Clinical and Pathological Characteristics of LRRK2 G2019S Patients with PD (original) (raw)

Abstract

The objective of this study is to describe the neuropathologic findings in three LRRK2 G2019S carriers with Parkinson's disease (PD). We cross-referenced a list of 956 PD individuals that had been previously genotyped in clinical studies at Columbia University, with 282 subjects with a parkinsonian syndrome who came to autopsy in our brain bank since 1991. We found three autopsies of G2019S mutation carriers. Pathological analyses of the samples were blind to the genetic findings. We retrospectively reviewed the clinical records of the three patients. All three had a clinical and pathological diagnosis of PD. Cognitive impairment was a late feature in two out of three patients. Cortical involvement varied significantly: one had diffuse Lewy body (LB) pathology, tau inclusions, and amyloid pathology consistent with advanced Alzheimer's disease; one had diffuse cortical LB; and one had only brainstem predominant LB pathology. Cognitive impairment may be a long-term complication in G2019S mutation carriers. However, the extent of cortical involvement is variable. Larger longitudinal follow-up of LRRK2 G2019S mutation carriers is required to assess for risk factors for cortical involvement and dementia.

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References

• Belarbi S, Hecham N et al (2010) LRRK2 G2019S mutation in Parkinson's disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort. Parkinsonism Relat Disord 16(10):676–679
  Article PubMed Google Scholar
• Braak H, Del Tredici K et al (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24(2):197–211
  Article PubMed Google Scholar
• Dachsel JC, Ross OA et al (2007) Lrrk2 G2019S substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathol 113(5):601–606
  Article PubMed Google Scholar
• Daniel SE, Lees AJ (1993) Parkinson's Disease Society Brain Bank, London: overview and research. J Neural Transm Suppl 39:165–172
  PubMed CAS Google Scholar
• Gaig C, Marti MJ et al (2007) G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies. J Neurol Neurosurg Psychiatr 78(6):626–628
  Article PubMed Google Scholar
• Gaig C, Ezquerra M et al (2008) Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration. J Neurol Sci 270(1–2):94–98
  Article PubMed CAS Google Scholar
• Giasson BI, Covy JP et al (2006) Biochemical and pathological characterization of Lrrk2. Ann Neurol 59(2):315–322
  Article PubMed CAS Google Scholar
• Gilks WP, Abou-Sleiman PM et al (2005) A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365(9457):415–416
  PubMed CAS Google Scholar
• Gomez A, Ferrer I (2010) Involvement of the cerebral cortex in Parkinson disease linked with G2019S LRRK2 mutation without cognitive impairment. Acta Neuropathol 120(2):155–167
  Article PubMed CAS Google Scholar
• Healy DG, Falchi M et al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 7(7):583–590
  Article PubMed CAS Google Scholar
• Hely MA, Reid WG et al (2008) The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov Disord 23(6):837–844
  Article PubMed Google Scholar
• Hughes AJ, Daniel SE et al (1992) Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatr 55(3):181–184
  Article PubMed CAS Google Scholar
• Lesage S, Durr A et al (2006) LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 354(4):422–423
  Article PubMed CAS Google Scholar
• Lippa CF, Smith TW et al (1994) Alzheimer's disease and Lewy body disease: a comparative clinicopathological study. Ann Neurol 35(1):81–88
  Article PubMed CAS Google Scholar
• Marder KS, Tang MX et al (2010) Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study. Arch Neurol 67(6):731–738
  Article PubMed Google Scholar
• Ozelius LJ, Senthil G et al (2006) LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 354(4):424–425
  Article PubMed CAS Google Scholar
• Ozelius LJ, Foroud T et al (2007) G2019S mutation in the leucine-rich repeat kinase 2 gene is not associated with multiple system atrophy. Mov Disord 22(4):546–549
  Article PubMed Google Scholar
• Rajput A, Dickson DW et al (2006) Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 67(8):1506–1508
  Article PubMed CAS Google Scholar
• Ross OA, Toft M et al (2006) Lrrk2 and Lewy body disease. Ann Neurol 59(2):388–393
  Article PubMed CAS Google Scholar
• Silveira-Moriyama L, Guedes LC et al (2008) Hyposmia in G2019S LRRK2-related parkinsonism: clinical and pathologic data. Neurology 71(13):1021–1026
  Article PubMed CAS Google Scholar
• Umeno J, Asano K et al (2011) Meta-analysis of published studies identified eight additional common susceptibility loci for Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 17(12):2407–2415
  Article PubMed Google Scholar
• Wider C, Dickson DW et al (2010) Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype-phenotype correlation. Neurodegener Dis 7(1–3):175–179
  Article PubMed CAS Google Scholar
• Zimprich A, Biskup S et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607
  Article PubMed CAS Google Scholar

Download references

Disclosures

Dr. Poulopoulos, Dr. Cortes, Dr. Vonsattel, Dr. Cote, and Ms. Moskowitz report no disclosures.

Dr. Fahn reports receiving support from consulting and advisory board membership with honoraria from Oxford Biomedica (Sept 2009), Proctor-Goodwin (Nov 2009), GE Healthcare (Nov 2009), RJG Foundation (March 2010), IMPAX Pharmaceuticals (May 2010), and Lundbeck (June 2010). He is receiving research support from the Parkinson's Disease Foundation (no salary support). He received a grant from the Smart Family Foundation (no salary support). He received a grant from the US Department of Defense's Telemedicine and Advanced Technology Research Center (TATRC) for the World Parkinson Congress 2010, and a grant from the National Institutes of Health for the World Parkinson Congress 2010. Dr. Fahn received lecture honoraria from Columbia University (July 2009), Sun Pharmaceuticals India (Sept 2009), World Association of Sleep Medicine (Nov 2009), American Academy of Neurology (April 2010), and Columbia University (July 2010). Dr. Fahn reports serving as an editor with author honoraria from “Current Neurology and Neurosurgery Report” (annual); Elsevier for co-author of book Principles and Practice of Movement Disorders.

Dr. Waters received speaking honorarium from Boehringer and Teva.

Dr. Honig is funded by NIH grant P50AG008702.

Dr. Clark is funded by NIH grants R21NS050487 (PI), R01NS60113 (PI), R01NS0738072 (CoPI), P50AG008702 (CoI), P50 NS038370 (CoI), the Parkinson’s Disease foundation and the Michael J Fox foundation.

Dr. Marder served on the editorial board of Neurology and is funded by NIH [NS36630 (PI), 1UL1 RR024156-01(Director PCIR), PO412196-G (Co-I), PO412196-G (Co-I)] and R01NS36630, and from the Parkinson Disease Foundation, Huntington's Disease Society of America, the Parkinson Study Group, and the Michael J. Fox foundation.

Dr. Alcalay is funded by NIH (K12 part of UL1 RR024156) and the Brookdale Foundation, the Parkinson's Disease Foundation, the Michael J. Fox foundation, and the Smart Foundation.

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Authors and Affiliations

1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
   Markos Poulopoulos, Stanley Fahn, Cheryl Waters, Carol Moskowitz, Karen S. Marder & Roy N. Alcalay
2. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA
   Etty Cortes, Jean-Paul G. Vonsattel, Lucien J. Cote, Carol Moskowitz, Lawrence S. Honig, Lorraine N. Clark, Karen S. Marder & Roy N. Alcalay
3. Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA
   Karen S. Marder
4. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
   Lorraine N. Clark
5. Center for Human Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
   Lorraine N. Clark
6. Department of Psychiatry, Columbia University Medical Center, New York, NY, USA
   Karen S. Marder
7. Neurological Institute, 710 West 168th street, New York, NY, 10032, USA
   Roy N. Alcalay

Authors

1. Markos Poulopoulos
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2. Etty Cortes
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3. Jean-Paul G. Vonsattel
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4. Stanley Fahn
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5. Cheryl Waters
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6. Lucien J. Cote
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7. Carol Moskowitz
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8. Lawrence S. Honig
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9. Lorraine N. Clark
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10. Karen S. Marder
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11. Roy N. Alcalay
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Corresponding author

Correspondence toRoy N. Alcalay.

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Study funding

This study was supported by NIH grants: R01NS36630 (Dr. Marder), R01NS060113 (Dr. Clark), P50AG008702 (Drs. Clark, Honig, Marder and Vonsattel), P50 NS038370 (Drs. Clark and Vonsattel) UL1 RR024156 (Dr. Alcalay) and the Parkinson’s Disease Foundation (Drs. Marder, Fahn and Clark). Dr. Poulopoulos is a Parkinson's Disease Foundation fellow

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Poulopoulos, M., Cortes, E., Vonsattel, JP.G. et al. Clinical and Pathological Characteristics of LRRK2 G2019S Patients with PD.J Mol Neurosci 47, 139–143 (2012). https://doi.org/10.1007/s12031-011-9696-y

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• Received: 11 October 2011
• Accepted: 12 December 2011
• Published: 23 December 2011
• Issue Date: May 2012
• DOI: https://doi.org/10.1007/s12031-011-9696-y

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