Daan C. Velseboer

Genome-wide association study confirms extant PD risk loci among the Dutch.

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinsons disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514 799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P=1.63 × 10−5, OR=1.325 and BST1, rs12502586: P=1.63 × 10−3, OR=1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3′ and 5′ ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P=1.22 × 10−4, OR=1.51; HLA, rs4248166: P=4.39 × 10−5, OR=1.36; and MAPT, rs3785880: P=1.9 × 10−3, OR=1.19).

Prevalence of orthostatic hypotension in Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND Although orthostatic hypotension (OH) is recognized as one of the main non-motor symptoms of Parkinsons disease (PD), there is inconsistent evidence about the prevalence of OH in PD. To estimate the prevalence of OH in PD more precisely we conducted a systematic review of the literature. METHODS From PubMed and Embase searches with predefined inclusion criteria, we identified studies published up till December 2009. Prevalence numbers from studies were pooled using a non-linear random-effects meta-analysis. RESULTS We found 25 studies from which the prevalence of OH could be calculated. The pooled estimate of the point prevalence of OH in PD was 30.1% (95% CI: 22.9% to 38.4%). We found a large statistical heterogeneity between studies which could not be reduced by several subgroup analyses. CONCLUSIONS The estimated prevalence of OH in PD is 30%. However, due to the large heterogeneity between studies this pooled estimate should be interpreted with caution. More data from unselected population-based cohorts are needed.

Evolution of mild cognitive impairment in Parkinson disease

Objective: We examined the development of Parkinson disease (PD)–mild cognitive impairment (MCI) in patients with newly diagnosed PD over 5 years using recently proposed consensus criteria, and we assessed the reliability of the criteria. Methods: Patients with PD (n = 123) underwent extensive neuropsychological testing at baseline and after 3 (n = 93) and 5 years (n = 59). Two neuropsychologists independently applied the PD-MCI criteria to examine the interrater and intrarater reliability. Results: At baseline, 35% of patients had PD-MCI. Three years later, 53% of the patients had PD-MCI. At 5-year follow-up, 20 patients who had PD-MCI at an earlier assessment had converted to PD dementia and 50% of the remaining patients without dementia had MCI. The interrater reliability (kappa) was 0.91. The intrarater reliabilities were 0.85 and 0.96. Conclusion: Approximately one-third of patients with newly diagnosed PD fulfill the consensus criteria for PD-MCI; after 5 years, this proportion is approximately 50% of patients without dementia. The criteria have good interrater and intrarater reliability.

Prognostic factors of motor impairment, disability, and quality of life in newly diagnosed PD

Objective: In Parkinson disease (PD), the rate of clinical progression is highly variable. To date, there are conflicting findings concerning the prognostic factors influencing the rate of progression. Methodologic issues such as the use of selected patients from therapeutic trials, and short durations of follow-up probably underlie this problem. We therefore designed a prospective follow-up study of a cohort of newly diagnosed patients with PD. Methods: A cohort of 129 patients with newly diagnosed PD was assessed at baseline, and 1, 2, 3, and 5 years later. The rate of progression and its prognostic factors on the level of motor impairments, disability, and quality of life were investigated using linear mixed-model analysis. Results: Annual increase of motor impairments measured with the Unified Parkinsons Disease Rating Scale–Motor Examination was estimated to be 2.46 points (95% confidence interval: 2.05–2.88). The main determinants of faster increase of motor impairments were male sex and cognitive dysfunction at the time of diagnosis. The main determinants of faster increase of disability were higher age at onset, cognitive dysfunction, and the presence of levodopa-nonresponsive motor symptoms at the time of diagnosis. No clinically relevant determinants were found for the decrease in quality of life. Conclusion: This study shows the importance of nondopaminergic symptoms at the time of diagnosis, because these symptoms are the main determinants of increased disability in the first 5 years of the disease.

Cognitive change in newly-diagnosed patients with Parkinson's disease: a 5-year follow-up study

Cognitive change is frequently observed in patients with Parkinsons disease (PD). However, the exact profile and extent of cognitive impairments remain unclear due to the clinical heterogeneity of PD and methodological issues in many previous studies. In this study, we aimed to examine the severity, frequency, and profile of cognitive changes in newly diagnosed PD patients over 5 years. At baseline and after 3 and 5 years, a hospital-based sample of PD patients (n = 59) and healthy controls (n = 40) were given neuropsychological tests covering six cognitive domains. Patients showed greater decline over time than healthy controls on all cognitive domains, except for attention. The profile of decline showed that psychomotor speed and memory were most affected. At the individual level 53% of the patients showed more cognitive decline than controls. Age at onset and memory impairment at baseline predicted cognitive decline. Cognitive functions in PD patients show greater decline in most domains than in healthy elderly over the course of 5 years. Due to selection bias as a result of attrition, the actual degree of decline may be greater than reported here.

Development and external validation of a prognostic model in newly diagnosed Parkinson disease.

Objective: To develop a prognostic model to predict disease outcomes in individual patients with Parkinson disease (PD) and perform an external validation study in an independent cohort. Methods: Model development was done in the Comorbidity and Aging in Rehabilitation Patients: The Influence on Activities (CARPA) cohort (Netherlands). External validation was performed using the Cambridgeshire Parkinsons Incidence from GP to Neurologist (CamPaIGN) cohort (UK). Both are longitudinal incident cohort studies that prospectively followed up patients with PD from the time of diagnosis. A composite outcome measure was made in which patients were classified as having an unfavorable prognosis when they had postural instability or dementia at the 5-year assessment (or at the last assessment before loss to follow-up), or had died before this time. The final model was derived with a backward selection strategy from candidate predictor variables that were measured at baseline. Results: In the resulting model, higher patient age, higher Unified Parkinsons Disease Rating Scale motor examination axial score, and a lower animal fluency score were all associated with a higher probability of an unfavorable outcome. External validation confirmed good discriminative ability between favorable and unfavorable outcomes with an area under the receiver operating characteristic curve of 0.85 (95% confidence interval 0.77–0.93) and a well-calibrated model with a calibration slope of 1.13 and no significant lack of fit (Hosmer-Lemeshow test: p = 0.39). Conclusion: We constructed a model that allows individual patient prognostication at 5 years from diagnosis, using a small set of predictor variables that can easily be obtained by clinicians or research nurses.

Association of BDNF Met66Met polymorphism with arm tremor in cervical dystonia

Cervical dystonia (CD) may be accompanied by a bilateral postural tremor of the arms. The mechanisms leading to dystonia and tremor are not clear; aberrant neuroplasticity may, however, play a role. The brainderived neurotrophic factor (BDNF, OMIM #113505) is involved in neuroplasticity modulation. A functional polymorphism Val66Met (rs6265) in BDNF has been described. Two small association studies have investigated the Val66Met polymorphism in CD, with contradicting results. In order to adequately clarify the role of the Val66Met polymorphism in CD, we investigated this variant in a large, clinically well-defined Dutch CD cohort. All CD patients (n 1⁄4 472) were examined by a movement disorders specialist. A subgroup of CD patients exhibited postural arm tremor, previously termed ‘‘tremor associated with dystonia.’’ An ageand sex-matched control group (711 subjects, not available for examination) was recruited from the Dutch National Blood Bank. All details regarding patient inclusion, genotyping, and data analysis can be found in the Supporting Information. The clinical characteristics of the CD cohort are listed in Table 1. The frequency of the 66Met-allele was 0.21 in the CD group and 0.20 in the unaffected group (P 1⁄4 .60, odds ratio [OR], 1.05; Fisher’s exact test). In addition, no genotype association was found (P 1⁄4 .67). To assess the genetic modifier effects of this polymorphism as they relate to CD, we defined phenotypic subgroups based on postural arm tremor and the spread of symptoms (Table 1). We compared the genotype frequencies of Val66Met between subgroups (Table 1) and found that Met66Met was not associated with an increased risk of segmental spread of dystonia (OR for Met66Met, 0.46; 95% confidence interval [CI], 0.13–1.59; P 1⁄4 .22), nor did it influence the age at onset (AaO, P 1⁄4 .98). Interestingly, we did find a significantly higher frequency of bilateral postural arm tremor in CD patients with the BDNF Met66Met polymorphism (53%), compared to 35% in Val66Met and 29% in Val66Val carriers (P 1⁄4 .02; OR, 2.52; 95% CI, 1.10–5.76). This result could not be attributed to AaO, disease duration, age at examination, or sex (adjusted ORs: 2.60, 2.51, 2.85, and 2.77, respectively). The effect is only present in the homozygous Met66Met and not in theVal66Met group (OR, 1.28; 95% CI, 0.84–1.95; P 1⁄4 .23). The literature tells us that subjects carrying the Met-allele lack training-dependent increases in the motor evoked potential (MEP) amplitude, show a reduced motor map reorganization and a differential response to repetitive transcranial magnetic stimulation (rTMS) plasticity induction protocols. Replication of the association between Met66Met and postural arm tremor in CD will require over 400 CD patients with arm tremor to reach 80% power to detect an equal effect as seen in the present study (OR 2.50 or higher). With a prevalence of arm tremor in CD of approximately 32%, a CD cohort of at least 1250 patients is required. Our findings suggest that the BDNF polymorphism is associated with arm tremor in CD. Further research is needed to investigate whether this effect is only present in CD patients or if BDNF is also a risk factor for other tremor syndromes, such as essential tremor.

Patient perception of deep brain stimulation hardware

Despite the large amount of publications on deep brain stimulation (DBS) hardware–related adverse effects, limited data exist regarding patients’ perception of the implanted hardware, that is, implantable pulse generator (IPG) and extension cables. Therefore, we conducted a survey among a large cohort of DBS patients and report their perception of the implanted materials. In addition, we investigated possible influencing factors on the frequency of hardware-related complaints, such as patientand hardware characteristics. A survey was conducted among 298 patients operated on between 1993 and 2009 to evaluate their perception of the IPG and extension cables connected to the electrodes. We did not send a questionnaire to the remaining 60 patients who were operated on in the same period for the following reasons: deceased, n 5 49; living abroad, n 5 3; DBS system explantation, n 5 5; and procedure abortion, n 5 3. A questionnaire similar to the one mentioned in the article by Sherif and colleagues was used. Patients received unilateral or bilateral single-channel IPGs (Itrel II or Soletra, Medtronic, Minneapolis, MN) or a dual-channel IPG (Kinetra, Medtronic, Minneapolis, MN). The influence of sex and IPG characteristics on the occurrence of hardware-related complaints was analyzed with the chi-square statistic and the Fisher exact test where appropriate. Because the number of patients per subgroup was small, the responses were dichotomized by merging the answers “a little bit,” “considerably,” “much,” and “very much” together as “complaints present.” Statistical analyses were performed with SPSS data collection (version 16.0; SPSS, Inc.). In total, 173 patients (responders; 58%) completed the questionnaire (61 women; mean age, 58.3 years, SD, 11.0 years). Seventy-six percent of the responders had Parkinson’s disease, 13% dystonia, and 12% tremor. The mean time between the first surgery and the questionnaire was 5.5 years (range, 1–17 years). Responders had a higher mean age and more often had Parkinson’s disease than the nonresponders. Overall, 35% of patients experienced discomfort and 15% reported pain from the IPG. The rates of discomfort and pain caused by the extension cables were in the same range: 30% and 17%, respectively. IPGs caused most problems while sleeping (36% of patients). Extension cables gave the most trouble while combing hair (24% of patients; see Table 1). IPG-related pain was more frequent in women than men (28% vs. 9%; P 5 .001). Also, discomfort related to the extension cables was reported twice as often and pain occurred 3 times as often in women compared with men (46% vs. 22% and 30% vs. 10%, respectively; both P 5 .001). Furthermore, women reported more cosmetic issues (31% vs. 17%; P 5 .047). In both sexes, bilaterally implanted single-channel IPGs caused more discomfort than unilaterally implanted dual-channel IPGs (P 5 .025). Six patients had additional surgery because of pain and discomfort from the hardware. In conclusion, a substantial number of patients experience discomfort, pain, and cosmetic issues because of the implanted hardware. These results are in line with the previous report from Sherif and colleagues. Women and patients with bilaterally implanted single-channel IPGs more often report hardware-related complaints. The rates of complaints seem high, but only in a small proportion of patients are they so severe that additional surgery is needed. Hardware perception rates should be incorporated into the information given to patients prior to DBS surgery.

Orthostatic Hypotension in Parkinson's Disease: The Relation of Blood Pressure Tests and Symptoms in Daily Life

Orthostatic hypotension (OH) is common in Parkinsons disease (PD), but the relation between the results of orthostatic blood pressure tests and orthostatic symptoms in daily life is not clear.