Parkinson Disease: Yamada M

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Ono K, Hirohata M, Yamada M. · Department of Neurology & Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. · Curr Pharm Des. · Pubmed #19075704 No free full text.

Abstract: Lewy bodies (LBs) and Lewy neurites (LNs) in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and are comprised of amyloid-like fibrils composed of a small protein ( approximately 14 kDa) named alpha-synuclein (alphaS). As the aggregation of (alphaS in the brain has been implicated as a critical step in the development of the diseases, the current search for disease-modifying drugs is focused on modification of the process of (alpha S deposition in the brain. In this article, the recent developments on the molecules that inhibit the formation of alpha-synuclein fibrils (falphaS) as well as the oligomerization of alphaS are reviewed. Recently, various compounds such as curcumin, nicotine and wine-related polyphenols have been reported to inhibit the formation of falphaS, and to destabilize preformed falphaS at pH 7.5 at 37 degrees C in vitro. Although the mechanisms by which these compounds inhibit falphaS formation from falphaS, and destabilize preformed falphaS are still unclear, they could be key molecules for the development of preventives and therapeutics for PD and other alpha-synucleinopathies.

Taki J, Yoshita M, Yamada M, Tonami N. · Department of Biotracer Medicine, Kanazawa University Graduate School of Medical Sciences, Japan. · Ann Nucl Med. · Pubmed #15515743 No free full text.

Abstract: Recently, reliable and clear evidence for the usefulness of 123I-MIBG scintigraphy in the diagnosis of Parkinson's disease (PD) has been accumulated and it has become increasingly popular as one of the most accurate means of diagnosing the disease. PD, one of the most common neurodegenerative disorders, is characterized by resting tremor, rigidity, bradykinesia or akinesia, and postural instability. The disease is characterized pathologically by distinctive neuronal inclusions called Lewy bodies in many surviving cells of dopaminergic neurons of the substantia nigra pars compacta and other specific brain regions. Furthermore Lewy body type degeneration in the cardiac plexus has been observed in PD. In PD, cardiac MIBG uptake is reduced markedly even in the early disease stages; therefore, MIBG imaging can be used as an indicator of the presence of PD rather than disease severity. Other parkinsonian syndromes such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration demonstrate normal cardiac MIBG uptake or only mild reduction of MIBG uptake, indicating that MIBG imaging is a powerful method to differentiate PD from other parkinsonian syndromes. Dementia with Lewy bodies (DLB) also shows severe reduction of MIBG uptake, whereas Alzheimer's disease (AD) demonstrates normal MIBG uptake, permitting differentiation of DLB from AD using MIBG scintigraphy. In pure autonomic failure, which shares similar pathological findings with PD and is thought to be associated with diffuse loss of sympathetic terminal innervation, cardiac MIBG uptake also decreases markedly. Considering all the data together, marked reduction of cardiac MIBG uptake seems to be a specific marker of Lewy body disease and thus extremely useful in the differentiation from other diseases with similar symptoms without Lewy bodies.

Yamada M, Yasuhara H. · Department of Psychiatry, Showa University Karasuyama Hospital, 6-11-11 Kitakarasuyama, Setagaya, Tokyo 157-8577, Japan. · Neurotoxicology. · Pubmed #14697896 No free full text.

Abstract: In this article, we review the clinical pharmacology of monoamine oxidase inhibitors (MAOIs). Now, MAOIs are used for the treatment of depressive disorders, anxiety disorders, Parkinson's disease, and Alzheimer's disease. The selective monoamine oxidase-B inhibitor selegiline and the selective and reversible inhibitor of monoamine oxidase-A (RIMA) moclobemide are free from the hypertensive crisis, the so-called "cheese effect." Therefore, selective MAO-B inhibitors and RIMAs hold promise as safer alternatives to classical MAOIs. It is clear that much remains to be investigated with regard to the clinical pharmacology of MAOIs. It seems obvious that a greater understanding of the pharmacodynamics and pharmacokinetics of MAOIs could result in improved treatment of the patients in the future.

Hirohata M, Ono K, Morinaga A, Ikeda T, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. · Exp Neurol. · Pubmed #19289119 No free full text.

Abstract: The alpha-synuclein aggregation in the brain is the hallmark of Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies, and multiple system atrophy. Some epidemiological studies have revealed that estrogen therapy reduces the risk of Parkinson's disease in females. We examined the effects of estriol, estradiol, estrone, androstenedione, and testosterone on the formation and destabilization of alpha-synuclein fibrils at pH 7.5 and 37 degrees C in vitro, using fluorescence spectroscopy with thioflavin S and electron microscopy. These sex hormones, especially estriol, significantly exert anti-aggregation and fibril-destabilizing effects; and hence, could be valuable preventive and therapeutic agents for alpha-synucleinopathies.

Takano K, Kitao Y, Tabata Y, Miura H, Sato K, Takuma K, Yamada K, Hibino S, Choshi T, Iinuma M, Suzuki H, Murakami R, Yamada M, Ogawa S, Hori O. · Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, Kanazawa City, Ishikawa, Japan. · Am J Physiol Cell Physiol. · Pubmed #17913843 links to  free full text

Abstract: The enhancement of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative disorders including Parkinson's disease (PD). During a search for compounds that regulate ER stress, a dibenzoylmethane (DBM) derivative 14-26 (2,2'-dimethoxydibenzoylmethane) was identified as a novel neuroprotective agent. Analysis in SH-SY5Y cells and in PC12 cells revealed that the regulation of ER stress by 14-26 was associated with its anti-oxidative property. 14-26 prevented the production of reactive oxygen species (ROS) when the cells were exposed to oxidants such as hydrogen peroxide and 6-hydroxydopamine (6-OHDA) or an ER stressor brefeldin A (BFA). 14-26 also prevented ROS-induced damage in both the ER and the mitochondria, including the protein carbonylation in the microsome and the reduction of the mitochondrial membrane potential. Further examination disclosed the presence of the iron-chelating activity in 14-26. In vivo, 14-26 suppressed both oxidative stress and ER stress and prevented neuronal death in the substantia nigra pars compacta (SNpc) after injection of 6-OHDA in mice. These results suggest that 14-26 is an antioxidant that protects dopaminergic neurons against both oxidative stress and ER stress and could be a therapeutic candidate for the treatment of PD.

Ono K, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. · Neurobiol Dis. · Pubmed #17169566 No free full text.

Abstract: Alpha-synuclein (alphaS) is the major component of the filamentous inclusions that constitute defining characteristics of Lewy body diseases (LBD) and multiple system atrophy (MSA). Clinically, antioxidant vitamins, such as vitamin E and the vitamin-like substance coenzyme Q10, have been used in the treatment of LBD with some efficacy. Using fluorescence spectroscopy with thioflavin S, electron microscopy and atomic force microscopy, here we examined the effects of ten antioxidant vitamins and vitamin-like substances, vitamin A (retinol, retinal and retinoic acid), beta-carotene, vitamins B2, B6, C, E, coenzyme Q10 and alpha-lipoic acid, on the formation of alphaS fibrils (falphaS) and on preformed falphaS. Among them, vitamin A, beta-carotene and coenzyme Q10 dose-dependently inhibited the formation of falphaS. Moreover, they also dose-dependently destabilized preformed falphaS. With such potent anti-fibrillogenic as well as fibril-destabilizing activities, these compounds could be useful in the treatment and prevention of LBD and MSA.

Mochizuki H, Yamada M, Mizuno Y. · Research Institute for Diseases of Old Age, Juntendo University, Bunkyo, Tokyo, Japan. · J Neural Transm Suppl. · Pubmed #17017543 No free full text.

Abstract: OBJECTIVES: To elucidate the role of alpha-synuclein in the pathogenesis of Parkinson's disease (PD), both human alpha-synuclein transgenic mice and targeted overexpression of human alpha-synuclein in rat substantia nigra (SN) by viral vector-based methods have been studied, however little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in the brains of patients with PD are recapitulated in these models. METHODS AND RESULTS: We used the recombinant adeno-associated viral (rAAV) vector system for human alpha-synuclein gene transfer to rat SN and observed approximately 50% loss of dopaminergic neurons in SN at 13 weeks after infection. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of PD, such as phosphorylation of alpha-synuclein at Ser129 and activation of caspase-9. Both findings were also evident in cortical tissues overexpressing alpha-synuclein via rAAV. CONCLUSIONS: Our results indicate that overexpression of alpha-synuclein via rAAV apparently recapitulates several important features of brains with PD and dementia with Lewy bodies (DLB), and thus alpha-synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of PD and DLB. This model is also useful for the gene therapy research.

Takano K, Tabata Y, Kitao Y, Murakami R, Suzuki H, Yamada M, Iinuma M, Yoneda Y, Ogawa S, Hori O. · Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa City, Ishikawa 920-8640, Japan. · Am J Physiol Cell Physiol. · Pubmed #16971492 links to  free full text

Abstract: Enhanced endoplasmic reticulum (ER) stress leads to cell death in various pathophysiological situations. During a search for compounds that regulate ER stress, we identified methoxyflavones, a group of flavonoids, as strong protective agents against ER stress. Analysis in mouse insulinoma MIN6 cells revealed that methoxyflavones mildly activated the eukaryotic initiation factor 2alpha and nuclear factor erythroid 2-related factor pathways, but not the XBP1 pathway, and induced downstream genes, including glucose-regulated protein (GRP) 78, a molecular chaperone in the ER. The protective effect of methoxyflavones was enhanced by agents that increase intracellular cAMP levels such as forskolin, dibutyryl-cAMP and IBMX, but suppressed by the protein kinase A (PKA) inhibitor H-89, suggesting involvement of the PKA pathway in the regulation of ER stress by methoxyflavones. Consistent with the results in cultured cells, pretreatment of mice with tangeretin, a methoxyflavone, enhanced expression of GRP78 and HO-1 without causing ER stress in renal tubular epithelium and prevented tunicamycin-induced cell death. Furthermore, preadministration of tangeretin in mice enhanced expression of GRP78 in the substantia nigra pars compacta and protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin that induces both oxidative and ER stress. These results suggest that methoxyflavones play an important role in the regulation of ER stress and could be a therapeutic target for the ER stress-related diseases.

Yoshita M, Taki J, Yokoyama K, Noguchi-Shinohara M, Matsumoto Y, Nakajima K, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. · Neurology. · Pubmed #16801649 No free full text.

Abstract: OBJECTIVE: To evaluate the diagnostic reliability of cardiac iodine-123 metaiodobenzylguanidine ((123)I-MIBG) radioactivity in discriminating dementia with Lewy bodies (DLB) from Alzheimer disease (AD) regardless of parkinsonism. BACKGROUND: The diagnosis of DLB may be confounded by the absence of parkinsonism. This highlights the need to improve the accuracy of antemortem diagnosis of DLB without parkinsonism. METHODS: Cardiac sympathetic denervation was examined using myocardial (123)I-MIBG scintigraphy in 37 patients with DLB, 42 patients with AD, and 10 normal elderly controls. The DLB patients consisted of seven patients without parkinsonism (DLB/P-) and 30 patients with parkinsonism (DLB/P+) at the time of the study. RESULTS: The heart-to-mediastinum uptake ratio (H/M ratio) of myocardial MIBG uptake was decreased in both the DLB groups vs the AD group (p < 0.0001) and control group (p < 0.0001). The washout rate (WR) was higher in the DLB group than in the control group (p < 0.0001) and AD group (p < 0.0001). No differences were found between the AD and control groups or between the DLB/P+ and DLB/P- groups in either the early or delayed H/M ratio or WR. In discriminating between DLB and AD, regardless of parkinsonism, the delayed H/M ratio had a sensitivity of 100%, a specificity of 100%, and a positive predictive value of 100% at a cutoff value of 1.68. CONCLUSIONS: Our results indicate that dementia with Lewy bodies results in cardiac sympathetic denervation and that iodine-123 metaiodobenzylguanidine myocardial scintigraphy is a sensitive tool for discriminating dementia with Lewy bodies from Alzheimer disease even in patients without parkinsonism.

Hayashita-Kinoh H, Yamada M, Yokota T, Mizuno Y, Mochizuki H. · Research Institute for Diseases of Old Age, Juntendo University, Tokyo, Japan. · Biochem Biophys Res Commun. · Pubmed #16460685 No free full text.

Abstract: Fibrillization and aggregation of alpha-synuclein may play a critical role in neurodegenerative diseases like Parkinson's diseases. Adeno-associated virus (AAV) vector delivery of an alpha-synuclein ribozyme was tested for its silencing effect on degenerating nigrostriatal neurons in the MPP(+) model of Parkinson's disease. We designed alpha-synuclein ribozyme against human alpha-synuclein gene expression and constructed alpha-synuclein ribozymes-carrying rAAV vector (designated rAAV-SynRz). Co-transfection of rAAV-SynRz and rAAV-alpha-synuclein into HEK293 cells resulted in down-regulation of alpha-synuclein protein expression in vitro. Then, rAAV-SynRz was injected into the substantia nigra (SN) of MPP(+)-treated rats. Cell counts of TH-positive neurons in the SN revealed that rAAV-SynRz significantly protected TH-positive cells against apoptotic death, compared with those of rAAV-EGFP or no rAAV injected rats. Our results indicate that the use of rAAV-SynRz allowed the survival of higher number of TH-positive neurons in SN in the MPP(+) model. Down-regulation of alpha-synuclein expression could be potentially a suitable target for gene therapy of Parkinson's disease.

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.

Yamada M, Mizuno Y, Mochizuki H. · Research Institute for Diseases of Old Age, Juntendo University, Tokyo 113-8421, Japan. · Hum Gene Ther. · Pubmed #15761265 No free full text.

Abstract: Parkin is known to mitigate alpha-synuclein-induced neuronal cell death in vitro, which suggests that the parkin gene therapy is a candidate for therapeutic strategies for Parkinson's disease (PD). In the present study, the parkin gene therapy was investigated for its ameliorative effects on alpha-synucleinopathy in substantia nigra (SN) of rats. A recombinant adeno-associated viral (rAAV) vector system has frequently been used for the gene transfer to rat SN, and we have previously demonstrated that this technique induced the alpha-synucleinopathy, which closely resembles pathogenetic changes in PD. Therefore, in the present study, the effect of parkin was examined by co-infection of rAAV-parkin with rAAV-alpha-synuclein into dopaminergic neurons in SN. At 13 weeks post-rAAV infection, alpha-synuclein overexpression induced dopaminergic neuron loss, while co-expression of parkin mitigated the alpha-synuclein toxicity. Moreover, alpha-synuclein-induced dopaminergic neuron loss consequently resulted in motor dysfunction, which was also mitigated by parkin. Taken together, our results indicate that the parkin gene therapy is effective against alpha-synucleinopathy, suggesting its potential suitability for patients with PD.

Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H. · Research Institute for Diseases of Old Age, Juntendo University, Bunkyo, Tokyo, Japan. · J Neurochem. · Pubmed #15447678 No free full text.

Abstract: To elucidate the role of alpha-synuclein in the pathogenesis of Parkinson's disease, both human alpha-synuclein transgenic mice and targeted overexpression of human alpha-synuclein in rat substantia nigra using viral vector-based methods have been studied, however, little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in brains with Parkinson's disease are recapitulated in these models. Here, we used the recombinant adeno-associated viral (rAAV) vector system for human alpha-synuclein gene transfer to rat substantia nigra and observed approximately 50% loss of dopaminergic neurons at 13 weeks after infection, which was comparably slower than the progression of neurodegeneration reported in other studies. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of Parkinson's disease, such as phosphorylation of alpha-synuclein at Ser129 and activation of caspase-9. Both findings were also evident in cortical tissues overexpressing alpha-synuclein via rAAV. Our results indicate that overexpression of alpha-synuclein via rAAV apparently recapitulates several important features of brains with Parkinson's disease and dementia with Lewy bodies, and thus alpha-synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of Parkinson's disease and dementia with Lewy bodies.

Mochizuki H, Hayakawa H, Migita M, Shibata M, Tanaka R, Suzuki A, Shimo-Nakanishi Y, Urabe T, Yamada M, Tamayose K, Shimada T, Miura M, Mizuno Y. · Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. · Proc Natl Acad Sci U S A. · Pubmed #11535810 links to  free full text

Abstract: Adeno-associated virus (AAV) vector delivery of an Apaf-1-dominant negative inhibitor was tested for its antiapoptotic effect on degenerating nigrostriatal neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. The wild-type caspase recruitment domain of Apaf-1 was used as a dominant negative inhibitor of Apaf-1 (rAAV-Apaf-1-DN-EGFP). An AAV virus vector was used to deliver it into the striatum of C57 black mice, and the animals were treated with MPTP. The number of tyrosine hydroxylase-positive neurons in the substantia nigra was not changed on the rAAV-Apaf-1-DN-EGFP injected side compared with the noninjected side. We also examined the effect of a caspase 1 C285G mutant as a dominant negative inhibitor of caspase 1 (rAAV-caspase-1-DN-EGFP) in the same model. However, there was no difference in the number of tyrosine hydroxylase-positive neurons between the rAAV-caspase-1-DN-EGFP injected side and the noninjected side. These results indicate that delivery of Apaf-1-DN by using an AAV vector system can prevent nigrostriatal degeneration in MPTP mice, suggesting that it could be a promising therapeutic strategy for patients with Parkinson's disease. The major mechanism of dopaminergic neuronal death triggered by MPTP seems to be the mitochondrial apoptotic pathway.

Yamada H, Murahashi M, Takahashi H, Kai K, Shibuya S, Jimi T, Wakayama Y, Yamada M. · Department of Medicine, Showa University, Fujigaoka Hospital. · Rinsho Shinkeigaku. · Pubmed #10835931 No free full text.

Abstract: To investigate the characteristics and clinical significance of respiratory function in patients with Parkinson's disease (PD), we studied 38 patients (male, 19; female, 19: mean age, 65.5 years: mean duration of disease, 6.7 years) who had no history of respiratory disease and smoking. Fifty three non-respiratory disease subjects (male, 26; female, 27: mean age, 67.6 years) were served as age-matched control. We measured spirometry and maximal expiratory flow-volume curve in all patients, and analyzed the relations between respiratory function variables and clinical profiles. The clinical disability of PD was indicated by Hoehn-Yahr (H-Y) scale. The number of PD patients was 15 in H-Y 2, 18 in H-Y 3 and 5 in H-Y 4, respectively. The values of % VC, %FEV 1, FEV 1/FVC, %PEFR, % V50 in H-Y 4 group were significantly smaller than those in H-Y 2 and 3 groups. Small airway dysfunction (SAD) was represented by abnormality of % V25, % V50/V25. The prevalence of impairment in % V25 and % V50/V25 was detected in 13 patients (34.2%) and 15 patients (39.5%), respectively, this was significantly higher than age-matched controls. However, the mean value and prevalence of impairment in % V25, % V50/V25 were not affected by H-Y scale and duration of disease or ideal body weight (%predicted value). Twenty seven patients showed normal ventilatory function based on % VC over 80% and FEV 1/FVC over 70%. The prevalence of impairment in % V25, % V50/V25 was detected in 8 patients (29.6%), 9 patients (33.3%), respectively, among 27 patients with normal ventilatory function. These results suggest that ventilatory dysfunction is concerned with clinical disability but SAD which is independent of clinical disability seen prevalently in patients with PD. It is widely accepted that patients with PD frequently have cardiac or bowel dysfunction based on the visceral autonomic dysfunction. We hypothesize that SAD may also be caused by possible autonomic dysfunction in patients with PD.