Parkinson Disease: Minoshima S

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.

Kitada T, Asakawa S, Matsumine H, Hattori N, Shimura H, Minoshima S, Shimizu N, Mizuno Y. · Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan. · Neurogenetics. · Pubmed #10983716 No free full text.

Abstract: Parkinson's disease (PD) is a neurodegenerative disease with clinical features resulting from deficiency of dopamine in the nigrostriatal system. Most PD cases are sporadic and the primary cause of the disease is still unknown. Recently, familial PD and parkinsonism have received much attention because these forms of the disease might provide clues to the genetic risk factors involved in the pathogenesis of idiopathic PD. To date, two causative genes, alpha-synuclein and the parkin gene, have been identified. alpha-Synuclein is involved in the pathogenesis of an autosomal dominant form of PD and constitutes a major component of the Lewy body, which is a pathological hallmark of idiopathic PD. In addition, mutations in the parkin gene have been identified as the cause of autosomal recessive juvenile parkinsonism (AR-JP). AR-JP manifests itself as a highly selective degeneration of the substantia nigra and the locus coeruleus, but without Lewy body formation. In addition to these two genes, four chromosomal loci have been linked to other forms of familial PD. Furthermore, there are a number of other pedigrees of familial PD in which linkage to known genetic loci has been excluded. Molecular cloning of these disease genes and elucidation of the function of their gene products will greatly contribute to our understanding of the pathogenesis of idiopathic PD.

Shimizu N, Minoshima S, Asakawa S. · Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan. · No To Shinkei. · Pubmed #10423750 No free full text.

This publication has no abstract.

Bohnen NI, Albin RL, Koeppe RA, Wernette KA, Kilbourn MR, Minoshima S, Frey KA. · Department of Radiology, Division of Nuclear Medicine, The University of Michigan Medical School, Ann Arbor, 48109-0028, USA. · J Cereb Blood Flow Metab. · Pubmed #16421508 No free full text.

Abstract: The type-2 vesicular monoamine transporter (VMAT2) might serve as an objective biomarker of Parkinson disease (PD) severity. Thirty-one subjects with early-stage PD and 75 normal subjects underwent continuous intravenous infusion of (+)-[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography (PET) imaging to estimate the striatal VMAT2 binding site density with equilibrium tracer modeling. Parkinson disease patients were evaluated clinically in the practically defined 'off' state with the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr Scale (HY), and the Schwab and England Activities of Daily Living Scale (SE). In normal subjects there was age-related decline in striatal DTBZ binding, approximating 0.5% per year. In PD subjects, specific DTBZ binding was reduced in the caudate nucleus (CD; -44%), anterior putamen (-68%), and posterior putamen (PP; -77%). The PP-to-CD ratio of binding was reduced significantly in PD subjects. Dihydrotetrabenazine binding was also reduced by approximately 50% in the PD substantia nigra. Striatal binding reductions correlated significantly with PD duration and SE scores, but not with HY stage or with UPDRS motor subscale (UPDRS(III)) scores. Striatal and midbrain DTBZ binding was asymmetric in PD subjects, with greatest reductions contralateral to the most clinically affected limbs. There was significant correlation between asymmetry of DTBZ binding and clinical asymmetry measured with the UPDRS(III). In HY stage 1 and 1.5 subjects (n=16), PP DTBZ binding contralateral to the clinically unaffected body side was reduced by 73%, indicating substantial preclinical nigrostriatal pathology in PD. We conclude that (+)-[(11)C]DTBZ-PET imaging displays many properties necessary of a PD biomarker.

Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T. · Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. · Nat Genet. · Pubmed #10888878 No free full text.

Abstract: Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.

Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, Asakawa S, Minoshima S, Yamamura Y, Shimizu N, Mizuno Y. · Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. · Ann Neurol. · Pubmed #10319893 No free full text.

Abstract: Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical entity characterized by a selective degeneration of nigral neurons. Recently, the parkin gene responsible for AR-JP has been identified. Now, we report the subcellular localization of Parkin protein in patients with AR-JP or Parkinson's disease (PD) and in controls by immunoblotting and immunohistochemistry using antibodies raised against the Parkin molecule. Parkin protein was absent in all regions of the brains of patients with AR-JP. Parkin protein was not decreased in the brains of sporadic PD patients. Immunoreactivity was detected in a few Lewy bodies. Parkin protein was located in both the Golgi complex and cytosol.

Wang M, Hattori N, Matsumine H, Kobayashi T, Yoshino H, Morioka A, Kitada T, Asakawa S, Minoshima S, Shimizu N, Mizuno Y. · Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. · Ann Neurol. · Pubmed #10319889 No free full text.

Abstract: We report polymorphism of the parkin gene in 160 sporadic Parkinson's disease (PD) patients and controls. Three polymorphisms were found: a G-to-A transition in exon 4 (S/N167), a C-to-T transition in exon 10 (R/W366), and a G-to-C transition in exon 10 (V/L380). Genotype distributions and allele frequencies of S/N167 and V/L380 did not differ significantly between the two groups. The R/W366 allele frequency was significantly lower in PD patients (1.2 vs 4.4%). The level of protection from PD provided by this allele was 3.60 (95% CI; range, 0.45-6.50), suggesting that it may be a protective factor against PD.

Bohnen NI, Minoshima S, Giordani B, Frey KA, Kuhl DE. · Department of Internal Medicine, The University of Michigan, Ann Arbor 48109-0028, USA. · Neurology. · Pubmed #10025784 No free full text.

Abstract: OBJECTIVE: To determine whether occipital reduction in regional cerebral glucose metabolism in PD reflects retinal versus nigrostriatal dopaminergic degeneration. We hypothesized that occipital glucose metabolic reduction should be symmetric if parkinsonian retinopathy is responsible for the reduction. METHODS: PD patients without dementia (n = 29; age 63 +/- 10 years) and normal controls (n = 27; age 60 +/- 12 years) underwent [18F]fluorodeoxyglucose PET imaging. Regional cerebral glucose metabolic rates were assessed quantitatively. RESULTS: When compared with normal controls, PD patients showed most severe glucose metabolic reduction in the primary visual cortex (mean -15%, p < 0.001). Occipital glucose metabolic reduction was greater in the hemisphere contralateral to the side of the body affected initially or more severely in PD. There was an inverse correlation between side-to-side asymmetries in finger-tapping performance and occipital glucose metabolic reduction (r = -0.45, p < 0.05; n = 28). The correlation was strongest in patients with a relatively early stage of PD with more unilateral motor impairment (Hoehn and Yahr stage I, r = -0.74, p < 0.01; n = 10). CONCLUSION: The results indicate a pathophysiologic association between nigrostriatal dysfunction and occipital glucose metabolic reduction in PD.