SUMMARY: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 Ͼ 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. (Lab Invest 2003, 83:409 -417).

The objective of this multicenter cross-sectional study was to determine the prevalence of fatigue and factors contributing to it in a large sample of Japanese patients with Parkinson's disease (PD). We used the 16-item Parkinson Fatigue Scale (PFS-16), which was designed to assess fatigue exclusively associated with PD. We carried out this study using PFS-16, the Unified Parkinson's Disease Rating Scale, Zung's Self-Rating Depression Scale, Parkinson's Disease Sleep Scale (PDSS), and the PD quality of life (QOL) scale (PDQ-39) by interview using questionnaires and physical examination by neurologists in 361 nondemented PD patients. Fatigue (an average PFS score of 3.3 or greater) was revealed in 151 patients (41.8%). Multiple logistic regression analysis indicated that the significant independent variables related to the presence of fatigue were the scores of PDSS and PDQ-39. Depression score was not a significant contributing factor. Our study revealed that the prevalence of fatigue in Japanese PD patients is as high as that in Western countries, and that fatigue is a relatively independent symptom, although sleep disturbance may be associated with fatigue. Since fatigue is significantly related to QOL reduction, therapeutic interventions including treatment of sleep disturbance are important.

Objective The long-term use of levodopa to treat Parkinson's disease (PD) is often limited by the development of motor complications (e.g. levodopa-induced dyskinesia, LID). We hypothesized that a non-ergot dopamine agonist with strong affinity for D3 dopamine receptors (pramipexole) may improve LID in patients taking an ergot D1/D2 dopamine agonist. Methods Patients with PD and LID being treated with levodopa in addition to an ergot dopamine agonist were randomized to either a group in which pramipexole was added to current medications or a group in which the ergot dopamine agonist was switched to pramipexole. Dyskinesia was evaluated using Core Assessment Program for Surgical Interventional Therapies scores. The Unified Parkinson's Disease Rating Scale scores, Modified Hoehn and Yahr stages (at 'on' time), Parkinson's Disease Questionnaire-39 scores and Clinical Global Impression-Improvement scores were also used for evaluation. Results At 24 weeks, pramipexole alleviated LID with more efficiency in the switch group. Conclusion Pramipexole may be a therapeutic option for treating LID because its effects on D3 dopamine receptors may balance the D1 dopamine receptor supersensitivity associated with LID.

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.

Objective The aim of this multicenter cross-sectional study was to assess the relation between fatigue in a large number of Japanese patients with Parkinson's disease (PD) and drugs taken to treat PD. Method We used the 16-item Parkinson Fatigue Scale (PFS-16), which was designed to assess fatigue exclusively associated with PD. Multiple logistic regression analyses were used to assess the relation between antiparkinson drugs and fatigue in PD. Results A total of 350 non-demented PD patients were enrolled. Fatigue (PFS score of !4) was revealed in 319 patients (91%). Pramipexole was administered to 24% of PD patients. Multiple logistic regression analysis revealed that the administration of Pramipexole was significantly related to low rates of fatigue in PD patients with Hoehn and Yahr stage <3 (p=0.011, odds ratio=5.23, 95% confidence interval; 1.47-18.63). Conclusion The reduced fatigue in PD patients was observed in taking Pramipexole.