Makoto Uchino

Histochemical detection of 4-hydroxynonenal protein in Alzheimer amyloid.

The presence of lipid peroxidation product in amyloid deposits from seven patients with Alzheimer disease and nine with non-Alzheimer disease was examined immunohistochemically by means of an affinity purified anti-HNE antibody to hydroxynonenal (HNE), a marker of lipid peroxidation. A positive reaction was found in amyloid deposits in all the specimens examined: most of the perivascular areas (89%) where amyloid deposition was confirmed by Congo red staining, showed immunoreactivity with the antibody in the specimens of Alzheimer disease. Twenty-one percent of senile plaques which were also stained by Congo red staining reacted with this antibody. Several perivascular cells were also stained by anti-HNE antibody. In other neurons both in Alzheimer and non-Alzheimer disease patients, only a few percent reacted with this antibody and no statistical difference was observed between them. These results verify that lipid peroxidation via free radical injury occurs in amyloid deposits in Alzheimer amyloid. Since HNE has been identified as a cytotoxic metabolite of free radical injury, amyloid deposits in the tissue may exhibit a toxic effect during the generation process of HNE.

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. METHODS The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. FINDINGS 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727). INTERPRETATION 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. FUNDING Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.

DWI abnormalities and clinical characteristics in TIA patients

Objective: To determine the clinical characteristics of diffusion-weighted images (DWIs) in patients with TIA. Methods: The authors performed prospectively MRI including DWI in 129 consecutively studied patients with TIA (mean age, 67 years; 68% men) within 14 days after TIA onset. They examined the frequency of TIA-related DWI abnormalities and compared the clinical background of patients with and without DWI abnormalities. Using multivariate statistical methods, the authors investigated the independent factors associated with detection of DWI abnormalities. Results: Fifty-seven patients with TIA (44%) had DWI abnormalities (positive group), whereas 72 (56%) had no abnormalities (negative group). Prolonged TIA duration (TIA duration ≥30 minutes), hemiparesis, monoparesis, disturbance of higher brain function, history of either stroke or TIA, diabetes mellitus, and atrial fibrillation were observed more frequently in the positive group than in the negative group. No difference in other symptoms, vascular risk factors, or emboligenic cardiac and arterial disease was observed between the two groups. A multiple logistic regression model demonstrated that prolonged TIA duration (odds ratio [OR], 3.7; 95% CI, 1.3 to 10.8) and disturbance of higher brain function (OR, 10.2; 95% CI, 2.2 to 46.9) are significant and independent factors in correlating with DWI abnormalities. Conclusions: TIA-related DWI abnormalities are associated with prolonged duration of TIA and disturbance of higher brain function. More sustained and extensive ischemia may contribute to DWI abnormalities in patients with TIA.

Liver transplantation for familial amyloidotic polyneuropathy: Impact on Swedish patients' survival

Liver transplantation (LTx) for familial amyloidotic polyneuropathy (FAP) is an accepted treatment for this fatal disease. However, the long‐term outcome with respect to that of nontransplanted patients has not been fully elucidated. The aim of this study was to compare the long‐term survival of Swedish LTx FAP patients with that of historical controls, especially with respect to the age at onset of the disease and gender. In order to evaluate the outcome of LTx as a treatment for FAP, survival was calculated from the onset of disease. One hundred forty‐one FAP patients, 108 transplanted and 33 not transplanted, were included in the study. Significantly increased survival was noted for LTx patients in comparison with controls. The outcome was especially favorable for those with an early onset of the disease (age at onset < 50 years) in comparison with early‐onset controls (P < 0.001). In contrast, no significant difference for late‐onset cases (≥50 years) was found. Transplanted late‐onset females had significantly improved survival in comparison with transplanted late‐onset males (P = 0.02). We were unable to find significant differences in survival between patients with long (≥7 years) or short (<7 years) disease duration at transplantation. The survival of male patients with late‐onset disease appeared not to improve with LTx. LTx is an efficacious treatment for improving the survival of early‐onset FAP patients. Further studies are needed to analyze the cause of the poorer outcome for late‐onset male patients. Liver Transpl 15:1229–1235, 2009.

Genetic localization of the familial adult myoclonic epilepsy (FAME) gene to chromosome 8q24

Objective: To identify the genetic locus for the familial adult myoclonic epilepsy (FAME) gene. Background: Idiopathic generalized epilepsy (IGE) represents a collection of disorders in which affected individuals present with recurring seizures that have diffuse onset on EEG. These individuals have no known structural cerebral lesions or other identifiable etiology. IGE accounts for approximately 40% of all epilepsies. FAME is a type of IGE characterized by autosomal dominant inheritance, adult onset, varying degrees of myoclonus in the limbs, rare tonic-clonic seizures, and a benign course. Methods: We investigated four previously reported Japanese kindreds and performed a genome-wide screen with genetic linkage analysis. Results: Clinical characterization and sampling of 30 individuals in four families revealed that 21 had the FAME phenotype. We defined a 4.6-cM region on chromosome 8q24 (maximum lod score of 4.86 at θ = 0) that contains the FAME gene. Conclusions: The identification and characterization of the FAME gene allows us to better understand the molecular basis of FAME. Such knowledge may provide clues to understanding the molecular basis of the clinically similar, and more common, juvenile myoclonic epilepsies, and other generalized seizure disorders that have thus far eluded genetic approaches.

Ocular manifestations of familial amyloidotic polyneuropathy type I: long term follow up

AIMS To obtain precise information on ocular manifestations of familial amyloidotic polyneuropathy (FAP) type I, the incidence of five main ocular manifestations—abnormal conjunctival vessels (ACV), keratoconjunctivitis sicca (KCS), pupillary abnormality, vitreous opacity, and glaucoma, were compared through long term follow up. METHODS Ocular examinations were performed in 37 FAP type I patients (Met30) from once to 12 times over a period of 1 to 12 years and 7 months. RESULTS The following incidences were observed on initial examination of each patient with FAP: ACV in 75.5%, pupillary abnormalities in 43.2%, KCS in 40.5%, glaucoma in 5.4%, and vitreous opacity in 5.4%. All ocular manifestations increased with the progression of FAP, and the incidence of ACV reached 100% during follow up: this may be helpful in the diagnosis of FAP. CONCLUSION Since no precise statistical ocular study on FAP with long term follow up has been performed, this report may provide important information to help elucidate the mechanism of the amyloid distributing process in the amyloid targeted organs of FAP and to provide the natural course of ocular manifestations of FAP.

Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy

Objective: Familial amyloid polyneuropathy (FAP), which is a fatal disorder inherited in an autosomal dominant fashion, is characterized by systemic accumulation of polymerized transthyretin (TTR) in the peripheral nerves and systemic organs. Liver transplantation has become an accepted treatment of this disorder because it stops the major production of amyloidogenic TTR. However, improved survival of transplant patients compared with that of nontransplant patients has not been sufficiently demonstrated. This study investigated whether transplantation improved the long-term outcome of patients by comparing the survival of patients who had transplantations with that of patients who had not had transplantations. Methods: Eighty consecutive patients with FAP Val30Met who visited Kumamoto University Hospital between January 1990 and December 2010 were studied. The transplant group consisted of 37 patients who had a partial hepatic graft via living donor transplantation in Japan or who underwent liver transplantation in Sweden, Australia, or the United States. The nontransplant group consisted of 43 patients with FAP. Survival was evaluated by using Kaplan-Meier analysis, and the difference in survival was examined via the log-rank test. Results: The transplant group had prolonged survival (p < 0.001) compared with the nontransplant group. The estimated probability of survival at 10 years was 56.1% for the nontransplant group vs 100% for the transplant group. Conclusion: Liver transplantation should be considered as an effective treatment in clinical management of patients with FAP Val30Met. Classification of evidence: This study provides Class III evidence that liver transplantation prolongs survival in patients with FAP Val30Met.

A different amyloid formation mechanism: de novo oculoleptomeningeal amyloid deposits after liver transplantation.

Background. Liver transplantation has served as a treatment for patients with familial amyloidotic polyneuropathy (FAP) because variant transthyretin (TTR), the pathogenic protein of FAP, is predominantly produced by the liver. However, the effect on amyloid formation of TTR that is synthesised by the retina and the choroid plexus remains to be elucidated in FAP patients with liver transplants. Objective. To investigate changes in ocular tissues and the central nervous system (CNS) of FAP patients after liver transplantation. Design. Clinical study. Setting. Graduate School of Medical Sciences, Kumamoto University, Japan. Intervention. Transplantation of livers from cadaveric or living donors. Measurements. Preoperative measures and postoperative (16–108 months) follow-up of clinical data, including routine ophthalmologic, neurologic, and laboratory evaluations. Results. In 22 patients with FAP related to the amyloidogenic TTR (ATTR) Val30Met and 3 patients with FAP ATTR Tyr114Cys, after liver transplantation, 3 patients began to show evidence of de novo glaucoma, and 1 had vitreous opacity that was caused by the variant TTR. Another three patients showed new amyloid deposits in the pupillary margin, which could lead to glaucoma and vitreous opacity. As for changes in the CNS and levels of total protein and TTR in cerebrospinal fluid (CSF), after liver transplantation, two FAP ATTR Tyr114Cys patients exhibited de novo amyloid deposition in the leptomeninges, and total protein and TTR levels in CSF were significantly increased. Conclusions. Oculoleptomeningeal involvement in FAP was not prevented by liver transplantation because variant TTR produced by the retina and the choroid plexus forms amyloid fibrils in situ.

Immunohistochemical dystrophin reaction in synaptic regions

To investigate the functional significance of dystrophin, we studied various tissues of control and mdx mice, and rats immunohistochemically, using anti-dystrophin antibodies. In control animals, we observed the immunohistochemical localization of dystrophin in synaptic regions such as neuromuscular junctions, the cornea and outer plexiform layer of the retina, the taste buds and neurons in the brain, as well as on the surface membrane of skeletal, cardiac and smooth muscle fibers. In mdx mice, dystrophin was absent from the surface membrane of muscle fibers and the outer plexiform layer of the retina. These results suggest that dystrophin plays an important physiological and/or structural role in the conduction system.

Aphasia during the acute phase in ischemic stroke.

Objectives: We investigated the incidence, clinical characteristics, outcome and factors associated with aphasia and early improvement in acute ischemic stroke. Methods: We consecutively studied 855 patients with acute ischemic stroke who were admitted to our hospital within 48 h after onset and who were not comatose on admission. Assessment of aphasia was performed on admission (day 0) and day 10. We examined the incidence, severity, and subtypes of aphasia, and compared the clinical background of patients with and without aphasia on admission, and also those with and without early improvement by day 10. In addition, we investigated the independent factors associated with the presence of aphasia on admission and with early improvement. Results: Of the 855 patients, 130 (15.2%) had aphasia on admission. The National Institutes of Health Stroke Scale (NIHSS) on admission (OR 1.21; 95% CI 1.17–1.26) was a significant and independent factor associated with the presence of aphasia on admission. Early improvement was seen in 56 of 121 aphasic patients (46.3%) who were still alive on day 10. A history of hypercholesterolemia (OR 3.27; 95% CI 1.14–9.39) was a significant and independent factor associated with early improvement in aphasia during the acute phase and NIHSS on admission (OR 0.95; 95% CI 0.90–0.99) was marginally significant. Conclusion: It is difficult to predict the outcome of aphasia within the first few days after the onset of ischemic stroke.