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Biomedical subjects

Takahiko Tokuda

Publications and source records attributed to Takahiko Tokuda.

At least 19 recordsLinked to original sources
PubMed2006

Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease.

There is ample biochemical, pathological, and genetic evidence that the metabolism of alpha-synuclein (alpha-syn) plays a crucial role in the pathogenesis of Parkinson disease (PD). To examine whether quantification of alpha-syn in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of PD, we developed a specific ELISA system and measured the concentration of alpha-syn in CSF from 33 patients with PD (diagnosed according to UK PD Society Brain Bank criteria) and 38 control subjects including 9 neurologically healthy individuals. We found that PD patients had significantly lower alpha-syn levels in their CSF than the control groups (p<0.0001) even after adjusting for gender and age. Age was independently associated with lower alpha-syn levels. Logistic regression analysis showed that reduction in CSF alpha-syn served as a significant predictor of PD beyond age and gender alone (area under ROC curve, c=0.882). Furthermore, we observed a close inverse correlation between alpha-syn levels in CSF and assigned Hoehn and Yahr score in this cohort of 71 living subjects (p<0.0001), even after adjusting for age. These findings identify in the quantification of alpha-syn from CSF a potential laboratory marker to aid the clinical diagnosis of PD.

Adolescent↗
PubMed2006

A case of biopsy-proven leptomeningeal amyloidosis and intravenous Ig-responsive polyneuropathy associated with the Ala25Thr transthyretin gene mutation.

A growing body of literature has described familial leptomeningeal amyloidosis, a rare phenotype resulting from deposition of transthyretin (TTR) amyloid within the leptomeninges. We report herein the case of a patient with leptomeningeal amyloidosis presenting with hearing loss, asymmetrical polyneuropathy and sensory ataxia. This is the first Japanese case displaying TTR mutation at codon 25, replacing alanine with threonine. Neurophysiological examinations suggested demyelinating polyradiculoneuropathy, which improved dramatically after high-dose intravenous immunoglobulin treatment. Demyelinating polyneuropathy in our patient may be attributable to massive leptomeningeal amyloidosis, and no systemic organ involvement was identified. These characteristic clinical manifestations may have resulted from the Ala25Thr TTR gene mutation.

Alanine↗
PubMed2005

Tacrolimus in refractory patients with myasthenia gravis: coadministration and tapering of oral prednisolone.

We prospectively investigated therapeutic and adverse effects of tacrolimus in seven patients with myasthenia gravis (MG) who were resistant to conventional therapies or could not be treated with thymectomy because of complications. Within two months of initiation of tacrolimus all the patients subjectively showed improvement of clinical symptoms, while both the quantitative MG score for disease severity and MG-activities of daily living profile were significantly decreased (p<0.05) 3 and 6 months after commencement compared with before. Nine months after initiation and later, MG temporarily exacerbated in two patients with rapid tapering of oral prednisolone and one non-thymectomized one. This drug is useful in the treatment of refractory patients with MG irrespective of thymectomy, particularly in the early phase after commencement. When tacrolimus is additionally used for treatment of MG, preceding drugs, particularly corticosteroids such as oral prednisolone, should be carefully tapered if necessary in order to prevent clinical exacerbation.

Administration, Oral↗
PubMed2005

Severe protein losing enteropathy with intractable diarrhea due to systemic AA amyloidosis, successfully treated with corticosteroid and octreotide.

This report concerns two patients with severe protein losing enteropathy and refractory diarrhea due to AA amyloidosis who were successfully treated with corticosteroid and octreotide. In these patients, biopsied tissues from the gastrointestinal (GI) tract showed extensive deposition of AA amyloid, which was caused by rheumatoid arthritis in one case and was of unidentified etiology in the other. Both patients manifested severe diarrhea unresponsive to conventional treatment with hypoproteinemia, and protein leakage from the small intestine to the ascending colon was confirmed by 99mTc-diethylene triamine pentaacetic acid human serum albumin (HSA-D) scintigraphy. Soon after starting a long-acting somatostatin analogue, octreotide, with co-administration of oral prednisolone, their general status improved in parallel with a rapid decrease in the volume of watery diarrhea and an increase in serum levels of albumin and IgG. Also on 99mTc-HSA-D scintigraphy protein leakage from the GI tract was apparently decreased in both patients. Combination therapy with a somatostatin analogue and corticosteroid may be effective for protein losing enteropathy with intractable diarrhea ascribable to GI amyloidosis. Because of the lack of specific therapies in this serious clinical situation, the described therapy should actively be considered as a therapeutic option not only in AA amyloidosis, but also in other types of systemic amyloidosis.

Adrenal Cortex Hormones↗
PubMed2005

Unexpectedly high incidence of visceral AA-amyloidosis in slaughtered cattle in Japan.

Experimental mouse AA amyloidosis can be transmissible by dietary ingestion of amyloid fibrils and it is well known that AA amyloidosis occasionally develops in aged cattle. Bovine liver and intestine have conventionally been used in Oriental foods, and the incidence of visceral AA amyloidosis in slaughtered cattle was evaluated. Renal tissues from 302 aged cattle older than 4 years were obtained from a local abattoir. Amyloid deposition was microscopically examined and amyloid protein was immunochemically determined. Renal amyloid deposition was seen in 15 out of 302 cattle with no previous history of diseas, an incidence of 5.0%. Amyloid protein in these cattle was AA and they had pathological findings in their visceral organs on gross examination. The incidence of visceral AA amyloidosis in slaughtered cattle in this study was disturbingly high compared with those (0.4-2.7%) previously reported from Japan and other foreign countries. AA amyloidosis is a life-threatening complication in patients with chronic inflammatory diseases and these patients at risk should avoid ingesting food that may possibly contain AA amyloid fibrils. More detailed information on cattle amyloidosis is required to guarantee the safety of our food.

Amino Acid Sequence↗
PubMed2005

Biochemical characteristics of variant transthyretins causing hereditary leptomeningeal amyloidosis.

Transthyretin (TTR) is a tetrameric protein that can dissociate into amyloidogenic monomers and cause TTR-related amyloidosis. A rare phenotype, called hereditary leptomeningeal TTR amyloidosis, in which TTR amyloid deposition occurs mainly in leptomeninges and subarachnoid vessels, has been reported in patients with several different TTR variants. In the present study, we examined TTR variants immunoprecipitated from the serum and cerebrospinal fluid (CSF) of patients with hereditary leptomeningeal TTR amyloidosis using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (IP-Mass method). The leptomeningeal-type TTR variants were not detected in the serum but were found at low levels in the CSF. The undetectable levels of the leptomeningeal-type TTR variants in serum could explain the minute amounts of systemic deposition of these variants. The relatively high level of unstable TTR variants in CSF, probably due to increased secretion from the choroid plexus, is considered to be the pathogenesis of the leptomeningeal-type of TTR amyloidosis.

Adult↗
PubMed2005

A Japanese patient with familial Mediterranean fever associated with compound heterozygosity for pyrin variant E148Q/M694I.

Familial Mediterranean fever (FMF) is an inherited inflammatory disease occurring mainly in Mediterranean and Middle Eastern populations. FMF is caused by mutations in the MEFV gene that encodes pyrin/marenostrin. Here, we report a Japanese female FMF patient with heterozygosity for the compound pyrin E148Q/M694I showing recurrent fever, serositis or delay in skin wound healing. Her father and elder sister were heterozygous for pyrin variant M694I alone and sometimes suffered from mild fever or delay in wound healing, but her mother was heterozygous for pyrin variant E148Q alone and had no symptoms. This suggested that the inheritance of FMF occurred not only in an autosomal recessive manner but also in an autosomal dominant manner in this Japanese family, and the severity of the disease differed among the family members in relation to the mutation. In the treatment of FMF, colchicine, reserpine or prazosin hydrochloride have been reported to prevent the attacks, but, in our patient such drugs were ineffective or caused side effects, and only the anti-allergic drug azelastine was of benefit in relieving the attacks.

Adult↗
PubMed2004

Anti-neuronal autoantibody in Hashimoto's encephalopathy: neuropathological, immunohistochemical, and biochemical analysis of two patients.

Hashimoto's encephalopathy (HE) is thought to be caused by disorders of immune mechanisms. Although immunologically mediated central nervous system vasculitis or unidentified anti-neuronal autoantibodies have been suspected of causing HE, its pathogenesis is still unclear. For the study presented here, two patients with typical clinical and laboratory/electrophysiological findings of HE were analyzed to clarify the role of anti-neuronal autoantibodies in the pathogenesis of HE. The autopsied brain of one of the patients was histopathologically examined. For Western blotting analysis and immunohistochemistry, serum and purified immunoglobulin G obtained from the other patient were used. Autopsy revealed no evidence of central nervous system vasculitis or other abnormal findings in the brain. The patient's serum contained an anti-neuronal autoantibody that immunohistochemically labeled neurons of mouse and human cerebral cortices and reacted with the 36-kDa antigenic protein present in a soluble fraction obtained from human cerebral cortex. Our results indicate that anti-neuronal autoantibodies may be associated with the pathogenesis of HE.

Animals↗
PubMed2004

Feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult-onset type II citrullinemia.

More than 20 patients with adult-onset type II citrullinemia have undergone liver transplantation, showing dramatic therapeutic effects. In Japan, living donor liver transplantation is the standard technique of liver transplantation because of the rare availability of cadaveric donors. The feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for adult-onset type II citrullinemia to overcome the problem of a small-for-size graft in living donor liver transplantation has not been defined. We recently performed APOLT for patients with type II citrullinemia. Here, we present 2 patients: patient 1 was a 32-year-old man and patient 2 was a 43-year-old woman. Both patients suffered from hepatic encephalopathy, and laboratory data showed highly elevated plasma levels of ammonia and citrulline. In patient 1, the liver graft was obtained from a patient with familial amyloid polyneuropathy as a domino liver transplant. In patient 2, APOLT was performed after graft donation from her husband. The postoperative clinical courses of both patients were uneventful, and the neurological symptoms were completely resolved. The plasma concentrations of ammonia and citrulline normalized rapidly in both patients. APOLT can provide an adequate hepatocyte mass to correct the underlying enzyme deficiency in adult patients with type II citrullinemia. In addition, APOLT can be carried out safely to overcome the limitation of graft volume in living donor liver transplantation.

Adult↗
PubMed2004

Soluble Abeta homeostasis in AD and DS: impairment of anti-amyloidogenic protection by lipoproteins.

In order to assess whether lipoproteins are physiologically able to balance and modulate the sAbeta homeostasis in vivo, soluble Abeta levels in lipoprotein-depleted plasma were measured as a function of age in normal controls, Alzheimer's disease (AD) patients, and Down's syndrome (DS) cases. The reshaping of sAbeta homeostasis, in particular the sAbeta42-lipoprotein interaction, takes place over normal-60's, whereas mild AD patients appear to have impaired this anti-amyloidogenic mechanism resulting in a significant increase of lipoprotein-free sAbeta42. Similar loss of function takes place in Down's syndrome patients. Lipoprotein-free sAbeta remains significantly elevated from the pre-symptomatic through the symptomatic stages of the disease, and declines with the progression of the AD-like pathology. The dissociation of sAbeta from lipoprotein-particles also occurs in brain parenchyma and the presence of soluble dimeric lipoprotein-free Abeta prior to its parenchymal deposition in AD brains would support the hypothesis that functionally declined lipoproteins may be major determinants in the production of metabolic conditions leading to higher levels of sAbeta species and cerebral amyloidosis.

Adolescent↗
PubMed2004

A patient with severe renal amyloidosis associated with an immunoglobulin gamma-heavy chain fragment.

The authors report a patient with progressive renal dysfunction caused by severe renal amyloidosis associated with a gamma-heavy chain variable region (V(H)) fragment. The patient was a 71-year-old woman who had renal insufficiency without nephrotic syndrome. Laboratory data showed a monoclonal IgG lambda component in her serum and urine. Renal biopsy results showed massive amyloid deposition in the mesangial region, but the glomerular basement membranes and epithelial cells were preserved. Because immunohistochemical studies using antibodies against a number of known amyloid fibril proteins failed to detect the amyloid protein, the amyloid protein extracted from a small piece of the biopsied renal tissue was subjected to biochemical analysis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the extracted amyloid protein showed a prominent band at 11-kDa, and this protein was identified by amino acid sequence analysis as a gamma-heavy chain variable region fragment (V(H)3 subgroup) without the first N-terminal residue. Our results indicate that the patient's renal amyloidosis was associated with a gamma-heavy chain variable region fragment. Microextraction and biochemical characterization of amyloid fibrils was of great use for reaching a definitive diagnosis.

Aged↗
PubMed2004

MRI analysis on a patient with the V30M mutation is characteristic of leptomeningeal amyloid.

We report a characteristic finding in gadolinium-enhanced magnetic resonance images (MRIs) of the central nervous system (CNS) in a 61-year-old man with a homozygous transthyretin (TTR) Val30Met mutation. Although he presented with polyneuropathy accompanied by autonomic dysfunction and vitreous opacities in both eyes, he has shown no overt signs or symptoms of CNS involvement. Total protein level in the cerebrospinal fluid was moderately elevated. In the gadolinium-enhanced T1-weighted MRIs of the brain and spinal cord, leptomeningeal enhancement was seen along the surfaces of the brain stem and more clearly in the spinal cord, suggesting leptomeningeal TTR-related amyloid deposition. Our result indicates that gadolinium-enhanced MRI of the CNS may be a very sensitive and useful method for detecting leptomeningeal amyloid deposition, since abnormal findings can be detected even at a presymptomatic stage of CNS involvement.

Amino Acid Substitution↗
PubMed2004

Deposition of transthyretin amyloid is not accelerated by the same amyloid in vivo.

Acceleration of amyloid deposition by administration of amyloid fibrils and transmissibility of disease have been reported in several types of amyloidoses. Families with a variant transthyretin (TTR V30M)-associated familial amyloidotic polyneuropathy (FAP) exhibit genetic anticipation, with TTR V30M-amyloid depositing at an earlier age in successive generations. The molecular bases of anticipation in FAP have remained to be determined. We asked if administration of TTR-amyloid fibrils (ATTR) extracted from the heart of an FAP TTR V30M patient would accelerate ATTR deposition in transgenic mice expressing the human mutant ttr gene responsible for FAP TTR V30M and indeed the administration did accelerate deposition of apolipoprotein A-II-amyloid fibrils (AApoAII), and not A TTR. Our experiments present, for the first time, evidence that the degree of inducibility of ATTR is low relative to AApoAII and we suggest that administration of ATTR may not explain the genetic anticipation which occurs in FAP.

Amyloid↗
PubMed2004

Malignant lymphoma associated with rheumatoid arthritis, developing shortly after initiation of oral methotrexate.

We report a patient with rheumatoid arthritis (RA) who developed malignant lymphoma of the diffuse large B-cell type in the right submandibular region shortly after initiation of oral methotrexate (MTX). Despite cessation of MTX, the lymphadenopathy did not regress, and only reached complete remission after 3 courses of CHOP therapy followed by irradiation. In this patient highly active RA itself was considered to be the main cause of malignant lymphoma, and MTX might have contributed to the development by modifying the immune system. When RA is highly active, MTX should be used carefully because of the possible development of malignant lymphoma as well as other serious complications.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Pravastatin at 10 mg/day does not decrease plasma levels of either amyloid-beta (Abeta) 40 or Abeta 42 in humans.

It has been assumed that statins work as a preventative drug for Alzheimer's disease (AD). Although some epidemiological observations raise doubts to the effectiveness of statins for AD, many in vitro and clinical studies insist on the effectiveness of statins decreasing amyloid-beta (Abeta) levels in medium or blood. To explore the effect of pravastatin on Abeta production, we followed the longitudinal plasma levels of both Abeta 40 and Abeta 42 during the allocation of pravastatin in 46 patients with hyperlipidemia. We found no correlation between plasma cholesterol levels or the decreasing values of total cholesterol and those of Abeta 40 or Abeta 42. Patients having Apolipoprotein E4 (ApoE4) had higher low-density lipoprotein levels and lower Abeta 40 levels in plasma, suggesting ApoE4 seems to influence plasma Abeta levels via cholesterol metabolism.

Adult↗
PubMed2003

Withdrawal of levodopa and other risk factors for malignant syndrome in Parkinson's disease.

A symptom complex identical to neuroleptic malignant syndrome (MS) is known to develop in patients with idiopathic Parkinson's disease (PD) or other forms of parkinsonism on long-term treatment with anti-parkinsonian drugs. In order to clarify the risk factors for parkinsonian MS, the authors retrospectively reviewed charts of consecutive inpatients with PD in the neurological departments at the three hospitals and found 16 episodes of parkinsonian MS in 14 patients. A survey of health status preceding MS disclosed that deterioration of parkinsonian symptoms alone may induce MS, while association of major risk factors, i.e. rapid discontinuation of anti-parkinsonian drugs, dehydration or infection may precipitate or exacerbate MS. Cerebral vascular disorders, mechanical brain injury or physiological stress could be other risk factors leading to MS.

Aged↗
PubMed2003

Energetic characteristics of the new transthyretin variant A25T may explain its atypical central nervous system pathology.

Transthyretin (TTR) is a tetrameric protein that must misfold to form amyloid fibrils. Misfolding includes rate-limiting tetramer dissociation, followed by fast tertiary structural changes that enable aggregation. Amyloidogenesis of wild-type (WT) TTR causes a late-onset cardiac disease called senile systemic amyloidosis. The aggregation of one of > 80 TTR variants leads to familial amyloidosis encompassing a collection of disorders characterized by peripheral neuropathy and/or cardiomyopathy. Prominent central nervous system (CNS) impairment is rare in TTR amyloidosis. Herein, we identify a new A25T TTR variant in a Japanese patient who presented with CNS amyloidosis at age 42 and peripheral neuropathy at age 44. The A25T variant is the most destabilized and fastest dissociating TTR tetramer published to date, yet, surprising, disease onset is in the fifth decade. Quantification of A25T TTR in the serum of this heterozygote reveals low levels relative to WT, suggesting that protein concentration influences disease phenotype. Another recently characterized TTR CNS variant (D18G TTR) exhibits strictly analogous characteristics, suggesting that instability coupled with low serum concentrations is the signature of CNS pathology and protects against early-onset systemic amyloidosis. The low A25T serum concentration may be explained either by impaired secretion from the liver or by increased clearance, both scenarios consistent with A25T's low kinetic and thermodynamic stability. Liver transplantation is the only known treatment for familial amyloid polyneuropathy. This is a form of gene therapy that removes the variant protein from serum preventing systemic amyloidosis. Unfortunately, the choroid plexus would have to be resected to remove A25T from the CSF-the source of the CNS TTR amyloid. Herein we demonstrate that small-molecule tetramer stabilizers represent an attractive therapeutic strategy to inhibit A25T misfolding and CNS amyloidosis. Specifically, 2-[(3,5-dichlorophenyl)amino]benzoic acid is an excellent inhibitor of A25T TTR amyloidosis in vitro.

Amyloid Neuropathies, Familial↗