Haruomi Nakamura

Cytoplasmic argyrophilic inclusions in neurons of pontine nuclei in patients with olivopontocerebellar atrophy: immunohistochemical and ultrastructural studies

SummaryPatients with olivopontocerebellar atrophy (OPCA) were studied, and cytoplasmic inclusions were observed in some of the remaining neurons of the pontine nuclei, nuclei reticularis tegmenti pontis and arcuate nuclei. The cytoplasmic argyrophilic inclusions were demonstrated by silver impregnation techniques such as Bielschowsky and Bodian staining. With hematoxylin and eosin stain, the inclusions were sharply demarcated and appeared pale. The inclusions were not stained by the following routine histological methods: Klüver-Barrera, phosphotungstic acid hematoxylin, Holzer, periodic acid-Schiff, Mallory azan, alcian blue, nile blue, Masson trichrome, Congo red, thioflavine S, oil red O and Sudan black B stains. Immunohistochemistry with anti-ubiquitin antiserum showed that these inclusions were ubiquitinated. However, the inclusions did not react with any of the following antibodies (Abs) or antisera: anti-phosphorylated neurofilament (NF) Ab, anti-nonphosphorylated NF Abs (160 and 200 kDa), anti-paired helical filament antiserum, anti-tau antiserum, anti-tubulin Abs (alpha and beta), anti-microtubule-associated proteins antiserum, anti-glial fibrillary acidic protein antiserum, anti-vimentin Ab, anti-desmin Ab, anti-cytokeratin Abs (low and high molecular weights), anti-actin antiserum, anti-skeletal myosin antiserum and anti-myelin basic protein Ab. Ultrastructurally, the inclusion bodies noted in OPCA were composed primarily of fibrils having a width ranging from about 24 to 40 nm, which were entirely coated with osmiophilic granular material along their whole length. They were occasionally intermingled with a few filaments about 10 nm in width. Electron microscopical examination on silver-impregnated specimens revealed that each granule-coated fibril had a great affinity for silver particles. In elucidating the pathogenesis of OPCA, it was considered to be an important neuropathological finding that some of the remaining pontine neurons affected by OPCA developed characteristic cytoplasmic argyrophilic inclusions.

Dendrites, dementia and the down syndrome

Findings from a Golgi study of the visual cortex in patients with the Down syndrome were compared with those from neurologically normal, age-matched control subjects. The dendritic atrophy seen in childhood continued into adulthood, with a marked decrease in dendritic branching, dendritic length, and spine frequency in elderly adults with the Down syndrome. Subject more than 30 years old occasionally had degenerating pyramidal neurons in the cerebral cortex and degenerated pyramidal neurons and aspiny stellate cells, particularly in the temporal cortex. These dendritic abnormalities may be related to mental retardation in children and early dementia in older adults who have the Down syndrome. The genetic and extrinsic factors may be important determinants of Alzheimer type dementia in the Down syndrome.

Cortical dysplasia in congenital muscular dystrophy with central nervous system involvement (Fukuyama type)

We report five cases of congenital muscular dystrophy with central nervous system involvement of the Fukuyama type (FCMD) in which cerebral cortical dysplasia was not uniform even in the same brain. We have categorized the dysplasia into three major patterns, each with a predictable topography despite individual variations. Cerebellar micropolygyria was localized to the dorsal halves of each hemisphere. Aberrant fascicles of myelinated nerve fibers, closely associated with micropolygyria, were found in the subarachnoid space of the dorsal cerebellar surface in all but one case. We discuss the characteristics of the cortical dysplasia of FCMD, particularly in relation to that of Walkers lissencephaly, pathogenesis, and the relationship between lesions of the central nervous system and skeletal muscle.

Argyrophilic ubiquitinated cytoplasmic inclusions of Leu-7-positive glial cells in olivopontocerebellar atrophy (multiple system atrophy)

SummaryWe described cytoplasmic inclusions in glial cells in 18 patients with olivopontocerebellar atrophy (OPCA) (multiple system atrophy, MSA). These glial inclusions showed intense argyrophilia with modified Bielschowskys and Bodians silver impregnation techniques, and were observed in the pons, cerebellar white matter, midbrain, medulla oblongata and basal ganglia, as well as cerebral white matter and spinal cord. None of the 54 control cases had glial argyrophilic inclusions. Immunohistochemically, these inclusions were intensely labeled by anti-ubiquitin antibody. Some of them reacted with an antibody to Rosenthal fiber (RF) protein. The cytoplasm of ubiquitinated inclusion-bearing glial cells was immunostained by anti-Leu-7 antibody, but not by anti-GFAP antibody. Ultrastructurally, the glial inclusions were composed primarily of approximately 24- to 40-nm fibrils, which were coated with osmiophilic granular material along their length in longitudinal section. These fibrils appeared as annuli in cross section. Often, a central granule approximately 5 nm in diameter was seen in the lucent lumen of a cross-sectioned fibril. The granule-coated fibrils were not seen in the glial filament-containing astrocytes. Electron microscopic examination of silver-impregnated specimens revealed that the granule-coated fibrils had strong affinity for silver. Immunoelectron microscopy using the indirect immunoperoxidase techniques with antibodies to ubiquitin and RF protein revealed that the electron-dense reaction products respective to both were located on constituents of glial inclusions. Our observation that Leu-7-positive glial cells, mainly oligodendroglial cells, had argyrophilic ubiquitinated inclusions may be of significance for the evaluation of the pathology of OPCA(MSA).

Cerebellar involvement in murine sphingomyelinosis: a new model of Niemann-Pick disease

Mice with sphingomyelinosis (spin) with a C57BL/KsJ inbred background showed hepatosplenomegaly as early as four weeks (wk) of age and cerebellar signs around seven wk. Almost all animals died by 14 wk. Sudanophilic lipid accumulated in the liver, spleen, and lymph nodes as well as in the brain. The striking neuropathologicaf change was a marked atrophy of the cerebellum, where Purkinje cells were predominantly involved. Loss of Purkinje cells started at the age of six wk before the cerebellar signs had become evident clinically. The cell loss appeared to be more marked in the vermis than in the hemispheres. Cytoplasmic inclusions in most cells consisted of myelin figures composed of concentric membranous lamellae. These inclusions were found mainly in the Purkinje cells at an early stage; thereafter, they were widely distributed in the granule cells, Golgi cells, some glial cells, macrophages and endothelial cells. The neuronal inclusions were frequently located in the vicinity of the Golgi apparatus; there were no unusual mitochondrial configurations. The clinicopathological characteristics of the mutant mice are similar to those of the human Niemann-Pick disease type C.

Cortical dysplasia in a 23-week fetus with Fukuyama congenital muscular dystrophy (FCMD)

SummaryA 23-week fetus who is thought to be affected with Fukuyama congenital muscular dystrophy (FCMD) is reported. Cortical dysplasia of the cerebrum was extensive and could be categorized into three major types. The cerebral cortex was thoroughly covered by glio-mesenchymal tissue (extracortical glial layer), in which neuronal clusters were irregularly scattered. Radial bundles of neuroglial tissue frequently extended from the cortex into the extra-cortical glial layer through the focally defective molecular layer and pia mater. The deep cerebral structures, such as basal ganglia, thalamus and white matter, appeared normal in contrast with extensive malformation in the cortex. Glial fibrillary acidic protein-immunoperoxidase stain revealed: (1) presence of abundant radial glial fibers in the ventricular, subventricular and intermediate zones; (2) focal or diffuse lack of glia limitans; (3) focal derangement of radial glial fibers; and (4) proliferation of stellate glial cells in the extra-cortical layer. It is suggested that ectopic accumulation of neurons into the extra-cortical glial layer seems a cardinal pathogenetic process to generate cortical dysplasia in FCMD. Early development of superficial glio-mesenchymal tissue seems essential for upward displacement of migrating neurons.

Skein-like inclusions in the anterior horn cells in motor neuron disease

Skein-like inclusions (SLIs) in the anterior horn cells of patients with motor neuron diseases, including familial amyotrophic lateral sclerosis with posterior column degeneration, sporadic lower motor neuron disease and classical amyotrophic lateral sclerosis, were investigated morphologically with hematoxylin and eosin preparations, immunostaining for ubiquitin and immunoelectron microscopy. The SLIs were thready linear or tubular structures which immunostained with antiubiquitin antibodies. They were detected on hematoxylin and eosin preparations as eosinophilic thread-like structures often surrounded by pale areas. SLIs were occasionally present as networks of threads or tubules. Sometimes, they were aggregated and formed larger pale inclusions. Ultrastructurally, the SLIs were bundles of filaments which appeared thicker than neurofilaments. The SLIs tended to have central hollow spaces which were devoid of filaments. When the SLIs were clustered, fuzzy thick filaments were randomly and loosely arranged among the individual SLIs. The SLIs were histologically and ultrastructurally distinct from other inclusions such as Bunina bodies and hyaline inclusions. This unique morphology of SLIs may provide a novel perspective on the degenerative processes of the anterior horn cells in MND.

Presence of two different fibril subtypes in the Pick body: an immunoelectron microscopic study.

SummaryA study of Pick bodies (PBs) was performed using immunohistochemical, ultrastructural and immunoelectron microscopic techniques. Ultrastructurally, the PBs in the granular neurons of the dentate fascia of Ammons horn were composed of randomly distributed straight fibrils (14.5±2.1 nm in diameter), intermingled with a few constricted fibrils. The constricted fibrils had a periodicity of 157±11 nm, and were 28.7±3.3 nm wide at their widest point midway between the constrictions and 15.3±3.2 nm wide at the point constriction. A few straight fibrils approximately 15 nm in diameter appeared to morphologically transform into fibrils with constrictions at approximately 160-nm intervals. Immunoelectron microscopy revealed that the straight fibrils, the constricted fibrils, and the transitional form (straight fibrils linked with constricted fibrils) had the same immunoreactivity to anti-tau antiserum. The two different subtypes of Pick fibrils, i.e., the straight fibrils and the constricted fibrils, have interchangeable appearances and a common pathomechanism is suggested to underlie the formation of these two subtypes.

Familial amyotrophic lateral sclerosis: Features of multisystem degeneration

SummaryTwo sibling cases of familial amyotrophic lateral sclerosis (ALS) revealed degerneration usually associated with other systemic degenerative disorders. The changes in the 41-year-old sister were compatible with those reported in other familial ALS cases affecting the upper and lower motor neurons, posterior columns, and spinocerebellar tracts. The 45-year-old sister revealed more wide-spread degenerative changes involving not only motor neuron systems, but also proprioceptive, general somatic afferent and spinocerebellar afferent systems. Intracytoplasmic hyaline inclusions were observed in the oculomotor nuclei. Clinical manifestations of urinary disturbance and oculomotor imparirment seldom seen in sporadic ALS were interpreted to be due to the unusual distribution of the morbid process. These pathologic findings suggest that familial ALS may be a multisystemic degenerative disorder, frequently involving the spinocerebellar tracts, but occasionally involving other systems as well.

Intra-axonalcorpora amylacea in ventral and lateral horns of the spinal cord

SummaryDeposits similar to corpora amylacea were observed by electron microscopy and light microscopy within thin myelinated axons in the spinal gray matter in various diseases. By electron microscopy the deposits consisted of randomly interlacing short linear structures of various thickness which were different from tangles of neurofilaments. Sometimes they contained dense granules and electron-dense floccules. Though their incidence was relatively high in some cases of degenerative or metabolic disease of the central nervous system, they were not specific to any disease but seemed to be related to aging, indicating a peculiar aspect of chronic degeneration of the axons.