Correlations between serotonin impairments and clinical indices in multiple system atrophy.

BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) is a neurodegenerative disease with characteristic motor and autonomic symptoms. Impaired brain serotonergic innervation can be associated with various clinical indices of MSA; however, the relationship between clinical symptoms and cerebrospinal fluid (CSF) levels of 5-hydroxyindole acetic acid (5-HIAA), a main serotonin metabolite, has not been fully elucidated. METHODS: To compare CSF 5-HIAA levels between patients with MSA and healthy controls, we included 33 controls and 69 MSA patients with either predominant parkinsonian or cerebellar ataxia subtypes. CSF 5-HIAA levels were measured using high-performance liquid chromatography. Additionally, we investigated correlations between CSF 5-HIAA and various clinical indices in 34 MSA patients. RESULTS: CSF 5-HIAA levels were significantly lower in MSA patients than in controls (p < 0.0001). Probable MSA patients had lower CSF 5-HIAA levels than possible MSA patients (p < 0.001). In MSA patients, CSF 5-HIAA levels were inversely correlated with scores in Parts 1, 2, and 4 of the Unified Multiple System Atrophy Rating Scale, and with systolic and diastolic blood pressure in Part 3. Structural equation modeling revealed significant paths between serotonin and clinical symptoms, and significance was highest for activities of daily living, walking, and body sway. CONCLUSIONS: Serotonin dysfunction, as assessed by CSF 5-HIAA levels, may implicate greater MSA severity.

Molecular aggregation in liquid-crystalline layers crucially affects their physics: smectic A (SmA)-nematic (N) phase transition.

Recently, two molecular packing modes of the alkyl chain in smectic A (SmA) liquid crystal phases were revealed: normal and tilted types, which are named by the orientation relative to the layer normal. This study reveals the relationship between the packing mode and thermodynamic order of the SmA-nematic (N) phase transition. Two normal type and three tilted type mesogens were subject to thermodynamic and structural experiments. The DSC results showed that the SmA-N phase transitions of the normal and tilted types are of the second and first order, respectively. The analysis of the intensities of reflections in wide-angle X-ray diffraction related to the periodicity of the SmA layer yielded the distribution of the mass centers of molecules along the normal to the SmA layers. The resultant distribution offered a rationale for the correlation of the thermodynamic order of the SmA-N phase transition and molecular packing modes in the SmA phases based on the Meyer-Lubensky theory.

Molecular dynamics and kinetics of isothermal cold crystallization with tunable dimensionality in a molecular glass former, 5'-(2,3-difluorophenyl)-2'-ethoxy-4-pentyloxy-2,3-difluorotolane.

This paper characterizes the molecular mobility that triggers the cold crystallization abilities in 5'-(2,3-difluorophenyl)-2'-ethoxy-4-pentyloxy-2,3-difluorotolane (short name DFP25DFT) material by broadband dielectric spectroscopy (BDS). We analyze the properties of identified molecular motions by referring to the Vogel-Fulcher-Tammann (VFT) model for the structural α-process associated with molecular rotation in isotropic liquid and the Eyring and Starkweather approach for the thermally activated processes, ß-process related to intramolecular movement in liquid and glassy state and emerging during cold crystallization α'-process ascribed to confined movements of molecules located adjacent to crystalline surfaces. To characterize the material, we employ single-crystal X-ray diffraction, differential scanning calorimetry (DSC), adiabatic calorimetry, and polarizing optical microscopy (POM), while we utilize molecular mechanics simulations (MM2) to explore molecular flexibility. Our study focuses on inter- and intramolecular interactions that determine the cold-crystallization tendency. We demonstrate that the solidification path is controlled by the fragility of the system, the dipole-dipole attraction, and the intramolecular dynamics. The study of cold crystallization kinetics under isothermal conditions reveals the complexity of the process: the formation of two crystalline phases, Cr2 and Cr3, proceeding in different modes. This feature discloses the possibility of switching the crystal growth between three- and two-dimensional in the cold-crystallization process driven by different mechanisms.

Alterations in Cognition-Related Cerebello-Cerebral Networks in Multiple System Atrophy.

We aimed to elucidate the effect of cerebellar degeneration in relation to cognition in multiple system atrophy (MSA). Thirty-two patients diagnosed with probable MSA and 32 age- and gender-matched healthy controls (HCs) were enrolled. We conducted voxel-based morphometry (VBM) for anatomical images and independent component analysis (ICA), dual-regression analysis, and seed-based analysis for functional images with voxel-wise gray matter correction. In the MSA group, a widespread cerebellar volume loss was observed. ICA and dual-regression analysis showed lower functional connectivity (FC) in the left executive control and salience networks in regions located in the cerebellum. Seed-based analysis using the identified cerebellar regions as seeds showed extensive disruptions in cerebello-cerebral networks. Global cognitive scores correlated with the FC values between the right lobules VI/crus I and the medial prefrontal/anterior cingulate cortices and between the same region and the amygdala/parahippocampal gyrus. Our study indicates that cerebellar degeneration in MSA causes segregation of cerebellar-cerebral networks. Furthermore, the cognitive deficits in MSA may be driven by decreased cerebello-prefrontal and cerebello-amygdaloid functional connections.

Structural MRI correlates of amyotrophic lateral sclerosis progression.

PURPOSE: Amyotrophic lateral sclerosis (ALS) presents with varying degrees of brain degeneration that can extend beyond the corticospinal tract (CST). Furthermore, the clinical course and progression of ALS varies widely. Brain degeneration detected using structural MRI could reflect disease progression. SUBJECTS AND METHODS: On study registration, 3-Tesla volumetric MRI and diffusion tensor imaging scans were obtained at baseline in 38 healthy controls and 67 patients with sporadic ALS. Patients had Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores of ≥36 and did not have the chromosome 9, open reading frame 72 repeat expansion. Six months later, changes in ALSFRS-R (ΔALSFRS-R) scores were calculated and patients were grouped into three categories, namely, patients with slow progression with ΔALSFRS-R scores ≤3 (n=19), intermediate progression with ΔALSFRS-R scores =4, 5 and 6 (n=36) and rapid progression with ΔALSFRS-R scores ≥7 (n=12). We analysed voxel-based morphometry and tract-based spatial statistics among these subgroups and controls. RESULTS: In comparison with controls, patients with ALS showed grey matter atrophy and decreased fractional anisotropy beyond the motor cortex and CST, especially in the frontotemporal lobes and basal ganglia. Moreover, the degree of change was highly proportional to ΔALSFRS-R at the 6-month assessment. CONCLUSION: A more rapid disease progression and poorer functional decline were associated with greater involvement of the extra-motor cortex and basal ganglia, suggesting that the spatial extent of brain involvement can be an indicator of the progression in ALS.

Early detection of speech and voice disorders in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation: a 1-year follow-up study.

We previously reported that Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) had distinct phenotypes of speech and voice disorders: hypokinetic dysarthria, stuttering, breathy voice, strained voice, and spastic dysarthria. However, changes over time remain unclear. In the present study, 32 consecutive PD patients were assessed before and up to 1 year after surgery (PD-DBS). Eleven medically treated PD patients were also assessed (PD-Med). Speech, voice, motor, and cognitive functions were evaluated. At baseline, the incidence of hypokinetic dysarthria (63% of PD-DBS vs. 82% of PD-Med), stuttering (50% vs. 45%), breathy voice (66% vs. 73%), and strained voice (3% vs. 9%) was similar between groups. At 1 year, a slight but significant deterioration in speech intelligibility (p < 0.001) and grade of dysphonia (p = 0.001) were observed only in PD-DBS group compared with baseline. During the follow-up, stuttering (9% vs. 18%) and breathy voice (13% vs. 9%) emerged in PD-DBS and PD-Med, but strained voice (28%) and spastic dysarthria (44%) emerged only in PD-DBS. After the stimulation was stopped, strained voice and spastic dysarthria improved in most patients, while stuttering and breathy voice improved in a minority of patients. These findings indicate that the most common DBS-induced speech and voice disorders are strained voice and spastic dysarthria and that STN-DBS potentially aggravates stuttering and breathy voice. An improved understanding of these types of disorders may help detect speech and voice deteriorations during the early phase and lead to appropriate treatments.

A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN.

OBJECTIVE: To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. METHODS: We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. RESULTS: We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34×10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10(-10)-1.1×10(-7)). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). CONCLUSIONS: We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.

Active brain changes after initiating fingolimod therapy in multiple sclerosis patients using individual voxel-based analyses for diffusion tensor imaging.

Voxel-based analysis (VBA) of diffusion tensor images (DTI) and voxel-based morphometry (VBM) in patients with multiple sclerosis (MS) can sensitively detect occult tissue damage that underlies pathological changes in the brain. In the present study, both at the start of fingolimod and post-four months clinical remission, we assessed four patients with MS who were evaluated with VBA of DTI, VBM, and fluid-attenuated inversion recovery (FLAIR). DTI images for all four patients showed widespread areas of increased mean diffusivity (MD) and decreased fractional anisotropy (FA) that were beyond the high-intensity signal areas across images. After four months of continuous fingolimod therapy, DTI abnormalities progressed; in particular, MD was significantly increased, while brain volume and high-intensity signals were unchanged. These findings suggest that VBA of DTI (e.g., MD) may help assess MS demyelination as neuroinflammatory conditions, even though clinical manifestations of MS appear to be in complete remission during fingolimod.

Distinct phenotypes of speech and voice disorders in Parkinson's disease after subthalamic nucleus deep brain stimulation.

OBJECTIVES: To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinson's disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: We conducted a cross-sectional study on 76 PD patients treated with bilateral STN-DBS (PD-DBS) and 33 medically treated PD patients (PD-Med). Speech and voice functions, electrode positions, motor function and cognitive function were comprehensively assessed. Moreover, speech and voice functions were compared between the on-stimulation and off-stimulation conditions in 42 PD-DBS patients. RESULTS: Speech and voice disorders in PD-DBS patients were significantly worse than those in PD-Med patients. Factor analysis and subsequent cluster analysis classified PD-DBS patients into five clusters: relatively good speech and voice function type, 25%; stuttering type, 24%; breathy voice type, 16%; strained voice type, 18%; and spastic dysarthria type, 17%. STN-DBS ameliorated voice tremor or low volume; however, it deteriorated the overall speech intelligibility in most patients. Breathy voice did not show significant changes and stuttering exhibited slight improvement after stopping stimulation. In contrast, patients with strained voice type or spastic dysarthria type showed a greater improvement after stopping stimulation. Spastic dysarthria type patients showed speech disorders similar to spastic dysarthria, which is associated with bilateral upper motor neuron involvement. Strained voice type and spastic dysarthria type appeared to be related to current diffusion to the corticobulbar fibres. CONCLUSIONS: Stuttering and breathy voice can be aggravated by STN-DBS, but are mainly due to aging or PD itself. Strained voice and spastic dysarthria are considered corticobulbar side effects.

Characteristic laryngoscopic findings in Parkinson's disease patients after subthalamic nucleus deep brain stimulation and its correlation with voice disorder.

Speech and voice disorders are one of the most common adverse effects in Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). However, the pathophysiology of voice and laryngeal dysfunction after STN-DBS remains unclear. We assessed 47 PD patients (22 treated with bilateral STN-DBS (PD-DBS) and 25 treated medically (PD-Med); all patients in both groups matched by age, sex, disease duration, and motor and cognitive function) using the objective and subjective voice assessment batteries (GRBAS scale and Voice Handicap Index), and laryngoscopy. Laryngoscopic examinations revealed that PD-DBS patients showed a significantly higher incidence of incomplete glottal closure (77 vs 48 %; p = 0.039), hyperadduction of the false vocal folds (73 vs 44 %; p = 0.047), anteroposterior hypercompression (50 vs 20 %; p = 0.030) and asymmetrical glottal movement (50 vs 16 %; p = 0.002) than PD-Med patients. On- and off-stimulation assessment revealed that STN-DBS could induce or aggravate incomplete glottal closure, hyperadduction of the false vocal folds, anteroposterior hypercompression, and asymmetrical glottal movement. Incomplete glottal closure and hyperadduction of the false vocal folds significantly correlated with breathiness and strained voice, respectively (r = 0.590 and 0.539). We should adjust patients' DBS settings in consideration of voice and laryngeal functions as well as motor function.

Comfort with motherhood in late pregnancy facilitates maternal role attainment in early postpartum.

Quality of life, comfort, and wellbeing during pregnancy are essential for every country in the world. Pregnancy is considered a preparation period for becoming a mother. Maternal role development, including confidence and satisfaction as a mother, is important in the transition to motherhood. Negative psychosocial affect, such as increased anxiety and distress, during pregnancy adversely influences the childbirth experience and childcare, which contributes to postpartum depression. However, the impact of positive feelings on the maternal role development remains unclear. Therefore, the study purpose was to clarify the relationship between comfort in late pregnancy and maternal role attainment and childcare during early postpartum. We designed a descriptive, longitudinal, correlational study by using the Prenatal Comfort Scale, the Postpartum Maternal Role Confidence Scale, and the Postpartum Maternal Satisfaction Scale. Among 339 participants who had received care at a university hospital located in Sendai city in Japan, 215 subjects completed the longitudinal study by answering a questionnaire for the respective Scale late in their pregnancy or during early postpartum. The subjects consisted of 114 primipara (32.0 ± 5.4 years) and 101 multipara (33.4 ± 4.9 years). In primipara, comfort with motherhood was significantly correlated with maternal confidence regarding knowledge and childcare skills and maternal satisfaction. In multipara, comfort in late pregnancy was related to maternal confidence and satisfaction. Positive affect was related to maternal confidence and maternal satisfaction in early postpartum. Therefore, a prenatal nursing intervention helps women become more comfortable with impending motherhood, thereby promoting maternal role attainment after delivery.

Neck weakness is a potent prognostic factor in sporadic amyotrophic lateral sclerosis patients.

OBJECTIVE: To clarify the emergence of muscle weakness in regions of the body that affect survival, and deterioration in activities of daily living (ADL) in amyotrophic lateral sclerosis (ALS) patients. METHODS: We conducted a multicentre-based prospective cohort study of patients with ALS. We enrolled 401 sporadic patients with ALS. Death or the introduction of invasive ventilation was defined as the primary endpoint, and the time to five clinical markers of ADL deterioration associated with bulbar paralysis or limb weakness were defined as ADL milestones. Muscle weakness was assessed in the neck flexor muscles; the bilateral abductors of the shoulders; the bilateral wrist extensor muscles; the bilateral flexor muscles of the hips; and the bilateral ankle dorsiflexion muscles. We performed Cox proportional hazards regression analyses for the primary endpoint and the five ADL milestones, adjusting for known covariate prognostic factors for ALS. RESULTS: The Medical Research Council (MRC) score for the neck flexors was the most significant prognostic factor for the primary endpoint (HR 0.74, p<0.001), loss of speech (HR 0.66, p<0.001), and loss of swallowing function (HR 0.73, p<0.001), and was one of the significant prognostic factors for loss of upper limb function, difficulty turning in bed, and loss of walking ability (p=0.001, 0.002, and 0.008, respectively). The MRC score for the neck flexors was also a significant prognostic factor for covariates of the previously reported prognostic factors. CONCLUSIONS: Neck weakness is an independent prognostic factor for survival and deterioration in ADL in Patients with ALS.

Cortical and subcortical brain atrophy in Parkinson's disease with visual hallucination.

BACKGROUND: The aim of this study was to investigate the cortical and subcortical brain structures in Parkinson's disease (PD) with visual hallucination (VH), and to elucidate the association between the proposed hypothesis of VH in PD and regional brain volume changes. METHODS: We used 3T magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to investigate the brain structures of PD patients with VH (PD-VH; n = 13) and PD patients without VH (PD-C; n = 13). RESULTS: The PD-VH patients showed significant cortical atrophy compared to the PD-C patients in the bilateral dorsolateral prefrontal cortex, left rostral region of the prefrontal cortex, left ventral section of the cingulate cortex, bilateral primary visual cortex, and secondary visual cortex including the left inferior occipital gyrus, right lingual cortex, right supramarginal gyrus, and left fusiform gyrus. Significant subcortical atrophic changes were observed in the white matter of the right parahippocampal gyrus, the bilateral posterior part of the cingulate gyrus, the left lingual gyrus, and the right middle occipital gyrus. CONCLUSIONS: VH in PD can occur due to distinctive neuroanatomical involvement.

[Limitations of the Second Consensus Statement on the Diagnosis of Multiple System Atrophy].

The Second Consensus Statement on the Diagnosis of Multiple System Atrophy (MSA), issued in 2008, has unified the concept of MSA and significantly advanced clinical and drug discovery research. However, subsequent developments in research have revealed several critical findings that would affect the diagnostic sensitivity, specificity, and positive predictive value of the consensus statement. In this review, we discuss the limitations of diagnostic sensitivity for early diagnosis; positioning of orthostatic hypotension; diagnostic categories; exclusion criteria such as elderly onset, family history, and dementia; differentiation from progressive supranuclear palsy; and imaging findings of the Second Consensus Statement.

Multiple System Atrophy: Advances in Diagnosis and Therapy.

This review summarizes improvements in understanding the pathophysiology and early clinical symptoms of multiple system atrophy (MSA) and advancements in diagnostic methods and disease-modifying therapies for the condition. In 2022, the Movement Disorder Society proposed new diagnostic criteria to develop disease-modifying therapies and promote clinical trials of MSA since the second consensus was proposed in 2008. Regarding pathogenesis, cutting-edge findings have accumulated on the interactions of α-synuclein, neuroinflammation, and oligodendroglia with neurons. In neuroimaging, introducing artificial intelligence, machine learning, and deep learning has notably improved diagnostic accuracy and individual analyses. Advancements in treatment have also been achieved, including immunotherapy therapy against α-synuclein and serotonin-targeted and mesenchymal stem cell therapies, which are thought to affect several aspects of the disease, including neuroinflammation. The accelerated progress in clarifying the pathogenesis of MSA over the past few years and the development of diagnostic techniques for detecting early-stage MSA are expected to facilitate the development of disease-modifying therapies for one of the most intractable neurodegenerative diseases.

Long-term response to immunotherapy in patients with hypertrophic pachymeningitis.

Objective: In this study, we aimed to clarify the relationship between initial treatment response, prednisolone (PSL) dosage, clinical type, and recurrence in patients with hypertrophic pachymeningitis (HP). Methods: The study cohort comprised eight patients with HP who had been admitted to our hospital from April 2015 to June 2020. Diagnostic criteria for HP included neurological abnormalities and dural thickening on magnetic resonance gadolinium-enhanced T1-weighted images. Results: Relevant characteristics of the eight study patients are as follows. There were two men and six women. The average age at onset was 58.3 (range: 29-79) years. Three of them had myeloperoxidase-antineutrophil cytoplasmic antibody-related vasculitis, one immunoglobulin G4-related disease, and one ulcerative colitis. The remaining three patients had idiopathic HP. The average maximum dosage of PSL was 0.79 mg/kg/day, and the average daily maintenance dosage 0.18 mg/kg/day. Three patients needed additional immunosuppressive drugs. Both idiopathic and secondary HP initially responded well to PSL, with improvement in activities of daily living. Six patients had some sequelae related to cranial nerve involvement. No relapses occurred while the patients were taking moderate doses of PSL; however, all patients with idiopathic HP had recurrences when their PSL dosage was reduced. Conclusions: Patients with idiopathic HP and HP associated with immune disorders respond to steroids and immunosuppressive drugs and recover well. However, there is a high rate of relapse after reduction of PSL dosage, mainly in those with idiopathic HP.

Associations of Alzheimer's-related plasma biomarkers with cognitive decline in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with cognitive decline through multiple mechanisms, including Alzheimer's disease (AD) pathology and cortical Lewy body involvement. However, its underlying mechanisms remain unclear. Recently, AD-related plasma biomarkers have emerged as potential tools for predicting abnormal pathological protein accumulation. We aimed to investigate the association between AD-related plasma biomarkers and cognitive decline in PD patients. METHODS: Plasma biomarkers were measured in 70 PD patients (49 with nondemented Parkinson's disease (PDND) and 21 with Parkinson's disease dementia (PDD)) and 38 healthy controls (HCs) using a single-molecule array. The study evaluated (1) the correlation between plasma biomarkers and clinical parameters, (2) receiver operating characteristic curves and areas under the curve to evaluate the discrimination capacity of plasma biomarkers among groups, and (3) a generalized linear model to analyze associations with Addenbrooke's Cognitive Examination-Revised and Montreal Cognitive Assessment-Japanese version scores. RESULTS: Plasma glial fibrillary acidic protein significantly correlated with cognitive function tests, including all subdomains, with a notable increase in the PDD group compared with the HC and PDND groups, while plasma neurofilament light chain captured both cognitive decline and disease severity in the PDND and PDD groups. Plasma beta-amyloid 42/40 and pholphorylated-tau181 indicated AD pathology in the PDD group, but plasma beta-amyloid 42/40 was increased in the PDND group compared with HCs and decreased in the PDD group compared with the PDND group. CONCLUSIONS: AD-related plasma biomarkers may predict cognitive decline in PD and uncover underlying mechanisms suggesting astrocytic pathologies related to cognitive decline in PD.

Enzymatic properties and clinical associations of serum alpha-galactosidase A in Parkinson's disease.

OBJECTIVE: Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha-galactosidase A (GLA) and compared them with the clinical parameters of PD. METHODS: The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km ) and maximal velocity (Vmax ) by Lineweaver-Burk plot analysis. Serum GLA protein concentration was measured by enzyme-linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. RESULTS: Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent Vmax (P = 0.0131), but no change in the apparent Km value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery. INTERPRETATION: This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity.

Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy.

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.

[Long COVID: Pathogenesis and Therapeutic Approach].

A group of patients with coronavirus disease 2019 (COVID-19) exhibited various persistent or new systemic symptoms, including psychiatric symptoms, sleep disturbances, exercise intolerance, arthralgia, headache, cognitive decline, brain fog, and autonomic symptoms, all of which persisted long after the resolution of infectious symptoms. Several imaging studies have shown that long COVID cases present with decreased glucose metabolism and progressive brain atrophy. Although no single pathological hypothesis thoroughly explains the varied clinical presentations and timings, the following have attracted attention: 1) persistent viral infection, 2) persistent inflammation, 3) involvement of the autoimmune system, and 4) mitochondrial dysfunction. In all these hypotheses, inflammatory cytokines may be involved in orthostatic dysregulation by decreasing the expression and activity of ACE2, consequently changing the blood pressure through vagus nerve hyperactivation. Myopathy and peripheral neuropathy may also be caused by direct infection of the muscles and nerves, hypoxia, mitochondrial damage, and cytokine storm. Furthermore, multiple theories regarding the mechanisms by which systemic inflammatory findings affect the central nervous system have been postulated, including neuroinflammation caused by inflammatory cells crossing the blood-brain barrier via choroid plexus cells and the involvement of various autoantibodies. Despite these findings, no definitive consensus has been reached due to the complexity and diversity of COVID-19 pathophysiology. Thus, it is essential to understand the neurological symptoms and pathophysiology involved in long COVID.