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Intermittent administration of L-dopa in Parkinson's disease is associated with L-dopa-induced dyskinesia (LID). Long-acting dopamine agonists may reduce the risk of LID by continuous dopaminergic stimulation. We examined the LID-like behavior, preprodynorphin messenger ribonucleic acid (mRNA) expression in the striatum (a neurochemical LID hallmark), and the volume of the entopeduncular nucleus (a pathological LID hallmark) in Parkinson's disease rat models that were treated with L-dopa and cabergoline. Cabergoline co-treatment with L-dopa reduced LID, striatal preprodynorphin mRNA expression, and hypertrophy of the entopeduncular nucleus, indicating that cabergoline has an anti-LID effect independent of the L-dopa-sparing effect.

Transactivation response DNA-binding protein 43 (TDP-43)-immunoreactive neuronal cytoplasmic inclusions (NCIs) are the histopathological hallmarks of amyotrophic lateral sclerosis (ALS). They are classified as skein-like inclusions, round inclusions, dot-like inclusions, linear wisps, and diffuse punctate cytoplasmic staining (DPCS). We hypothesized that TDP-43-immunoreactive DPCS may form the early-stage pathology of ALS. Hence, we investigated phosphorylated TDP-43 pathology in the upper and lower motor neurons of patients with ALS and control participants. We designated patients whose disease duration was ≤1 year as short-duration ALS (n = 7) and those whose duration equaled 3–5 years as standard-duration ALS (n = 6). DPCS and skein-like inclusions were the most common NCIs in short-duration and standard-duration ALS, respectively. The density of DPCS was significantly higher in short-duration ALS than that in standard-duration ALS and was inversely correlated with disease duration. DPCS was not ubiquitinated and disappeared after proteinase K treatment, suggesting that it was not aggregated. Immunoelectron microscopy revealed that DPCS corresponded to nonfibrillar TDP-43 localized to the ribosomes of the rough endoplasmic reticulum (ER). These findings suggest that nonfibrillar TDP-43 accumulation in the rough ER is the earliest TDP-43 pathology in ALS, which may be helpful in developing future TDP-43 breakdown strategies for ALS.

α-Synuclein (α-Syn) binds to vesicle-associated membrane protein-binding protein B (VAPB) in the endoplasmic reticulum membrane. Recent studies have shown that α-Syn-immunoreactive Lewy pathology is characterized by membrane crowding, including vesicular structures. To elucidate the role of VAPB and vesicular structures in Parkinson's disease (PD) and in dementia with Lewy bodies (DLB), the relationships among VAPB, vesicular structures, and Lewy pathology were investigated by immunohistochemistry and immunoelectron microscopy in 8 PD and 4 DLB autopsy cases. The proportions of VAPB-negative neurons in the substantia nigra in PD and in the temporal cortex in DLB were significantly higher than those in 5 controls. In PD, the incidence of α-Syn inclusions in VAPB-negative neurons was significantly higher (77.4%) than in VAPB-positive neurons (1.6%) in the substantia nigra. In DLB, the incidence of α-Syn inclusions in VAPB-negative neurons was also significantly higher (65.3%) than in VAPB-positive neurons (2.8%) in the temporal cortex. Immunoelectron microscopy revealed that α-Syn and VAPB were localized to filamentous structures of Lewy bodies (LBs). However, only a few vesicular structures labeled with anti-α-Syn were observed within LBs. These findings suggest that reduction of VAPB is involved in the disease processes of PD and DLB, although vesicular structures may not directly contribute to the formation of LBs.

Aims: Synaptic dysfunction in Parkinson's disease is caused by propagation of pathogenic alpha-synuclein between neurons. Previously, in multiple system atrophy (MSA), pathologically characterised by ectopic deposition of abnormal alpha-synuclein predominantly in oligodendrocytes, we demonstrated that the occurrence of memory impairment was associated with the number of alpha-synuclein-positive neuronal cytoplasmic inclusions (NCIs) in the hippocampus. In the present study, we aimed to investigate how abnormal alpha-synuclein in the hippocampus can lead to memory impairment., Methods: We performed pathological and biochemical analyses using a mouse model of adult-onset MSA and human cases (MSA, N = 25; Parkinson's disease, N = 3; Alzheimer's disease, N = 2; normal controls, N = 11). In addition, the MSA model mice were examined behaviourally and physiologically., Results: In the MSA model, inducible human alpha-synuclein was first expressed in oligodendrocytes and subsequently accumulated in the cytoplasm of excitatory hippocampal neurons (NCI-like structures) and their presynaptic nerve terminals with the development of memory impairment. alpha-Synuclein oligomers increased simultaneously in the hippocampus of the MSA model. Hippocampal dendritic spines also decreased in number, followed by suppression of long-term potentiation. Consistent with these findings obtained in the MSA model, post-mortem analysis of human MSA brain tissues showed that cases of MSA with memory impairment developed more NCIs in excitatory hippocampal neurons along with alpha-synuclein oligomers than those without., Conclusions: Our results provide new insights into the role of alpha-synuclein oligomers as a possible pathological cause of memory impairment in MSA.

Non-motor symptoms (NMSs) negatively impact the health-related quality of life (HrQOL) of patients with Parkinson’s disease (PD). The Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) is a comprehensive scale for evaluating PD. It remains unclear whether the NMSs evaluated with MDS-UPDRS are predictive of HrQOL. This study aimed to investigate whether NMSs, as evaluated with the MDS-UPDRS, could predict the HrQOL of patients with PD. We conducted a 2-year retrospective observational cohort study assessing 108 patients with PD who were recruited from a single tertiary center between January 2015 and December 2017. MDS-UPDRS was used to assess NMSs and motor symptoms and Parkinson’s Disease Questionnaire-39 (PDQ-39) to measure patients’ HrQOL. The median age of patients was 69 years, and 65.7% were female. The median MDS-UPDRS part I, part II, part III, and PDQ-39-summary index scores were 8, 10, 22, and 25, respectively. The final stepwise multiple linear regression model showed that female sex (standard partial regression coefficient β = 0.131, P

The pathological hallmark of multiple system atrophy (MSA) is fibrillary aggregates of α‐synuclein (α‐Syn) in the cytoplasm and nucleus of both oligodendrocytes and neurons. In neurons, α‐Syn localizes to the cytosolic and membrane compartments, including the synaptic vesicles, mitochondria, and endoplasmic reticulum (ER). α‐Syn binds to vesicle‐associated membrane protein‐binding protein B (VAPB) in the ER membrane. Overexpression of wild‐type and familial Parkinson's disease mutant α‐Syn perturbs the association between the ER and mitochondria, leading to ER stress and ultimately neurodegeneration. We examined brains from MSA patients (n = 7) and control subjects (n = 5) using immunohistochemistry and immunoelectron microscopy with antibodies against VAPB and phosphorylated α‐Syn. In controls, the cytoplasm of neurons and glial cells was positive for VAPB, whereas in MSA lesions VAPB immunoreactivity was decreased. The proportion of VAPB‐negative neurons in the pontine nucleus was significantly higher in MSA (13.6%) than in controls (0.6%). The incidence of cytoplasmic inclusions in VAPB‐negative neurons was significantly higher (42.2%) than that in VAPB‐positive neurons (3.6%); 67.2% of inclusion‐bearing oligodendrocytes and 51.1% of inclusion‐containing neurons were negative for VAPB. Immunoelectron microscopy revealed that α‐Syn and VAPB were localized to granulofilamentous structures in the cytoplasm of oligodendrocytes and neurons. Many vesicular structures labeled with anti‐α‐Syn were also observed within the granulofilamentous structures in the cytoplasm and nucleus of both oligodendrocytes and neurons. These findings suggest that, in MSA, reduction of VAPB is involved in the disease process and that vesicular structures are associated with inclusion formation., Reduction of VAPB is involved in the disease process of MSA. Vesicular structures are associated with inclusion formation in MSA.

Posttranslational modifications by phosphorylation, ubiquitination, neddylation and other pathways have emerged as major regulators of cellular functions. NEDD8 ultimate buster 1, NUB1, is an adaptor protein, which negatively regulates the levels of the ubiquitin‐like protein NEDD8 as well as neddylated proteins through proteasomal degradation. We previously reported that NUB1 is highly involved in the pathogenesis of synucleinopathy including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). In general, since phosphorylation is strongly related to the alteration of protein propensity, we examined if the fundamental function of NUB1 can be modulated by its phosphorylation. We created a series of phosphomimic mutants of NUB1. Among them, we found that phosphorylation of NUB1 at S46 (P‐NUB46) efficiently degrades aggregates using a cell‐based assay. Immunohistochemical studies have shown that specific antibodies against P‐NUB46 reacted with Lewy bodies in PD and DLB but not with glial cytoplasmic inclusions in MSA. Moreover, P‐NUB46 levels were significantly higher in the brains of patients with DLB than in control brains, and P‐NUB46 was extracted in an insoluble fraction of DLB. These findings suggest that the phosphorylation of NUB1 is modulated during the pathological process of Lewy body disease.

Primary central nervous system vasculitis (PCNSV) is an uncommon vasculitis restricted to the small- and medium-sized vessels in the brain and spinal cord. Previously, only 9 cases have been reported that initially manifested as an isolated spinal cord lesion with subsequent brain involvement, where the longest interval from the onset to brain involvement was 1 year and 11 months. We herein report the case of an isolated spinal cord lesion with subsequent brain involvement appearing seven years and five months later. This case shows that brain lesions can develop after an extended interval from spinal onset in PCNSV.

Phosphorylated transactivation response DNA-binding protein 43 kDa (p-TDP-43)-immunoreactive neuronal and glial cytoplasmic inclusions are a histopathological hallmark of sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43. We report an autopsy case of lower motor neuron-predominant ALS in a 47-year-old Japanese man who committed suicide 5 months after onset. Histopathologically, neuronal loss was restricted to the anterior horn of the spinal cord, and no obvious neuronal loss was noted in the motor cortex or brainstem motor nuclei. Bunina bodies were found in the spinal anterior horn cells and the facial and hypoglossal nuclei. Immunohistochemically, p-TDP-43-immunoreactive neuronal, but not glial, cytoplasmic inclusions were frequently found in the spinal anterior horn and facial and hypoglossal nuclei, and rarely in the motor cortex. We considered the present case to be an example of lower motor neuron-predominant ALS. p-TDP-43-immunoreactive aggregates in neurons, but not in glial cells, may be an early-stage pathology of ALS.

Globular glial tauopathy (GGT) is a group of 4-repeat tauopathies characterized by widespread globular glial inclusions (GGIs). GGT is now classified into three subtypes based on the distribution and morphology of the GGIs. We report an autopsy case of GGT in an 85-year-old woman who presented with semantic dementia, a rare phenotype in GGT. Postmortem examination revealed marked atrophy of the frontotemporal and motor cortices and corticospinal tract degeneration with widespread occurrence of globular neurofibrillary tangles and GGIs. The distribution of the pathology was similar to that seen in GGT type III. However, the morphology of astrocytic inclusions in the present case differed from that in type III. Moreover, the tau burden in the primary motor area was more severe in the gray than in the white matter, and globular oligodendroglial inclusions were more numerous than astrocytic inclusions, corresponding to GGT type II. By contrast, the tau pathology in the temporal lobe was chiefly globular oligodendroglial inclusions in the white matter, corresponding to GGT type I. Thus, the present case exhibited a combination of GGT types I and II pathology. Our findings appear to extend the pathological heterogeneity of GGT.

BackgroundIt remains unclear why patients with young-onset Parkinson’s disease more often develop levo-dihydroxyphenylalanine (L-dopa)-induced dyskinesia (LID) and have a more severe form than patients with old-onset Parkinson’s disease. Previous studies using animal models have failed to show young-onset Parkinson’s disease enhances LID.ObjectivesTo evaluate the association of age at dopaminergic denervation (onset age) and initiation of L-dopa treatment (treatment age) with LID development in model rats.MethodsWe established rat models of young- and old-lesioned Parkinson’s disease (6-hydroxydopamine lesions at 10 and 88 weeks of age, respectively). Dopaminergic denervation was confirmed by the rotational behavior test using apomorphine. Rats in the young-lesioned group were allocated to either L-dopa treatment at a young or old age, or saline treatment. Rats in the old-lesioned group were allocated to either L-dopa treatment or saline group. We evaluated L-dopa-induced abnormal involuntary movements during the 14-day treatment period. We also examined preprodynorphin mRNA expression in the striatum (a neurochemical hallmark of LID) and the volume of the medial globus pallidus (a pathological hallmark of LID).ResultsLID-like behavior was enhanced in L-dopa-treated young-lesioned rats compared with L-dopa-treated old-lesioned rats. Preprodynorphin mRNA expression was higher in L-dopa-treated young-lesioned rats than in in L-dopa-treated old-lesioned rats. The volume of the medial globus pallidus was greater in L-dopa-treated young-lesioned rats than in L-dopa-treated old-lesioned rats. Treatment age did not affect LID-like behavior or the degree of medial globus pallidus hypertrophy in the young-lesioned model.ConclusionBoth dopaminergic denervation and L-dopa initiation at a young age contributed to the development of LID; however, the former may be a more important factor.

Tumor necrosis factor-alpha (TNF-α) inhibitors are increasingly used for various autoimmune diseases. Demyelinating events in the CNS, including myelitis, are reportedly associated with TNF-α inhibitor exposure. Behcet's disease rarely involves the spinal cord. A 51-year-old Japanese woman presented with back pain, leg weakness, and numbness during golimumab administration, a TNF-α inhibitor, for Behcet's disease. Magnetic resonance imaging revealed multifocal myelitis in the cervical and thoracic spinal cords. Discontinuation of golimumab and steroid therapy were effective and the symptoms have not relapsed. Although it is possible that the patient's myelitis was part of the symptoms of neuro-Behcet's disease, we believe that golimumab likely played a role in the myelitis development.

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been detected in inflammatory demyelinating central nervous system diseases. A 30-year-old woman had blurred vision, marked optic nerve disc swelling, serous retinal detachment at the macular on optic coherence tomography, and MOG-IgG seropositivity. The patient was thought to have optic papillitis associated with MOG-IgG. Her symptoms rapidly improved after high-dose methylprednisolone therapy. We hypothesize that serous retinal detachment was secondary, arising from optic papillitis. This is the first report of the concurrence of optic papillitis with MOG-IgG and serous retinal detachment. MOG-IgG should be tested in patients with marked optic disc swelling.

Background Paraneoplastic neurological syndromes (PNS) are rare disorders associated with cancer and are believed to be immune mediated. Patients with autonomic PNS suffer from variable combinations of parasympathetic and sympathetic failure. Autonomic PNS are usually associated with other PNS, such as encephalomyelitis and sensory neuropathy; however, autonomic symptoms may rarely manifest as PNS symptoms. Autonomic symptoms, therefore, may be overlooked in patients with cancer. Case presentation We described a 65-year-old Japanese man who was diagnosed with autonomic PNS due to small-cell lung carcinoma (SCLC) with Eastern Cooperative Oncology Group (ECOG) performance status 3, who suffered from orthostatic hypotension, and urinary retention needing a urethral balloon. Laboratory studies showed decreased levels of noradrenaline, and were positive for anti-ganglionic acetylcholine receptor antibody, type 1 antineuronal nuclear antibody, and sry-like high mobility group box 1 antibody. Nerve conduction evaluations and 123I-metaiodobenzylguanidine myocardial scintigraphy showed no abnormalities. Abdominal contrast-enhanced computed tomography revealed marked colonic distention. The patient’s autonomic symptoms resolved following integrated treatment (symptomatic treatment, immunotherapy, and additional chemotherapy) enabling the patient to walk, remove the urethral balloon, and endure further chemotherapy. ECOG performance status remained at 1, 10 months after admission. Conclusions Integrated treatment for autonomic PNS may improve autonomic symptoms and ECOG performance status of patients with cancer.

Miller Fisher syndrome (MFS) can be difficult to diagnose, particularly in mild cases where some of the standard triad of symptoms (external ophthalmoplegia, ataxia, and loss of deep tendon reflex) are absent. We herein report a case of the incomplete form of MFS diagnosed in a 54-year-old Japanese man who presented only with ataxia symptoms and was positive for the anti-GQ1b antibody. However, the patient also suffered from dysgeusia, a significant impairment of taste perception. We propose that dysgeusia in acute-onset ataxia cases may constitute an important clinical feature to aid in the diagnosis of the incomplete form of MFS.

An 83-year-old Japanese man was admitted with dysarthria and right hemiparesis. He had had a large intracranial aneurysm on the left internal carotid artery 5 years before admission and had been followed up under conservative treatment. On admission, diffusion-weighted imaging revealed a hyperintense signal on the left anterior choroidal artery territory. Time-of-flight magnetic resonance angiography demonstrated poor visibility of the middle and anterior cerebral arteries and the inferior giant aneurysm, suggesting distal emboli from aneurysm thrombosis or a reduction of blood outflow due to aneurysm thrombosis. Arterial spin labeling (ASL) signal increased in the giant aneurysm, suggesting blood stagnation within the aneurysmal sac, and decreased in the left hemisphere. We diagnosed cerebral infarction due to aneurysm thrombosis, and started antithrombotic therapy. On day 2, he suddenly died of subarachnoid hemorrhage due to rupturing of the giant aneurysm. When thrombosis occurs in a giant aneurysm, increasing ASL signal within the aneurysm and decreasing ASL signal with poor visibility on magnetic resonance angiography in the same arterial territory may indicate the danger of impending rupture of the giant aneurysm.

• Serotonin and norepinephrine transporters are capable of dopamine reuptake in the parkinsonian striatum.

Unilateral oculomotor nerve palsy can result from various neurological disorders. We herein report the case of a 68-year-old man with complete unilateral oculomotor nerve palsy following campylobacter infection. Based on the antecedent infection and the patient's decreased tendon reflexes, incomplete Miller Fisher syndrome (MFS) without ataxia was suspected. His serum tested positive for anti-GQ1b antibodies. He recovered over a period of 87 days without immunotherapy. We conclude that incomplete MFS following campylobacter infection can cause unilateral oculomotor nerve palsy without ataxia. Mild MFS should be considered in patients presenting with unilateral isolated ophthalmoplegia and decreased tendon reflexes.

A 72-year-old woman presented with a 6-week history of gait disturbance and mild disturbance of consciousness. For 9 months, she had been treated for advanced non-small cell lung cancer with atezolizumab. MRI revealed symmetrical high signal in the thalamus bilaterally (figure). She did not have evidence of cancer recurrence or metastases. Serum autoimmune antibodies were absent (anti-AQP4, anti-MOG, anti-amphiphysin, CV2, PNMA2 [Ma2/Ta], Ri, Yo, Hu, recoverin, SOX1, titin, zic4, GAD65, and Tr [DNER]). In the CSF, she had high immunoglobulin G index and positive oligoclonal bands but normal myelin basic protein, absent anti-NMDA receptor and anti-MOG antibodies, and no evidence of infection. Cytology was normal. She was diagnosed with autoimmune encephalitis associated with atezolizumab treatment and treated with steroids and IV immunoglobulin 9 weeks after the onset of symptoms. The size of the lesions decreased after immunotherapy started, but she remained bedridden.

A 41-year-old Korean man was admitted to our hospital with a 1-day history of headache and abnormal left visual field. Neurological examination revealed left homonymous hemianopia and difficulty in fine movement of the left finger. Laboratory studies indicated hyperlipidemia and hyperhomocysteinemia. Diffusion-weighted imaging showed a hyperintense signal on the right posterior cerebral-middle cerebral artery watershed area. Computed tomography angiography and carotid angiography revealed the bottle neck sign on the right internal carotid artery (ICA) with occlusion of the distal right ICA, but not the left ICA. Carotid angiography showed moyamoya vessels as well as occlusion of the distal right ICA. The right carotid canal was hypoplasic. We diagnosed the patient with unilateral moyamoya disease and carotid canal hypoplasia. This case demonstrates that unilateral carotid canal hypoplasia may co-exist with ipsilateral moyamoya disease. A unilateral bottle neck sign may indicate the presence of carotid canal hypoplasia. Evaluation of the bony carotid canal may be useful when it is necessary to distinguish between secondary vascular stenosis due to arteriosclerosis and MMD. Keywords: Moyamoya disease, Carotid canal, Bottle neck sign

Background Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients. Aim The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs. Material and methods Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7). Results Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration. Conclusion The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.

Bunina bodies (BBs) coexisting with TDP-43-immunoreactive (TDP-43-IR) skein-like inclusions (SIs) and round inclusions (RIs) in lower motor neurons are a frequent feature of sporadic amyotrophic lateral sclerosis (sALS). Since previous studies have shown that BBs and TDP-43-IR inclusions are often detected in association with autophagy-related structures (autophagosomes and autolysosomes), we examined the anterior horn cells (AHCs) of the spinal cord from 15 patients with sALS and 6 control subjects, using antibodies against autophagy-related proteins (LC3, cathepsin B, and cathepsin D). Among AHCs with SIs, 43.9% contained BBs, whereas 51.7% of AHCs with RIs did so. The cytoplasm of AHCs showed diffuse immunoreactivity for LC3, cathepsin B and cathepsin D in both sALS and controls. Ultrastructurally, SIs and mature BBs contained autophagosomes and autolysosomes. Mature BBs were localized in the vicinity of SIs. RIs also contained autophagosomes, autolysosomes, and early-stage BBs. These findings suggest that autophagy is a common degradation pathway for BBs and TDP-43-IR inclusions, which may explain their frequent coexistence.

Lewy body disease (LBD) is characterized by the presence of Lewy bodies (LBs) and Lewy neurites and comprises a diagnostic spectrum that includes Parkinson's disease (PD), PD with dementia, and dementia with LBs. LBs and Lewy neurites are insoluble aggregates composed mainly of phosphorylated α-synuclein and can be widely distributed throughout the central and peripheral nervous systems. The distribution of LBs may determine the LBD phenotype. Braak hypothesized that Lewy pathology progresses ascendingly from the peripheral nervous system to the olfactory bulbs and brainstem and then to other brain regions. Braak's PD staging suggests that LBD is a prion-like disease. Most typical PD cases fit with Braak's PD staging, but the scheme fails in some cases. Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, frontotemporal lobar degeneration, Creutzfeldt-Jakob disease, cerebrovascular diseases, and essential tremor are common misdiagnoses for pathologically confirmed LBD. LBD exhibits considerable heterogeneity in both clinical and pathological settings, which makes clinical diagnosis challenging.

Myelin-associated oligodendrocytic basic protein (MOBP) plays a role in structural maintenance of the myelin sheath in the central nervous system. Recent genome analyses have revealed that mutation in MOBP is a risk factor for various neurodegenerative diseases, including Alzheimer's disease (AD), tauopathies and transactivation response DNA-binding protein 43 kDa proteinopathies. Proteomics analysis has shown that MOBP is a component of cortical Lewy bodies (LBs). However, the immunohistochemical localization of MOBP in the human brain is not known. Using immunohistochemistry, we examined the brain, spinal cord and peripheral ganglia from patients with various neurodegenerative diseases and control subjects. In normal controls, MOBP immunoreactivity was evident in the myelin in the central and peripheral nervous systems (PNS), and neuronal cytoplasm in both the central and PNS. In Parkinson's disease and dementia with LBs, MOBP immunoreactivity was found in the core of LBs in the brainstem, cingulate cortex and sympathetic ganglia. No MOBP immunoreactivity was found in a variety of other neuronal or glial inclusions in other disorders, including multiple system atrophy, AD, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Considering that up-regulation of MOBP has been reported in neurotoxic conditions, accumulation of MOBP in LBs may imply a cytoprotective mechanism in LB disease.

INTRODUCTION The loss of epidermal nerve fibers is regarded as an early pathological change in human diabetes. We investigated epidermal Aδ nerve fiber function by examining pain threshold by means of intraepidermal electrical stimulation (IES) in early diabetic neuropathy. METHODS We recruited 20 asymptomatic diabetic patients. Eighteen age-matched, healthy subjects served as controls. We placed the IES electrode onto the skin of the foot dorsum and delivered weak electrical stimulation. We defined pain threshold as the minimum electrical intensity at which a subject felt a pricking sensation. RESULTS The mean pain thresholds in the patient group were significantly higher (0.053 ± 0.036 mA; P

Introduction Impulse control behaviors (ICBs) are impulsive–compulsive behaviors often associated with dopamine replacement therapy in Parkinson's disease (PD). Although remission can occur in ICB, only four reports on the ratio of remission and the persistence of ICB have been published, and the associated factors with ICB remission or persistence have been little known. Therefore, we conducted a longitudinal assessment of the remission, persistence, and development of ICB and those associated factors in patients with PD. Methods We retrospectively investigated a PD database at Aomori Prefectural Central Hospital, Japan. One hundred and forty‐eight patients with PD who could be followed up for 2 years were enrolled. ICB was assessed using the Questionnaire for Impulsive–Compulsive Disorders in Parkinson's disease. Motor severity (Hoehn and Yahr scale and United Parkinson's Disease Rating Scale), cognitive function (Mini–Mental State Examination), and other clinical variables (sex, age, onset age, disease duration, olfactory dysfunction, and dyskinesia) and medications used to treat PD were assessed. Univariate analyses were performed. Results Seven patients were excluded because of the exclusion criteria, and 141 patients were analyzed. Thirty patients (21.3%) had ICB at baseline, and these patients also had significantly higher use of pergolide. The ICB remission rate was 60%, the ICB persistence ratio was 40%, and the ICB development ratio was 12.6% over 2 years. Statistically, younger age and pergolide use were associated with ICB persistence. Being male, having dyskinesia, and rotigotine, entacapone, zonisamide, and istradefylline use were associated with ICB development. Conclusion This study suggests that younger age and pergolide use may be the new associated factors with ICB persistence and that entacapone, zonisamide, and istradefylline use may be associated with the development of ICB. Drug profiles and medication practices in Japan may explain the association of these factors with ICB.

A 16-year-old boy with a history of optic neuritis and brainstem lesions due to myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease complained of visual disturbance. He had no headache or other neurologic symptoms. Brain MRI showed contrast enhancement of hypertrophic dura mater in the posterior fossa (figure), but no abnormal dura elsewhere. Increasing prednisolone and adding tacrolimus following steroid pulse therapy improved the abnormality (figure). The clinical phenotype of MOG antibody-associated disease includes optic neuritis, myelitis, acute or multiphasic disseminated encephalomyelitis, and encephalitis.1 Although oligodendrocytes are not normally present in the dura matter, heterotopic neuroglial tissues were reported.2 The interactions of MOG antibody with heterotopic neuroglial tissue in the dura mater may contribute to the pathophysiology in this case.

The histological hallmark of multiple system atrophy (MSA) is accumulation of phosphorylated α-synuclein in oligodendrocytes. However, it is uncertain whether phosphorylated α-synuclein accumulates in astrocytes of MSA patients. We immunohistochemically examined the frontal and temporal lobes, basal ganglia, cerebellum, brainstem and spinal cord of patients with MSA (n = 15) and Lewy body disease (n = 20), and also in control subjects (n = 20). Accumulation of abnormally phosphorylated and aggregated α-synuclein was found in subpial and periventricular astrocytes in six of the 15 patients with MSA (40%). The structures were confined to the subpial surface of the ventro-lateral part of the spinal cord and brainstem, as well as the subependymal region of the lateral ventricles. They were not visualized by Gallyas-Braak staining, and were immunonegative for ubiquitin and p62. Immunoelectron microscopy revealed that the phosphorylated α-synuclein-immunoreactive structures in astrocytes were non-fibrillar and associated with granular and vesicular structures. The extent of phosphorylated α-synuclein-immunoreactive astrocytes was correlated with disease duration. No such structures were found in Lewy body disease or controls. Accumulation of phosphorylated α-synuclein can occur in subpial and periventricular astrocytes in patients with MSA, especially in those with a long disease duration.

Nuclear receptor subfamily 4, group A, member 3 (NR4A3), also known as neuron-derived orphan receptor-1, is a nuclear receptor which plays key roles in cell cycle, neuronal differentiation, apoptosis and metabolism. These processes may be involved in the pathogenesis of certain neurodegenerative diseases. Previous studies have shown that there are high levels of NR4A3 mRNA in the CNS. Moreover, NR4A2, a transcription factor with homology to NR4A3, has been reported to contribute to the pathogenesis of Parkinson's disease. However, it is uncertain whether NR4A3 is also involved in diseases such as dementia with Lewy bodies, multiple system atrophy, and other neurodegenerative disorders such as tauopathies, TDP-43 proteinopathies and polyglutamine diseases. In the present study we used immunohistochemistry to examine the brain and spinal cord from patients with various neurodegenerative diseases and normal control subjects using two polyclonal anti-NR4A3 antibodies. In controls, the cytoplasm of neurons and glial cells was faintly immunostained with anti-NR4A3 antibodies. In tissues from patients with neurodegenerative diseases, immunoreactivity for NR4A3 was observed in cortical and brainstem-type Lewy bodies in Parkinson's disease and in dementia with Lewy bodies, as well as in neuronal and glial cytoplasmic inclusions in multiple system atrophy. A double-labeled immunofluorescence study showed co-localization of NR4A3 and phosphorylated α-synuclein in these inclusions. Neuronal and glial inclusions in other neurodegenerative disorders were NR4A3 negative. These findings suggest that accumulation of NR4A3 is specific to α-synucleinopathy.

Neurosarcoidosis is difficult to diagnose, because definite diagnosis requires detailed histology of the central nervous system. Three-dimensional contrast-enhanced fluid-attenuated inversion recovery (CE-FLAIR) is more useful for detecting leptomeningeal lesions compared with 3D CE-T1 weighted imaging. However, the clinical diagnostic utility of 3D CE-FLAIR for neurosarcoidosis is unclear. We describe a case of a 46-year-old Japanese woman who was admitted to our department due to chronic headache with fever and diplopia. Using 3D CE-FLAIR, we performed brain biopsy from right cerebellar lesion. The histological examination revealed typical non-caseating granulomas, indicating neurosarcoidosis. Our findings suggest that 3D CE-FLAIR may detect leptomeningeal lesions that are candidates for biopsy in chronic meningitis undetermined etiology.