AUTHOR COPY. Non-Motor Symptoms Profile and Burden in Drug Naïve Versus Long-Term Parkinson s Disease Patients. Research Report

Transcription

1 Journal of Parkinson s Disease 4 (2014) DOI /JPD IOS Press Research Report 541 Non-Motor Symptoms Profile and Burden in Drug Naïve Versus Long-Term Parkinson s Disease Patients Panagiotis Zis a, Alexandra Rizos a, Pablo Martinez Martin b, Suvankar Pal c,g,h, Monty Silverdale d, Jagdish C. Sharma e, Anna Sauerbier a and Kallol Ray Chaudhuri a,f, a National Parkinson Foundation International Centre of Excellence, King s College Hospital NHS Foundation Trust, London, UK b National Center of Epidemiology and CIBERNED, Carlos III Institute of Health, Madrid, Spain c Department of Neurology, Forth Valley Royal Hospital, NHS Forth Valley d Salford Royal NHS Foundation Trust, Manchester, UK e United Lincolnshire Hospitals NHS Trust, Lincoln, UK f King s College London, UK g Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, UK h Division of Clinical Neurosciences, Western General Hospital, Edinburgh Abstract. Background: Recent studies have demonstrated that, contrary to common perception non-motor symptoms (NMS) occur and may dominate early and untreated stage of Parkinson s disease (PD). Objective: The aim of this ongoing study was to describe the overall NMS profile and burden in drug naïve PD patients (DNPD) compared to a group of long-term PD patients (LTPD, disease duration 15 years). Methods: Cross sectional UK data from a multicenter (16 sites) collaboration were obtained and specifically NMS dataset from validated scales were analysed in DNPD and LTPD patients. The NMS scale (NMSS) was used as the primary outcome variable. Results: Out of a current database of 468 PD patients, 57 were DNPD (58% males, mean age 64.8 years, median Hoehn and Yahr stage 1) and 25 were LTPD (44%, mean age 67.6 years, median Hoehn and Yahr stage 3). DNPD patients had a significantly lower (p = 0.001) NMSS score (mean 45.5, range 1 150) compared to the LTPD patients (mean 74.0, range 6 155), but 26.3% had severe and 19.3% had very severe burden of NMSS using NMSS cutoff scores. In comparison, 20.0% of the LTPD patients had severe and 60.0% very severe burden of NMS (p = 0.003). Conclusions: NMS are common in DNPD patients and over 45% may have severe to very severe burden of NMS, which is a key determinant of quality of life. In LTPD patients not only the burden of very severe NMS is significantly higher, but there are also differences in the profile of expression of NMS. Keywords: Parkinson s disease, non-motor symptoms, NMS scale, drug naïve INTRODUCTION Correspondence to: K. Ray Chaudhuri, NPF International Parkinson s Centre of Excellence, Neurology, 9th Floor Ruskin Wing, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK. Tel.: ; Fax: ; ray.chaudhuri@nhs.net. Non-motor symptoms (NMS) are a key component of Parkinson s disease (PD) [1] and are a key determinant of quality of life (QoL) and phenotypic expression [1, 2]. Moreover, there is growing evidence, that the overall burden of NMS may have a greater impact on QoL than motor symptoms [2]. ISSN /14/$ IOS Press and the authors. All rights reserved

2 542 P. Zis et al. / NMS in Drug Naïve vs Long-Term PD Patients Little is known about the progression and the natural history regarding the large range of NMS that complicate the journey of a patient with PD. The NMS are recognized to be present from the pre-motor stage [3] to the final palliative stage of PD [4]. Interestingly, while motor progression in PD appears to follow a largely linear pattern, NMS are more complicated and while few remain static, other may improve and some may worsen [5]. However, the fact that NMS may arise as part of drug related effects and side effects confounds this issue further. Recently, the importance of measuring NMS using validated tools, such as the NMS Questionnaire (NMSQuest) [6] and the NMS Scale (NMSS) [7] has been described in two independent case control studies in drug naïve PD [8] and early PD [9] patients. In this paper, we describe a cross-sectional multicenter study comparing the overall non-motor profile and burden of drug naïve PD patients (DNPD) and long-term PD patients (LTPD), arbitrarily defined as PD patients with disease duration of 15 years or more. METHODS Study group and data collection Data of consecutive patients collected from 16 different PD specialist centers in the United Kingdom (UK) taking part in an ongoing non-motor naturalistic longitudinal study (NILS, UK clinical research network number 10084) were used in this study. All patients who were included had a confirmed diagnosis of PD as per the UK brain bank criteria [10] and had provided a written informed consent to take part in NILS. Untreated PD patients were assigned as DNPD, while we considered patients who had a confirmed diagnosis of PD for equal to or more than 15 years as LTPD patients. Collected data included demographic characteristics, motor stage of PD according to the Hoehn and Yahr (HY) scale [11], the SCOPA motor scale examination section [12], the hospital anxiety and depression scale (HADS) [13], the mini mental state examination (MMSE) [14] and the Non-Motor Symptom Scale (NMSS) [7]. The SCOPA motor scale examination scale is contains 21 items in three sections; examination, activities of daily living and complications. The first section, the SCOPA motor scale examination section, comprises eight items assessed through neurological examination, plus two items (freezing during on and swallowing) scored through historical information. Scores for each item of the S-MS range from 0 (normal) to 3 (severe). Items for evaluation of rest tremor, postural tremor, rapid alternating movements of hands, and rigidity are scored in each arm separately. Hence, possible scores range from 0 to 42 for the examination section [12]. The HADS is a 14-item scale that generates ordinal data. Seven of the items relate to anxiety and seven relate to depression. Score for each item range from 0 to 3. Hence, possible scores range from 0 to 21 for the anxiety, as well as the depression domain. [13]. The NMSS is a 30-item clinician rated scale designed to assess the NMS in PD. The 30 items are grouped into nine domains: cardiovascular (2 items), sleep/fatigue (4 items), mood/cognition (6 items), perceptual problems (3 items), attention/memory (3 items), gastrointestinal (3 items), urinary (3 items), sexual function (2 items) and miscellaneous (4 items: pain, change in ability to taste or smell, change in weight, excessive sweating). Score for each item is based on a multiple of severity (from 0 to 3) and frequency scores (from 0 to 4). Therefore, the NMSS has the ability to capture symptoms that are severe but relatively infrequent and those that may be less severe but persistent. Each item s score ranges from 0 to 12 and the total NMSS score ranges from 0 to 360. Based on the total NMSS score, there are 5 stratified levels of burden: no NMS (0), mild (1 20), moderate (21 40), severe (41 70) and very severe ( 71) [15]. Approval was gained from the local Research Ethics Committee at each center. Statistical analyses A database was developed using the Statistical Package for Social Science (version 16.0 for Mac; SPSS). Frequencies and descriptive statistics were examined for each variable. Comparisons between DNPD patients and LTPD patients were made using Student s t-tests for normally distributed continuous data, Mann-Whitney s U test for nonnormally distributed and chi-square test for categorical data. Where statistically significant differences between DNPD and LTPD patients NMSS scores were found, multivariate linear regression analysis was applied to adjust for age, gender, depression and cognition. A value of p < 0.05 was considered to be statistically significant.

3 P. Zis et al. / NMS in Drug Naïve vs Long-Term PD Patients 543 RESULTS Table 1 Characteristics of drug naïve and long term PD patients Between March 2011 and April 2014, 476 patients have participated to the NILS. Full dataset was available in 57 DNPD patients (57.9% males, mean age 64.8 years) and 25 LTPD patients (44.0% males, mean age 67.6 years). Table 1 summarizes the demographic and clinical characteristics of the two subgroups. Regarding the motor stage of PD, LTPD patients had a more advanced stage (median 3, interquartile range 3-4) compared to the DNPD patients (median 1, interquartile range 1-2). Regarding the non-motor characteristics, DNPD patients had a significantly lower (p = 0.001) NMSS score (mean 45.5, range 1 150) compared to the LTPD patients (mean 74.0, range 6 156). However, among the DNPD patients, using NMS cutoff scores, 28.1% had mild, 26.3% moderate, 26.3% severe and 19.3% very severe burden of NMS while among the LTPD patients, using NMS cutoff scores, 12.0% had mild, 8.0% moderate, 20.0% severe and 60.0% very severe burden of NMS (p = 0.003). Interestingly, the MMSE score, the HADS anxiety score and the HADS depression score did not differ significantly between the two groups. Figure 1 summarizes the means for each of the 30 items of the NMSS for both groups. The five most outstanding problems for the DNPD group were fatigue, feeling sad, change in sense of smell or taste, pain and urinary urgency when for the LTPD group the five most outstanding problems were fatigue, change in sense of smell or taste sleep difficulties, daytime sleepiness and nocturia. Compared to the LTPD patients, the DNPD patients showed significantly lower sub-scores in the following domains: sleep/fatigue, perceptual problems, memory, gastrointestinal and miscellaneous, which includes hyperhidrosis, unexplained weight change and hyposmia. After adjusting for age, sex, SCOPA motor examination score, HADS depression score and MMSE score in the multiple linear regression analysis, being drug naïve is negatively associated with NMSS total score ( = 0.264, p = 0.002), with NMSS sleep/fatigue score ( = 0.255, p = 0.011), with NMSS perceptual problems score ( = 0.353, p = 0.002), with NMSS gastrointestinal score, ( = 0.223, p = 0.026) and with NMSS miscellaneous score ( = 0.308, p = 0.006). Also, after adjusting for age, sex, SCOPA motor examination score and HADS depression score in the multiple linear regression analysis, being drug naïve is negatively associated with NMSS memory score ( = 0.260, p = 0.012). Table 2 summarizes the results of the multivariate analysis. Long term PD (n = 25) Drug naïvepd(n = 57) p Demographic Characteristics Age, in years (SD) 67.6 (9.1) 64.8 (14.0) Male gender (%) 11 (44.0) 33 (57.9) Clinical characteristics Disease Duration 20.4 (5.1) 1.5 (1.7) <0.001 Motor Hoehn and Yahr Stage Median 3 1 Interquartile range SCOPA Motor Scale - Examination 11.7 (5.8) 10.3 (5.0) Non-motor MMSE 28.0 (2.3) 28.7 (1.9) HADS - Anxiety 6.3 (4.0) 5.6 (4.2) HADS - Depression 5.5 (3.2) 4.8 (3.5) NMSS Total (SD) 74.0 (36.6) 45.5 (33.4) NMSS Cardiovascular including falls (SD) 3.2 (4.8) 2.0 (2.4) NMSS Sleep/fatigue (SD) 14.8 (10.8) 8.1 (7.6) NMSS Mood/cognition (SD) 8.4 (12.4) 10.0 (14.4) NMSS Perceptual problems/ hallucinations (SD) 3.8 (5.9) 0.6 (1.9) <0.001 NMSS Attention/Memory (SD) 8.0 (7.3) 3.8 (4.8) NMSS Gastrointestinal tract (SD) 7.8 (8.4) 3.7 (5.5) NMSS Urinary (SD) 9.3 (9.7) 6.1 (8.0) NMSS Sexual function (SD) 4.9 (6.9) 3.4 (6.3) NMSS Miscellaneous (SD) 13.7 (9.1) 7.7 (7.2) PD, Parkinson s disease; SD, standard deviation; HY, Hoehn and Yahr stage; NMSS, non-motor symptoms scale; MMSE, mini mental state examination; HADS, hospital anxiety and depression scale.

4 544 P. Zis et al. / NMS in Drug Naïve vs Long-Term PD Patients Fig. 1. Mean score for each of the 30 items of the non-motor symptoms scale between the long term Parkinson s disease (LTPD) and the drug naïve (DNPD) patients. Maximum score possible for each item = 12. *p < 0.05, **p < Table 2 Multivariate linear regression models of NMSS total scores and NMSS domains, r 2 adjusted R square, NMSS, non-motor symptoms scale; MMSE, mini mental state examination; HADS, hospital anxiety and depression scale Dependent Variable Variable Standardized p NMSS Total score (r 2 = 0.488; p < 0.001) Age Male gender Drug naïve group SCOPA motor scale - examination score HADS depression score <0.001 MMSE score NMSS Sleep/Fatigue (r 2 = 0.270; p < 0.001) Age Male gender Drug naïve group SCOPA motor scale - examination score HADS depression score MMSE score NMSS Perceptual problems (r 2 = 0.117; p = 0.017) Age Male gender Drug naïve group SCOPA motor scale - examination score HADS depression score MMSE score NMSS Memory (r 2 = 0.208; p < 0.001) Age Male gender Drug naïve group SCOPA motor scale - examination score HADS depression score NMSS Gastrointestinal (r 2 = 0.261; p < 0.001) Age Male gender Drug naïve group SCOPA motor scale - examination score HADS depression score MMSE score NMSS Miscellaneous (r 2 = 0.100; p = 0.029) Age Male gender Drug naïve group SCOPA motor scale - examination score HADS depression score MMSE score

5 P. Zis et al. / NMS in Drug Naïve vs Long-Term PD Patients 545 DISCUSSION Our study presents a cross-sectional analysis of pilot data, derived from an ongoing longitudinal multicenter study, conducted in the United Kingdom. Our data indicates the following key points: 1. More than 45% of DNPD cases may have a severe or a very severe burden of NMS in spite of the mild motor state (mean HY score of 1.7). Severe or very severe burden of NMS however is significantly greater in LTPD at 15 years (80%). 2. Cardiovascular, Mood/cognition, sexual and the urinary NMS domains are affected similarly in both DNPD and LTPD patients. 3. NMS such as fatigue, hyposmia and ageusia appear to be intrusive NMS in both DNPD and LTPD. Importantly, in DNPD depression, urinary difficulties (increased urgency) and pain were recorded as very intrusive NMS while in LTPD sleep problems, nocturia and dribbling of saliva dominate the profile of NMS. 4. Until recently, only few studies have focused in non-motor symptoms in drug naïve patients using the NMSS. The NMSS can be used both to address the overall burden of NMS in PD [15] as well as to characterize the severity and the frequency of 30 different NMS clustered in nine domains [7]. In 2009, Kim et al were the first to use the NMSS in 23 DNPD patients in Korea [16]. The total NMSS score was significantly higher in DNPD compared to healthy controls, suggesting thus that NMS are present in early stages of PD. In their study, the five most intrusive NMS of DNPD patients were urinary urgency, increased urinary frequency, nocturia, fatigue and restless legs. In our study population we also found that fatigue and urinary urgency are also intrusive in DNPD patients. The differences regarding the other NMS could possibly be explained by the different ethnicity of the two populations and by the small number of DNPD patients studied in the Korean study. More recently, in a large single-center study of the DeNoPa cohort, non-motor characteristics of 159 drug naive PD were assessed with the Parkinson s Disease Sleep Scale (PDSS) [17], the Scale for Outcomes in PD for Autonomic Symptoms (Scopa-AUT) scale [18], the NMSQuest and the NMSS and were compared to the non-motor characteristics of healthy controls [8]. In that study, it was shown that drug-naïve PD patients present with significantly higher scores in the PDSS scale, the Scopa-AUT scale, the NMSQuest and the NMSS compared to the controls. Although, subdomain scores of the NMSS were not analysed, the DeNoPa study group compared the subdomain scores of the Scopa-AUT scale showing that all autonomic subdomains (gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor and sexual) are affected in drug naïve PD patients compared to controls. We confirm this observation as autonomic symptoms were also prevalent in our DNPD group and some, such as urinary urgency, were as troublesome in DNPD as in LTPD. Interestingly, however, cardiovascular, gastrointestinal and sexual subdomain scores (markers of dysautonomia) were significantly higher in LTPD patients. This fact suggests that these aspects of NMS may indeed be of a progressive nature. NMS profile in LTPD merits discussion as, only a few studies focusing on non-motor symptoms of LTPD patients (disease duration exceeding 15 years) have been published until now [19]. The Sydney Multicenter Study of PD followed up a selected group of patients entering a bromocriptine versus levodopa study for up to 20 years after diagnosis [20] and concluded that after 15 years of disease, the major causes of disability in PD patients are falls, autonomic disturbance, neuropsychiatric symptoms and dementia and outweigh the motor disability [21]. This is concordant with our results as we also found that autonomic disturbance (sexual dysfunction, dribbling of saliva, urinary difficulties etc.) and neuropsychiatric symptoms (sadness, hallucinations, forgetfulness etc.) are among the most intrusive NMS experienced by LTPD (Fig. 1). Memory and cognitive dysfunction in DNPD is an interesting observation and one that is evident in some of our DNPD cases. The explanation for this is unclear and may reflect an age related cognitive decline in some cases. Halliday et al proposed a pathological model of onset of PD and underlined heterogeneity in respect to deposition of Lewy bodies at onset; early onset have dominantly brainstem Lewy bodies while late onset have cortical Lewy bodies at presentation [22]. By default the latter group therefore, could express cognitive dysfunction and also could explain our finding. Executive dysfunction in early PD has also been described previously in other studies [23]. Our results should be interpreted with some caution given several limitations of our design. Our study was not controlled and we have only relied on NMSS domain scores, which have been, however, validated against cognitive scales in original validation studies [7]. Moreover, we adjusted for age, gender, HADS

6 546 P. Zis et al. / NMS in Drug Naïve vs Long-Term PD Patients depression score, MMSE score and SCOPA motor scale examination score showing that the differences we found remained significant after adjusting for these co-variables. However, we should mention that we do not have data on co-morbidities or other medication received. Moreover, although the groups did not differ significantly regarding the mean age, they differed significantly regarding the symptoms duration; therefore the two groups were dissimilar in that the age of onset of the long-term patients was much younger than the de novo patients. The small number of LTPD cases is also a concern although such patients are difficult to obtain. Finally, our study comprised users of UK centers and results may not be generalisable to other settings. However, our data contributes significantly to the existing literature by describing the holistic non-motor profile of the DNPD group. CONFLICT OF INTEREST None. ACKNOWLEDGMENTS This paper presents independent research funded by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Suvankar Pal is funded by a research fellowship from NHS Research Scotland. We are sincerely thankful to the UK NILS collaborators Dr Belinda Kessel, Prof Antony Schapira, Dr Cathy Ellis, Dr Paul Worth and Dr Rani Sophia for their contribution to the study. We would also like to express our gratitude to the patients who participated to the study. REFERENCES [1] Sauerbier A, & Ray Chaudhuri K (2014) Non-motor symptoms: The core of multi-morbid Parkinson s disease. Br J Hosp Med (Lond), 75(1), [2] Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, Validation Group NMSS, (2011) The impact of non-motor symptoms on health-related quality of life of patients with Parkinson s disease. Mov Disord, 26(3), [3] Tolosa E, Gaig C, Santamaría J, & Compta Y (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology, 72(7 Suppl), S12-S20. [4] Hely MA, Reid WG, Adena MA, Halliday GM, & Morris JG (2008) The Sydney multicenter study of Parkinson s disease: The inevitability of dementia at 20 years. Mov Disord, 23(6), [5] Antonini A, Barone P, Marconi R, Morgante L, Zappulla S, Pontieri FE, Ramat S, Ceravolo MG, Meco G, Cicarelli G, Pederzoli M, Manfredi M, Ceravolo R, Mucchiut M, Volpe G, Abbruzzese G, Bottacchi E, Bartolomei L, Ciacci G, Cannas A, Randisi MG, Petrone A, Baratti M, Toni V, Cossu G, Del Dotto P, Bentivoglio AR, Abrignani M, Scala R, Pennisi F, Quatrale R, Gaglio RM, Nicoletti A, Perini M, Avarello T, Pisani A, Scaglioni A, Martinelli PE, Iemolo F, Ferigo L, Simone P, Soliveri P, Troianiello B, Consoli D, Mauro A, Lopiano L, Nastasi G, & Colosimo C (2012) The progression of non-motor symptoms in Parkinson s disease and their contribution to motor disability and quality of life. J Neurol, 259(12), [6] Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, Brown RG, Koller W, Barone P, MacPhee G, Kelly L, Rabey M, MacMahon D, Thomas S, Ondo W, Rye D, Forbes A, Tluk S, Dhawan V, Bowron A, Williams AJ, & Olanow CW (2006) International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson s disease: The NMSQuest study. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson s disease: The NMSQuest study. Mov Disord, 21(7), [7] Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, Ondo W, Abe K, Macphee G, Macmahon D, Barone P, Rabey M, Forbes A, Breen K, Tluk S, Naidu Y, Olanow W, Williams AJ, Thomas S, Rye D, Tsuboi Y, Hand A, & Schapira AH (2007) The metric properties of a novel nonmotor symptoms scale for Parkinson s disease: Results from an international pilot study. Mov Disord, 22(13), [8] Mollenhauer B, Trautmann E, Sixel-Döring F, Wicke T, Ebentheuer J, Schaumburg M, Lang E, Focke NK, Kumar KR, Lohmann K, Klein C, Schlossmacher MG, Kohnen R, Friede T, Trenkwalder C, DeNoPa Study, Group (2013) Nonmotor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort. Neurology, 81(14), [9] Khoo TK, Yarnall AJ, Duncan GW, Coleman S, O Brien JT, Brooks DJ, Barker RA, & Burn DJ (2013) The spectrum of nonmotor symptoms in early Parkinson disease. Neurology, 80(3), [10] Hughes AJ, Daniel SE, Kilford L, & Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson s disease: A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry, 55(3), [11] Hoehn MM, & Yahr MD (1967) Parkinsonism: Onset, progression and mortality. Neurology, 17(5), [12] Martínez-Martín P, Benito-León J, Burguera JA, Castro A, Linazasoro G, Martínez-Castrillo JC, Valldeoriola F, Vázquez A, Vivancos F, del Val J, van Blercom N, & Frades B (2005) The SCOPA-Motor Scale for assessment of Parkinson s disease is a consistent and valid measure. J Clin Epidemiol, 58(7), [13] Zigmond AS, & Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand, 67(6), [14] Folstein MF, Folstein SE, & McHugh PR (1975) "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res, 12(3), [15] Ray Chaudhuri K, Rojo JM, Schapira AH, Brooks DJ, Stocchi F, Odin P, Antonini A, Brown RJ, & Martinez-Martin P (2013) A proposal for a comprehensive grading of Parkinson s

7 P. Zis et al. / NMS in Drug Naïve vs Long-Term PD Patients 547 disease severity combining motor and non-motor assessments: Meeting an unmet need. PLoS One, 8(2), e doi: /journal.pone Epub 2013 Feb 27. [16] Kim HJ, Park SY, Cho YJ, Hong KS, Cho JY, Seo SY, Lee DH, & Jeon BS (2009) Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment. J Neurol Sci, 287(1-2), [17] Trenkwalder C, Kohnen R, Högl B, Metta V, Sixel-Döring F, Frauscher B, Hülsmann J, Martinez-Martin P, & Chaudhuri KR (2011) Parkinson s disease sleep scale validation of the revised version PDSS-2. Mov Disord, 26(4), [18] Visser M, Marinus J, Stiggelbout AM, & Van Hilten JJ (2004) Assessment of autonomic dysfunction in Parkinson s disease: The SCOPA-AUT. Mov Disord, 19(11), [19] Marttila RJ, & Rinne UK (1991) Progression and survival in Parkinson s disease. Acta Neurol Scand Suppl, 136, [20] Hely MA, Reid WG, Adena MA, Halliday GM, & Morris JG (2008) The Sydney multicenter study of Parkinson s disease: The inevitability of dementia at 20 years. Mov Disord, 23(6), [21] Hely MA, Morris JG, Reid WG, & Trafficante R (2005) Sydney Multicenter Study of Parkinson s disease: Non-Ldopa-responsive problems dominate at 15 years. Mov Disord, 20(2), [22] Halliday G, Lees A, & Stern M (2011) Milestones in Parkinson s disease clinical and pathologic features. Mov Disord, 26(6), [23] Dirnberger G, & Jahanshahi M (2013) Executive dysfunction in Parkinson s disease: A review. J Neuropsychol, 7(2),