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INTRODUCTION: Multiple system atrophy (MSA) typically presents with parkinsonism, ataxia and/or autonomic dysfunction. Occasionally, clinically atypical (ca-MSA) cases masquerade as progressive supranuclear palsy (PSP). We aimed to investigate whether different neuroimaging modalities could facilitate differentiation and whether histopathologic characteristics could explain the atypical presentation. METHODS: We identified 3 neuropathologically-defined ca-MSA patients with clinically diagnosed PSP who underwent various antemortem brain imaging: MRI and PET imaging using (11)C-Pittsburgh compound B, (18)F-flortaucipir, and (18)F-fluorodeoxyglucose. We compared clinical features, brainstem planimetry, and radiotracer standardized uptake value ratios in ca-MSA to 10 autopsy-confirmed PSP patients and 10 healthy controls (imaging only). We also compared histologic count of neuronal loss, iron deposition and α-synuclein-immunoreactive glial cytoplasmic inclusion burden to 10 autopsy-confirmed MSA-parkinsonism (MSA-P) cases. RESULTS: Ca-MSA had better PSP Saccadic Impairment Scale scores (p=0.003) and more frequent good levodopa response (p=0.061) than PSP. Ca-MSA showed higher midbrain-to-pons ratio and lower Magnetic Resonance Parkinsonism Index than PSP (each, p=0.036) and exhibited lower glucose metabolism in the putamen and globus pallidus versus PSP (p=0.017) and controls (p=0.007). These same regions showed higher flortaucipir uptake in ca-MSA than PSP (p=0.007 for putamen, p=0.049 for pallidum) and controls (p=0.012). Lower flortaucipir retention was observed in the subthalamic nucleus versus PSP (p=0.007). The putamen-to-subthalamic ratio distinguished ca-MSA from PSP. No histopathological differences were observed for ca-MSA versus typical MSA-P. CONCLUSION: Severity of saccadic impairment, levodopa responsiveness, MRI planimetric measurements, and different patterns of fluorodeoxyglucose and flortaucipir uptake can help improve antemortem differentiation of MSA masquerading as PSP from true PSP.

Intraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer’s disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity. Using summary statistics from Parkinson’s disease and Alzheimer’s disease genome wide association studies we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β, and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217 and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson’s disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer’s disease co-pathology. In an ordinal logistic regression model the Alzheimer’s disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson’s disease risk score and specific to the subset of samples without significant concomitant Alzheimer’s disease related neuropathology. Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson’s and Alzheimer’s disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer’s disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.

In the current consensus criteria, onset after age 75 is considered as non-supporting for diagnosis of multiples system atrophy (MSA); however, some MSA patients present after age 75. Clinical and pathological characteristics of such later onset MSA (LO-MSA) compared to usual onset MSA (UO-MSA) remain poorly understood.The clinical cohort included patients from Kobe University Hospital and Amagasaki General Medical Center Hospital, while the autopsy cohort was from the brain bank at Mayo Clinic Florida. We identified 83 patients in the clinical cohort and 193 patients in the autopsy cohort. We divided MSA into two groups according to age at onset: UO-MSA (≤ 75) and LO-MSA ( 75). We compared clinical features and outcomes between the two groups in the clinical cohort and compared the findings to the autopsy cohort.LO-MSA accounted for 8% in the clinical cohort and 5% in the autopsy cohort. The median time from onset to death or to life-saving tracheostomy was significantly shorter in LO-MSA than in UO-MSA in both cohorts (4.8 vs 7.9 years in the clinical cohort and 3.9 vs 7.5 years in the autopsy cohort; P = 0.043 and P 0.0001, respectively). The median time from diagnosis to death was less than 3 years in LO-MSA in the clinical cohort.Some MSA patients have late age of onset and short survival, limiting time for clinical decision making. MSA should be considered in the differential diagnosis of elderly patients with autonomic symptoms and extrapyramidal and/or cerebellar syndromes.

Neuropathological assessment at autopsy is the gold standard for diagnosing neurodegenerative disorders. We aimed to develop a pipeline for diagnosing Alzheimer's disease and other tauopathies, including corticobasal degeneration, globular glial tauopathy, Pick’s disease, and progressive supranuclear palsy. We used deep learning (DL)-based approach called clustering-constrained-attention multiple instance learning (CLAM) on whole slide images (WSIs) of tau immunohistochemistry in three brain regions from 120 patients. We also augmented gradient-weighted class activation mapping (Grad-CAM) to the model for visualizing cellular-level evidence in the model’s decisions. The model using the sections of cingulate and superior frontal gyri achieved the highest area under the curve (0.970±0.037) and diagnostic accuracy (0.873±0.087). Grad-CAM showed the highest attention in known pathognomonic tau lesions for each disease (e.g., Pick bodies for Pick’s disease). Our findings supported the feasibility of the DL-based approach for the classification task on WSIs, which encouraged further investigation, especially focusing on clinicopathological correlation studies.

Background: As part of the CurePSP brain donation program, a questionnaire was developed to capture basic information from the next-of-kin or someone familiar with the brain donor with respect to symptoms and clinical course. The usefulness of information from the questionnaire has not been assessed. Objective: To assess the value of information from the brain donation questionnaire as it relates to differential diagnosis of parkinsonian disorders. Methods: We reviewed 150 questionnaires, including 50 patients, each with a neuropathologic diagnosis of Lewy body disease (LBD), multiple system atrophy (MSA), or progressive supranuclear palsy (PSP). The frequency of clinical features recorded in the questionnaires was compared for the three disorders, and machine learning algorithm, XGBoost, was applied to tabulated information from the questionnaires to identify features that had predictive value with respect to neuropathologic diagnosis. Results: The information from the questionnaires correlated with core clinical features for each disorder - hallucinations for LBD, autonomic dysfunction for MSA, and early falls for PSP. Age at onset and early falls were identified as the key variables that contributed most to prediction of neuropathology. Conclusion: While less optimal than prospectively collected information, a questionnaire can provide useful clinical information for clinicopathological correlative studies.

Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions (GCIs). Synucleinopathies can be divided into two major disease entities: Lewy body disease (LBD) and multiple system atrophy (MSA). Common clinical presentations of LBD are Parkinson's disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). There are currently no disease-modifying therapies for the synucleinopathies, but elucidation of genetics and mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and GCI) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from LBD and MSA are distinct "strains" having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissues. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a review of classification and staging schemes for LBD. We also review evidence supporting the existence of distinct α-synuclein strains in LBD and MSA.

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. GCIs and NIs are late-stage pathology features relative to AS oligomers and may not represent early pathological changes in MSA. To reveal the early pathology of MSA, it is necessary to examine the early aggregation of AS, i.e., AS oligomers. Here, we adopted a proximity ligation assay (PLA) to examine the distribution of AS oligomers in brain tissue samples from patients with MSA and other diseases. Surprisingly, MSA brains showed a widespread distribution and abundant accumulation of oligomeric AS in neurons as well as oligodendrocytes of the neocortex. In several regions, oligomeric AS signal intensity was higher in cases with MSA than in cases with Parkinson’s disease. In contrast to previous studies, AS–PLA revealed abundant AS oligomer accumulation in Purkinje cells in MSA brains, identifying oligomeric AS accumulation as a possible cause of Purkinje cell loss. This wide distribution of AS oligomers in MSA brain neurons has not been described previously and indicates a pathological mechanism of NL in MSA.

A 49-year-old woman with intellectual disability and a food preference for fried chicken entered a nursing home. After nursing home diet, she developed episodic attacks of hyperammonemic encephalopathy. Her characteristic food preference and the negative results for brain and liver imaging studies suggested urea cycle disorder. A high plasma citrulline level on amino acid analysis and a genetic test for citrine gene confirmed a citrine deficiency (adult-onset type II citrullinemia). Although a low-carbohydrate diet was insufficient, a combination therapy of a low-carbohydrate diet and a medium-chain triglyceride (MCT) oil was effective. MCT oil may be a promising treatment option.

A 27 year-old Canadian man suffered from fluctuating muscle weakness in the past several years. The patient had a past history of intestinal bleeding, bifid uvula and hypothyroidism in his childhood. Repetitive nerve stimulation tests showed a decrement pattern in the left deltoid muscle. The single fiber electromyography of the left extensor digitorum muscle showed an increment of jitter. Both findings were improved by the edrophonium test. He was diagnosed as having phosphoglucomutase 1 (PGM1) deficiency, as the compound heterozygote mutation of the PGM1 gene was recognized in the whole-exome sequencing and the enzyme activity of PGM1 was defective in the biopsied muscle. Treatment with the galactose lead to improvement of the fluctuating muscle weakness and decremental pattern in the repetitive stimulation test. PGM1 deficiency should be listed in the differential diagnosis of the neuromuscular junction disorder, when the patient is seronegative for antibodies related with myasthenia gravis and shows symptoms or signs consistent with PGM1 deficiency.

Background Although the usefulness of susceptibility-weighted imaging (SWI) for detecting basal ganglia germinoma has been reported, the technique is not widely used. We recently encountered an unusual case of primary cerebellar germinoma, presenting with progressive ataxia and cranial nerve palsy, characterized by gradually enlarging low-intensity lesions visible with both T2*-weighted imaging (T2*WI), which were the key to the diagnosis. Case presentation A 30-year-old man was referred to our hospital because of slowly progressive dizziness and mild ataxia. Magnetic resonance imaging (MRI) revealed a small, low-intensity spot in the left cerebellar peduncle on the T2*WI and SWI without enhancement. Cerebral angiography revealed no vascular abnormality. The serum α-fetoprotein value was normal. A steroid-pulse was administered as a therapeutic and diagnostic trial, but the symptoms improved little. The patient was discharged from the hospital but soon developed brainstem dysfunction, characterized by dyspnea or hiccups, and he was readmitted. T2*WI imaging revealed expanded and extended spotty lesions in the cerebellum and brainstem, which had not enhanced with contrast agent previously. Targeted stereotactic biopsy of the newly enhanced cerebellar lesion was performed; histopathological examination of the tissue revealed pure germinoma. Serum and cerebral spinal fluid values of beta-human chorionic gonadotropin were not significantly elevated. Chemotherapy with carboplatin and etoposide was initiated. The enhanced lesion disappeared promptly, but the patient continued to require assisted automatic ventilation because of paralysis of respiratory muscles. Conclusions We conclude that enlarging low-intensity lesions on T2*WI and SWI may be a reliable clue to the diagnosis of germinomas, irrespective of their location, even without enhancement. Biopsy of the tumor at an early stage is the only way to make the diagnosis conclusively and enable prompt start of treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12883-015-0516-9) contains supplementary material, which is available to authorized users.

A 57-year-old man presented with subacute progression of cognitive impairment (MMSE 22/30). He had been diagnosed as AIDS two years before and taking atazanavir, abacavir, and lamivudine. HIV RNA of plasma had been negative. On admission, HIV RNA was 4,700 copy/ml and 5,200 copy/ml in plasma and in cerebrospinal fluid respectively, suggesting treatment failure of cART. The brain magnetic resonance imaging showed high intensity areas in the white matter of the both frontal lobes and brain stem. The drug-resistance test revealed the resistance of lamivudine and abacavir. We introduced the CNS penetration effectiveness (CPE) score to evaluate the drug penetration of HIV drugs. As the former regimen had low points (7 points), we optimized the regimen to raltegravir, zidovudine, and darunavir/ritonavir (scoring 10 points). His cognitive function improved as normal (MMSE 30/30) in 2 weeks and HIV-RNA became undetectable both in plasma and CSF in a month. In spite of the cognitive improvement, the white matter hyperintensity expanded. To rule out malignant lymphoma or glioblastoma, the brain biopsy was performed from the right frontal lobe. It revealed microglial hyperplasia and diffuse perivascular infiltration by CD8+/CD4-lymphocytes. No malignant cells were found and the polymerase chain reaction analyses excluded other viruses. Considering the drug penetration to the central nervous system is important for treating HIV encephalopathy.

Cryptococcosis is a fungal infection, which mainly invades the lungs and central nervous system. In Japan, most cases of cryptococcosis are caused by Cryptococcus neoformans(C. neoformans). Until now, only three cases which the infectious agent was Cryptococcus neoformans var. gattii(C. gattii)have been reported. As compared with cryptococcosis caused by C. neoformans, which is often observed in immunocompromised hosts, cryptococcosis caused by C. gattii occurs predominantly in immunocompetent hosts and is resistant to antifungal drugs. Here, we report a case of refractory cerebral cryptococcoma that was successfully treated by surgical resection of the lesions. A 33-year-old man with no medical history complained of headache, hearing disturbance, and irritability. Pulmonary CT showed a nodular lesion in the left lung. Cerebrospinal fluid examination with Indian ink indicated cryptococcal meningitis, and PCR confirmed infection with C. gattii. C. gattii is usually seen in the tropics and subtropics. Since this patient imported trees and soils from abroad to feed stag beetles, parasite or fungal infection was, as such, suspected. Although he received 2 years of intravenous and intraventricular antifungal treatment, brain cryptococcomas were formed and gradually increased. Because of the refractory clinical course, the patient underwent surgical resection of the cerebral lesions. With continuation of antifungal drugs for 6 months after the surgeries, Cryptococcus could not be cultured from cerebrospinal fluid, and no lesions were seen on MR images. If cerebral cryptococcosis responds poorly to antifungal agents, surgical treatment of the cerebral lesion should be considered.

Background and Purpose: Transient ischemic attack (TIA) and minor ischemic stroke is critical warning sign of following disabling stroke. Recently, the concept of acute cerebrovascular syndrome (ACVS) is advocated for early diagnosis and management of TIA or minor stroke. We thought to determine whether the early examination findings at admission can predict the recurrent stroke or death during 1 year after the qualifying event. Methods: Between April 2006 and July 2009, 621patients with TIA or minor ischemic stroke (defined as an National Institutes of Health Stroke Scale [NIHSS] score ≤3) were admitted to our stroke center within 7 days after the onset. Among them, 494 patients obtained outcome at 1year were analyzed. Background data including the findings of laboratory examination, brain MRI diffusion weighted image (DWI), brain MRA and carotid ultrasound were obtained within 3 days after the admission. Information about recurrent stroke and/or death from any cause within 1 year after the qualifying event was obtained from clinical record or telephone interview. Results: During 1 year after the qualifying events, further stroke were identified in 46 (9.3%) patients, 19 (3.9%) patients died, and a total of 60 (12.2%) patients had composite incident of recurrent stroke or death. Multivariate logistic regression analysis showed that age ≥ 60 years old (hazard ratio, 3.00), female sex (hazard ratio, 1.98), history of previous stroke (hazard ratio, 2.10), serum CRP level ≥ 0.2mg/dL (hazard ratio, 2.59), intracranial or carotid artery stenosis ≥ 50% (hazard ratio, 1.76) and acute infarction on DWI (hazard ratio, 3.62) were found to be independent risk factors for recurrent stroke or death. A four-point score derived from these results (acute infarction on DWI [present = 1], CRP level [≥ 0.2mg/dL = 1], vascular stenosis of intracranial or carotid artery [≥ 50% = 1], and stroke history [present = 1]: ACVS) was highly predictive of 1-year risk of recurrent stroke or death (p < 0.001, Figure ). Conclusions: Risk of stroke or death during 1 year after TIA or minor stroke seemed to be highly predictable. Although further validations are needed, the ACVS score may be useful in clinical practice to identify high-risk individuals who need careful treatment and follow up.