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Background: Vertical perturbations are one major cause of falling. Incidentally, while conducting a comprehensive study comparing effects of vertical versus horizontal perturbations, we commonly observed a stumbling-like response induced by upward perturbations. The present study describes and characterizes this stumbling effect. Methods: Fourteen individuals (10 male; 27 ± 4 yr) walked self-paced on a treadmill embedded in a moveable platform and synchronized to a virtual reality system. Participants experienced 36 perturbations (12 types). Here, we report only on upward perturbations. We determined stumbling based on visual inspection of recorded videos, and calculated stride time and anteroposterior, whole-body center of mass (COM) distance relative to the heel, i.e., COM-to-heel distance, extrapolated COM (xCOM) and margin of stability (MOS) before and after perturbation. Results: From 68 upward perturbations across 14 participants, 75% provoked stumbling. During the first gait cycle post-perturbation, stride time decreased in the perturbed foot and the unperturbed foot (perturbed = 1.004 s vs. baseline = 1.119 s and unperturbed = 1.017 s vs. baseline = 1.125 s, p < 0.001). In the perturbed foot, the difference was larger in stumbling-provoking perturbations (stumbling: 0.15 s vs. non-stumbling: 0.020 s, p = 0.004). In addition, the COM-to-heel distance decreased during the first and second gait cycles after perturbation in both feet (first cycle: 0.58 m, second cycle: 0.665 m vs. baseline: 0.72 m, p-values

We previously reported on interhemispheric cortical hyper synchronization in PD. The aim of the present study was to address the hypothesis that increased interhemispheric cortical synchronization in PD is related to dopamine deficiency and is correlated with motor function.We studied participants with PD and characterized cortical synchronization with reference to brain regions. Electroencephalography (EEG) was recorded from 20 participants with PD while OFF and ON their dopaminergic medications (two separate visits), during quiet standing and straight-line walking. Cortical interactions in the theta, alpha, beta, and gamma brain wave frequency bands were evaluated using interhemispheric phase synchronization (inter-PS).Inter-PS values were found to be significantly higher during the OFF state as compared to the ON state in standing and walking trials for theta, alpha and beta bands. In addition, inter-PS reduction from OFF to ON was associated with mobility improvement evaluated by the Timed Up and Go test, and with daily levodopa equivalent dose across individuals. Higher differences in inter-PS values between OFF and ON states were evident mainly in the occipital-parietal cortex.Persons with PD have increased inter-PS during the OFF state compared to their ON state, and this increase in inter-PS is associated with the clinical improvement between OFF and ON. We speculate that these findings, together with previous evidence of higher inter-PS in PD as compared to healthy older adults, reflect neuronal processes consequential to asymmetric subcortical dopamine deficiency.

Introduction Parkinson's disease (PD) is characterized by gait disturbances, which become severe during the advanced stages of the disease. Though gait impairments in Parkinson's disease have been extensively described in terms of spatiotemporal gait parameters, little is known regarding associated patterns of cortical activity. The objective of the present study is to test if interhemispheric synchronization differs between participants with PD and healthy elderly controls (NPD). We analyzed electroencephalography (EEG) signals recorded during bilateral movements, i.e., locomotion and hand tapping. Methods Fifteen participants with PD (‘OFF’ their anti-parkinsonian medications) and eight NPD were assessed during quiet standing, straight-line walking, turning, and hand tapping tasks. Using a 32-electrode EEG array, we quantified the synchronization in periodic cortical activation between the brain hemispheres (interhemispheric phase synchronization; inter-PS). Theta, alpha, beta, and gamma bands were evaluated. Results In all bands, inter-PS was significantly higher for the PD group as compared with the NPD group during standing and walking (p Conclusions Persons with PD exhibit increased inter-PS as compared with NPD participants. These findings support previous evidence from animal studies, that bilateral cortical hypersynchronization emerges from the asymmetric neural degeneration that is at the base of the disease. Future studies should elucidate the long-term temporal development of this hypersynchronization and its clinical relevance (e.g., can it ‘serve’ as prodromal marker?).

Background Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. Methods Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. Results Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. Conclusions The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. (c) 2019 International Parkinson and Movement Disorder Society

BackgroundVirtual reality (VR) has emerged as a therapeutic tool facilitating motor learning for balance and gait rehabilitation. The evidence, however, has not yet resulted in standardized guidelines. The aim of this study was to systematically review the application of VR-based rehabilitation of balance and gait in 6 neurologic cohorts, describing methodologic quality, intervention programs, and reported efficacy.MethodsThis study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. VR-based treatments of Parkinson disease, multiple sclerosis, acute and chronic poststroke, traumatic brain injury, and cerebral palsy were researched in PubMed and Scopus, including earliest available records. Therapeutic validity (CONTENT scale) and risk of bias in randomized controlled trials (RCT) (Cochrane Collaboration tool) and non-RCT (Newcastle-Ottawa scale) were assessed.ResultsNinety-seven articles were included, 68 published in 2013 or later. VR improved balance and gait in all cohorts, especially when combined with conventional rehabilitation. Most studies presented poor methodologic quality, lacked a clear rationale for intervention programs, and did not utilize motor learning principles meticulously. RCTs with more robust methodologic designs were widely recommended.ConclusionOur results suggest that VR-based rehabilitation is developing rapidly, has the potential to improve balance and gait in neurologic patients, and brings additional benefits when combined with conventional rehabilitation. This systematic review provides detailed information for developing theory-driven protocols that may assist overcoming the observed lack of argued choices for intervention programs and motor learning implementation and serves as a reference for the design and planning of personalized VR-based treatments.RegistrationPROSPERO CRD42016042051.

The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson disease (PD) are unclear, but plausibly involve common pathways. 129Ser-phosphorylated α-synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins are involved in melanomagenesis. Conversely, genes associated with CMM affect PD risk. PD/CMM-targeted cells share neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. Ann Neurol 2016;80:811-820.

Providing care to people with Parkinson's disease (PD) poses challenges for family carers, including experiencing stigmatic beliefs -i.e., family stigma. However, to the best of our knowledge, there is no empirical study examining the stigmatic experiences of family members of people with PD. This was the aim of the present study. Three focus groups with 22 Israeli spouses of people with PD were conducted. Data were analyzed using theory-led thematic analysis. Overall, the spouses in our study shared mainly experiences of the stigma attached to the illness and/or to their loved ones, and not to themselves as carers. Three major themes emerged: the stereotypes that typify PD, stigmatizing behaviors towards the person with the disease, and structural stigma. Our findings highlight the profound stigma confronting carers of persons with PD, particularly when it comes to structural stigma.

The law of intersegmental coordination (Borghese et al. 1996) may be altered in pathological conditions. Here we investigated the contribution of the basal ganglia (BG) and the cerebellum to lower limb intersegmental coordination by inspecting the plane’s orientation and other parameters pertinent to this law in patients with idiopathic Parkinson’s disease (PD) or cerebellar ataxia (CA). We also applied a mathematical model that successfully accounts for the intersegmental law of coordination observed in control subjects (Barliya et al. 2009). In the present study, we compared the planarity index (PI), covariation plane (CVP) orientation, and CVP orientation predicted by the model in 11 PD patients, 8 CA patients, and two groups of healthy subjects matched for age, height, weight, and gender to each patient group (Ctrl_PD and Ctrl_CA). Controls were instructed to alter their gait speed to match those of their respective patient group. PD patients were examined after overnight withdrawal of anti-parkinsonian medications (PD-off-med) and then on medication (PD-on-med). PI was above 96% in all gait conditions in all groups suggesting that the law of intersegmental coordination is preserved in both BG and cerebellar pathology. However, the measured and predicted CVP orientations rotated in PD-on-med and PD-off-med compared with Ctrl_PD and in CA vs. Ctrl_CA. These rotations caused by PD and CA were in opposite directions suggesting differences in the roles of the BG and cerebellum in intersegmental coordination during human locomotion. NEW & NOTEWORTHY Kinematic and muscular synergies may have a role in overcoming motor redundancies, which may be reflected in intersegmental covariation. Basal ganglia and cerebellar networks were suggested to be involved in crafting and modulating synergies. We thus compared intersegmental coordination in Parkinson’s disease and cerebellar disease patients and found opposite effects in some aspects. Further research integrating muscle activities as well as biomechanical and neural control modeling are needed to account for these findings.

Kufor-Rakeb syndrome (KRS)/PARK9 presents with autosomal recessive young onset Parkinson's disease (YOPD), spastic paraparesis, abnormal eye movements and facial myokymia. KRS is caused by homozygous/compound heterozygous inactivating mutations in ATP13A2. Two affected siblings (born to non-consanguineous Jewish parents) presenting a similar KRS phenotype (onset age 27, 23), carried compound heterozygous pathogenic variants in ATP13A2:c. 217_218insG and c. 3057delC. Allele frequency of the c. 3057delC mutation was about 100 times higher in Ashkenazi controls in our study (1/190 = 0.00526) and in the Genome Aggregation Database, (GnomAD, 27/10132 = 0.002665) versus non-Ashkenazi controls worldwide in GnomAD (9/264566 = 0.000034018, p < 0.0001). The c.217 218insG mutation is novel and not found in controls or GnomAD. The c.3057delC mutation should be included in the genetic workup of Ashkenazi YOPD patients.

BACKGROUND Vascular risk factors and lack of formal education may increase the risk of Alzheimer's disease (AD). OBJECTIVE To determine the contribution of vascular risk factors and education to the risk of mild cognitive impairment (MCI) and AD and to estimate the risk for conversion from MCI to AD. METHODS This door-to-door survey was performed by an Arab-speaking team in Wadi Ara villages in Israel. All consenting residents aged ≥ 65 years were interviewed for medical history and underwent neurological and cognitive examinations. Individuals were cognitively classified as normal (CN), MCI, AD, vascular dementia, or unclassifiable. MCI patients were re-examined at least one year later to determine conversion to AD. The contributions of age, gender, school years, and vascular risk factors to the probability of conversion were estimated using logistic regression models. RESULTS Of the 906 participants, 297 (33%) had MCI and 95 (10%) had AD. Older age (p = 0.0008), female gender (p = 0.023), low schooling (p < 0.0001), and hypertension (p = 0.0002) significantly accounted for risk of MCI versus CN, and diabetes was borderline (p = 0.051). The risk of AD versus CN was significantly associated with age (p < 0.0001), female gender (p < 0.0001), low schooling (p = 0.004) and hypertension (p = 0.049). Of the 231 subjects with MCI that were re-examined, 65 converted to AD. CONCLUSIONS In this population, age, female gender, lack of formal education, and hypertension are risk factors for both AD and MCI. Conversion risk from MCI to AD could be estimated as a function of age, time interval between examinations, and hypertension.

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).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), HY 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.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, p0.001). 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.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 interaction between visual perception and proprioception is essential during locomotion. Manipulating visual flow and surface inclination facilitates the investigation of the mechanisms underlying this sensorimotor integration. Some studies suggest that visual flow leads to adjustment of postural control and modulates walking speed on inclined surfaces. However, this interaction must be better elucidated before it can be applied to improve gait in a clinical rehabilitation context. The aim of this study is to evaluate gait adaptation in healthy adults exposed to conflictive visual flow depicting inclined surfaces during level walking. Eighteen healthy participants (nine male; age: 29±4 years; BMI: 23.2±3.2 kg/m2) walked on a level treadmill (in self-paced mode) synchronized to a motion capture system. Simultaneously, a fully immersive virtual reality system projected a virtual environment depicting a one-lane road on a full-room dome-shaped screen. This paper reports on three walking conditions (out of nine randomly presented): [1]: level visual flow, [2]: visual flow switches to uphill (+10°), and [3]: visual flow switches to downhill (−10°). In conditions 2 & 3, visual flow changed when the participant reached steady-state velocity, and the new visual flow lasted for 70 seconds. We compared walking during non-conflicting level visual flow with the other conditions and characterized the temporal pattern of the visual conflict effect. In addition, we evaluated changes in spatiotemporal parameters (step and stride length) as well as joint angles (knee, elbow and pelvis) during the course of the effect. Conflictive visual flow significantly influenced gait. Walking speed increased in uphill (p=0.038) and decreased in downhill (p=0.002) visual conflictive conditions, as compared to the level condition. Further, walking speed differed between the uphill and downhill visual conflict conditions (p=0.001). An early-stage effect peaked at 10.7 and 9.9 seconds, and returned to baseline at 23.8 and 20.7 seconds, respectively, after onset of visual conflict. Range of motion in the assessed joint angles increased during the effect (p

Introduction In this retrospective study, we compared motor disease progression in Ashkenazi-Jewish (AJ) Parkinson's disease (PD) patients carrying the LRRK2*G2019S mutation with that of noncarriers. Methods Consecutive PD patients were recruited between 2004 and 2011. Disease progression of carriers versus noncarriers was compared using survival analysis, where the end-point was the time from PD onset to reaching Hoehn and Yahr stage 3 (HY3). Results Overall, 405 AJ PD patients (males = 241[60%]) were genotyped, of whom 60 (males = 30) were LRRK2*G2019S mutation carriers. Time to HY3 did not differ significantly between mutation carriers and noncarriers (hazard ratio = 1.21, 95%CI = 0.83-1.77, P = 0.33). Age at PD onset was younger for carriers than for noncarriers (59.1 ± 9.8 vs. 63.2 ± 12.0 years, respectively; P = 0.005). In both groups, young age at onset was strongly associated with longer time to HY3, (P

Objective Creative thinking requires a combination of originality, flexibility, and usefulness. Several reports described enhanced artistic creativity in Parkinson disease (PD) patients treated with dopaminergic agents. We aimed to examine PD patients' ability to perform creativity tasks compared to healthy controls and to verify whether creativity is related to an impulse control disorder (ICD) as a complication of dopaminergic therapy. Methods Right-handed PD patients treated with dopamine agonists and/or levodopa, and age- and education- matched neurologically healthy controls were assessed using the Montreal Cognitive Assessment, semantic verbal fluency, Beck Depression Inventory, and Questionnaire for Impulsive–Compulsive Disorders in Parkinson Disease Rating Scale (QUIP-RS). Creativity assessment included Comprehension of Novel Metaphors (CNM), Remote Association Test, and Tel Aviv Creativity Test (TACT). Groups were compared using analyses of variance, t tests, and correlation analyses. Results Twenty-seven PD patients (age, mean ± standard deviation = 62 ± 7 years; education = 16 ± 3 years; disease duration = 5.8 ± 3.9 years) and 27 controls (age = 59 ± 9 years; education 17 ± 3 years) participated. PD patients performed significantly better than controls in divergent thinking tasks; specifically, the TACT-Visual for both fluency (33.48 ± 11.83 vs 25.59 ± 10.27, p = 0.034) and quality (15.78 ± 7.6 vs 11.19 ± 6.22, p = 0.025). Comprehension of Novel Metaphors was better in PD patients vs controls (0.71 ± 0.23 vs 0.55 ± 0.29, p = 0.04). QUIP-RS scores did not correlate with creativity measures. Interpretation PD patients treated with dopaminergic drugs demonstrated enhanced verbal and visual creativity as compared to neurologically healthy controls. This feature was unrelated to ICD. Dopaminergic agents might act through the reduction of latent inhibition, resulting in widening of the associative network and enriched divergent thinking. Ann Neurol 2014;75:935–942

Levodopa-induced dyskinesias (LID) present a common but elusive complication of levodopa therapy in Parkinson's disease (PD). In order to identify genetic factors associated with LID, 352 (213 males) levodopa-treated Israeli PD patients were genotyped for 34 polymorphisms within three candidate genes affecting dopaminergic activity and synaptic plasticity: dopamine transporter gene (DAT1 or SLC6A3) [14 single nucleotide polymorphisms (SNPs) and 40-bp variable number tandem repeat (VNTR)], DRD2 [11 SNPs and dinucleotide CA short tandem repeat (STR)], and BDNF (7 SNPs). A comparison of patients with and without LID was performed by applying a time-oriented approach, with survival analyses evaluating LID development hazard rate over time [Cox proportional hazards and accelerated failure time (AFT) lognormal models]. Overall, 192 (54.5 %) participants developed LID, with a mean latency of 5.0 (±4.5) years. After adjusting for gender, age at PD onset, duration of symptoms prior to levodopa exposure, and multiple testing correction, one SNP in SLC6A3 (with 81 % genotyping success) was significantly associated with LID latency: the C allele of the rs393795 extended the time to LID onset, time ratio = 4.96 (95 % CI, 2.3-10.9; p = 4.1 × 10(-5)). This finding should be validated in larger, ethnically diverse PD populations, and the biological mechanism should be explored.

The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson disease (PD) are unclear, but plausibly involve common pathways. 129Ser-phosphorylated α-synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins are involved in melanomagenesis. Conversely, genes associated with CMM affect PD risk. PD/CMM-targeted cells share neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. Ann Neurol 2016;80:811-820.

The prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have not been well been studied in Arab populations. In a door-to-door study of all residents aged ≥ 65 years in Wadi-Ara, an Arab community in northern Israel, we estimated the prevalence of AD, MCI, and the risk of conversion to AD. Subjects were classified as cognitively normal, MCI, AD, or other based on neurological and cognitive examination (in Arabic). MCI subjects were re-examined (interval ≥ 1 year) to determine conversion to AD and contributions of age, gender, and education to the probability of conversion. Of the 944 participants (96.6% of those approached; 49.4% men), 92 (9.8%) had AD. An unusually high prevalence of MCI (n = 303, 32.1%) was observed. Since the majority of women (77.2%) had no schooling, we estimated the effect of gender on the risk of AD and MCI among subjects without schooling and of school years among men. Among subjects with no schooling (n = 452), age (p = 0.02) and female gender (p < 0.0001) were significant predictors of AD, whereas risk of MCI increased only with age (p = 0.0001). Among men (n = 318), age increased the risk (p < 0.0001), school years reduced the risk of AD (p = 0.039) and similarly for MCI [age (p = 0.0001); school years (p = 0.0007)]. Age (p = 0.013), but not gender or school years, was a significant predictor of conversion from MCI to AD (annual rate 5.7%). The prevalence of MCI and AD are unusually high in Wadi Ara, while the rate of conversion from MCI to AD is low. Yet unidentified genetic factors might underlie this observation.

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 patients9 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.

Benign hereditary chorea (BHC, MIM 118700) is a rare autosomal dominant disorder manifesting with chorea in conjunction with hypothyroidism and respiratory problems, a triad also named "brain-lung-thyroid syndrome". BHC is characterized by childhood onset with minimal or no progression into adult life and normal cognitive function. The genetic basis of BHC has been partially resolved, when mutations in the TTF1 gene on chromosome 14q13 encoding the thyroid transcription factor-1 have been identified in a number of BHC patients, suggesting that aberration of TTF1 transcriptional function or haploinsufficiency is associated with this disorder. TTF1 (also known as TITF1, TEBP or NKX2-1), belonging to the NKX2 homeodomain transcription factor family, has been implicated in several important molecular pathways essential for brain, thyroid and lung morphogenesis. Clinical evaluation of TTF1 gene mutations carrier patients exposed the involvement of each of the triad's components characterized by heterogeneity between index cases and even within families. This review highlights the current updates on expanded clinical aspects of BHC, imaging and treatment experience, its genetic markers, proposed molecular mechanisms, animal models and link to cancer.

Alzheimer's disease (AD) is highly prevalent in Wadi Ara despite the low frequency of apolipoprotein E 4 in this genetically isolated Arab community in northern Israel. We hypothesized that the reduced genetic variability in combination with increased homozygosity would facilitate identification of genetic variants that contribute to the high rate of AD in this community. AD cases (n = 124) and controls (n = 142) from Wadi Ara were genotyped for a genome-wide set of more than 300,000 single nucleotides polymorphisms (SNPs) which were used to calculate measures of population stratification and inbreeding, and to identify regions of autozygosity. Although a high degree of relatedness was evident in both AD cases and controls, controls were significantly more related and contained more autozygous regions than AD cases (p = 0.004). Eight autozygous regions on seven different chromosomes were more frequent in controls than the AD cases, and 116 SNPs in these regions, primarily on chromosomes 2, 6, and 9, were nominally associated with AD. The association with rs3130283 in AGPAT1 on chromosome 6 was observed in a meta-analysis of seven genome-wide association study (GWAS) datasets. Analysis of the full Wadi Ara GWAS dataset revealed 220 SNP associations with AD at p ≤ 10 −5 , and seven of these were confirmed in the replication GWAS datasets (p < 0.05). The unique population structure of Wadi Ara enhanced efforts to identify genetic variants that might partially explain the high prevalence of AD in the region. Several of these variants show modest evidence for association in other Caucasian populations.

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.

Background: We describe the four decades follow-up of 14 parkin patients belonging to two large eight-generation-long in-bred Muslim-Arab kindreds. Results: All patients had a single base-pair of adenine deletion at nucleotide 202 of exon 2 (202A) of the parkin gene (all homozygous, one heterozygous). Parkinson's disease onset age was 17–68 years. Special features were intractable axial symptoms (low back pain, scoliosis, camptocormia, antecollis), postural tremor, and preserved cognition. Conclusions: The 202A deletion of the parkin gene causes early-onset Parkinson's disease with marked levodopa/STN-DBS–resistant axial features. Postural tremor and preserved cognition, even after 40 years of disease, were also evident. © 2010 Movement Disorder Society

Mild Cognitive Impariment (MCI) and healthy aging have been shown to be associated with Mild Parkinsonian Signs (MPS). We performed a door-to-door observational and follow-up study amongst consenting residents of Wadi Ara Arab villages in northern Israel aged ≥ 65 years (n = 687) to examine whether MPS represent a risk factor for MCI and/or conversion from MCI to Alzheimer’s disease (AD). In Phase 1, 223 cognitively normal (CN) and 173 MCI subjects were assessed by interview for medical history, neurological examination, motor part of the Unified Parkinson Disease Rating Scale (mUPDRS) (divided into item-clusters: axial, limb bradykinesia, tremor and rigidity) and cognitive tests. MCI subjects (n = 111) were reevaluated in Phase 2 for conversion to AD at least one year after initial assessment. MCI subjects had a higher frequency of axial dysfunction (8.7% vs. 1.3%) and limb bradykinesia (10.4% vs. 1.3%) than CN subjects (p < 0.001, both). Stepwise logistic regression analysis estimating the probability of MCI vs. CN revealed higher mUPDRS (OR = 1.19, 95% CI, 1.05 to 1.35, p = 0.006) and higher limb bradykinesia scores (OR = 1.75, 95% CI, 1.2 to 2.56, p = 0.003) and not age as explanatory variables. Presence of MPS did not predict conversion to AD after adjustment for age and time-interval. These results suggest that axial and bradykinetic parkinsonian signs represent risk factors for MCI but MPS may not predict conversion from MCI to AD.

This article proposes the establishment of a United States–Israel Longitudinal Database for Healthy Aging and Preclinical Dementia as a prototype model for the eventual creation of an international database. It is envisioned that such a comprehensive international database, as a shared research resource, will provide the foundation for a systems approach to solve the dual public health problems of: (1) Early detection of individuals at an elevated risk of developing Alzheimer's disease, and (2) Developing interventions to delay onset of, or prevent, chronic brain disorders later in life.

The occurrence of dementia in genetic Parkinson's disease is heterogeneous. The onset and progression of diverse forms of familial Parkinson's disease might be different than that of sporadic disease. Since dementia is an age related process, its risk increases with advanced disease severity and duration. The onset and progression of dementia is expected to vary between genetic forms, which present at diverse ages with different symptomatologies. It seems that genetic Parkinson's disease variants in which Lewy bodies are the prominent pathological hallmark - such as in PARK1, PARK4 and PARK8 - dementia is part of the phenotype. On the contrary, in PARK2 which is not accompanied by Lewy body accumulation, patients do not show a systematic cognitive decline. This review presents information on dementia in genetic forms of Parkinson's disease.

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 ≧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.

Although the risk for most cancers appears to be relatively low in patients with Parkinson's disease (PD), skin cancers and melanomas occur more frequently in the PD population as compared to controls. This article summarizes the findings of cohort studies on skin cancer in Parkinson's disease. Given that melanoma may precede use of L-dopa, the increased risk of melanoma for PD patients cannot be attributed to L-dopa. On the basis of these observations it may be reasonable to recommend that all patients with PD, whether treated with L-dopa or not, should undergo regular dermatological screening for neoplastic or pre-neoplastic skin lesions, especially melanoma.

Essential tremor (ET) is much more prevalent than Parkinson's disease (PD) in Western countries. We estimated ET and PD prevalence in Wadi Ara Arabic villages in Northern Israel. In this door-to-door survey, all consenting residents aged >or=65 years were systematically examined by an Arabic speaking team. No prescreening questionnaires were used. A random sample of 900 subjects [437 males, mean age (SD) = 72.6 years (6.6)] of the 2,163 eligible residents were evaluated. Sixteen subjects had an action, intentional tremor. Tremor prevalence was estimated as 1.78% (95% CI 1.1-2.87). Nine of these had another likely cause of tremor. Only 7 patients were diagnosed as ET [prevalence 0.78% (95% CI 0.38-1.6)]. PD was diagnosed in 13 subjects. PD prevalence was 1.44% (95% CI 0.84-2.45). ET is unusually uncommon in this population and possibly even less frequent than PD. The PD prevalence in Wadi Ara is similar to that reported in Western countries.

Benign hereditary chorea (BHC) is a rare autosomal dominant nonprogressive movement disorder. In some cases the phenotype includes, besides choreoathetosis, thyroid dysfunction and pulmonary infections in infancy, as expressed by the name "Brain-Thyroid-Lung syndrome". Mutations in the thyroid transcription factor-1 (TITF-1) gene have been identified in some BHC families. We present the phenotypic features of a family with chorea, hypothyroidism, and lung dysfunction. All affected individuals suffered from a nonprogressive chorea with infancy onset. All showed short stature and some webbed neck. One patient suffered from psychosis at the age of 27 years another from lung carcinoma. In all affected individuals, a novel mutation consisting of heterozygous C to A substitution at position 650 of the coding sequence of the TITF-1 gene, exon 3 was detected, leading to a premature stop at codon 217 (S217X). We describe the unique phenotypic features and intrafamilial variability expressing this novel mutation.

Introduction This review on micrographia aims to draw the clinician's attention to non-Parkinsonian etiologies, provide clues to differential diagnosis, and summarize current knowledge on the phenomenology, etiology, and mechanisms underlying micrographia. Methods A systematic review of the existing literature was performed. Results Micrographia, namely small sized handwriting has long been attributed to Parkinson's disease. However, it has often been observed as part of the clinical picture of additional neurodegenerative disorders, sometimes antedating the motor signs, or following focal basal ganglia lesions without any accompanying parkinsonism, suggesting that bradykinesia and rigidity are not sine-qua-non for the development of this phenomenon. Therefore, micrographia in a patient with no signs of parkinsonism may prompt the clinician to perform imaging in order to exclude a focal basal ganglia lesion. Dopaminergic etiology in this and other cases is doubtful, since levodopa ameliorates letter stroke size only partially, and only in some patients. Parkinsonian handwriting is often characterized by lack of fluency, slowness, and less frequently by micrographia. Deviations from kinematic laws of motion that govern normal movement, including the lack of movement smoothness and inability to scale movement amplitude to the desired size, may reflect impairments in motion planning, possible loss of automaticity and reduced movement vigor. Conclusions The etiology, neuroanatomy, mechanisms and models of micrographia are discussed. Dysfunction of the basal ganglia circuitry induced by neurodegeneration or disruption by focal damage give rise to micrographia.

To estimate the prevalence of essential tremor (ET) in Arabic villages of Wadi Ara. The prevalence ET which is higher than Parkinson’s disease in North America and Europe, differs according to study population and methodology. Since hospital record based epidemiology carries referral bias and might provide low estimates of ET prevalence, we carried a population based survey. This door-to-door survey comprised the Arabic villages of Wadi Ara in Northern Israel. Consecutive residents who agreed to participate in the study and were older than 64 years at prevalence day, underwent neurological examination. Medical and family history, medication and response to medication were recorded. Of the 444 subjects that were approached, 428 agreed to participate in the study (refusal rate 3.6%). Four were excluded owing to severe systemic disease. The study population consisted of 424 subjects (54% men, mean age 74 ± 7 years). A clearly oscillatory action tremor of moderate amplitude was observed in 8 patients (age 75 ± 7 years). Six patients had another possible cause of tremor. The prevalence of ET was calculated as 1.89% (95% CI 1.76–2.0) when all tremor cases were accepted as possible ET and 0.47% (95 CI 0.43–0.52) when patients with other causes of tremor were excluded. The prevalence of ET in Arabic villages of Wadi Ara is low.

Several lines of evidence support for a role of angiotensin converting enzyme (ACE) in Alzheimer disease (AD). Most genetic studies have focused on an Alu insertion/deletion (I/D) polymorphism in the ACE gene (DCP1) and have yielded conflicting results. We evaluated the association between 15 single-nucleotide polymorphisms (SNPs) in DCP1, including the I/D variant, and AD in a sample of 92 patients with AD and 166 nondemented controls from an inbred Israeli Arab community. Although there was no evidence for association between AD and I/D, we observed significant association with SNPs rs4343 (P = .00001) and rs4351 (P = .01). Haplotype analysis revealed remarkably significant evidence of association with the SNP combination rs4343 and rs4351 (global P = 7.5 x 10(-7)). Individuals possessing the haplotype "GA" (frequency 0.21 in cases and 0.01 in controls) derived from these SNPs had a 45-fold increased risk of developing AD (95% CI 6.0-343.2) compared with those possessing any of the other three haplotypes. Longer range haplotypes including I/D were even more significant (lowest global P = 1.1 x 10(-12)), but the only consistently associated alleles were in rs4343 and rs4351. These results suggest that a variant in close proximity to rs4343 and rs4351 modulates susceptibility to AD in this community.

We screened LRRK2 mutations in exon 41 in 904 parkin-negative Parkinson's disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.3%) among 868 PD probands, including 2 sporadic cases and 8 (6.2%) of 130 autosomal dominant PD families. The LRRK2 mutations in exon 41 exhibited relatively common and worldwide distribution. Among the three mutations in exon 41, it has been reported that Caucasian patients with G2019S mutation have a single-founder effect. In the present study, Japanese patients with G2019S were unlikely to have a single founder from the Caucasian patients. In contrast, I2020T mutation has a single-founder effect in Japanese patients. Clinically, patients with LRRK2 mutations had typical idiopathic PD. Notably, several patients developed dementia and psychosis, and one with I2020T had low cardiac 123I-metaiodobenzylguanidine (MIBG) heart/mediastinum ratio, although the ratio was not low in other patients with I2020T or G2019S. Clinical phenotypes including psychosis, dementia, and MIBG ratios are also heterogeneous, similar to neuropathology, in PD associated with LRRK2 mutations. © 2006 Movement Disorder Society

Retinal dopamine loss in Parkinson disease (PD) is reflected by visual neurophysiological dysfunction. We measured the thickness of the circumpapillary retinal nerve fiber layer (RNFL) in PD patients using optical coherence tomography. The thickness in the inferior quadrant of PD patients (147 +/- 20 microns) was significantly thinner than that of controls (173 +/- 12 microns; p=0.002), while the inferotemporal area was the thinnest (146 +/- 24 vs. 191 +/- 21 microns; p=0.0003). The results show significant loss of RNFL thickness in PD at specific sites.

I read with interest about the artist John McLean, who experiences greater creativity since receiving the diagnosis of Parkinson’s disease and says that levodopa might be fuelling his recently enriched artistic skills. …

Background While Parkinson's disease (PD) phenotype in leucine-rich repeat kinase 2 gene (LRRK2)-associated and sporadic PD seems similar, there is paucity of data on the possible effect of mutations in LRRK2 on response to and complications of dopaminergic therapy. Objective To assess the impact of the LRRK2 Gly2019Ser (G2019S) carrier status on the time to the onset of levodopa-induced dyskinesias (LID). Methods Consecutive PD patients treated with levodopa were genotyped for the LRRK2 G2019S mutation. The relationship between mutation carrier status and the time to LID onset was explored after matching carriers to non-carriers for age at PD onset, gender, and time from PD diagnosis to levodopa initiation, using Kaplan-Meier curves and the Cox proportional hazards model, using LID onset as an end-point. Results Overall, 349 Israeli PD patients [222 Ashkenazi-Jewish (AJ), 60.5% males, mean age at diagnosis: 60.6 ± 13.2 years] participated in the study. Of these, 33 patients (9.5%, 30 AJ) carried the LRRK2 G2019S mutation. The prevalence of LID was non-significantly higher among carriers (22/33, 66.7%) than non-carriers (168/316, 53.2%, p = 0.15). The mean duration of therapy from levodopa initiation to the development of LID or last follow-up (in cases who were LID-free) was 5.1 ± 5.4 years for carriers and 4.4 ± 4.0 years in non-carriers (p = 0.47) and the survival curves in carriers and matched non-carriers were not significantly different (Cox proportional hazards test and log-rank test; p = 0.79). Conclusions The LRRK2 G2019S mutation status has no discernable effect on the prevalence of LID or on LID latency in Israeli levodopa-treated PD patients.

With the continuing rise in the elderly population, Alzheimer’s disease (AD) and dementia represent an increasing public health concern worldwide. In recent years, research has focused on the relationship between AD and ethnicity. Israel, a multiethnic society, provides a natural laboratory for research on ethnicity and health. The largest ethnic group is that of Israeli Jews, followed by Arab citizens, mostly Arab Muslims, with smaller numbers of Arab Christians in addition to Druze, Circassians, and others. The aim of this review is to clarify ethnic differences in prevalence and risk factors for Alzheimer’s disease. We review available literature on ethnic differences in epidemiologic and risk factors for Alzheimer’s disease, including genetic differences as well as disparities in health access and quality of health services. We will conclude with research and policy implications.

The increasing prevalence with age of antiphospholipid antibodies (aPL), of dementia and of stroke complicates the study of a causal relationship between antiphospholipid syndrome (APS) and dementia. Prolonged aPTT due to circulating anticoagulants (CAC) may serve as a more specific laboratory marker of APS. In a hospital-based study, we examined all patients with CAC and included 23 who fulfilled standard criteria for primary APS. These patients were assessed for dementia, vascular brain disease, autoimmune disease activity and dementia risk factors. Among CAC-positive APS patients, 13 of the 23 (56%) were demented and these were significantly older (mean age+/-S.E., 68+/-3 years) than the nondemented APS group (n=10, 51+/-4 years; p