Showing papers by "Anat Mirelman published in 2017"

Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry.

Abstract: Background Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80. Methods The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at 8 sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included when available. Results Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% confidence interval [CI]: 26.3%-65.8%) to age 80, which is not significantly higher than the previously estimated 25% (95% CI: 16.7%-34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the noncarrier relatives, as seen in Ashkenazi Jewish relatives. Conclusions The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25% to 42.5% at age 80 in all populations analyzed. © 2017 International Parkinson and Movement Disorder Society

Impaired dual tasking in Parkinson's disease is associated with reduced focusing of cortico-striatal activity.

Abstract: See Bell et al. (doi:10.1093/awx063) for a scientific commentary on this article. Impaired dual tasking, namely the inability to concurrently perform a cognitive and a motor task (e.g. 'stops walking while talking'), is a largely unexplained and frequent symptom of Parkinson's disease. Here we consider two circuit-level accounts of how striatal dopamine depletion might lead to impaired dual tasking in patients with Parkinson's disease. First, the loss of segregation between striatal territories induced by dopamine depletion may lead to dysfunctional overlaps between the motor and cognitive processes usually implemented in parallel cortico-striatal circuits. Second, the known dorso-posterior to ventro-anterior gradient of dopamine depletion in patients with Parkinson's disease may cause a funnelling of motor and cognitive processes into the relatively spared ventro-anterior putamen, causing a neural bottleneck. Using functional magnetic resonance imaging, we measured brain activity in 19 patients with Parkinson's disease and 26 control subjects during performance of a motor task (auditory-cued ankle movements), a cognitive task (implementing a switch-stay rule), and both tasks simultaneously (dual task). The distribution of task-related activity respected the known segregation between motor and cognitive territories of the putamen in both groups, with motor-related responses in the dorso-posterior putamen and task switch-related responses in the ventro-anterior putamen. During dual task performance, patients made more motor and cognitive errors than control subjects. They recruited a striatal territory (ventro-posterior putamen) not engaged during either the cognitive or the motor task, nor used by controls. Relatively higher ventro-posterior putamen activity in controls was associated with worse dual task performance. These observations suggest that dual task impairments in Parkinson's disease are related to reduced spatial focusing of striatal activity. This pattern of striatal activity may be explained by a loss of functional segregation between neighbouring striatal territories that occurs specifically in a dual task context.

Intervention modalities for targeting cognitive-motor interference in individuals with neurodegenerative disease: a systematic review.

Abstract: Introduction: Individuals with neurodegenerative disease (NDD) commonly have elevated cognitive-motor interference, change in either cognitive or motor performance (or both) when tasks are performed simultaneously, compared to healthy controls. Given that cognitive-motor interference is related to reduced community ambulation and elevated fall risk, it is a target of rehabilitation interventions.Areas covered: This review details the collective findings of previous dual task interventions in individuals with NDD. A total of 21 investigations focusing on 4 different neurodegenerative diseases and one NDD precursor (Parkinson’s disease, multiple sclerosis, Alzheimer’s disease (AD), dementia other than AD, and mild cognitive impairment) consisting of 721 participants were reviewed.Expert commentary: Preliminary evidence from interventions targeting cognitive-motor interference, both directly and indirectly, show promising results for improving CMI in individuals with neurodegenerative diseases. Metho...

When is Higher Level Cognitive Control Needed for Locomotor Tasks Among Patients with Parkinson's Disease?

Abstract: Turning has been implicated as a complex task that requires both motor and cognitive resources. Accumulating evidence shows that patients with Parkinson’s disease (PD) require more steps and more time to complete a turn, however, the role of the prefrontal cortex during turning is not clear. Forty nine patients with PD without freezing of gait (mean age 71.7 ± 1.0 years; 67% men, disease duration 9.7 ± 1.3 years) performed motor and cognitive tests. Prefrontal activation, specifically in Brodmann area 10 (BA10), during turning and usual walking was measured using functional near infrared spectroscopy (fNIRS). The patients with PD were further divided into two subgroups with high and low functional status based on limitations in community ambulation. General Linear Model analysis adjusted for age, gender, disease duration and turn duration was used to assess differences between tasks and subgroups of patients with PD. In addition, Pearson’s correlation was performed to assess association between BA10 activation and motor and cognitive scores. Activation in BA10 increased during walking (p < 0.001), while it decreased during turning (p = 0.006). A comparison between the two subgroups of patients with PD revealed that patients with relatively better ambulation decreased prefrontal activation during turning, as compared to patients with relatively worse ambulation (p < 0.001). These findings are the first to show that BA10 plays a different role during turning and walking and that ambulation status may alter BA10 activation during turning. Higher prefrontal activation during turning in the subgroup of patients with relatively worse ambulation may reflect a compensatory attempt at improving performance.

An innovative training program based on virtual reality and treadmill: effects on gait of persons with multiple sclerosis.

Abstract: Aim: In this single blind randomized controlled trial, we examined the effect of a virtual reality-based training on gait of people with multiple sclerosis.Methods: Twenty-five individuals with multiple sclerosis with mild to moderate disability were randomly assigned to either the control group (n = 11) or the experimental group (n = 14). The subjects in the control group received treadmill training. Subjects in the experimental group received virtual reality based treadmill training. Clinical measures and gait parameters were evaluated.Result: Subjects in both the groups significantly improved the walking endurance and speed, cadence and stride length, lower limb joint ranges of motion and powers, during single and dual task gait. Moreover, subjects in the experimental group also improved balance, as indicated by the results of the clinical motor tests (p < 0.05). Between-group comparisons revealed that the experimental group improved significantly more than control group in hip range of motion ...

The role of the prefrontal cortex in freezing of gait in Parkinson’s disease: insights from a deep repetitive transcranial magnetic stimulation exploratory study

Abstract: Freezing of Gait (FOG) is one of the most debilitating gait impairments in Parkinson’s disease (PD), leading to increased fall risk and reduced health-related quality of life The utility of parkinsonian medications is often limited in the case of FOG and it frequently becomes dopamine resistant Recent studies have suggested that pre-frontal cortex (PFC) dysfunction contributes to FOG; however, most previous findings provide only indirect evidence To better understand the role of the PFC, we aimed to investigate the impact of high frequency, deep, repetitive transcranial magnetic stimulation (drTMS) of the medial PFC on FOG and its mediators Nine patients with advanced PD participated in a randomized, cross-over exploratory study We applied drTMS over the medial PFC for 16 weeks, with real and sham conditions; each condition included an intensive (ie, 3 times a week) phase and a maintenance (once a week) phase Scores on a FOG-provoking test, the motor part of the Unified Parkinson’s Disease Rating Scale, and gait variability significantly improved after real drTMS, but not after the sham condition Self-report of FOG severity and cognitive scores did not improve Due to discomfort and pain during treatment, two patients dropped out and the study was halted These initial findings support the cause-and-effect role of the pre-frontal cortex in FOG among patients with PD Due to the small sample size, findings should be interpreted cautiously Further studies are needed to more fully assess the role of the medial PFC in the underlying mechanism of FOG and the possibility of using non-invasive brain stimulation to modify FOG

DaT-SPECT assessment depicts dopamine depletion among asymptomatic G2019S LRRK2 mutation carriers

Abstract: Identification of early changes in Dopamine-Transporter (DaT) SPECT imaging expected in the prodromal phase of Parkinson's disease (PD), are usually overlooked. Carriers of the G2019S LRRK2 mutation are known to be at high risk for developing PD, compared to non-carriers. In this work we aimed to study early changes in Dopamine uptake in non-manifesting PD carriers (NMC) of the G2019S LRRK2 mutation using quantitative DaT-SPECT analysis and to examine the potential for early prediction of PD. Eighty Ashkenazi-Jewish subjects were included in this study: eighteen patients with PD; thirty-one NMC and thirty-one non-manifesting non-carriers (NMNC). All subjects underwent a through clinical assessment including evaluation of motor, olfactory, affective and non-motor symptoms and DaT-SPECT imaging. A population based DaT-SPECT template was created based on the NMNC cohort, and data driven volumes-of-interest (VOIs) were defined. Comparisons between groups were performed based on VOIs and voxel-wise analysis. The striatum area of all three cohorts was segmented into four VOIs, corresponding to the right/left dorsal and ventral striatum. Significant differences in clinical measures were found between patients with PD and non-manifesting subjects with no differences between NMC and NMNC. Significantly lower uptake (p<0.001) was detected in the right and left dorsal striatum in the PD group (2.2±0.3, 2.3±0.4) compared to the NMC (4.2±0.6, 4.3±0.5) and NMNC (4.5±0.6, 4.6±0.6), and significantly (p = 0.05) lower uptake in the right dorsal striatum in the NMC group compared to NMNC. Converging results were obtained using voxel-wise analysis. Two NMC participants, who later phenoconverted into PD, demonstrated reduced uptake mainly in the dorsal striatum. No significant correlations were found between the DaT-SPECT uptake in the different VOIs and clinical and behavioral assessments in the non-manifesting groups. This study shows the clinical value of quantitative assessment of DaT-SPECT imaging and the potential for predicting PD by detection of dopamine depletion, already at the pre-symptomatic stage. Clinical registration numbers: NCT01089270 and NCT01089283.

Fall-prone older people's attitudes towards the use of virtual reality technology for fall prevention

Abstract: Background: Virtual reality (VR) technology is a relatively new rehabilitation tool that can deliver a combination of cognitive and motor training for fall prevention. The attitudes of older people to such training are currently unclear. Objective: This study aimed to investigate: (1) the attitudes of fall-prone older people towards fall prevention exercise with and without VR; (2) attitudinal changes after intervention with and without VR; and (3) user satisfaction following fall prevention exercise with and without VR. Methods: A total of 281 fall-prone older people were randomly assigned to an experimental group receiving treadmill training augmented by VR (TT+VR, n = 144) or a control group receiving treadmill training alone (TT, n = 137). Two questionnaires were used to measure (1) attitudes towards fall prevention exercise with and without VR (AQ); and (2) user satisfaction (USQ). AQ was evaluated at baseline and after intervention. USQ was measured after intervention only. Results: The AQ revealed that most participants had positive attitudes towards fall prevention exercise at baseline (82.2%) and after intervention (80.6%; p = 0.144). In contrast, only 53.6% were enthusiastic about fall prevention exercise with VR at baseline. These attitudes positively changed after intervention (83.1%; p < 0.001), and 99.2% indicated that they enjoyed TT+VR. Correlation analyses showed that postintervention attitudes were strongly related to user satisfaction (USQ: r = 0.503; p < 0.001). Conclusions: Older people's attitudes towards fall prevention exercise with VR were positively influenced by their experience. From the perspective of the user, VR is an attractive training mode, and thus improving service provision for older people is important.

A cognitive fMRI study in non-manifesting LRRK2 and GBA carriers

Abstract: Mutations in the GBA and LRRK2 genes account for one-third of the prevalence of Parkinson's disease (PD) in Ashkenazi Jews. Non-manifesting carriers (NMC) of these mutations represent a population at risk for future development of PD. PD patient who carry mutations in the GBA gene demonstrates more significant cognitive decline compared to idiopathic PD patients. We assessed cognitive domains using fMRI among NMC of both LRRK2 and GBA mutations to better understand pre-motor cognitive functions in these populations. Twenty-one LRRK2-NMC, 10 GBA-NMC, and 22 non-manifesting non-carriers (NMNC) who participated in this study were evaluated using the standard questionnaires and scanned while performing two separate cognitive tasks; a Stroop interference task and an N-Back working memory task. Cerebral activation patterns were assessed using both whole brain and predefined region of interest (ROI) analysis. Subjects were well matched in all demographic and clinical characteristics. On the Stroop task, in spite of similar behavior, GBA-NMC demonstrated increased task-related activity in the right medial frontal gyrus and reduced task-related activity in the left lingual gyrus compared to both LRRK2-NMC and NMNC. In addition, GBA-NMC had higher activation patterns in the incongruent task compared to NMNC in the left medial frontal gyrus and bilateral precentral gyrus. No whole-brain differences were noted between groups on the N-Back task. Paired cognitive and task-related performance between GBA-NMC, LRRK2-NMC, and NMNC could indicate that the higher activation patterns in the incongruent Stroop condition among GBA-NMC compared to LRRK2-NMC and NMNC may represent a compensatory mechanism that enables adequate cognitive performance.

Subthalamic Neurons Encode Both Single- and Multi-Limb Movements in Parkinson's Disease Patients.

Abstract: The subthalamic nucleus (STN) is the main target for neurosurgical treatment of motor signs of Parkinson’s disease (PD). Despite the therapeutic effect on both upper and lower extremities, its role in motor control and coordination and its changes in Parkinson’s disease are not fully clear. We intraoperatively recorded single unit activity in ten patients with PD who performed repetitive feet or hand movements while undergoing implantation of a deep brain stimulator. We found both distinct and overlapping representations of upper and lower extremity movement kinematics in subthalamic units and observed evidence for re-routing to a multi-limb representation that participates in limb coordination. The well-known subthalamic somatotopy showed a large overlap of feet and hand representations in the PD patients. This overlap and excessive amounts of kinematics or coordination units may reflect pathophysiology or compensatory mechanisms. Our findings thus explain, at the single neuron level, the important subthalamic role in motor control and coordination and indicate the effect of PD on the neuronal representation of movement.

Real-Time Constant Monitoring of Fall Risk Index by Means of Fully-Wireless Insoles.

Abstract: Constant monitoring of gait in real life conditions is considered the best way to assess Fall Risk Index (FRI) since most falls happen out of the ideal conditions in which clinicians are currently analyzing the patient's behavior. This paper presents the WIISEL platform and results obtained through the use of the first full-wireless insole devices that can measure almost all gait related data directly on the feet (not in the upper part of the body as most existing wearable solutions). The platform consists of a complete tool-chain: insoles, smartphone & app, server & analysis tool, FRI estimation and user access. Results are obtained by combining parameters in a personalized way to build individual fall risk index assessed by experts with the help of data analytics. New FRI has been compared with standards that validate the quality of its prediction in a statistically significant way. That qualitatively relevant information is being provided to the platform users, being either end-users/patients, relatives or caregivers and the related clinicians to ideally assess about their long term evolution.