Currently, there are no reported genetic predictors of motor symptom progression in Parkinson’s disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson’s patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson’s Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57–10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96–2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.
Citation: Ritz B, Rhodes SL, Bordelon Y, Bronstein J (2012) α-Synuclein Genetic Variants Predict Faster Motor Symptom Progression in Idiopathic Parkinson Disease. PLoS ONE 7(5): e36199. https://doi.org/10.1371/journal.pone.0036199
Editor: Patrick Lewis, UCL Institute of Neurology, United Kingdom
Received: December 23, 2011; Accepted: April 3, 2012; Published: May 15, 2012
Copyright: © 2012 Ritz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Study funding was provided by National Institutes of Health (NIH) grants R01-ES010544, U54-ES012078, P01-ES016732, and P50-NS038367. Initial pilot funding from NIH P30-ES07048, a Community Fast Track grant by the MJFox Foundation, and a pilot grant by the American Parkinson Disease Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Parkinson’s disease (PD) is a neurological condition characterized by progressive functional decline in motor function leading to disability and loss of quality of life . Rate and severity of decline vary among patients but in all cases deterioration is inevitable as there are no current disease-modifying therapies that prevent or slow the neurodegenerative processes that cause PD . More than a decade ago, clinical predictors of motor symptom progression were identified  including postural instability/gait disturbances, low Activities of Daily Living score, and dementia early in PD; since then only age at onset of symptoms has been added to this list . One possible reason for the continuing paucity of information on risk factors for motor progression is that most PD patient cohorts with longitudinal data are comprised of non-representative groups of patients such as volunteers for clinical trials or referral patients at tertiary care centers. Such cohorts typically contain little information on non-clinical factors thereby presenting challenges for the identification of risk factors for progression beyond the most common clinical characteristics (such as age of symptom onset or motor subtype). Also, larger, mostly record-based studies are limited by the available outcomes (usually only comorbidities and mortality), typically lack of systematic motor symptom assessment, and generally have not collected lifestyle, environmental, or genetic risk factor data.
There are only a few population-based (community) studies publishing on motor progression using multiple motor symptom assessments over time, i.e., with longitudinally followed PD patients , , . While one study  enrolled incident cases, two others ,  enrolled prevalent cases with long (>5 years) mean duration of disease prior to baseline assessment thereby preventing observation of the early stages of disease progression and therefore perhaps overlooking critical factors involved in faster motor symptom decline . Furthermore, these previous longitudinal studies started with fewer than 250 PD cases at baseline and all had only 50–60% of subjects remaining for follow-up assessment rendering them under-powered to examine all but the most common predictors of motor decline.
Recent publications have called for prospective cohorts of PD patients assembled early in disease  and clinico-genetic studies  to help unlock the heterogeneity of PD and its progression. Identifying genetic predictors may aid clinical decision-making, help target patients for treatment trials, and improve our understanding of disease processes. Thus far, genetic predictors of motor decline have not been reported in longitudinally followed incident PD cohorts, largely due to the limited number of such cohorts with biosamples.
Prior research has demonstrated a robust association between risk of PD occurrence and genetic variation in the α-synuclein (SNCA) gene –. SNCA has been a candidate gene for idiopathic PD ever since the localization of the PARK1 loci to the SNCA gene region in a large Italian kindred  and identification of SNCA protein in Lewy bodies . By far the most frequently investigated genetic variant in SNCA is the microsatellite D4S3481 (SNCA-Rep1), located in the promoter, approximately 10 kb upstream of SNCA, and first reported in the Alzheimer literature . While the first PD association study of SNCA-Rep1  did not observed a difference in allele distribution between PD patients with a family history of PD and unaffected controls, it did find a significant difference in allele distribution between PD patients without a family history and unaffected controls. Two following studies ,  observed a higher frequency of the 263 base pair (bp) repeat allele in PD cases compared with healthy controls. In 2006, a meta-analysis of 11 study populations including over 5000 subjects provided strong evidence that the 263bp allele was more frequent in cases increasing risk of PD (OR 1.43, 95% CI 1.22–1.69, dominant model) and that the 259bp allele was more frequent in controls decreasing risk of PD (OR = 0.85, 95% CI 0.76–0.96, dominant model); while the 261bp allele did not differ between PD cases and unaffected controls .
The linkage disequilibrium (LD) structure of SNCA suggests two distinct haplotype blocks, one covering an area from the 5′ end of the gene (the region of SNCA-Rep1) to exon 4 and the other covering from intron 4 to the 3′ region of the gene , . While many studies have investigated haplotypes containing the SNCA-Rep1 promoter variant in conjunction with other single nucleotide polymorphisms (SNPs) in the 5′ region , , –, use of promoter SNPs in place of or in addition to SNCA-Rep1 has not yet demonstrated improvement in risk estimation , . In the 3′ region of SNCA most studies have investigated either rs356165 (first reported in Pals et al ; meta-analysis of 11 Caucasian studies, OR 1.32, 95%CI: 1.23–1.42 ) or rs356219 (first reported in Mueller et al ; meta-analysis of 18 Caucasian studies, OR = 1.28, 95%CI: 1.23–1.32 ). These two SNPs are in very high LD (D’ = 1, r2 = 0.962, LOD = 26.27 ) and either one uniquely identifies the two most common 3′ region haplotypes as reported in Pankratz et al . In contrast, correlation between SNCA-Rep1 and rs356219 was found to be very low (r2 = 0.09) in a recent large study  supporting the hypothesis of two regions contributing to genetic risk of PD . However, others hypothesized that the SNCA-Rep1 263bp allele arose on the haplotype background defined by the ‘G’ allele at rs356165 (or rs356219) thereby indicating a single genetic effect .
While findings from studies investigating SNCA 5′ and 3′ region genetic variants and age of onset of PD have been inconsistent , , , , , –, there is data supporting biologic effects for genetic variants in SNCA possibly modifying the PD phenotype. Both SNCA-Rep1 ,  and 3′ region alleles  have been associated with increased gene expression; and 3′ region risk alleles have been reported to correlate with higher plasma alpha-synuclein levels in PD patients . Gene duplication ,  and triplication ,  in familial PD have been linked to increased mRNA expression levels – and to severity of disease , . Furthermore, the α-synuclein protein product, a major component of Lewy bodies , likely contributes significantly to PD neurodegeneration and consequently to motor symptom decline. Therefore, in this large, longitudinally followed population-based incident PD cohort we investigate, for the first time, whether genetic variation in the SNCA gene, a known risk factor for PD onset, contributes to PD motor symptom decline.
This study was approved by the human subjects committee of the University of Los Angeles (UCLA). Subjects participated in the study after written informed consent was obtained; prospective participants and their families/guardians were asked to discuss the consent documents; consent on behalf of participants deemed incapable of consenting was obtained from those determined to be legal proxies for the patient.
This longitudinal patient cohort is derived from a case-control study that enrolled PD patients and population-based controls between 2001 and 2007 in Central California. Recruitment methods ,  and case definition criteria  have been described in detail elsewhere. Briefly, of 1,167 PD patients initially invited, 604 did not meet eligibility criteria primarily due to having a first physician diagnosis of PD more than 3 years prior to baseline. Of the 563 eligible patients, 473(84%) were examined by our movement disorder specialists (JB and YB) at least once; 104 did not meet published criteria for idiopathic PD  and 6 had incomplete data. The remaining 363 idiopathic PD patients compose the PD cohort that is the basis of this longitudinal follow-up investigation.
At first re-contact 83(22.9%) patients were deceased, 25(6.9%) withdrew, 9(2.5%) could not be found, and 4(1.1%) were too ill to participate. For follow-up, 242(66.6%) cases were successfully re-contacted with 6 patients participating by mail/phone only (no in-person follow-up exam and therefore not contributing to this analysis) and 3 patients re-classified by us during follow-up as not having idiopathic PD. Of 233 patients re-examined and confirmed to have idiopathic PD, 178(76.4%) were seen twice and 55 were seen only once during follow-up (21 were deceased prior to the second exam and 14 are still pending second exams, 8 were too ill to participate, 4 could not be not located, 3 withdrew, and 5 participated by mail/phone only). For these analyses, 232 of the 233 patients with at least one follow-up had SNCA genotype data available. All patients completed an interview to collect demographic and risk factor data; and provided blood samples for DNA.
Assessment of PD Motor Symptom Progression
Baseline and follow-up Unified Parkinson’s Disease Rating Scale (UPDRS)  exams were performed at a clinic near the patient’s residence or at that residence if the patient was unable to travel. Patients were examined off PD medications (i.e. overnight medication withdrawal prior to exam) whenever possible (82% of patients were off medication for baseline exam, 80% for follow-up exams). For patients and time points without an off exam, we estimated the off exam score by adding to the patient’s on exam score the difference of the study population’s mean off- and mean on-scores. At each exam 6% of PD patients were unable to perform one or more motor UPDRS exam items (e.g. patients unable to walk due to a missing lower limb); we replaced missing exam items either assuming no change from baseline to follow-up for patients with available baseline data or assuming the population mean for patients with neither baseline nor follow-up values available, an approach likely to bias our estimates towards the null and therefore a conservative approach.
Annual rate of change in UPDRS motor score was calculated as the difference of the last follow-up and the baseline motor scores divided by the interval of time (in years) between exams. We did not assume a linear association between the SNCA genetic variants and rates of motor progression since our analyses would be too crude to predict actual levels of synuclein. Therefore, given that a 5 points/year change in motor UPDRS has been reported for early untreated PD patients in placebo arms of clinical trials  and is considered a clinically relevant change when assessing improvement due to treatment , we defined “fast” motor symptom decline as a 5 or more point increase in the annual rate of change.
Determination of SNCA Variants
SNCA genetic variants were genotyped according to previously published methods , . The SNCA microsatellite Rep1 (D4S3481) was genotyped using fluorescent-labeled forward and reverse primers designed to the α-synuclein promoter locus (accession no. U46895), Fam5′-CCT GGC ATA TTT GAT TGC AA-3′ and 5′-GAC TGG CCC AAG ATT AAC CA-3′. Detection and analysis was performed on an ABI 3730 DNA Analyzer (Applied Biosystems, Inc.) with Genemapper software. SNCA rs356165 in the 3′ untranslated region (3′UTR) was genotyped on an ABI 7900 Genome Analyzer using ABI Taqman® chemistry.
Hardy-Weinberg equilibrium was assessed for each variant using Mendel 10.0 . Logistic regression analyses (SAS 9.1.3, SAS Institute, Cary, NC) were employed to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age at PD diagnosis (continuous), gender (male/female), smoking status (never/ever), duration of time between diagnosis and baseline assessment (in years), and baseline UPDRS motor score. Subgroup analyses were performed limited to (1) subjects with off-medication exams only to investigate the influence of estimating missing off exam scores from on-medications motor exam scores (excludes 83 subjects who were unable to be assessed off PD medications at either baseline or follow-up) and limited to (2) subjects with complete UPDRS data at both baseline and follow-up exams to investigate the influence of replacing missing UPDRS motor exam items as described above (excludes 26 subjects who were unable to perform one or more motor UPDRS exam items at either baseline or follow-up, e.g. patients unable to walk due to a missing lower limb).
The repeat lengths of SNCA-Rep1 were analyzed in the manner originally presented by Maraganore et al : a dominant genetic model comparing 263/263 and 263/X vs. X/X, where X is either the 259 or the 261 allele; and a dominant genetic model comparing 259/259 and 259/X vs. X/X, where X is either the 261 or the 263 allele. The SNCA SNP rs356165 was analyzed under an additive (or allele dosage) genetic model similarly to prior studies , , . Assuming that the 5′ SNCA-Rep1 and the 3′ rs356165 regions represent independent contributors to genetic risk of PD , , , and possibly also to progression of motor symptoms, we investigated potential statistical interaction between SNCA-Rep1 263bp allele and the rs356165 ‘G’ allele. P-values presented are uncorrected; for multiple comparisons considerations, four tests were performed and a p-value of 0.0125 was considered the experiment-wide significance level. Sensitivity analyses were performed to assess model robustness to additional possible covariates and the outcome cut-point.
The characteristics of PD patients in this report are summarized in tables 1 and 2. We followed patients on average for 5.1 (std dev 2.2) years and categorized 35 (15.1%) patients as “fast progressors” for motor symptom decline as measured by the motor UPDRS. Fast progressors were older at time of PD diagnosis, had a lower UPDRS motor exam score at baseline, a shorter follow-up, and had lower baseline bradykinesia, rigidity, and tremor subscores (table 2), but did not differ from slow progressors in other risk factors including predominant motor type (akinetic : 74% and 81%, respectively; p-value = 0.24). Deceased patients were older, had a higher baseline UPDRS motor score, higher bradykinesia and gait/balance subscores, a lower Mini Mental State Exam (MMSE) , and a higher Geriatric Depression Score (GDS)  than both slow and fast progressors. Participants lost to follow-up but not deceased were not different from slow progressors on demographics or risk factors. Neither deceased patients nor those lost to follow-up differed from slow progressors on SNCA-Rep1 or rs356165 genetic variants (table 3). Finally, although carriers of the 263bp SNCA-Rep1 risk allele were on average younger (64 years) than non-carriers (67 years) at time of PD diagnosis, this difference was not formally statistically significant (p>0.10).
In logistic regression analyses adjusting for age, gender, smoking, duration of time between diagnosis and baseline assessment, and baseline UPDRS motor score, we observed no association between the SNCA-Rep1 259 allele and progression under a dominant genetic model although the odds ratio is in the expected (“protective”) direction (table 4). In contrast, PD patients carrying at least one 263bp allele in SNCA-Rep1 exhibited 4-fold higher odds of fast progression (OR = 4.03; 95% CI: 1.57–10.4; table 5). Separately, the G allele of SNCA rs356165 increased risk of faster progression 60% (one copy) or 270% (two copies) under an additive genetic model (table 6), albeit this association did not reach statistical significance. Effect estimates were robust to adjustment for education, minority status, PD family history, and bradykinesia, rigidity, tremor, and gait/balance subscores.
In subgroup analyses restricted to patients with only off medication UPDRS exams or subjects with complete UPDRS data, the estimated effects were similar to or stronger than those for the full study sample (tables 4, 5, 6) although the confidence intervals were wider due to smaller sample sizes. Our results were relatively insensitive to lowering the cut-point for fast progression (e.g. top quartile rate of change vs. others, SNCA-Rep1 OR = 2.66; 95% CI: 1.14–6.19). Finally, although we did not observe statistical interaction, patients with the ‘GG’ risk genotype at rs356165 and without the SNCA-Rep1 263bp risk allele exhibited a smaller increase in risk of faster progression than patients with the ‘GG’ risk genotype and with at least one copy of the SNCA-Rep1 263bp risk allele; additionally, we observed a strong trend across categories of the combined genetic variants (table 7; p-value for trend 0.002).
Heterogeneity in clinical presentation is widely acknowledged in PD  and the rate of disease progression and motor symptom decline is known to vary strongly . The α-synuclein protein is a major component of Lewy bodies and participates in the molecular pathogenesis of PD. Mutations and multiplications of the SNCA gene cause familial parkinsonism and genetic variations are recognized as risk factors for idiopathic PD . Here we present the first evidence that SNCA is an important and strong predictor of faster motor symptom decline in idiopathic PD: we observed a 4-fold higher risk of PD for carriers of the SNCA-Rep1 263bp allele and, when considering both Rep1 263bp and rs356165 ‘G’ allele, we observed a strong trend for faster motor decline across categories of the combined genetic variants.
SNCA-Rep1 allelic variants and 3′UTR variants (including rs356165) are correlated with SNCA mRNA expression in human postmortem brain tissues , . Furthermore, in familial parkinsonism with gene duplication or triplication increased mRNA expression has been linked to severity of disease (e.g. younger onset, faster decline, cognitive impairment) . Thus, evidence that these PD-associated SNCA variants have functional consequences is accumulating rapidly. In our population-based idiopathic PD cohort, both the SNCA-Rep1 promoter and 3′UTR risk variants in combination with the promoter predicted faster motor symptom decline and these findings suggest that α-synuclein levels in idiopathic PD are strongly associated with progression as well as with disease risk.
Apart from clinical trials of mostly younger onset patients –, and hospital-based studies of prevalent cases , , , only three prior population-based studies conducted in New York , Norway , and the UK  collected longitudinal UPDRS data for evaluating PD motor progression. All three population-based studies were limited by follow-up sample size (<150 subjects remaining after 4 years or more); whereas our study has 232 subjects at on average 5.1 years of follow-up, and thus is the largest population-based longitudinal study of PD motor symptoms in the literature to date. Additionally, two studies ,  assessed only prevalent cases with long mean duration of disease prior to baseline (6.8–9.1 years), thus missing early stages of disease progression, a potentially critical time for neurodegeneration of the dopamine system . Faster motor decline in early disease is consistent with an early accelerated dopaminergic neurodegeneration and an exponential demise of neurons shortly after PD onset that levels off over time . This early stage of PD might be the most sensitive and effective period for interventions aimed at slowing disease progression.
Our PD cohort is population-based and, thus, we expect it to adequately represent the range of disease phenotypes and treatment protocols found in the general U.S. PD population. Our study design also ensured representativeness of our patients to idiopathic PD patients seen in the health care system in general, different from more common PD progression studies that assembled homogeneous groups of very select patients from clinical trials or tertiary care facilities. The average age and age range of our PD patient cohort at diagnosis (68.3 years; range 34–88) is as expected in population based studies of PD; and similar to what was reported in the longitudinal study of incident PD in the UK (70.1 years; range 37–94) , , and to the age range in both prevalence progression studies in NY (range 25–93)  and Norway (range 27–85) . Moreover, the distributions of SNCA Rep1 and rs356165 variants observed in our cohort of PD cases are very similar to those observed for PD cases in studies indexed by PDGene (www.pdgene.org ). Thus, the results observed in our population-based cohort are more likely to be generalizable to the U.S. PD population than results of placebo arms of clinical trials that limit enrollment to a select age range or stage of disease.
Consistent with observations from a recent longitudinal imaging study  the motor symptoms of our PD patients age 66 and younger declined at a slower rate than those of our patients age 67 and older (2.13 points/year vs. 2.80 points/year, p = 0.043). Adjusting for age demonstrated that our observed genetic associations are independent of age. In fact, age-stratified analyses (< = 66 and >66), while underpowered, produced similar odds ratio estimates as the combined sample.
Due to the logistics of a population based study, we were unable to follow our patients on an annual or more regular basis, but our average annual rate of change measure accounts for differences in follow-up intervals. Moreover, our slow progressors were followed for a slightly longer interval thereby somewhat minimizing the extent to which slow progressing subjects were misclassified due to follow-up duration, since patients are less likely to improve once reaching a more advanced state of motor symptom decline. Finally, analysis limited to subjects with an interval from baseline to follow-up of 3 years or more (mean 5.82 years follow-up) produced odds ratios similar to analyses of the full sample (e.g. ORRep1 263 = 4.05, 95%CI: 1.42–11.6).
We lost a third of all patients between baseline and follow-up, mostly because participants had died. Other population-based studies of PD have similar or greater losses at follow-up: NY  lost 45% at 4 years, Norway  lost 38% at 4 years, and UK  48% at 6.6 years of follow-up. Of our subjects lost to follow-up, 69% had died during follow-up; this is similar to the only other study of incident PD cases  where 64% of lost subjects had died during follow-up. Relevant to our findings, when we examined the genetic variants of SNCA in those lost due to death and lost due to other reasons, we observed no differences from the comparison group of slow progressors (p>0.10).
Unlike many longitudinal PD studies, we attempted to examine all patients in a practically defined off PD medication state, but this was not achieved in about 20% of exams. While this could have caused non-differential outcome misclassification with regard to genetic factors and an underestimation of the rate of progression and the effect size, we observed an overall mean change in UPDRS motor score of 2.52 points/year (average follow-up 5.1 years) which is very similar to the rate observed by the only other population-based incident study that estimated a mean change of 2.24 points/year (average follow-up 6.6 years) albeit this rate represents results from “on-on” exams .
Since motor symptom severity predicts increased mortality in PD independent of age and disease duration , identifying genetic predictors of faster motor decline is critical to pinpointing biological mechanisms as targets for therapies and identifying patients who will most benefit from early interventions. While replication of our results in similarly well-characterized population-based incidence PD cohorts that have been longitudinally followed is still needed, our findings strongly suggest that α-synuclein and related pathogenic pathways have great promise as potential disease modifying and therapeutic targets.
We are exceptionally grateful to all study participants, whose generosity made this research possible. We thank Matthew Farrer, PhD of the Department of Medical Genetics, University of British Columbia, Vancouver, B.C., Canada for α-synuclein genotyping.
Conceived and designed the experiments: BR SR. Performed the experiments: JB YB. Analyzed the data: SR BR. Wrote the paper: BR SR. Interpreted the data: BR SR YB JB.
- 1. Global PD Survey Steering Committee (2002) Factors impacting on quality of life in Parkinson’s disease: results from an international survey. Mov Disord 17: 60–67.Global PD Survey Steering Committee2002Factors impacting on quality of life in Parkinson’s disease: results from an international survey.Mov Disord176067
- 2. Poewe W (2006) The need for neuroprotective therapies in Parkinson’s disease: a clinical perspective. Neurology 66: S2–9.W. Poewe2006The need for neuroprotective therapies in Parkinson’s disease: a clinical perspective.Neurology66S29
- 3. Louis ED, Tang MX, Cote L, Alfaro B, Mejia H, et al. (1999) Progression of parkinsonian signs in Parkinson disease. Arch Neurol 56: 334–337.ED LouisMX TangL. CoteB. AlfaroH. Mejia1999Progression of parkinsonian signs in Parkinson disease.Arch Neurol56334337
- 4. Jankovic J, Kapadia AS (2001) Functional decline in Parkinson disease. Arch Neurology 58: 1611–1615.J. JankovicAS Kapadia2001Functional decline in Parkinson disease.Arch Neurology5816111615
- 5. Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP (2005) Progression of motor impairment and disability in Parkinson disease: a population-based study. Neurology 65: 1436–1441.G. AlvesT. Wentzel-LarsenD. AarslandJP Larsen2005Progression of motor impairment and disability in Parkinson disease: a population-based study.Neurology6514361441
- 6. Evans JR, Mason SL, Williams-Gray CH, Foltynie T, Brayne C, et al. (2011) The natural history of treated Parkinson’s disease in an incident, community based cohort. J Neurol Neurosurg Psychiatry 82: 1112–1118.JR EvansSL MasonCH Williams-GrayT. FoltynieC. Brayne2011The natural history of treated Parkinson’s disease in an incident, community based cohort.J Neurol Neurosurg Psychiatry8211121118
- 7. Maetzler W, Liepelt I, Berg D (2009) Progression of Parkinson’s disease in the clinical phase: potential markers. Lancet Neurol 8: 1158–1171.W. MaetzlerI. LiepeltD. Berg2009Progression of Parkinson’s disease in the clinical phase: potential markers.Lancet Neurol811581171
- 8. Post B, Merkus MP, de Haan RJ, Speelman JD, CARPA Study Group (2007) Prognostic factors for the progression of Parkinson’s disease: a systematic review. Mov Disord 22: 1839–1851.B. PostMP MerkusRJ de HaanJD SpeelmanCARPA Study Group2007Prognostic factors for the progression of Parkinson’s disease: a systematic review.Mov Disord2218391851
- 9. Wickremaratchi MM, Ben-Shlomo Y, Morris HR (2009) The effect of onset age on the clinical features of Parkinson’s disease. Eur J Neurol 16: 450–456.MM WickremaratchiY. Ben-ShlomoHR Morris2009The effect of onset age on the clinical features of Parkinson’s disease.Eur J Neurol16450456
- 10. Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, et al. (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296: 661–670.DM MaraganoreM. de AndradeA. ElbazMJ FarrerJP Ioannidis2006Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease.JAMA296661670
- 11. Pankratz N, Nichols WC, Elsaesser VE, Pauciulo MW, Marek DK, et al. (2009) Alpha-synuclein and familial Parkinson’s disease. Mov Disord 24: 1125–1131.N. PankratzWC NicholsVE ElsaesserMW PauciuloDK Marek2009Alpha-synuclein and familial Parkinson’s disease.Mov Disord2411251131
- 12. Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, et al. (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41: 1308–1312.J. Simón-SánchezC. SchulteJM BrasM. SharmaJR Gibbs2009Genome-wide association study reveals genetic risk underlying Parkinson’s disease.Nat Genet4113081312
- 13. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, et al. (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42: 781–785.TH HamzaCP ZabetianA. TenesaA. LaederachJ. Montimurro2010Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease.Nat Genet42781785
- 14. International Parkinson Disease Genomics Consortium (2011) Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet 377: 641–649.Consortium International Parkinson Disease Genomics2011Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies.Lancet377641649
- 15. Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, et al. (2011) Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet 7: e1002141.CB DoJY TungE. DorfmanAK KieferEM Drabant2011Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease.PLoS Genet7e1002141
- 16. Cardo LF, Coto E, de Mena L, Ribacoba R, Lorenzo-Betancor O, et al. (2011) A Search for SNCA 3' UTR Variants Identified SNP rs356165 as a Determinant of Disease Risk and Onset Age in Parkinson’s Disease. J Mol Neurosci. LF CardoE. CotoL. de MenaR. RibacobaO. Lorenzo-Betancor2011A Search for SNCA 3' UTR Variants Identified SNP rs356165 as a Determinant of Disease Risk and Onset Age in Parkinson’s Disease.J Mol Neurosci
- 17. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276: 2045–2047.MH PolymeropoulosC. LavedanE. LeroySE IdeA. Dehejia1997Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease.Science27620452047
- 18. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, et al. (1997) Alpha-synuclein in Lewy bodies. Nature 388: 839–840.MG SpillantiniML SchmidtVM LeeJQ TrojanowskiR. Jakes1997Alpha-synuclein in Lewy bodies.Nature388839840
- 19. Xia MS, Rohan de Silva HA, Rosi BL, Yamaoka LH, Rimmler JB, et al. (1996) Genetic studies in Alzheimer’s disease with an NACP/synuclein polymorphism. Ann Neurol 40: 207–215.MS XiaHA Rohan de SilvaBL RosiLH YamaokaJB Rimmler1996Genetic studies in Alzheimer’s disease with an NACP/synuclein polymorphism.Ann Neurol40207215
- 20. Parsian A, Racette B, Zhang ZH, Chakraverty S, Rundle M, et al. (1998) Mutation, sequence analysis, and association studies of alpha-synuclein in Parkinson’s disease. Neurology 51: 1757–1759.A. ParsianB. RacetteZH ZhangS. ChakravertyM. Rundle1998Mutation, sequence analysis, and association studies of alpha-synuclein in Parkinson’s disease.Neurology5117571759
- 21. Krüger R, Vieira-Saecker AM, Kuhn W, Berg D, Müller T, et al. (1999) Increased susceptibility to sporadic Parkinson’s disease by a certain combined alpha-synuclein/apolipoprotein E genotype. Ann Neurol 45: 611–617.R. KrügerAM Vieira-SaeckerW. KuhnD. BergT. Müller1999Increased susceptibility to sporadic Parkinson’s disease by a certain combined alpha-synuclein/apolipoprotein E genotype.Ann Neurol45611617
- 22. Tan EK, Matsuura T, Nagamitsu S, Khajavi M, Jankovic J, et al. (2000) Polymorphism of NACP-Rep1 in Parkinson’s disease: an etiologic link with essential tremor? Neurology 54: 1195–1198.EK TanT. MatsuuraS. NagamitsuM. KhajaviJ. Jankovic2000Polymorphism of NACP-Rep1 in Parkinson’s disease: an etiologic link with essential tremor?Neurology5411951198
- 23. Myhre R, Toft M, Kachergus J, Hulihan MM, Aasly JO, et al. (2008) Multiple alpha-synuclein gene polymorphisms are associated with Parkinson’s disease in a Norwegian population. Acta Neurol Scand 118: 320–327.R. MyhreM. ToftJ. KachergusMM HulihanJO Aasly2008Multiple alpha-synuclein gene polymorphisms are associated with Parkinson’s disease in a Norwegian population.Acta Neurol Scand118320327
- 24. Trotta L, Guella I, Soldà G, Sironi F, Tesei S, et al. (2012) SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population. Parkinsonism Relat Disord 18: 257–262.L. TrottaI. GuellaG. SoldàF. SironiS. Tesei2012SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population.Parkinsonism Relat Disord18257262
- 25. Farrer M, Maraganore DM, Lockhart P, Singleton A, Lesnick TG, et al. (2001) alpha-Synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet 10: 1847–1851.M. FarrerDM MaraganoreP. LockhartA. SingletonTG Lesnick2001alpha-Synuclein gene haplotypes are associated with Parkinson’s disease.Hum Mol Genet1018471851
- 26. Pals P, Lincoln S, Manning J, Heckman M, Skipper L, et al. (2004) Alpha-Synuclein promoter confers susceptibility to Parkinson’s disease. Ann Neurol 56: 591–595.P. PalsS. LincolnJ. ManningM. HeckmanL. Skipper2004Alpha-Synuclein promoter confers susceptibility to Parkinson’s disease.Ann Neurol56591595
- 27. Mellick GD, Maraganore DM, Silburn PA (2005) Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson’s disease. Neurosci Lett 375: 112–116.GD MellickDM MaraganorePA Silburn2005Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson’s disease.Neurosci Lett375112116
- 28. Mueller JC, Fuchs J, Hofer A, Zimprich A, Lichtner P, et al. (2005) Multiple regions of alpha-synuclein are associated with Parkinson’s disease. Ann Neurol 57: 535–541.JC MuellerJ. FuchsA. HoferA. ZimprichP. Lichtner2005Multiple regions of alpha-synuclein are associated with Parkinson’s disease.Ann Neurol57535541
- 29. Parsian AJ, Racette BA, Zhao JH, Sinha R, Patra B, et al. (2007) Association of alpha-synuclein gene haplotypes with Parkinson’s disease. Parkinsonism Relat Disord 13: 343–347.AJ ParsianBA RacetteJH ZhaoR. SinhaB. Patra2007Association of alpha-synuclein gene haplotypes with Parkinson’s disease.Parkinsonism Relat Disord13343347
- 30. Ross OA, Gosal D, Stone JT, Lincoln SJ, Heckman MG, et al. (2007) Familial genes in sporadic disease: common variants of alpha-synuclein gene associate with Parkinson’s disease. Mech Ageing Dev 128: 378–382.OA RossD. GosalJT StoneSJ LincolnMG Heckman2007Familial genes in sporadic disease: common variants of alpha-synuclein gene associate with Parkinson’s disease.Mech Ageing Dev128378382
- 31. Winkler S, Hagenah J, Lincoln S, Heckman M, Haugarvoll K, et al. (2007) α-Synuclein and Parkinson disease susceptibility. Neurology 69: 1745–1750.S. WinklerJ. HagenahS. LincolnM. HeckmanK. Haugarvoll2007α-Synuclein and Parkinson disease susceptibility.Neurology6917451750
- 32. Sutherland GT, Halliday GM, Silburn PA, Mastaglia FL, Rowe DB, et al. (2009) Do polymorphisms in the familial Parkinsonism genes contribute to risk for sporadic Parkinson’s disease? Mov Disord 24: 833–838.GT SutherlandGM HallidayPA SilburnFL MastagliaDB Rowe2009Do polymorphisms in the familial Parkinsonism genes contribute to risk for sporadic Parkinson’s disease?Mov Disord24833838
- 33. PDGene: A database for Parkinson’s disease genetic association studies. 14: PDGene: A database for Parkinson’s disease genetic association studies.14Available: http://www.pdgene.org/. Accessed 2012 Feb. Available: http://www.pdgene.org/. Accessed 2012 Feb.
- 34. International HapMap Project. 14: International HapMap Project.14Available: http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap27_B36/. Accessed 2012 Feb. Available: http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap27_B36/. Accessed 2012 Feb.
- 35. Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, et al. (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 124: 593–605.N. PankratzJB WilkJC LatourelleAL DeStefanoC. Halter2009Genomewide association study for susceptibility genes contributing to familial Parkinson disease.Hum Genet124593605
- 36. Mata IF, Shi M, Agarwal P, Chung KA, Edwards KL, et al. (2010) SNCA variant associated with Parkinson disease and plasma alpha-synuclein level. Arch Neurol 67: 1350–1356.IF MataM. ShiP. AgarwalKA ChungKL Edwards2010SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.Arch Neurol6713501356
- 37. Simón-Sánchez J, van Hilten JJ, van de Warrenburg B, Post B, Berendse HW, et al. (2011) Genome-wide association study confirms extant PD risk loci among the Dutch. Eur J Hum Genet 19: 655–661.J. Simón-SánchezJJ van HiltenB. van de WarrenburgB. PostHW Berendse2011Genome-wide association study confirms extant PD risk loci among the Dutch.Eur J Hum Genet19655661
- 38. Hadjigeorgiou GM, Xiromerisiou G, Gourbali V, Aggelakis K, Scarmeas N, et al. (2006) Association of alpha-synuclein Rep1 polymorphism and Parkinson’s disease: influence of Rep1 on age at onset. Mov Disord 21: 534–539.GM HadjigeorgiouG. XiromerisiouV. GourbaliK. AggelakisN. Scarmeas2006Association of alpha-synuclein Rep1 polymorphism and Parkinson’s disease: influence of Rep1 on age at onset.Mov Disord21534539
- 39. Kay DM, Factor SA, Samii A, Higgins DS, Griffith A, et al. (2008) Genetic association between alpha-synuclein and idiopathic Parkinson’s disease. Am J Med Genet B Neuropsychiatr Genet 147B: 1222–1230.DM KaySA FactorA. SamiiDS HigginsA. Griffith2008Genetic association between alpha-synuclein and idiopathic Parkinson’s disease.Am J Med Genet B Neuropsychiatr Genet147B12221230
- 40. Rajput A, Vilariño-Güell C, Rajput ML, Ross OA, Soto-Ortolaza AI, et al. (2009) Alpha-synuclein polymorphisms are associated with Parkinson’s disease in a Saskatchewan population. Mov Disord 24: 2411–2414.A. RajputC. Vilariño-GüellML RajputOA RossAI Soto-Ortolaza2009Alpha-synuclein polymorphisms are associated with Parkinson’s disease in a Saskatchewan population.Mov Disord2424112414
- 41. Brighina L, Frigerio R, Schneider NK, Lesnick TG, de Andrade M, et al. (2008) Alpha-synuclein, pesticides, and Parkinson disease: a case-control study. Neurology 70: 1461–1469.L. BrighinaR. FrigerioNK SchneiderTG LesnickM. de Andrade2008Alpha-synuclein, pesticides, and Parkinson disease: a case-control study.Neurology7014611469
- 42. Chung SJ, Armasu SM, Biernacka JM, Lesnick TG, Rider DN, et al. (2011) Common variants in PARK loci and related genes and Parkinson’s disease. Mov Disord 26: 280–288.SJ ChungSM ArmasuJM BiernackaTG LesnickDN Rider2011Common variants in PARK loci and related genes and Parkinson’s disease.Mov Disord26280288
- 43. Elbaz A, Ross OA, Ioannidis JP, Soto-Ortolaza AI, Moisan F, Genetic Epidemiology of Parkinson’s Disease (GEO-PD) Consortium (2011) Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 69: 778–792.A. ElbazOA RossJP IoannidisAI Soto-OrtolazaF. MoisanConsortium Genetic Epidemiology of Parkinson’s Disease (GEO-PD)2011Independent and joint effects of the MAPT and SNCA genes in Parkinson disease.Ann Neurol69778792
- 44. Chiba-Falek O, Nussbaum RL (2001) Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet 10: 3101–3109.O. Chiba-FalekRL Nussbaum2001Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system.Hum Mol Genet1031013109
- 45. Chiba-Falek O, Touchman JW, Nussbaum RL (2003) Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene. Hum Genet 113: 426–431.O. Chiba-FalekJW TouchmanRL Nussbaum2003Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene.Hum Genet113426431
- 46. McCarthy JJ, Linnertz C, Saucier L, Burke JR, Hulette CM, et al. (2011) The effect of SNCA 3' region on the levels of SNCA-112 splicing variant. Neurogenetics 12: 59–64.JJ McCarthyC. LinnertzL. SaucierJR BurkeCM Hulette2011The effect of SNCA 3' region on the levels of SNCA-112 splicing variant.Neurogenetics125964
- 47. Ibáñez P, Bonnet AM, Débarges B, Lohmann E, Tison F, et al. (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet 364: 1169–1171.P. IbáñezAM BonnetB. DébargesE. LohmannF. Tison2004Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease.Lancet36411691171
- 48. Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, et al. (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364: 1167–1169.MC Chartier-HarlinJ. KachergusC. RoumierV. MourouxX. Douay2004Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease.Lancet36411671169
- 49. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, et al. (2003) Alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302: 841.AB SingletonM. FarrerJ. JohnsonA. SingletonS. Hague2003Alpha-Synuclein locus triplication causes Parkinson’s disease.Science302841
- 50. Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, et al. (2004) Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 55: 174–179.M. FarrerJ. KachergusL. FornoS. LincolnDS Wang2004Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications.Ann Neurol55174179
- 51. Miller DW, Hague SM, Clarimon J, Baptista M, Gwinn-Hardy K, et al. (2004) Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62: 1835–1838.DW MillerSM HagueJ. ClarimonM. BaptistaK. Gwinn-Hardy2004Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication.Neurology6218351838
- 52. Mutez E, Leprêtre F, Le Rhun E, Larvor L, Duflot A, et al. (2011) SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes. Hum Mutat 32: E2079–2090.E. MutezF. LeprêtreE. Le RhunL. LarvorA. Duflot2011SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes.Hum Mutat32E20792090
- 53. Ross OA, Braithwaite AT, Skipper LM, Kachergus J, Hulihan MM, et al. (2008) Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann Neurol 63: 743–750.OA RossAT BraithwaiteLM SkipperJ. KachergusMM Hulihan2008Genomic investigation of alpha-synuclein multiplication and parkinsonism.Ann Neurol63743750
- 54. Ibáñez P, Lesage S, Janin S, Lohmann E, Durif F, et al. (2009) Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Arch Neurol 66: 102–108.P. IbáñezS. LesageS. JaninE. LohmannF. Durif2009Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.Arch Neurol66102108
- 55. Costello S, Wahner A, Bronstein J, Cockburn M, Zhang X, et al. (2009) Paraquat and Maneb exposure and Parkinson’s disease in the California Central Valley. Am J Epidemiol 169: 919–926.S. CostelloA. WahnerJ. BronsteinM. CockburnX. Zhang2009Paraquat and Maneb exposure and Parkinson’s disease in the California Central Valley.Am J Epidemiol169919926
- 56. Gatto NM, Rhodes SL, Manthripragada AD, Bronstein J, Cockburn M, et al. (2010) α-Synuclein gene may interact with environmental factors in increasing risk of Parkinson’s disease. Neuroepidemiology 35: 191–195.NM GattoSL RhodesAD ManthripragadaJ. BronsteinM. Cockburn2010α-Synuclein gene may interact with environmental factors in increasing risk of Parkinson’s disease.Neuroepidemiology35191195
- 57. Kang GA, Bronstein JM, Masterman DL, Redelings M, Crum JA, et al. (2005) Clinical characteristics in early Parkinson’s disease in a central California population-based study. Mov Disord 20: 1133–1142.GA KangJM BronsteinDL MastermanM. RedelingsJA Crum2005Clinical characteristics in early Parkinson’s disease in a central California population-based study.Mov Disord2011331142
- 58. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ (1992) What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. Neurology 42: 1142–1146.AJ HughesY. Ben-ShlomoSE DanielAJ Lees1992What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study.Neurology4211421146
- 59. Fahn S, Elton RL (1987) Members of the UPDRS development committee: unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Goldstein M, Calne D, editors. Recent developments in Parkinson’s disease. New York: Macmillan. S. FahnRL Elton1987Members of the UPDRS development committee: unified Parkinson’s disease rating scale.S. FahnCD MarsdenM. GoldsteinD. CalneRecent developments in Parkinson’s diseaseNew YorkMacmillan
- 60. Shulman LM, Gruber-Baldini AL, Anderson KE, Fishman PS, Reich SG, et al. (2010) The clinically important difference on the unified Parkinson’s disease rating scale. Arch Neurol 67: 64–70.LM ShulmanAL Gruber-BaldiniKE AndersonPS FishmanSG Reich2010The clinically important difference on the unified Parkinson’s disease rating scale.Arch Neurol676470
- 61. Farrer M, Maraganore DM, Lockhart P, Singleton A, Lesnick TG, et al. (2001) α-synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet 10: 1847–1851.M. FarrerDM MaraganoreP. LockhartA. SingletonTG Lesnick2001α-synuclein gene haplotypes are associated with Parkinson’s disease.Hum Mol Genet1018471851
- 62. Lange K, Sinsheimer JS, Sobel E (2005) Association testing with Mendel. Genet Epidemiol 29: 36–50.K. LangeJS SinsheimerE. Sobel2005Association testing with Mendel.Genet Epidemiol293650
- 63. Schiess MC, Zheng H, Soukup VM, Bonnen JG, Nauta HJ (2000) Parkinson’s disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis. Parkinsonism Relat Disord 6: 69–76.MC SchiessH. ZhengVM SoukupJG BonnenHJ Nauta2000Parkinson’s disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis.Parkinsonism Relat Disord66976
- 64. 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: 189–198.MF FolsteinSE FolsteinPR McHugh1975“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician.J Psychiatr Res12189198
- 65. Yesavage JA (1988) Geriatric Depression Scale. Psychopharmacol Bull 24: 709–711.JA Yesavage1988Geriatric Depression Scale.Psychopharmacol Bull24709711
- 66. Schrag A, Dodel R, Spottke A, Bornschein B, Siebert U, et al. (2007) Rate of clinical progression in Parkinson’s disease. A prospective study. Mov Disord 22: 938–945.A. SchragR. DodelA. SpottkeB. BornscheinU. Siebert2007Rate of clinical progression in Parkinson’s disease. A prospective study.Mov Disord22938945
- 67. Linnertz C, Saucier L, Ge D, Cronin KD, Burke JR, et al. (2009) Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PLoS One 4: e7480.C. LinnertzL. SaucierD. GeKD CroninJR Burke2009Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues.PLoS One4e7480
- 68. The Parkinson Study Group (1993) Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 328: 176–183.The Parkinson Study Group1993Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease.N Engl J Med328176183
- 69. Olanow CW, Hauser RA, Gauger L, Malapira T, Koller W, et al. (1995) The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol 38: 771–777.CW OlanowRA HauserL. GaugerT. MalapiraW. Koller1995The effect of deprenyl and levodopa on the progression of Parkinson’s disease.Ann Neurol38771777
- 70. The Parkinson Study Group (1996) Effect of lazabemide on the progression of disability in early Parkinson’s disease. Ann Neurol 40: 99–107.The Parkinson Study Group1996Effect of lazabemide on the progression of disability in early Parkinson’s disease.Ann Neurol4099107
- 71. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, et al. (2002) Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 59: 1541–1550.CW ShultsD. OakesK. KieburtzMF BealR. Haas2002Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline.Arch Neurol5915411550
- 72. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, et al. (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351: 2498–2508.S. FahnD. OakesI. ShoulsonK. KieburtzA. Rudolph2004Levodopa and the progression of Parkinson’s disease.N Engl J Med35124982508
- 73. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, et al. (2009) A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 361: 1268–1278.CW OlanowO. RascolR. HauserPD FeiginJ. Jankovic2009A double-blind, delayed-start trial of rasagiline in Parkinson’s disease.N Engl J Med36112681278
- 74. Harrison MB, Wylie SA, Frysinger RC, Patrie JT, Huss DS, et al. (2009) UPDRS activity of daily living score as a marker of Parkinson’s disease progression. Mov Disord 24: 224–230.MB HarrisonSA WylieRC FrysingerJT PatrieDS Huss2009UPDRS activity of daily living score as a marker of Parkinson’s disease progression.Mov Disord24224230
- 75. Greffard S, Verny M, Bonnet AM, Beinis JY, Gallinari C, et al. (2006) Motor score of the Unified Parkinson Disease Rating Scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra. Arch Neurol 63: 584–588.S. GreffardM. VernyAM BonnetJY BeinisC. Gallinari2006Motor score of the Unified Parkinson Disease Rating Scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra.Arch Neurol63584588
- 76. Foltynie T, Brayne CE, Robbins TW, Barker RA (2004) The cognitive ability of an incident cohort of Parkinson’s patients in the UK. The CamPaIGN study. Brain 127: 550–560.T. FoltynieCE BrayneTW RobbinsRA Barker2004The cognitive ability of an incident cohort of Parkinson’s patients in the UK. The CamPaIGN study.Brain127550560
- 77. Tandberg E, Larsen JP, Nessler EG, Riise T, Aarli JA (1995) The epidemiology of Parkinson’s disease in the county of Rogaland, Norway. Mov Disord 10: 541–549.E. TandbergJP LarsenEG NesslerT. RiiseJA Aarli1995The epidemiology of Parkinson’s disease in the county of Rogaland, Norway.Mov Disord10541549
- 78. de la Fuente-Fernández R, Schulzer M, Kuramoto L, Cragg J, Ramachandiran N, et al. (2011) Age-specific progression of nigrostriatal dysfunction in Parkinson’s disease. Ann Neurol 69: 803–810.R. de la Fuente-FernándezM. SchulzerL. KuramotoJ. CraggN. Ramachandiran2011Age-specific progression of nigrostriatal dysfunction in Parkinson’s disease.Ann Neurol69803810
- 79. Forsaa EB, Larsen JP, Wentzel-Larsen T, Alves G (2010) What predicts mortality in Parkinson disease: a prospective population-based long-term study. Neurology 75: 1270–1276.EB ForsaaJP LarsenT. Wentzel-LarsenG. Alves2010What predicts mortality in Parkinson disease: a prospective population-based long-term study.Neurology7512701276