Biochemical Staging of Synucleinopathy and Amyloid Deposition in Dementia With Lewy Bodies

Inserm Unit 815, Lille, France.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 04/2006; 65(3):278-88. DOI: 10.1097/01.jnen.0000205145.54457.ea
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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.

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    • "Dans la premiè re version des critè res de McKeith, l'accent est mis sur la large pré dominance des dé pô ts amyloı¨des sur les dé gé né rescences neurofibrillaires dans la DCL, la distinguant nettement de la MA. Or si la charge lé sionnelle est en moyenne moins importante que dans la MA a ` statut cognitif e ´ quivalent, l'extension des lé sions de dé gé né rescence neurofibrillaire est trè s variable (Deramecourt et al., 2006 ; Gearing et al., 1999) et rarement né gligeable (score de Braak 3, dont 70 % 5 dans une e ´ tude (Gearing et al., 1999)). "
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    ABSTRACT: Dementia with Lewy bodies (DLB) is the second cause of degenerative dementia in autopsy studies. In clinical pratice however, the prevalence of DLB is much lower with important intercenter variations. Among the reasons for this low sensitivity of DLB diagnosis are (1) the imprecision and subjectivity of the diagnostic criteria; (2) the underestimation of non-motor symptoms (REM-sleep behavior disorder, dysautonomia, anosmia); mostly (3) the nearly constant association of Lewy bodies with Alzheimer's disease pathology, which dominates the clinical phenotype. With the avenue of targeted therapies against the protein agregates, new clinical scales able to apprehend the coexistence of Lewy pathology in Alzheimer's disease are expected.
    Revue Neurologique 11/2013; 169(11):844–857. DOI:10.1016/j.neurol.2013.05.004 · 0.66 Impact Factor
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    • "Lewy body pathology is considered inversely correlated to the severity of atherosclerosis, infarcts and small-vessel disease. On the other hand cerebral amyloid angiopathy (CAA), associated to AD features, is frequent in patients with LBD [6] [7]. "
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    ABSTRACT: Background: The co-existence of vascular pathology in patients with Lewy body dementia (LBD) is still a matter of debate. This study analyses the prevalence and the severity of cerebrovascular lesions in post-mortem brains of patients with LBD. Patients and methods: Twenty brains of demented patients with autopsy-proven Lewy body disease were compared to 14 brains of age-matched controls. Results: Associated Alzheimer disease (AD) features, stages I-IV, were present in 70% of the LBD brains and in 7% of the controls (P<0.001). Cerebral amyloid angiopathy (CAA) was only present in 30% and lipohyalinosis in 10%. A semi-quantitative analysis, performed on a coronal section of a whole cerebral hemisphere and on a horizontal section through the pons and the cerebellum, revealed significantly more mini-bleeds in the LBD brains (P=0.007), predominantly in the cerebral cortex (P=0.03). Other cerebrovascular lesions were only rarely observed. Comparison of the LDB brains, with and without moderate AD features and CAA, showed no difference in the severity of the cerebrovascular lesions including mini-bleeds. Conclusions: The prevalence of mini-bleeds in LBD brains appears to be independent from the co-existence of moderate AD pathology and CAA. It is more probably due to disturbances of the blood-brain barrier, related to the neurodegenerative process itself.
    Clinical neurology and neurosurgery 12/2012; 115(7). DOI:10.1016/j.clineuro.2012.11.005 · 1.13 Impact Factor
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    • "The brain extraction procedure was performed as described by Deramecourt et al. with minor modifications [37]. Briefly, 100–150 mg of brain tissue was homogenized on ice in 1 mL Tris-buffer (10 mM Tris–HCl, pH 6.8) containing complete protease inhibitor (Roche Diagnostics GmBH). "
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    ABSTRACT: Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn₁₋₁₄₀) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn₁₋₁₃₉ and Ac-α-syn₁₋₁₀₃) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA).
    Neurochemical Research 06/2011; 36(11):2029-42. DOI:10.1007/s11064-011-0527-x · 2.59 Impact Factor
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