T. Yamano

Loss of serotonin‐containing neurons in the raphe of patients with myotonic dystrophy A quantitative immunohistochemical study and relation to hypersomnia

Hypersomnia occurs frequently in patients with myotonic dystrophy (MyD). We performed a quantitative immunohistochemical study of serotonin (5—HT) containing neurons linked to hypersomnia in the dorsal raphe nucleus (DRN) and the superior central nucleus (SCN) in 8 patients with MyD, 5 of whom showed hypersomnia, and in 12 age-matched controls. The densities of 5—HT neurons in the DRN and the SCN were significantly lower in MyD patients with hypersomnia than in MyD patients without hypersomnia and controls. These data suggest that the loss of 5—HT neurons of the DRN and the SCN is associated with the presence of hypersomnia in MyD.

Loss of catecholaminergic neurons in the medullary reticular formation in myotonic dystrophy

Objective: To clarify the possible relation between the extent of involvement of catecholaminergic neurons and the presence of alveolar hypoventilation in patients with myotonic dystrophy (MyD). Background: Respiratory insufficiency has been reported frequently in MyD patients. Recent data support the hypothesis that this respiratory failure results from a primary dysfunction of the CNS. Methods: The authors performed a quantitative immunoreactive study of tyrosine hydroxylase immunoreactive (TH+) neurons linked to hypoventilation in the dorsal central medullary nucleus (DCMN), the ventral central medullary nucleus (VCMN), and the subtrigeminal medullary nucleus (SMN)-where the automatic respiratory center is thought to be located-in eight MyD patients and in 10 age-matched control subjects. Alveolar hypoventilation of the central type was present in three of the MyD patients but not in the remaining MyD patients or the control subjects. Results: The densities of TH+ neurons of the DCMN, the VCMN, and the SMN in MyD patients with hypoventilation were significantly lower than in those without hypoventilation (p < 0.02, p < 0.01, and p < 0.01, respectively) and control subjects (p < 0.01, p < 0.01, and p < 0.01, respectively). Conclusions: These data suggest that the loss of TH+ neurons of the DCMN, the VCMN, and the SMN is associated with the presence of hypoventilation in MyD and may be an important feature of MyD.

Increased expression of TDP-43 in the skin of amyotrophic lateral sclerosis

Suzuki M, Mikami H, Watanabe T, Yamano T, Yamazaki T, Nomura M, Yasui K, Ishikawa H, Ono S. Increased expression of TDP‐43 in the skin of amyotrophic lateral sclerosis. Acta Neurol Scand: 2010: 122: 367–372.

Decreased type IV collagen of skin and serum in patients with amyotrophic lateral sclerosis

Objective: To study type IV collagen of skin and serum in patients with ALS. Background: Collagen abnormalities of skin have been reported in ALS patients. However, little is known concerning type IV collagen in ALS. Methods: We studied type IV collagen immunoreactivity of skin and measured serum levels of the 7S fragment of the N-terminal domain of type IV collagen (7S collagen) in patients with ALS and control subjects. Results: The basement membrane as well as blood vessels of skin in ALS patients was weakly positive for type IV collagen as compared with those of diseased control subjects. This weak immunostaining became more pronounced as ALS progressed. The optical density for type IV collagen immunoreactivity in ALS patients was significantly lower (p < 0.001) than in diseased control subjects and was significantly decreased with duration of illness(r = -0.85, p < 0.01). Serum 7S collagen levels in patients with ALS were significantly decreased (p < 0.01) as compared with those in diseased and healthy control subjects and were negatively and significantly associated with duration of illness (r= -0.81, p < 0.001). There was an appreciable positive correlation between concentrations of serum 7S collagen and the density for type IV collagen immunoreactivity in ALS patients (r = 0.81, p < 0.02). Conclusions: These data suggest that a metabolic alteration of type IV collagen may take place in the skin of ALS patients and that the decreased levels of serum 7S collagen may reflect a decreased type IV collagen immunoreactivity of skin in patients with ALS.

Collagen abnormalities in the spinal cord from patients with amyotrophic lateral sclerosis

During the last 10 years, we have demonstrated morphological and biochemical abnormalities of skin extracellular matrices in amyotrophic lateral sclerosis (ALS). However, currently little is known concerning collagen of the spinal cord in ALS. We measured the amount of collagen and characterized collagen at light and electron microscopic levels in posterior funiculus, posterior half of lateral funiculus and anterior horn of cervical enlargement of the spinal cord obtained from ten patients with ALS, 11 patients with other neurologic diseases (control group A), and ten patients without neurologic ones (control group B). In posterior half of lateral funiculus and anterior horn, (1) by light microscopy, there was no significant difference in vessel wall area between ALS patients and control groups A and B; (2) ultrastructurally, collagen bundles were more fragmented and widely separated, and the fibrils were randomly oriented in the perivascular space of capillaries in ALS patients, which were not observed in any areas of control groups or in posterior funiculus of ALS patients; and (3) the collagen contents in ALS were significantly lower (P<0.001 and P<0.001, respectively) than those in control groups A and B. Fragmented and widely separated collagen bundles in the interstitial tissue surrounding capillaries and markedly decreased amount of collagen in posterior half of lateral funiculus and in anterior horn of ALS could be related to the degeneration of the upper and lower motor neurons in the spinal cord in ALS, that is, selective neuronal vulnerability in ALS.

Alterations of skin glycosaminoglycans in patients with ALS

Background and Objective: Collagen abnormalities of skin have been reported among patients with ALS. However, little is known concerning glycosaminoglycans of the skin in ALS. Our objective was to clarify morphologic and biochemical findings of skin glycosaminoglycans among patients with ALS. Methods: We performed morphologic studies and biochemical analysis of glycosaminoglycans of skin from 8 patients with ALS, 6 patients with other neurologic or muscular diseases (control group A), and 7 patients without neurologic disorders (control group B). Results: The wide spaces that separate collagen bundles reacted strongly with Alcian blue stain in skin from patients with ALS and stained more markedly as ALS progressed. Staining with Alcian blue was virtually eliminated by Streptomyces hyaluronidase. The content of hyaluronic acid was significantly higher (p < 0.001) among patients with ALS than in control groups A and B. There was a significant positive correlation between content of hyaluronic acid and duration of illness among patients with ALS (r = 0.88, p < 0.01). However, there was no significant difference in content of dermatan sulfate, chondroitin sulfate-4S, or chondroitin sulfate-6S between patients with ALS and control groups A and B. There was also an appreciable positive correlation between optical density of Alcian blue and content of hyaluronic acid among patients with ALS (r = 0.92, p < 0.01). Conclusions: The data suggest that a metabolic alteration of glycosaminoglycans related to the increased amount of hyaluronic acid may take place in the skin of patients with ALS.

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.

Decreased plasma levels of fibronectin in amyotrophic lateral sclerosis.

Objectives– Fibronectin (FN) possesses a wide range of biological functions. However, the role of plasma FN in vivo has not yet been established and there have been no published studies of plasma FN in ALS. The aim of this study was to measure plasma FN in ALS patients. Material and methods– We measured plasma FN levels in 28 ALS patients, 18 control subjects with other neurologic or muscular diseases (control group A) and 21 healthy adults (control group B). The age and sex distributions among the 3 groups were comparable. Results– Plasma FN levels were significantly lower in ALS patients than in control groups A and B. There was also a significant negative correlation between plasma FN levels and duration of illness in ALS patients. Conclusion– These data suggest that a metabolic alteration of FN may take place in ALS and that the measurement of plasma FN may serve as an indicator of clinical progression of this disorder.

Decreased urinary concentrations of type IV collagen in amyotrophic lateral sclerosis

Objectives ‐ Type IV collagen (IV‐C) abnormalities of skin and serum have been reported in patients with amyotrophic lateral sclerosis (ALS). However, there has been no study of urinary IV‐C in ALS. The present study investigates urinary IV‐C and the relation to its skin content in patients with ALS. Material and methods ‐ We studied IV‐C immunoreactivity of skin and measured urinary levels of IV‐C in ALS patients and controls. Results ‐ The basement membrane as well as blood vessels of skin in ALS patients was weakly positive for IV‐C as compared with those of controls. Immunostaining became even weaker as ALS progressed. The urinary level of IV‐C in ALS patients was significantly decreased as compared to diseased controls (P<0.001) and healthy controls (P<0.001), and was negatively and significantly associated with duration of symptoms (r=‐0.85, P<0.001). There was an appreciable positive correlation between urinary IV‐C levels and the density for IV‐C immunoreactivity in ALS patients (r=0.84, P<0.01). Conclusion ‐ These data suggest that a metabolic alteration of IV‐C may occur in ALS patients and decreased levels of urinary IV‐C may be related to the decreased IV‐C immunoreactivity of skin in ALS.

Serum markers of type I collagen synthesis and degradation in amyotrophic lateral sclerosis

Collagen abnormalities in the skin and spinal cord have been reported in amyotrophic lateral sclerosis (ALS) patients. Serum carboxyterminal propeptide of type I procollagen (PICP) and the carboxyterminal cross-linked telopeptide of type I collagen (ICTP) reflect type I collagen synthesis and degradation, respectively. However, there has been no study concerning PICP or ICTP in ALS. We studied collagen contents of the skin and measured serum levels of PICP and ICTP in patients with ALS and control subjects. Serum PICP levels were significantly lower in ALS patients than in controls. Serum ICTP levels were significantly higher in ALS patients than in controls, and there was an appreciable positive correlation between serum ICTP levels and the duration of illness in ALS patients. In ALS patients, the collagen content of the skin was significantly smaller than in controls and indicated a progressive decrease in relation to illness. In addition, there was a significant negative correlation between serum ICTP concentrations and the collagen content of the skin in ALS patients. These data suggest that increased ICTP levels and decreased serum PICP levels may reflect unique changes in the skin, with a predominance of degradation compared to the synthesis of type I collagen in ALS.