DLB and PDD: a role for mutations in dementia and Parkinson disease genes?

Abstract

Based on the substantial overlap in clinical and pathological characteristics of dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) with Alzheimer disease (AD) and Parkinson disease (PD) we hypothesized that these disorders might share underlying genetic factors. The contribution of both sequence and copy number variants (CNVs) in known AD and PD genes to the genetic etiology of DLB and PDD however is currently unclear. Therefore, we performed a gene-based mutation analysis of all major AD and PD genes in 99 DLB and 75 PDD patients, including familial and sporadic forms, from Flanders, Belgium. Also, copy number variants in APP, SNCA, and PARK2 were determined. In the AD genes we detected proven pathogenic missense mutations in PSEN1 and PSEN2, and 2 novel missense variants in PSEN2 and MAPT. In the PD genes we identified 1 SNCA duplication, the LRRK2 R1441C founder mutation and 4 novel heterozygous missense variants with unknown pathogenicity. Our results suggest a contribution of established AD and PD genes to the genetic etiology of DLB and PDD though to a limited extent. They do support the hypothesis of a genetic overlap between members of the Lewy body disease spectrum, but additional genes still have to exist.

Introduction

Dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) are recognized as diverse manifestations of a distinctive disease process leading to the abnormal processing and aggregation of the synaptic protein α-synuclein (Baba et al., 1998). The core clinical features of DLB and PDD are very similar and both diseases are primarily distinguished by the different temporal manifestation of dementia (McKeith et al., 1996). By definition, patients developing dementia prior to parkinsonism or during the first year of disease are diagnosed with DLB. In PDD patients the onset of motor symptoms precedes dementia by at least 1 year. DLB is the second most frequent neurodegenerative dementia with an estimated prevalence up to 30% (Zaccai et al., 2005) of all dementias, which is confirmed by neuropathological examination (Parkkinen et al., 2001). In contrast, the prevalence of PDD is stated to be only 3.6% of all dementia cases based on studies focusing on dementia (Aarsland et al., 2005). However, up to 30% of all Parkinson disease (PD) patients develop dementia during the course of their disease (Aarsland et al., 2003), increasing the actual prevalence of PDD. The concept of DLB and PDD being separate conditions is relatively new and to date there are no markers that unequivocally differentiate both diseases.

Over the last 15 years, DLB and PDD research has mainly focused on clinical and pathological issues related to these spectrum disorders in order to establish appropriate diagnostic criteria for improved patient detection in routine patient care and clinical interventions. Amyloid beta (Aβ) deposition appears to be more frequent and widespread in DLB and is considered a potential pathological marker for differentiating DLB from PDD (Jellinger and Attems, 2006). In line with this finding, the use of Pittsburgh Compound B (PIB)-positron emission tomography (PET) neuroimaging for screening the cortical Aβ burden was shown to be a promising diagnostic tool (Gomperts et al., 2008, Maetzler et al., 2009). In addition, 1 study reported significantly higher levels of oxidized Aβ₄₀ in cerebrospinal fluid (CSF) of DLB patients compared with PDD patients (Bibl et al., 2006).

Molecular genetic etiology studies of both diseases may also prove to be valuable in the identification of disease markers because a considerable part of our current understanding on the pathomechanisms of overlapping neurodegenerative brain diseases (NBD) originates from genetic findings. Although DLB and PDD are mainly envisaged to be sporadic diseases, families in which a mixed phenotype of dementia and parkinsonism is inherited in a Mendelian manner are reported as well (Bogaerts et al., 2007, Bonner et al., 2003, Brett et al., 2002, Denson et al., 1997, Galvin et al., 2002, Golbe et al., 1990, Ohara et al., 1999, Tsuang et al., 2002, Wakabayashi et al., 1998, Waters and Miller, 1994). A recent study even observed a statistical significant aggregation of DLB and its core features within families (Nervi et al., 2011). Genetic research in a limited number of these families already supported a potential role for genes that are known to be implicated in classic forms of either Alzheimer disease (AD; APP [Guyant-Marechal et al., 2008], PSEN1 [Ishikawa et al., 2005], PSEN2 [Piscopo et al., 2008], PGRN [Benussi et al., 2009], PRNP [Koide et al., 2002]) or PD (SNCA [Morfis and Cordato, 2006, Nishioka et al., 2010, Singleton et al., 2003, Zarranz et al., 2004], SNCB [Nishioka et al., 2010, Ohtake et al., 2004], LRRK2 [Haubenberger et al., 2007, Ross et al., 2006], GBA [Clark et al., 2009, Farrer et al., 2009, Goker-Alpan et al., 2006, Mata et al., 2008]) in the development of DLB and PDD. Despite these strong hints for a genetic component in the etiology of both diseases and their relatively high prevalence, comprehensive mutation analyses of all major dementia and PD related genes in extended, well-phenotyped clinical and/or pathologically confirmed DLB and PDD populations are still lagging behind. The primary aim of this study was to systematically determine whether mutations in dementia and PD genes play a role in the development of DLB and PDD in Flanders, Belgium.