Parkinson Disease: Hasegawa K

Miziuno Y, Okuma Y, Kikuchi S, Kuno S, Hashimoto T, Hasegawa K, Mano Y, Miwa H, Murata M, Yamamoto M, Yokochi F, Okiyama R, Kanazawa A, Shinpo K, Chuma T, Higashi T, Maruyama T, Mizuta E, Yamazaki S, Anonymous00188. · Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan · Rinsho Shinkeigaku. · Pubmed #12708433 No free full text.

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Hasegawa K, Toyoshima I. · Department of Neurology, Sagamihara Hospital, 18-1 Saku-radai, Sagamihara 228-8522, Japan. · Brain Nerve. · Pubmed #19378815 No free full text.

Abstract: Parkinson disease (PD) and dystonia are two major part of neurodegenerative disorders. The underlying cause of PD development has been considered to be a combination of genetic factors and environmental substrates. In case of dystonia, which includes primary sporadic dystonia, such as task specific dystonia, cervical dystonia and so on, are also considered to associate with unknown vulnerable genetic factors. In this paper, the clinical features and causative genes for PD and dystonia were described; especially in particular, the description of those genes associated with the PARK and DYT series were provided. Most of the identified causative genes for PD are associated with the protein degradation and cell death process via convergent mechanisms such as ubiquitin-proteasome system, mitochondrial dysfunction, oxidative stress, and lysosomal system (autophagia). On the other hand, the pathogenic mechanism for dystonia is gradually discovered to be divergent suggested by identified genes, such as torsinA, GCH1, etc, which is compatible and well understood with the divergent expression of dystonia phenotype. Another breakthroughs are required to investigate the treatment of both PD and dystonia based on the pathogenic mechanisms.

Hasegawa K. · Department of Neurology, National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan. · No To Shinkei. · Pubmed #16986673 No free full text.

This publication has no abstract.

Hasegawa K. · Department of Neurology, National Hospital Organization, National Sagamihara Hospital. · Nippon Rinsho. · Pubmed #15462382 No free full text.

Abstract: Approximately 74-94% patients with Parkinson's disease have sleep disorders: such as frequent awakening, excessive daytime sleepiness, nightmares, nocturnal cramps, REM sleep behavior disorders and so on. In contrast, the relationship between physiological mechanism of sleep and the dopamine systems are still obscure, because the dopamine systems are not directly related neither initiating or maintaining sleep system nor awaking system. However, most of all the dopaminergic drugs were reported to induce sleepiness or sleep attacks in the patients with Parkinson's disease. So, physicians must inform patients with Parkinson's disease warning the excessive daytime sleepiness and sleep attack. In this article, I suggest the mechanisms of sleep disorders on Parkinson's disease from the physiological points of view, and how to manage these problems.

Hasegawa K. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #13677892 No free full text.

This publication has no abstract.

Hasegawa K. · Division of Neurology, Sagamihara National Hospital. · Nippon Rinsho. · Pubmed #11068448 No free full text.

Abstract: The purpose of the new drugs for Parkinson's disease is control of the long-term levodopa treatment syndromes, especially wearing-off phenomenon and dyskinesia. Therefore, they show long T1/2. Most of them are classified into dopamine agonists. Others are monoamine oxidase B inhibitor and cathecole-o-methyltransferase inhibitor. Marketed dopamine agonists are bromocriptine, pergolide, talipexole, and cabergoline in Japan. Except talipexole, they are all ergot alkaloid derivatives. Their affinity for dopamine receptor is D2 group, and their T1/2 are longer than levodopa. Bromocriptine is an oldest dopamine agonist. Other 3 drugs and bromocriptine had made each other double blinded cross over trial previously. The result of double blinded studies show that their efficacy for PD treatment were equal, 40-50% patients with PD. However, in clinical usage, some difference is observed as described below. Efficacy of pergolide is strong compared with bromocriptine; however, pergolide is easy to arise dyskinesia. Talipexole is strong in the hypnosis effect. As for cabergoline, it takes long time to show medical effect, so that it is expected to control wearing-off phenomenon. Monoamine oxidase B inhibitor, Selegiline, is useful as an economizer effect to levodopa. As for the cathechole-o-methyltransferase inhibitor (COMT-I) will be make double-blinded trial in future. The efficacy for PD treatment of COMT-I is prolonged levodopa effect for PD, so that wearing-off phenomenon will be controlled. To use these drugs successfully is important with the treatment of PD. In the future, the development of the cause therapy in addition to the systematic therapy is wanted.

Mizuno Y, Yanagisawa N, Kuno S, Yamamoto M, Hasegawa K, Origasa H, Kowa H, Anonymous00443. · Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan. · Mov Disord. · Pubmed #14534919 No free full text.

Abstract: We compared the efficacy and safety of pramipexole (PPX) with placebo in the treatment of advanced Parkinson's disease (PD) as an adjunct to levodopa. A bromocriptine (BR) group was included to enable determination of the noninferiority of PPX relative to BR as the standard treatment.

Hasegawa K, Stoessl AJ, Yokoyama T, Kowa H, Wszolek ZK, Yagishita S. · Division of Neurology, National Hospital Organization, Sagamihara National Hospital, Japan. · Parkinsonism Relat Disord. · Pubmed #18804399 No free full text.

Abstract: BACKGROUND: Since the causative gene linked to PARK8 parkinsonism was identified as LRRK2, LRRK2 gene mutations have been found to occur in about 4% of patients with hereditary Parkinson disease (PD); this percentage is even higher in certain populations. Moreover, no clear clinical differences between PARK8-linked parkinsonism and sporadic PD have been identified. Neuropathologic findings have been diverse in PARK8 parkinsonism, but few of the clinicopathologic examinations have been performed in the same family tree. We aimed to describe PET and neuropathologic findings in members of the same family tree with PARK8 parkinsonism. METHODS: We conducted PET of 2 subjects and neuropathologically examined 8 subjects in the same family from the Sagamihara district, the original source of PARK8-linked parkinsonism (I2020T mutation). RESULTS: The results of the PET scans were virtually identical to those seen in sporadic PD. The neuropathologic study results showed pure nigral degeneration with no Lewy bodies in 6 cases. One case, however, showed the presence of Lewy bodies and was similar neuropathologically to conventional PD with Lewy bodies. Another case had multiple system atrophy pathology. CONCLUSIONS: Our study of PARK8-linked parkinsonism affecting several members of the same pedigree shows that the same gene mutation can induce diverse neuropathologies, even if the clinical picture and PET findings are virtually identical.

Mizuta I, Tsunoda T, Satake W, Nakabayashi Y, Watanabe M, Takeda A, Hasegawa K, Nakashima K, Yamamoto M, Hattori N, Murata M, Toda T. · Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka, 565-0871, Japan. · Hum Genet. · Pubmed #18568448 No free full text.

Abstract: Parkinson's disease (PD), one of the most common human neurodegenerative disorders, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Our recent case-control association study of 268 SNPs in 121 candidate genes identified alpha-synuclein (SNCA) as a susceptibility gene for sporadic PD (P = 1.7 x 10(-11)). We also replicated the association of fibroblast growth factor 20 (FGF20) with PD (P = 0.0089). To find other susceptibility genes, we added 34 SNPs to the previous screen. Of 302 SNPs in a total 137 genes, but excluding SNCA, SNPs in NDUFV2, FGF2, CALB1 and B2M showed significant association (P < 0.01; 882 cases and 938 control subjects). We replicated the association analysis for these SNPs in a second independent sample set (521 cases and 1,003 control subjects). One SNP, rs1805874 in calbindin 1 (CALB1), showed significance in both analyses (P = 7.1 x 10(-5); recessive model). When the analysis was stratified relative to the SNCA genotype, the odds ratio of CALB1 tended to increase according to the number of protective alleles in SNCA. In contrast, FGF20 was significant only in the subgroup of SNCA homozygote of risk allele. CALB1 is a calcium-binding protein that widely is expressed in neurons. A relative sparing of CALB1-positive dopaminergic neurons is observed in PD brains, compared with CALB1-negative neurons. Our genetic analysis suggests that CALB1 is associated with PD independently of SNCA, and that FGF20 is associated with PD synergistically with SNCA.

Mizuno Y, Abe T, Hasegawa K, Kuno S, Kondo T, Yamamoto M, Nakashima M, Kanazawa I, Anonymous00374. · Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan. · Mov Disord. · Pubmed #17618525 No free full text.

Abstract: We report the results of a randomized, double-blind, placebo-controlled, 16-week study to evaluate the efficacy and safety of ropinirole, 0.75 to 15.0 mg/day, as an adjunct to levodopa. A total of 243 patients were randomly assigned into placebo or ropinirole groups. The mean (standard deviation) dose of ropinirole at endpoint was 7.12 (2.88) mg/day. The primary endpoint-the mean reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) total motor score-was significantly greater for the ropinirole group than the placebo group (-9.5 vs. -4.5, P = 0.00001). The mean reduction in the UPDRS total activities of daily living (ADL) score was also significantly greater for ropinirole than for placebo (-2.7 vs. -1.0, P = 0.0002). The percentage of patients showing at least a 20% reduction in the percentage of time spent "off" was significantly greater for the ropinirole group than for the placebo group (58.7% vs. 38.6%, P = 0.030). A total of 84.3 and 65.6% of the patients experienced adverse events while receiving ropinirole or placebo, respectively. The results showed that ropinirole was more effective than placebo in improving motor function and ADL when used as an adjunct to levodopa in patients with advanced Parkinson's disease.

Satake W, Mizuta I, Suzuki S, Nakabayashi Y, Ito C, Watanabe M, Takeda A, Hasegawa K, Sakoda S, Yamamoto M, Hattori N, Murata M, Toda T. · Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan. · Neuroreport. · Pubmed #17515805 No free full text.

Abstract: A genetic association between the fibroblast growth factor 20 (FGF20) gene and Parkinson's disease has been found by the pedigree disequilibrium test. This association, however, was not replicated by a case-control association study. In order to clarify the association between the FGF20 gene and Parkinson's disease, we attempted to replicate this association by a case-control association study using a large number of Japanese samples (1388 patients and 1891 controls). rs1721100 exhibited a significant difference in allele C versus G (P=0.0089), and in genotype CC+CG versus GG (P=0.0053). Haplotype association analysis showed that haplotype 2 was the protective haplotype for Parkinson's disease (permutation-P=0.0075). These results suggest that the FGF20 gene is a susceptibility gene for Parkinson's disease in the Japanese population.

Ohta E, Hasegawa K, Gasser T, Obata F. · Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan. · Neurosci Lett. · Pubmed #17395370 No free full text.

Abstract: To understand the genetic origin of I2020T mutation in the kinase domain of leucine rich repeat kinase 2 (LRRK2), we investigated the original PARK8 Japanese family (Sagamihara family) and a German family (family 32), both of which were found to harbor I2020T as the causal mutation for autosomal dominant familial Parkinson's disease (PD). Microsatellite-haplotype analysis around the LRRK2 gene indicated that the mutation-carrying haplotypes of the two families were distinct from each other. This indicated that the I2020T mutation, an essential pathogenic mutation of PARK8-related PD, had occurred independently in the two PD families.

Murata M, Hasegawa K, Kanazawa I, Anonymous00826. · Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan. · Neurology. · Pubmed #17200492 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy, safety and tolerability of daily doses of 25, 50, and 100 mg of zonisamide (ZNS) administered as adjunctive treatment in patients with Parkinson disease (PD). METHODS: We conducted a multicenter, randomized, double-blind, parallel-treatment, placebo-controlled study in Japan. Patients with PD who showed insufficient response to levodopa treatment were given placebo for 2 weeks and then treated for 12 weeks with 25, 50, or 100 mg/day of ZNS or placebo, in addition to levodopa, followed by a 2-week dose-reduction period. The primary endpoint was change from baseline in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III at the final assessment point. Secondary endpoints included changes from baseline in total daily "off" time; total scores of UPDRS Parts I, II, and IV; and Modified Hoehn and Yahr Scale score. Safety analysis was based on the incidence of adverse events. RESULTS: There was significant improvement in the primary endpoint in the 25-mg and 50-mg groups vs placebo. The duration of "off" time was significantly reduced in the 50-mg and 100-mg groups vs placebo. Dyskinesia was not increased in ZNS groups. The incidence of adverse effects was similar between the 25-mg, 50-mg, and placebo groups but higher in the 100-mg group. CONCLUSIONS: Zonisamide is safe, effective and well tolerated at 25 to 100 mg/day as an adjunctive treatment in patients with Parkinson disease.

Tomiyama H, Li Y, Funayama M, Hasegawa K, Yoshino H, Kubo S, Sato K, Hattori T, Lu CS, Inzelberg R, Djaldetti R, Melamed E, Amouri R, Gouider-Khouja N, Hentati F, Hatano Y, Wang M, Imamichi Y, Mizoguchi K, Miyajima H, Obata F, Toda T, Farrer MJ, Mizuno Y, Hattori N. · Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. · Mov Disord. · Pubmed #16622854 No free full text.

Abstract: We screened LRRK2 mutations in exon 41 in 904 parkin-negative Parkinson's disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.3%) among 868 PD probands, including 2 sporadic cases and 8 (6.2%) of 130 autosomal dominant PD families. The LRRK2 mutations in exon 41 exhibited relatively common and worldwide distribution. Among the three mutations in exon 41, it has been reported that Caucasian patients with G2019S mutation have a single-founder effect. In the present study, Japanese patients with G2019S were unlikely to have a single founder from the Caucasian patients. In contrast, I2020T mutation has a single-founder effect in Japanese patients. Clinically, patients with LRRK2 mutations had typical idiopathic PD. Notably, several patients developed dementia and psychosis, and one with I2020T had low cardiac (123)I-metaiodobenzylguanidine (MIBG) heart/mediastinum ratio, although the ratio was not low in other patients with I2020T or G2019S. Clinical phenotypes including psychosis, dementia, and MIBG ratios are also heterogeneous, similar to neuropathology, in PD associated with LRRK2 mutations.

Ono K, Hasegawa K, Naiki H, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. · Neurochem Int. · Pubmed #16343694 No free full text.

Abstract: Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the destabilization of preformed fAbeta in the central nervous system would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). Many studies have demonstrated that oxidative damage plays a central role in AD pathogenesis, as well as Parkinson disease (PD). Among the antioxidant strategies proposed, increasing evidence points to the possibility of achieving neuroprotection by dopamine agonists, as well as monoamine oxidase B (MAO-B) inhibitors. Actually, the beneficial effect of selegiline, a MAO-B inhibitor, in AD has been noted in several clinical studies. On the reverse, antimuscarinic agents have been reported to accelerate beta-amyloidosis and senile plaque formation in PD. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of anti-Parkinsonian agents, dopamine, levodopa, pergolide, bromocriptine, selegiline, and trihexyphenidyl on the formation, extension, and destabilization of fAbeta(1-40) and fAbeta(1-42) at pH 7.5 at 37 degrees C in vitro. The anti-Parkinsonian agents other than trihexyphenidyl dose-dependently inhibited fAbeta formation from Abeta(1-40) and Abeta(1-42), as well as their extension. Moreover, these agents dose-dependently destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of: dopamine>selegiline>levodopa=pergolide>bromocriptine. Although the exact mechanism of the anti-amyloidogenic activity of these agents is unclear, these and other structurally related compounds could be key molecules for the development of therapeutics for AD and other conformational diseases.

Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Tsuji S, Obata F. · Division of Clinical Immunology, Kitasato University Graduate School of Medical Sciences, Tokyo, Japan. · Ann Neurol. · Pubmed #15880653 No free full text.

Abstract: We detected a missense mutation in the kinase domain of the LRRK2 gene in members with autosomal dominant Parkinson's disease of the Japanese family (the Sagamihara family) who served as the basis for the original defining of the PARK8 Parkinson's disease locus. The results of the Sagamihara family, in combination with the unique pathological features characterized by pure nigral degeneration without Lewy bodies, provided us with valuable information for elucidating the protein structure-pathogenesis relationship for the gene product of LRRK2. We did not detect this mutation or other known mutations of the LRRK2 gene in Japanese patients with sporadic Parkinson's disease.

Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. · Departments of Pediatrics, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. · Ann Neurol. · Pubmed #11891824 No free full text.

Abstract: We performed genomewide linkage analysis of a Japanese family with autosomal dominant parkinsonism, which exhibits clinical features compatible with those of common Parkinson's disease. Parametric two-point linkage analysis yielded a highest log odds (LOD) score of 4.32 at D12S345 (12p11.21). Parametric multipoint linkage analysis of the 13.6cM interval around this marker yielded LOD scores almost uniformly of >4.0 with a Z(max) of 4.71 at D12S85 (12q12). Haplotype analysis detected two obligate recombination events at D12S1631 and D12S339 and defined the disease-associated haplotype in the 13.6cM interval in 12p11.2-q13.1. This haplotype was shared by all the patients and by some unaffected carriers, suggesting that disease penetration in this family is incomplete. This low penetrance suggests that environmental or other genetic factors modify expression of the disease. Nonparametric two-point and multipoint linkage analyses, which are penetrance-independent, yielded Z(max) LOD scores of 14.2 and 24.9 at D12S345, respectively, strongly supporting the mapping of the parkinsonism locus in this family to 12p11.23-q13.11. This chromosome region is different from any known locus for hereditary parkinsonism, in keeping with the unique genetic features of the parkinsonism in this family. The nomenclature of PARK8 was assigned to the new locus.