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Cognitive dysfunction in Tunisian LRRK2 associated Parkinson’s disease
Parkinsonism and Related Disorders 18 (2012) 243e246
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Cognitive dysfunction in Tunisian LRRK2 associated Parkinson’s disease Samia Ben Sassi a, *, Fatma Nabli a, Emna Hentati a, Houda Nahdi a, Meriam Trabelsi a, Hela Ben Ayed a, Rim Amouri a, John Eric Duda b, Matthew John Farrer c, Fayçal Hentati a a
Neurology Department, National Institute of Neurology, La Rabta-1007, Tunis, Tunisia Parkinson’s Disease Research, Education and Clinical Center, Philadelphia VA Medical Center, Philadelphia, USA c Department of Medical Genetics, University of British Columbia, Vancouver, Canada b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 July 2011 Received in revised form 16 September 2011 Accepted 12 October 2011
Background: Cognitive impairment and dementia are frequent and debilitating features associated with idiopathic Parkinson’s disease (PD). However the prevalence and the pattern of these complications are lacking for LRRK2 (leucine-rich kinase 2)-associated PD patients. Purpose: The purpose of this study was to assess cognitive function in LRRK2- associated PD patients. Material and methods: 55 patients diagnosed with PD-related LRRK2 G2019S mutation were included in the study and compared to the same number of G2019S non-carriers PD patients. Age, sex, disease duration, the movement disorder society-unified Parkinson’s Disease rating scale (MDS-UPDRS), Hoehn and Yahr stage, Schwab and England scale and the 30-item geriatric depression scale (GDS) scores were noted. Cognitive assessment included MMSE (Mini-Mental Examination), MOCA (Montreal Cognitive Assessment) and FAB (Frontal Assessment Battery). Results: MMSE, MOCA and FAB performance in G2019S carriers PD patients was similar to that of noncarriers. In both groups, performance was primarily impaired on visuospatial and executive tasks. Cognitive impairment was associated with older age, lower educational level and increased severity of motor impairment. Conclusion: Cognitive functions were similarly affected in PD patients with and without LRRK2 G2019S mutation with mainly impaired visuospatial and executive abilities. However, these results need to be confirmed by further large and prospective studies. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Parkinson’s disease PARK8 LRRK2 gene G2019S mutation Neuropsychological study
1. Introduction Although the etiology of Parkinson’s disease (PD) remains unclear, it’s generally considered to be a combination of complex genetic and environmental factors [1]. Mutations in the Leucinerich repeat kinase 2 gene (LRRK2) at the PARK8 locus on chromosome 12q12 showed to be a significant cause of late-onset autosomal dominant forms of PD. The LRRK2 6055G/A, which causes a glycine to serine amino acid substitution (Gly2019Ser), represents the most common pathogenic mutation identified in PD so far. Its frequency varies greatly according to geographical or ethnic origin with the highest values seen in North Africans and Ashkenazi Jews. The LRRK2 G2012S mutation accounts for up to 30% of simplex PD and 41% of familial PD in Tunisia versus a worldwide frequency of respectively 1% and 4% [2,3]. Various studies have been carried in order to investigate of whether LRRK2-related disease represents the classical PD or a different entity.
* Corresponding author. Tel.: þ216 21362050; fax: þ216 71963799. E-mail address: [email protected] (S. Ben Sassi). 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.10.009
Functional imaging and neuropathological findings in patients with LRRK2-associated PD were largely indistinguishable from idiopathic PD patients [4e6]. Clinically, the LRRK2-related PD is characterized by a core motor feature consistent with idiopathic PD: an asymmetrical, tremor-predominant parkinsonism with bradykinesia and rigidity that responds to dopamine replacement [6]. However, the non-motor symptoms and especially the cognitive profile are less well characterized. In order to assess cognitive function in LRRK2 eassociated PD, we performed a detailed neuropsychological evaluation in 55 PARK8 G2019S carriers and compared them with non-carriers PD patients. 2. Patients and methods 2.1. Subjects Data from the movement disorders’ outpatient clinic PD database at the National institute of neurology, Tunis, Tunisia was used in this study. This Database contains standardized data elements on PD patients consecutively ascertained in our movement disorders outpatient’ clinic, since September 2009, who underwent clinical evaluation and genetic testing for the LRRK2 G2019S mutation after informed consent. If the G2019S mutation was identified in
244
S. Ben Sassi et al. / Parkinsonism and Related Disorders 18 (2012) 243e246
a proband, field studies were conducted and information on the other family members with certain PD was also reported to the database. The diagnosis of PD was made by Neurologists using criteria consistent with the UK Parkinson’s Disease Society (UKPDS) Brain Bank criteria excepting the exclusion of family history of PD. In this study, 55 LRRK2 G2019S PD patients and 55 apparently sporadic G2019S non-carriers PD patients were randomly recruited from the database. Ethical approval for the research was obtained from the local ethics committees at the National Institute and Ministry of Health in Tunis. 2.2. Mutation analysis DNA was extracted from a peripheral venous blood sample by standard procedures and LRRK2 6055G/A was assayed on an ABI7900 analyzer (Applied Biosystems, Foster City, CA, USA). 2.3. Clinical assessment Clinical and demographic data were collected using standardized case-report forms which included the movement disorder society-unified Parkinson’s disease rating scale (MDS-UPDRS), the Hoehn and Yahr scale, the Schwab and England scale and the 30-item geriatric depression scale (GDS). The neuropsychological battery was performed in one session. It included the 30-item mini-mental state examination (MMSE) and the Montreal cognitive assessment (MoCA) which were used to assess global intellectual efficiency and the frontal assessment battery (FAB) to evaluate executive functions. The MMSE has been standardized and validated in Tunisia and adjusted for age and education. The MoCA was applied only to literate patients. A memory task dedicated to illiterate patients with free recall and identification of a series of 6 verbalized pictures was also used. 2.4. Statistical analysis The SPSS 15.00 software (SPSS Inc., Chicago, IL) was used. Comparisons between mutation carriers and non-carriers were computed using chisquare, t-test and Mann-Whitey U-test. A value of p < 0.05 was considered significant. Correlates of cognitive impairment variables were determined using Pearson’s correlation method.
frequency in the G2019S carriers and non-carriers. The only significant difference (p ¼ 0.04) was found in the geriatric depression scale with lower scores in the G2019S carriers. 3.2. Neuropsychological assessment Neuropsychological examination did not reveal major differences in general cognitive efficiency (MMSE, MoCA) between LRRK2 G2019S carriers and non-carriers [Table 2]. MMSE scores were low (cut-off score of 24) in 29% of G2019S carriers and in 32% of non-carriers with the worst performance obtained on pentagon copying. MoCA showed cognitive impairment (cut-off score of 26) in 65% of G2019S carriers and in 69% of non-carriers. The visuospatial and executive subscores were particularly low in both groups. Memory evaluation did not reveal a significant difference in working memory (digit spans) and episodic memory (the five word test and the 6-picture test) among the two groups. Executive function abnormalities were not significant between LRRK2 G2019S carriers and non-carriers. Frontal lobe deficits (as shown by FAB scores) were found in 54% of carriers and 66% of non-carriers with a deficit particularly affecting the lexical fluency in both groups [Table 2]. The MMSE and the FAB scores were correlated well with the patient age and educational level, the disease duration and the score of motor MDS-UPDRS, Hoehn and Yahr stage and Schwab and England functional capacity. However, we found no correlation between the MoCA score and education or PD severity [Table 3]. The total scores on the MMSE, the FAB and the six-picture test were highly correlated. In contrast, we found no-significant correlation between the MMSE and the MoCA.
3. Results 4. Discussion 3.1. General demographic and clinical assessment The comparison of some general demographic and clinical features between G2019S carriers and non-carriers is reported in Table 1. Most patients in the two groups had a low educational level. Mean onset age and disease duration in the G2019S carriers were respectively 54.4 years and 7.3 years, values that were similar to the mean onset age and disease duration of non-carriers. MDSUPDRS, Hoehn and Yahr stage and Schwab and England scores were similar in the two groups. Hallucinations occurred with the same Table 1 General demographic and clinical characteristics of Parkinson’s disease patients.
Sex ratio (M/F) Age, years Education (years) Age of PD onset, years Duration of disease, years Motor phenotype: M/T/AR MDS-UPDRS III Hoehn and Yahr Schwab and England L-DOPA dose Geriatric depression scale, >20 Hallucination score (MDS-UDPRS I)
G2019S carriers N ¼ 55
G2019S non-carriers N ¼ 55
34/21 61.9 11.8 3.8 5 54.4 10.3 7.3 4.7
30/25 64.6 8.6 3.1 5.4 55.3 8.6 8.1 8.8
40/7/8 42.4 22.9 2.3 0.9 67.8 23.8 558.1 321.7 16.8 5.9 32%
36/9/10 42.4 21.6 2.7 1.9 66.2 23.2 517.7 229.5 20.2 10.1 45%
0.2 0.5
0.3 0.6
P
0.04
M,mixed; T, tremor-dominant; AR, akineto-rigid; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale.
We investigated the frequency and profile of cognitive impairment in 55 LRRK2 G2019S mutation carriers PD patients in Table 2 Cognitive assessment of Parkinson’s disease patients with and without G2019S LRRK2 mutation.
MMSE score, £24 Orientation Registration Attention and calculation Recall language Copying two pentagons FAB score, < 13 Similarities Lexical fluency Motor series Conflicting instructions Go-No-Go 6-picture test free recall/identification MOCA, < 26 Visuospatial and executive Naming Attention Language Abstraction Delayed recall Orientation
G2019S carriers
G2019S non-carriers
N ¼ 55 25.5 3.2, 29% 8.7 1.7 2.9 0.2 4.5 1.2 2 0.9 6.3 1.1 0.2 0.4 10.6 4.5, 54% 1.8 1.2 1.0 1 1.9 1 1.5 1.3 1.3 1.1 N ¼ 35 4.8 0.9/5.4 0.9 N ¼ 20 21.8 4.3, 65% 2.9 1.6 2.6 0.7 4.0 1.6 1.7 1 1.7 0.6 2.2 1.4 5.9 0.4
N ¼ 55 25.16 2.85, 32% 8.4 1.5 3 4.6 1,1 1.7 1 6.3 0.9 0.2 0.4 9.4 3.9, 66% 1.5 1 1.4 1 1.8 1.2 1.2 1 1.2 1.3 N ¼ 38 4.1 1.4/5.2 1.3 N ¼ 17 21.8 3.7, 69% 3.2 1.4 2.9 0.3 4.4 1.2 1.5 0.8 1.3 0.8 2 1.8 5.9 0.3
MMSE, Mini-Mental State Exam; FAB, Frontal Assessment Battery; MOCA, Montreal cognitive assessment Global scores are highlighted in bold.
S. Ben Sassi et al. / Parkinsonism and Related Disorders 18 (2012) 243e246
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Table 3 Correlations between cognitive tests and general clinical characteristics (Spearman correlation coefficient (rs)) in LRRK2 Parkinson’s disease patients. MMSE Age Education Age of PD onset Disease duration MDS-UPDRS III Hoehn and Yahr Schwab and England GDS Hallucinations L-DOPA dose
0.3a 0.49 0.24b 0.34b 0.37 0.32a 0.41 0.18 0.16 0.10
(p (p (p (p (p (p (p (p (p (p
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
0.00) 0.00) 0.014) 0.012) 0.00) 0.00) 0.00) 0.07) 0.3) 0.28)
6-picture test free recall/I
FAB
0.32b/0.2 0.23/0.21 0.23/0.031b 0.325/0.59 1.45/3.4 0.34/0.34b 0.1/0.25b 0.21/0.14 0.13/0.24b 0.15/0.2
0.48 0.36 0.053 0.27b 0.37 0.31 0.36a 0.12 0.11 0.019
(p (p (p (p (p (p (p (p (p (p
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
0.07/0.08) 0.059/0.083) 0.05/0.8) 0.07/0.00) 0.2/0.05) 0.05/0.04) 0.38/0.036) 0.86/0.24) 0.26/0.04) 0.22/0.1)
MOCA (p (p (p (p (p (p (p (p (p (p
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
0.00) 0.00) 0.37) 0.048) 0.00) 0.01) 0.00) 0.22) 0.24) 0.84)
0.36b 0.24 0.41b 0.27 0.2 0.16 0.064 0.15 0.01 0.10
(p (p (p (p (p (p (p (p (p (p
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
0.033) 0.18) 0.019) 0.24) 0.24) 0.38) 0.74) 0.38) 0.9) 0.28)
MMSE, Mini-Mental State Exam; FAB, Frontal Assessment Battery; MoCA, Montreal Cognitive Assessment; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; GDS, Geriatric Depression Scale. a Correlations significant at the 0.01 level (2-tailed). b Correlations significant at the 0.05 level (2-tailed).
Table 4 Summary of LRRK2 Parkinson’s disease cognitive dysfunction studies.
Patients’ origin Number LRRK2 PD/IPD M/F Age Age at onset Disease duration MMSE < 24 FAB < 13 Cognitive I LRRK2/IPD
Lesage et al, 2005 [8]
Goldwurm et al, 2006 [9]
Belarbi et al, 2010 [10]
Healy et al, 2008 [3]
Our study
France/North Africa 21/168 9/12 65.0 12.3 55.3 13.0 9.7 6.6 28.5% e NS difference
Italy 24/e 11/13 53.79 12.42 57.88 5.78 11.37 5.65 29% 35% e
Algeria 23/48 11/12 66.9 6.5 56.13 6.2 10.39 2.9 56% 43% NS difference
Worldwide 162/340 e e 58.1 14.0 10.9 7.8 23% e LRRK2 < IPD
Tunisia 55/55 34/21 61.9 11.8 54.4 10.3 7.3 4.7 29% 54% NS difference
M, male; F, female; MMSE, Mini-Mental State Exam; FAB, Frontal Battery Assessment, I: impairment; NS, no-significant; IPD, idiopathic Parkinson’s disease patients.
comparison with the same number of non-carriers. The first reports based on small series of LRRK2 patients [6,7] suggested a lower prevalence of cognitive impairment in LRRK2-related PD than in idiopathic PD. The results of further large clinical studies, resumed in Table 4, were discordant. In our study, we used brief neuropsychological tests (MMSE, MOCA and FAB) which are reliable screening cognitive tools in PD but may lack sensitivity for the diagnosis of early or minor cognitive changes. Cognitive functions were similarly affected in our patients with and without LRRK2 G2019S mutation as in previous reports [9,10]. Better MMSE scores were however reported in the International LRRK2 consortium G2019S carriers with PD. when compared to non-carriers, although this difference could be explained by a shorter disease duration in the former. We found low MMSE values in 29% of our LRRK2 PD patients in accordance with a previous Italian study [9]. 65% of the tested LRRK2 patients (20 out of 55) had cognitive impairment according to their MoCA score. Despite the limited number of patients who underwent the MOCA, these results could suggest a better sensitivity of this test in comparison with the MMSE as already highlighted by Weintraub et al. [11]. FAB scores were low in up to 54% of LRRK2 patients. As the FAB proved to be influenced by education, according to Beato et al. [12], frontal dysfunction was probably overestimated in our population which has a high illiteracy level. The cognitive deficit in our LRRK2 patients particularly affected the verbal fluency and the visuospatial skills. This result should also be considered in light of a probable biais due to our patients’ low educational level. We should also take into account a possible practice effect related to an overlap between the different tests. In contrast to MMSE and FAB, the MoCA was not correlated with education, duration of disease or severity of motor symptoms. This
finding was unexpected and could be explained by the small number of tested patients and by a probable ceiling effect for education, the MoCA being done only in well-educated patients. GDS showed severe depression in 32% of the G2019S mutation carrier patients but overall, they had lower mean scores than the non-carrier patients, in contrast with previous reports [9,10]. This finding does not support the hypothesis of a greater involvement of the limbic system in LRRK2 PD. Despite the fact that our study as well as the previous neuropsychological reports [3,8,9,10] on LRRK2 PD involved in most cases patients with the same G2019S mutation, results were discordant. This discordance could be attributed to methodological biais and to different ethnic backgrounds with potential environmental and genetic modifying factors. In conclusion, cognitive profile seems to be similar in LRRK2related PD and idiopathic PD. However, these results need to be confirmed by prospective studies in different populations. Further comparative neuropsychological studies between manifesting and non-manifesting LRRK2 mutation carriers and between LRRK2 PD and other genetic forms of PD are also warranted and would assess the significance of cognitive impairment as a potential endophenotype in Parkinson’s disease. Acknowledgments This study was supported by a grant from the Michael J. Fox Foundation. References [1] Eriksen JL, Wszolek Z, Petrucelli L. Molecular pathogenesis of Parkinson’s disease. Arch Neurol 2005;62:353e7. [2] Hulihan MM, Ishihara PL, Kachergus J, Warren L, Amouri R, Elango R, et al. LRRK2 Gly2019Ser penetrance in ArabeBerber patients from Tunisia: a casecontrol genetic study. Lancet Neurol 2008;7:591e4.
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[3] Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, et al. International LRRK2 Consortium. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7:583e90. [4] Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, et al. Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388e93. [5] Paisan-Ruiz C, Saenz A, Lopez de Munain A, Marti I, Martinez Gil A, MartiMasso JF, et al. Familial Parkinson’s disease: clinical and genetic analysis of four Basque families. Ann Neurol 2005;57:365e72. [6] Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, 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 2005;128:2786e96. [7] Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, Van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 2004;44:595e600.
[8] Lesage S, Ibanez P, Lohmann E, Pollak P, Tison F, Tazir M, et al. G2019S LRRK2 mutation in French and North African families with Parkinson’s disease. Ann Neurol 2005;58:784e7. [9] Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons EJ, et al. LRRK2 G2019S mutation and Parkinson’s disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord 2006;12:410e9. [10] Belarbi S, Hecham N, Lesage S, Kediha MI, Smail N, Benhassine T, et al. LRRK2 G2019S mutation in Parkinson’s disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort. Parkinsonism Relat Disord 2010;15:1e4. [11] Nazem S, Siderowf AD, Duda JE, Have TT, Colcher A, HorN SS, et al. Montreal cognitive assessment performance in patients with Parkinson’s disease with "Normal" global Cognition according to mini-mental State examination score. J Am Geriatr Soc 2009;57:304e8. [12] Beato RG, Nitrini R, Formigoni AP, Caramelli P. Brazilian version of the frontal assessment Battery (FAB): preliminary data on administration to healthy elderly. Dement Neuropsychol 2007;1:59e65.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Cognitive dysfunction in Tunisian LRRK2 associated Parkinson’s disease Samia Ben Sassi a, *, Fatma Nabli a, Emna Hentati a, Houda Nahdi a, Meriam Trabelsi a, Hela Ben Ayed a, Rim Amouri a, John Eric Duda b, Matthew John Farrer c, Fayçal Hentati a a
Neurology Department, National Institute of Neurology, La Rabta-1007, Tunis, Tunisia Parkinson’s Disease Research, Education and Clinical Center, Philadelphia VA Medical Center, Philadelphia, USA c Department of Medical Genetics, University of British Columbia, Vancouver, Canada b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 July 2011 Received in revised form 16 September 2011 Accepted 12 October 2011
Background: Cognitive impairment and dementia are frequent and debilitating features associated with idiopathic Parkinson’s disease (PD). However the prevalence and the pattern of these complications are lacking for LRRK2 (leucine-rich kinase 2)-associated PD patients. Purpose: The purpose of this study was to assess cognitive function in LRRK2- associated PD patients. Material and methods: 55 patients diagnosed with PD-related LRRK2 G2019S mutation were included in the study and compared to the same number of G2019S non-carriers PD patients. Age, sex, disease duration, the movement disorder society-unified Parkinson’s Disease rating scale (MDS-UPDRS), Hoehn and Yahr stage, Schwab and England scale and the 30-item geriatric depression scale (GDS) scores were noted. Cognitive assessment included MMSE (Mini-Mental Examination), MOCA (Montreal Cognitive Assessment) and FAB (Frontal Assessment Battery). Results: MMSE, MOCA and FAB performance in G2019S carriers PD patients was similar to that of noncarriers. In both groups, performance was primarily impaired on visuospatial and executive tasks. Cognitive impairment was associated with older age, lower educational level and increased severity of motor impairment. Conclusion: Cognitive functions were similarly affected in PD patients with and without LRRK2 G2019S mutation with mainly impaired visuospatial and executive abilities. However, these results need to be confirmed by further large and prospective studies. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Parkinson’s disease PARK8 LRRK2 gene G2019S mutation Neuropsychological study
1. Introduction Although the etiology of Parkinson’s disease (PD) remains unclear, it’s generally considered to be a combination of complex genetic and environmental factors [1]. Mutations in the Leucinerich repeat kinase 2 gene (LRRK2) at the PARK8 locus on chromosome 12q12 showed to be a significant cause of late-onset autosomal dominant forms of PD. The LRRK2 6055G/A, which causes a glycine to serine amino acid substitution (Gly2019Ser), represents the most common pathogenic mutation identified in PD so far. Its frequency varies greatly according to geographical or ethnic origin with the highest values seen in North Africans and Ashkenazi Jews. The LRRK2 G2012S mutation accounts for up to 30% of simplex PD and 41% of familial PD in Tunisia versus a worldwide frequency of respectively 1% and 4% [2,3]. Various studies have been carried in order to investigate of whether LRRK2-related disease represents the classical PD or a different entity.
* Corresponding author. Tel.: þ216 21362050; fax: þ216 71963799. E-mail address: [email protected] (S. Ben Sassi). 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.10.009
Functional imaging and neuropathological findings in patients with LRRK2-associated PD were largely indistinguishable from idiopathic PD patients [4e6]. Clinically, the LRRK2-related PD is characterized by a core motor feature consistent with idiopathic PD: an asymmetrical, tremor-predominant parkinsonism with bradykinesia and rigidity that responds to dopamine replacement [6]. However, the non-motor symptoms and especially the cognitive profile are less well characterized. In order to assess cognitive function in LRRK2 eassociated PD, we performed a detailed neuropsychological evaluation in 55 PARK8 G2019S carriers and compared them with non-carriers PD patients. 2. Patients and methods 2.1. Subjects Data from the movement disorders’ outpatient clinic PD database at the National institute of neurology, Tunis, Tunisia was used in this study. This Database contains standardized data elements on PD patients consecutively ascertained in our movement disorders outpatient’ clinic, since September 2009, who underwent clinical evaluation and genetic testing for the LRRK2 G2019S mutation after informed consent. If the G2019S mutation was identified in
244
S. Ben Sassi et al. / Parkinsonism and Related Disorders 18 (2012) 243e246
a proband, field studies were conducted and information on the other family members with certain PD was also reported to the database. The diagnosis of PD was made by Neurologists using criteria consistent with the UK Parkinson’s Disease Society (UKPDS) Brain Bank criteria excepting the exclusion of family history of PD. In this study, 55 LRRK2 G2019S PD patients and 55 apparently sporadic G2019S non-carriers PD patients were randomly recruited from the database. Ethical approval for the research was obtained from the local ethics committees at the National Institute and Ministry of Health in Tunis. 2.2. Mutation analysis DNA was extracted from a peripheral venous blood sample by standard procedures and LRRK2 6055G/A was assayed on an ABI7900 analyzer (Applied Biosystems, Foster City, CA, USA). 2.3. Clinical assessment Clinical and demographic data were collected using standardized case-report forms which included the movement disorder society-unified Parkinson’s disease rating scale (MDS-UPDRS), the Hoehn and Yahr scale, the Schwab and England scale and the 30-item geriatric depression scale (GDS). The neuropsychological battery was performed in one session. It included the 30-item mini-mental state examination (MMSE) and the Montreal cognitive assessment (MoCA) which were used to assess global intellectual efficiency and the frontal assessment battery (FAB) to evaluate executive functions. The MMSE has been standardized and validated in Tunisia and adjusted for age and education. The MoCA was applied only to literate patients. A memory task dedicated to illiterate patients with free recall and identification of a series of 6 verbalized pictures was also used. 2.4. Statistical analysis The SPSS 15.00 software (SPSS Inc., Chicago, IL) was used. Comparisons between mutation carriers and non-carriers were computed using chisquare, t-test and Mann-Whitey U-test. A value of p < 0.05 was considered significant. Correlates of cognitive impairment variables were determined using Pearson’s correlation method.
frequency in the G2019S carriers and non-carriers. The only significant difference (p ¼ 0.04) was found in the geriatric depression scale with lower scores in the G2019S carriers. 3.2. Neuropsychological assessment Neuropsychological examination did not reveal major differences in general cognitive efficiency (MMSE, MoCA) between LRRK2 G2019S carriers and non-carriers [Table 2]. MMSE scores were low (cut-off score of 24) in 29% of G2019S carriers and in 32% of non-carriers with the worst performance obtained on pentagon copying. MoCA showed cognitive impairment (cut-off score of 26) in 65% of G2019S carriers and in 69% of non-carriers. The visuospatial and executive subscores were particularly low in both groups. Memory evaluation did not reveal a significant difference in working memory (digit spans) and episodic memory (the five word test and the 6-picture test) among the two groups. Executive function abnormalities were not significant between LRRK2 G2019S carriers and non-carriers. Frontal lobe deficits (as shown by FAB scores) were found in 54% of carriers and 66% of non-carriers with a deficit particularly affecting the lexical fluency in both groups [Table 2]. The MMSE and the FAB scores were correlated well with the patient age and educational level, the disease duration and the score of motor MDS-UPDRS, Hoehn and Yahr stage and Schwab and England functional capacity. However, we found no correlation between the MoCA score and education or PD severity [Table 3]. The total scores on the MMSE, the FAB and the six-picture test were highly correlated. In contrast, we found no-significant correlation between the MMSE and the MoCA.
3. Results 4. Discussion 3.1. General demographic and clinical assessment The comparison of some general demographic and clinical features between G2019S carriers and non-carriers is reported in Table 1. Most patients in the two groups had a low educational level. Mean onset age and disease duration in the G2019S carriers were respectively 54.4 years and 7.3 years, values that were similar to the mean onset age and disease duration of non-carriers. MDSUPDRS, Hoehn and Yahr stage and Schwab and England scores were similar in the two groups. Hallucinations occurred with the same Table 1 General demographic and clinical characteristics of Parkinson’s disease patients.
Sex ratio (M/F) Age, years Education (years) Age of PD onset, years Duration of disease, years Motor phenotype: M/T/AR MDS-UPDRS III Hoehn and Yahr Schwab and England L-DOPA dose Geriatric depression scale, >20 Hallucination score (MDS-UDPRS I)
G2019S carriers N ¼ 55
G2019S non-carriers N ¼ 55
34/21 61.9 11.8 3.8 5 54.4 10.3 7.3 4.7
30/25 64.6 8.6 3.1 5.4 55.3 8.6 8.1 8.8
40/7/8 42.4 22.9 2.3 0.9 67.8 23.8 558.1 321.7 16.8 5.9 32%
36/9/10 42.4 21.6 2.7 1.9 66.2 23.2 517.7 229.5 20.2 10.1 45%
0.2 0.5
0.3 0.6
P
0.04
M,mixed; T, tremor-dominant; AR, akineto-rigid; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale.
We investigated the frequency and profile of cognitive impairment in 55 LRRK2 G2019S mutation carriers PD patients in Table 2 Cognitive assessment of Parkinson’s disease patients with and without G2019S LRRK2 mutation.
MMSE score, £24 Orientation Registration Attention and calculation Recall language Copying two pentagons FAB score, < 13 Similarities Lexical fluency Motor series Conflicting instructions Go-No-Go 6-picture test free recall/identification MOCA, < 26 Visuospatial and executive Naming Attention Language Abstraction Delayed recall Orientation
G2019S carriers
G2019S non-carriers
N ¼ 55 25.5 3.2, 29% 8.7 1.7 2.9 0.2 4.5 1.2 2 0.9 6.3 1.1 0.2 0.4 10.6 4.5, 54% 1.8 1.2 1.0 1 1.9 1 1.5 1.3 1.3 1.1 N ¼ 35 4.8 0.9/5.4 0.9 N ¼ 20 21.8 4.3, 65% 2.9 1.6 2.6 0.7 4.0 1.6 1.7 1 1.7 0.6 2.2 1.4 5.9 0.4
N ¼ 55 25.16 2.85, 32% 8.4 1.5 3 4.6 1,1 1.7 1 6.3 0.9 0.2 0.4 9.4 3.9, 66% 1.5 1 1.4 1 1.8 1.2 1.2 1 1.2 1.3 N ¼ 38 4.1 1.4/5.2 1.3 N ¼ 17 21.8 3.7, 69% 3.2 1.4 2.9 0.3 4.4 1.2 1.5 0.8 1.3 0.8 2 1.8 5.9 0.3
MMSE, Mini-Mental State Exam; FAB, Frontal Assessment Battery; MOCA, Montreal cognitive assessment Global scores are highlighted in bold.
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Table 3 Correlations between cognitive tests and general clinical characteristics (Spearman correlation coefficient (rs)) in LRRK2 Parkinson’s disease patients. MMSE Age Education Age of PD onset Disease duration MDS-UPDRS III Hoehn and Yahr Schwab and England GDS Hallucinations L-DOPA dose
0.3a 0.49 0.24b 0.34b 0.37 0.32a 0.41 0.18 0.16 0.10
(p (p (p (p (p (p (p (p (p (p
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
0.00) 0.00) 0.014) 0.012) 0.00) 0.00) 0.00) 0.07) 0.3) 0.28)
6-picture test free recall/I
FAB
0.32b/0.2 0.23/0.21 0.23/0.031b 0.325/0.59 1.45/3.4 0.34/0.34b 0.1/0.25b 0.21/0.14 0.13/0.24b 0.15/0.2
0.48 0.36 0.053 0.27b 0.37 0.31 0.36a 0.12 0.11 0.019
(p (p (p (p (p (p (p (p (p (p
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
0.07/0.08) 0.059/0.083) 0.05/0.8) 0.07/0.00) 0.2/0.05) 0.05/0.04) 0.38/0.036) 0.86/0.24) 0.26/0.04) 0.22/0.1)
MOCA (p (p (p (p (p (p (p (p (p (p
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
0.00) 0.00) 0.37) 0.048) 0.00) 0.01) 0.00) 0.22) 0.24) 0.84)
0.36b 0.24 0.41b 0.27 0.2 0.16 0.064 0.15 0.01 0.10
(p (p (p (p (p (p (p (p (p (p
¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼
0.033) 0.18) 0.019) 0.24) 0.24) 0.38) 0.74) 0.38) 0.9) 0.28)
MMSE, Mini-Mental State Exam; FAB, Frontal Assessment Battery; MoCA, Montreal Cognitive Assessment; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; GDS, Geriatric Depression Scale. a Correlations significant at the 0.01 level (2-tailed). b Correlations significant at the 0.05 level (2-tailed).
Table 4 Summary of LRRK2 Parkinson’s disease cognitive dysfunction studies.
Patients’ origin Number LRRK2 PD/IPD M/F Age Age at onset Disease duration MMSE < 24 FAB < 13 Cognitive I LRRK2/IPD
Lesage et al, 2005 [8]
Goldwurm et al, 2006 [9]
Belarbi et al, 2010 [10]
Healy et al, 2008 [3]
Our study
France/North Africa 21/168 9/12 65.0 12.3 55.3 13.0 9.7 6.6 28.5% e NS difference
Italy 24/e 11/13 53.79 12.42 57.88 5.78 11.37 5.65 29% 35% e
Algeria 23/48 11/12 66.9 6.5 56.13 6.2 10.39 2.9 56% 43% NS difference
Worldwide 162/340 e e 58.1 14.0 10.9 7.8 23% e LRRK2 < IPD
Tunisia 55/55 34/21 61.9 11.8 54.4 10.3 7.3 4.7 29% 54% NS difference
M, male; F, female; MMSE, Mini-Mental State Exam; FAB, Frontal Battery Assessment, I: impairment; NS, no-significant; IPD, idiopathic Parkinson’s disease patients.
comparison with the same number of non-carriers. The first reports based on small series of LRRK2 patients [6,7] suggested a lower prevalence of cognitive impairment in LRRK2-related PD than in idiopathic PD. The results of further large clinical studies, resumed in Table 4, were discordant. In our study, we used brief neuropsychological tests (MMSE, MOCA and FAB) which are reliable screening cognitive tools in PD but may lack sensitivity for the diagnosis of early or minor cognitive changes. Cognitive functions were similarly affected in our patients with and without LRRK2 G2019S mutation as in previous reports [9,10]. Better MMSE scores were however reported in the International LRRK2 consortium G2019S carriers with PD. when compared to non-carriers, although this difference could be explained by a shorter disease duration in the former. We found low MMSE values in 29% of our LRRK2 PD patients in accordance with a previous Italian study [9]. 65% of the tested LRRK2 patients (20 out of 55) had cognitive impairment according to their MoCA score. Despite the limited number of patients who underwent the MOCA, these results could suggest a better sensitivity of this test in comparison with the MMSE as already highlighted by Weintraub et al. [11]. FAB scores were low in up to 54% of LRRK2 patients. As the FAB proved to be influenced by education, according to Beato et al. [12], frontal dysfunction was probably overestimated in our population which has a high illiteracy level. The cognitive deficit in our LRRK2 patients particularly affected the verbal fluency and the visuospatial skills. This result should also be considered in light of a probable biais due to our patients’ low educational level. We should also take into account a possible practice effect related to an overlap between the different tests. In contrast to MMSE and FAB, the MoCA was not correlated with education, duration of disease or severity of motor symptoms. This
finding was unexpected and could be explained by the small number of tested patients and by a probable ceiling effect for education, the MoCA being done only in well-educated patients. GDS showed severe depression in 32% of the G2019S mutation carrier patients but overall, they had lower mean scores than the non-carrier patients, in contrast with previous reports [9,10]. This finding does not support the hypothesis of a greater involvement of the limbic system in LRRK2 PD. Despite the fact that our study as well as the previous neuropsychological reports [3,8,9,10] on LRRK2 PD involved in most cases patients with the same G2019S mutation, results were discordant. This discordance could be attributed to methodological biais and to different ethnic backgrounds with potential environmental and genetic modifying factors. In conclusion, cognitive profile seems to be similar in LRRK2related PD and idiopathic PD. However, these results need to be confirmed by prospective studies in different populations. Further comparative neuropsychological studies between manifesting and non-manifesting LRRK2 mutation carriers and between LRRK2 PD and other genetic forms of PD are also warranted and would assess the significance of cognitive impairment as a potential endophenotype in Parkinson’s disease. Acknowledgments This study was supported by a grant from the Michael J. Fox Foundation. References [1] Eriksen JL, Wszolek Z, Petrucelli L. Molecular pathogenesis of Parkinson’s disease. Arch Neurol 2005;62:353e7. [2] Hulihan MM, Ishihara PL, Kachergus J, Warren L, Amouri R, Elango R, et al. LRRK2 Gly2019Ser penetrance in ArabeBerber patients from Tunisia: a casecontrol genetic study. Lancet Neurol 2008;7:591e4.
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[8] Lesage S, Ibanez P, Lohmann E, Pollak P, Tison F, Tazir M, et al. G2019S LRRK2 mutation in French and North African families with Parkinson’s disease. Ann Neurol 2005;58:784e7. [9] Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons EJ, et al. LRRK2 G2019S mutation and Parkinson’s disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord 2006;12:410e9. [10] Belarbi S, Hecham N, Lesage S, Kediha MI, Smail N, Benhassine T, et al. LRRK2 G2019S mutation in Parkinson’s disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort. Parkinsonism Relat Disord 2010;15:1e4. [11] Nazem S, Siderowf AD, Duda JE, Have TT, Colcher A, HorN SS, et al. Montreal cognitive assessment performance in patients with Parkinson’s disease with "Normal" global Cognition according to mini-mental State examination score. J Am Geriatr Soc 2009;57:304e8. [12] Beato RG, Nitrini R, Formigoni AP, Caramelli P. Brazilian version of the frontal assessment Battery (FAB): preliminary data on administration to healthy elderly. Dement Neuropsychol 2007;1:59e65.