Nir Giladi

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease

BACKGROUND Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gauchers disease, among patients with Parkinsons disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinsons 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 Parkinsons 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 Parkinsons disease.

The Role of Executive Function and Attention in Gait

Until recently, gait was generally viewed as a largely automated motor task, requiring minimal higher‐level cognitive input. Increasing evidence, however, links alterations in executive function and attention to gait disturbances. This review discusses the role of executive function and attention in healthy walking and gait disorders while summarizing the relevant, recent literature. We describe the variety of gait disorders that may be associated with different aspects of executive function, and discuss the changes occurring in executive function as a result of aging and disease as well the potential impact of these changes on gait. The attentional demands of gait are often tested using dual tasking methodologies. Relevant studies in healthy adults and patients are presented, as are the possible mechanisms responsible for the deterioration of gait during dual tasking. Lastly, we suggest how assessments of executive function and attention could be applied in the clinical setting as part of the process of identifying and understanding gait disorders and fall risk.

Characterization of freezing of gait subtypes and the response of each to levodopa in Parkinson's disease

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 Parkinsons 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.

Understanding and treating freezing of gait in parkinsonism, proposed working definition, and setting the stage

Although the term “freezing of gait” (FOG) was not used by early authors and notably not by Parkinson himself,1 the typical propulsive high frequency stepping associated with this gait disturbance was described by him as a feature of Parkinson’s disease (PD). Martin2 also reported examples of an inability to initiate locomotion accompanied by disturbed stepping patterns in postencephalitic parkinsonism with a dramatic response to visual cues. It was not until the early 1970s that FOG started to get increased attention, based on the realization that its response to levodopa was more complex than that of bradykinesia and rigidity. During those early days, it was first suggested that levodopa can sometimes induce or even worsen FOG.3 Based on those reports and the occurrence of FOG in atypical parkinsonism, it has long been considered a levodopa-resistant symptom. It took 30 years of experience with levodopa treatment to understand that this is a misconception. Schaafsma et al. demonstrated that “off”-related FOG episodes were significantly shorter in duration and markedly fewer in frequency when turning from “off” to “on.”4 However, the concept of a complex relationship with levodopa treatment still holds, as is evidenced by the continued manifestation of FOG in the “on” period, and its relationship with other levodopa-resistant symptoms such as postural instability.5,6 Despite its fascinating and unique nature, its common appearance among people with advanced PD, and its significant contribution to the development of major disability and frequent falls,7 research about the pathophysiology and treatment of FOG moved slowly forward. One possible reason for that delay is the unpredictable and episodic nature of freezing, which makes it very difficult to capture true spontaneous episodes. In addition, FOG appears most frequently at home during unobserved behavior and in response to specific environmental triggers8 and rarely in the gait lab.9 Another difficulty that might have slowed down FOG research is its lack of definition. This is of special importance, considering the fact that FOG is very heterogeneous in nature and can frequently be confused with bradykinesia or akinesia. Taking all those difficulties together, we thought it is time to join forces and move research about FOG forward to a better understanding of its mechanisms and hopefully with time leading to more effective treatment. This supplement is the result of a satellite symposium which was held just prior to the Kyoto International Movement Disorders Congress in late October 2006. In this meeting, a number of state-of-the-art presentations were put forward, summarizing the most recent clinical and research findings. All speakers and two additional leading figures in the field of FOG research were subsequently invited to contribute to this first ever supplement devoted to FOG in parkinsonism. As part of the introduction to this supplement, we propose a working definition of FOG. We are aware of the difficulties inherent to this task but believe that this first step has to be taken to improve communication and upgrade the quality of scientific terminology among researchers. The most common feature associated with FOG is the unique subjective feeling of patients describing that “their feet get glued to the ground.” As suggested in one of the supplement papers on the clinimetrics of FOG,10 this characteristic feeling may aid in accurate history *Correspondence to: Alice Nieuwboer, Departement Revalidatiewetenschappen, Faculteit Bewegingsen Revalidatiewetenschappen, Katholieke Universiteit Leuven, Tervuursevest 101, 3001-B Leuven (Heverlee), Belgium. E-mail: alice.nieuwboer@faber.kuleuven.be Received 26 November 2007; Accepted 29 November 2007 Published online 25 July 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21927 Movement Disorders Vol. 23, Suppl. 2, 2008, pp. S423–S425

Validation of the freezing of gait questionnaire in patients with Parkinson's disease

To revalidate the Freezing of Gait Questionnaire (FOG‐Q), patients with Parkinsons disease (PD) were randomly assigned to receive rasagiline (1 mg/day) (n = 150), entacapone (200 mg with each dose of levodopa) (n = 150), or placebo (n = 154). Patients were assessed at baseline and after 10 weeks using the FOG‐Q, Unified Parkinsons Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), and Parkinsons Disease Questionnaire (PDQ‐39). FOG‐Q dimensionality, test–retest reliability, and internal reliability were examined. Convergent and divergent validities were assessed by correlating FOG‐Q with UPDRS, BDI, and PDQ‐39. Comparisons between FOG‐Q item 3 and UPDRS item 14 were also made. Principal component analysis indicated that FOG‐Q measures a single dimension. Test–retest reliability and internal reliability of FOG‐Q score was high. FOG‐Q was best correlated to items of the UPDRS relating to walking, general motor issues, and mobility. Correlations between baseline and endpoint suggested that FOG‐Q item 3 is at least as reliable as UPDRS item 14. At baseline, 85.9% of patients were identified as “Freezers” using FOG‐Q item 3 (≥1) and 44.1% using UPDRS item 14 (≥1) (P < 0.001). FOG‐Q was a reliable tool for the assessment of treatment intervention. FOG‐Q item 3 was effective as a screening question for the presence of FOG.

Executive Function and Falls in Older Adults: New Findings from a Five-Year Prospective Study Link Fall Risk to Cognition

Background Recent findings suggest that executive function (EF) plays a critical role in the regulation of gait in older adults, especially under complex and challenging conditions, and that EF deficits may, therefore, contribute to fall risk. The objective of this study was to evaluate if reduced EF is a risk factor for future falls over the course of 5 years of follow-up. Secondary objectives were to assess whether single and dual task walking abilities, an alternative window into EF, were associated with fall risk. Methodology/Main Results We longitudinally followed 256 community-living older adults (age: 76.4±4.5 yrs; 61% women) who were dementia free and had good mobility upon entrance into the study. At baseline, a computerized cognitive battery generated an index of EF, attention, a closely related construct, and other cognitive domains. Gait was assessed during single and dual task conditions. Falls data were collected prospectively using monthly calendars. Negative binomial regression quantified risk ratios (RR). After adjusting for age, gender and the number of falls in the year prior to the study, only the EF index (RR: .85; CI: .74–.98, p = .021), the attention index (RR: .84; CI: .75–.94, p = .002) and dual tasking gait variability (RR: 1.11; CI: 1.01–1.23; p = .027) were associated with future fall risk. Other cognitive function measures were not related to falls. Survival analyses indicated that subjects with the lowest EF scores were more likely to fall sooner and more likely to experience multiple falls during the 66 months of follow-up (p<0.02). Conclusions/Significance These findings demonstrate that among community-living older adults, the risk of future falls was predicted by performance on EF and attention tests conducted 5 years earlier. The present results link falls among older adults to cognition, indicating that screening EF will likely enhance fall risk assessment, and that treatment of EF may reduce fall risk.

Medical treatment of freezing of gait

Freezing of gait (FOG) is frequently considered as one of the dopamine‐resistant motor symptoms of Parkinsonism. Recent studies have clearly demonstrated that the Off‐related FOG is improved by levodopa (L‐dopa) or entacapone treatment. L‐dopa can decrease duration of each FOG episode as well as its frequency. On‐related FOGs are not common and difficult to diagnose. Only in the most advanced stages of the disease, FOGs are resistant to treatment as many other symptoms. Off‐related FOGs are likely to be improved by dopamine agonists (DAs), but this has never been looked at systematically. In contrast, DA treatment might provoke FOG, and in two pivotal studies when DAs were compared to L‐dopa in early stages of Parkinsons disease, the DA‐treated arms experienced more FOGs. MAO‐B inhibitors (selegiline and rasagiline) can decrease FOG frequency or severity, but its clinical significance is still unknown. L‐Threo‐DOPS has been reported to have a symptomatic beneficial effect in patients with pure freezing syndrome, but small‐scale, controlled trials in Parkinsons disease could not support those early observations. Botulinum toxin injected into the calf muscles has been suggested to have a symptomatic benefit. However, double‐blind, prospective studies could not support that early observation and increased fall risk in the injected patients has put this direction of treatment on hold. The potential benefit of amantadine, antidepressive drugs, acetylcholine esterase inhibitors, and methylphenidate on FOG has been studied in small‐scale studies, and there is a need for prospective studies to understand the future role of those drugs.

Gait alterations in healthy carriers of the LRRK2 G2019S mutation

To test for an association between the LRRK2‐G2019S mutation and gait, we studied 52 first‐degree relatives of patients with Parkinsons 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. Ann Neurol 2010

Do we always prioritize balance when walking? Towards an integrated model of task prioritization

Previous studies suggest that strategies such as “posture first” are implicitly employed to regulate safety when healthy adults walk while simultaneously performing another task, whereas “posture second” may be inappropriately applied in the presence of neurological disease. However, recent understandings raise questions about the traditional resource allocation concept during walking while dual tasking. We propose a task prioritization model of walking while dual tasking that integrates motor and cognitive capabilities, focusing on postural reserve, hazard estimation, and other individual intrinsic factors. The proposed prioritization model provides a theoretical foundation for future studies and a framework for the development of interventions designed to reduce the profound negative impacts of dual tasking on gait and fall risk in patients with neurological diseases.

A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci

Crohns disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.