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Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.

ABSTRACT: Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

SUBMITTER: Bras J

PROVIDER: S-EPMC4222357 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.

Bras Jose J Guerreiro Rita R Darwent Lee L Parkkinen Laura L Ansorge Olaf O Escott-Price Valentina V Hernandez Dena G DG Nalls Michael A MA Clark Lorraine N LN Honig Lawrence S LS Marder Karen K Van Der Flier Wiesje M WM Lemstra Afina A Scheltens Philip P Rogaeva Ekaterina E St George-Hyslop Peter P Londos Elisabet E Zetterberg Henrik H Ortega-Cubero Sara S Pastor Pau P Ferman Tanis J TJ Graff-Radford Neill R NR Ross Owen A OA Barber Imelda I Braae Anne A Brown Kristelle K Morgan Kevin K Maetzler Walter W Berg Daniela D Troakes Claire C Al-Sarraj Safa S Lashley Tammaryn T Compta Yaroslau Y Revesz Tamas T Lees Andrew A Cairns Nigel N Halliday Glenda M GM Mann David D Pickering-Brown Stuart S Dickson Dennis W DW Singleton Andrew A Hardy John J

Human molecular genetics 20140627 23

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analys ...[more]

PMID: 24973356

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Project description:Swallowing dysfunction is an increasingly recognized problem in patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which can result in aspiration pneumonia and death. Few studies have examined potential ways of improving swallowing function in this fragile patient group. The aim of this study was to evaluate swallowing dysfunction and carbonated liquid using videofluoroscopy in DLB and PDD patients.A total of 48 patients with DLB and PDD were referred for a clinical examination with videofluoroscopy. Descriptive overall assessments were provided at the time of the examination regarding swallowing function and the effects of different modifications, including carbonated thin liquid (CTL). Additionally, a repeated measures quantitative retrospective analysis has been performed comparing 1) thin liquids; 2) thickened liquids and 3) CTLs, with regard to the quantitative variables 1) pharyngeal transit time (PTT); 2) pharyngeal retention and 3) tracheal penetration.In all, 40/48 (83%) of the patients had a swallowing dysfunction, which was confirmed on videofluoroscopy, with 34/40 (85%) patients having a pharyngeal-type dysfunction. A total of 14/40 (35%) patients with an objective swallowing impairment did not have any subjective swallowing symptoms. Out of the patients with swallowing dysfunction, 87% had an overall improved swallowing function with carbonated liquid. PTT for carbonated liquid (median 633 ms, interquartile range [IQR] 516-786 ms) was quicker than for thin liquid (760 ms, IQR 613-940 ms, P=0.014) and thickened liquid (880.0 ms, IQR 600-1,500 ms, P<0.001). No significant effect was seen in residue or penetration.The majority of patients with DLB or PDD had a swallowing dysfunction, sometimes without subjective swallowing symptoms, which improved with carbonated liquid. This highlights the importance of investigating patients with videofluoroscopy and to carry out a prospective interventional study to further evaluate carbonated liquid, also addressing the effects on quality of life, aspiration and mortality.

Dataset Information

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.

Publications

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.

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