Keiko Toyooka

Cognitive function in amyotrophic lateral sclerosis

Cognitive function in patients with amyotrophic lateral sclerosis (ALS) has drawn recent attention. However, the pathogenesis of cognitive dysfunction in patients with ALS remains uncertain. To explore the underlying mechanism for cognitive dysfunction further, we studied 26 patients with ALS (15 male and 11 female; age from 36 to 67 years) by using neuropsychological batteries, magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT). We also evaluated these patients and an additional 26 age- and sex-matched normal controls using neuropsychological batteries with special attention to the frontal lobe function. On the basis of neuropsychological examination, we classified patients into three groups using cluster analysis. Age, education level and severity were comparable across these subgroups. Neuropathologic examination was subsequently carried out in six patients. Patients in Group 1 and 2 had low scores on all measures compared to patients in Group 3 and normal controls. Patients in Group 1 and 2 had frontal atrophy on MRI and reduced isotope uptake in the frontal region on SPECT, which was more evident in patients in Group 1. On neuropathologic examination, patients in Group 1 showed spongy degeneration and neuronal loss in the frontal lobe. Patients in Group 3 showed no notable pathology in the frontal region. The gradient distribution of the scores for attention and executive function, as well as SPECT findings suggested the presence of a continuum of cognitive disability in patients with ALS corresponding to the pathologic process in the frontal lobe ranging from significant impairment to normality. We, therefore, believe that inattention and executive dysfunction alternatives may evolve in patients with ALS corresponding to the pathologic process in the frontal lobe.

Involvement of the central nervous system in myotonic dystrophy

To investigate the etiological factors responsible for intellectual impairment and mood changes in patients with myotonic dystrophy (DM), we evaluated 14 patients with DM by means of neuropsychological evaluation and magnetic resonance images (MRI). There were significant differences between patients and controls in regard to the Barthel index, Zungs depression scale, attention, verbal fluency and digit span. All patients had ventricular enlargement and white matter abnormalities on MRI. However, the severity was variable and there was no difference in neuropsychological testing between patients with mild ventricular dilatation and those with severe dilatation. On the other hand, significant differences were present between patients with mild white matter lesions and those with severe white matter abnormalities in regard to verbal fluency and attention. Neuropathologic examination of an autopsied brain showed an increase in the interfascicular space of the white matter which produced pallor on myelin staining. The present findings suggested that the white matter abnormalities were the cause of cognitive impairment among patients with DM.

Alzheimer-type pathology in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).

Abstract A 53-year-old Japanese woman with a point mutation in mitochondrial DNA (tRNALeu(UUR), nt3243) consistent with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and Alzheimer-type brain pathology is reported. This woman had suffered myopathy and psychosis without any clinical evidence of, stroke-like episodes during the last 10 years of her life, and had died after an accident. At autopsy 30 h post mortem, a part of the brain was snap frozen for biochemical and histochemical studies, and the remaining part was processed for a routine examination and electron microscopy. In the brain there were no ischemic lesions. Instead, primitive/diffuse senile plaques were found throughout the brain, predominantly in the frontal and temporal lobes, while Alzheimer neurofibrillary tangles were found only in the parahippocampal gyrus. These plaques were positive for β-protein and mostly negative for tau protein, ubiquitin, neurofilaments, α-choline acetyltransferase, and acetylcholinesterase. Mutations in codon 331 of the ND2 gene as well as codons 693, 713 and 717 of the β-amyloid precursor protein gene, known to be responsible for some cases of familial Alzheimer disease, were not found. Furthermore, coincidental Down syndrome was ruled out by chromosome analysis. The results suggest a possible correlation between this mitochondrial DNA abnormality and Alzheimer-type pathology.

A cross-sectional study for glucose intolerance of myotonic dystrophy

We made a cross-sectional study to analyze glucose intolerance of myotonic dystrophy type 1 (DM1) with several examination including oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and adiponectin. Ninety-five DM1 patients participated in this study. Health examination data from general people were used as controls. In DM1, homeostasis model assessment-insulin resistance (HOMA-IR) was higher than control even in the lowest fasting blood sugar (FBS) stage (<80 mg/dl) and insulin sensitivity assessed by ITT was low regardless of their FBS. Insulinogenic index of DM1 was positively correlated to HOMA-IR. Insulinogenic index and sum of IRI in OGTT were markedly elevated in the lowest FBS stage and declined along with elevation of FBS. Consequently, as many as 13.3% of DM1 patients with 90-110 mg/dl of FBS exhibited DM pattern, while only 1.9% in control. Adiponectin was higher in DM1 than control. Although age correlated with adiponectin in both control and DM1, its impact was stronger in DM1. DM1 predisposes insulin resistance and compensatory hyperinsulinemia exist even in patients with low FBS. We should pay attention to glucose intolerance of DM1 patients earlier than that of the general population. It seemed that 90 mg/dl of FBS is an important index as an indication of careful managements.

Focal cytochrome c oxidase deficiency in the brain and dorsal root ganglia in a case with mitochondrial encephalomyopathy (tRNAIle 4269 mutation): histochemical, immunohistochemical, and ultrastructural study

This is the first report with histochemical and immunohistochemical techniques of an autopsy case with mitochondrial encephalomyopathy caused by the mitochondrial tRNA(Ile) (nt4269) A to G mutation showing focal cytochrome c oxidase (COX) deficiency of neuronal cells. The 18-year-old male patient had cardiomyopathy, hearing disability, mental retardation, and seizures. Muscle biopsy exhibited many ragged-red fibers and focal COX deficiency. A postmortem histochemical study on frozen sections of the cerebral cortex, cerebellum, brain stem, and dorsal root ganglia revealed a loss of COX activity in some neuronal cells. On immunohistochemical staining, COX was also defective in a mosaic pattern. Focal COX deficiency may cause variable neurological manifestations in mitochondrial encephalomyopathies.

Familial amyloid polyneuropathy associated with transthyretin Gly42 mutation: a quantitative light and electron microscopic study of the peripheral nervous system

We performed extensive quantitative analyses of the peripheral nervous system (PNS) of two siblings with familial amyloid polyneuropathy (FAP) caused by a transthyretin (TTR) Gly42 mutation. Pronounced amyloid deposition was found in the sympathetic ganglia (SyG), dorsal root ganglia (DRG) and throughout the length of the peripheral nerve fibers with some accentuation in the more proximal portion. There was severe neuronal loss in the SyG and DRG together with nerve fiber depletion in the nerve trunk, while only a small amount of amyloid deposition with mild fiber loss was seen in the spinal roots. Sprouts of regenerating axons were very scanty even in the spinal nerves or roots. A teased fiber study mainly showed demyelinating fibers, but axonal degeneration was also present throughout peripheral nerves. An electron microscopic study showed fine amyloid fibrils in direct contact with the axoplasmic membrane of demyelinated axons and destruction of axons in some areas. Amyloid deposition within the PNS in this type of FAP resembled that in type I FAP (TTR Met30). However, direct axonal damage by amyloid fibrils appeared to be more prominent in our cases than in type I FAP. Lectin histochemistry using Ulex europaeus agglutinin I demonstrated preferential depletion of small neurons in the DRG and their primary afferent fibers in the spinal dorsal horn. Primary axonal degeneration and ganglionopathy due to amyloid deposition appear to be the pathogenetic mechanisms for peripheral neuropathy in this type of FAP.

Nephrosialidosis: ultrastructural and lectin histochemical study.

SummaryThe neuropathological findings in a Japanese male with nephrosialidosis are reported. Clinically, coarse face, psychomotor retardation, macular cherryred spot and proteinuria were noted at 1 year and 7 months. He was diagnosed to have nephrosialidosis on the basis of a deficiency of α-neuraminidase activity in both lymphocytes and cultured skin fibroblasts, and of severe glomerular and tubular involvement on renal biopsy. He died of multiple organ failure at 8 years and 6 months. There were numerous vacuoles and storage materials in visceral organs, particularly in the glomerular and tubular epithelial cells of the kidney and Kupffer cells as well as hepatocytes in the liver. Neuropathological examination revealed severe neuronal storage in the selected part of the central nervous system; lower motor neurons of the brain stem and spinal anterior horn cells, as well as neurons in the basal nucleus of Meynert. In the peripheral nervous system, sympathetic ganglia were severely affected. There was little or no neuronal storage in the basal ganglia, cerebral cortex or cerebellum, and demyelination was not found. Electron microscopic examination showed fine wavy multilamellar structures in the spinal anterior horn cells or Zebra body-like structures in the neurons of the Meynerts basal nucleus. Lectin histochemistry was positive for wheat germ agglutinin, Ricinus communis agglutinin-1 and peanut agglutinin within distended neurons. We conclude that the neuropathological feature in nephrosialidosis is not specific except for the selectiveness of the anatomical sites of involvement. It shares some aspects found in other types of sialidosis or galactosialidosis.

Demyelination in severe combined immunodeficient mice by intracisternal injection of cerebrospinal fluid cells from patients with multiple sclerosis: neuropathological investigation

Abstract Demyelinating lesions have been observed in severe combined immunodeficient (SCID) mice after intracisternal administration of cerebrospinal fluid cells (CSFC) from patients with multiple sclerosis (MS). Further investigation in our laboratory revealed that CSFC from 6 of 15 patients at exacerbation of MS caused demyelination. The factor leading to demyelination appears to be the high frequency of relapses during a short period, but not the severity of the disease. Neuropathological and immunohistochemical studies revealed that a lack of inflammatory mononuclear cell infiltration within and around the demyelinating lesions or in leptomeninges was a common characteristic in all SCID mice with CSFC-induced demyelination. In affected mice killed 2–3 weeks after intracisternal administration of CSFC, foamy/vacuolar lesions with a small or moderate number of lipid-laden macrophages were seen in the white mater. Ultrastructurally, relative preservation of axons, in contrast to myelinoclastic features, as well as some remyelinated axons were observed. In affected SCID mice killed 4–6 weeks after intracisternal administration, more widespread foamy macrophages and necrotic foci with poor remyelination were seen. The findings were similar to those seen in experimental allergic encephalomyelitis, though without lymphocytic infiltration, but were quite different from the lesions observed in Theiler’s murine encephalitis virus infection. The absence of an immunohistochemical reaction to the human leukocyte common antigen in the infiltrating mononuclear cells suggested that the graft-versus-host reaction was an unlikely cause of the demyelinating lesions.

Microvascular disturbance with decreased pericyte coverage is prominent in the ventral horn of patients with amyotrophic lateral sclerosis

In amyotrophic lateral sclerosis (ALS) there is emerging evidence for vasculature disturbance. The aim of this study was to investigate the area of predominant vasculature disturbance in ALS. We used immunohistochemistry to quantitatively evaluate the microvascular density (MVD) and pericyte coverage (PC) in the lumbar spinal cord of 25 ALS patients and six controls. In controls, MVD was almost equal in the ventral horn (VH) and dorsal horn (DH). In the VH of ALS, MVD was significantly increased, and PC was significantly decreased compared with the DH in ALS and the VH in controls (p < 0.001), possibly reflecting that PC is an essential requirement for the vasculature in the VH. We then found a significant relationship between the severity of aberrant angiogenesis and the use of artificial respiratory support (ARS). In conclusion, vasculature disturbance is observed in all ALS patients including patients with ARS. Therefore, breakdown of the blood-spinal cord barrier due to aberrant angiogenesis with decreased PC may be responsible for the predominant neuronal death in the VH in ALS.

Adult-onset multiple acyl CoA dehydrogenation deficiency associated with an abnormal isoenzyme pattern of serum lactate dehydrogenase.

We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content.