Disease severity and prefrontal cortex activation during obstacle negotiation among patients with Parkinson's disease: Is it all as expected?

BACKGROUND: Previous reports indicate that patients with Parkinson's disease (PD) activate the prefrontal cortex (PFC) during complex activities such as obstacle negotiation to compensate for impaired motor function. However, the influence of disease severity on PFC activation has not been systematically evaluated. Here, we examined the effects of disease severity on PFC activation during obstacle negotiation. METHODS: 74 patients with PD (age 68.26 ± 7.54 yrs; 62.2% men) were divided into three groups based on Hoehn and Yahr stages. All patients walked along an obstacle course while negotiating anticipated and unanticipated obstacles (long/low available response time) at heights of 50 mm and 100 mm. PFC activation was measured using functional near-infrared spectroscopy (fNIRS) and was compared between groups and tasks using mixed model analyses. RESULTS: Participants with more advanced PD (i.e., Hoehn & Yahr 3) had higher PFC activation levels when negotiating anticipated obstacles, compared to participants with milder PD (i.e., Hoehn & Yahr 1, 2) (p < 0.001). Moreover, higher LEDD correlated with higher prefrontal activation during the higher anticipated obstacle. In contrast, during the negotiation of unanticipated obstacles, the differences in PFC activation were not associated with disease severity in a linear manner. CONCLUSIONS: The present study suggests that with increased disease severity, patients with PD rely more on the PFC when negotiating anticipated obstacles, perhaps to compensate for attention and motor deficits. These findings support the role of cognition in fall risk and the need to improve attention and cognition in fall prevention programs, especially among patients with more advanced disease.

Which obstacle attributes place additional demands on higher-level cognitive function in patients with Parkinson's disease?

BACKGROUND: Previous reports show that patients with Parkinson's disease (PD) rely on prefrontal activation to compensate for impaired motor function during complex activities such as obstacle negotiation. However, the influence of the properties of the obstacles on prefrontal activation has not been systematically evaluated. Here, we examined the effects of obstacle height and anticipation time on prefrontal activation in patients with PD and older adults. METHODS: 34 patients with PD (age: 67.4 ± 5.7 years; 14 women) and 26 older adults (age: 71.3 ± 8.9 years; 11 women) walked in an obstacle course while negotiating anticipated and unanticipated obstacles (long/short available time response, ART) at heights of 50 mm and 100 mm. Prefrontal activation was measured using functional Near-Infrared Spectroscopy (fNIRS); obstacle negotiation performance was measured using Kinect cameras. RESULTS: PD patients showed greater increases in prefrontal activation during and after obstacle crossing compared to the older adults (p < 0.001). Obstacle height affected prefrontal activity only when crossing anticipated obstacles (ARTxheight interaction, p = 0.011), in which case higher obstacles were accompanied by higher prefrontal activity. PD patients showed higher levels of activation during unanticipated obstacles, compared to older adults (groupXART: p = 0.015). Different correlations between prefrontal activation and obstacle negotiation strategies were observed in patients and controls. CONCLUSIONS: These results point to the use of prefrontal activation as a compensatory mechanism in PD. Moreover, the higher activation observed when negotiating more challenging obstacles suggests that there is greater reliance on cognitive resources in these demanding situations that may contribute to the higher risk of falls in PD patients.

A new approach to quantifying the EEG during walking: Initial evidence of gait related potentials and their changes with aging and dual tasking.

BACKGROUND: The electroencephalogram (EEG) can be a useful tool to investigate the neurophysiology of gait during walking. Our aims were to develop an approach that identify and quantify event related potentials (ERPs) during a gait cycle and to examine the effects of aging and dual tasking on these gait related potentials (GRPs). METHODS: 10 young and 10 older adults walked on a treadmill while wearing a wireless 20-channels EEG and accelerometers on the ankles. Each heel strike extracted from the accelerometers was used as an event to which the electrical brain activity pattern was locked. The subjects performed usual and dual task walking that included an auditory oddball task. GRPs amplitude and latency were computed, and a new measure referred to as Amplitude Pattern Consistency (APC) was developed to quantify the consistency of these GRP amplitudes within a gait cycle. The results were compared between and within groups using linear mixed model analysis. RESULTS: The electrical pattern during a gait cycle consisted of two main positive GRPs. Differences in these GRPs between young and older adults were observed in Pz and Cz. In Pz, older adults had higher GRPs amplitude (p = 0.006, p = 0.010), and in Cz lower APC (p = 0.025). Alterations were also observed between the walking tasks. Both groups showed shorter latency during oddball walking compared to usual walking in Cz (p = 0.040). In addition, the APC in Cz was correlated with gait speed (r = 0.599, p = 0.011) in all subjects and with stride time variability in the older adults (r = -0.703, p = 0.023). CONCLUSIONS: This study is the first to define specific gait related potentials within a gait cycle using novel methods for quantifying waveforms. Our findings show the potential of this approach to be applied broadly to study the EEG during gait in a variety of contexts. The observed changes in GRPs with aging and walking task and the relationship between GRPs and gait may suggest the neurophysiologic foundation for studying walking and for developing new approaches for improving gait.

Who will remain tremor dominant? The possible role of cognitive reserve in the time course of two common Parkinson's disease motor subtypes.

In a prospective 5-year study among Parkinson's disease (PD) tremor-dominant (TD) patients, we investigated who will remain TD and who will later convert into the postural instability gait difficulty (PIGD) phenotype. At follow-up, 38% were still considered TD. At baseline the TD non-convertors had more years of education and better cognitive function than the convertors and significantly smaller deterioration in gait, balance, cognitive function and other non-motor symptoms. These results highlight the potential role of cognition in protecting against the development of PIGD symptoms.

Age-associated changes in obstacle negotiation strategies: Does size and timing matter?

INTRODUCTION: Tripping over an obstacle is one of the most common causes of falls among older adults. However, the effects of aging, obstacle height and anticipation time on negotiation strategies have not been systematically evaluated. METHODS: Twenty older adults (ages: 77.7±3.4years; 50% women) and twenty young adults (age: 29.3±3.8years; 50% women) walked through an obstacle course while negotiating anticipated and unanticipated obstacles at heights of 25mm and 75mm. Kinect cameras captured the: (1) distance of the subject's trailing foot before the obstacles, (2) distance of the leading foot after the obstacles, (3) clearance of the leading foot above the obstacles, and (4) clearance of the trailing foot above the obstacles. Linear-mix models assessed changes between groups and conditions. RESULTS: Older adults placed their leading foot closer to the obstacle after landing, compared to young adults (p<0.001). This pattern was enhanced in high obstacles (group*height interaction, p=0.033). Older adults had lower clearance over the obstacles, compared to young adults (p=0.007). This was more pronounced during unanticipated obstacles (group*ART interaction, p=0.003). The distance of the leading foot and clearance of the trailing foot after the obstacles were correlated with motor, cognitive, and functional abilities. CONCLUSIONS: These findings suggest that there are age-related changes in obstacle crossing strategies that are dependent on the specific characteristics of the obstacle. The results have important implications for clinical practice, suggesting that functional exercise should include obstacle negotiation training with variable practice of height and available response times. Further studies are needed to better understand the effects of motor and cognitive abilities.

Do cognition and other non-motor symptoms decline similarly among patients with Parkinson's disease motor subtypes? Findings from a 5-year prospective study.

Among patients with Parkinson's disease (PD), a wide range of motor and non-motor symptoms (NMS) are evident. PD is often divided into tremor dominant (TD) and postural instability gait difficulty (PIGD) motor subtypes. We evaluated the effect of disease duration and aimed to characterize whether there are differences in the deterioration of cognitive function and other NMS between the PIGD and TD subtypes. Sixty-three subjects were re-evaluated at the follow-up visit about 5 years after baseline examination. Cognitive function and other NMS were assessed. At follow-up, the PIGD and TD groups were similar with respect to medications, comorbidities and disease-related symptoms. There was a significant time effect for all measures, indicating deterioration and worsening in both groups. However, cognitive scores, particularly those related to executive function, became significantly worse in the PIGD with a more moderate decrease in the TD group. For example, the computerized global cognitive score declined in the PIGD group from 94.21 ± 11.88 to 83.91 ± 13.76, p < 0.001. This decline was significantly larger (p = 0.03) than the decrease observed in the TD group (96.56 ± 10.29 to 92.21 ± 14.20, p = 0.047). A significant group × time interaction effect was found for the change in global cognitive score (p = 0.047), the executive function index (p = 0.002) and accuracy on a motor-cognitive catch game (p = 0.008). In contrast, several NMS including depression, health-related quality of life and fear of falling deteriorated in parallel in both subtypes, with no interaction effect. The present findings highlight the difference in the natural history of the disease between the two PD "motor" subtypes. While the PIGD group demonstrated a significant cognitive decline, especially in executive functions, a more favorable course was observed in the TD subtype. This behavior was not seen in regards to the other NMS.

Altered brain activation in complex walking conditions in patients with Parkinson's disease.

INTRODUCTION: Behavioral studies suggest that deficits in cognitive domains and sensory-motor processes associated with Parkinson's disease (PD) impair the ability to walk in complex environments. However, the neural correlates of locomotion in complex environments are still unclear. METHODS: Twenty healthy older adults (mean age 69.7 ± 1.3 yrs) and 20 patients with PD (mean age 72.9 ± 1.6 yrs; disease duration: 6.8 ± 1.3 yrs; UPDRSIII: 29.8 ± 2.4) were asked to imagine themselves walking while in the MRI scanner. Three imagined walking tasks, i.e., usual walking, obstacle negotiation, and navigation were performed. Watching the same virtual scenes without imagining walking served as control tasks. Whole brain analyses were used. RESULTS: Compared to usual walking, both groups had increased activation during obstacle negotiation in middle occipital gyrus (MOG) (pFWEcorr<0.001), middle frontal gyrus (MFG) (pFWEcorr<0.005), and cerebellum (pFWEcorr<0.001). Healthy older adults had higher activation in precuneus and MOG (pFWEcorr<0.023) during navigation, while no differences were observed in patients with PD. Between group comparisons revealed that patients with PD had a significantly higher activation in usual walking and obstacle negotiation (pFWEcorr<0.039) while during navigation task, healthy older adults had higher activation (pFWEcorr<0.047). CONCLUSIONS: Patients with PD require greater activation during imagined usual walking and obstacle negotiation than healthy older adults. This increased activation may reflect a compensatory attempt to overcome inefficient neural activation in patients with PD. This increased activation may reduce the functional reserve needed during more demanding tasks such as during navigation which may contribute to the high prevalence of falls and dual tasking difficulties among patients with PD.

Management of dystonia in Europe: a survey of the European network for the study of the dystonia syndromes.

BACKGROUND AND PURPOSE: Dystonia is difficult to recognize due to its large phenomenological complexity. Thus, the use of experts in dystonia is essential for better recognition and management of dystonia syndromes (DS). Our aim was to document managing strategies, facilities and expertise available in various European countries in order to identify which measures should be implemented to improve the management of DS. METHODS: A survey was conducted, funded by the Cooperation in Science and Technology, via the management committee of the European network for the study of DS, which is formed from representatives of the 24 countries involved. RESULTS: Lack of specific training in dystonia by general neurologists, general practitioners as well as other allied health professionals was universal in all countries surveyed. Genetic testing for rare dystonia mutations is not readily available in a significant number of countries and neurophysiological studies are difficult to perform due to a lack of experts in this field of movement disorders. Tetrabenazine is only readily available for treatment of dystonia in half of the surveyed countries. Deep brain stimulation is available in three-quarters of the countries, but other surgical procedures are only available in one-quarter of countries. CONCLUSIONS: Internationally, collaboration in training, advanced diagnosis, treatment and research of DS and, locally, in each country the creation of multidisciplinary teams for the management of dystonia patients could provide the basis for improving all aspects of dystonia management across Europe.

The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease.

GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.

Nucleoside 5'-phosphorothioate derivatives are highly effective neuroprotectants.

The brain is especially sensitive to oxidative stress due to its high rate of oxidative metabolism, relatively low levels of antioxidant enzymes, and high concentrations of Fe/Cu ions. During the neurodegeneration process, the aggregation of proteins Aß, accompanies oxidative stress. We explored the potential of thiophosphate derivatives to rescue neurons from oxidative stress and Aß toxicity. We evaluated the neuroprotective effect of ATP-γ-S, ADP-ß-S, and GDP-ß-S on primary cortical neuronal cells exposed to several insults, including treatment with FeSO4, co-application of H2O2 and FeSO4, and addition of Aß42. Upon treatment with FeSO4, phosphorothioate analogues exhibited up to 3000-fold better neuroprotectant activity than the corresponding parent nucleotides. Likewise, phosphorothioate analogues proved to be up to 30-fold better neuroprotectants than the corresponding parent nucleotides upon treatment with both H2O2 and FeSO4. When we exposed primary neuron and astrocyte cultures to 50 µM Aß42-induced cell death, we found that ATP-γ-S significantly improved cell morphology and maintained culture viability with an IC50 value of 0.8 µM. Finally, we evaluated the viability of neuroblastoma cells under hypoxic conditions in the presence of ATP-γ-S and found that the latter was involved in the regulation of HIF-1a and stabilized mRNA levels of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), which promote cell survival and proliferation. Based on its high potency as a neuroprotectant, we propose ATP-γ-S as a highly promising, biocompatible, and water-soluble drug candidate for the treatment of neurodegenerative disorders.

Mobility, mood and site of care impact health related quality of life in Parkinson's disease.

OBJECTIVE: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson's disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). BACKGROUND: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. METHODS: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. RESULTS: The variability in the PDQ-39 summary index score correlated with H&Y stage (R(2) = 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. CONCLUSIONS: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices.

Introducing a new definition of a near fall: intra-rater and inter-rater reliability.

Near falls (NFs) are more frequent than falls, and may occur before falls, potentially predicting fall risk. As such, identification of a NF is important. We aimed to assess intra and inter-rater reliability of the traditional definition of a NF and to demonstrate the potential utility of a new definition. To this end, 10 older adults, 10 idiopathic elderly fallers, and 10 patients with Parkinson's disease (PD) walked in an obstacle course while wearing a safety harness. All walks were videotaped. Forty-nine video segments were extracted to create 2 clips each of 8.48 min. Four raters scored each event using the traditional definition and, two weeks later, using the new definition. A fifth rater used only the new definition. Intra-rater reliability was determined using Kappa (K) statistics and inter-rater reliability was determined using ICC. Using the traditional definition, three raters had poor intra-rater reliability (K<0.054, p>0.137) and one rater had moderate intra-rater reliability (K=0.624, p<0.001). With the traditional definition, inter-rater reliability between the four raters was moderate (ICC=0.667, p<0.001). In contrast, the new NF definition showed high intra-rater (K>0.601, p<0.001) and excellent inter-rater reliability (ICC=0.815, p<0.001). A priori, it is easy to distinguish falls from usual walking and NFs, but it is more challenging to distinguish NFs from obstacle negotiation and usual walking. Therefore, a more precise definition of NF is required. The results of the present study suggest that the proposed new definition increases intra and inter-rater reliability, a critical step for using NFs to quantify fall risk.

A cross-sectional multicenter study of cognitive and behavioural features in multiple system atrophy patients of the parkinsonian and cerebellar type.

Imaging and neuropathology studies have demonstrated significant abnormalities not only in subcortical, but also in cortical regions of patients with multiple system atrophy (MSA). This raises the possibility that cognitive dysfunction may contribute to the clinical spectrum of this disorder to a greater extent than it is currently not widely appreciated. In this cross-sectional multicenter study from the European multiple system atrophy study group ( http://www.emsa-sg.org ), we applied an extensive neuropsychological test battery in a series of 61 clinically diagnosed probable MSA patients. The results demonstrated that general cognitive decline as assessed by MMSE was uncommon (2 out of 61 patients <24). In contrast, frontal lobe-related functions (as measured by FAB) were impaired in 41 % of patients, with abstract reasoning and sustained attention less compromised. This pattern was similar to our control group of 20 patients with Parkinson's disease (matched for disease duration and age at onset). There was no difference in cognitive performance between MSA patients with the parkinsonian versus the cerebellar variant. Behaviourally, MSA patients had greater depression than PD and in the case of MSA of the cerebellar variant significantly lower anxiety. Our data show that cognitive abnormalities are relatively frequent in multiple system atrophy and this involves primarily frontal-executive functions. Their contribution to clinical disability and disease progression needs to be addressed in larger prospective studies.

Estimation of Parkinson's disease survival in Israeli men and women, using health maintenance organization pharmacy data in a unique approach.

The aim of this work was to estimate in an incident cohort of pharmacy-based PD patients the survival of men and women accounting for age at treatment initiation and to compare their gender-specific survival with that of the general Israeli population. A population-based cohort of 4,848 incident pharmacy-based PD cases with definite/probable/possible certainty was previously identified using a drug-tracer approach for 1999-2008. Survival analysis was performed for two time scales: survival after treatment initiation (disease duration), and life-time survival (life expectancy). Kaplan-Meier curves and Cox regressions were used to compare survival across gender. Gender-specific SMRs were calculated from national rates and were compared using Poisson regression. During the follow-up from first purchase of any anti-parkinsonian drug (mean 4.0 ± 2.6 years, range 2 months-10 years), 1,266 (26 %) of the cases died. Younger age at first anti-parkinsonian drug purchase and female gender were associated with increased survival after treatment initiation (HR = 1.089, 95 % CI 1.080-1.098 for 1-year age increase; HR = 0.716, 95 % CI 0.640-0.800, females vs. males). Life-time survival increased with older age at first anti-parkinsonian drug purchase and female gender (HR = 0.759, 95 % CI 0.746-0.771 for 1-year age increase; HR = 0.694, 95 % CI 0.621-0.776, females vs. males). Sensitivity analysis on a sub-cohort of definite cases (n = 2501) yielded similar results. In comparison to the general Israeli population, mortality among pharmacy-based PD patients was significantly increased (SMR(men) = 1.69, 95 % CI 1.57-1.81, SMR(women) = 1.49, 95 % CI 1.37-1.62), differently between genders (p < 0.01). Female gender was associated with longer, perhaps more benign disease course, and longer life expectancy. Earlier age at anti-parkinsonian drug initiation increased disease duration, but was associated with shorter life expectancy.

Subjective memory complaints in elders: depression, anxiety, or cognitive decline?

OBJECTIVES: To study the association of subjective memory complaints (SMC) with affective state and cognitive performance in elders. MATERIALS AND METHODS: We studied community dwelling elderly persons with normal physical examination. Participants completed questionnaires regarding memory difficulties and lifestyle habits, the Geriatric Depression Scale (GDS) and the Spielberger State-Trait Anxiety Inventory (STAI). Depending on their answers to the question about their memory condition, participants were divided into complainers and non-complainers and to five groups according to their MMSE scores. These data have been compared to objective cognitive performance according to Mindstreams - a computerized neuropsychological battery. A logistic regression was performed to evaluate odds ratios (OR) and 95% confidence intervals (CI) for those factors, which were associated with SMС (dependent variable). RESULTS: Of 636 consecutive subjects (61% females), 507 participants (79.7%) had SMС. Presence of SMC was inversely correlated with MMSE scores, (r = -0.108; P for trend = 0.007). GDS and STAI scores were higher among subjects with SMC (OR = 1.23: CI 95%: 1.1-1.36 and OR = 1.03: CI 95%: 1.01-1.07, respectively). SMC did not correlate with objective cognitive performance measured by Mindstreams. CONCLUSIONS: Subjective memory complaints are associated with sub-syndromal depression and anxiety in healthy cognitively normal elders.

Vasomotor reactivity as a predictor for syncope in patients with orthostatism.

OBJECTIVES: Syncope in patients with orthostatic hypotension (OH) may be the result of impaired cerebral autoregulation. Cerebral autoregulation status can be determined by assessing cerebral vasomotor reactivity (VMR). We assessed and compared VMR in patients with OH with and without syncope. MATERIAL AND METHODS: Twenty-nine patients with OH underwent transcranial Doppler (TCD) and the Diamox test (1 g acetazolamide IV) for assessing VMR during elaboration of their OH syndrome. The percent difference between cerebral blood flow velocities (BFV) in the middle cerebral (MCA) and vertebral (VA) arteries before and after acetazolamide was defined as VMR%. We considered increases of BFV of ≥ 40% as being indicative of good VMR and classified our study patients as having good or impaired VMRs accordingly. RESULTS: Mean VMR% values of the MCA and VA in patients with OH with syncope (n = 12) were significantly lower as compared with patients with OH without syncope (n = 17): 25.2 ± 20.5% and 42.5 ± 18.6%; 20.9 ± 15.5% and 40.8 ± 28.5%, respectively (P < 0.05). CONCLUSIONS: Among patients with OH, we found an association between the presence of syncope and impaired VMR. Assessment of VMR among patients with OH may predict those who are at higher risk to faint and fall and to support more aggressive intervention.

An instrumented timed up and go: the added value of an accelerometer for identifying fall risk in idiopathic fallers.

The Timed Up and Go (TUG) test is a widely used measure of mobility and fall risk among older adults that is typically scored using a stopwatch. We tested the hypothesis that a body-fixed accelerometer can enhance the ability of the TUG to identify community-living older adults with a relatively high fall risk of unknown origin. Twenty-three community-living elderly fallers (76.0 ± 3.9 years) and 18 healthy controls (68.3 ± 9.1 years) performed the TUG while wearing a 3D-accelerometer on the lower back. Acceleration-derived parameters included Sit-to-Stand and Stand-to-Sit times, amplitude range (Range), and slopes (Jerk). Average step duration, number of steps, average step length, gait speed, acceleration-median, and standard-deviation were also calculated. While the stopwatch-based TUG duration was not significantly different between the groups, acceleration-derived TUG duration was significantly higher (p = 0.007) among the fallers. Fallers generally exhibited lower Range and Jerk (p < 0.01). While TUG stopwatch duration successfully identified 63% of the subjects, an accelerometer-derived three-measure-combination correctly classified 87% of the subjects. Accelerometer-derived measures were generally not correlated with TUG duration. These findings demonstrate that fallers have difficulty with specific TUG aspects that can be quantified using an accelerometer. Without compromising simplicity of testing, an accelerometer can apparently be combined with TUG duration to provide complementary, objective measures that allow for a more complete, sensitive TUG-based fall risk assessment.

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.

Progressive nature of a higher level gait disorder: a 3-year prospective study.

The objective of the study was to characterize the natural history of patients with a higher level gait disorder (HLGD) of the cautious/disequilibrium type in a 3-year prospective study. Subjects were taken from an outpatient setting in a movement disorders clinic. Twenty-two mobile, community-living patients with a HLGD of the cautious/disequilibrium type and 26 age- and gender-matched healthy controls were evaluated at baseline and approximately 3 years later. Detailed medical history, a complete, structured geriatric and neurological examination, mental and affective state, gait and balance assessment were obtained. At follow-up, marked declines were observed in gait, mobility and functional independence in the patients, but not in the controls. For example, 23% of the patients could not complete the Timed Up and Go test, compared to only 4% of the control group, and among those who could complete the test, time to completion was almost three times longer (P < 0.0001) in the patients (23 s), compared to the controls (8 s). At follow-up, 50% of the patients required a personal live-in caregiver compared to only 4% of the controls (P < 0.0001). Although mild extra-pyramidal, pyramidal, cognitive and affective alterations were observed at baseline in the patients, those symptoms were stable over time. Unexpectedly, there was no association between the presence of HLGD or its progression and vascular risk factors. HLGD is a debilitating, rapidly progressive disease. The profound deterioration in functional independence in a relatively short period of time suggests that early multidisciplinary interventions may be the appropriate clinical approach to the treatment of these patients who are at risk for a rapid decline in functional abilities.

LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease.

GBA and LRRK2 mutations increase susceptibility to Parkinson disease (PD), which is characterized by various disabling symptoms. An extended cohort of 600 Ashkenazi PD patients was screened for the LRRK2 G2019S and for eight GBA mutations. Reported initial symptoms were compared between three genotypic groups of patients: carriers of GBA mutations, carriers of LRRK2 G2019S mutation, and non-carriers. More LRRK2 G2019S carriers reported muscle stiffness (rigidity, p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness (bradykinesia, p = 0.021). These results suggest distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD.