Exploring determinants of progression in Parkinson's disease. Is there a difference among Jewish ethnic groups?

INTRODUCTION: Parkinson's disease (PD) displays an individually variable rate of progression, of which the underlying mechanisms are largely unknown, but may involve genetic factors. In this study, we aimed to explore the effect of ethnic origin on PD progression rate in Israeli Jews, as expressed by time from onset until reaching Hoehn and Yahr stage 3 (HY3). METHODS: Consecutive patients with PD followed bi-annually at the Movement Disorders Institute at Sheba Medical Center, were included. Demographic data and clinical information, including age at PD onset (AO), H&Y staging, and family history of PD, were collected. Ethnicity was determined based on the parents' origin and was categorized as Ashkenazi Jews (AJ), Yemenite Jews (YJ), North African Jews (NAJ) and Oriental Jews (OJ) excluding YJ. Associations between the above variables and the time to HY3 were determined using Cox proportional hazards model. Survival curves were derived from the model. RESULTS: Of 707 patients [430 males, AJ: 458, YJ: 37, NAJ: 75 and OJ: 137] included in the analysis, 343 had reached HY3. In a multivariate analysis, a longer time to HY3 was significantly associated with a younger AO (HR = 1.07, p < 0.001). YJ showed a significantly shorter time to HY3 compared to AJ and OJ, but not compared to NAJ. Time to HY3 was significantly shorter for NAJ than for OJ. CONCLUSION: Jewish PD patients of Yemenite and North African origin may have a more rapid progression of PD, compared to those of Ashkenazi and Oriental origin, suggesting distinctive genetic influences.

The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers.

OBJECTIVE: In view of the fact that cancer patterns in patients with Parkinson disease (PD) differ from the general population, we aimed to verify whether patients with PD with LRRK2 mutations have an increased risk for particular cancer types. METHODS: In this cross-sectional study, eligible consenting Jewish patients with PD were genotyped for the predominant LRRK2 G2019S mutation. Oncologic data were obtained by personal interview and reviewing patients' files. Stepwise logistic regression was applied to model the probability of cancer occurrence in carriers vs noncarriers. RESULTS: Overall, 79/490 (16.1%) genotyped patients carried the G2019S mutation. Seventy-seven (16%) were diagnosed with cancer; of those, 67 (14%) with a non-skin cancer. Eighteen (23%) carriers vs 49 (12%) noncarriers had a non-skin cancer (p = 0.01, odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.19-3.99). A significant ethnicity effect was noted (p = 0.045, OR = 1.84, 95% CI 1.02-3.34). Among Ashkenazi patients, age and LRRK2 emerged as significant using stepwise logistic regression including age, gender, and LRRK2 status as explanatory variables. The OR for LRRK2 mutation carriers adjusted for age was 3.38 (95% CI 1.64-6.97, p = 0.0009). CONCLUSIONS: Ashkenazi Jewish patients with PD who harbor the G2019S LRRK2 mutation are more likely to have a concomitant non-skin cancer than noncarriers.

High prevalence of malignant melanoma in Israeli patients with Parkinson's disease.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.

Hypertension increases the probability of Alzheimer's disease and of mild cognitive impairment in an Arab community in northern Israel.

BACKGROUND: We aimed to determine whether vascular risk factors are associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in an elderly Arab population. METHODS: An Arabic-speaking team performed a door-to-door survey of consecutive residents aged > or =65 years. We estimated the odds of AD or MCI versus normal controls as a function of age, gender, education and presence of vascular factors by multinomial logistic regression with interactions. RESULTS: Out of 767 subjects (54% men), 444 were cognitively normal, 234 had MCI and 89 had AD. AD was significantly associated with hypertension (p = 0.01; OR = 2.08; 95% CI: 1.18-3.65), age (p < 0.0001; OR = 1.19; 95% CI: 1.14-1.24), female gender (p = 0.0016; OR = 3.06; 95% CI: 1.53-6.15) and education (p = 0.0002; OR = 0.75; 95% CI: 0.65-0.88). MCI was significantly associated with hypertension (p = 0.0042; OR = 1.69; 95% CI: 1.25-2.44), age (p < 0.0001; OR = 1.06; 95% CI: 1.03-1.09) and education (p < 0.0001; OR = 0.76; 95% CI: 0.71-0.83), but not with gender. CONCLUSIONS: Hypertension, older age and low education significantly increase the probability of AD and MCI. The effect of hypertension on the odds of AD versus controls is over and above the effects of age, gender and education. For MCI versus controls there is no gender effect, and the effect of hypertension is over and above the effects of age and education.

Onset and progression of disease in familial and sporadic Parkinson's disease.

Lately different and rare genetic forms of Parkinson's disease (PD) have been described. Complete genomic screening has suggested that still undefined multiple genetic factors might underlie the development of PD. The course of PD patients with and without genetic background might be different. We compared the age at onset and progression of PD with (FH) and without (NFH) family history. Two hundred forty PD patients attending the outpatient Movement Disorders Clinic were evaluated. The age of onset (AO), the duration of disease until stage III of Hoehn and Yahr (YST3), until dementia (YDEM) and family history of PD were determined by interview, examination of medical files and of affected family members. Patients with young onset who reported another PD patient among their siblings were tested for parkin mutations. Statistical analysis used ANOVA, Fisher's Least Significant Difference, log-rank and Wilcoxon's tests for Kaplan-Meier survival curves taking stage III and dementia as end-points. Of the 240 patients (age 73.3 +/- 10.9 years), 29 (12%) had positive FH. Six of them carried parkin mutations. The AO was 33.5 +/- 8.1 (range 19-42) years for parkin carriers, 59.3 +/- 11.3 (range 34-76) for FH and 66.5 +/- 11.8 (27-91) years for NFH (P < 0.0001). The three groups were significantly different from each other (alpha = 0.05). Stage III and dementia were reached only in non-parkin patients. YST3 was 12.6 +/- 6.6 years for FH and 6.5 +/- 5.0 years for NFH (P < 0.0001). YDEM was 10.1 +/- 6.0 years for FH versus 4.7 +/- 4.5 years for NFH (P = 0.002). Kaplan-Meier survival analysis revealed faster motor (P = 0.0016) and mental decline (P = 0.02) in NFH versus FH. Our results showed that the AO of PD is younger in patients with FH. Motor and mental deterioration, however, showed a less steep course in familial PD patients.

Mental and motor switching in Parkinson's disease.

Switching difficulties in Parkinson's disease (PD) are expressed in both mental and motor tasks. The authors of the present study investigated whether those deficits coexist in the same patient and are positively correlated. They tested 8 nondemented PD patients and 6 age-matched control participants by using the modified Wisconsin Card Sorting Test and a motor switching paradigm that is based on the task of reaching toward visual targets, the location of which could unexpectedly be altered within the reaction time. In both mental and motor tasks, patients performed significantly worse than controls. There were no significant correlations between the two types of pathology in individual patients. Mental and motor switching deteriorate in PD patients, but the deficits are not necessarily of parallel severity.

Acute mania and hemichorea.

A 61-year-old man suddenly became euphoric and talkative. Later the same day, he developed hemichoreic movements of the left limbs. The patient fulfilled the DSM-IV criteria for a manic episode by abnormally and persistently elevated mood, decreased need for sleep, high distractibility, pressured speech, increased goal-directed activity, and hypersexuality. The mood changes persisted for several weeks. Magnetic resonance imaging of the brain showed a right thalamic infarction. The co-occurrence of hemichorea and mania caused by focal thalamic lesion is very rare. It may be explained by dysfunction in basal ganglia thalamocortical circuitry.

Parkin gene causing benign autosomal recessive juvenile parkinsonism.

Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset parkinsonism caused by exonic deletions or point mutations in the parkingene. The relationship between the type of the genetic defect and the clinical presentation, the response to therapy, and the evolution have not been yet determined. The authors describe a single-basepair deletion at nucleotide 202 in exon 2 of the parkin gene in a kindred with a benign clinical course.

Oculopharyngeal MD among Bukhara Jews is due to a founder (GCG)9 mutation in the PABP2 gene.

OBJECTIVE: To determine whether all cases of oculopharyngeal muscular dystrophy (OPMD) among Bukhara Jews share the same founder mutation. BACKGROUND: Autosomal dominant OPMD is caused by a (GCG)8-13 repeat expansion in the polyadenylation binding protein 2 (PABP2) gene. The disease has a worldwide distribution but is particularly prevalent in Bukhara Jews and in French Canadians, in whom it was introduced by three sisters in 1648. METHODS: We established the size of the PABP2 mutation in 23 Bukhara Jewish patients belonging to eight unrelated families. In all families, we constructed haplotypes for the carrying chromosomes composed of the alleles for eight chromosome 14q polymorphic markers. RESULTS: All patients share a (GCG)9 PABP2 mutation and a four-marker haplotype. Furthermore, a shared intron single nucleotide polymorphism (SNP) in the PABP2 gene 2.6Kb from the mutation was not observed in 22 families with (GCG)9 mutations from nine different countries. The smaller size of the chromosomal region in linkage disequilibrium around the mutation in Bukhara Jews, as compared with French Canadians, suggests a founder effect that occurred more than 350 years ago. Based on the Luria-Delbrück corrected "genetic clock," we estimate that the mutation appeared or was introduced once in the Bukhara Jewish population between AD 872 and 1512 (mean, AD 1243). CONCLUSION: OPMD among Bukhara Jews is the result of a shared, historically distinct, PABP2 (GCG)9 mutation that likely arose or was introduced in this population at the time they first settled in Bukhara and Samarkand during the 13th or 14th centuries.

A comparison of dopamine agonists and catechol-O-methyltransferase inhibitors in Parkinson's disease.

To compare the efficacy and tolerability of three dopamine agonists--pergolide (PRG), pramipexole (PRX), and ropinirole (ROP)-and two catechol-O-methyltranferase (COMT) inhibitors-tolcapone (TOL) and entacapone (ENT)-as add-on therapies to levodopa (L-Dopa) in Parkinson's disease, we analyzed randomized, double-blind, placebo-controlled, multicenter studies. To our knowledge, they had not yet been evaluated in comparison with each other. Statistical analyses used odds ratios, numbers needed to harm, and Fisher's inverse chi2 method. Seven studies meeting the inclusion criteria included treatment of 1,756 patients. The common efficacy measures were the reduction of L-Dopa dose and "off' duration. The reported reduction in L-Dopa dose was significant for all drugs in relation to placebo, but was most significant for PRX and ENT (p < 0.0001). The most significant reduction in "off' duration was with PRG, PRX, and ENT (p < 0.001). The common tolerability measures were the percentage of patients withdrawn because of side effects, because of any reason, and because of the development of dyskinesias. Ropinirole, PRX, and ENT caused fewer withdrawals related to side effects. Pergolide was better than other analyzed drugs concerning withdrawals for any reason. All drugs caused more dyskinesias than placebo (p < 0.0001), with overlapping confidence intervals, except for TOL 600 mg, which caused more dyskinesias than dopamine agonists and ENT. Pramipexole and ENT had the best efficacy and tolerability profile in this analysis.

Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson's disease: a double-blind study as adjunctive therapy to levodopa.

Rasagiline mesylate (TVP-1012) is a potent, selective, non-reversible MAO-B inhibitor, without the tyramine-potentiating effect and with neuroprotective activities. The benefit of rasagiline as monotherapy in patients with early Parkinson's disease (PD) has already been reported. To evaluate the safety, tolerability, and clinical effect of rasagiline as adjunctive therapy to levodopa, a multicenter, double-blind, randomized, placebo-controlled, parallel-group study (0.5, 1, and 2 mg/d) was conducted for 12 weeks in 70 patients with PD (mean age, 57.4 y; mean disease duration, 5.7 y; 32 patients had motor fluctuations). A beneficial clinical effect was observed in fluctuating patients treated with rasagiline (all doses), expressed as a decrease in total Unified Parkinson's Disease Rating Scale (UPDRS) score (23.0% vs 8.5% in the placebo group). The treatment effect was still evident 6 weeks after drug discontinuation (in all doses). The safety and tolerability of rasagiline were good. Adverse events were no different than those of patients taking placebo. Almost complete platelet MAO-B inhibition was obtained at all rasagiline doses. This study has demonstrated that rasagiline (up to 2 mg/day) has a good safety profile and a beneficial clinical effect in fluctuating patients with PD when given as an add-on to chronic levodopa therapy.

Autosomal-recessive juvenile parkinsonism in a Jewish Yemenite kindred: mutation of Parkin gene.

We report a Jewish family of Yemenite origin in which three brothers born from a consanguineous marriage had juvenile parkinsonism. The DNA samples from three affected brothers and one healthy brother were analyzed for the linkage to markers covering the autosomal-recessive juvenile parkinsonism (AR-JP) locus. A perfect homozygous cosegregation to the markers was found, giving a maximal lod score of 3.11 at D6S1579, D6S305, and D6S411, all of which are 0 cm apart from each other (nonparametric linkage score, 8.041; p = 0.000977). Exon 3 of the Parkin gene was homozygously deleted in all patients. The AR-JP gene also exists in the Jewish population.

A statistical method for quantitative evaluation of the progression of chronic diseases: the mean score graph (MSG).

We present a quantitative method of evaluation of the clinical course of chronic disease with long-term progressive deterioration. The method takes into account information on all patients, whatever their duration of follow-up. We present the 'mean score graph' as a descriptive device which is an extension of a survival graph. The description of progression of idiopathic torsion dystonia, comparing progression in males and females, is used as an example of the application. A test for group comparison is described.

Motor switching abilities in Parkinson's disease and old age: temporal aspects.

OBJECTIVES: To investigate capabilities of arm trajectory modification in patients with Parkinson's disease and elderly subjects using a double step target displacement paradigm. METHODS: Nine patients with Parkinson's disease and seven age matched control subjects were instructed to move a stylus towards visual targets presented on a digitising table. Within each session, in some trials the target location was changed before initiation of movement and the subjects were to modify their movements towards the new target (switching trials). In other trials the target location was not changed (control trials). This procedure was repeated for four different target configurations, using interstimulus time intervals of six different durations. The subjects' hand trajectories were recorded and their kinematic characteristics were analysed. RESULTS: In switching trials, about 40% of the movements were aimed directly toward the final target location in both groups. When the trajectories were initially directed toward the first target and then modified toward the second, the reaction time (RT) to the second stimulus (RT2) was longer than to the first stimulus (RT1). The RT2/RT1 ratio was significantly larger in patients with Parkinson's disease than in healthy elderly subjects. CONCLUSIONS: Patients with Parkinson's disease and elderly subjects are substantially slower in responding to a required modification of their movement than in responding to the required movement initiation. Patients with Parkinson's disease have impaired capabilities in processing simultaneously the motor responses to two visual stimuli presented in rapid succession.