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. Author manuscript; available in PMC: 2016 Apr 15.
Published in final edited form as: Mov Disord. 2015 Feb 4;30(5):728–733. doi: 10.1002/mds.26161

Cognitive Profile of LRRK2-related Parkinson’s Disease

Sindhu Srivatsal 1,*, Brenna Cholerton 2,3,*, James B Leverenz 4, Zbigniew K Wszolek 5, Ryan J Uitti 5, Dennis W Dickson 5, Daniel Weintraub 6,7,8, John Q Trojanowski 9,10, Vivianna M Van Deerlin 9, Joseph F Quinn 11,12, Kathryn A Chung 11,12, Amie L Peterson 11,12, Stewart A Factor 13, Cathy Wood-Siverio 13, Jennifer G Goldman 14, Glenn T Stebbins 14, Bryan Bernard 14, Beate Ritz 15,16,17, Rebecca Rausch 17, Alberto J Espay 18, Fredy J Revilla 18, Johnna Devoto 18, Liana S Rosenthal 19, Ted M Dawson 19,20,21, Marilyn S Albert 19, Ignacio F Mata 2, Shu-Ching Hu 2,22, Kathleen S Montine 23, Catherine Johnson 24, Thomas J Montine 23, Karen L Edwards 24, Jing Zhang 23, Cyrus P Zabetian 2,22
PMCID: PMC4397146  NIHMSID: NIHMS653539  PMID: 25650144

Abstract

Background

There is increasing evidence that genetic factors play a role in the variability associated with cognitive performance in Parkinson’s disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized.

Methods

A cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models.

Results

LRRK2 mutation carriers (n=29) demonstrated better performance on the Mini Mental State Examination (P=0.03) and the Letter-Number Sequencing Test (P=0.005). A smaller proportion of LRRK2 carriers were demented (P=0.03).

Conclusions

Our cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline.

Keywords: cognition, LRRK2, neuropsychological tests, Parkinson disease, working memory

INTRODUCTION

Recent evidence suggests that genetic factors could play an important role in the substantial variation in the pattern of cognitive deficits seen in Parkinson’s disease (PD).1, 2 The APOE ε4 allele and mutations in the GBA gene are both associated with a higher frequency of dementia in PD yet appear to impact largely distinct cognitive domains prior to the onset of dementia.3–7 Additional information stands to be gained by examining cognition in monogenic forms of PD because the molecular mechanisms underlying neurodegeneration are likely to be more homogenous than those involved in “idiopathic” PD.

Mutations in the leucine-rich repeat kinase 2 (LRRK2; OMIM #609007) gene are the most common cause of monogenic PD.8, 9 The motor characteristics of LRRK2-associated PD and idiopathic PD are thought to be generally indistinguishable.10,11 However, mixed results have been reported with respect to non-motor features, including cognition. Some studies have found that LRRK2 mutation carriers with PD exhibit milder cognitive symptoms and more gradual cognitive decline than non-carriers with PD,8, 12 while others have not.13–15,16–20 To help reconcile the differences reported in the literature, we compared the performance of LRRK2 mutation carriers and non-carriers on a detailed neuropsychological assessment in a large, well-characterized multicenter PD cohort.

METHODS

Subjects

The study included 1,447 participants with PD from eight sites that comprise the PD Cognitive Genetics Consortium (PDCGC), who were screened for known LRRK2 mutations as described previously21 and in the e-Supplement. Participants were required to meet the United Kingdom PD Society Brain Bank clinical diagnostic criteria for PD22 with the exception of those from UCLA who satisfied clinical diagnostic criteria for PD as described elsewhere.23 Four participants failed genotyping and 21 subjects (all mutation non-carriers) were missing disease duration data and were thus excluded from analyses. Sixty-seven subjects (all mutation non-carriers) who did not complete greater than half of the cognitive measures were excluded from analyses involving continuous measures but not from those involving the categorical diagnostic variable (demented vs. non-demented). The institutional review board of each participating institution approved the study, and all participants provided written informed consent.

Cognitive/clinical variables

Seven cognitive tests were administered by at least seven of eight sites, including the Mini Mental State Examination (MMSE24) and tests measuring specific cognitive domains: learning/memory (Hopkins Verbal Learning Test-Revised [HVLT]25), attention/executive function (Letter-Number Sequencing Test [LNST]26 and Trailmaking Parts A and B27), language processing (semantic and phonemic verbal fluency28), and visuospatial abilities (Benton Judgment of Line Orientation [JOLO]29). Motor symptom severity (see e-Supplement) was obtained at seven of eight sites.

Cognitive data at six of the eight sites were discussed at a clinical consensus diagnosis conference, and participants were diagnosed as demented or non-demented using all available neuropsychological and clinical data at each site, as described elsewhere.4, 30, 31 At the two remaining sites, participants were not assigned clinical cognitive diagnoses (see e-Supplement).

Statistical methods

The association between LRRK2 mutation carrier status and clinical/cognitive variables was assessed by separate linear regression analyses, applying the generalized estimating equation to account for relatedness in the study sample. Exact logistic regression was performed to determine the association between clinically diagnosed dementia and LRRK2 mutation status. Analyses were adjusted for age at testing, sex, site, disease duration (time since diagnosis at UCLA and time since symptom onset at all other sites), and years of education. For analyses involving Trailmaking Part B, Trailmaking Part A was also included as a covariate. Statistical tests were two-tailed; the significance threshold was set at P < 0.05. Given the exploratory nature of the study, no adjustments for multiple comparisons were made. Stata version 12 was used for all analyses (StataCorp, College Station, TX).

RESULTS

Twenty-nine participants with LRRK2 mutations were identified, including two members from each of three families and three members from another family. Twenty-two were heterozygous for the G2019S mutation, two were homozygous for G2019S, and five were heterozygous for the R1441C mutation. Sample demographic, clinical, and cognitive characteristics for mutation carriers and non-carriers are shown in Table 1. Demographic and clinical data stratified by site are presented in Table e-1 (e-Supplement).

Table 1.

Demographic and clinical data for LRRK2 mutation carriers vs. non-carriers

LRRK2 Status P a
Non-Mutation Carriers [n=1326] Mutation Carriers [n=29]
Age at visit
 Mean (SD) 68.9 (9.3) 67.9 (9.6) 0.56
 Range 34.8 – 94.5 50.2 – 86.9
Sex
 N (%) female 439 (33.1%) 10 (34.5%) 0.84
Education
 Mean (SD) 15.5 (2.7) 16.3 (2.7) 0.09
 Range 7 – 20 12 – 20
Disease Durationb
 Mean (SD) 8.4 (5.6) 8.9 (7.0) 0.64
 Range 0 – 43 1 – 32
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Abbreviation: SD = standard deviation

a

Pairwise P-value using t-tests (age, education, disease duration) or Fisher’s Exact Test (sex)

b

Disease duration was based on age at diagnosis at UCLA and age at onset at all other sites

Adjusted linear regression results for cognitive test scores are presented in Table 2. LRRK2 mutation carriers performed significantly better than non-carriers on the LNST and MMSE. The effect sizes, shown by the β coefficients, indicate the expected difference in mean LNST scores was 1.19 and in MMSE scores was 0.74, given the same values for all other covariates. Mutation carriers also had less severe motor symptoms, as assessed by the MDS-UPDRS III, than non-carriers. These associations held when the analyses were restricted to G2019S heterozygotes (Table e-2, supplement).

Table 2.

Cognitive test scores and clinical features: LRRK2 mutation carriers vs. non-carriers

Cognitive Measures N (Total) N (Mutation carriers) Scores (raw) Standard (z-scores) Regression Resultsa
Non-Mutation Carriers
Mean (SD) Range		 Mutation Carriers
Mean (SD) Range		 Non-Mutation Carriers
Mean (SD) Range		 Mutation Carriers
Mean (SD) Range		 Coeff.b Std. Error 95% CI P
MMSE 1237 27 27.7 (2.4)
11 – 30		 28.6 (1.6)
24 – 30		 −1.10 (1.87)
−13.84 – 0.86		 −0.42 (1.32)
−4.3 – 0.86		 0.74 0.35 0.05, 1.42 0.034c
Fluency: Semantic 1344 28 17.2 (6.1)
0 – 37		 19.9 (6.8)
7 – 35		 −0.63 (1.05)
−3.89 – 2.83		 −0.17 (1.21)
−2.34 – 2.31		 1.79 1.16 −0.48, 4.05 0.122
Fluency: Phonemic 1317 28 35.6 (14.3)
2 – 93		 41.4 (14.6)
12 – 69		 −0.09 (1.09)
−2.81 – 5.47		 0.35 (1.34)
−2.17 – 2.91		 4.35 2.83 −1.20, 9.90 0.124
HVLT: Total Learning 1203 25 21.4 (6.3)
0 – 35		 23.2 (4.8)
12 – 33		 −0.82 (1.25)
−5.04 – 2.25		 −0.46 (0.91)
−2.07 – 1.58		 1.25 0.83 −0.39, 2.88 0.135
HVLT: Delayed 1201 25 6.8 (3.6)
0 – 12		 7.9 (3.3)
0 – 12		 −0.98 (1.59)
−5.45 – 1.54		 −0.49 (1.42)
−4.94 – 1.30		 0.77 0.48 −0.17, 1.71 0.111
HVLT: RDI 1190 25 9.3 (2.4)
−2 – 12		 9.6 (2.5)
2 – 12		 n/a n/a 0.13 0.39 −0.64, 0.90 0.737d
Judgment of Line Orientation 1149 27 11.2 (3.0)
0 – 15		 11.7 (2.1)
8 – 15		 0.71 (2.13)
−2.45 – 3.99		 0.91 (2.02)
−1.22 – 3.99		 0.39 0.45 −0.49, 1.28 0.386d
Letter Number Sequencing 1118 23 8.4 (3.1)
0 – 18		 9.8 (2.3)
4 – 14		 −0.06 (1.07)
−3.0 – 3.0		 0.49 (0.84)
−1.67 – 2.0		 1.19 0.43 0.35, 2.02 0.005
Trailmaking, Part Be 1123 25 143.6 (87.5)
28 – 300		 99.8 (78.3)
35 – 300		 −1.44 (1.94)
−6.80 – 1.31		 −0.55 (2.06)
−6.80 – 1.04		 −9.72 13.31 −35.80, 16.37 0.465f
Clinical Features Non-Mutation Carriers Mutation Carriers
MDS-UPDRS III 1153 28 28.64 (12.9)
3 – 79		 23.54 (9.1)
3 – 43		 - - −5.17 1.58 −8.27, −2.08 0.001
Dementia N (%)
Cognitive Status 1057 25 210 (19.9) 1 (4.0) - - −1.99 - −5.76, −0.07 0.029
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Abbreviations: HVLT = Hopkins Verbal Learning Test-Revised, MDS-UPDRS III= Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part III, MMSE = Mini Mental State Examination, RDI = Recognition Discrimination Index, SD = standard deviation

a

Analyses involving cognitive measures adjusted for age, sex, education, site, and disease duration; Trailmaking, Part B analyses also adjusted for Trailmaking, Part A time. MDS-UPDRS analyses adjusted for age, sex, site, and disease duration. Linear regression analyses were used for continuous measures, exact logistic regression procedures were used to compare proportion of demented/nondemented participants

b

Coeff. = beta coefficient, indicates the expected change in mean test score when carrying a LRRK2 mutation given the same values for all adjustment covariates

c

When cube transformed scores were used, P = 0.05

d

When cube transformed scores were used, P values remained non-significant

e

Lower score denotes better performance

f

When log-transformed scores were used, P values remained non-significant

LRRK2 mutation carriers demonstrated a lower prevalence of dementia than non-carriers (4% vs. 19.6%). Exact logistic regression analyses that controlled for age, sex, education, disease duration, and site demonstrated that this difference was statistically significant (Table 2).

Discussion

The current study offers evidence that mutations in the LRRK2 gene might result in differences in cognitive phenotype in PD patients, specifically higher global cognition and lower prevalence of dementia, as well as better working memory (executive) performance when compared to non-mutation carriers. Less severe overall motor dysfunction exhibited by LRRK2 mutation carriers in conjunction with better cognitive test performance suggests the possibility of overall milder disease in these patients, although these findings require replication.

Early descriptive studies suggested that LRRK2 mutation carriers diagnosed with PD might show milder cognitive symptoms in comparison to non-carriers with PD,8, 12,15 while in contrast, others found no difference in MMSE scores between LRRK2 mutation carriers and non-carriers with PD.13, 14, 16, 19, 32 In the current study, we observed a significantly lower rate of dementia and higher mean MMSE scores in LRRK2 mutation carriers compared with non-carriers. We also found a notable difference in the range of MMSE scores, such that LRRK2 mutation carriers all had scores of 24 or higher in the absence of differences in mean disease duration. Similar to our findings, Estanga et al.20 found a lower proportion of dementia cases among LRRK2 mutation carriers compared to non-carriers, although this difference failed to reach significance. The suggestion that LRRK2 mutations are associated with a lower likelihood of developing cognitive impairment might be explained in part by the neuropathologic features of LRRK2-related PD. Although widely heterogeneous,33, 34 in a recent meta-analysis of 37 LRRK2 mutation-positive autopsy cases with a clinical diagnosis of PD,35 a substantial proportion (20/37, 54%) lacked Lewy body pathology and this finding was not restricted to specific LRRK2 mutations. Further, the presence of Lewy body pathology was associated with a higher proportion of cognitive impairment (including dementia) diagnosed prior to death, while the group without Lewy body pathology displayed a predominantly motor phenotype. Given the association between Lewy body disease and more severe cognitive dysfunction in patients with PD reported by these authors and others,36, 37 it is perhaps not surprising that LRRK2 cohorts, which are likely enriched with Lewy body-negative cases, might exhibit overall milder cognitive symptoms.

Importantly, for the first time we demonstrate a difference between LRRK2 mutation carriers and non-carriers with PD on a sensitive measure of working memory (an executive function). Previous studies that evaluated aspects of executive functioning found no differences in performance between LRRK2 mutation carriers and non-carriers.16–19 Often, however, the more frontally mediated tasks used in these studies involved motor skills or timed task performance. Here, we found a significant difference between LRRK2 mutation carriers and non-carriers on a sensitive working memory task that does not require motor involvement and is not timed. These findings suggest that LRRK2 mutation carrier status might be associated with less impairment on working memory, an area of cognition that is frequently impacted early in PD. This result conflicts with a recently published study20 of LRRK2 R1441G mutation carriers with PD that found no difference across several sensitive cognitive measures, including LNST. However, our sample was largely composed of G2019S carriers (24/29, 83%), suggesting that specific LRRK2 mutations might be associated with differential test performance.

Our study had some limitations. Importantly, this study is cross-sectional; only longitudinal research will provide evidence for whether the overall cognitive course differs between LRRK2 mutation carriers and non-carriers. In addition, although we examined a large, well-defined PD cohort, our sample of LRRK2 mutation carriers remains relatively small. Given the exploratory nature of the study, we did not correct for multiple comparisons. Finally, the pattern of performance across cognitive measures, when looking at raw scores, suggests that we might have lacked adequate power to detect statistically significant differences on several other cognitive tests.

Our findings add to a growing body of evidence which suggests that genetic factors play an important role in determining cognitive performance in PD. Given the near ubiquitous, yet heterogeneous nature of cognitive impairment in PD, identification of subgroups associated with better or worse cognitive outcomes is an important step toward tailoring appropriate interventions, and could inform inclusion for enrollment in long-term cognitive treatment and prevention trials. Future large, longitudinal investigations will be needed to reveal whether LRRK2 mutation carrier status predicts a more stable cognitive course.

Supplementary Material

Supp MaterialS1

Acknowledgments

This research was supported by the National Institutes of Health (K23 NS060949, P50 NS062684, P50 NS053488, P50 NS038367, P50 NS038377, P50 NSO72187, R01 NS065070, R01 NS057567 and U01 NS082133), the Department of Veterans Affairs (1I01BX000531), the Parkinson’s Disease Foundation, the Nancy and Buster Alvord Endowment, the Jane and Lee Seidman Fund, the Consolidated Anti-Aging Foundation, and gifts from Carl Edward Bolch, Jr, and Susan Bass Bolch. The funding sources did not provide scientific input for the study. We thank our research subjects and family members for their participation in this study.

Author disclosures

Dr. Cholerton reports no relevant disclosures and is funded by NIH.

Dr. Srivatsal reports no relevant disclosures; she received an honorarium from APDA.

Dr. Leverenz reports consulting fees from Boehringer-Ingelheim, Piramal Healthcare, and Navidea Biopharmaceuticals and is funded by grants from the Department of Veterans Affairs, American Parkinson Disease Association, Michael J. Fox Foundation, NIH, and the Parkinson’s Disease Foundation.

Dr. Wszolek receives support from the NIH/NINDS, Mayo Clinic Center for Regenerative Medicine, and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch. Mayo Clinic and Dr. Wszolek have a financial interest in technologies entitled, “Identification of Mutations in PARK8, a Locus for Familial Parkinson’s Disease” and “Identification of a Novel LRRK2 Mutation, 6055G>A (G2019S), Linked to Autosomal Dominant Parkinsonism in Families from Several European Populations”. Those technologies have been licensed to commercial entities, and to date, Dr. Wszolek has received royalties <$1.500 through Mayo Clinic in accordance with its royalty sharing policies.

Dr. Uitti serves as Associate Editor for Neurology for which he receives some personal compensation and is funded by NIH grants

Dr. Dickson reports no relevant disclosures and is funded by the NIH.

Dr. Weintraub reports consulting or advisory board membership with honoraria from Teva Pharmaceuticals, Eli Lilly and Company, Lundbeck Inc., Biogen, Pfizer, Avanir Pharmaceuticals, and Merck & Co.. Honoraria from Michael J. Fox Foundation for Parkinson’s Research, American Psychiatric Publishing, Teva Pharmaceuticals, CHDI Foundation, and Alzheimer’s Disease Cooperative Study. Intellectual property rights from licensing fees from the University of Pennsylvania. Research funding support from National Institutes of Health, Michael J. Fox Foundation, and Novartis Pharmaceuticals.

Dr. Trojanowski serves as an Associate Editor of Alzheimer’s & Dementia; may accrue revenue on patents held by the University of Pennsylvania wherein he is inventor. Modified avidin-biotin technique, Method of stabilizing microtubules to treat Alzheimer’s disease, Method of detecting abnormally phosphorylated tau, Method of screening for Alzheimer’s disease or disease associated with the accumulation of paired helical filaments, Compositions and methods for producing and using homogeneous neuronal cell transplants, Rat comprising straight filaments in its brain, Compositions and methods for producing and using homogeneous neuronal cell transplants to treat neurodegenerative disorders and brain and spinal cord injuries, Diagnostic methods for Alzheimer’s disease by detection of multiple MRNAs, Methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases, Compositions and methods for producing and using homogenous neuronal cell transplants, Method of identifying, diagnosing and treating alpha-synuclein positive neurodegenerative disorders, Mutation-specific functional impairments in distinct tau isoforms of hereditary frontotemporal dementia and parkinsonism linked to chromosome-17: genotype predicts phenotype, Microtubule stabilizing therapies for neurodegenerative disorders, and Treatment of Alzheimer’s and related diseases with an antibody; and he receives research support from the NIH (AG 10124, AG 17586, AG-19724AG 024904, NS053488,AG029213 and the Marian S. Ware Alzheimer Program).

Dr. Van Deerlin reports no disclosures.

Dr. Quinn reports consulting fees from Merck and speaking fees from Novartis. Dr. Quinn is also reimbursed by Elan, Baxter, Bristol-Meyers Squibb, and Roche for the conduct of clinical trials. Dr. Quinn is also funded by grants from the NIH and Department of Veterans Affairs.

Dr. Chung reports no disclosures and is funded by a VA Merit Pilot grant.

Dr. Peterson reports no disclosures and is funded by a VA Career Development Award and by the Michael J. Fox Foundation and NIH.

Dr. Goldman serves on the advisory boards for Acadia and Pfizer, and has received honoraria from the Movement Disorders Society and the American Academy of Neurology. She receives grant support from the NIH, Michael J. Fox Foundation, Parkinson’s Disease Foundation, Rush University, and Teva (Moderato study, site-PI).

Dr. Stebbins serves as a consultant for Adamas Pharmaceuticals, Inc., Ceregene, Inc., CHDI Management, Inc., Ingenix Pharmaceutical Services (i3 Research), Neurocrine Biosciences, Inc. He receives honoraria from Movement Disorder Society, American Academy of Neurology, and Michael J. Fox Foundation for Parkinson’s Research. He serves on the editorial board for the Journal of Clinical and Experimental Neuropsychology. He receives grant support from the NIH, Michael J. Fox Foundation for Parkinson’s Research, and Dystonia Coalition, CHDI Management, Inc.

Dr. Bernard reports no disclosures.

Dr. Ritz reports no disclosures and is funded by grants from the NIH.

Dr. Rausch reports no disclosures and received support from NIH P50 NS038367.

Dr. Factor reports consulting fees from Ipsen Biopharmaceuticals and Merz. Grant support from Teva Neurosciences, Ipsen Biopharmaceuticals, EMD Serono, Ceregene, Michael J Fox Foundation, NIH/NHLBI (PO1 eS 016731-01 (PI Gary Miller, PhD), NIH 1 RO1 NS065070-01A1 (PI Cyrus Zabetian, MD, MSc), NINDS U01 NS052592-2CARE (PI Merit Cudkowica, MD), Royalties from UpToDate, Blackwell Futura, Demos.

Ms. Wood-Siverio reports no disclosures.

Dr. Espay is supported by the K23 career development award (NIMH, 1K23MH092735); has received grant support from CleveMed/Great Lakes Neurotechnologies, and Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Solvay (now Abbvie), Chelsea Therapeutics, TEVA, Impax, Merz, Pfizer, Solstice Neurosciences, Eli Lilly, and USWorldMeds; royalties from Lippincott Williams & Wilkins and Cambridge; and honoraria from Novartis, UCB, TEVA, the American Academy of Neurology, and the Movement Disorders Society. He serves as Associate Editor of Movement Disorders and Frontiers in Movement Disorders and on the editorial board of The European Neurological Journal.

Dr. Revilla is a consultant and speaker for Lundbeck Speaker’s Bureau and UCB Speaker’s Bureau.

Dr. Devoto is supported by the Michael J Fox Foundation.

Dr. Rosenthal reports no disclosures; she receives a lecture honorarium from the Edmund Safra Foundation.

Dr. Dawson acknowledges the Adrienne Helis Malvin and Diana Henry Helis Medical Research Foundations and their direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and The Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Programs. Funding for a portion of Dr. Dawson’s research was provided by Merck KGAA. Under a licensing agreement between Merck KGAA and The Johns Hopkins University, Dr. Dawson and the University shared fees received by the University on licensing some of the reagents used in his research. Dr. Dawson also was a paid consultant to Merck KGAA. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies. His work is also supported by NIH/NINDS P50NS038377, NIH/NINDS R01NS067525, NIH/NINDS U01NS082133, NIN/NIDA P50 DA00266, the JPB Foundation and the MDSCRF 2007-MSCRFI-0420-00, 2009-MSCRFII-0125-00, MDSCRF 2013-MSCRFII-0105-00. Dr. Dawson is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. Dr. Dawson is chair of the Scientific Advisory Board and a member of the Board of Directors of the Bachmann Strauss Dystonia and Parkinson’s Disease Foundation. Dr. Dawson is a member of Scientific Advisory Board of CurePSP. Dr. Dawson is a member of American Gene Technologies International Inc., advisory board. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Dr. Albert has served on scientific advisory boards for Eli Lilly, Eisai, Genentech, Biogen and Agenebio, and has received research support from GE Healthcare.

Dr. Mata reports no disclosures and is funded by grants from the Department of Veterans Affairs, NIH, and Parkinson’s Disease Foundation.

Dr. Hu reports no disclosures and is supported by the NIH.

Dr. K. Montine reports no disclosures.

Dr. Johnson reports no disclosures.

Dr. Edwards reports no disclosures and is funded by grants from the NIH.

Dr. T. Montine reports honoraria from invited scientific presentations to universities and professional societies not exceeding $5,000 per year and is funded by grants from the NIH.

Dr. Zhang reports no disclosures.

Dr. Zabetian reports no disclosures and is funded by grants from the American Parkinson Disease Association, Department of Veterans Affairs, NIH, Northwest Collaborative Care, and Parkinson’s Disease Foundation.

Footnotes

Documentation of Author Roles
  1. Research project: A. Conception: CPZ, SS, JBL, TJM B. Organization: CPZ, SS C. Execution – SS, CPZ, BC, JBL, ZKW, RJU, DWD, DW, JQT, VMV, JFQ, KAC, ALP, SAF, CWS, JGG, GTS, BB, BR, AJE, FJR, JD, LSR, TMD, MSA, IFM, S-CH, KSM, CJ, TJM, KLE, JZ
  2. Statistical Analysis: A. Design – KLE, CJ, BC, CPZ B. Execution – CJ, BC, KLE C. Review and Critique: SS, CPZ, BC, JBL, ZKW, RJU, DWD, DW, JQT, VMV, JFQ, KAC, ALP, SAF, CWS, JGG, GTS, BB, BR, AJE, FJR, JD, LSR, TMD, MSA, IFM, S-CH, KSM, CJ, TJM, KLE, JZ
  3. Manuscript Preparation: A. Writing of the first draft-SS, KSM, BC, CPZ B. Review and Critique- SS, BC, JBL, ZKW, RJU, DWD, DW, JQT, VMV, JFQ, KAC, ALP, SAF, CWS, JGG, GTS, BB, BR, AJE, FJR, JD, LSR, TMD, MSA, IFM, S-CH, KSM, CJ, TJM, KLE, JZ

Financial Disclosure/Conflict of Interest:

This research was supported by the National Institutes of Health (K23 NS060949, P50 NS062684, P50 NS053488, P50 NS038367, P50 NS038377, P50 NSO72187, R01 NS065070, R01 NS057567, and U01 NS082133), the Department of Veterans Affairs (1I01BX000531), the Parkinson’s Disease Foundation, the Nancy and Buster Alvord Endowment, the Jane and Lee Seidman Fund, the Consolidated Anti-Aging Foundation, and gifts from Carl Edward Bolch, Jr, and Susan Bass Bolch. The funding sources did not provide scientific input for the study.

References

  • 1.Aarsland D, Andersen K, Larsen JP, et al. The rate of cognitive decline in Parkinson disease. Arch Neurol. 2004;61(12):1906–1911. doi: 10.1001/archneur.61.12.1906. [DOI] [PubMed] [Google Scholar]
  • 2.Janvin CC, Larsen JP, Aarsland D, Hugdahl K. Subtypes of mild cognitive impairment in Parkinson’s disease: progression to dementia. Mov Disord. 2006;21(9):1343–1349. doi: 10.1002/mds.20974. [DOI] [PubMed] [Google Scholar]
  • 3.Alcalay RN, Caccappolo E, Mejia-Santana H, et al. Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology. 2012;78(18):1434–1440. doi: 10.1212/WNL.0b013e318253d54b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Chahine LM, Qiang J, Ashbridge E, et al. Clinical and biochemical differences in patients having Parkinson disease with vs without GBA mutations. JAMA neurology. 2013;70(7):852–858. doi: 10.1001/jamaneurol.2013.1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Mata I, Leverenz J, Weintraub D, et al. Variations in APOE, but not MAPT or SNCA, predicts cognitive performance in Parkinson’s disease. JAMA neurology. doi: 10.1001/jamaneurol.2014.1455. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Pankratz N, Byder L, Halter C, et al. Presence of an APOE4 allele results in significantly earlier onset of Parkinson’s disease and a higher risk with dementia. Movement disorders: official journal of the Movement Disorder Society. 2006;21(1):45–49. doi: 10.1002/mds.20663. [DOI] [PubMed] [Google Scholar]
  • 7.Tsuang D, Leverenz JB, Lopez OL, et al. APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA neurology. 2013;70(2):223–228. doi: 10.1001/jamaneurol.2013.600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Healy DG, Falchi M, O’Sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet neurology. 2008;7(7):583–590. doi: 10.1016/S1474-4422(08)70117-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Kay DM, Zabetian CP, Factor SA, et al. Parkinson’s disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics. Movement disorders: official journal of the Movement Disorder Society. 2006;21(4):519–523. doi: 10.1002/mds.20751. [DOI] [PubMed] [Google Scholar]
  • 10.Yahalom G, Orlev Y, Cohen OS, et al. Motor progression of Parkinson’s disease with the leucine-rich repeat kinase 2 G2019S mutation. Movement disorders: official journal of the Movement Disorder Society. 2014 doi: 10.1002/mds.25931. [DOI] [PubMed] [Google Scholar]
  • 11.Khan NL, Jain S, Lynch JM, et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain: a journal of neurology. 2005;128(Pt 12):2786–2796. doi: 10.1093/brain/awh667. [DOI] [PubMed] [Google Scholar]
  • 12.Aasly JO, Toft M, Fernandez-Mata I, et al. Clinical features of LRRK2-associated Parkinson’s disease in central Norway. Annals of neurology. 2005;57(5):762–765. doi: 10.1002/ana.20456. [DOI] [PubMed] [Google Scholar]
  • 13.Alcalay RN, Mejia-Santana H, Tang MX, et al. Self-report of cognitive impairment and mini-mental state examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson’s disease. Journal of clinical and experimental neuropsychology. 2010;32(7):775–779. doi: 10.1080/13803390903521018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Ben Sassi S, Nabli F, Hentati E, et al. Cognitive dysfunction in Tunisian LRRK2 associated Parkinson’s disease. Parkinsonism & related disorders. 2012;18(3):243–246. doi: 10.1016/j.parkreldis.2011.10.009. [DOI] [PubMed] [Google Scholar]
  • 15.Lesage S, Ibanez P, Lohmann E, et al. G2019S LRRK2 mutation in French and North African families with Parkinson’s disease. Annals of neurology. 2005;58(5):784–787. doi: 10.1002/ana.20636. [DOI] [PubMed] [Google Scholar]
  • 16.Belarbi S, Hecham N, Lesage S, et al. LRRK2 G2019S mutation in Parkinson’s disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort. Parkinsonism & related disorders. 2010;16(10):676–679. doi: 10.1016/j.parkreldis.2010.09.003. [DOI] [PubMed] [Google Scholar]
  • 17.Goldwurm S, Zini M, Di Fonzo A, et al. LRRK2 G2019S mutation and Parkinson’s disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism & related disorders. 2006;12(7):410–419. doi: 10.1016/j.parkreldis.2006.04.001. [DOI] [PubMed] [Google Scholar]
  • 18.Lohmann E, Leclere L, De Anna F, et al. A clinical, neuropsychological and olfactory evaluation of a large family with LRRK2 mutations. Parkinsonism & related disorders. 2009;15(4):273–276. doi: 10.1016/j.parkreldis.2008.06.008. [DOI] [PubMed] [Google Scholar]
  • 19.Shanker V, Groves M, Heiman G, et al. Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson’s disease. Movement disorders: official journal of the Movement Disorder Society. 2011;26(10):1875–1880. doi: 10.1002/mds.23746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Estanga A, Rodriguez-Oroz MC, Ruiz-Martinez J, et al. Cognitive dysfunction in Parkinson’s disease related to the R1441G mutation in LRRK2. Parkinsonism & related disorders. 2014 doi: 10.1016/j.parkreldis.2014.07.005. [DOI] [PubMed] [Google Scholar]
  • 21.Mata IF, Cosentino C, Marca V, et al. LRRK2 mutations in patients with Parkinson’s disease from Peru and Uruguay. Parkinsonism & related disorders. 2009;15(5):370–373. doi: 10.1016/j.parkreldis.2008.09.002. [DOI] [PubMed] [Google Scholar]
  • 22.Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. Journal of neurology, neurosurgery, and psychiatry. 1988;51(6):745–752. doi: 10.1136/jnnp.51.6.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Kang GA, Bronstein JM, Masterman DL, Redelings M, Crum JA, Ritz B. Clinical characteristics in early Parkinson’s disease in a central California population-based study. Movement disorders: official journal of the Movement Disorder Society. 2005;20(9):1133–1142. doi: 10.1002/mds.20513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Folstein MF, Folstein SE, McHugh PR. “Mini-mental state” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–198. doi: 10.1016/0022-3956(75)90026-6. [DOI] [PubMed] [Google Scholar]
  • 25.Benedict RHB, Schretlen D, Groninger L, Brandt J. The Hopkins Verbal Learning Test-Revised: Normative data and analysis of inter-form and inter-rater reliability. The Clinical Neuropsychologist. 1998;12:43–55. [Google Scholar]
  • 26.Wechsler D. WAiS-III® Administration and Scoring Manual. San Antonio, TX: The Psychological Corporation Harcourt Brace & Company; 1997. [Google Scholar]
  • 27.Army Individual Test Battery: Manual of directions and scoring. Washington, DC: War Department, Adjutant General’s Office; 1944. [Google Scholar]
  • 28.Tombaugh TN, Kozak J, Rees L. Normative data stratified by age and education for two measures of verbal fluency: FAS and animal naming. Archives of clinical neuropsychology: the official journal of the National Academy of Neuropsychologists. 1999;14(2):167–177. [PubMed] [Google Scholar]
  • 29.Benton AL, Sivan AB, Hamsher K, Varney N, Spreen O. Contributions to Neuropsychological Assessment-A Clinical Manual. Lutz, FL: Psychological Assessment Resources; 1994. [Google Scholar]
  • 30.Cholerton BA, Zabetian CP, Quinn JF, et al. Pacific Northwest Udall Center of excellence clinical consortium: study design and baseline cohort characteristics. Journal of Parkinson’s disease. 2013;3(2):205–214. doi: 10.3233/JPD-130189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Goldman JG, Holden S, Bernard B, Ouyang B, Goetz CG, Stebbins GT. Defining optimal cutoff scores for cognitive impairment using Movement Disorder Society Task Force criteria for mild cognitive impairment in Parkinson’s disease. Movement disorders: official journal of the Movement Disorder Society. 2013;28(14):1972–1979. doi: 10.1002/mds.25655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Trinh J, Amouri R, Duda JE, et al. Comparative study of Parkinson’s disease and leucine-rich repeat kinase 2 p. G2019S parkinsonism. Neurobiology of aging. 2014;35(5):1125–1131. doi: 10.1016/j.neurobiolaging.2013.11.015. [DOI] [PubMed] [Google Scholar]
  • 33.Poulopoulos M, Cortes E, Vonsattel JP, et al. Clinical and pathological characteristics of LRRK2 G2019S patients with PD. Journal of molecular neuroscience: MN. 2012;47(1):139–143. doi: 10.1007/s12031-011-9696-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Paisan-Ruiz C, Lewis PA, Singleton AB. LRRK2: cause, risk, and mechanism. Journal of Parkinson’s disease. 2013;3(2):85–103. doi: 10.3233/JPD-130192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kalia LV, Lang AE, Hazrati LN, et al. Clinical Correlations With Lewy Body Pathology in LRRK2-Related Parkinson Disease. JAMA neurology. 2014 doi: 10.1001/jamaneurol.2014.2704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Aarsland D, Perry R, Brown A, Larsen JP, Ballard C. Neuropathology of dementia in Parkinson’s disease: a prospective, community-based study. Annals of neurology. 2005;58(5):773–776. doi: 10.1002/ana.20635. [DOI] [PubMed] [Google Scholar]
  • 37.Irwin DJ, White MT, Toledo JB, et al. Neuropathologic substrates of Parkinson disease dementia. Annals of neurology. 2012;72(4):587–598. doi: 10.1002/ana.23659. [DOI] [PMC free article] [PubMed] [Google Scholar]

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