Decreased Amount of Collagen in The Skin of Amyotrophic Lateral Sclerosis in The Kii Peninsula of Japan.

PURPOSE: The Kii Peninsula of Japan, together with Guam and West New Guines, has one of the highest incidences of amyotrophic lateral sclerosis (Kii ALS) in the world. There is a controversy whether the etiology is the same or not between sporadic ALS and Kii ALS. Skin studies from patients with sporadic ALS have shown unique pathological and biochemical abnormalities. However, there has been no report of collagen content of the skin Kii ALS patients. METHODS: The skin tissues from Kii ALS patients were studied by electron microscopy and their collagen contents were examined. RESULTS: On electron microscopy the most conspicuous finding in Ki ALS was the smaller diameter of collagen fibrils. The collagen content per dry weight (mg) of the samples in Kii LAS was significantly decreased (P<0.001) than in controls. In Kii ALS patients the more severely affected pathological samples showed the greater decrease. In addition, there was a significant negative correlation (r = -0.88, P<0.01) between the collagen and duration of illness in the Kii ALS patients, but there was no such correlation in controls. CONCLUSION; These results indicate that the metabolism of skin collagen might be affected in the disease process of Kii ALS.

An immunohistochemical study of increased tumor necrosis factor-α in the skin of patients with amyotrophic lateral sclerosis.

Tumor necrosis factor-α (TNF-α) is a major inflammatory cytokine that elicits a wide range of biological responses and is implicated in the pathogenesis of neurodegenerative diseases. Skin studies from patients with amyotrophic lateral sclerosis (ALS) have shown unique pathological and biochemical abnormalities. The lack of bedsore formation is considered characteristic of ALS. We undertook a quantitative immunohistochemical study of TNF-α in the skin from patients with ALS and controls with other neurologic or muscular diseases. Immunohistochemistry for TNF-α demonstrated cytoplasmic activity in the epidermis and in some blood vessels and glands. The proportion of TNF-α-positive (TNF-α+) cells in the epidermis in patients with ALS was significantly higher (p<0.001) than in controls. There was a significant positive relationship (r=0.87, p<0.001) between this proportion and duration of illness in patients with ALS, but there was no such relationship in control subjects. The optical density of TNF-α+ cells in the epidermis in patients with ALS was markedly higher (p<0.001) than in controls. There was a significant positive relationship (r=0.70, p<0.001) between the immunoreactivity and duration of illness in patients with ALS. However, there was no such relationship in controls. In addition, there was an appreciable positive correlation (r=0.59, p<0.01) in patients with ALS between the proportion of TNF-α+ cells and the optical density of these cells, but with no correlation in controls. These data suggest that changes in TNF-α identified in the skin of patients with ALS are likely to be related to the disease process and that metabolic alterations of TNF-α may take place in the skin of patients with ALS.

Immunohistochemical studies of angiogenin in the skin of patients with amyotrophic lateral sclerosis.

Angiogenin (ANG) is a member of the ribonuclease superfamily which is implicated in angiogenesis. ANG maintains normal vasculature and thereby protects motor neurons from various stress conditions. It is suggested that ANG may play a role in pathomechanism of amyotrophic lateral sclerosis (ALS). However, there have been no studies of ANG in ALS skin. We made a quantitative immunohistochemical study of the expression of ANG in the skin from 20 patients with sporadic ALS, 20 patients with other neurologic or muscular disorders (control group A), and 20 patients without neurologic or muscular disorders (control group B). The nuclei of the epidermal cells showed a weak ANG immunoreactivity in ALS patients. These findings became more marked as ALS progressed. The optical density for ANG immunoreactivity of the nucleus in the epidermal cells in ALS patients was significantly lower (p<0.001) than in control groups A and B. There was a significant negative relationship (r=-0.82, p<0.001) between the optical density for ANG immunoreactivity of the nucleus and duration of illness in ALS patients. These data suggest that changes of ANG in ALS skin are related to the disease process and that metabolic alterations of ANG may take place in the skin of ALS patients.

Increased expression of valosin-containing protein in the skin of patients with amyotrophic lateral sclerosis.

Valosin-containing protein (VCP) may have a pivotal role in ubiquitin-dependent protein degradation and is implicated in the pathogenesis of neurodegenerative diseases. Skin studies from patients with amyotrophic lateral sclerosis (ALS) have shown unique abnormalities. We undertook a quantitative immunohistochemical study of VCP in the skin from patients with ALS and control participants. The proportion of VCP-positive (VCP+) cells in the epidermis in patients with ALS was significantly higher (p<0.001) than in controls. There was a significant positive relationship (r=0.59, p<0.01) between this proportion and duration of illness in patients with ALS. The optical density of VCP+ cells in the epidermis in patients with ALS was higher (p<0.001) than in controls. There was a significant positive relationship (r=0.61, p<0.01) between the immunoreactivity and duration of illness in patients with ALS. These data suggest that changes in VCP identified in skin from patients with ALS are likely to be related to the disease process.

Increased progranulin in the skin of amyotrophic lateral sclerosis: an immunohistochemical study.

It has been demonstrated that progranulin (PGRN) is a neurotrophic factor that enhances neuronal survival and axonal growth. Several lines of evidence have indicated that PGRN plays a role in the pathomechanism of amyotrophic lateral sclerosis (ALS). However, there has no study of PGRN in ALS skin. We made a quantitative immunohistochemical study of the expression of PGRN in the skin from 18 patients with sporadic ALS and 13 control subjects. Immunohistochemistry for PGRN demonstrated cytoplasmic activity in the epidermis and in some blood vessels and glands. Numerous PGRN-positive (PGRN+) cells were observed in the epidermis in ALS patients, which became more marked as ALS progressed. PGRN immunoreactivity of PGRN+cells was markedly positive in the epidermis in ALS patients. The proportion of PGRN+cells in the epidermis in ALS patients was significantly higher (p<0.001) than in controls. There was a significant positive relationship (r = 0.83, p<0.001) between the proportion and duration of illness in ALS patients. These data suggest that changes of PGRN in ALS skin are related to the disease process and that metabolic alteration of PGRN may take place in the skin of patients with ALS.

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.

An immunohistochemical study of ubiquitin in the skin of sporadic amyotrophic lateral sclerosis.

Ubiquitin (UB)-immunoreactive filamentous inclusions, absent in normal cases and in any other disorder, have been found in patients with amyotrophic lateral sclerosis (ALS) and it has been suggested that they may be characteristic of this disorder. However, there has been no study of UB in ALS skin. We made a quantitative immunohistochemical study of the expression of UB in the skin from 19 patients with sporadic ALS and 19 control subjects. The proportion of UB-positive (UB+) cells in the epidermis in ALS patients was significantly higher (p<0.001) than in controls. There was a significant positive relationship (r=0.92, p<0.001) between the proportion and duration of illness in ALS patients. The optical density of UB+ cells in the epidermis in ALS patients is markedly stronger (p<0.001) than in controls. There was a significant positive relation (r=0.58, p<0.01) between the immunoreactivity and duration of illness in ALS patients. These data suggest that changes of UB in ALS skin are related to the disease process and that metabolic alterations of UB may take place in the skin of patients with ALS.

Adult dermatomyositis with severe polyneuropathy: does neuromyositis exist?

Peripheral nerve involvement in dermatomyositis (DM) has been known as neuromyositis. However, the pathogenic mechanism is not clear, and the association between DM and peripheral neuropathy is still controversial. Our patient exhibited symptomatic polyneuropathy that was documented electrophysiologically in addition to typical features of DM. The sural nerve biopsy showed evidence of a continuing neuropathic process of axonal type. There was no finding of inflammatory cells infiltrating the vessels. Neither methylprednisolone nor intravenous immunoglobulin (IVIg) improved neurological symptoms including muscle weakness and sensory disturbance. Clinical, electrophysiological, and neuropathological features in our case demonstrate the association of DM and polyneuropathy. The possibility that the same pathological process affecting skin and skeletal muscles also affected peripheral nerves in our patient should be considered.

Immunohistochemical studies of vascular endothelial growth factor in skin of patients with amyotrophic lateral sclerosis.

Vascular endothelial growth factor (VEGF) is a disulfide-linked dimeric glycoprotein that enhances vascular permeability, induces chemotaxis and activation of monocytes/macrophages, and promotes growth of vascular endothelial cells. Furthermore, VEGF is a multifunctional cytokine, which influences neural cells directly, enhancing neuronal survival, axonal outgrowth, and Schwann cell proliferation. So far studies of the skin of amyotrophic lateral sclerosis (ALS) have shown unique pathological and biochemical abnormalities in collagen, elastic fibers, and the ground substance. However, the expression of VEGF in ALS skin has not previously been studied. We made a quantitative immunohistochemical study of the expression of VEGF in the skin from 15 patients with ALS and 15 control subjects. VEGF immunoreactivity was markedly positive in the epidermis and moderately positive in some dermal blood vessels and glands in ALS patients. These findings became more conspicuous as ALS progressed. The optical densities for VEGF immunoreactivity of the epidermis in ALS patients were significantly higher (p<0.001) than in control subjects. In addition, there was an appreciable positive correlation (r=0.85, p<0.001) in ALS patients between the densities for VEGF immunoreactivity and duration of illness, but there was no such correlation in control subjects. These data suggest that changes of VEGF in ALS skin are likely to be related to the disease process and that metabolic alterations of VEGF may take place in the skin of patients with ALS.

Amyotrophic lateral sclerosis associated with IgG anti-GalNAc-GD1a antibodies.

A variety of immunological abnormalities have been reported in some patients with amyotrophic lateral sclerosis (ALS). It has been postulated that a disturbance of immunoregulation may play a role in the degeneration of motor neurons in ALS. We describe a 62-year-old man with a 9-month history of slowly progressive muscular weakness and atrophy of the upper and lower extremities and dysarthria. Neurological examinations revealed weakness and atrophy with fasciculation in the skeletal muscles including the face and tongue. In the limbs, distal muscles were affected predominantly. Electromyography showed chronic neurogenic changes with denervation potentials. Serum antibody testing demonstrated an increased titer of anti-N-acetylgalactosaminyl GD1a (GalNAc-GD1a) antibodies (IgGx160; normal, less than x40). The patient was treated with intravenous immunoglobulin (IVIg) therapy which was repeated two times at an interval of 2 months. However, the response to IVIg was negligible. To the authors' knowledge, this is the first report on ALS, in which the patient had anti-GalNAc-GD1a IgG antibody.

Familial amyotrophic lateral sclerosis with Gly93Ser mutation in Cu/Zn superoxide dismutase: a clinical and neuropathological study.

We describe a 39-year-old Japanese woman with familial amyotrophic lateral sclerosis (FALS) in whom we identified a missense mutation (Gly93-->Ser) in exon 4 of the Cu/Zn superoxidase dismutase-1 (SOD1) gene in which no pathological data have been available. The disease duration was 16 years, and she died of respiratory failure. The initial sign was weakness of the lower limbs. She had no clear upper motor neuron involvement. Respiratory muscle weakness had developed 1 year before her death. Neuropathological examinations showed simultaneous involvement of the pyramidal tract and lower motor neurons as well as degeneration in the Clarke's nucleus, the spinocerebellar tract, the posterior column, the dentatorubral system, and anterolateral columns of the spinal cord. However, the patient has no Lewy body-like hyaline inclusions (LBHIs), which are characteristic features of mutant SOD1-related FALS with posterior column involvement. Based on clinical, genetic and pathological findings with a review of the literature, we suggest that degeneration of the dentatorubral system and the absence of LBHIs in our case are pathological features in FALS with the Gly93Ser mutation.

[Skin changes in amyotrophic lateral sclerosis].

It has been repeatedly noted, but never as yet fully explained, that patients with amyotrophic lateral sclerosis (ALS) do not develop bedsores even at the terminal stage. Furthermore, the skin of ALS patients feels supple, like tanned leather, and loses elasticity. When the skin is stretched, it returns only sluggishly to its original position. We termed this property of skin "delayed return phenomenon (DRP)"; it is usually seen more than 2.5 years after the onset of symptoms. Although it is thought that a phenomena such as DRP and the absence of bedsores are characteristic of this disease, little attention has been paid to these unique features in ALS patients. In this review we summarize recent developments in research on skin from ALS patients. From our own works cited in this review it is clear that not only the motor neuron but also the skin is affected in ALS, and that abnormalities of collagen, glycosaminoglycans, vascular endotherial growth factor (VEGF) and neurotrophic factors like ciliary neurotrophic factor (CNTF), neurotrophin-3 (NT-3) and insulin-like growth factor-1 (IGF-1) do occur in the skin of ALS. Examination of the skin in patients with ALS would be easy to carry out as an additional examination. Further analysis of the complex skin abnormalities will be useful in elucidating the basic pathological mechanism of ALS.

[Skin collagen abnormalities in a Japanese patient with extracranial internal carotid artery dissection followed by extracranial vertebral artery dissection].

A 41-year-old man with hypertension and hyperlipidemia who complained of left hemiparesis after a temporal headache was admitted to our hospital. A cervical MRI with gadolinium enhancement revealed an intramural hematoma is compatible with right extracranial internal carotid artery dissection. Two weeks later, he complained of sudden onset of pain in the right side of his neck. The right extracranial internal carotid artery dissection followed by the right extracranial vertebral artery dissection was diagnosed. Spontaneous cervical artery dissection (SCAD) is one of the causes of stroke in young adults. The pathogenesis of SCAD remains unknown. Minor trauma like an excessive sneeze, migraine, and connective tissue disorders such as fibromuscular dysplasia and Ehlers-Danlos syndrome are well-known as risk factors for SCAD. Pathologically skin collagen abnormalities have been seen in German patients with SCAD without clinical evidence for any specific connective tissue disorder. We examined the ultrastructural morphology of the Japanese patient's dermal connective tissue components by electron microscopy. The patient's collagen fibers contained fibrils with highly variable diameters, and there were other ultrastructural abnormalities, including flower-like fibrils and large-diameter composite fibrils. This is the first report of a case of ultrastructural abnormalities of dermal connective tissue in a Japanese patient with SCAD.

Ischemic symptoms induced by occlusion of the unilateral vertebral artery with head rotation together with contralateral vertebral artery dissection--case report.

We report a 45-year-old woman whose unilateral vertebral artery (VA) was potentially occluded with head rotation at the C1-C2 level and her ischemic symptoms suddenly appeared because of contralateral VA dissection. She noticed first pain around the posterior part of her neck on the right side, and then dizziness when turning the head to the right side. The dizziness disappeared immediately after her head returned to the natural position. Digital subtraction angiography (DSA) showed a string sign of the right VA. DSA and computed tomography angiography (CTA) showed high grade extrinsic compression of the left VA at the C1-C2 level with head rotation more than 90 degrees to the right. Three-dimensional (3D) CTA also showed clearly kinking of the left VA at the C2 neuroforamina. Her symptoms disappeared completely with conservative therapy, and recanalization of the right VA was also confirmed by 3D-CTA. 3D-CTA was thought to be valuable to diagnose and manage the rotational compression of the artery. VA dissection must be remembered to differentially diagnose the etiology of transient attacks of posterior circulation ischemia due to rotational contralateral VA occlusion.

ALS-like skin changes in mice on a chronic low-Ca/Mg high-Al diet.

Epidemiologic studies of endemic foci of amyotrophic lateral sclerosis (ALS) have shown low concentrations of Ca/Mg and high concentrations of Al/Mn in the drinking water and garden soil, which may play a causative role in the pathogenesis of endemic ALS. We studied the effects of chronic exposure to a low-Ca/Mg high-Al maltol diet on the skin of experimental animals. In ALS patients, atrophy of the epidermis, edematous changes with separated collagen fibrils and an accumulation of amorphous materials between collagen bundles were regarded as pathognomonic skin changes of ALS. Mice chronically fed a low-Ca/Mg high-Al maltol diet showed neuronal degeneration and loss in the spinal cords and cerebral cortices, as well as skin changes including atrophy, separation of collagen fibrils and accumulation of amorphous materials, similar to the skin changes characteristic of ALS. This is the first report of skin changes in animal models similar to those of ALS. We speculate that environmental factors such as chronic low-Ca/Mg high-Al condition play some causative role in the pathogenesis of Kii-ALS.

Decreased galectin-1 immunoreactivity of the skin in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving motor neurons. In addition to motor neuron signs and symptoms, a lack of bedsores has been considered a feature of ALS. Recently, we revealed that galectin-1 is a component of the axonal spheroid, which is an early pathological change of the spinal cord in ALS. To investigate whether galectin-1 is associated with skin changes in ALS, we performed an immunohistochemical investigation using anti-galectin-1 antibodies. The present study revealed that galectin-1 immunoreactivity is reduced in the skin of patients with ALS, suggesting that cutaneous galectin-1 is involved in the pathological process of ALS.

Chronic low-Ca/Mg high-Al diet induces neuronal loss.

To evaluate the causative role of environmental aluminum (Al) in the development of neurodegeneration in Kiiamyotrophic lateral sclerosis (ALS), we examined how chronic exposure to a low-Ca/Mg and high-Al diet induced neuronal loss and tau-related neuronal degeneration in experimental animals. Optical microscopic examination showed tau-positive cells, atrophic neurons with darkly stained cytoplasms or swollen perikarya in the cerebrum, hippocampus and the brainstem of mice fed a low-Ca/Mg high-Al diet (Group 3). The neuronal loss was found in the frontal and parietal cortices of the mice and was not due to a classical apoptosis as detected by the terminal de ynucl otidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method. Neuronal degeneration and spheroid formation was also seen in the spinal cord of the Group 3 mice. The Morin fluorescence technique showed Al and Ca deposition in the cortical neurons and vessels in the basal ganglia of these mice. An electron microscopic examination showed intranuclear filamentous structures, intracytoplasmic vacuoles and/or darkly stained cytoplasm in the cortical neurons of Group 3 mice. These findings were seen in mice of the 11-month-experimental period and increased until the 25-month-experimental period. The present findings suggested that chronic exposure to a low-Ca/Mg high Al condition induced an accumulation of hyperphosphorylated tau in the cortical neurons, swelling of the neuronal cytoplasm and loss in the cerebrum and spinal cord of mice. Environmental factors such as a low-Ca/Mg high Al exposure might be one of the risk factors for the development of neuronal degeneration of ALS in the Kii Peninsula.

Dentatorubropallidoluysian atrophy with chronic renal failure in a Japanese family.

We describe a Japanese family with molecularly confirmed DRPLA associated with chronic renal failure of unclear etiology on hemodialysis. The clinical symptoms and laboratory data show that the renal failure in our DRPLA patients is not associated with known familial renal diseases. Thus, we suggest a possible unifying hypothesis that the coexistence of DRPLA and chronic renal failure may be caused by the same etiology.