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Hashimoto’s encephalopathy with serum anti-NH2-terminal of α-enolase (NAE) antibodies occasionally displays clinical symptoms such as cerebellar ataxia and parkinsonism. We studied the frequency of anti-NAE antibodies in patients with Parkinson-plus syndrome. We examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson’s disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis. Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients. Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.

Summary Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy. Methods We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879. Findings Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI –2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [–1·6 to 3·6], –0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related. Interpretation A similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy. Funding AbbVie Inc.

Background and purpose Corticobasal syndrome (CBS) is pathologically characterized by tau deposits in neuronal and glial cells and by reactive astrogliosis. In several neurodegenerative disorders, 18 F-THK5351 has been observed to bind to reactive astrocytes expressing monoamine oxidase B. In this study, the aim was to investigate the progression of disease-related pathology in the brains of patients with CBS using positron emission tomography with 18 F-THK5351. Methods Baseline and 1-year follow-up imaging were acquired using magnetic resonance imaging and positron emission tomography with 18 F-THK5351 in 10 subjects: five patients with CBS and five age-matched normal controls (NCs). Results The 1-year follow-up scan images revealed that 18 F-THK5351 retention had significantly increased in the superior parietal gyrus of the patients with CBS compared with the NCs. The median increases in 18 F-THK5351 accumulation in the patients with CBS were 6.53% in the superior parietal gyrus, 4.34% in the precentral gyrus and 4.33% in the postcentral gyrus. In contrast, there was no significant increase in the regional 18 F-THK5351 retention in the NCs. Conclusions Longitudinal increases in 18 F-THK5351 binding can be detected over a short interval in the cortical sites of patients with CBS. A monoamine oxidase B binding radiotracer could be useful in monitoring the progression of astrogliosis in CBS.

Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a phenotypically and genetically heterogeneous group of neurological disorders that typically presents as early-onset lower limb dystonia with diurnal fluctuation, and exhibits a marked, persistent response to levodopa. Heterozygous loss-of-function mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) are the most common cause of DRD. In addition to the classic form of the disease, there have been a number of studies addressing atypical clinical features of GCH1 related DRD with variable age of onset. This report describes a 37-year-old Japanese male patient with a 10-year history of focal upper limb dystonia that initially emerged as task-specific, guitarist’s cramp. The dystonic symptoms responded very well to levodopa treatment, and genetic analysis identified a novel heterozygous mutation in the C-terminal catalytic domain of GCH1. Insufficient recognition of this treatable condition often leads to misdiagnosis, which causes delays in the patient receiving adequate dopamine replenishing therapy. A diagnostic trial with levodopa should be considered in all patients with relatively young-onset dystonia, whether they have classic features of DRD or not.

Highlights • Pathological basis of primary progressive aphasia is heterogeneous. • Logopenic primary progressive aphasia can precede dementia with Lewy bodies (DLB). • Cholinesterase inhibitor can improve logopenic aphasia with DLB.

Introduction Patients with HIV infection may have a higher prevalence of osteoporosis and osteopenia, as well as an increased risk of bone fracture compared with non-HIV-infected individuals. Antiretroviral therapy is thought to be one of factors associated to osteoporosis-related bone fractures. Objective The aim of this study was to assess the effects of long-term exposure to tenofovir disoproxil fumarate (TDF) on the cumulative risk of osteoporosis-related bone fractures in Japanese patients with HIV infection. Design This observational cohort study comprised a joint HIV-related drug survey of patients treated with TDF between April 2004 and March 2013. Methods Thirty-five healthcare facilities in Japan participated in the survey. The incidence of osteoporosis-related fractures was extracted from all adverse events (AEs) using standardized Medical Dictionary for Regulatory Activities queries, and used to calculate the fracture rate per 10,000 patient-years (PY). Kaplan–Meier analysis was used to estimate the cumulative probability of fracture during the study period. Results A total of 3251 patients who received TDF or TDF/emtricitabine between April 2004 and March 2013 were analyzed in this study; 93.5% of patients were male. The fracture rate was 13.5 per 10,000 PY in males and 42.2 per 10,000 PY in females. The mean age for male patients with osteoporosis-related fracture was 43.2 years, whereas it was 65.7 years in female patients. The cumulative probability of osteoporosis-related fracture increased after ≥ 5 years of TDF exposure. The rate of hip fracture (95% confidence interval) was 7.2 (3.1–14.2) per 10,000 PY. Conclusions Among HIV-infected patients in Japan, treatment with TDF for ≥ 5 years increases the risk of bone fractures in younger men, in addition to that seen in older post-menopausal women.

Focal segmental glomerulosclerosis (FSGS) is caused by various etiologies, with mitochondrial dysfunction being one of the causes. FSGS is known to be associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is a subclass of mitochondrial disease. However, it has rarely been reported in other mitochondrial disease subclasses. Here, we reported a 20-year-old man diagnosed with FSGS associated with chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) 3243A>G mutation. He presented with left ptosis, short stature, mild sensorineural deafness, and cardiac conduction block. A renal biopsy sample showed segmental sclerosis and adhesions between capillaries and Bowman’s capsule, indicating FSGS. Electron microscopy demonstrated abnormal aggregated mitochondria in podocytes, and the basement membrane and epithelial cells of Bowman’s capsule. Skeletal muscle biopsy also showed accumulation of abnormal mitochondria. mtDNA analysis identified heteroplasmic mtDNA 3243A>G mutation with no large-scale deletions. From these findings, we diagnosed the case as CPEO with multi-organ involvement including FSGS. Our report demonstrates that CPEO, as well as MELAS, can be associated with FSGS. Because mitochondrial disease presents with a variety of clinical symptoms, atypical cases with non-classical manifestations are observed. Thus, mitochondrial disease should be considered as an underlying cause of FSGS with systemic manifestations even with atypical phenotypes.

Two transferrin (Tf) glycan-isoforms were previously found in cerebrospinal fluid (CSF); one appears to be derived from serum (Tf-2) and the other from choroid plexus, a CSF-producing tissue (Tf-1). To analyse metabolic differences associated with the two isoforms, their ratio (Tf-2/Tf-1) was defined as the Tf index. Here we report that Tf indices of patients with tauopathies including Alzheimer's disease (2.29 + 0.64) were similar to those of neurological controls (2.07 + 0.87) (P = 0.147). In contrast, Tf indices with Parkinson's disease (PD, 3.38 ± 1.87) and multiple system atrophy (MSA, 3.15 ± 1.72) were higher than those of the controls (2.07 ± 0.87), the P-values being < 0.001 and 0.024, respectively. Tf indices of PD and MSA did not appear to be normally distributed. Indeed, detrended normal Quantile-Quantile plot analysis revealed the presence of an independent subgroup showing higher Tf indices in PD and MSA. The subgroup of PD showed higher levels of CSF α-synuclein (38.3 ± 17.8 ng/ml) than the rest (25.3 ± 11.3 ng/ml, P = 0.012). These results suggest that PD (and MSA) includes two subgroups, which show different metabolism of CSF transferrin and α-synuclein.

International audience; Objective : Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case–control series.Methods : We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.Results : In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel–Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14–5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15–5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10−3).Interpretation : The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Freezing of gait (FOG) is one of the factors that reduce the quality of life in patients with Parkinson's disease (PD). Imagining bicycling before gait start provided improvement in FOG in 2 PD patients. Imagining and mimicking bicycling after the initiation of gait allowed the rhythmic gait to continue without interruption. We suggest that imagining and mimicking bicycling, which are nonexternal cues, could serve as a helpful therapeutic approach for the intractable freezing and interruption of gait of PD patients.

Demyelinating polyneuropathy associated with amyotrophic lateral sclerosis (ALS) is quite rare. We herein present the case of a woman patient with a 12-year history of chronic inflammatory demyelinating polyneuropathy (CIDP)-like polyneuropathy who later developed bulbar palsy and respiratory failure. The autopsy findings revealed neuronal loss in the anterior horn and primary motor cortex with degeneration of the corticospinal tracts. Diffuse phosphorylated TAR DNA-binding protein of 43 kDa inclusions were observed in the anterior horn and cerebral cortices, including the temporal lobe. The final diagnosis was ALS with CIDP-like polyneuropathy. Compared with other reports of ALS with CIDP-like polyneuropathy, the present patient was younger and followed a relatively long clinical course, with no upper motor neuron signs.

Dementia is one of the most debilitating symptoms of Parkinson's disease (PD), but the development of dementia is still difficult to predict at early stages of the disease. We recently found that hyposmia, one of the most typical non-motor features of PD, was a predictive feature of Parkinson's disease with dementia (PDD). In that work, multivariate logistic analysis identified severe hyposmia and visuoperceptual impairment as independent risk factors for subsequent dementia within 3 years. The patients with severe hyposmia had an 18.7-fold increase in their risk of dementia for each 1 SD (2.8) decrease in scores on the odor stick identification test for Japanese (OSIT-J). We also found an association between severe hyposmia and a specific pattern of cerebral metabolic decline, which was identical to findings observed in PDD. Furthermore, volumetric magnetic resonance imaging analyses demonstrated close relationships between olfactory dysfunction and atrophy of focal brain structures, including the amygdala and other limbic structures. Our findings suggest that brain regions related to olfactory function are closely associated with cognitive decline and that severe hyposmia is a prominent clinical feature that predicts the subsequent development of PDD. We have now started a randomized, double-blind study using donepezil for the PD group with severe hyposmia. We hope that this clinical trial will allow us to establish a therapeutic intervention that can improve the prognosis of advanced PD.

Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disease involving parkinsonism, ataxia, and autonomic failure, in any combination. The unifying histopathological hallmark of MSA is the appearance of α-synuclein (αSYN)-positive, triangular-shaped glial cytoplasmic inclusion (GCI) in affected brain regions including striatonigral and/or olivopontocerebellar systems. It is known that GCI follows the regions showing neuronal loss and gliosis, and the incidence of GCI is well correlated with disease severity and duration, suggesting that the oligodendroglial αSYN pathology in MSA would be a prerequisite for the disease rather than a consequence of glio-neuronal degeneration. The mechanisms underlying the neuronal cell loss followed by oligodendroglial degeneration in MSA still remain elusive; however, recent observations from cultured cells, animal models, neuropathological and genetic studies have highlighted the several etiopathological factors including mitochondrial dysfunction, oxidative stress, aberrant misfolded protein processing and neuroinflammation. In the present review, we summarize a general overview of potential pathogenic processes and discuss the topics for debate especially focusing on the mechanisms by which αSYN accumulation in oligodendrocytes can secondarily lead to neuronal cell death.

Objective:To determine whether 18F-THK5351 PET can be used to visualize tau deposits in brain lesions in live patients with corticobasal syndrome (CBS).Methods:We evaluated the in vitro binding of 3H-THK5351 in postmortem brain tissues from a patient with corticobasal degeneration (CBD). In clinical PET studies, 18F-THK5351 retention in 5 patients with CBS was compared to that in 8 age-matched normal controls and 8 patients with Alzheimer disease (AD).Results:3H-THK5351 was able to bind to tau deposits in the postmortem brain with CBD. In clinical PET studies, the 5 patients with CBS showed significantly higher 18F-THK5351 retention in the frontal, parietal, and globus pallidus than the 8 age-matched normal controls and patients with AD. Higher 18F-THK5351 retention was observed contralaterally to the side associated with greater cortical dysfunction and parkinsonism.Conclusions:18F-THK5351 PET demonstrated high tracer signal in sites susceptible to tau deposition in patients with CBS. 18F-THK5351 should be considered as a promising candidate radiotracer for the in vivo imaging of tau deposits in CBS.

We occasionally observe long-term remission of cervical dystonia after several botulinum toxin treatments. However, botulinum toxin transiently acts on neuromuscular junctions. We herein report that a cervical dystonia patient with spinocerebellar ataxia type 1 could have long-term remission as a result of the depression of hypermetabolism in the bilateral putamen and primary sensorimotor cortex after botulinum toxin therapy. We suggest that botulinum toxin impacts the central nervous system, causing prolonged improvement through the normalization of basal ganglia circuits in addition to its effects at neuromuscular junctions.

Objective To investigate the cortical metabolic alterations that precedes longitudinal cognitive decline in Parkinson's disease (PD). Methods We analyzed the data of 46 PD patients who did not have dementia at baseline and completed 3-year follow-up. Based on the results of general cognitive, memory and visuospatial tests, patients were classified into cognitively normal PD (PD-CogNL), PD with mild cognitive impairment (PD-MCI), and PD dementia (PDD). The regional cerebral glucose metabolism at rest was measured using 18F-fluorodeoxyglucose positron emission tomography. Voxel-wise effect size analyses were performed to delineate abnormal metabolic patterns associated with changes in cognitive status in PD. Results At baseline, 29 patients had PD-CogNL, and 17 patients had PD-MCI. At follow-up, 28 patients had PD-CogNL, 12 patients had PD-MCI, and 6 patients developed PDD. Seventeen of 29 PD-CogNL patients remained to be PD-CogNL, and 9 PD-CogNL patients converted to PD-MCI. Eleven PD-MCI patients reverted to normal cognition during follow-up. 3 PD-CogNL and 3 PD-MCI patients developed PDD. Cognitively stable PD-CogNL group had frontal predominant hypometabolism. PDD converters showed parieto-occipital hypometabolism at baseline regardless of whether a patient's initial cognitive status is PD-CogNL or PD-MCI. Conclusions Parieto-occipital hypometabolism is a good predictor of early dementia conversion in PD.

Dementia is one of the most debilitating symptoms of Parkinson's disease. A recent longitudinal study suggests that up to 80% of patients with Parkinson's disease will eventually develop dementia. Despite its clinical importance, the development of dementia is still difficult to predict at early stages. We previously identified olfactory dysfunction as one of the most important indicators of cortical hypometabolism in Parkinson's disease. In this study, we investigated the possible associations between olfactory dysfunction and the risk of developing dementia within a 3-year observation period. Forty-four patients with Parkinson's disease without dementia underwent the odour stick identification test for Japanese, memory and visuoperceptual assessments, (18)F-fluorodeoxyglucose positron emission tomography scans and magnetic resonance imaging scans at baseline and 3 years later. A subgroup of patients with Parkinson's disease who exhibited severe hyposmia at baseline showed more pronounced cognitive decline at the follow-up survey. By the end of the study, 10 of 44 patients with Parkinson's disease had developed dementia, all of whom had severe hyposmia at baseline. The multivariate logistic analysis identified severe hyposmia and visuoperceptual impairment as independent risk factors for subsequent dementia within 3 years. The patients with severe hyposmia had an 18.7-fold increase in their risk of dementia for each 1 SD (2.8) decrease in the score of odour stick identification test for Japanese. We also found an association between severe hyposmia and a characteristic distribution of cerebral metabolic decline, which was identical to that of dementia associated with Parkinson's disease. Furthermore, volumetric magnetic resonance imaging analyses demonstrated close relationships between olfactory dysfunction and the atrophy of focal brain structures, including the amygdala and other limbic structures. Together, our findings suggest that brain regions related to olfactory function are closely associated with cognitive decline and that severe hyposmia is a prominent clinical feature that predicts the subsequent development of Parkinson's disease dementia.

The histopathological hallmark of multiple system atrophy is the appearance of intracellular inclusion bodies, named glial cytoplasmic inclusions, which are mainly composed of alpha-synuclein fibrils. In vivo visualization of alpha-synuclein deposition should be used for the diagnosis and assessment of therapy and severity of pathological progression in multiple system atrophy. Because 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole could stain alpha-synuclein-containing glial cytoplasmic inclusions in post-mortem brains, we compared the carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole positron emission tomography findings of eight multiple system atrophy cases to those of age-matched normal controls. The positron emission tomography data demonstrated high distribution volumes in the subcortical white matter (uncorrected P < 0.001), putamen and posterior cingulate cortex (uncorrected P < 0.005), globus pallidus, primary motor cortex and anterior cingulate cortex (uncorrected P < 0.01), and substantia nigra (uncorrected P < 0.05) in multiple system atrophy cases compared to the normal controls. They were coincident with glial cytoplasmic inclusion-rich brain areas in multiple system atrophy and thus, carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole positron emission tomography is a promising surrogate marker for monitoring intracellular alpha-synuclein deposition in living brains.

Background and Objective:Calcium channel antagonists (calcium channel blockers [CCBs]) are often used in the treatment of patients with hypertension to achieve strict blood pressure (BP) targets. In the present study, we compared the antihypertensive effects (determined by home BP [HBP] measurements) and the effects on renal function of benidipine (hydrochloride) and amlodipine (mesylate), a commonly used CCB. Methods:Changes in HBP and urinary albumin excretion (UAE) were investigated in 47 benidipine and 37 amlodipine recipients with essential hypertension and albuminuria between January 2007 and December 2007. Results:Both benidipine and amlodipine significantly reduced morning and evening HBP over a 12-month period. Both medications also significantly reduced UAE compared with pretreatment values; however, the reduction in UAE observed in the benidipine group occurred independent of the drug’s antihypertensive effects, whereas a positive correlation was shown between the reduction in morning systolic BP and UAE in the amlodipine group. Conclusion:These results demonstrate that benidipine favourably affects renal function in patients with essential hypertension compared with amlodipine, suggesting that the clinical benefits of benidipine as an antihypertensive drug include a renoprotective effect.

We experienced 2 patients of valvular heart disease in Parkinson's patients taking cabergoline. Patient 1 was a 79-year-old woman who began taking 4 mg cabergoline daily after being diagnosed with Parkinson's disease (PD) in June 2003. She presented with dyspnea in November 2005. The patient had cardiomegaly, pulmonary congestion, and pleural effusion, and an echocardiogram showed valvular heart disease in the form of aortic regurgitation (AR) (grade I), tricuspid regurgitation (TR) (grade I), and mitral regurgitation (MR) (grade III). Cabergoline was thought to have caused these phenomena, so it was replaced with pramipexole, and after administration of diuretics and angiotensin-converting enzyme inhibitors (ACEIs) the patient's symptoms gradually disappeared. MR, AR and TR also disappeared 3 months later. Patient 2 was a 74-year-old woman who presented with sluggish movement in April 2001 and subsequently developed Parkinson's. While being administered 700 mg levodopa (Menesit) and 4 mg cabergoline, the patient presented with shortness of breath in April 2005. An echocardiogram showed valvular heart disease in the form of MR (grade I) and TR (grade I). Heart function improved with the administration of diuretics. However, heart function again worsened in November 2005, and the patient presented with edema of the lungs and lower limbs. An echocardiogram in January 2006 showed worsening MR (grade III) and TR (grade II), and the patient also had pulmonary hypertension. ACEIs were administered along with diuretics and cabergoline was replaced with pramipexole, but the patient also developed malignant syndrome and disseminated intravascular coagulation (DIC) and later died. Patient 2 is the first case in Japan of death due to heart failure caused by the side effects of cabergoline. Caution is usually needed when treating a Parkinson's patient for valvular heart disease due to a dopamine agonist, and periodic checks for heart murmurs and echocardiography are crucial. When signs of heart failure develop during treatment with an ergot preparation of dopamine agonist, it is essential to immediately either stop the administration of the ergot preparation or change to a non-ergot preparation of dopamine agonist.

Olfactory dysfunction in Parkinson's disease (PD) has been described for more than thirty years and known as one of the commonest non-motor symptoms in PD. Recently, it attracts widespread attention as one of early symptoms preceding motor impairments and a potential good marker for the preclinical diagnosis of PD. However, some previous reports demonstrated that olfactory function was also impaired in other dementing disorders such as Alzheimer's disease and it was not specific for PD. But recent pathological re-evaluation suggests that olfactory dysfunction is strongly associated with Lewy body pathology rather than other pathological hallmarks including neurofibrillary tangles. Thus olfactory tests may improve diagnostic accuracy of PD. Increasing evidence suggests that olfactory dysfunction is one of the most important non-motor symptoms in PD.

A 59-year-old woman without underlying disease was admitted to a local hospital because of lung abscess, cytopenias and renal failure. 3 days before admission, she was diagnosed as influenza infection and was under antiviral therapy. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus (MSSA). She was transferred to our hospital on the 15th day at the local hospital because the clinical manifestations could not improve even though she was treated with multiple intravenous antibiotics directed against MSSA. Sputum cultures yielded methicillin-resistant S. aureus (MRSA) producing toxic shock syndrome toxin-1 (TSST-1) and serologic test indicated hypercytokinemia. She was diagnosed as rapidly progressive glomerulonephritis and hemophagocytic syndrome associated with staphylococcal infection. The pulmonary lesions, cytopenias and renal dysfunction improved as a result of long-term antimicrobial treatment including vancomycin, hemodialysis, short-term administration of corticosteroid and other supportive cares. She was finally weaned from hemodialysis on the 73rd hospital day. In recent years, the number of cases of S. aureus producing TSST-1 and enterotoxin has been increasing and in cases of staphylococcal infections, close attention should be given to toxin-mediated as well as non-toxin-mediated clinical manifestations.

Mutations in alpha-synuclein cause some cases of familial Parkinson's disease (PD), but the mechanism by which alpha-synuclein promotes degeneration of dopamine-producing neurons is unknown. We report that human neural cells expressing mutant alpha-synuclein (A30P and A53T) have higher plasma membrane ion permeability. The higher ion permeability caused by mutant alpha-synuclein would be because of relatively large pores through which most cations can pass non-selectively. Both the basal level of [Ca2+]i and the Ca2+ response to membrane depolarization are greater in cells expressing mutant alpha-synuclein. The membrane permeable Ca2+ chelator BAPTA-AM significantly protected the cells against oxidative stress, whereas neither L-type (nifedipine) nor N-type (omega-conotoxin-GVIA) Ca2+ channel blockers protected the cells. These findings suggest that the high membrane ion permeability caused by mutant alpha-synuclein may contribute to the degeneration of neurons in PD.

8-hydroxy-2′-deoxyguanosine (8-OHdG) or 8-hydroxyguanosine (8-OHG), a product of oxidized DNA or RNA, is a good marker of oxidative cellular damage. In this study, we measured the 8-OHdG/8-OHG levels in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) and multiple system atrophy (MSA). Compared to age-matched controls, the mean levels of serum 8-OHdG/8-OHG were significantly higher in PD (P < 0.0001). Although no gender differences were observed in the controls, the mean values of serum 8-OHdG/8-OHG were significantly higher in female PD cases (P < 0.005) than in male patients. 8-OHdG/8-OHG levels in CSF were also increased significantly in patients with PD and MSA, however, their relative values were generally much lower than those in the serum. Together with previous studies showing increased peripheral 8-OHdG levels in Alzheimer's disease and amyotrophic lateral sclerosis, the data presented here suggest that systemic DNA/RNA oxidation is commonly observed in neurodegenerative diseases. Our results also imply that female patients with PD show higher levels of oxidative stress, which may explain the faster progression of this disease in females.

123 l) myocardial meta-iodobenzylguanidine abstract We aimed to study whether either ( 123 l) myocardial meta-iodobenzylguanidine (MIBG) myocardial scintigraphy or the odor stick identification test for Japanese (OSIT-J) is effective in differentiating Parkinson's disease (PD) from multiple system atrophy (MSA). We compared the MIBG accumulation and olfactory score between 42 PD and 42 MSA (19 MSA-P and 23 MSA-C) patients in the early stages. ( 123 l) MIBG myocardial scintigraphy showed higher sensitivity and the olfactory test higher specificity in differentiating PD from MSA. There were significant differences between PD and MSA-C (p ¼ 0.0019) instead of MSA-P (p > 0.05) in the MIBG accumulation, while there were significant differences between PD and MSA-P (p ¼ 0.0003) or MSA-C (p ¼ 0.0003) in the OSIT-J score. Our data suggest that the olfactory test can be useful as a clinical tool with its higher speci ficity in differ- entiating PD from MSA in the early stages and, moreover, support the discrimination of PD from MSA-P.

This study examined effects of hedonic tones produced by odor stimuli on human mental performance. Thirty subjects were equally assigned to one of three olfactory stimulus groups: a control group with blank air, a Rose and a Ylang-ylang scented air group. From a preliminary study, we selected the latter as an unpleasant odor stimulus. The subjects of a different group received a different olfactory stimulus into a their nostril while they performed an audio-visual dual task. In this task the subjects were required to discriminate the difference in duration of a tone stimulus and to press a right hand key when they found the tone shorter. Engaging in this performance they had to attend to a red light rested in front of them and to press a left hand key when the light was turned off. For this visual performance the subjects of the Ylangylang group improved the detection of the signals in the first odor block. For the auditory performance, however, they made more errors than those of other groups. These results suggested that whiffs of an unpleasant odor would enhance detectability of the visual signal, but inhibit cognitive processes associated with discrimination in the dual task performance.

A 74 year-old man with progressive supranuclear palsy (PSP) was adimitted to our hospital. He developed bradykinesia 13 years previously. Neurological examination showed cognitive dysfunction, supranuclear vertical gaze palsy, pseudobulbar palsy, and parkinsonism such as akinesia, rigidity, and resting tremor. His chief complaint was glossoptosis with jaw-opening dystonia associated with rapid dose-elevation and/or overdose of dopaminergic drugs. After gradual tapering of dopaminergic drugs, he could keep his mouth closed all day. Drug-induced dystonia is a frequently encountered but often overlooked symptom of neurological disorders. The motor symptoms of PSP sometimes respond to dopamine replacement therapy; however, it should be kept in mind that rapid dose-elevation and/or overdose of dopaminergic agents may cause jaw-opening dystonia.

Objective Dysphagia is one of the cardinal symptoms of Parkinson’s disease (PD). It is closely related to the quality of life and longevity of PD patients. The aim of the study is to clarify the pathophysiological mechanisms responsible for dysphagia in PD. Design A cross-sectional and longitudinal comparative study. Setting Tohoku University Hospital. Participants Eight patients with dysphagia, 15 patients without dysphagia and 10 normal control subjects. Main outcome measures The time needed for swallowing initiation and changes in brain glucose metabolism at baseline and after a 3-year follow-up period. Results The time needed for swallowing initiation was significantly longer in the patients with dysphagia compared with the patients without dysphagia at baseline and after the 3-year follow-up period (p

Background Abnormal cardiac uptake of 123I-metaiodobenzylguanidine (123I-MIBG) is a diagnostic marker of Lewy body diseases (LBDs), e.g., Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Planar imaging is generally used to assess cardiac sympathetic dysfunction in 123I-MIBG scintigraphy; however, its clinical utility requires further improvement. We hypothesized that the co-registration of single-photon emission tomography (SPECT) and computed tomography (CT) images would improve the diagnostic accuracy of 123I-MIBG cardiac scintigraphy for LBDs. This study sought to evaluate the effects of SPECT/CT imaging on 123I-MIBG cardiac scintigraphy for diagnosing LBDs. Methods We retrospectively investigated data of 54 patients (consecutive 18 patients in each PD, DLB, and idiopathic normal pressure hydrocephalus [iNPH] groups) who underwent 123I-MIBG cardiac scintigraphy (planar and SPECT/CT) because of suspected LBDs at the Tohoku University hospital from June 2012 to June 2015. We compared the diagnostic accuracies of the conventional planar 123I-MIBG method and SPECT/CT methods (manual and semi-automatic). Results In the conventional planar analysis, 123I-MIBG uptake decreased only in the DLB group compared with the iNPH group. In contrast, the SPECT/CT analysis revealed significantly lower 123I-MIBG uptake in both the PD and DLB groups compared with the iNPH group. Furthermore, a receiver operating characteristic analysis revealed that both the manual and semi-automatic SPECT/CT methods were superior to the conventional planar method in differentiating the 3 disorders. Conclusions SPECT/CT 123I-MIBG cardiac scintigraphy can detect mild cardiac sympathetic dysfunction in LDBs. Our results suggest that the SPECT/CT technique improves diagnostic accuracy for LBDs.

Psychological effects of two kinds of scents were investigated on a discrimination task. Twenty undergraduates, involving 7 male students, were assigned into four scent groups of 5 subjects in each. Olfactory stimuli were scents, Lemon and Rose, and each of which had different concentrations. Either of the scent stimuli or pure air delivered to a subject's nostril for 30 sec just before the task. During the task section, either of the longer (450 msec) or the shorter (300 msec) 1, 000 Hz pure-tone signal was presented randomly twenty times with an interval of 3 sec. The subjects were required to press a key when they found the shorter tone. This task section was repeated three times that forms one block; one session a day consisted of five blocks. All the subjects participated in the experiment of three sessions over three days in total. Among five blocks, the control stimulus of pure air was delivered in the first, third, and fifth block, and in others one of the scent stimuli delivered. Subjects' performances were assessed by measuring reaction times to the tone signal and number of response errors. In addition, measurement of heart-rate and ratings of mood were taken throughout the 5 experimental blocks. The results indicated that the scent stimuli with a higher concentration could improve the performance accuracy: the less number of error. This effect appeared to be larger in the Rose group than in the Lemon. In the second block, both kinds of scent with the higher concentrations produced larger changes on ratings of mood than with lower concentrations. It seemed that such effects of the scents on mood were different from those on the task performance.

症例は28歳,一年程前より上肢を長時間動かすと倦怠感と立ちくらみを自覚.今回台所仕事中に意識消失し搬送された.意識清明なるも脈は触知せず,血圧も測定不可であった.頸部に血管雑音聴取し,血管造影にて左右鎖骨下動脈は描出されず,右総頸動脈に狭窄を認めた.血液検査にて炎症反応を認め,大動脈炎症候群と診断した.左右鎖骨下動脈,右総頸動脈に計3個のステントを留置し症状は消失,プレドニン,トラニラスト,シロスタゾール投与下に経過良好である.

The authors describe the case of a 39-year-old man who presented to our hospital with easy fatigability and malaise. On physical examination, hypertension was noted without any cushingoid appearance. Laboratory testing revealed normochromic-normocytic anaemia with positive results of occult blood in the stool, hyperglycaemia and hypokalemia. Upper endoscopy revealed active gastric ulcer with Helicobacter pylori infection, likely causing gastrointestinal bleeding. Endocrine examinations showed that both serum adrenocorticotropic hormone and cortisol were elevated with loss of diurnal variation. A diagnosis of Cushing’s disease secondary to pituitary adenoma was made as results of brain MRI and blood sampling from inferior petrosal sinus. In a patient with peptic ulcer disease, physician should be alert to the possible endocrine background.

Fragrance materials such as perfumes have long been known to exert effects on the mind and body. Throughout histry, perfumes have been used as sedatives and stimulants. However, there are very few psychophysiological studies in aromachology with regard to the effect of odor itself on human subjects.In this study, the effects of odors on cardiac response patterns were investigated during the foreperiod of the two-stimulus paradigm in a simple reaction time task. Changes in the cardiac response pattern were typically triphasic during the foreperiod between the worning stimulus (WS) and imperative stimulus (IS).Heart rate decelelation (DE) usually seen just prior to IS is thought to reflect the process of anticipation or attention. Thus, stimulative odors are expected to activate those processes while sedative odors are thought to exert a suppressive effect.This experiment was designed to estimate the effect of some kinds of odors by the DE amplitude. Olfactory stimulation (some different aromatic air samples and odorless air) was provided to subjects by the blast method.A trial consisted of a 5-second rest period, followed by a 20-second period in which the olfactory stimulus was presented, a 10-second foreperiod lasting from the WS tone to the IS tone signaling the subject to press the response key, and a 15-second post-foreperiod after the IS tone.The odor of lemon, traditionally thought to be stimulative, had the effect of activating anticipation or attention process. This effect tended to be stronger by increasing odor intensity. On the other hand, the rose odor, thought to be sedative, had the effect of suppressing this process, and these effect was observed across all intensity levels.Futhermore, We carried out an experiment in the same method, to estimate the effects of 3 kinds of perfumes for the development of odor using for certain skincare products.We believe this investigational method with two-stimulus paradigm could be a useful one to determine the psychophysiological effects of odor especially in stimulative-sedative continuum of its effect.

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extended transverse myelitis (LETM). The clinical and laboratory features of NMO are different from multiple sclerosis (MS).1 An autoantibody to aquaporin-4 (AQP4) has been detected exclusively in the NMO sera.1 Moreover, we demonstrated an extensive loss of AQP4 and glial fibrillary acidic protein immunoreactivities in the perivascular regions with complement and immunoglobulin deposition in NMO that suggests astrocytic impairment. However, when AQP4 antibody is produced in patients with NMO is unknown, and thus it remains unresolved whether there are long-term asymptomatic AQP4 antibody–positive carriers, whether AQP4 antibody alone can be pathogenic, and whether AQP4 antibody is produced secondarily as a result of tissue destruction in attacks of NMO. We herein report a case of NMO in which AQP4 antibody was detected years before the NMO onset. ### Case report. A 34-year-old healthy woman without previous history of inflammatory or neurologic diseases noticed temporary skin eruptions on her chest and shoulders in June 2007. A dermatologist made the diagnosis of eczema. Three weeks later, when the skin eruptions subsided, she noted progressive paresthesia in the chest and toes. Within a few days, she could not walk well due to right leg weakness, and then she was hospitalized. Neurologic examination on …

A 50-year-old man without family history of metabolic bone disease was referred to our hospital with a 5-year history of progressively worsening spinal and bilateral diffuse leg pain and proximal muscle weakness. Two years before admission, he was diagnosed as ankylosing spondylitis by a rheumatologist and was maintained on low-dose prednisone therapy without benefit. He developed progressive spinal and thoracic deformities, resulting in a 10 cm loss in height in the preceding 2 years. On physical examination, marked thoracic kyphosis and pectus carinatum was noted. Plain radiograph revealed pseudofracture in the right femoral neck. Laboratory findings showed a normal level of serum calcium, elevated level of serum alkaline phosphatase and inappropriately increased urinary phosphate excretion despite extreme hypophosphatemia. He was diagnosed as adult-onset hypophosphatemic osteomalacia caused by renal phosphate wasting. Serum fibroblast growth factor 23 was the upper limit of normal despite extreme hypophosphatemia and no neoplastic lesion potentially inducing hypophosphatemic osteomalacia could be identified in a thorough search including imaging studies of his entire body. Oral administration of phosphate and activated vitamin D together with dipyridamole relieved the persistent pain and weakness, and he became fully ambulatory.

A 56-year-old woman was admitted because of a high fever, right ptosis, chemosis, proptosis and ocular muscle palsy. Cranial MRI revealed a cavernous sinus thrombosis and a subarachnoid abscess. Carotid angio-gram demonstrated marked stenosis as well as aneurismal formation of the right internal carotid artery at the intracavernous portion. Chest radiograph showed bilateral multiple pulmonary nodules, some of which contained a cavity. Blood culture was positive for Streptococcus constellatus. She was diagnosed with septic cavernous sinus thrombosis complicated by narrowing of the internal carotid artery, subarachnoid abscess and multiple pulmonary septic emboli. She recovered with partial ocular sequelae as a result of seven weeks of intravenous antimicrobial therapy.

Some pathological similarities between Alzheimer’s disease and muscle diseases with rimmed vacuoles (RV) have been pointed out. For example, several pathological hallmark proteins have been reported to be immunopositive in the lesions of both diseases. Since apoptotic processes or primary DNA damage are suggested to play a role in the pathomechanism of Alzheimer’s disease, we examined DNA double-strand breaks (DSB) and single-strand breaks (SSB) in the muscle biopsy specimens of several diseases, including muscle diseases with RV. Although no DSB-positive myonuclei were detected in any muscles examined, the number of SSB-positive myonuclei markedly increased in the muscles from cases with polymyositis and muscle diseases with RV. In polymyositis, SSB-positive myonuclei were observed in regenerating fibers and muscle fibers in the vicinity of inflammatory infiltrates, suggesting that the increase of SSB is due to muscle fiber regeneration following necrosis and inflammation. In muscle diseases with RV, however, SSB-positive myonuclei were observed in small angulated fibers and in morphologically normal fibers, regardless of necrosis, regeneration or inflammation. These findings suggest that muscle diseases with RV may share a common pathological process involving DNA damage.

A 61-year-old man presented with diffuse myalgia and arthralgia. The physical examination showed diffuse musculoskeletal tenderness and joint stiffness without the presence of synovitis or arthritis. Nerve conduction study showed combined mild axonal degenerative and demyelinating change. Muscle biopsy analysis showed unspecific mild muscle atrophy with myopathic changes found on electromyography. A diagnosis of isolated adrenocorticotropic hormone deficiency was made on the basis of endocrinological evaluation. The widespread musculoskeletal pain resolved as a result of administration of physiological dose of hydrocortisone replacement. In a patient with unexplained rheumatic symptoms, adrenocortical insufficiency should be considered in the possible aetiology.

Organising pneumonia (OP) is an inflammatory lung disease with distinctive clinicopathological features. OP can be evident during the course of rheumatoid arthritis (RA) with increased disease activity. The authors report an OP associated with RA case in which pulmonary symptoms preceded the onset of joint symptoms. An OP patient with elevated serum anticyclic citrullinated peptide antibody is likely to manifest RA in the near future, reflecting its high disease activity. Thus, an early rheumatologic consultation should be taken into consideration to make an early decision to initiate disease-modifying antirheumatic drugs therapy.

This is a report on the clinical courses and pathological findings in two gay male patients with acquired immunodeficiency syndrome (AIDS) infected in Japan. Case 1. A 39 year-old Japanese homosexual male was diagnosed as amebic dysentery complicated with liver abscess on admission. He was placed on Metronidazole with complete relief. Serological tests was positive for AIDS. On second admission, he was found to have pneumocystis carinii pneumonia (PCP) and cytomegalo-viral uveitis. Administration of Pentamidine was partially effective, however the therapy with Azidothimidine was discontinued by bone marrow suppression. On his third admission, he suffered from cryptococcal meningitis and therapy-resistant fungusemia. Finally he died of recurrent pneumonia regardless of appropriate therapies. Autopsy proved extended cryptococcal infection in the brain, meninx, lungs, liver and kidney, and cytomegalo-infection in the lungs, liver and kidney. Furthermore, atypical mycobacteriosis was found in the lymph nodes. There was no active findings compatible with PCP. Case 2. A 44 year-old Japanese homosexual male was admitted with oral candidiasis and diagnosed as AIDS related complex. He suffered from pneumonia with marked improvement on sulfamethoxazole-Trimethoprim. On his second admission, he developed diarrhea and was found to be infected with Giardia lambia. In addition, cytomegalo-viral infection damaged his eye sight. He died of pneumonia and meningitis shortly there after. Autopsy proved a cytomegalo-viral infection in the lung and colon, old lesions possibly caused by PCP in the lungs, and suppurative meningitis in the meninx. These experiences confirm that AIDS patients can be exposed to several opportunistic infections at the same time in the multiple organs. Furthermore, it is suggested that homosexual patients with AIDS may have unique opportunistic infections such as amebic dysentery or Giardia lamblia unlike other AIDS patients related to hemophilia.