Yoji Goto

Morphological Purkinje cell changes in spinocerebellar ataxia type 6

Abstract Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant spinocerebellar ataxia associated with a small CAG repeat expansion of the gene encoding an α 1 A-voltage-dependent calcium channel gene subunit on chromosome 19p13. In this study 50-μm-thick sections of cerebellar tissue from one patient with SCA6 were subjected to free-floating immunohistochemical staining with calbindin-D and parvalbumin antibodies. Severe loss of Purkinje cells was found, particularly in the vermis, and various morphological changes in Purkinje cells and their dendritic arborizations were demonstrated. Many of the remaining Purkinje cells were found to have heterotopic, irregularly shaped nuclei, an unclear cytoplasmic membrane outline, and somatic sprouts. Increased numbers of spine-like protrusions from swelling dendritic arborizations were found in the molecular layer. The axonal arrangement was disordered, and many torpedos were found in the granular layer and white matters. These morphological changes are completely different from those observed in paraneoplastic cerebellar degeneration (PCD) and multiple system atrophy (MSA) and are considered to be related to the genetic abnormality that causes abnormal development of Purkinje cells.

Advanced glycation end products co-localized with astrocytes and microglial cells in Alzheimer's disease brain

Abstract   In the previous study [Takeda et al. (1996) Neurosci Lett 221: 17–21], we reported that the advanced glycation end products (AGEs) in the external space of neuronal perikarya (extraneuroperikaryal AGE deposits) were significantly abundant in the Alzheimer’s brain. In this study, we investigated the spatial relationship of the extraneuroperikaryal AGE (carbocymethyllysine and pentosidine) deposits in astrocytes and microglial cells in the Alzheimer’s disease brain using double immunolabelling for AGEs and astrocyte or microglial cell markers. Most of the extraneuroperikaryal AGE deposits were co-localized with glial fibrillary acidic protein-positive astrocytes. AGE deposit-bearing astrocytes also contained Gomori-positive granules. Furthermore, some of the extraneuroperikaryal AGE deposits were co-localized with microglial cells. These extraneuroperikaryal AGEs may activate astrocyte and microglia, and play a role in pathogenesis of Alzheimer’s disease.

CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy

Genetic and phenotypic heterogeneities are considerably high in adult‐onset leukoencephalopathy, in which comprehensive mutational analyses of the candidate genes by conventional methods are too laborious. We applied exome sequencing to conduct a comprehensive mutational analysis of genes for autosomal dominant leukoencephalopathies. Genomic DNA samples from four patients of three families with autosomal dominantly inherited adult‐onset leukodystrophy were subjected to exome sequencing. On the basis of the results, 21 patients with adult‐onset sporadic leukodystrophy and one patient with pathologically proven HDLS were additionally screened for CSF1R mutations. Exome sequencing identified heterozygous CSF1R mutations (p.I794T and p.R777W) in two families. I794T has recently been reported as a causative mutation for hereditary diffuse leukoencephalopathy with spheroids (HDLS), and R777W is a novel mutation. Although mutational analysis of CSF1R in 21 sporadic cases revealed no mutations, another novel CSF1R mutation, p.C653Y, was identified in one patient with autopsy‐proven HDSL. These variants were located in the PTK domain where the causative mutations cluster. Functional prediction of the mutant CSF1R as well as cross‐species conservation of the affected amino acids supports the notion that these variants are pathogenic for HDLS. Exome sequencing is useful for a comprehensive mutational analysis of causative genes for hereditary leukoencephalopathies, and CSF1R should be considered a candidate gene for patients with autosomal dominant leukoencephalopathies.

Neuronal and glial advanced glycation end product [Nε-(carboxymethyl)lysine] in Alzheimer's disease brains

Abstract. The cellular distribution of an advanced glycation end product [Nε-(carboxymethyl)lysine (CML)] in aged and Alzheimers disease (AD) brains was assessed immunohistochemically. CML was localized in the cytoplasm of neurons, astrocytes, and microglia in both aged and AD brains. Glial deposition was far more marked in AD brains than in aged brains, and neuronal deposition was also increased. On electron microscopic immunohistochemistry, neuronal CML formed granular or linear deposits associated with lipofuscin, and glial deposits formed lines around the vacuoles. Neuronal and glial deposits were prominent throughout the cerebral cortex and hippocampus, but were sparse in the putamen, globus pallidus, substantia nigra, and cerebellum, with glial deposits being far more prominent in AD brains. The distribution of neuronal and glial deposits did not correspond with the distribution of AD pathology. The extent of CML deposits was inversely correlated with neurofibrillary tangle formation, particularly in the hippocampus. Most hippocampal pyramidal neurons with neurofibrillary tangles did not have CML, and most of the neurons with heavy CML deposits did not have neurofibrillary tangles. In the hippocampus, neuronal CML was prominent in the region where neuronal loss was mild. These observations suggest that CML deposition does not directly cause neurofibrillary tangle formation or neuronal loss in AD.

VZV vasculopathy associated with myelo-radiculoganglio-meningo-encephalitis: An autopsy case of an immunocompetent 66-year-old male

Encephalitis is the most severe manifestation of central nervous system (CNS) infection by Varicella-Zoster-Virus (VZV). VZV associated encephalitis is now recognized to be a vasculopathy that affects large or small cerebral arteries. This report describes an autopsy case of an immunocompetent 66-year-old male who developed a progressive small vessel vasculopathy and clinically presented with a zosteriform rash and myelo-radiculoganglio-meningo-encephalitis followed by subarachnoid bleeding. This is an extremely rare manifestation of VZV vasculopathy associated with widespread CNS damage, and what is more, the spinal lesions were different from those of the cerebrum, brainstem and cerebellum, where the former were predominantly demyelinative changes and the latter were ischemic. To the best of our knowledge, few cases have been described pathologically in an immunocompetent individual. Further studies are needed to investigate the pathogenesis and treatment of VZV vasculopathy.

Pathological correlate of the slitlike changes on MRI at the putaminal margin in multiple system atrophy.

Sirs: The slitlike signal changes at the lateral margin of the putamen on magnetic resonance imaging (MRI) is a characteristic finding in patients with multiple system atrophy (MSA) involving the extrapyramidal system [1–3]. The degree of signal change is correlated with the severity of extrapyramidal symptoms. However, in spite of some speculation whether to sign is due to demyelination, gliosis, iron deposition [2, 4], or increased extracellular fluid [1], the nature of the abnormal signal intensity has remained uncertain. We report the pathology and magnetic resonance imaging of the putaminal margin in a case of MSA. The patient was a 63-year-old woman with a 9-year history of parkinsonism. Neurological findings at age 59years were mild dementia, masked face, moderate bradykinesia with rigidity, small steppage gait with mild ataxia, mild incoordination, orthostatic hypotension, and dysuria. Study by 0.5-T MRI demonstrated a normal pontocerebellar system and slit-hyperintensity in outer marigin of the left putamen in the T2-weighted image. Antiparkinsonism drugs failed to improve her movement disorder. By the age of 60 she had become bedridden, and died of cardiac arrest at age 63. Six months prior to her death, 0.5-T MRI showed pontocerebellar system atrophy, slit-hyperintensity in both outer putaminal margins and the inner margin of the left putamen in T2weighted image (Fig.1), and linear hypointensity in the T1-weighted image (Fig.2). Hypointensity on T2weighted MRI was observed in the globus pallidus and putamen. The brain, removed at autopsy, was mildly atrophic in the frontal lobe and severely atrophic in the pons and cerebellum and weighted 1240g. The coronal section disclosed severe bilateral, symmetrical atrophy of the putamen which was brown in color (Fig.3). The caudate nuclei and globus pallidus were fairly well spared. The rarefaction or tissue space was observed at the outer putaminal margin in both sides and at the inner margin in the left side. Microscopic examination revealed diffuse rarefaction of the putamen associated with almost total loss of neurons and concomitant proliferation of astroglia. Iron deposition was present in the extracellar space and in the remaining cells of the putamen, especially in the dorsolateral portion. The neurons in the caudate nuclei, globus pallidus, and thalamus were well preserved. In the substantia nigra, there was moderate pigmented neuronal loss accompanied by astrocytosis. Loss of pigmented neurons was also observed in the locus caeruleus. Marked neuronal loss with gliosis was also observed in the pontine nuclei and inferior olive. In the cerebellum, Purkunje cell loss was marked in the vermis and moderate in the hemispheres, and the white matter was extremely atrophic with considerable gliosis. Glial cytoplasmic inclusions were observed in a widespread region of the brain. The patient had shown signs and symptoms of MSA, and the diagnosis was confirmed by postmortem studies. MRI during life revealed an abnormality that closely matched those of gross pathological findings in the putamina. The putaminal atrophy resulted in the formation of the intertissue space between the putamen and external capsule as well as LETTER TO THE EDITORS J Neurol (1999) 246 :142–143

Early Pathologic Changes in Hereditary Diffuse Leukoencephalopathy With Spheroids

Abstract Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a familial neurodegenerative disease clinically characterized by progressive cognitive and motor dysfunction. Mutations in the colony-stimulating factor 1 receptor (CSF1R) gene have recently been identified in HDLS patients. The presence of diffuse axonal spheroids, myelin loss, and pigmented microglia in the white matter are pathologic hallmarks of HDLS; however, early pathologic findings have not been described in HDLS patients. We report a Japanese family with HDLS. A novel heterozygous c.653 C>Y mutation in the CSF1R gene was identified in the female proband who died at the age of 63 years; postmortem findings were compatible with HDLS. We also autopsied her sister who was considered to be neurologically asymptomatic and died of tuberculosis at the age of 44 years. Postmortem studies revealed patchy axonal degeneration and myelin loss, predominantly in the subcortical white matter. Pigmented microglia were distributed diffusely throughout the cerebral white matter and expressed CSF1R poorly. In conclusion, our observations suggest that the pathology of HDLS may initially be characterized by multifocal lesions in subcortical white matter regions. Moreover, pigmented microglia poorly express CSF1R and are distributed diffusely throughout the white matter at the early disease stage, preceding axonal damage and myelin loss.

Hypophosphataemic neuropathy during total parenteral nutrition

Intravenous glucose administration is the most common cause of hypophosphataemia in hospitalised patients. While most of these cases are asymptomatic, severe hypophosphataemia, when combined with phosphorus depletion, can cause acute neuropathy that mimics Guillain–Barré syndrome. A malnourished patient who received intravenous hyperalimentation (IVH) without intravenous phosphate (IP) developed hypophosphataemia and acute sensorimotor neuropathy. F waves in the peripheral nerve trunk were absent or diminished, while nerve conduction velocities were nearly normal. The sural nerve biopsy revealed the presence of some subperineurial oedema and mild axonal atrophy. Prompt IP administration reversed the patients’ neurological symptoms and normalised F waves. Our data suggest that hypophosphataemia plays a role in the pathogenesis of neuropathy that develops in patients following IVH without IP.

Hypophosphataemic neuropathy in a patient who received intravenous hyperalimentation

A malnourished patient that received intravenous hyperalimentation (IVH) without inorganic phosphate (IP) developed hypophosphataemia and acute sensorimotor neuropathy. F waves in the peripheral nerve trunk were absent or diminished, while nerve conduction velocities were nearly normal. The sural nerve biopsy revealed the presence of some subperineurial oedema and mild axonal atrophy. Prompt IP administration reversed the patients’ neurological symptoms and normalised F waves. Our data suggest that hypophosphataemia plays a role in the pathogenesis of neuropathy that develops in patients following IVH without IP. Figure 1 Sural nerve pathology. Transverse section of the right sural nerve of the patient (toluidine blue stain). (A) Oedematous tissue is shown in the subperineural space (arrowheads). (B) Myelinated fibre densities were well preserved but there were signs of mild axonal atrophy. Intravenous glucose administration is the most common cause of hypophosphataemia in hospitalised patients.1 While most of these cases are asymptomatic, severe hypophosphataemia, when combined with phosphorus depletion, can cause acute neuropathy that mimics Guillain–Barre syndrome. However, prompt IP administration can reverse this clinical condition. While there have been several reports of acute neuropathies caused by hypophosphataemia, most are anecdotal and no report has described an associated peripheral nerve pathology. Thus the clinical and pathological features of acute neuropathy that develops as a result of hypophosphataemia have not been well characterised. A 60-year-old Japanese man who had suffered from diabetes for 5 years and a prior myocardial infarction was admitted to our hospital with melaena and diarrhoea. Colonoscopy confirmed a diagnosis of ulcerative colitis. Despite treatment with mesalamine and low dose prednisolone, the diarrhoea did …

[Aggregatibacter segnis endocarditis mimicking antineutrophil cytoplasmic antibody-associated vasculitis presenting with cerebral hemorrhage: a case report].

A 56-year-old man who underwent a tooth extraction in the previous year presented with weakness of the right upper extremity. Brain CT and MRI scans showed subcortical hemorrhage in the left frontal lobe. His body temperature was 37.5°C. Blood examination revealed anemia, elevated levels of C-reactive protein, and a positive result for PR3-ANCA. Aggregatibacter segnis was identified in the incubated blood cultures, and transesophageal echocardiograms showed infectious growth in the anterior mitral leaflet. He was diagnosed with infectious endocarditis. After treatment with ceftriaxione, the clinical symptoms were improved. We concluded that infectious endocarditis caused cerebral hemorrhage and that the positive result for PR3-ANCA was a false positive. Infectious endocarditis can mimic ANCA-associated vasculitis. When ANCA-associated vasculitis is suspected, infectious endocarditis must be ruled out.