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000162639 041__ $$aEnglish
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000162639 1001_ $$0P:(DE-2719)2811916$$aBrockmann, Kathrin$$b0$$eFirst author$$udzne
000162639 245__ $$aAssociation between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies.
000162639 260__ $$aLondon$$bBiomed Central$$c2021
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000162639 520__ $$aThe clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.
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000162639 650_7 $$2Other$$aCSF
000162639 650_7 $$2Other$$aGBA
000162639 650_7 $$2Other$$aPD
000162639 650_7 $$2Other$$aParkin
000162639 650_7 $$2Other$$aRT-QuIC
000162639 650_7 $$2Other$$aα-Syn seeding
000162639 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000162639 650_2 $$2MeSH$$aHumans
000162639 650_2 $$2MeSH$$aLewy Body Disease: cerebrospinal fluid
000162639 650_2 $$2MeSH$$aLewy Body Disease: genetics
000162639 650_2 $$2MeSH$$aLewy Body Disease: pathology
000162639 650_2 $$2MeSH$$aParkinson Disease: cerebrospinal fluid
000162639 650_2 $$2MeSH$$aParkinson Disease: genetics
000162639 650_2 $$2MeSH$$aParkinson Disease: pathology
000162639 650_2 $$2MeSH$$aalpha-Synuclein: cerebrospinal fluid
000162639 7001_ $$aQuadalti, Corinne$$b1
000162639 7001_ $$0P:(DE-2719)2812186$$aLerche, Stefanie$$b2$$udzne
000162639 7001_ $$aRossi, Marcello$$b3
000162639 7001_ $$0P:(DE-2719)2812736$$aWurster, Isabel$$b4$$udzne
000162639 7001_ $$aBaiardi, Simone$$b5
000162639 7001_ $$0P:(DE-2719)2811830$$aRöben, Benjamin$$b6$$udzne
000162639 7001_ $$aMammana, Angela$$b7
000162639 7001_ $$0P:(DE-2719)9000951$$aZimmermann, Milan$$b8$$udzne
000162639 7001_ $$0P:(DE-2719)2351249$$aHauser, Ann-Kathrin$$b9$$udzne
000162639 7001_ $$0P:(DE-2719)2812432$$aDeuschle, Christian$$b10$$udzne
000162639 7001_ $$0P:(DE-2719)9000366$$aSchulte, Claudia$$b11$$udzne
000162639 7001_ $$aWaniek, Katharina$$b12
000162639 7001_ $$aLachmann, Ingolf$$b13
000162639 7001_ $$aSjödin, Simon$$b14
000162639 7001_ $$aBrinkmalm, Ann$$b15
000162639 7001_ $$aBlennow, Kaj$$b16
000162639 7001_ $$aZetterberg, Henrik$$b17
000162639 7001_ $$0P:(DE-2719)2320009$$aGasser, Thomas$$b18$$udzne
000162639 7001_ $$00000-0002-9444-9524$$aParchi, Piero$$b19
000162639 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-021-01276-6$$gVol. 9, no. 1, p. 175$$n1$$p175$$tActa Neuropathologica Communications$$v9$$x2051-5960$$y2021
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