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The current paradigm on Parkinson's disease (PD) pathogenesis and course suggests the involvement of multiple genes and the interaction between them. Recently, it was reported that a variation (rs2435207) in the MAPT gene region influenced the age of motor symptoms onset (AO) in 44 PD patients from 19 families, carriers of leucine-rich repeat kinase 2 (LRRK2) mutations, all of European and North American origin. To examine whether genetic factors within the MAPT locus exert a similar effect on AO in a different population of LRRK2-associated PD patients, 99 unrelated Ashkenazi patients with the LRRK2 p.G2019S mutation were analyzed. Three SNPs in the MAPT region were studied, rs393152, rs2435207, and rs11079727; the latter is located in the first intron of MAPT. Among carriers of the single LRRK2 p.G2019S mutation that did not carry a founder Ashkenazi GBA mutation too (n = 84), the AO in minor rs11079727 A allele carriers (C/A genotype) was significantly older (62.5 ± 10.6 years) compared to the AO (55.7 ± 11.6) among carriers of the C/C genotype (p = 0.025). Our results further support a possible interaction between genetic factors in the MAPT region and the LRRK2 gene, which influence the clinical course of PD patients.

Objective: To examine whether PARK16, which was recently identified as a protective locus for Parkinson disease (PD) in Asian, white, and South American populations, is also associated with PD in the genetically homogeneous Ashkenazi Jewish population., Design: Case-control study., Setting: A medical center affiliated with a university. Subjects  Five single-nucleotide polymorphisms (SNPs) located between RAB7L1 and SLC41A1 were analyzed in 720 patients with PD and 642 controls, all of Ashkenazi Jewish origin., Main Outcome Measures: Haplotypes were defined and risk estimates were determined for each SNP and haplotype. Bioinformatic analysis defined the putative promoter region of RAB7L1 and the transcription factor binding sites that are potentially affected by 2 of the tested SNPs., Results: All tested SNPs were significantly associated with PD (odds ratios = 0.64-0.76; P = .0002-.014). Two of them, rs1572931 and rs823144, were localized to the putative promoter region of RAB7L1 and their sequence variations altered the predicted transcription factor binding sites of CdxA, p300, GATA-1, Sp1, and c-Ets-1. Only 0.4% of patients were homozygous for the protective rs1572931 genotype (T/T), compared with 3.0% among controls (P = 5 × 10(-5)). This SNP was included in a haplotype that reduced the risk for PD by 10- to 12-fold (P = .002-.01) in all patients with PD and in a subgroup of patients who do not carry the Ashkenazi founder mutations in the GBA or LRRK2 genes., Conclusions: Our data demonstrate that specific SNP variations and haplotypes in the PARK16 locus are associated with reduced risk for PD in Ashkenazim. Although it is possible that alterations in the putative promoter of RAB7L1 are associated with this effect, the role of other genes in this locus cannot be ruled out.

Background: Parkinson's disease (PD) has a long pre-diagnosis phase that may span as long as 10-20 years. The ability to identify at risk populations raises the possibility of early intervention to delay or prevent the onset of motor symptoms. In Israel, there is a large group of Ashkenazi Jews at risk of developing PD due to high frequency of PD associated mutations in 2 genes (GBA and LRRK2)., Objective: To describe our unique experience with a clinical counseling service for 1st degree relatives of PD patients from the Ashkenazi origin who carry the G2019S mutation in the LRRK2 gene., Method: One hundred, self declared, healthy, first degree relatives of PD patients who carry the G2019S mutation in the LRRK2 gene were tested clinically and genetically in a cross sectional study. Those who have requested information on their risk to develop PD were invited to a free of charge, clinical counseling session to provide information on their risk of developing PD and potential risk modifiers that can be applied. Genetic status was not disclosed and the counselor was unaware of the subjects' G2019S mutation status., Results: 46 subjects (mean age 48.2±10.7; 46% males) came for clinical counseling provided by a Movement Disorders specialist. Siblings and off-springs of the same proband were seen together. Counseling provided general information about the pre-diagnosis phase of PD, the concept of population at risk and habitual and behavioral recommendations that may delay PD motor symptoms onset., Conclusion: A high percentage of individuals at risk for developing PD requested clinical counseling on modifiers of the risk to develop PD. Counseling provided information as well as recommendations for behavioral modifications and drug treatment. Screening population at risk increases the awareness as well as early diagnosis of PD. Prospective information is needed in order to improve our knowledge base and assess the long term impact of such a counseling service., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A strong association was established between the GBA gene and Parkinson's disease (PD) worldwide. The most frequent GBA mutation among the Ashkenazi population (p.N370S) was previously associated with the c.1051T>C (p.F351L) alteration in the closely located MTX1 gene. We further studied the association between these two genes and its possible effect on PD. The entire coding region and exon-intron boundaries of MTX1 were analyzed in 81 PD patient carriers of GBA mutations, 15 healthy controls that carry GBA mutations, and in 25 non-carrier patients. Among them, the MTX1 c.184T>A (p.S63T) variation was detected in 93% of GBA mutation carriers (both patients and healthy controls) and in 64% of non-carrier patients (p = 0.0008). This alteration was analyzed in 600 consecutively recruited Ashkenazi PD patients and in 353 controls, all genotyped for the LRRK2 p.G2019S and GBA founder mutations. A significantly higher frequency of the MTX1 c.184A allele was found in carriers of GBA mutations compared to non-carriers (0.67 and 0.45, respectively, p < 0.0001). The homozygous MTX1 c.184A/A genotype was associated with a significantly earlier age of motor symptoms onset in patients with GBA mutations compared to other groups of patients tested (5.1-5.9 years younger, p = 0.002-0.01). A significantly higher frequency of early-onset PD (<50 years) was detected among patients carrying both GBA mutation and the homozygous MTX1 c.184A/A genotype (35.9%, compared to 13.6-17.5%, p = 0.028). Our results raise the possibility that alteration on the opposite allele, which is in trans to the GBA mutant allele, may affect the clinical course of GBA-associated PD.

Background: Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations., Results: Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status., Conclusions: Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD.

Recent studies have demonstrated that cognitive loading aggravates the gait impairments that are typically seen in Parkinson's disease (PD). To better understand the relationship between cognition and gait in PD, we evaluated 30 subjects with PD who suffer from motor response fluctuations. The subjects were clinically and cognitively assessed using standard clinical (e.g., Unified Parkinson's Disease Rating Scale) and cognitive tests while in the "ON" period of the medication cycle. In addition, the subjects wore force-sensitive insoles to quantify the timing of the gait cycles during 80-m walks at a self-selected, comfortable pace during three randomly presented gait conditions: (1) usual-walking, (2) dual tasking (DT), performing serial 3 subtractions (DT&#95;S3), and (3) DT&#95;S7. Stride length, gait speed, gait variability and bilateral coordination of gait were affected by DT, compared to the usual-walking (P < 0.001) as was gait asymmetry (P = 0.024). Stepwise regression analyses showed that a subset of the cognitive performance scores accounted for the changes seen in the gait parameters during DT, e.g., set shifting capabilities as expressed by the Trial Making Test Scores (P < 0.001). Affect (e.g., anxiety) was not associated with DT-related gait changes. For most gait features, DT had a large impact on the DT&#95;S3 condition with only minimal additional effect in the DT&#95;S7 condition. These results demonstrate that the complex cognitive-motor interplay in the control of gait in patients with PD who suffer from motor response fluctuations has a profound and marked effect during DT conditions on gait variability, asymmetry and bilateral coordination, even in the "ON" state when patients are likely to be most active, mobile and vulnerable to the negative effects of dual tasking.

To test for an association between the LRRK2-G2019S mutation and gait, we studied 52 first-degree relatives of patients with Parkinson's disease (PD) who carry this mutation. An accelerometer quantified gait during usual-walking, fast-walking, and dual-tasking. Noncarriers (n = 27) and carriers (n = 25) were similar with respect to age, gender, height, and gait speed during all conditions. During dual-tasking and fast-walking, gait variability and the amplitude of the dominant peak of the accelerometer signal were significantly altered among the carriers. These findings support the possibility of previously unidentified, presymptomatic motor changes among relatives who have an increased risk of developing PD., (Copyright © 2010 American Neurological Association.)

Estimating rates of Parkinson's disease (PD) is essential for health services planning and studies of disease determinants. However, few PD registries exist. We aimed to estimate annual prevalence and incidence of PD in a large Israeli population over the past decade using computerized drug purchase data. Based on profiles of anti-parkinsonian drugs, age at first purchase, purchase density, and follow-up time, we developed a refined algorithm for PD assessment (definite, probable or possible) and validated it against clinical diagnoses. We used the prescription database of the second largest Health Maintenance Organization in Israel (covers ~25% of population), for the years 1998-2008. PD rates by age, gender and year were calculated and compared using Poisson models. The algorithm was found to be highly sensitive (96%) for detecting PD cases. We identified 7,134 prevalent cases (67% definite/probable), and 5,288 incident cases (65% definite/probable), with mean age at first purchase 69 ± 13 years. Over the years 2000-2007, PD incidence rate of 33/100,000 was stable, and the prevalence rate increased from 170/100,000 to 256/100,000. For ages 50+, 60+, 70+, median prevalence rates were 1%, 2%, 3%, respectively. Incidence rates also increased with age (RR = 1.76, 95%CI 1.75-1.77, ages 50+, 5-year interval). For ages 50+, rates were higher among men for both prevalence (RR = 1.38, 95%CI 1.37-1.39) and incidence (RR = 1.45, 95%CI 1.42-1.48). In conclusion, our refined algorithm for PD assessment, based on computerized drug purchases data, may be a reliable tool for population-based studies. The findings indicate a burden of PD in Israel higher than previously assumed.

Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like α-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas., (© 2010 Movement Disorder Society.)

Multiple sclerosis (MS) is the most common disabling chronic disease of the central nervous system among young adults. These patients suffer from variety of symptoms that have a profound affect on their working ability, activities of daily living and general quality of life. Treatment of these symptoms is important in order to relief them and improve daily function and quality of life. Many of these symptoms are often resistant to treatment. Botulinum toxin A (BTX) is mainly used for spasticity and bladder dysfunction in MS. It is an effective treatment option for spasticity of the thigh adductor, pes equinus, striatal toe or adductor of the shoulder joint. BTX injections are effective in reducing incontinence episodes and urinary urgency, daytime frequency and nocturia, as well as sustained improvements in quality of life of MS patients with detrusor overreactivity. In addition, BTX is potentially effective in treating pain, trigeminal neuralgia, tremor, neuro-ophthalmologic complications, facial myokymia, gastroparesis, sialorrhea, and hyperhidrosis, however no studies have confirmed its efficacy in MS patients.

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.

Introduction: The Timed Up and Go (TUG) test is a widely used measure of mobility and fall risk in older adults and in Parkinson's disease (PD). We tested the hypothesis that body-fixed accelerometers can provide insight into TUG performance in PD patients., Methods: We examined 17 patients with PD (Hoehn and Yahr score: 2.7+/-0.7; ON state) and 15 age-matched healthy controls; mean ages were 66.8+/-5.9 years, 67.6+/-9.6 years, respectively. Subjects wore a 3D-accelerometer (ADXL330, Analog Devices) on the lower back while performing the TUG test. Sit-to-Stand and Stand-to-Sit times were extracted from the anterior-posterior (AP) signal. Parameters included Sit-to-Stand, Stand-to-Sit durations, amplitude range (Range) and slopes (Jerk). Acceleration median and standard deviation (SD) were also calculated., Results: Stopwatch-based TUG duration tended to be higher for the PD patients compared to the control group, although not significantly (p=0.08). In contrast, the TUG duration that was extracted from the acceleration signal was significantly (p<0.02) higher in the PD group compared to the control group. Many acceleration-parameters were also significantly different (p<0.05) between groups; most were not correlated with TUG duration., Conclusions: Accelerometer-derived parameters are sensitive to group differences, indicating that PD patients have poorer mobility during specific aspects of the TUG. In addition to test duration, these measures may serve as complementary and objective bio-markers of PD to augment the evaluation of disease progression and the response to therapeutic interventions., ((c) 2009 IPEM. Published by Elsevier Ltd. All rights reserved.)

We evaluated cognitive functions and mood in two groups of patients with multiple system atrophy (MSA) in order to determine the influence of mood on cognitive performance. Our aim was to differentiate between parkinsonism-predominant (MSA-P) and cerebellar-predominant (MSA-C) MSA based on those parameters. Fifteen MSA-P and 10 MSA-C patients underwent neuropsychological tests that examined executive functions (working memory, response inhibition, and verbal reproduction), verbal learning and memory, verbal and visual reasoning, and processing speed. Anxiety and depression were also assessed. The findings on their cognitive performance and mood were compared to those of healthy controls and also discussed in relation to a group of Parkinson's disease (PD) patients. The results showed that cognitive and mood characteristics could distinguish MSA-P from MSA-C and that anxiety and depression are related to cognitive decline. Compared with healthy controls, MSA-P patients showed reduced verbal retrieval (immediate, P < 0.019; long-term, P < 0.018) while MSA-C patients had difficulties in learning new verbal information (P < 0.022) and in controlling attention (P < 0.023). These data indicate that MSA-P and MSA-C appear to have, at least in part, different cognitive and mood profiles. The neuropsychological assessments of MSA patients should test for and then take into account their level of anxiety and depression, insofar as it might have an adverse effect on their cognitive performance.

The understanding of the biology of Parkinson's disease (PD) has advanced rapidly over the past 3 decades. In particular, the early pathological changes described by Braak et al. and the awareness of extensive and clinically relevant premotor manifestations are of diagnostic and therapeutic importance. We review those manifestations and their contribution to the clarification of the pathophysiologic processes of PD, and discuss the implications for treatment of the 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.

Background: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease., Methods: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers., Results: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations., Conclusions: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease., (2009 Massachusetts Medical Society)

The clinical diagnosis of multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/-7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P., ((c) 2008 Movement Disorder Society)

Background: Mutations in GBA and LRRK2 genes have been implicated in Parkinson disease (PD), particularly in Ashkenazi Jews., Methods: An Israeli Ashkenazi cohort of 420 patients with PD, 333 elderly controls, and 3,805 young controls was screened for eight GBA mutations, which are associated with mild (N370S, R496H) and severe (84GG, IVS2 + 1, V394L, D409H, L444P, RecTL) Gaucher disease. Patients with PD and elderly controls were also genotyped for LRRK2 G2019S., Results: GBA carrier frequency was 17.9% in patients with PD compared to 4.2% in elderly and 6.35% in young controls. The proportion of severe mutation carriers among PD patient GBA carriers was 29% compared to 7% among young controls. Severe and mild GBA mutations increased the risk of developing PD by 13.6- and 2.2-fold, and affected the average age at PD onset (AAO), 55.7 and 57.9 years, compared to 60.7 years in patients without known GBA or LRRK2 mutations., Conclusions: These data demonstrate genotype-phenotype correlations between different GBA mutations and Parkinson disease (PD) risk and AAO in Ashkenazi Jews. Additionally, an earlier AAO was observed in LRRK2 G2019S carrier PD patients. Finally, these data demonstrate that a surprisingly high frequency, more than one third of our patient population, carried a mutation in GBA or LRRK2.

Background: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson disease (PD) identified to date, and have been implicated in both familial and sporadic forms of the disease. The G2019S change in LRRK2 exon 41 has been associated with disease at varying frequencies in Asian, European, North American, and North African populations, and is particularly prevalent among Ashkenazi Jews., Methods: We assessed the occurrence of the LRRK2 G2019S, I2012T, I2020T, and R1441G/C/H mutations in our cohort of Jewish Israeli patients with PD, and determined the LRRK2 haplotypes in 76 G2019S-carriers detected and in 50 noncarrier Ashkenazi patients, using six microsatellite markers that span the entire gene., Results: Only the G2019S mutation was identified among our patients with PD, 14.8% in the Ashkenazi and 2.7% in the non-Ashkenazi patients, and in 26% and 10.6% of the Ashkenazi familial and apparently sporadic cases. The carrier frequencies in the Ashkenazi and non-Ashkenazi control samples were 2.4% and 0.4%. A common shared haplotype was detected in all non-Ashkenazi and half-Ashkenazi carriers and in all full-Ashkenazi carriers tested, except two. Women and patients with a positive family history of PD were significantly over-represented among the G2019S mutation carriers. Age at disease onset was similar in carriers and noncarriers., Conclusions: Our data suggest that the LRRK2 G2019S mutation plays an important role in the causality of familial and sporadic Parkinson disease (PD) in Israel and that gender affects its frequency among patients. Although testing symptomatic patients may help establish the diagnosis of PD, the value of screening asymptomatic individuals remains questionable until the penetrance and age-dependent risk of this mutation are more accurately assessed, and specific disease prevention or modifying interventions become available.

Background: Psychological impact of bariatric surgery has been described mostly in terms of reduction of psychopathology. This exploratory study examines the impact of bariatric surgery in terms of positive psychological growth and development., Methods: 57 patients who underwent LAGB were recruited to this study; 31 patients (54.4%) completed a questionnaire battery 1 year or more following surgery. Positive impact was assessed using the posttraumatic growth questionnaire. Mental and physical health were assessed using the SF-36. Family support was assessed using the perceived family support questionnaire and weight loss measure was assessed using measured weight differences prior to and 1 year after surgery., Results: Positive impact was apparent in all dimensions including greater appreciation of life, increased sense of personal strength and improvement in relating to others. Positive impact appears to be independent of physical and mental health as well as of family social support., Conclusion: Positive impact of bariatric surgery is a substantial outcome and should be examined further. Positive impact of bariatric surgery should be taken into account as a therapeutic tool in positive oriented psychological interventions following bariatric surgery.

Objective: To assess the effect on freezing of gait (FOG) of botulinum toxin type A (BTX-A) injections in advanced Parkinson's disease (PD) patients., Method: BTX-A 150 IU or normal saline was injected into each leg's calf muscles by a blinded investigator. FOG severity was assessed at set intervals (6-month follow-up)., Results: Eleven age- and disease severity-matched PD patients with disabling FOG participated. Six patients received BTX-A and 5 received saline. No improvement was observed in either group over time. Leg weakness and falls lead to early termination., Conclusion: BTX-A injections to the legs did not improve FOG and might increase fall risk.

To assess severity and progression of self-perceived dysautonomia and their impact on health-related quality of life (Hr-QoL) in multiple system atrophy (MSA), twenty-seven patients were recruited by the European MSA Study Group (EMSA-SG). At baseline, all patients completed the Composite Autonomic Symptom Scale (COMPASS) and the 36 item Short Form Health Survey (SF-36), and they were assessed using the 3-point global disease severity scale (SS-3) and the Unified MSA Rating Scale (UMSARS). After 6 months follow-up, the self completed COMPASS Change Scale (CCS), the SF-36, SS-3, and UMSARS were obtained. MSA patients showed marked self-perceived dysautonomia at baseline visit and pronounced worsening of dysautonomia severity on the CCS at follow-up. Severity and progression of dysautonomia did not correlate with age, disease duration, motor impairment and overall disease severity at baseline. There were no significant differences between genders and motor subtypes. Baseline COMPASS scores were, however, inversely correlated with SF-36 scores. Progression of self-perceived dysautonomia did not correlate with global disease progression. Hr-QoL scores were stable during follow-up. This is the first study to investigate self-perceived dysautonomia severity in MSA and its evolution over time. Our data suggest that dysautonomia should be recognized as a key target for therapeutic intervention in MSA.

Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients' own evaluation of their illness and factors associated with poor health-related quality of life (Hr-QoL). We, therefore, assessed Hr-QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA-Study Group (EMSA-SG) Natural History Study: Medical Outcome Study Short Form (SF-36), EQ-5D, Beck Depression Inventory (BDI), Mini-Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), Hoehn & Yahr (H&Y) Parkinson's disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson's Disease Sleep Scale (PDSS). Forty-six percent of patients had moderate to severe depression (BDI > or = 17); Hr-QoL scores on the SF-36 and EQ-5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA-P (predominantly parkinsonian motor subtype) than MSA-C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr-QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate-to-strong predictors for the SF-36 physical summary score and the BDI and UMSARS motor scores for the SF-36 mental summary score. This report is the first study to show that Hr-QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr-QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr-QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease.

Parkinson's disease (PD), multiple system atrophy (MSA) and pure autonomic failure (PAF) are neurodegenerative disorders frequently associated with orthostatic hypotension and syncope, though with different underlying mechanisms. Cerebral hemodynamic responses in these three neurodegenerative diseases are still incompletely studied and it is possible that they would be differentially affected. We measured blood flow velocity (BFV) in the middle cerebral artery (MCA) and vertebral artery (VA) in patients with these disorders and investigated whether cerebral vasomotor reactivity (VMR) differs in these three disorders. Twenty-four patients (9 with PD, 10 with MSA and 5 with PAF) were studied. VMR was assessed in the MCA and VA, using transcranial Doppler (TCD) and Diamox test (injection of 1 g acetazolamide i.v.) with the patients in a recumbent position. The percent difference between BFV before and after acetazolamide injection was defined as VMR% and the results were compared by ANOVA. The mean MCA and VA blood flow velocities were similar in the three disorders and within normal limits for our laboratory. The mean MCA VMR values were 37.5+/-24.0%, 27.9+/-28.0% and 38.0+/-33.9% in PD, MSA and PAF, respectively. The VA VMR values were 22.9+/-23.6%, 32.4+/-38.0% and 18.9+/-18.3%, respectively, with no significant differences between the groups. We conclude that BFV is normal in PD, MSA and PAF and that the VMR, as investigated by TCD and the Diamox test, did not disclose differences in cerebral vasomotor responses between these conditions.

Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

Purpose of Review: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurones, but it is increasingly recognized to be a more disseminated disease. The autonomic nervous system may also be involved. Here we review the literature with specific emphasis on autonomic functions in ALS., Recent Studies: Ample evidence exists for subclinical dysfunction of cardiovascular, sudomotor, gastrointestinal, salivary and lacrimal regulation, even in early ALS cases. Autonomic disturbances may lead to circulatory collapse or sudden death in respirator dependent patients. Several studies suggest the existence of sympathetic hyperactivity in ALS. We discuss some possible pathophysiological mechanisms of the subtle abnormalities and some clinical and treatment implications., Summary: The wide range of autonomic involvement, together with results suggesting cognitive and extrapyramidal dysfunction, supports the view that ALS is a multisystem degenerative disease.

Objective: To evaluate and systematically characterize a group of older adults with disturbed gait of unknown origin., Design: Cross-sectional study., Setting: Outpatient clinic in a movement disorders unit., Participants: Twenty-five patients (mean age 78.4 years) with a disturbed gait of unknown origin were compared with twenty-eight age matched "healthy" controls (mean age 78.2)., Measurement: Detailed medical history, geriatric and neurological assessments., Results: Patients walked more slowly (P<0.0001) and with shorter strides (P<0.0001) compared with controls. Muscle strength was lower, and static and dynamic balance and gait performance were worse among the patients (P<0.0001). The patients also tended to be more depressed (P<0.0001),more anxious (P<0.002), had a greater fear of falling (P<0.0001) and had lower scores on the Mini-Mental State Examination (P<0.005). There was no difference in the frequency of cerebellar or pyramidal signs in the two groups. However, neurological testing revealed that extrapyramidal (P<0.0001) and frontal release signs (P<0.0001) were more common among the patients. Neuroradiological findings were rare among the patients and they did not explain the changes in gait speed or fear of falling., Conclusions: Older adults with a disturbed gait of unknown origin appear to share common characteristics. They walk more slowly than "healthy" controls with increased unsteadiness and with excessive fear of falling. The extrapyramidal, frontal lobe, and limbic systems apparently play an important role, to different degrees, in what can be viewed as a multisystem neurodegenerative syndrome clearly different from "aging."

Many older adults walk with a cautious and impaired gait of unknown origin, however, the relationship between fear of falling and the observed gait changes is not well understood. To better understand the "cautious" gait of the elderly, we tested the hypothesis that temporal gait variability, putatively a marker of intrinsic walking unsteadiness, is increased among older adults with a cautious gait and a higher-level gait disorder (HLGD), an altered gait that cannot be attributed to a well-defined cause. Twenty-five older adults (mean age: 78 years) with a HLGD were compared to healthy controls of similar age and sex (n=28). The clinical characteristics (e.g., neurological status, fear of falling), the magnitude of the stride-to-stride variations in gait cycle timing (a measure of temporal gait variability), and a fractal index of gait (a measure of the stride dynamics independent of the magnitude of the variability) were studied in both groups. Gait variability was significantly increased (P<0.0001) in HLGD subjects (52+/-26 ms) compared to controls (27+/-9 ms). Changes in frontal lobe and extra-pyramidal function were also found in the patient group. Among HLGD subjects, gait variability was not associated (P>0.05) with age, gender, MMSE score, muscle strength, # of co-morbidities, balance, cerebellar signs, or pyramidal signs, but was significantly associated with scores on the Geriatric Depression Scale (r=0.46, P<0.02) and fear of falling (r=0.69, P<0.0001). Among HLGD subjects, only a fractal index was significantly different in fallers and non-fallers. These findings underscore the idea that the gait changes in older adults who walk with fear may be an appropriate response to unsteadiness, are likely a marker of underlying pathology, and are not simply a physiological or psychological consequence of normal aging.

Objective: To investigate whether the cardiac R-R interval variation (RRIV) is of value in differentiating patients with Parkinson's disease (PD) from multiple system atrophy (MSA)., Background: RRIV assessment is a simple procedure, reflecting mainly vagal efferent activity. Reduced RRIV was reported in MSA., Methods: RRIV at rest and after 120 s of deep breathing was assessed blindly to clinical diagnosis in 22 PD and 20 MSA patients. The results were compared with data from 23 age-matched healthy subjects., Results: RRIV at rest was 7.1 +/- 2.7% in PD and 9.7 +/- 7.2% in MSA, increasing after deep breathing to 11.2 +/- 6.3 and 12.3 +/- 6.6% correspondingly. The frequency of the RRIV abnormalities in the PD group (4/22, 18.2%) and MSA (6/20, 30%) were higher than among controls (P < 0.004)., Conclusions: RRIV, either at rest or after deep breathing, may be abnormal both in PD and MSA, but does not distinguish between these disorders.

Objectives: To study the efficacy of cholinesterase inhibitors in the treatment of dementia in patients with Parkinson's disease (PD)., Methods: We treated twenty-eight demented patients with PD openly for 26 weeks with rivastigmine (mean daily dose 7.2 +/- 3.3 mg/day). Baseline scores were compared with those at weeks 12, 26 and after 8 weeks of washout., Results: Twenty patients completed 26 weeks of treatment and eight dropped out because of side effects. The Unified Parkinson's Disease Rating Scale mental subscore improved significantly at week 26 (P < 0.01) while the motor score (part III) did not change. The mean ADAScog total score improved by 7.3 points at week 26 (P < 0.002). The subscores for recognition, word finding, remembering instructions and concentration items of the ADAScog improved significantly as well (P < 0.02, P < 0.05, P < 0.005 and P < 0.003, respectively)., Conclusions: Rivastigmine may improve the cognitive functions in PD patients with dementia with no worsening of motor function.

Background: The pathophysiology of freezing of gait (FOG) is unclear., Objective: To assess the relationships between FOG and other parkinsonian features in Parkinson's disease (PD), focusing on levodopa effects., Methods: Nineteen PD patients with significant FOG in "off" were assessed while "off" and "on". Three observers independently viewed videotapes of a 130-m walk and scored FOG frequency. The Unified Parkinson's disease Rating Scale was used to evaluate clinical state., Results: FOG frequency was not correlated with other parkinsonian features in "off" and only with speech and writing in "on". Levodopa significantly decreased FOG frequency (p<0.001). This reduction was strongly correlated with improvement of tremor (R=0.80, p<0.01) and speech (R=0.62, p<0.05), but not with improvement in rigidity, bradykinesia, or balance., Conclusion: Levodopa decreases FOG in PD. FOG is apparently an independent motor symptom, caused by a paroxysmal pathology that is different from that responsible for bradykinesia, rigidity or postural instability.

Modulated kinesitherapy (MK) is a new method based on synchronization of vegetative and motor components in walking at a pace corresponding to actual heart rate which is maintained during the procedure with cardiotrainer Marafon. MK produced the following therapeutic effects: optimization of cardiovascular functions (weakening of postload on the heart with lowering of arterial pressure; improvement of coronary blood flow, stabilization of the heart rate and cardiac pump function); marked antiarrhythmic effect, normalization of autonomic nervous system tonicity, neurohumoral and psychoemotional state. MK is indicated in ischemic heart disease, essential hypertension, cardiac arrhythmia, vegetovascular asthenia.

Objectives: Patients with Parkinson's disease (PD) have an increased risk of falling that has yet to be fully explained. To better understand the gait disturbance in PD and the factors that contribute to falls, we quantitatively evaluated: (1) the relationship between gait variability (a marker of fall risk in other populations), fall history, and other parkinsonian features, and (2) the effects of levodopa on these relationships., Methods: The average stride time and stride-to-stride variability were measured using force-sensitive insoles during comfortable walking. Fall frequency, motor control, function, and mental health were measured using the Unified Parkinson's Disease Rating Scale (UPDRS), the Mini-Mental State Exam (MMSE), and the timed motor tests of the Core Assessment Program for Intracerebral Transplantations (CAPIT) in 32 subjects with idiopathic PD, in an "off" (unmedicated) state and again in an "on" (medicated) state., Results: Average stride time was not associated with any UPDRS or CAPIT measure and was similar in fallers and non-fallers in "off" and "on" states (p>0.27). Stride time variability was significantly associated with fall frequency as well as with total scores on the CAPIT and the UPDRS, ADL abilities, and motor function. Stride time variability and falls were not related to tremor, rigidity or bradykinesia in the "off" state. 41% of subjects reported one or more falls. Stride time variability was 8.8+/-7.9% in fallers and 4.2+/-1.3% in non-fallers (p<0.009). Stride time variability significantly improved in response to levodopa, both in fallers and non-fallers, but remained increased in fallers (vs. non-fallers)., Conclusions: The patho-physiology responsible for impaired stride-to-stride regulation of gait timing is apparently independent of other cardinal features of PD, i.e., tremor, rigidity, or bradykinesia, but is responsive to levodopa. Stride-to-stride variability is especially impaired among PD subjects with a history of falls, suggesting, for the first time, the possibility of exaggerated impairment of internal clock function in PD fallers.

To assess the effect of levodopa on distinct freezing of gait (FOG) subtypes in patients with 'off' FOG. Nineteen patients (12 men, mean age 62.0 +/- 8.4 years) with Parkinson's disease and clinically significant FOG during 'off' states were videotaped whilst walking 130 m during 'off' and 'on' states. Three independent observers characterized the type, duration, and clinical manifestations and quantified FOG by analyzing the videotapes. Their combined mean scores were used for statistical analysis. The intra-class correlation coefficient assessed inter-observer reliability. Wilcoxon and Friedman tests evaluated differences in mean frequencies of FOG characteristics. During 'off' states, FOG was elicited by turns (63%), starts (23%), walking through narrow spaces (12%) and reaching destinations (9%). These respective values were only 14, 4, 2 and 1% during 'on' states (P < 0.011). Moving forward with very small steps and leg trembling in place were the most common manifestations of FOG; total akinesia was rare. Most FOG episodes took <10 s and tended to be shorter during 'on' states. Levodopa significantly decreased FOG frequency (P < 0.0001) and the number of episodes with akinesia (P < 0.001). Distinction amongst FOG subtypes enables evaluation of distinctive therapeutic response. Levodopa helps in reducing the frequency and duration of 'off'-related FOG.

Patients with Parkinson's disease (PD) often experience freezing of gait, a debilitating phenomenon during which the subject suddenly becomes unable to start walking or to continue to move forward. Little is known about the gait of those subjects with PD who experience freezing of gait or the pathophysiology of freezing. One possibility is that freezing of gait is a truly paroxysmal phenomenon and that the usual walking pattern of subjects who experience freezing of gait is not different than that of other patients with PD who do not experience these transient episodes of freezing of gait. On the other hand, a recent study noted gait changes just prior to freezing and concluded that dyscontrol of the cadence of walking contributes to freezing. To address this question, we compared the gait of PD subjects with freezing of gait to PD subjects without freezing of gait. Given the potential importance of the dyscontrol of the cadence of walking in freezing, we focused on two aspects of gait dynamics: the average stride time (the inverse of cadence, a measure of the walking pace or rate) and the variability of the stride time (a measure of "dyscontrol," arrhythmicity and unsteadiness). We found that although the average stride time was similar in subjects with and without freezing, stride-to-stride variability was markedly increased among PD subjects with freezing of gait compared to those without freezing of gait, both while "on" (P<0.020) and "off" (P<0.002) anti-parkinsonian medications. Further, we found that increased gait variability was not related to other measures of motor control (while off medications) and levodopa apparently reduced gait variability, both in subjects with and without freezing. These results suggest that a paradigm shift should take place in our view of freezing of gait. PD subjects with freezing of gait have a continuous gait disturbance: the ability to regulate the stride-to-stride variations in gait timing and maintain a stable walking rhythm is markedly impaired in subjects with freezing of gait. In addition, these findings suggest that the inability to control cadence might play an important role in this debilitating phenomenon and highlight the key role of dopamine-mediated pathways in the stride-to-stride regulation of walking.

Background: Freezing of gait (FOG) is a mysterious symptom, observed in different parkinsonian syndromes, but considered to be rare in multiple system atrophy (MSA)., Objective: To assess the frequency of FOG in patients with MSA., Method: We studied the presence of FOG in 28 patients with clinical diagnosis of MSA. 21 patients had probable MSA and 7 had possible MSA. The clinical diagnosis was based on neurological examination performed by at least two experienced movement disorders specialists as well as on the results of ancillary examinations and the course of the disease. In 22 patients MSA was predominated by parkinsonism (MSA-P) and in 6 by cerebellar signs (MSA-C). The patients' mean age was 66.8+/-10.3 years, mean disease duration 6.4+/-4.0 years and mean worst Hoehn and Yahr (H&Y) stage was 3.6+/-0.6. Presence and severity of FOG was assessed during the last office visit, by the recently validated FOG questionnaire (FOG-Q), with a maximal score of 24, while patients that received at least one point in the last four questions were classified as having FOG. Severity of FOG was determined by the sum of these last four out of six questions (maximal score is 16). FOG-Q total score reflected general function and walking ability disturbances, caused by FOG. The comparison between groups of patients was performed by way of the Mann-Whitney two-sample test and chi-square or Fisher's exact tests. Correlations between various parameters were calculated using Spearman's correlation coefficient., Results: Twenty-one patients were able to walk and 7 were bedridden at the time of the study. FOG appeared in a total of 75% of all MSA patients (in 82% of patients with MSA-P and in 50% patients with MSA-C). In the MSA-P group disease duration was about the same among 'freezers' and 'non-freezers', while among the MSA-C patients it was significantly shorter in the non-freezers. Mean score of the freezing subdivision of the FOG-Q was 8.2+/-5.1 for MSA-P group and 4.5+/-5.1 for MSA-C one. Mean FOG-Q total score was 9.1+/-4.0 and 6.2+/-4.6 (p>0.05) for MSA-P and MSA-C patients, respectively., Conclusion: Freezing of gait is a common symptom in MSA, both in MSA-P and MSA-C.

Ninety-one consecutive patients with Parkinson's disease (PD) were asked to grade their general satisfaction from life (GSL) and completed the PDQ-39 and the quality of sexual life questionnaire (QoSL-Q). The reliability of the QoSL-Q was 0.74. Satisfaction from sexual life as reflected by the QoSL-Q significantly decreased with aging (P<0.01) and advanced disease (P<0.05). No correlation was found between the PDQ-39 and the QoSL index. The correlation between the PDQ-39 and GSL (r=-0.334) improved by adding the QoSL-Q, as a 9th dimension to the PDQ-39 (r=-0.405). The QoSL-Q is a reliable tool assessed a unique and important dimension not evaluated by the PDQ-39.

Objective: To evaluate data of quantitative anal sphincter EMG in normal controls and to compare them with patients with multiple system atrophy (MSA)., Methods: Quantitative anal sphincter EMG were performed on 100 normal controls and 11 patients with MSA to characterise EMG data in these two groups., Results: In the normal controls, there was a trend for increased motor unit potential (MUP) amplitude, duration, area, and polyphasicity with advancing age. Patients with MSA exhibited similar MUP size and fibre density. Significant differences were found only in parameters of the recruitment pattern, which were reduced in MSA, with a diminution in the number of active MUPs during rest., Conclusions: These results may reflect either decreased number of motor cells in Onuf's nucleus without significant consequential reinnervation, or upper motor neuron involvement affecting the anal sphincter in MSA. They further underline the importance of comparative data for age matched controls.

Background: Freezing of gait (FOG) is a common and very disabling parkinsonian symptom, which is poorly understood and responds unsatisfactorily to medical treatment. We recently reported a unique patient with Parkinson's disease (PD) who had significant alleviation of FOG shortly after she was injected with botulinum toxin type A (BTX-A) for foot dystonia (Giladi et al. 1997)., Objective: To assess the effect of BTX-A injections into the calf muscles of parkinsonian patients on FOG., Method: BTX-A was injected in an open fashion into the calf muscles of 10 parkinsonian patients (age 55-75 years) with FOG as a predominant symptom. Response of FOG was assessed subjectively by the patient from worsening (-1) to marked improvement (+3). One patient was injected in a single blind fashion with saline or BTX-A after he had an initial good response., Results: Seven patients reported different rates of improvement of FOG severity in 15 out of 17 therapeutic sessions. Four patients (40%) reported marked improvement (+3) of FOG in 5 sessions. Two patients reported no effect in two sessions. The mean duration of improvement was 6 weeks (range 1-12 weeks) with definite deterioration afterwards. The patient who was injected in a single blind fashion did not respond to saline injections but improved significantly with BTX-A treatment., Conclusions: We observed a clear temporal relationship between BTX-A injections into the calf muscles of parkinsonian patients and improvement of FOG. A double blind placebo controlled prospective study is needed before any conclusions can be drawn about the role of BTX-A injection in FOG.