Reliability and consistency of the Japanese version of the Primary Lateral Sclerosis Functional Rating Scale.

BACKGROUND: Primary lateral sclerosis (PLS) is an extremely rare condition; therefore, to date no clinical studies have been conducted. The Primary Lateral Sclerosis Functional Rating Scale (PLSFRS) was developed in the United States of America. The PLSFRS is a crucial assessment scale for international collaborative research and future clinical trials for PLS. It is useful for evaluating medical conditions through face-to-face assessments and telephone interviews such as when a face-to-face assessment is not possible due to disasters or the burden of hospital visits. This study assessed the reliability and consistency of in-person and telephone interviews using the Japanese version of the PLSFRS. METHODS: We enrolled 19 Japanese patients who met the specific criteria for inclusion at the six collaborating institutions. The PLSFRS assessments were performed by two evaluators at defined time points and analyzed for intra-rater and inter-rater reliability and consistency between the in-person and telephone interviews. RESULTS: The Japanese version of the PLSFRS was developed by a specialized company and translator, and modified to consider the Japanese lifestyle through a consensus among motor neuron specialists. The quadratic-weighted kappa coefficients for the intra-rater and the inter-rater agreement were substantial (intra-rater: 0.691-1.000, inter-rater: 0.634-1.000). Moreover, the intraclass correlation coefficient for the PLSFRS total score was 0.997 (95% confidence interval, 0.992-0.999). CONCLUSIONS: This study provides results regarding the Japanese version of the PLSFRS intra-rater and inter-rater reliability and consistency between in-person and telephone interviews.

Primary cauda equina lymphoma confirmed by autopsy: A case report.

Compared with those involving the central nervous system, lymphomas involving the peripheral nervous system, namely neurolymphomatosis, are extremely rare. Neurolymphomatosis is classified as primary or secondary; the former is much rarer than the latter. Herein, we present an autopsied case of primary cauda equina lymphoma (PCEL), a type of primary neurolymphomatosis, with a literature review of autopsied cases of PCEL as well as primary neurolymphomatosis other than PCEL (non-PCEL primary neurolymphomatosis). A 70-year-old woman presented with difficulty walking, followed by paraplegia and then bladder and bowel disturbance. On magnetic resonance imaging, the cauda equina was diffusely enlarged and enhanced with gadolinium. The brainstem and cerebellum were also enhanced with gadolinium along their surface. The differential diagnosis of the patient included meningeal tumors (other than lymphomas), lymphomas, or sarcoidosis. The biopsy of the cauda equina was planned for a definite diagnosis, but because the patient deteriorated so rapidly, it was not performed. Eventually, she was affected by cranial nerve palsies. With the definite diagnosis being undetermined, the patient died approximately 1.5 years after the onset of disesase. At autopsy, the cauda equina was replaced by a bulky mass composed of atypical B-lymphoid cells, consistent with diffuse large B-cell lymphoma (DLBCL). The spinal cord was heavily infiltrated, as were the spinal/cranial nerves and subarachnoid space. There was metastasis in the left adrenal. The patient was finally diagnosed postmortem as PCEL with a DLBCL phenotype. To date, there have been a limited number of autopsied cases of PCEL and non-PCEL primary neurolymphomatosis (nine cases in all, including ours). The diagnosis is, without exception, B-cell lymphoma including DLBCL, and the histology features central nervous system parenchymal infiltration, nerve root involvement, and subarachnoid dissemination (lymphomatous meningitis). Metastases are not uncommon. All clinicians and pathologists should be aware of lymphomas primarily involving the peripheral nervous system.

The predominance of "astrocytic" intranuclear inclusions in neuronal intranuclear inclusion disease manifesting encephalopathy-like symptoms: A case series with brain biopsy.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder represented by eosinophilic intranuclear inclusions (EIIs) and GGC/CGG repeat expansion in the NOTCH2NLC gene. We report here two adult cases of NIID, genetically confirmed, with manifestation of encephalopathy-like symptoms and address the histopathologic findings obtained by brain biopsies, with a focus on "astrocytic" intranuclear inclusions (AIIs). Case 1 presented with paroxysmal restlessness, vertigo, or fever and was later involved in severe dementia and tetraparesis. Case 2 presented with forgetfulness and then with paroxysmal fever and headache. In both cases, delimited areas with gadolinium enhancement on magnetic resonance imaging and corresponding hyperperfusion were detected, leading to brain biopsies of the cortex. On histology, Case 1 showed an abnormal lamination, where the thickness of layers was different from usual. Both neurons and astrocytes showed some dysmorphologic features. Notably, astrocytes rather than neurons harbored EIIs. Case 2 showed a cortex, where neurons tended to be arrayed in a columnar fashion. Astrocytes showed some dysmorphologic features. Notably, much more astrocytes than neurons harbored EIIs. By a double-labeling immunofluorescence study for p62/NeuN and p62/glial fibrillary acidic protein, the predominance of AIIs was confirmed in both cases. Considering the physiological functions of astrocytes for the development and maintenance of the cortex, the encephalopathy-like symptoms, dynamic change of cerebral blood flow, and cortical dysmorphology can reasonably be explained by the dysfunction of EII-bearing astrocytes rather than EII-bearing neurons. This study suggests the presence of a subtype of NIID where AIIs rather than "neuronal" intranuclear inclusions are likely a key player in the pathogenesis of NIID, particularly in cases with encephalopathy-like symptoms. The importance of AIIs ("gliopathy") should be more appreciated in future studies of NIID.

Mouse Model of Parkinson's Disease with Bilateral Dorsal Striatum Lesion with 6-Hydroxydopamine Exhibits Cognitive Apathy-like Behavior.

Among the symptoms of Parkinson's disease (PD), apathy comprises a set of behavioral, affective, and cognitive features that can be classified into several subtypes. However, the pathophysiology and brain regions that are involved in these different apathy subtypes are still poorly characterized. We examined which subtype of apathy is elicited in a mouse model of PD with 6-hydroxydopamine (6-OHDA) lesions and the behavioral symptoms that are exhibited. Male C57/BL6J mice were allocated to sham (n = 8) and 6-OHDA (n = 13) groups and locally injected with saline or 4 µg 6-OHDA bilaterally in the dorsal striatum. We then conducted motor performance tests and apathy-related behavioral experiments. We then pathologically evaluated tyrosine hydroxylase (TH) immunostaining. The 6-OHDA group exhibited significant impairments in motor function. In the behavioral tests of apathy, significant differences were observed between the sham and 6-OHDA groups in the hole-board test and novelty-suppressed feeding test. The 6-OHDA group exhibited impairments in inanimate novel object preference, whereas social preference was maintained in the three-chamber test. The number of TH+ pixels in the caudate putamen and substantia nigra compacta was significantly reduced in the 6-OHDA group. The present mouse model of PD predominantly showed dorsal striatum dopaminergic neuronal loss and a decrease in novelty seeking as a symptom that is related to the cognitive apathy component.

Neuropathological features of adult-onset neuronal intranuclear inclusion disease with fluid-attenuated inversion recovery high-intensity signals in the cerebellar paravermal area from an early stage: A case report.

Neuronal intranuclear inclusion disease (NIID) is a neurological disorder characterized by eosinophilic intranuclear inclusions (INI) in systemic organs and various cell types. High-intensity signals along the corticomedullary junction on diffusion-weighted imaging and presence of cellular p62-INI in skin biopsy are known indicators for NIID. Furthermore, GGC repeat expansion in NOTCH2NLC is a characteristic genetic alteration in patients with NIID. This report presents the clinical and detailed pathological features of a male older adult with NIID. We also confirmed the presence of fluid-attenuated inversion recovery high-intensity signals in the cerebellar paravermal area, showing similar pathological changes in high-intensity signals along the corticomedullary junction on diffusion-weighted imaging.

Expanding on the professional role of dental hygienists as key managers of medical-dental and hospital-dental clinic collaboration in a local Japanese hospital without a dentistry department: From a questionnaire survey after a web seminar.

INTRODUCTION: Perioperative oral management (POM) was introduced into the Japanese universal health insurance system in 2012. Collaboration with dental clinics is important for hospitals without a dentistry department. A dental hygienist newly assigned as a member of the patient flow management centre led a seminar to promote collaboration via the web. This study represents the first step to explore the possible role of the hospital-based dental hygienist in the field of regional medical-dental cooperation of POM by assessing their willingness to participate in providing this type of care by a survey. METHODS: The rate of attendees' satisfaction and the current problems of the collaboration for POM were evaluated through a questionnaire survey after the web seminar. RESULTS: All respondents reported satisfaction with the web seminar although it was the first experience of an online seminar for half of the respondents. All hospital dentists, but only 47.8% of dentists working at clinics, had participated in POM. Dental hygienist tended to show greater desire to participate in POM than dentists. All respondents appreciated the role played by the dental hygienist as a key manager of medical-dental collaboration between the hospital and local clinics. CONCLUSION: The hospital-based dental hygienist can play a role in planning and management of web seminars for POM, to raise awareness and promote regional medical-dental cooperation of POM.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

The difference in the diaphragmatic physiological measures between inspiratory and expiratory phases in ALS.

INTRODUCTION: We aimed to clarify the differences in static and dynamic diaphragm parameters between the expiratory and inspiratory phases in amyotrophic lateral sclerosis (ALS). METHODS: Twenty patients with early-stage ALS and 16 healthy controls were enrolled in the study. We measured the amplitudes of compound muscle action potential (phCMAP) by electrical stimulation of the phrenic nerve and the zone of apposition wall thickness of the diaphragm (DT) using ultrasonography. We analyzed the differences in phCMAP (∆phCMAP) and DT (∆DT) between the end-inspiratory and end-expiratory phases and their correlation with forced vital capacity (FVC). RESULTS: The ΔphCMAP (mean 129.7 ± SD 204.7 µV) and ∆DT (0.80 ± 0.88 cm) in patients were significantly smaller than those in controls (348.6 ± 247.7 µV, p = 0.0003 and 1.89 ± 1.10 cm, p = 0.0002, respectively). Although ∆DT was significantly correlated with FVC, we found no correlation between ∆phCMAP and FVC. The phCMAP was paradoxically smaller during inspiration than during expiration in 35% of patients but in none of the controls. CONCLUSION: Dynamic parameters of the diaphragm were abnormal in early-stage ALS. The paradoxical reduction in phCMAP during inspiration may reflect early respiratory dysfunction. Assessment of dynamic abnormalities of the diaphragm may provide helpful information for respiratory management in patients with ALS.

Tufted astrocyte-like glia in two autopsy cases of multiple system atrophy: Is it a concomitant neurodegenerative disorder with multiple system atrophy and progressive supranuclear palsy?

Tufted astrocytes are one of the core histopathological features of progressive supranuclear palsy (PSP). To our knowledge, only three cases of multiple system atrophy (MSA) with PSP pathology have been reported. Here, we report two autopsy cases of MSA associated with the appearance of tufted astrocyte-like glia (TuALG). Clinically, the patients' symptoms were atypical of MSA; one showed vertical gaze palsy, and the other was a long-term survivor who progressed to a bedridden state shortly after the onset of the disease. These neuropathological observations were characterized by the copresence of MSA-specific changes and TuALG in some of the cerebral cortices but few or none of the other PSP tau pathologies. These cases might emphasize the significance of TuALG in non-PSP neurodegenerative disorders.

Therapeutic Effects of Quetiapine and 5-HT1A Receptor Agonism on Hyperactivity in Dopamine-Deficient Mice.

Some diseases that are associated with dopamine deficiency are accompanied by psychiatric symptoms, including Parkinson's disease. However, the mechanism by which this occurs has not been clarified. Previous studies found that dopamine-deficient (DD) mice exhibited hyperactivity in a novel environment. This hyperactivity is improved by clozapine and donepezil, which are used to treat psychiatric symptoms associated with dopamine deficiency (PSDD). We considered that DD mice could be used to study PSDD. In the present study, we sought to identify the pharmacological mechanism of PSDD. We conducted locomotor activity tests by administering quetiapine and drugs that have specific actions on serotonin (5-hydroxytryptamine [5-HT]) receptors and muscarinic receptors. Changes in neuronal activity that were induced by drug administration in DD mice were evaluated by examining Fos immunoreactivity. Quetiapine suppressed hyperactivity in DD mice while the 5-HT1A receptor antagonist WAY100635 inhibited this effect. The number of Fos-positive neurons in the median raphe nucleus increased in DD mice that exhibited hyperactivity and was decreased by treatment with quetiapine and 5-HT1A receptor agonists. In conclusion, hyperactivity in DD mice was ameliorated by quetiapine, likely through 5-HT1A receptor activation. These findings suggest that 5-HT1A receptors may play a role in PSDD, and 5-HT1A receptor-targeting drugs may help improve PSDD.

Effects of Edaravone on Nitric Oxide, Hydroxyl Radicals and Neuronal Nitric Oxide Synthase During Cerebral Ischemia and Reperfusion in Mice.

BACKGROUND: The purpose of this study was to investigate the effects of edaravone on nitric oxide (NO) production, hydroxyl radical (OH-) metabolism, and neuronal nitric oxide synthase (nNOS) expression during cerebral ischemia and reperfusion. METHODS: Edaravone (3 mg/kg) was administered intravenously to 14 C57BL/6 mice just before reperfusion. Eleven additional mice received saline (controls). NO production and OH- metabolism were continuously monitored using bilateral striatal in vivo microdialysis. OH- formation was monitored using the salicylate trapping method. Forebrain ischemia was produced in all mice by bilateral occlusion of the common carotid artery for 10 minutes. Levels of NO metabolites, nitrite (NO2-) and nitrate (NO3-), were determined using the Griess reaction. Brain sections were immunostained with an anti-nNOS antibody and the fractional area density of nNOS-immunoreactive pixels to total pixels determined. RESULTS: Blood pressure and regional cerebral blood flow were not significantly different between the edaravone and control groups. The levels of NO2- did not differ significantly between the 2 groups. The level of NO3- was significantly higher in the edaravone group compared with the control group after reperfusion. 2,3-dihydroxybenzoic acid levels were lower in the edaravone group compared with those in the control group after reperfusion. Immunohistochemistry showed nNOS expression in the edaravone group to be significantly lower than that in the control group 96 hours after reperfusion. CONCLUSIONS: These in vivo data indicate that edaravone may have a neuroprotective effect by reducing levels of OH- metabolites, increasing NO production and decreasing nNOS expression in brain cells.

Effect of the Hybrid Assistive Limb on the Gait Pattern for Cerebral Palsy.

Background and objectives: Cerebral palsy (CP) is the most frequent childhood motor disability. Achieving ambulation or standing in children with CP has been a major goal of physical therapy. Recently, robot-assisted gait training using the Hybrid Assistive Limb® (HAL) has been effective in improving walking ability in patients with CP. However, previous studies have not examined in detail the changes in gait pattern after HAL training for patients with spastic CP, including gait symmetry. This study aimed to evaluate the immediate effect of HAL training on the walking ability and the changes in gait pattern and gait symmetry in patients with spastic CP. Materials and Methods: We recruited 19 patients with spastic CP (13 male and six female; mean age, 15.7 years). Functional ambulation was assessed using the 10-Meter Walk Test and gait analysis in the sagittal plane before and after a single 20-min HAL intervention session. Results: The walking speed and stride length significantly increased after HAL intervention compared to the pre-intervention values. Two-dimensional gait analysis showed improvement in equinus gait, increase in the flexion angle of the swing phase in the knee and hip joints, and improvement in gait symmetry. Immediate improvements in the walking ability and gait pattern were noted after HAL training in patients with spastic CP. Conclusions: The symmetry of the joint angle of the lower limb, including the trunk, accounts for the improvement in walking ability after HAL therapy.

Effect of Yokukansan on Nitric Oxide Production and Hydroxyl Radical Metabolism During Cerebral Ischemia and Reperfusion in Mice.

BACKGROUND: The purpose of this study was to investigate the effects of yokukansan on forebrain ischemia. Because we can measure nitric oxide production and hydroxyl radical metabolism continuously, we investigated the effect of yokukansan on nitric oxide production and hydroxyl radical metabolism in cerebral ischemia and reperfusion. METHODS: Yokukansan (300 mg per kg per day) was mixed into feed and given to 16 mice for 10days. Sixteen additional mice received normal feed (control). Nitric oxide production and hydroxyl radical metabolism were continuously monitored using the salicylate trapping method. Forebrain ischemia was producedin all mice by occluding the common carotid artery bilaterally for 10minutes. Levels of the nitric oxide metabolites nitrite and nitrate were determined using the Griess reaction. Survival rates of hippocampal CA1 neurons were calculated and 8-hydroxydeoxyguanosine-immunopositive cells were counted to evaluate the oxidative stress in hippocampal CA1 neurons 72hours after the start of reperfusion. RESULTS: Arterial blood pressure and regional cerebral blood flow were not significantly different between the 2 groups. The level of nitrate was significantly higher in the yokukansan group than in the control group during ischemia and reperfusion. Levels of 2,3- and 2,5-dihydroxybenzoic acid were significantly lower in the yokukansan group than in the control group during ischemia and reperfusion. Although survival rates in the CA1 did not differ significantly, there were fewer 8-hydroxydeoxyguanosine-immunopositive cells in animals that had received yokukansan than in control animals. CONCLUSIONS: These data suggest that yokukansan exerts reducing hydroxyl radicals in cerebral ischemic injury.

Effects of Memantine on Nitric Oxide Production and Hydroxyl Radical Metabolism during Cerebral Ischemia and Reperfusion in Mice.

BACKGROUND: The purpose of this study was to investigate the effects of memantine on brain ischemia. Because we can measure nitric oxide (NO) production and hydroxyl radical metabolism continuously, we investigated the effect of memantine on NO production and hydroxyl radical metabolism in cerebral ischemia and reperfusion. METHODS: Memantine (25 µmol/kg) was administered intraperitoneally to 6 C57BL/6 mice 30 minutes before ischemia. Seven additional mice received no injection (controls). NO production and hydroxyl radical metabolism were continuously monitored using bilateral striatal microdialysis in vivo. Hydroxyl radical formation was monitored using the salicylate trapping method. Forebrain ischemia was produced in all mice by occluding the common carotid artery bilaterally for 10 minutes. Levels of the NO metabolites nitrite (NO2-) and nitrate (NO3-) were determined using the Griess reaction. Survival rates of hippocampal CA1 neurons were calculated and 8-hydroxydeoxyguanosine (8-OHdG)-immunopositive cells were counted to evaluate the oxidative stress in hippocampal CA1 neurons 72 hours after the start of reperfusion. RESULTS: The regional cerebral blood flow was significantly higher in the memantine group than in the control group after reperfusion. Furthermore, the level of 2,3-dihydroxybenzoic acid was significantly lower in the memantine group than in the control group during ischemia and reperfusion. Levels of NO2- and NO3- did not differ significantly between the 2 groups. Although survival rates in the CA1 did not differ significantly, there were fewer 8-OHdG-immunopositive cells in animals that had received memantine than in control animals. CONCLUSIONS: These data suggest that memantine exerts partially neuroprotective effects against cerebral ischemic injury.

Safety and immediate effect of gait training using a Hybrid Assistive Limb in patients with cerebral palsy.

[Purpose] This study aimed to determine the safety and immediate effect of a single training session with the Hybrid Assistive Limb (CYBERDYNE) on walking ability in patients with cerebral palsy. [Participants and Methods] This study included 20 patients with cerebral palsy (15 males, 5 females, mean age 15.0 ± 6.3 years; 19 with spastic cerebral palsy, 1 with athetoid cerebral palsy; Gross Motor Function Classification System level I: 4, II: 3, III: 9, and IV: 4). Participants completed a single 20-minute gait training session using the Hybrid Assistive Limb. The safety and immediate effect were evaluated. The immediate outcomes were gait speed and mean step length, and cadence before and after training. [Results] Two participants were excluded because they were not tall enough to use the Hybrid Assistive Limb. Eighteen participants performed the training. There were no serious adverse events during the training. Since 14 participants were able to walk on their own, walking evaluations were performed before and after training. Statistically significant improvements were observed in gait speed and mean step length. [Conclusion] Gait training using the Hybrid Assistive Limb is safe for patients with cerebral palsy and can produce immediate effects on walking ability in ambulatory patients with cerebral palsy.

Immediate effects of a single session of robot-assisted gait training using Hybrid Assistive Limb (HAL) for cerebral palsy.

[Purpose] Robot-assisted gait training (RAGT) using Hybrid Assistive Limb (HAL, CYBERDYNE) was previously reported beneficial for stroke and spinal cord injury patients. Here, we investigate the immediate effect of a single session of RAGT using HAL on gait function for cerebral palsy (CP) patients. [Subjects and Methods] Twelve patients (average age: 16.2 ± 7.3 years) with CP received a single session of RAGT using HAL. Gait speed, step length, cadence, single-leg support per gait cycle, hip and knee joint angle in stance, and swing phase per gait cycle were assessed before, during, and immediately after HAL intervention. [Results] Compared to baseline values, single-leg support per gait cycle (64.5 ± 15.8% to 69.3 ± 12.1%), hip extension angle in mid-stance (149.2 ± 19.0° to 155.5 ± 20.1°), and knee extension angle in mid-stance (137.6 ± 20.2° to 143.1 ± 19.5°) were significantly increased immediately after intervention. Further, the knee flexion angle in mid-swing was significantly decreased immediately after treatment (112.0 ± 15.5° to 105.2 ± 17.1°). Hip flexion angle in mid-swing also decreased following intervention (137.2 ± 14.6° to 129.7 ± 16.6°), but not significantly. Conversely, gait speed, step length, and cadence were unchanged after intervention. [Conclusion] A single-time RAGT with HAL improved single-leg support per gait cycle and hip and knee joint angle during gait, therapeutically improving gait function in CP patients.

The therapy of the motor symptoms in the advanced stage of Parkinson's disease.

This review focuses on the medical treatment strategies for the advanced stages of Parkinson disease (PD), according to the therapeutic guideline for PD by the committee of Japanese Society of Neurology in 2011. Levodopa still remains the gold standard for the treatment of motor symptoms of PD in advanced stage, but dopamine agonists, monoamine oxidase B inhibitors and catechol-O-methyltransferase inhibitors have--also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to prevent and improve levodopa-induced motor complications, including wearing off phenomenon and peak-dose dyskinesia. A number of non-dopaminergic receptors are expressed on different parts of the basal ganglia motor circuits and have become targets of PD drug development. Zonisamide, which has multimodal effects on the dopaminergic and non-dopaminergic systems, and istradefylline, the first adenosine A2A antagonist, have shown positive evidence for improved motor fluctuations.

Medial temporal regional argyrophilic grain as a possible important factor affecting dementia in Parkinson's disease.

Argyrophilic grain (ArG) is the main pathological feature of argyrophilic grain disease (AGD) and is clinically characterized by cognitive impairment, behavioral abnormalities, personality changes, and emotional imbalances. However, ArG can not only be found in AGD but also in various other neurological disorders, including Parkinson's disease (PD). The association of ArG with psychosis and/or dementia in various neurological disorders remains unknown; in this study, we have investigated this in PD. The distribution and degree of ArG deposition, spongiform change in the transentorhinal cortex (TER SpC), and phosphorylated alpha-synuclein-positive neurites in CA2/3 were assessed, and we used formalin-fixed, paraffin-embedded specimens obtained from the anterior/posterior medial temporal region of 20 autopsy cases diagnosed as PD. These cases were clinically divided into two groups: PD without dementia (PDND) and PD with dementia (PDD). Most PDD cases revealed scattered to numerous ArG or moderate to severe TER SpC, both of which were rarely observed in the PDND group. Furthermore, by the degree of ArG density and TER SpC, the PDD group was further divided into three subtypes: PDD with ArG, with TER SpC and without ArG/TER SpC. Scattered-to-numerous ArG and/or moderate-to-severe TER SpC were observed only in PDD, which suggested that both ArG and TER SpC could be important factors affecting dementia in PD and that their distribution and degree are equally important.

A novel WDR45 mutation in a patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA).

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is an X-linked dominant neurodegenerative disorder, and is classified as a subtype of neurodegeneration with brain iron accumulation. Recently, de novo heterozygous mutations in WDR45 at Xp11.23 have been reported in patients with SENDA. We report the clinical and neuroradiological findings of a patient with SENDA with a novel c.322del mutation in WDR45. In this patient, characteristic MRI findings were useful for diagnosis.

G protein-coupled receptors related to autoimmunity in postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is characterized by exaggerated orthostatic tachycardia in the absence of orthostatic hypotension. The pathophysiology of POTS may involve hypovolemia, autonomic neuropathy, a hyperadrenergic state, and cardiovascular deconditioning, any of which can co-occur in the same patient. Furthermore, there is growing evidence of the role of autoimmunity in a subset of POTS cases. In recent years, investigators have described an increased rate of autoimmune comorbidities as evidenced by the finding of several types of neural receptor autoantibody and non-specific autoimmune marker in patients with POTS. In particular, the association of the disease with several types of anti-G protein-coupled receptor (GPCR) antibodies and POTS has frequently been noted. A previous study reported that autoantibodies to muscarinic AChRs may play an important role in POTS with persistent, gastrointestinal symptoms. To date, POTS is recognized as one of the sequelae of coronavirus disease 2019 (COVID-19) and its frequency and pathogenesis are still largely unknown. Multiple autoantibody types occur in COVID-related, autonomic disorders, suggesting the presence of autoimmune pathology in these disorders. Herein, we review the association of anti-GPCR autoantibodies with disorders of the autonomic nervous system, in particular POTS, and provide a new perspective for understanding POTS-related autoimmunity.