Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation.

The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington's disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal ß-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic ß-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood-brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.

A new device-aided cognitive function test, User eXperience-Trail Making Test (UX-TMT), sensitively detects neuropsychological performance in patients with dementia and Parkinson's disease.

BACKGROUND: A newer generation neuropsychological tests can take advantage of touch screen and mobile technology. We have developed a new Android application termed "User eXperience-Trail Making Test (UX-TMT)" for neurocognitive assessment and training. This study investigated the utility, including the reliability and the validity, of the UX-TMT as a screening test for cognitive decline in adults. METHODS: A total of 84 individuals aged 27-86 years were divided into three groups; healthy controls ([HC] n = 29), people with Parkinson's disease (PD; n = 28), and people with mild cognitive impairment (MCI) and dementia (MCI&D; n = 27). We examined the distributions of the scores and the time required, and the effects of age and group on these distributions. We analyzed internal consistency and convergent validity in all samples and applied receiver operator characteristic (ROC) analysis to determine a cutoff score that could differentiate the MCI & D group from the HC group. RESULTS: 97.6% of the participants completed all of the tasks, and the average total test time required for UX-TMT was 428.8 (± 109.1) s in the HC, 542.0 (± 168.7) s in the PD, and 777.5 (± 256.1) s in the MCI&D groups, respectively. The MCI&D group showed significantly lower UX-TMT scores and longer total time in completing the task than the HC group. In an ROC analysis, a score of 21 showed high sensitivity (.83) and specificity (.92), and the UX-TMT score plus age improved sensitivity to .96. Additionally, the UX-TMT scores showed significant correlation with the Mini-Mental State Examination (Japanese version) scores (r = .77, p = .001), and Cronbach's alpha (.71-.83) indicated acceptable internal consistency. CONCLUSION: The UX-TMT demonstrated high reliability and validity to detect cognitive decline in Japanese adults, highlighting its utility as a screening tool for epidemiological and clinical research.

p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies.

Oligomer formation and accumulation of pathogenic proteins are key events in the pathomechanisms of many neurodegenerative diseases, such as Alzheimer disease, ALS, and the polyglutamine (polyQ) diseases. The autophagy-lysosome degradation system may have therapeutic potential against these diseases because it can degrade even large oligomers. Although p62/sequestosome 1 plays a physiological role in selective autophagy of ubiquitinated proteins, whether p62 recognizes and degrades pathogenic proteins in neurodegenerative diseases has remained unclear. In this study, to elucidate the role of p62 in such pathogenic conditions in vivo, we used Drosophila models of neurodegenerative diseases. We found that p62 predominantly co-localizes with cytoplasmic polyQ protein aggregates in the MJDtr-Q78 polyQ disease model flies. Loss of p62 function resulted in significant exacerbation of eye degeneration in these flies. Immunohistochemical analyses revealed enhanced accumulation of cytoplasmic aggregates by p62 knockdown in the MJDtr-Q78 flies, similarly to knockdown of autophagy-related genes (Atgs). Knockdown of both p62 and Atgs did not show any additive effects in the MJDtr-Q78 flies, implying that p62 function is mediated by autophagy. Biochemical analyses showed that loss of p62 function delays the degradation of the MJDtr-Q78 protein, especially its oligomeric species. We also found that loss of p62 function exacerbates eye degeneration in another polyQ disease fly model as well as in ALS model flies. We therefore conclude that p62 plays a protective role against polyQ-induced neurodegeneration, by the autophagic degradation of polyQ protein oligomers in vivo, indicating its therapeutic potential for the polyQ diseases and possibly for other neurodegenerative diseases.

Nitrogen K-edge x-ray absorption near edge structure of pyrimidine-containing nucleotides in aqueous solution.

X-ray absorption near edge structure (XANES) was measured at energies around the N K-edge of the pyrimidine-containing nucleotides, cytidine 5'-monophosphate (CMP), 2'-deoxythymidine 5'-monophosphate (dTMP), and uridine 5'-monophosphate (UMP), in aqueous solutions and in dried films under various pH conditions. The features of resonant excitations below the N K-edge in the XANES spectra for CMP, dTMP, and UMP changed depending on the pH of the solutions. The spectral change thus observed is systematically explained by the chemical shift of the core-levels of N atoms in the nucleobase moieties caused by structural changes due to protonation or deprotonation at different proton concentrations. This interpretation is supported by the results of theoretical calculations using density functional theory for the corresponding nucleobases in the neutral and protonated or deprotonated forms.

Nitrogen K-edge X-ray absorption near edge structure (XANES) spectra of purine-containing nucleotides in aqueous solution.

The N K-edge X-ray absorption near edge structure (XANES) spectra of the purine-containing nucleotide, guanosine 5'-monophosphate (GMP), in aqueous solution are measured under various pH conditions. The spectra show characteristic peaks, which originate from resonant excitations of N 1s electrons to π* orbitals inside the guanine moiety of GMP. The relative intensities of these peaks depend on the pH values of the solution. The pH dependence is explained by the core-level shift of N atoms at specific sites caused by protonation and deprotonation. The experimental spectra are compared with theoretical spectra calculated by using density functional theory for GMP and the other purine-containing nucleotides, adenosine 5'-monophosphate, and adenosine 5'-triphosphate. The N K-edge XANES spectra for all of these nucleotides are classified by the numbers of N atoms with particular chemical bonding characteristics in the purine moiety.

Focal task-specific hand dystonia related to esports in a rhythm gamer: A case report.

Herein, we report a novel case of focal task-specific dystonia of the upper extremity that occurred in a 27-year-old man who presented with flexion of the left third, fourth, and fifth fingers exclusively during rhythm gameplay. Dystonia during electronic sports should be recognized as a new type of occupational dystonia.

[Current Pharmacological Treatment for Parkinson's Disease].

Parkinson's disease (PD) is the second most common neurodegenerative disorder and its global incidence is on the rise. A well-established dopamine replacement therapy for PD is based on dopamine deficiency, primarily due to dopaminergic neuronal loss in the substantia nigra. Current dopaminergic pharmacotherapy for PD consists of levodopa and other dopaminergic drugs, such as a dopamine agonist (DA) and monoamine oxidase B (MAOB) inhibitor, and patients with PD are administered these mainly according to age, disability of parkinsonism, and tolerance of the drugs. In the advanced stage, patients with PD usually experience motor complications, mainly the wearing-off phenomenon and dyskinesias, resulting in disabled activities of daily life. Many pharmacological options are available against motor fluctuations in patients with advanced PD, including long-acting DAs, MAOB inhibitors, and catechol-O-methyltransferase inhibitors, as adjunct alternatives for dopamine-replacement therapy. Non-dopaminergic pharmacological approaches, including zonisamide and istradefylline, which have been mainly developed in Japan, are also available. Amantadine and anticholinergic drugs may be useful in specific situations. Device-aided therapies, such as deep brain stimulation and levodopa-carbidopa intestinal gel infusion therapy, can be performed at the advanced stage. In this article, we provide an overview of recent pharmacological treatments for PD.

X-ray induced luminescence spectroscopy for DNA damaging intermediates aided by a monochromatic synchrotron radiation.

PURPOSE: To identify the bonding sites of initial radiation interaction with DNA and to trace the following chemical reaction sequences on the pathway of damage induction, we carry out a spectroscopy XIL (X-ray induced luminescence) using soft X-ray synchrotron radiation. This is a nondestructive analysis of the excited intermediate species produced in a molecular mechanism on the damage induction pathway. MATERIALS AND METHODS: We introduce aqueous samples of UMP (uridine-5'-monophosphate) in the vacuum by the use of a liquid micro-jet technique. The luminescence in the region of UV-VIS (from visible to ultraviolet) radiation induced after the absorption of monochromatic soft X-ray by aqueous UMP is measured with sweeping the soft X-ray energy in the region of 370-560 eV. RESULTS: The enhanced XIL intensities for aqueous UMP in the region of soft X-ray of 410-530 eV (in "water window" region) are obtained. The enhancement of XIL intensities in the UV-VIS region, relative to the water control, is explained by the excitation and ionization of a K-shell electron of nitrogen atoms in the uracil moiety. The enhanced XIL intensities do not match the structure of XANES (X-ray absorption near-edge structure) of the aqueous UMP. This suggests that the XIL intensities reflect the quantum yields of luminescence, or the quantum yields for conversion by UMP of an absorbed X-ray into UV-VIS radiation. In this paper, spectra of luminescence are shown to be resolved by combining low pass filters. The filtered luminescence spectra are obtained at the center of gravity (λc) of the band pass wavelength regions at λc = 270nm, 295 nm, 340 nm, 385 nm, 450 nm, and 525 nm., which show a trend similar to the fluorescence of nucleobases induced by ultraviolet radiation. CONCLUSION: It is concluded that the origin of the observed XIL is the hydrated uracil moiety in aqueous UMP, decomposition of which is suppressed by the migration of excess charge and internal energy after the double ionization due to Auger decay.

Performance upgrade in the JAEA actinide science beamline BL23SU at SPring-8 with a new twin-helical undulator.

The soft X-ray beamline BL23SU at SPring-8 has undergone an upgrade with a twin-helical undulator of in-vacuum type to enhance the experimental capabilities of the endstations. The new light source with a fast helicity-switching operation allows not only the data throughput but also the sensitivity in X-ray magnetic circular dichroism (XMCD) to be improved. The operational performance and potential are described by presenting XMCD results of paramagnetic ß-US(2) measured with a 10 T superconducting magnet.

Current Evidence for the Association between Air Pollution and Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, and its global incidence is on the rise. There is increasing interest in understanding the role of air pollution in the development of human disease. Although the precise mechanisms are not understood, several epidemiological studies have reported a positive association between air pollution and the risk of PD. However, the various pollutants studied, endpoints measured, and differences in study design yield conflicting results. This review summarizes recent evidence regarding the relationship between particulate matter, ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide and PD. Limitations and challenges are also discussed, with suggestions for future work to understand the true effects of air pollution on PD.

Combination of Astrogliosis and Phosphorylated Tau for the Preclinical Diagnosis of Alzheimer Disease Using 3-Dimensional Stereotactic Surface Projection Images With 18 F-THK5351.

ABSTRACT: The Alzheimer disease (AD) brain is characterized microscopically by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles consisting of phosphorylated tau aggregations. 18 F-THK5351 is a first-generation PET tau tracer that also binds to monoamine oxidase B, which represents astrogliosis, and is useful to evaluate some non-AD neurodegenerative disorders. We examined the utility of 18 F-THK5351 in preclinical AD using 3-dimensional stereotactic surface projection images optimized for its pathological accumulation by comparison with a normal dataset. By using this 18 F-THK5351 3-dimensional stereotactic surface projection procedure, which can evaluate phosphorylated tau and neuroinflammation, we could diagnose preclinical AD effectively.

Pathologically Verified Corticobasal Degeneration Mimicking Richardson's Syndrome Coexisting with Clinically and Radiologically Shunt-Responsive Normal Pressure Hydrocephalus.

Background: Normal pressure hydrocephalus (NPH) manifests as gait instability, cognitive impairment, and urinary incontinence. This clinical triad of NPH sometimes occurs with ventriculomegaly in patients with neurodegenerative disease. Patients with pathologically verified neurodegenerative diseases, such as progressive supranuclear palsy (PSP), have received antemortem diagnoses of NPH. Objectives: This study presents clinical and pathological features of a patient with pathologically verified corticobasal degeneration (CBD) coexisting with clinically shunt-responsive NPH. Methods: We performed clinical, radiological, and pathological evaluations in a patient with CBD whose antemortem diagnosis was PSP Richardson's syndrome (PSP-RS) coexisting with shunt-responsive NPH. Results: A 59-year-old woman developed bradykinesia and gait instability and then frequent falls, urinary incontinence, and supranuclear vertical gaze palsy followed. At 63 years of age, her gait disturbance and urinary incontinence had deteriorated rapidly, and cognitive impairment was disclosed. There were typical findings of NPH with ventriculomegaly and disproportionately enlarged subarachnoid space hydrocephalus as well as a 2-layer appearance with decreased and increased cerebral blood perfusion. Shunt placement ameliorated gait instability for more than 1 year and improved radiological indicators of NPH. However, atrophy of the midbrain progressed with time after transient increases in size. Although the antemortem diagnosis was probable PSP-RS, pathological evaluation verified CBD. There were severe discontinuities of the ependymal lining of the lateral ventricles and subependymal rarefaction and gliosis with tau-positive deposition. Conclusions: Shunt surgery could ameliorate NPH symptoms in patients with 4-repeat tauopathies. Careful assessments of clinical findings are necessary to predict the benefits of shunts as a therapeutic option for patients with neurodegenerative diseases coexisting with NPH.

Pathologic and Neuropathologic Study of a Case of COVID-19.

A 68-year-old woman with a history of schizophrenia developed coronavirus disease (COVID)-19 and was transferred to our hospital. Despite treatment, she died of respiratory failure 16 days after the onset. At the time of autopsy, polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA using swabs from the nasopharynx and the lung was positive; however, the cerebrospinal fluid was negative. An autopsy showed diffuse alveolar damage and recent multiple cerebral infarcts. Acute splenitis was observed with thrombi adhering to the vascular endothelium in areas of severe neutrophilic infiltration. Immunohistochemistry using an antibody against the SARS-CoV-2 nucleocapsid showed immunoreactivity along the hyaline membrane of the lung; however, the antibody showed no immunoreactivity in the medulla, the thalamus, the frontal lobe, and the pituitary. Future pathologic studies should clarify the mechanisms involved in a variety of clinical and pathological changes related to COVID-19.

Idiopathic rapid eye movement sleep behavior disorder in Japan: An observational study.

INTRODUCTION: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy. METHODS: This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG. RESULTS: Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score. CONCLUSION: Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores.

Pneumomediastinum while using mechanical insufflation-exsufflation after recovery from riluzole-induced interstitial lung disease.

We, herein, report a 61-year-old male patient with amyotrophic lateral sclerosis (ALS) complicated pneumomediastinum while using mechanical insufflation-exsufflation (MI-E) after recovery from riluzole (RZ)-induced interstitial lung disease (RZ-ILD). After the treatment of RZ-ILD, he required non-invasive mechanical ventilation (NIV) at minimal pressure settings and MI-E to manage ALS-related breathing and airway-clearance issues, respectively. After a while, he developed progressive worsening dyspnoea, and chest computed tomography revealed extensive pneumomediastinum that had spread to the area surrounding the oesophagus, the retrosternal space, and the pericardial space. He was treated with immediate discontinuation of MI-E; however, he had to keep using NIV to support his severe respiratory muscle involvement. Pneumomediastinum gradually reduced in size and no recurrence of pneumomediastinum occurred. The clinical course of our patient suggests that excessive coughing associated with MI-E combined with his previous RZ-ILD, which potentially renders his lungs vulnerable to airway pressure, may have been the aetiological factors for secondary pneumomediastinum, i.e. barotrauma. Clinicians should be aware of the risk of pneumomediastinum while using MI-E in patients with ALS, who have other pre-existing risk factors for pneumomediastinum, such as drug-induced ILD in our case.

Visualization of Motor Cortex Involvement by 18F-THK5351 PET Potentially Strengthens Diagnosis of Amyotrophic Lateral Sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) involves both upper motor neurons (UMNs) and lower motor neurons. The detection of UMN involvement, a core component of ALS criteria, is primarily dependent on neurological examination because of a lack of definitive biomarkers. We present the 18F-THK5351 PET images of a 76-year-old man diagnosed with ALS comorbid with Alzheimer disease, demonstrating marked accumulation of 18F-THK5351 in the bilateral precentral gyri. Because 18F-THK5351 binds to monoamine oxidase B highly expressed in astrocytes, where the neurodegenerative process is ongoing, our case highlights that 18F-THK5351 tracer should be a useful marker for detecting UMN neurodegeneration in ALS.

Microstructures and Interface Magnetic Moments in Mn2VAl/Fe Layered Films Showing Exchange Bias.

Heusler alloys are a material class exhibiting various magnetic properties, including antiferromagnetism. A typical application of antiferromagnets is exchange bias that is a shift of the magnetization curve observed in a layered structure consisting of antiferromagnetic and ferromagnetic films. In this study, a layered sample consisting of a Heusler alloy, Mn2VAl and a ferromagnet, Fe, is selected as a material system exhibiting exchange bias. Although the fully ordered Mn2VAl is known as a ferrimagnet, with an optimum fabrication condition for the Mn2VAl layer, the Mn2VAl/Fe layered structure exhibits exchange bias. The appearance of the antiferromagnetic property in the Mn2VAl is remarkable; however, the details have been unclear. To clarify the microscopic aspects on the crystal structures and magnetic moments around the Mn2VAl/Fe interface, cross-sectional scanning transmission electron microscope (STEM) observation, and synchrotron soft X-ray magnetic circular dichroism (XMCD) measurements were employed. The high-angle annular dark-field STEM images demonstrated clusters of Mn2VAl with the L21 phase distributed only around the interface to the Fe layer in the sample showing the exchange bias. Furthermore, antiferromagnetic coupling between the Mn- and Fe-moments were observed in element-specific hysteresis loops measured using the XMCD. The locally ordered L21 phase and antiferromagnetic Mn-moments in the Mn2VAl were suggested as important factors for the exchange bias.

Riluzole for the treatment of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the death of motor neurons. Riluzole is a benzothiazole derivative that blocks glutamatergic neurotransmission in the CNS, which is thought to exert neuroprotective effects. Riluzole was approved by the US FDA in 1995 as the first drug to treat ALS. Although riluzole is generally safe and well tolerated in clinical practice, its efficacy in ALS is modest, prolonging tracheostomy-free survival by only 2-3 months. In this article, we will first provide an overview of the ALS field, followed by a discussion of riluzole regarding its physical properties; pharmacology; clinical efficacy in ALS; safety and tolerability; and recommended administration.

Riluzole-induced interstitial lung disease is a rare and potentially life-threatening adverse event successfully treated with high-dose steroid therapy: Case reports and review of the literature.

Riluzole (RZ)-induced interstitial lung disease (RZ-ILD) is a rare and potentially life-threatening adverse event in amyotrophic lateral sclerosis (ALS) patients, which is rarely reported. Therefore, the optimal treatment for RZ-ILD is unclear. We describe herein three Japanese cases of ALS complicated with RZ-ILD, of which two were successfully treated with high-dose steroid therapy. In our all ALS cases with RZ-ILD, the duration of RZ exposure until RZ-ILD onset was within 2 months. All three cases showed respiratory symptoms, dorsal predominant ground-glass opacities by imaging analysis, and abnormal laboratory findings associated with interstitial lung diseases, such as Krebs von den Lungen-6 and surfactant protein-D. Intravenous high-dose steroid therapy together with the discontinuation of RZ in two cases with respiratory symptoms markedly ameliorated their symptoms and abnormal findings of RZ-ILD. One case showed mild respiratory symptoms compared with the others and recovered after the withdrawal of RZ only. According to previous case reports and our cases, RZ-ILD may develop 2 months after initiating RZ and exacerbate respiratory symptoms rapidly in ALS patients with severe respiratory muscle involvement or complicating aspiration pneumonia. Transient high-dose steroid therapy in addition to discontinuation of RZ might be a good therapeutic option for RZ-ILD.

Lidocaine injections and neck corset wearing improve dropped head syndrome in Parkinson's disease and related disorders.

BACKGROUND: Patients with Parkinson's disease and related disorders (PDRD) may exhibit dropped head syndrome (DHS), which does not yet have an effective treatment. OBJECTIVES: To evaluate the effect of combining lidocaine injection into the bilateral scalene muscles and neck corset wearing on dropped head syndrome. METHODS: We performed needle electromyography assessments of the scalene, sternocleidomastoid (SCM), levator scapulae, splenius capitis, and trapezius muscles. Patients received 2.5-5 ml injections of 1% lidocaine into both sides of the scalene muscles for 4/5 consecutive days and were instructed to wear a neck corset. We measured the neck flexion angle, which formed between the horizontal line and the straight line passing through the ear canal and orbital fossa, before (baseline) and after (Day 8 and Day 90) the intervention. RESULTS: Seven males and eight females (mean age, 68.9 years; range 56 to 85 years) who had PDRD with dropped head syndrome were enrolled in this study. Needle electromyography examination revealed abnormal discharge of the scalene muscles in all patients when the neck position was corrected; however, some patients did not show abnormal discharge of the SCM muscle. At Day 8, we observed an improvement of the neck flexion angle in 13 of the 15 patients, from an average of 27.7°â€¯±â€¯13.9° to 11.7 ±â€¯14.6°. At Day 90, the average neck flexion angle was 15.3°â€¯±â€¯17.2°. CONCLUSIONS: Combining lidocaine injection into the scalene muscles and neck corset wearing is an effective treatment regimen for DHS in patients with PDRD.