Shiro Matsubara

Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells

The klotho gene was identified in 1997 as the gene whose severe insufficiency (kl/kl) causes a syndrome resembling human aging, such as osteoporosis, arteriosclerosis, gonadal atrophy, emphysema, and short life span in a mouse strain. Regarding the gait disturbance reported in kl/kl mice, the present study examined the spinal cord of kl/kl mice, and revealed decreases in the number of large anterior horn cells (AHCs), the amount of cytoplasmic RNA, the number of ribosomes and rough endoplasmic reticulum (rER), and the activity of ribosomal (r) RNA gene transcription without significant loss of the total number of neurons in the ventral gray matter. Increased immunostaining of phosphorylated neurofilament in the AHCs and of glial fibrillary acidic protein in reactive astrocytes in the anterior horn of kl/kl mice were also observed. On the other hand, the posterior horn was quite well preserved. The results suggest that the kl/kl insufficiency causes atrophy and dysfunction of the spinal AHCs through decreased activity of rRNA gene transcription, which may reduce the amount of cytoplasmic RNA and the number of ribosomes and rER. These findings resemble those found in the spinal cord of patients with classic amyotrophic lateral sclerosis (ALS). The results show that klotho gene insufficiency causes dysfunction of the protein synthesizing system in the AHCs, and might indicate the klotho gene is involved in the pathological mechanism of classic ALS. The kl/kl is a new animal model of AHC degeneration, and may provide clues to understanding the etiology of classic ALS.

Complex fasciculation potentials and survival in amyotrophic lateral sclerosis

OBJECTIVE We investigated the relationship between fasciculation potentials (FPs) and survival in patients with ALS. METHODS In 85 ALS patients, we prospectively performed needle EMG in five to seven muscles of each patient. The shape of the detected FPs was analyzed by inspection, and FPs with >4 phases were judged as complex FPs. We analyzed the correlation between complex FPs and survival period using the Cox proportional hazard model. RESULTS Complex FPs were observed in 47 patients, more frequently in the muscles with normal strength or mild weakness. The presence of complex FPs was associated with shorter survival (hazard ratio 3.055; p=0.004). The greater the number of muscles with complex FPs, the shorter the survival and the faster the progression speed. CONCLUSION Wide distribution of complex FPs is associated with shorter survival in ALS. SIGNIFICANCE Complex FPs are useful to predict prognosis of ALS patients and should be evaluated in the EMG examination.

Marked preservation of the visual and olfactory pathways in ALS patients in a totally locked-in state.

MATERIALS AND METHODS The present paper examines the brains and spinal cords in 7 patients with amyotrophic lateral sclerosis (ALS) receiving artificial respirator support in a totally locked-in state (TLS) neuropathologically in order to clarify whether any anatomical structures in the central nervous system are preserved. RESULTS AND CONCLUSION We found that the visual and olfactory pathways, hypothalamus, nucleus basalis of Meynert, and commissura anterior were remarkably well preserved, whereas the somatosensory, auditory, and gustatory pathways in the brain stem and/or spinal cord showed severe deterioration.

Hyperosmolar hyperglycemic state in advanced amyotrophic lateral sclerosis

Abstract Our objective was to describe cases of hyperosmolar hyperglycemic state (HHS) in advanced amyotrophic lateral sclerosis (ALS) patients and discuss its pathophysiology. Five ventilator-dependent patients with ALS, with no previous history of diabetes, showed development of marked hyperglycemia (plasma glucose levels of 755–1544 mg/dl) after preceding infectious episodes. All patients had severe generalized muscle wasting and tetraplegia. The initial manifestations of HHS were fever, drowsiness, or polyuria. Hydration and intravenous insulin therapy were markedly effective, resulting in favorable recovery without the necessity of chronic medication for hyperglycemia in all cases. Seventy-five grams oral glucose tolerance tests performed via feeding tubes in two patients after the successful treatment of HHS revealed increased insulin resistance and diminished early-phase insulin secretion with preserved total insulin secretion. In conclusion, a marked loss of skeletal muscle, the largest glucose consumer of the human body, with background abnormality of early-phase insulin secretion, might be a causative factor of HHS in advanced ALS.

Wernicke's Encephalopathy in a Patient with Peptic Ulcer Disease

We report a 74-year-old man with Wernickes encephalopathy (WE) whose only prior illness was peptic ulcer disease. Upper gastrointestinal endoscopy demonstrated gastric ulcer scars accompanied by marked deformity, without pathologic evidence of malignancy. WE due to peptic ulcer disease in previous reports was substantially associated with thiamine deficiency due to recurrent vomiting or surgical procedures. In our case, however, there was no history of vomiting or gastrointestinal surgery. Besides, we thoroughly ruled out other known clinical settings related to WE. There is the possibility that peptic ulcer disease itself provoked thiamine deficiency due to malabsorption.

Ultrastructural changes of skeletal muscles in polyarteritis nodosa and in arteritis associated with rheumatoid arthritis

SummaryMuscle biopsies from two cases of polyarteritis nodosa (PN) and one of arteritis in association with rheumatoid arthritis (RA) were examined by electron microscopy.The histological changes were similar in all three cases. The endothelial cells of the small blood vessels were often hypertrophied. Inflammatory reaction was present mainly in the vicinity of the blood vessels. Individual muscle fibres showed mostly nonspecific degenerative changes. In a case of PN, however, annulate lamellae were present in a small number of the muscle fibres. The annulate lamellae have been reported, to our knowledge, in the human skeletal muscles only in a few cases of polymyositis. In addition, two cases, one of PN and one of arteritis with RA, showed fine filamentous inclusions in the muscle fibres. Changes were also noted in the motor end-plate.A sural nerve biopsy in a case of arteritis with RA showed changes both in axons and myelin sheaths, in addition to the changes in the blood vessels similar to those in the muscle.

Neuropathological features of Japanese familial amyotrophic lateral sclerosis with p.N352S mutation in TARDBP

In this case report, for the first time, we provide descriptive cliniconeuropathological features of a case of familial amyotrophic lateral sclerosis (familial ALS, FALS) with p.N352S mutation in TARDBP. The present Japanese patient (Figure 1, II-4, the proband) was born in Wakayama Prefecture. At 74 years, he experienced weakness in the muscles of both hand. He visited our neurology department with complaints of impaired fine motor skills of both hands at 76 years, and his neurological examination showed muscle weakness and muscular atrophy of both hands. At 77 years, his muscle weakness descended to both thighs, leading to difficulty in walking by himself. While his tongue revealed slight atrophy and fasciculation, there were no detectable upper motor neurone (UMN) signs, cognitive impairment, dysphagia, dysarthria, sensory disturbances, or gait disturbances. Electromyography disclosed active denervation of muscle potentials in both the upper and lower extremities, and he was diagnosed with ALS. His respiratory function gradually worsened, and he died of respiratory failure at 78 years, 4 years after onset. In the patient’s pedigree, his niece (III-2), who is now 60 years old, was also affected by ALS. She had complaints of muscle weakness of the lower extremities at 45 years and is currently on ventilatory support. She can still communicate using lip movements. Informed consent for the gene study was obtained from the patient and his family. Genomic DNA was extracted from peripheral blood leucocytes using standard methods. All exons and exon–intron boundaries of copper/zinc superoxide dismutase (SOD1) and TARDBP were analysed by polymerase chain reaction and direct sequencing, as previously reported [1,2]. TARDBP analysis identified a c.1055A>G heterozygous missense mutation at codon 352 (p.N352S) and no mutation of SOD1. The present study was approved by the ethics committees of all participating institutions. Neuropathologically, brain weight after fixation was 1295 g. Macroscopically, both the cerebrum and cerebellum were preserved. In the brainstem, medullary pyramid volumes were slightly decreased. The spinal cord was relatively preserved, except for slightly decreased volumes of both the cervical and lumbar enlargements and slightly atrophic spinal anterior roots. Major neuropathological features of the present case are summarized in Table 1. Microscopically, even though the shape of the spinal cord was preserved (Figure 2a), the spinal anterior horn was mildly affected by neuronal loss and gliosis (Figure 2b). A large number of axonal spheroids were noted in the spinal anterior horn (Figure 2c). In the residual anterior horn neurones, Bunina bodies were obvious (Figure 2d). The posterior funiculus, lateral and posterior horns and Clarke’s columns were well preserved. In the brainstem, slight neuronal atrophy and loss of both neurones and fibres with gliosis were observed in the hypoglossal, facial and motor nuclei of the trigeminal nerve. In addition, a Bunina body was observed in the hypoglossal nuclei and left motor nucleus of the trigeminal nerve. Other brainstem nuclei revealed no significant features. In the pyramidal tract, slight fibre loss with macrophage reaction was observed in both the lateral and anterior corticospinal tracts and in the medullary pyramids. In the precentral gyrus, slight atrophy and loss of Betz cells were observed, although no neuronophagia was detected. Other cerebral regions, including the frontal and temporal cortices, cerebral limbic system, striatonigral system, and cerebellum were preserved. The distribution of neurofibrillary tangles and senile plaques corresponded to Braak’s stage I and C, respectively [3,4]. The degree of neurogenic muscular atrophy was mild to moderate in the diaphragm, mild in the intercostal and iliopsoas muscles, and slight in the sternocleidomastoid muscle. Immunohistochemically, a few phosphorylated TAR DNA-binding protein of 43 kDa (pTDP-43)-positive rough dot-shaped neuronal cytoplasmic inclusions (NCIs) were observed in the spinal anterior horn neurones (Figure 2e). Moreover, a few glial cells with pTDP-43-positive crescentshaped glial intracytoplasmic inclusions (GCIs) were observed at the thoracic cord level (Figure 2f). Neurones with pTDP-43-positive NCIs were also detected in the dentate gyrus of the hippocampus, subiculum and cornu ammonis 2 area, but only a single affected neurone was

A Japanese patient with familial ALS and a p.K510M mutation in the gene for FUS (FUS) resulting in the totally locked‐in state

We describe a Japanese patient with familial amyotrophic lateral sclerosis (ALS) and a p.K510M mutation in the fused in sarcoma gene (FUS). The patients condition was characterized clinically by an early onset and rapid progression. The patient eventually required mechanical ventilation and progressed to the totally locked‐in state. Neuropathologically, multiple system degeneration with many FUS‐immunoreactive structures was observed. The involvement of the globus pallidus, subthalamic nucleus, substantia nigra, cerebellar efferent system, and both upper and lower motor neurons in the present patient was comparable to that described for ALS patients with different mutations in FUS, all of whom progressed to the totally locked‐in state. However, the patient also exhibited degeneration of the cerebellar afferent system and posterior column. Furthermore, the appearance of non‐compact FUS‐immunoreactive neuronal cytoplasmic inclusions and many FUS‐immunoreactive glial cytoplasmic inclusions were unique to the present patient. These features suggest that the morphological characteristics of the FUS‐immunoreactive structures and distribution of the lesions vary with the diversity of mutations in FUS.

Lateralized Cortical Involvement and Contralateral Parkinsonism without Basal Ganglia Involvement in Two Autopsy Cases of Corticobasal Syndrome-Alzheimer's Disease

Corticobasal syndrome (CBS) is characterized by lateralized motor disturbance due to levodopa nonresponsive parkinsonism and progressive apraxia. Although CBS is neuropathologically heterogeneous, it remains unclear whether the clinical features of all CBS cases are the same. We report two autopsy cases diagnosed clinically as CBS and pathologically as Alzheimers disease characterized by lateralized cerebral cortical degeneration and absence of significant nigrostriatial lesions. Cerebral cortical degeneration in both cases was contralateral to their motor disturbances. Thus, nigrostriatial lesions and contralateral cerebral cortical lesions can cause motor disturbances in CBS, necessitating the need for bedside examination in patients with CBS.

Differences in excitability between median and superficial radial sensory axons

OBJECTIVE The aim of this study was to investigate differences in excitability properties of human median and superficial radial sensory axons (e.g., axons innervating the glabrous and hairy skin in the hand). Previous studies have shown that excitability properties differ between motor and sensory axons, and even among sensory axons between median and sural sensory axons. METHODS In 21 healthy subjects, threshold tracking was used to examine excitability indices such as strength-duration time constant, threshold electrotonus, supernormality, and threshold change at the 0.2 ms inter-stimulus interval in latent addition. In addition, threshold changes induced by ischemia for 10 min were compared between median and superficial radial sensory axons. RESULTS Compared with radial sensory axons, median axons showed shorter strength-duration time constant, greater threshold changes in threshold electrotonus (fanning-out), greater supernormality, and smaller threshold changes in latent addition. Threshold changes in both during and after ischemia were greater for median axons. CONCLUSIONS These findings suggest that membrane potential in human median sensory axons is more negative than in superficial radial axons, possibly due to greater activity of electrogenic Na(+)/K(+) pump. These results may reflect adaptation to impulses load carried by median axons that would be far greater with a higher frequency. SIGNIFICANCE Biophysical properties are not identical in different human sensory axons, and therefore their responses to disease may differ.