Parkinson Disease: Pasquier F

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.

Chapuis J, Moisan F, Mellick G, Elbaz A, Silburn P, Pasquier F, Hannequin D, Lendon C, Campion D, Amouyel P, Lambert JC. · Inserm, U744, Institut Pasteur de Lille, Université de Lille 2, Lille, France. · Hum Mol Genet. · Pubmed #18579580 No free full text.

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD), the two most common neurodegenerative disorders in the elderly, have been hypothesized to share genetic determinants. Recently, Li et al. proposed that a variant in the NEDD9 gene may be one of these common genetic factors. We attempted to confirm this initial observation by conducting an equivalent analysis in terms of pathologies and sample size. We genotyped the NEDD9 rs760678 SNP in three independent AD case-control studies (n = 3176) and two independent PD case-control studies (n = 1855). However, we failed to detect an association of this SNP with the risk of developing AD or PD, in any of these populations. In conclusion, these data indicate that the rs760678 SNP of the NEDD9 gene is at best a weak genetic determinant of AD or PD.

Rovelet-Lecrux A, Deramecourt V, Legallic S, Maurage CA, Le Ber I, Brice A, Lambert JC, Frébourg T, Hannequin D, Pasquier F, Campion D. · Inserm U 614, Faculty of Medicine, Institute for Biomedical Research, 76000 Rouen, France. · Neurobiol Dis. · Pubmed #18479928 No free full text.

Abstract: Progranulin gene (PGRN) mutations cause ubiquitin-positive frontotemporal lobar degeneration linked to chromosome 17 (FTLDU-17). The spectrum of known mutations strongly suggests that neurodegeneration results from a partial loss of PGRN function and leads to the hypothesis that PGRN gene deletions could be present in a subset of patients. We analysed 63 unrelated French patients with frontotemporal lobar degeneration (FTLD) for PGRN gene dosage alteration by quantitative multiplex PCR of short fluorescent fragments (QMPSF). We identified in one patient with typical PGRN neuropathology a near complete deletion, removing exons 1-11, of the PGRN gene. This deletion, which resulted from a nonhomologous recombination event, was equally present in one affected sister presenting with Parkinson disease (PD). This observation provides a final argument that PGRN mutations exert their pathogenic effect through haploinsufficiency and underlines the diversity of clinical presentations associated with these PGRN alterations.

Deramecourt V, Bombois S, Maurage CA, Ghestem A, Drobecq H, Vanmechelen E, Lebert F, Pasquier F, Delacourte A. · Inserm Unit 815, Lille, France. · J Neuropathol Exp Neurol. · Pubmed #16651889 No free full text.

Abstract: The primary feature of dementia with Lewy bodies (DLB) is the aggregation of alpha-synuclein into characteristic lesions: Lewy bodies (LBs) and Lewy neurites. However, in most of DLB cases, LBs are associated with neurofibrillary tangles and amyloid plaques (both Alzheimer disease [AD]-related lesions). We wanted to determine if this overlap of lesions is statistical, as a result of the late onset of both diseases, or results from a specific physiopathological synergy between synucleinopathy and either tauopathy or amyloid pathology. All patients with DLB from our prospective and multidisciplinary study were analyzed. These cases were compared with cases with pure AD and patients with Parkinson disease and controls. All cases were analyzed thoroughly at the neuropathologic and biochemical levels with a biochemical staging of aggregated alpha-synuclein, tau, and Abeta species. All sporadic cases of DLB were associated with abundant deposits of Abeta x-42 that were similar in quality and quantity to those of AD. Amyloid precursor protein (APP) dysfunction is a risk factor for AD as demonstrated by pathogenic mutations and Abeta accumulation. The constant and abundant Abeta x-42 deposition in sporadic DLB suggests that synucleinopathy is also promoted by APP dysfunction. Therefore, we conclude that APP is a therapeutic target for both AD and DLB.

Perriol MP, Dujardin K, Derambure P, Marcq A, Bourriez JL, Laureau E, Pasquier F, Defebvre L, Destée A. · Neurophysiologie clinique, Hôpital Salengro, Centre Hospitalier Universitaire, F-59037 Lille Cedex, France. · J Neurol Neurosurg Psychiatry. · Pubmed #15608006 links to  free full text

Abstract: INTRODUCTION: Prepulse inhibition (PPI) is considered to mirror an organism's ability to filter out irrelevant sensory or cognitive information. The disruption of PPI has never been studied in individuals suffering from dementia with Lewy bodies (DLB). As attention deficits largely contribute to cognitive impairment in DLB, an investigation with a PPI paradigm is useful for differential diagnosis of DLB versus Alzheimer's disease (AD) and Parkinson's disease dementia (PDD).Objective and METHODS: PPI of the N1/P2 component of auditory evoked potentials was used to investigate the early stages of attention selectivity in 10 DLB, 10 AD, and 10 PDD patients, as well as in 10 healthy controls. The PPI paradigm consisted of the presentation of sound pulses (40 ms, 115 dB) preceded by a prepulse (40 ms, 80 dB). Sound stimuli were presented in a total of 80 trials in a pseudo-random order. RESULTS: Non-parametric analyses of variance revealed a significant group effect on the 120 ms lead interval. Retrospective analyses revealed that PPI was significantly reduced in DLB compared to healthy controls and AD. In the PDD group, the disturbance was of intermediate intensity. CONCLUSION: The present study revealed a severe disturbance of PPI in DLB patients. The DLB patients displayed a specific disruption profile in terms of magnitude as well as time course.

Defebvre LJ, Leduc V, Duhamel A, Lecouffe P, Pasquier F, Lamy-Lhullier C, Steinling M, Destée A. · Department of Neurology A, Hôpital Roger Salengro, CHRU, Lille, France. · J Nucl Med. · Pubmed #10452310 links to  free full text

Abstract: The aim of this study was to compare the regional cerebral blood flow measurements studied by SPECT in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) to determine the contribution of SPECT to the differential diagnosis of these two diseases. METHODS: SPECT analysis with 99mTc-hexamethyl propyleneamine oxime (HMPAO) was performed in 20 patients with probable DLB, 20 patients with probable AD and 20 patients with idiopathic Parkinson's disease (IPD). Ten pairs of regions of interest were analyzed. Tracer uptake was expressed as a corticocerebellar activity ratio. RESULTS: Compared with IPD, in the DLB group there was a global decrease of HMPAO uptake in cortical regions of interest except in the posterior frontal and occipital regions; in the AD group there was limited left temporal and parietal hypoperfusion. In the DLB group, frontal HMPAO uptake was significantly lower than in the AD group. Two predictive scores were established by a factorial discriminant analysis from six left cortical indices (medial frontal, lateral frontal, posterior frontal, temporoparietal, parietal and parietooccipital) and the Mini-Mental State Examination, which correctly classified 53 of 60 patients (88%) (DLB, 18 of 20; AD, 16 of 20; IPD, 19 of 20). CONCLUSION: These findings indicate the presence of diffuse cortical abnormalities in DLB and suggest that SPECT may be useful in discriminating in vivo DLB from AD, revealing mainly frontal hypoperfusion in the former group. We estimate that SPECT study increases the possibility of separating DLB and AD because both disorders share different patterns of cerebral blood flow abnormality.

Boller F, Ganansia-Ganem A, Lebert F, Pasquier F. · INSERM U 324, Centre Paul Broca, 2 ter rue d'Alesia, 75014 Paris, France. · Eur J Neurol. · Pubmed #10053224 No free full text.

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