Galactosialidosis: neuropathological findings in a case of the late-infantile type

Summary The neuropathological findings in a 13-year-old Japanese male showing decrease of sialidase and -galactosidase activities are reported. The patient was the product of normal pregnancy to consanguineous parents. He started to sit at 8 months, stand at 20 months and walk at the age of 2; mental retardation, visual disturbance, cerebellar ataxia, myoclonus and epilepsy developed by the age of 10, and he died at 13. Neuropathological investigation revealed neuronal loss and storage. Severe loss of neurons was observed in the thalamus, globus pallidus, lateral geniculate body, gracile nucleus, Purkinje and retinal ganglion cells. Marked ballooning was seen in the Betz cells and neurons in the basal forebrain, the motor neurons in the cranial nerve nuclei and spinal cord, and in the trigeminal and spinal ganglia. The storage material varied in staining from region to region and from neuron to neuron. Electron microscopic investigation revealed a variety of intracytoplasmic and intranuclear inclusions: membranous cytoplasmic bodies, parallel, wavy-lamellar or tortuous tubular structures, lipofuscin-like irregular-shaped pleomorphic bodies, and cytoplasmic vacuoles with fine granules and lamellar materials. The severity of the neuronal loss did not seem to correlate with the amount of the storage materials, but with the presence of tortuous tubular inclusion.     

Pathological study on a severe sialidosis (α-neuraminidase deficiency)

Summary A 56-day-old infant with -neuraminidase deficiency, whose clinical features included severe edema of extremities and ascites which resembled those in severe infantile sialidosis, was autopsied. Perforation, whose pathogenesis was unclear, was found on the descending portion of the duodenum. Light and electron microscope studies showed that neurons in the cerebral and cerebellar corticies, and the thoracic spinal cord contained membrane-bound vacuoles but no membranous cytoplasmic bodies. Zebra bodies were found only in the neurons of the spinal cord. The neurons in the paraganglion and in the Auerbach's myenteric plexus were also distended with numerous membrane-bound vacuoles. Hepatocytes, endothelial cells and Kupffer cells in the liver and glomerular and tubular epithelial cells in the kidney were swollen with a number of vacuoles although the patient showed none of the clinical features of renal involvement. These pathological changes were similar to those in nephrosialidosis reported by Le Sec et al. [Arch Fr Pediatr 35:819–829 (1978)].     

Accumulation of phosphorylated α-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy

We immunohistochemically examined the brain and peripheral sympathetic ganglia from eight patients with multiple system atrophy (MSA), using an antibody specific for phosphorylated -synuclein (anti-PSer129). Phosphorylated -synuclein was deposited in five cellular locations: oligodendroglial cytoplasm and nucleus, and neuronal cytoplasm, processes and nucleus. Many neuronal cytoplasmic inclusions (NCIs) were found in the pontine and inferior olivary nuclei and, to a lesser extent, in the substantia nigra, locus ceruleus, and neocortical and hippocampal neurons. NCIs were also found in the sympathetic ganglia in two out of the eight cases. Moreover, anti-PSer129 immunohistochemistry revealed extensive neuropil pathology; swollen neurites were abundant in the pontine nucleus, delicate neurites were observed in the deeper layers of the cerebral cortex and thalamus, and neuropil threads and dot-like structures were distributed in the basal ganglia and brainstem. Diffuse neuronal cytoplasmic staining (pre-NCI) was frequently found in the pontine and inferior olivary nuclei. Thus, the widespread accumulation of phosphorylated -synuclein in both glial and neuronal cells is a pathological feature in patients suffering from MSA.     

Neuropathology of mice with targeted disruption of Hexa gene,a model of Tay-Sachs disease

A murine model of Tay-Sachs disease, the prototype of the GM₂ gangliosidoses, was produced through the targeted disruption of the Hexa gene encoding the subunit of -hexosaminidase A. The mice were completely devoid of -hexosaminidase A activity and accumulated GM₂ ganglioside in the CNS in an age-dependent manner. Neurons with membranous cytoplasmic bodies (MCBs), identical to those described in Tay-Sachs disease, were identified in the brain of these mice. The neurons with MCBs were periodic acid-Schiff-positive on frozen sections and immunostained with anti-GM₂ ganglioside antibody. However, unlike Tay-Sachs disease in which neurons throughout the brain are affected, the localization of storage neurons in these mice appeared to be limited to certain regions, i.e., cerebral cortex, the hippocampus, amygdala, hypothalamus, mammillary nucleus, etc. Storage neurons were absent in the olfactory bulb, cerebellar cortex and spinal anterior horns. The difference in the distribution of storage neurons suggests a difference of ganglioside metabolism between humans and mice. This model is useful for the study of the pathogenic mechanisms of neuronal storage in Tay-Sachs disease and for the evaluation of therapeutic strategies.     

Enzyme-histochemical studies of “retrograde” reaction in motor neurones of immature rats

Summary Changes in immature rats in motor neurones after axotomy were studied by enzyme-histochemical methods.Increased activity of dehydrogenases in these neurones demonstrates enhanced metabolism and there was also increase of acid phosphatases. Decreased activity of acetylcholinesterase and indoxylacetate esterase in the neurones and their processes seems to indicate impaired neuronal function to transmit impulses.Retrograde reaction in the immature and the grown up animal is in general of the same kind but takes place quicker in the immature rat. However in new-born and very young animals, it is difficult to recognize alterations in the anterior horn of the spinal cord. Therefore, nervous tissue of new-born animals seems not to respond as it does some days later in ontogenesis.     

Fabry disease: immunocytochemical characterization of neuronal involvement.

Fabry disease is an X-linked glycosphingolipid storage disease caused by deficiency of alpha-galactosidase. Storage of globotriaosylceramide, also known as ceramide trihexoside, is maximal in blood vessels but also occurs in neurons. We performed neuropathological histochemical studies on the brains and spinal cords of 2 patients with confirmed Fabry disease. Luxol fast blue-positive deposits were found in blood vessels throughout the central and peripheral nervous system and within selected neurons in spinal cord and ganglia, brainstem, amygdala, hypothalamus, and entorhinal cortex. Regions adjacent to involved neuronal groups, including nucleus basalis, striatum, globus pallidus, and thalamus, were spared. Electron microscopy showed lamellar cytoplasmic neuronal inclusion bodies. Using a monoclonal antibody reactive with ceramide trihexoside, we found more extensive neuronal deposition than evident by Luxol-fast blue staining and new areas of neuronal storage in the spinal cord and cerebral cortex. Blood vessels throughout the nervous system were strongly immunoreactive. The highly selective pattern of neuronal involvement we found suggests that glycosphingolipid exposure, uptake, or catabolism varies greatly with respect to neuronal morphology and distribution. The degree of toxicity to neurons and the clinical significance of this neuronal storage remains to be defined.     

Neuropathological findings of an autopsy case of adult β-galactosidase and neuraminidase deficiency

Summary An autopsy case of a Japanese male with familial -galactosidase and neuraminidase deficiency is reported. The clinical picture was characterized by adult onset, a gargoyle-like face, cerebellar ataxia, myoclonus, convulsions, retinal degeneration and cortical blindness.Histopathologically, most neurons seemed to have become degenerated in the whole cerebral cortex. Moreover, the calcarine cortex appeared spongy with depopulation of nerve cells. Stuffed neurons or neuronal storage changes were found throughout the brain, especially in the motor nuclei of the spinal cord and brain stem.The inclusions in the stuffed neurons revealed various profiles on the electron microscope. They were composed of membranous lamellar and/or multilamellar structures, often accompanying vacuoles and reminiscent of lipofuscin-like profiles.     

An autopsy case of early (“minimal change”) olivopontocerebellar atrophy (multiple system atrophy-cerebellar)

We report a 57-year-old woman with multiple system atrophy (MSA) of 15-month duration. The patient developed dysarthria, followed by impaired balance of gait, mild limb ataxia, and saccadic eye movement. A postmortem examination performed after she was found dead in a bathtub revealed neuronal loss restricted to the olivopontocerebellar system, being more severe in the pontine nucleus. Mild neuronal loss was also found in the anterior vermis and inferior olivary nucleus. -Synuclein immunohistochemistry demonstrated widespread occurrence of glial cytoplasmic inclusions in the central nervous system, which were more numerous in the pontine base and cerebellar white matter. In contrast, neuronal -synuclein accumulation was confined to the pontine and inferior olivary nuclei. The number of neuronal intranuclear inclusions was much higher than that of neuronal cytoplasmic inclusions. Moreover, -synuclein accumulation was more severe in the neurites than in the cytoplasm or nucleus. This case demonstrates the early pattern of brain pathology in MSA-cerebellar (olivopontocerebellar atrophy).     

Tuft-shaped astrocytes in Lewy body disease

We investigated the occurrence and distribution of tuft-shaped astrocytes (TuSAs) in 60 brains from patients with Lewy body disease (LBD), which were clinically diagnosed as Parkinsons disease (PD) or dementia with Lewy bodies (DLB), and 85 brains from control subjects. TuSAs have been documented as a neuropathological hallmark of progressive supranuclear palsy (PSP). We found phosphorylated tau (p-tau)-positive and -synuclein-negative TuSAs in 10 of 60 patients with LBD and 3 of 85 control cases. TuSAs were mainly located within the precentral and premotor gyri of the frontal lobe cortex. There were only few TuSAs, but the distribution pattern and morphological and immunohistological features were similar to that in PSP. Furthermore, other p-tau positive structures, including aggregates in neurons, coiled-like glial cells and threads showed a similar distribution to those in PSP; mainly in the hippocampus, striatum, subthalamic nucleus, precentral and premotor gyri, brainstem nucleus, and dentate nucleus. In these cases, however, neuronal loss and gliosis were not seen in the regions involved in PSP, such as the subthalamic nucleus, pallidum, inferior olivary, cerebellar dentate nuclei, and periaqueductal gray matter. Clinical features were indistinguishable between the LBD with and without TuSAs. The appearance of TuSAs was not related to the frequency of Lewy bodies, neurofibrillary tangles, and senile plaques, but was significantly more pronounced with advancing age in both LBD and controls. These findings suggest that in a subgroup of elderly individual cases, especially associated with LB pathology, the glial and neuronal p-tau accumulation is increased and has a distributional pattern similar to PSP.     

Neurofibrillary tangles in Niemann-Pick disease type C

Niemann-Pick disease type C (NPC) is an autosomal recessive disease, belonging to a clinically heterogeneous group of lipid storage diseases, distinguished by a unique error in cellular trafficking of exogenous cholesterol, associated with lysosomal accumulation of unesterified cholesterol. Unlike Niemann-Pick disease types A and B, there is no primary genetic defect in sphingomyelinase in NPC. During the routine neuropathological study of NPC patients, we found neurofibrillary tangles (NFT) in a series of cases with a slowly progressive chronic course. These were not associated with -amyloid deposits. The NFT were most frequent in the orbital gyrus, cingulate gyrus and entorhinal region of the cerebral cortex, but were also frequently found in the basal ganglia, thalamus and hypothalamus. In one of the most severely affected case, the NFT were even found in the neurons in the inferior olivary nucleus and in the spinal cord. The NFT were immunostained with Alz 50, and cosisted of paired helical filaments. The distribution of the neurons bearing the NFT was generally similar to that of the swollen storage neurons, and storage neurons often contained NFT in their perikarya and/or in the meganeurites. However, neurons with NFT could be noted without swollen perikarya. The coexistence of neuronal storage and NFT in NPC without amyloid deposits suggests that perturbed cholesterol metabolism and/or lysosomal membrane trafficking may play a role in the formation of NFT, and that amyloid deposits are not necessarily the prerequisite for NFT formation. The results of our study also suggest that NFT formation may be a rather nonspecific cellular reaction of neurons to certain slowly progressive metabolic perturbations of an as yet undefined nature.Part of this study was presented at the Annual Meeting of the Canadian Association of Neuropathologists, Whistler, BC, Canada, September 1993     

Resolution of the pathway taken by implanted Schwann cells to a spinal cord lesion by prior infection with a retrovirus encoding β-galactosidase

Summary This series of experiments is designed to follow the fate of implanted Schwann cells by first labeling them with a recombinant retrovirus encoding the bacterial -galactosidase gene, then injecting them into the spinal cord after a demyclinating lesion has been produced. The label provides a means of distinguishing the exogenous Schwann cells from endogenous ones and of determining their travel pattern and myelinating or ensheathing behavior in the central nervous system (CNS). Neonatal rat primary Schwann cells were stimulated to divide by administering glial growth factor and forskolin. Fresh virus-containing supernatant from Psi2 cells producing retrovirus LZ1 was placed in cell culture to label the cells. The capacity of infected Schwann cells to form myelin was verified by coculturing in vitro with neurons from embryonic dorsal root ganglia. Infected cells were injected into the right side of adult syngenic rat spinal cords after a lysolecithin-induced demyelinating lesion had been produced 1 cm caudal on the left side. After 3 weeks the animals were killed, perfused for electron microscopy, and spinal cord sections histochemically stained for -galactosidase activity using the chromogenic substrate 5-bromo-4-chloro-3-indoyl--d-galactosidase (X-Gal) which forms a blue precipitate in infected cells. The labeled cells, easily recognized macro-and microscopically, were clustered at the cell injection site, in the dorsal meninges and, at the area of demyelination, bilaterally in the superficial aspect of the dorsal funiculi. Labeled cells were not evident in the neuropil midway between the injection and demyelination sites. In the electron microscope, the cells containing the electron-dense precipitate from the hydrolysis of X-Gal were identified at the lesion site and some of these cells ensheathed axons. These data suggest that implanted Schwann cells migrate to a demyelinating lesion in the subarachnoid space rather than through the parenchyma.Supported by grants from the American Paralysis Association (LAL) and National Multiple Sclerosis Society (GCO)     

Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation

We performed clinicopathological analyses of two amyotrophic lateral sclerosis (ALS) patients with homozygous Q398X optineurin (OPTN) mutation. Clinically, both patients presented signs of upper and lower motor neuron degeneration, but only Patient 1 showed gradual frontal dysfunction and extrapyramidal signs, and temporal lobe and motor cortex atrophy. Neuropathological examination of Patient 1 revealed extensive cortical and spinal motor neuron degeneration and widespread degeneration of the basal ganglia. Bilateral corticospinal tracts exhibited degeneration. Loss of spinal anterior horn cells (AHCs) and gliosis were observed, whereas posterior columns, Clarke's columns, intermediate lateral columns, and the Onuf's nucleus were spared. In the brainstem, moderate neuronal loss and gliosis were noted in the hypoglossal and facial motor nuclei. No Bunina bodies were found in the surviving spinal and brainstem motor neurons. Transactivation response (TAR) DNA‐binding protein 43 (TDP‐43)‐positive neuronal and glial cytoplasmic inclusions were observed throughout the central nervous system. The Golgi apparatus in motor neurons of the brainstem and spinal cord was often fragmented. Immunoreactivity for OPTN was not observed in the brain and spinal cord, consistent with nonsense‐mediated mRNA decay of OPTN. The TDP‐43 pathology of Q398X was similar to that of an autosomal dominant E478G mutation. This result suggests that the loss‐of‐function, but not the proteinopathy itself, of OPTN results in TDP‐43 deposits in neuronal and glial cytoplasm and Golgi apparatus fragmentation, leading to multisystem neurodegeneration.     

Diagnostic staging of Parkinson’s disease: conceptual aspects

Summary. Insidious onset of mild, unspecific, sensitive, vegetative, psychopathological, cognitive and perceptive disturbances, i.e. visual and olfactory dysfunction, with a resulting change of personal behaviour, i.e. reduced stress tolerance, precede the initially intermittendly occurring motor symptoms in patients with Parkinsons disease (PD). Novel neuropathological findings suggest an expansion pattern of the neurodegenerative process beyond the nigral dopaminergic neurons with the initial event located outside the brain. We related these clinical observations of premotor symptoms of PD to this novel neuropathological concept of emerging neurodegeneration, which starts in the enteric system and then rises via spinal cord and brainstem to nigral and subsequent cortical neurons. We describe an initial premotor phase, which starts in non dopaminergic areas, and subdivide it according to the onset of gastrointestinal and brainstem associated and sensory deficits. Then motor symptoms occur and increase in the further course of PD similar to the Hoehn and Yahr stages. Our proposed diagnostic concept aims to an earlier diagnosis of PD. In addition, attention should be given to diseases of the gastrointestinal tract and psychosomatic disorders, all of which, if not or ineffectively treated, may contribute to an enhanced vulnerability for PD. The concept takes into account, that an as far unknown pathogen, e.g. viral infection or nutritional component, that meets a genetically predisposed person with a long lasting disturbed enteric nervous system, may be at risk for PD. Earlier premotor diagnosis of PD will enable more convincing future results on the therapeutic efficacy of neuroprotective compounds.     

Distribution of B-50(GAP-43) mRNA and protein in the normal adult human spinal cord

B-50(GAP-43) is a phosphoprotein mainly found in the nervous system which plays a major role in neurite growth during development and regeneration as well as in synaptic remodelling. In the mature intact central nervous system, intense B-50 immunoreactivity (B-50-IR) can still be detected in regions which maintain residual capacity for structural re-organization. B-50 expression has been studied extensively in laboratory animals; however, its distribution and regulation in the human spinal cord is largely unknown. As a first step to analyze lesion-induced structural alterations, we investigated the distribution of B-50 protein and mRNA in the normal adult human spinal cord and dorsal root ganglia. Intense B-50-IR was localized to the superficial laminae of the dorsal horn at all segmental levels, the intermediolateral nucleus at thoracic levels and Onuf’s nucleus at sacral levels. Scattered neurons, particularly in the ventral horn of lumbar and sacral segmental levels (and occasionally also in Clarke’s nucleus) displayed intense B-50-IR in close apposition to the perikaryal and proximal dendritic surfaces. Nonradioactive in situ hybridization indicated that B-50 mRNA could also be detected in neurons of the ventral horn and also in the intermediolateral nucleus. The distribution of B-50 mRNA and protein in the normal human spinal cord shows a marked similarity to that reported in experimental animals, including the selective labelling of Onuf’s nucleus. However, the strong B-50-IR on the surface of some large anterior horn motor neurons has not been observed in other mammals. This finding might reflect a particular state of readiness for synaptic plasticity. Received: 4 August 1997 / Accepted: 27 October 1997     

Immunocytochemical localization of argininosuccinate synthetase in the rat brain.

The neuronal distribution of argininosuccinate synthetase (ASS) was mapped in the rat brain. Argininosuccinate synthetase is one of the enzymes of the arginine metabolic pathway and catabolizes the synthesis of argininosuccinate from aspartate and citrulline. Since arginine is the precursor of nitric oxide, argininosuccinate synthetase may act as part of the nitric oxide producing pathway. Argininosuccinate is also suggested to have a messenger function in the nervous system. Therefore, the localization of ASS is of great interest. Polyclonal antisera against purified rat liver argininosuccinate synthetase revealed a characteristic distribution pattern of argininosuccinate synthetase-like immunoreactivity: (1) many neurons with strong argininosuccinate synthetase-like immunoreactivity were observed in the septal area, basal forebrain, anterior medial and premammillary nuclei of the hypothalamus, anterior and midline thalamic nuclei, dorsal endopiriform nucleus of the amygdala, basal nucleus of Meynert, subthalamic nucleus, laterodorsal tegmental nucleus, raphe nuclei, nucleus ambiguus, and the area postrema, (2) neuropile staining was dense in the septal areas, hypothalamus, area postrema, nucleus of the solitary tract, and the laminae I and II of the caudal subnucleus of the spinal trigeminal nucleus and the spinal dorsal horn, (3) relay nuclei of the specific sensory systems such as the dorsal lateral geniculate nucleus and the ventral nuclei of the thalamus were devoid of argininosuccinate synthetase-like immunoreactivity, (4) no staining was seen in the large white matter structures such as the internal capsule, corpus callosum, and the anterior commissure, and (5) most of the neurons stained were small or medium in size and appeared to be interneurons. The results suggest that argininosuccinate synthetase affects the widely distributed, neuromodulatory system in the brain.     

A case of adult neuronal ceroid-lipofuscinosis with the appearance of membranous cytoplasmic bodies localized in the spinal anterior horn

Summary An autopsy case of adult neuronal ceroid-lipofuscinosis was examined. The clinical picture was charaterized by gait disturbance, bulbar palsy and dementia. Histopathologically, diffuse neuronal loss was found throughout the central nervous system. The remaining neurons, predominantly in the motor nuclei of the spinal cord and brain stem, were swollen with storage material. Observed under the electron microscope the storage material showed various ultrastructures, such as lipofuscin-like bodies, pleomorphic lipid bodies, curvilinear profiles and finger-print profiles, in different regions of the central nervous system. In the ballooned neurons of the spinal anterior horn, many membranous cytoplasmic bodies and curvilinear profiles were intermingled within the same cell and were continuous with each other. Biochemically,N-acetyl neuraminic acid content was significantly increased in the spinal anterior horn. These findings suggest the localized increase of ganglioside in that region.     

Evidence for sequential degeneration of the neurons in the intermediate zone of the spinal cord in amyotrophic lateral sclerosis: a topographic and quantitative investigation

Summary To elucidate the degenerating mechanism of the neurons in the intermediate zone of the spinal cord in classical amyotrophic lateral sclerosis (ALS), the spinal neurons in a patient with ALS, whose muscular strength was fairly well preserved up to death, were examined quantitatively and topographically, and compared with the data of advanced ALS patients and age-matched control subjects reported previously. In advanced ALS patients, anterior horn cells completely disappeared and the medium-sized (nuclear area; 71–150 m²) and large (nuclear area; greater than 151 m²) neurons in the intermediate zone were severely reduced. In the present case, however, the loss of anterior horn cells was severe but the degree was not equal to that of advanced ALS patients, and the neurons in the intermediate zone were quite well preserved. The finding indicates that the primary degeneration may occur in the anterior horn cells and the neurons in the intermediae zone degenerate sequentially in the spinal gray matter in ALS.Supported in part by a Grant-in-Aid for Scientific Research (A) No. 60440046 from the Ministry of Education, Science and Culture, Japan     

A study of infantile motor neuron disease with neurofilament and ubiquitin immunocytochemistry

We report a patient with infantile motor neuron disease who had pathologic findings consistent with multisystem degeneration. Although the muscle showed denervation atrophy and spinal anterior horn cells showed either atrophy or ballooning degeneration consistent with lower motor neuron disease, the infant was hypertonic and spastic. Degenerative changes were also detected in the dorsal root ganglia, cerebellum, and thalamus. Immunohistochemical studies showed a paucity of neurofilament (NF) staining in the corticospinal tract and accumulation of phosphorylated NF in ballooned neurons. Antibodies to ubiquitin immunostained ballooned neurons in the dorsal root ganglia, anterior horns, and thalamus. Accumulation of ubiquitinated and phosphorylated NF epitopes in degenerating neurons suggest that basic abnormalities in the neuronal cytoskeleton may be instrumental in the pathogenesis of this disorder.     

Functional recovery of locus coeruleus noradrenergic neurons after DSP-4 lesion: effects on dopamine levels and neuroleptic induced – Parkinsonian symptoms in rats

Summary. Noradrenaline has been shown to control dopamine turnover and release in rat brain. Noradrenergic lesion with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) decreases dopamine release in the striatum and enhances catalepsy in experimental models of Parkinsons disease. However, in due course, sprouting of remaining noradrenergic axons, to compensate for the decreased noradrenaline is said to occur in specific brain regions. Though this is to some extent understood, the longstanding effects of noradrenergic lesion on dopaminergic neurons of the basal ganglia and in Parkinsonian behavior is not known. Here the question is addressed, whether locus coeruleus lesion with DSP-4 in rats alters dopamine concentration of the basal ganglia and influences Parkinsonian behavior in a long term (6 months). Parkinsonian behavior was assessed by catalepsy and activity cage after challenging with subthreshold dose of haloperidol (0.2mg/kg), on 7, 30, 90, 120 and 180 days after DSP-4 lesion. The concentrations of noradrenaline and dopamine and its metabolites were estimated by HPLC. 6 months after DSP-4 lesion, increased concentration of noradrenaline was found in prefrontal cortex and hippocampus. Other regions remain unaffected. The concentration of dopamine remained unchanged. However, dopamine turnover appeared to be increased in prefrontal cortex and reduced in striatum and nucleus accumbens. Catalepsy and hypoactivity were observed in DSP-4 lesioned animals after haloperidol challenge on 7^th, 30^th and 60^th day. Though dopamine turnover was reduced after 6 months in the striatum, haloperidol-induced catalepsy was not observed after 60 days. These results indicate a gradual functional recovery, perhaps hyperinnervation of noradrenergic neurons after DSP-4 treatment and the reversal of its effects on dopaminergic neurons and on Parkinsonian symptoms.     

Familial amyotrophic lateral sclerosis with Cys111Tyr mutation in Cu/Zn superoxide dismutase showing widespread Lewy body-like hyaline inclusions

We described a 43-year-old Japanese man with familial amyotrophic lateral sclerosis (FALS) in whom we identified a missense mutation (Cys111→Tyr) in exon 4 of the Cu/Zn superoxidase dismutase-1 (SOD1) gene in which no pathological data have been reported. The disease duration was 5 years, and he died of respiratory failure. The initial sign was weakness of the right leg. He had no clear upper motor involvement. Neuropathological examinations showed neuronal intracytoplasmic Lewy body-like hyaline inclusions (LBHIs) not only in the anterior horn cells of the spinal cord, but also in many other affected neurons. LBHIs were seen in the anterior horn cells, Onufrowicz nucleus, Clarke's nucleus, intermediolateral nucleus, and posterior gray horn of the spinal cord. In addition, LBHIs were observed in the periaqueductal gray matter, nucleus raphe dorsalis, locus ceruleus, trigeminal motor nucleus, vestibular nucleus, dorsal vagal nucleus, hypoglossal nucleus, and reticular formation of the brain stem. These are very specific findings that neuronal LBHIs in our case are for more widespread reported cases, and similar cases to ours have never reported in FALS.