Perirhinal accumulation of neuronal alpha-synuclein in a multiple system atrophy patient with dementia.

We report the case of a 79-year-old Japanese woman who developed cerebellar ataxia followed by rigidity, dysautonomia and cognitive disorders, and was thus clinically diagnosed as having possible MSA with dementia. Neuropathological findings demonstrated not only olivopontocerebellar and striatonigral degeneration with frequent glial cytoplasmic inclusions (GCIs), but also degenerative changes in the parahippocampal region, accentuated in the anterior portion of perirhinal cortex, where neuronal cytoplasmic inclusions (NCIs) and NFTs were numerous while GCIs were limited. NCIs were frequent in the deep layer, whereas NFTs were more frequent in superficial cortical layers. Other hippocampal subregions including subiculum, dentate fascia and cornu ammonis were minimally involved. NCIs in the perirhinal cortex showed intense argyrophilia with the Campbell-Switzer silver impregnation method, but not argyrophilic with the Gallyas method. Most neuronal alpha-synuclein aggregates in dendrosomatic fraction formed globular/tadpole-like, and ultrastructurally comprised granular-coated fine fibrils 12-24 nm in diameter. To the best of our knowledge, alpha-synuclein-related neuronal pathology localized in the perirhinal region without hippocampal involvement has not been previously reported in MSA, and may provide clues to elucidate how neuronal pathology evolves in the hippocampal/parahippocampal regions in MSA, particularly in cases with dementia.

How to demix Alzheimer-type and PSP-type tau lesions out of their mixture -hybrid approach to dissect comorbidity.

Neurofibrillary tangles (NFTs), are shared between progressive supranuclear palsy (PSP) and Alzheimer disease (AD). Histological distinction of PSP and AD is possible based on the distribution of NFTs. However, neuropathologists may encounter diagnostic difficulty with comorbidity of PSP and AD. In this study, we tried to circumvent this difficulty by analyzing five autopsied brains harboring both PSP and AD pathology. Tau-positive lesions were sorted based on their cell type (neuron versus glia), and tau isoforms: three-repeat (3R) versus four-repeat (4R) tau. 16 regions were selected to map these lesions throughout the brain. 4R-tau lesions were present in all areas examined. Among them, 3R-tau lesions were absent in some areas. These 4R selective (4R+/3R-) areas dictate prototypic distribution of PSP, not usually found in AD, such as pontine nucleus, red nucleus, inferior olivary nucleus, dentate nucleus, globus pallidus and putamen, each contained both glial and neuronal lesions. In contrast, additional 3R-tau lesions were found in hippocampal formation to neocortex, where 3R immunoreactivity (IR) was predominant over the 4R counterpart mainly in neurons as found in AD but not in PSP. Although tau lesions in central grey matter, substantia nigra and locus coeruleus are found in both AD and PSP, 4R-selectivity with glial component suggests PSP origin. Even if the presence of 3 R IR in these areas suggests AD pathology, it does not exclude the involvement of PSP-type lesion because distinction of 4R IR into PSP or AD is not yet possible. Further demixing may be possible if biochemical difference of 4R tau between PSP and AD is identified.

Brainstem tau pathology in Alzheimer's disease is characterized by increase of three repeat tau and independent of amyloid ß.

INTRODUCTION: Alzheimer-type neuropil threads (NTs) and neurofibrillary tangles (NFTs) are comprised of either 4 repeat (4R)-tau, 3 repeat (3R)-tau, or a mixture of both. In the hippocampus, the number of NFTs, and the proportion of 3R tau progressively increases. If this preferential accumulation of 3R tau also occurs in the brainstem, it may be fundamentally related to progression of Alzheimer pathology. METHODS: Midbrain and pontine sections of brainstems from 23 cases (Braak-NFT stages I/II: 8, III/IV: 8, and V/VI: 7) were double immunofluorolabeled for 4R and 3R tau. High-resolution (0.645 µm/pixel), in-focus snapshots were tiled to cover entire brain sections using a virtual slide system. Each lesion was classified by size (NT < 200 µm2 < NFT) and staining profile (3R/4R). In addition, the localization and quantity of amyloid ß (Aß) deposits were examined in adjacent sections for comparison with tau. RESULTS: The data sets obtained from approximately 286 gigabytes of image files consisted of 847,763 NTs and 7859 NFTs. The proportion of 3R tau-positive NTs and NFTs in the midbrain, and 3R tau-positive NTs in the pons gradually increased with advancing NFT stages, while the proportion of 3R tau-positive NFTs in the pons was already elevated at early stages. Aß deposits were absent at NFT stages I/II, and when present at later stages, their regional distribution was different from that of tau. These observations suggest that a progressive increase in the proportion of 3R tau occurs independently of Aß deposits. CONCLUSIONS: This is the first quantitative analysis of NFTs and NTs in the human brainstem. We demonstrate that the proportion of 3R tau in the brainstem neurofibrillary changes increases with disease progression. Because this phenomenon is shared between the brainstem and the hippocampus, this increase may be fundamental to the pathogenesis of Alzheimer disease.

Elsberg syndrome related to varicella zoster virus infection with painless skin lesions in an elderly woman with poorly controlled type 2 diabetes mellitus.

Patients with diabetes mellitus (DM) are at increased risk of infections, with the urinary tract being the most frequent infection site. Incomplete bladder emptying, frequent urination and abdominal distension are typical symptoms of urinary tract infections (UTIs). A 68-year-old female with a long history of poorly controlled type 2 DM (T2DM) visited our hospital complaining of urinary retention, which was initially diagnosed as cystitis by another doctor. The urologist at our hospital identified a skin rash extending from the left hip to her genital area. A dermatologist was consulted. She was clinically diagnosed with herpes zoster (HZ) involving the left sacral dermatome area. As Elsberg syndrome (ES) was suspected, a lumbar puncture was performed, revealing aseptic meningitis associated with varicella zoster virus (VZV) infection. Intravenous acyclovir with urinary catheterization in combination with methylprednisolone pulse therapy resulted in a good clinical course. HZ very uncommonly involves sacral dermatomes, but it can develop in patients with prolonged poorly controlled DM. Furthermore, early diagnosis can be difficult when patients have diabetic peripheral neuropathy, which may mask symptoms related to skin lesions. Because this disease is potentially severe, detailed examination is important for clinicians managing patients with DM who have complaints indicative of urinary tract disorders.

Idiopathic Hypertrophic Spinal Pachymeningitis.

A 63-year-old man revealed a four-month history of muscle weakness of the lower limbs, hypoesthesia of the L5 and S1 area and ischuria. On MRI, the spinal cord was compressed by an encircled mass, which showed hypointensity on T1- and T2-weighted images with gadolinium enhancement at the Th11 to Th12 vertebra. Because of the rapid progression of myelopathy, posterior decompression was performed and idiopathic hypertrophic spinal pachymeningitis (HSP) was finally diagnosed. The patient's neurological signs markedly improved with postoperative corticosteroid treatment. Idiopathic HSP is a clinical emergency and early surgical intervention is essential to prevent irreversible damage to the nervous system.