Elsevier

Parkinsonism & Related Disorders

Volume 31, October 2016, Pages 98-103
Parkinsonism & Related Disorders

LRRK2 variation and dementia with Lewy bodies

https://doi.org/10.1016/j.parkreldis.2016.07.015Get rights and content

Highlights

  • We studied 417 DLB patients and 1790 controls in our primary analysis.

  • 7 pathogenic LRRK2 variants and 18 common LRRK2 variants were assessed.

  • We identified 1 DLB patient who was a carrier of the LRRK2 p.G2019S mutation.

  • The p.N551K-R1398H-K1423K haplotype showed a non-significant trend toward a protective association with DLB risk.

  • These findings suggest that LRRK2 variation may play a limited role in susceptibility to DLB.

Abstract

Introduction

The leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB.

Methods

417 clinical DLB patients and 1790 controls were included in the primary analysis. Additionally, 355 Lewy body disease patients assessed as having a high likelihood of clinical DLB based on neuropathological findings were included in secondary analysis. Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2 PD-risk variant were evaluated for association with DLB.

Results

We identified carriers of 2 different pathogenic LRRK2 variants. One clinical DLB patient was a p.G2019S carrier, while in the pathological high likelihood DLB series there was one carrier of the p.R1441C mutation. However, examination of clinical records revealed the p.R1441C carrier to have PD with dementia. Evaluation of common variants did not reveal any associations with DLB risk after multiple testing adjustment. However, a non-significant trend similar to that previously reported for PD was observed for the protective p.N551K-R1398H-K1423K haplotype in the clinical DLB series (OR: 0.76, P = 0.061).

Conclusion

LRRK2 does not appear to play a major role in DLB, however further study of p.G2019S and the p.N551K-R1398H-K1423K haplotype is warranted to better understand their involvement in determining DLB risk.

Introduction

Dementia with Lewy bodies (DLB) is one of the most common types of dementia in the elderly population, and has clinical and neuropathological similarities with both Alzheimer's disease (AD) and Parkinson's disease (PD) [1]. DLB is characterized clinically by progressive dementia, parkinsonism, visual hallucinations, fluctuations in cognition, and REM sleep behavior disorder [2]. Neuropathologically, DLB is classified as an α-synucleinopathy along with PD and PD with dementia (PDD) owing to the typical widespread presence of cortical Lewy bodies, and this is often observed along with pathological features of AD such as neurofibrillary tangles (NFTs) and senile plaques [2]. Genetic causes of DLB are not well understood, however recent studies have implicated genes involved in both AD and PD. Specifically, strong associations with DLB have been observed for the apolipoprotein E (APOE) ε4 allele which is a major risk factor for AD, and also for variants in the glucocerebrosidase (GBA) and α-synuclein (SNCA) genes, which are both well-known risk factors for PD [3], [4], [5].

The common clinical and neuropathological features between DLB and PD and the identification of shared genetic risk factors for these two diseases suggests that other PD-genes may be promising candidates for study in relation to risk of DLB. The leucine-rich repeat kinase 2 (LRRK2) gene has a well-known role in PD, containing both disease-causing mutations such as p.G2019S and p.R1441C, as well as common disease-risk-modifying variants including p.M1646T in Caucasians, p.G2385R and p.R1628P in Asians, and a protective p.N551K-R1398H-K1423K haplotype in both ethnic groups [6], [7], [8], [9], [10]. However, LRRK2 has not been well-studied in the context of DLB. Specifically, the association between common LRRK2 variation and DLB risk has not been systematically examined to date, and assessment of pathogenic LRRK2 mutations has been limited to a few relatively small case series' and one familial study [11], [12], [13], [14]. In this study, we utilized a series of more than 700 patients with either clinically diagnosed DLB or neuropathologically-assessed Lewy body disease with a high likelihood of DLB in order to estimate the frequencies of pathogenic LRRK2 variants and also to evaluate associations between common LRRK2 variants and risk of DLB.

Section snippets

Study subjects

Included in the primary analysis of this study were 417 clinical DLB patients and 1790 controls. The clinical DLB patients were seen at the Mayo Clinic in either Jacksonville, FL (N = 152) or Rochester, MN (N = 265) between 1987 and 2014, and DLB diagnosis (384 probable DLB, 33 possible DLB) was made in accordance with published criteria [2]. Clinical DLB patients collected at both Mayo sites were part of NIH-funded studies on aging and dementia (Alzheimer's Disease Research Center or Mayo

Pathogenic LRRK2 mutations in DLB

We identified one LRRK2 p.G2019S carrier (0.2%) who was part of the clinical DLB series. This patient was a 76-year-old, functionally independent man who initially presented with concurrent onset of REM-sleep behavior disorder, decline in attention and word-finding ability, and right-sided resting tremor. An initial neuropsychological examination was significant for mild impairment in divided attention and poor learning and retrieval, but no rapid forgetting. Two years after symptom onset, a

Discussion

LRRK2 mutations are the most common genetic cause of PD that have been identified thus far, however little is known about its role in DLB. To date, there have been no pathogenic LRRK2 mutations that have been reported in clinically diagnosed DLB patients, and associations with DLB for common LRRK2 variants have been only minimally assessed. In our study of 417 clinically diagnosed DLB patients, we identified one clinical DLB p.G2019S mutation carrier, and we also observed a non-significant

Acknowledgements

We are grateful to all patients, family members, and caregivers who agreed to brain donation; without their donation these studies would have been impossible. We also acknowledge expert technical assistance of Linda Rousseau and Virginia Phillips for histology and Monica Castanedes-Casey for immunohistochemistry. We appreciate the assistance of Mayo Clinic Udall Center administrator, Audrey Strongosky. We also acknowledge support from the Michael J. Fox Foundation, Mayo Clinic AD and related

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