MSA) and 26 healthy controls, and the sign was observed in 50%, 23%, and no subjects, respectively. ALS patients with the "zebra sign" demonstrated a higher UMN burden score than those without the sign. The "zebra sign" on PADRE is not specific to ALS, also present in MSA, but might reflect the degeneration of the UMN within the motor cortex in neurodegenerative disorders.

The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy.

Multiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. We previously reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10, are associated with MSA. Here, we report functional deficiencies in mitochondrial respiration and the antioxidative system in induced pluripotent stem cell (iPSC)-derived neurons from an MSA patient with compound heterozygous COQ2 mutations. The functional deficiencies were rescued by site-specific CRISPR/Cas9-mediated gene corrections. We also report an increase in apoptosis of iPSC-derived neurons from MSA patients. Coenzyme Q10 reduced apoptosis of neurons from the MSA patient with compound heterozygous COQ2 mutations. Our results reveal that cellular dysfunctions attributable to decreased coenzyme Q10 levels are related to neuronal death in MSA, particularly in patients with COQ2 variants, and may contribute to the development of therapy using coenzyme Q10 supplementation.

Extending the range of differential diagnosis of chronic traumatic encephalopathy of the boxer: Insights from a case report / Ampliando a gama de diagnósticos diferencias da encefalopatia traumática crônica do pugilista: um relato de caso ilustrativo

ABSTRACT Sports activities associated with repetitive cranial trauma have become a fad and are popular in gyms and even among children. It is important to consistently characterize the consequences of such sports activities in order to better advise society on the real risks to the central nervous system. We present the case of a former boxer reporting cognitive and behavioral symptoms that began six years after his retirement as a boxer, evolving progressively with parkinsonian and cerebellar features suggestive of probable chronic traumatic encephalopathy (CTE). Using our case as a paradigm, we extended the range of differential diagnosis of CTE, including corticobasal degeneration, multiple system atrophy, vitamin B12 deficiency, neurosyphilis, frontotemporal dementia and Alzheimer's disease.

RESUMO As atividades esportivas associadas ao trauma craniano repetitivo tornaram-se uma moda e são populares nas academias e entre as crianças. É importante fazer uma caracterização consistente das consequências de tais atividades esportivas, a fim de aconselhar melhor uma sociedade sobre os riscos reais para o sistema nervoso central. Apresentamos um antigo boxeador relatando sintomas cognitivos e comportamentais que começaram seis anos após sua aposentadoria como boxeador e evoluiu progressivamente com características parkinsonianas e cerebelares sugestivas de provável encefalopatia traumática crônica (ETC). Usando nosso caso como paradigma, ampliamos a gama de diagnóstico diferencial de ETC, incluindo degeneração corticobasal, atrofia de múltiplos sistemas, deficiência de vitamina B12, neurossífilis, demência frontotemporal e doença de Alzheimer.

Coenzyme Q10 Supplementation in Orthostatic Hypotension and Multiple-System Atrophy: A Report on 7 Cases.

BACKGROUND: Multiple-system atrophy is a neurologic disorder characterized by orthostatic hypotension, Parkinsonian signs, and cerebellar signs. Mutations in COQ2, an enzyme involved in coenzyme Q10 synthesis, were recently associated with familial and sporadic cases of multiple-system atrophy. I hypothesized that people with orthostatic hypotension with or without other symptoms of multiple-system atrophy might benefit from oral coenzyme Q10 administration. METHODS: Seven patients with symptomatic orthostatic hypotension were treated in an unrandomized manner with 257 ± 37 mg coenzyme Q10 daily for 10 ± 3 months. RESULTS: Before starting coenzyme Q10, patients' systolic blood pressure fell 30 ± 4 mm Hg upon standing from a sitting position. After treatment with coenzyme Q10, their systolic blood pressure decreased 7 ± 5 mm Hg upon standing from a sitting position (P = .007 for change in systolic blood pressure decrease by paired t test). CONCLUSIONS: These data suggest that orthostatic hypotension could improve with coenzyme Q10 administration and that a randomized clinical trial to test this hypothesis should be begun.

Three-Year Follow-Up of High-Dose Ubiquinol Supplementation in a Case of Familial Multiple System Atrophy with Compound Heterozygous COQ2 Mutations.

We report a 3-year follow-up of high-dose ubiquinol supplementation in a case of familial multiple system atrophy (MSA) with compound heterozygous nonsense (R387X) and missense (V393A) mutations in COQ2. A high-dose ubiquinol supplementation substantially increased total coenzyme Q10 levels in cerebrospinal fluid as well as in plasma. The patient was at the advanced stage of MSA, and the various scores of clinical rating scales remained stable without changes during the 3 years. The cerebral metabolic ratio of oxygen measured by 15O2 PET, however, increased by approximately 30% after administration of ubiquinol, suggesting that ubiquinol can improve mitochondrial oxidative metabolism in the brain. It also suggests the therapeutic potential of ubiquinol for patients with MSA with COQ2 mutations. Further clinical trials of administration of high-dose ubiquinol to MSA patients are warranted.

Plasma Coenzyme Q10 Levels in Patients With Multiple System Atrophy.

IMPORTANCE: Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA. OBJECTIVE: To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls. DESIGN, SETTING, AND PARTICIPANTS: We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level. MAIN OUTCOMES AND MEASURES: Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype. RESULTS: Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] µg/mL; P = .01) (difference between medians: -0.14; 95% CI, -0.25 to -0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) µg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02). CONCLUSIONS AND RELEVANCE: Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

Decreased Coenzyme Q10 Levels in Multiple System Atrophy Cerebellum.

In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.

Strand-specific RNA-sequencing analysis of multiple system atrophy brain transcriptome.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease. The major pathological hallmark of MSA is the accumulation of α-synuclein in oligodendrocytes. In contrast to Parkinson's disease no definitive familial etiology for MSA has been determined. Yet, there is a growing body of evidence that perturbation of transcriptional processes leads to MSA pathology. Here we present the results of the first ribosomal-depleted strand-specific RNA-sequencing profile of the MSA brain frontal cortex tissue. Among the 123 differentially expressed genes over 50% were categorized as putative long intervening non-coding RNAs (lincRNAs). Along with the dysregulation of the non-coding portion of the transcriptome, the expression of protein coding genes was also affected, including serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 (SERPINA3), interleukin 1 receptor-like 1 (IL1RL1) and hemoglobin, beta (HBB). Also of interest was the alternative splicing of SNCA, along with the presence of an antisense transcript overlapping the 3' exon of SNCA. Moreover, we demonstrate widespread antisense transcription throughout the frontal cortex that is largely not affected by MSA-specific neurodegenerative process. MSA causes a large disruption of lincRNAs in the human brain along with protein coding genes related to iron metabolism and immune response regulation. Most of the lincRNAs specific for MSA were novel. Hence our study uncovers another level of complexity in transcriptional pathology of MSA.

The PROMESA-protocol: progression rate of multiple system atrophy under EGCG supplementation as anti-aggregation-approach.

Formation of toxic α-synuclein oligomers appears to be a key underlying pathological mechanism of synucleinopathies such as Parkinson's disease or multiple system atrophy (MSA). Given that Epigallocatechin-gallate has been shown to inhibit α-synuclein aggregation, it might represent a causal treatment option. Therefore, we set out to evaluate the safety, tolerability and a potential disease-modifying effect of Epigallocatechin-gallate in patients with MSA after 48 weeks of treatment. Power calculation was performed on existing natural history data on the progression of the Unified MSA Rating Scale as primary readout parameter. To assess the efficacy of Epigallocatechin-gallate versus placebo regarding the reduction of disease progression measured during the study period (80 % power, 5 % p level, 50 % effect size) 36 patients per group are needed. Considering a drop-out rate of 20 % a total of 86 patients will be recruited in this multicentre study. These data provide a solid rationale to investigate whether supplementation of Epigallocatechin-gallate can delay the progression of the MSA-related disability.