Focused Ultrasound Thalamotomy for Tremor Relief in Atypical Parkisnsonism.

Background: Magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) VIM-thalamotomy has established efficacy and safety in tremor relief in patients with essential tremor and Parkinson's disease. The efficacy and safety in patients with atypical parkinsonism have not been reported. Objective: To report on the efficacy and safety of FUS VIM-thalamotomy in 8 patients with parkinsonism, multiple system atrophy-Parkinsonian type (MSA-P) (n = 5), and dementia with Lewy bodies (DLB) (n = 3). Methods: Tremor was assessed in the treated hemibody using the Clinical Rating Scale for Tremor (CRST). The motor Unified MSA Rating Scale (UMSAR) was used in the MSA-P and motor sections of the Unified Parkinson's Disease Rating Scale (UPDRS-III) in DLB patients. Cognition was measured using the Montreal Cognitive Assessment (MoCA). Results: In MSA-P and DLB patients, there was immediate tremor relief. CRST scores measured on the treated side improved compared to baseline. During the follow-up of up to 1 year tremor reduction persisted. The change in CRST scores at different time points did not reach statistical significance, probably due to the small sample size. Adverse events were transient and resolved within a year. Conclusions: In our experience, FUS VIM-thalamotomy was effective in patients with MSA-P and DLB. Larger, controlled studies are needed to verify our preliminary observations.

Association of health behaviors with function and health-related quality of life among patients with Parkinson's disease.

BACKGROUND: Current evidence on chronic conditions favors promotion of health behaviors as a mean to positively impact health outcomes. In Parkinson's disease, performing health behaviors is indicated as a means to fight the long-lasting burden of the disease. Understanding actual engagement in health behaviors and patient activation and their association to function and health-related quality of life is therefore important. Our objectives were, among people with Parkinson's disease: (1) to characterize health behaviors including utilization of rehabilitative treatments, physical activity, and patient activation levels, and (2) to test the associations between these health behaviors and health outcomes. METHODS: A cross-sectional study of 88 people with Parkinson's disease (age 66.84 ± 8.8) was conducted. Participants answered questionnaires measuring health behaviors including utilization of health professions treatments, physical activity, patient activation, and health outcomes consisting of function and health-related quality of life. Linear regression models were conducted to test associations between measured health behaviors, function and health-related quality of life. RESULTS: Participants rarely engage in rehabilitative treatments, but showed high levels of patient activation. Controlled by demographics and disease severity, physical activity and patient activation were associated with function (b = 0.41, p < .001; b = 0.2, p = .02, respectively) and physical activity but not patient activation, which was associated with health-related quality of life (b = 0.19, p = .03). There was also interaction effects of physical activity and non-motor symptoms, and physical activity and motor symptoms on health-related quality of life (b = 0.19, p = .02 and b = - 0.22, p = .01, respectively). CONCLUSIONS: In respect to their potential health-related benefits for people with Parkinson's disease, health professionals' treatments are underutilized. Findings supported the importance of health behaviors for maintaining function and health-related quality of life among people with Parkinson's disease. They also show a differential contribution of motor and non-motor symptoms to the association between physical activity and quality of life. It is suggested that policy makers encourage opportunities for physical activity tailored for people with Parkinson's disease and adopt a proactive stance towards enhancing awareness and use of rehabilitation services. Trial registration NCT05211700, ClinicalTrials.gov ID: NCT05211700 first release 12/30/2021, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05211700.

Socio-Clinical factors associated with Parkinson's disease-related specific self-management behaviours.

OBJECTIVE: To test associations between socio-clinical factors, self-management and patient activation among patients with Parkinson's disease (PD), and to explore the use of regression tree to find the cut-off levels of socio-clinical factors which associate with lower or higher self-management behaviours and patient's activation. METHODS: A cross-sectional study of patients with PD (n = 62) who underwent assessment of their socio-clinical factors including age, gender, cognitive status, comorbidities, disease severity (motor and non-motor symptoms) and social support. The associations of these factors to specific aspects of self-management behaviours including utilization of rehabilitative treatments, physical activity and patient activation were tested. RESULTS: Most patients did not utilize rehabilitative treatments. Non-motor symptoms and cognitive status were significantly associated with physical activity (R2 = 0.35, F(3, 58) = 10.50, p < 0.001). Non-motor symptoms were significantly associated with patient activation (R2 = 0.30, F(1, 30) = 25.88, p < 0.001). Patients with Mini-Mental State Exam score ≤24 performed less physical activity, relative to those with a higher score. Patients with ≤5 non-motor symptoms showed higher activation relative to those with >5. CONCLUSION: In PD, disease-specific clinical characteristics overshadow other personal factors as determinants of self-management behaviours. The role of non-motor symptoms in reduced self-management behaviours and activation is highlighted.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

Focused Ultrasound Thalamotomy in Tremor Dominant Parkinson's Disease: Long-Term Results.

BACKGROUND: MRI-guided focused ultrasound (FUS) has established short-term efficacy in tremor relief. OBJECTIVE: We report our long-term experience of treating tremor with unilateral FUS unilateral VIM-thalamotomy in tremor dominant Parkinson's disease (TDPD) patients. METHODS: We report outcome of FUS thalamotomy in TDPD patients with 1-5 years of follow-up. OUTCOMES: tremor reduction assessed with Clinical Rating Scale for Tremor (CRST) and Unified Parkinson's Disease Rating Scale (UPDRS part III) overall and in the treated hemibody and safety. RESULTS: Twenty-six TDPD patients completed 1-5 years of follow-up (median follow-up 36 months, range 12-60 months). Median age was 60 years (range 46-79), with median disease duration of 6 years (range 2-16). Immediately, treatment resulted in 100%improvement in tremor in the treated arm in 23 patients and 90%improvement in 3 patients. In 15 patients with leg tremor, 2 patients with chin tremor and 1 patient with head tremor, tremor was significantly improved. Up to 5 years, median CRST score, median UPDRS score, overall and in treated hemibody, decreased significantly as compared with baseline (p < 0.0001). In 2 patients tremor returned completely and in 8 patients there was partial return of tremor. Adverse events were mild and resolved within 3 months. At baseline 4 patients were not receiving any medication vs. 3 at last follow-up and 15 were not taking levodopa vs.9 at last follow-up. CONCLUSION: Unilateral FUS VIM-thalamotomy in TDPD patients was effective and safe and provided long-term tremor relief in most patients. FUS thalamotomy for tremor may delay initiation of levodopa treatment.

Tremor Relief and Structural Integrity after MRI-guided Focused US Thalamotomy in Tremor Disorders.

Background MRI-guided focused US thalamotomy of ventral intermediate nucleus of the thalamus is a treatment for tremor disorders. Purpose To evaluate white matter integrity before and after thalamotomy and its correlation with clinical outcome. Materials and Methods Participants with essential tremor (ET) or Parkinson disease (PD) undergoing thalamotomy were prospectively recruited between March 2016 and October 2018. Tremor and quality of life were assessed before, 1 month after, and 6 months after thalamotomy. Participants underwent T1-weighted, T2-weighted fluid-attenuated image recovery, and diffusion-tensor MRI before and 1 day, 7-10 days, 1-3 months, and 6 months or longer after treatment. Diffusivity and fiber tractography measures were calculated. Repeated measures analysis of variance with post hoc paired t test and Skillings-Mack test with post hoc Wilcoxon signed-rank test were used for normally and nonnormally distributed data, respectively, and Bonferroni method corrected for multiple comparisons. Results Twenty-two study participants with ET (mean age, 72 years ± 6 [standard deviation]; 14 men), 17 participants with PD (mean age, 65 years ± 8; 13 men), and a replication set of 17 participants with ET (mean age, 73 years ± 6; 10 men) were evaluated. Long-term damage was found in the ablated core (mean fractional anisotropy [FA] at baseline, 0.41 ± 0.10, and at ≥6 months, 0.23 ± 0.09; P < .001) and thalamus to red nucleus tract (mean number of tracts at baseline, 1663, and at ≥6 months, 1070; P = .003). Negative correlation was observed between motor thalamus FA 1 day after ablation and tremor improvement (ET: R = -0.52 [P = .03]; PD: R = -0.61 [P = .003]). Better tremor relief in ET was associated with lower fractional anisotropy before treatment (R = -0.5; P = .02). Conclusion MRI-guided focused US thalamotomy resulted in short- and long-term white-matter changes. Diffusion-tensor imaging provided evidence for long-term damage in the ablation core and in the thalamus and red nucleus tract, and a correlation between preablation fractional anisotropy in the motor thalamus and clinical outcome. © RSNA, 2020 Online supplemental material is available for this article.

Magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: a 5-year single-center experience.

OBJECTIVE: The authors report their experience in treating patients suffering from medication-resistant essential tremor (ET) with MR-guided focused ultrasound (MRgFUS) thalamotomy over a 5-year period. METHODS: Forty-four ET patients treated with unilateral MRgFUS ventral intermediate nucleus (VIM) thalamotomy were assessed using the Clinical Rating Scale for Tremor (CRST) score and the Quality of Life in Essential Tremor Questionnaire (QUEST) over a 5-year span. RESULTS: Tremor was significantly improved immediately following MRgFUS in all patients and ceased completely in 24 patients. CRST scores in the treated hand at baseline (median 19; range 7-32, 44 patients) improved by a median of 16 at 1 month (44 patients; p < 0.0001), 17 at 6 months (31 patients; p < 0.0001), 15 at 1 year (24 patients; p < 0.0001), 18 at 2 years (15 patients; p < 0.0001), 19 at 3 years, (10 patients; p < 0.0001), 21 at 4 years (6 patients; p < 0.01), and 23 at 5 years (2 patients, significance not tested). Return of tremor that impacted activities of daily living was reported in 5 patients (11%). QUEST scores showed significant improvement, with median change of 35 points (p < 0.0001; 44 patients) at 1 month, 33 (p < 0.0001; 31 patients) at 6 months, 27 (p < 0.0001; 24 patients) at 1 year, 26 (p < 0.001; 15 patients) at 2 years, 25 (p < 0.001; 10 patients) at 3 years, 33 (p < 0.001; 6 patients) at 4 years, and 28 (significance not tested, 2 patients) at 5 years. Adverse events after the procedure were reversible in all but 5 patients (11%). CONCLUSIONS: MRgFUS thalamotomy for ET is an effective and safe procedure that provides long-term tremor relief and improvement in quality of life even in patients with medication-resistant disabling tremor. Additional studies with a larger group of patients is needed to substantiate these favorable results.

[EFFECT OF GENDER ON OUTCOME OF TREATMENT FOR TREMOR WITH MRI GUIDED FOCUSED ULTRASOUND].

INTRODUCTION: Thalamotomy is an effective treatment for medication-resistant tremor. MRI-guided focused ultrasound (MRgFUS) has been shown to be an effective and safe treatment for alleviating tremor. OBJECTIVES: We examined whether there is a gender difference in the efficacy and safety of thalamotomy using MRgFUS. METHODS: Seventy patients with moderate to severe medication-resistant tremor were treated with MRgFUS at Rambam Medical Center. Thermal ablation with ultrasound waves was carried out in the MRI suite while real-time monitoring of treatment efficacy and adverse events were recorded. A comparison was made between outcomes in men and women. RESULTS: Seventy patients, 47 men and 23 women with essential tremor, Parkinson's disease, paraneoplastic syndrome, and multiple system atrophy were treated. Both men and women reported the disappearance of tremor after MRgFUS with the exception of one patient with a paraneoplastic syndrome. In all patients, there was a significant decrease in the tremor scores (p <0.001), with no gender difference, and all patients reported a significant improvement in quality of life (p<0.001) regardless of gender. In ten patients, 8 men and 2 women, the tremor returned, but was bothersome in only 4, all men. This gender difference was not statistically significant. Transient adverse events were observed in the same frequency in men and women. The most common adverse event was transient gait instability and ataxia. CONCLUSIONS: In this series of patients, MRgFUS was an effective and safe treatment for both sexes with no significant difference in efficacy or adverse events.

The Role of the Anesthesiologist during Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Tremor: A Single-Center Experience.

Ablative incisionless neurosurgery has become possible through advances in focused ultrasound and magnetic resonance imaging (MRI). The great advantage of MRI-guided focused ultrasound (MRgFUS) is that the ablation is performed through an intact skull without surgery. Here, we review the new modality of MRgFUS for treating tremor and enlighten the role of the anesthesiologist in the unique procedural setting of the MRI suite. During the MRgFUS process, the patients should be awake and are required to cooperate with the medical staff to allow assessment of tremor reduction and potential occurrence of adverse effects. In addition, the patient's head is immobilized inside the MRI tunnel for hours. This combination presents major challenges for the attending anesthesiologist, who is required to try to prevent pain and nausea and when present, to treat these symptoms. Anxiety, vertigo, and vomiting may occur during treatment and require urgent treatment. Here, we review the literature available on anesthetic management during the procedure and our own experience and provide recommendations based on our collected knowledge.

Efficacy of Parenteral Amantadine Therapy in the Treatment of Multiple System Atrophy With Predominant Parkinsonism.

OBJECTIVE: The aim of this study was to assess clinical response to a high-dose intravenous (IV) amantadine given for 5 consecutive days in patients with multiple system atrophy parkinsonism (MSA-P). METHODS: Subjects with a diagnosis of MSA-P treated with IV amantadine were included. Patients' disease severity before and after therapy was evaluated using the Unified Multiple System Atrophy Rating Scale (UMSARS). RESULTS: Fourteen subjects (8 females) were included. In 10 subjects (71.4%), clinical improvement was noted. The UMSARS score after treatment decreased by 2 points (median [interquartile range, 0-3]) when compared with UMSARS score at baseline (P = 0.0020). Upon examining the walking parameter, a trend of improvement was shown (P = 0.0625) (range, 0-1 points). Neither specific demographic parameters nor occurrence of adverse effects was found to be a predictive factor for improvement. Adverse events were mild and transient except for one patient who experienced acute psychosis prompting treatment cessation, upon which psychosis resolved. CONCLUSIONS: Our preliminary data show that IV amantadine may be a safe and effective therapy in MSA-P. A double-blind placebo-controlled trial is needed to establish the true benefit of amantadine therapy.

An updated diagnostic approach to subtype definition of vascular parkinsonism - Recommendations from an expert working group.

This expert working group report proposes an updated approach to subtype definition of vascular parkinsonism (VaP) based on a review of the existing literature. The persistent lack of consensus on clear terminology and inconsistent conceptual definition of VaP formed the impetus for the current expert recommendation report. The updated diagnostic approach intends to provide a comprehensive tool for clinical practice. The preamble for this initiative is that VaP can be diagnosed in individual patients with possible prognostic and therapeutic consequences and therefore should be recognized as a clinical entity. The diagnosis of VaP is based on the presence of clinical parkinsonism, with variable motor and non-motor signs that are corroborated by clinical, anatomic or imaging findings of cerebrovascular disease. Three VaP subtypes are presented: (1) The acute or subacute post-stroke VaP subtype presents with acute or subacute onset of parkinsonism, which is typically asymmetric and responds to dopaminergic drugs; (2) The more frequent insidious onset VaP subtype presents with progressive parkinsonism with prominent postural instability, gait impairment, corticospinal, cerebellar, pseudobulbar, cognitive and urinary symptoms and poor responsiveness to dopaminergic drugs. A higher-level gait disorder occurs frequently as a dominant manifestation in the clinical spectrum of insidious onset VaP, and (3) With the emergence of molecular imaging biomarkers in clinical practice, our diagnostic approach also allows for the recognition of mixed or overlapping syndromes of VaP with Parkinson's disease or other neurodegenerative parkinsonisms. Directions for future research are also discussed.

Magnetic resonance-guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson's disease and essential tremor cases.

OBJECTIVE Thalamotomy of the ventral intermediate nucleus (VIM) is effective in alleviating medication-resistant tremor in patients with essential tremor (ET) and Parkinson's disease (PD). MR-guided focused ultrasound (MRgFUS) is an innovative technology that enables noninvasive thalamotomy via thermal ablation. METHODS Patients with severe medication-resistant tremor underwent unilateral VIM thalamotomy using MRgFUS. Effects on tremor were evaluated using the Clinical Rating Scale for Tremor (CRST) in patients with ET and by the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with PD and ET-PD (defined as patients with ET who developed PD many years later). Quality of life in ET was measured by the Quality of Life in Essential Tremor (QUEST) questionnaire and in PD by the PD Questionnaire (PDQ-39). RESULTS Thirty patients underwent MRgFUS, including 18 with ET, 9 with PD, and 3 with ET-PD. The mean age of the study population was 68.9 ± 8.3 years (range 46-87 years) with a mean disease duration of 12.1 ± 8.9 years (range 2-30 years). MRgFUS created a lesion at the planned target in all patients, resulting in cessation of tremor in the treated hand immediately following treatment. At 1 month posttreatment, the mean CRST score of the patients with ET decreased from 40.7 ± 11.6 to 9.3 ± 7.1 (p < 0.001) and was 8.2 ± 5.0 six months after treatment (p < 0.001, compared with baseline). Average QUEST scores decreased from 44.8 ± 12.9 to 13.1 ± 13.2 (p < 0.001) and was 12.3 ± 7.2 six months after treatment (p < 0.001). In patients with PD, the mean score of the motor part of the UPDRS decreased from 24.9 ± 8.0 to 16.4 ± 11.1 (p = 0.042) at 1 month and was 13.4 ± 9.2 six months after treatment (p = 0.009, compared with baseline). The mean PDQ-39 score decreased from 38.6 ± 16.8 to 26.1 ± 7.2 (p = 0.036) and was 20.6 ± 8.8 six months after treatment (p = 0.008). During follow-up of 6-24 months (mean 11.5 ± 7.2 months, median 12.0 months), tremor reappeared in 6 of the patients (2 with ET, 2 with PD, and 2 with ET-PD), to a lesser degree than before the procedure in 5. Adverse events that transiently occurred during sonication included headache (n = 11), short-lasting vertigo (n = 14) and dizziness (n = 4), nausea (n = 3), burning scalp sensation (n = 3), vomiting (n = 2) and lip paresthesia (n = 2). Adverse events that lasted after the procedure included gait ataxia (n = 5), unsteady feeling (n = 4), taste disturbances (n = 4), asthenia (n = 4), and hand ataxia (n = 3). No adverse event lasted beyond 3 months. Patients underwent on average 21.0 ± 6.9 sonications (range 14-45 sonications) with an average maximal sonication time of 16.0 ± 3.0 seconds (range 13-24 seconds). The mean maximal energy reached was 12,500 ± 4274 J (range 5850-23,040 J) with a mean maximal temperature of 56.5° ± 2.2°C (range 55°-60°C). CONCLUSIONS MRgFUS VIM thalamotomy to relieve medication-resistant tremor was safe and effective in patients with ET, PD, and ET-PD. Current results emphasize the superior adverse events profile of MRgFUS over other surgical approaches for treating tremor with similar efficacy. Large randomized studies are needed to assess prolonged efficacy and safety.

Vib-bracelet: a passive absorber for attenuating forearm tremor.

Tremor is a rhythmic, involuntary, oscillatory movement of a limb produced by alternating contractions of reciprocally innervated muscles. More than 4% of the population over 40 years old suffer from tremor. There is no cure for most tremors, and while psychological therapy is sometimes helpful, tremors are usually treated with either medication or invasive surgery including thalamotomy and deep brain stimulation. Both medications and surgery may have adverse effects, and thus, there is a growing interest in developing non-invasive vibration attenuation devices. This paper presents a passive absorber device for attenuating pronation/supination tremor, dubbed Vib-bracelet. It is based on the principles of dynamic vibration absorption and is tuned to the frequency of the tremor. Prototypes were manufactured and tested on a mechanical model of the human forearm. Simulations and experiments demonstrate the efficiency of the device in attenuating vibrations in the range of 4-6 Hz, which is the range of frequency of observed tremor, with maximum amplitude attenuation of 85%.

MRI-Guided Focused Ultrasound in Parkinson's Disease: A Review.

MRI-guided focused ultrasound is a new technology that enables intracranial ablation. Since lesioning ameliorates some of the symptoms of PD, this technology is being explored as a possible treatment for medication resistant symptoms in PD patients. The purpose of this paper is to review the clinical use and treatment outcomes of PD patients treated to date with this technology.

Post-stroke dementia - a comprehensive review.

Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing.

LRRK2, GBA and SMPD1 Founder Mutations and Parkinson's Disease in Ashkenazi Jews.

BACKGROUND/AIM: Parkinson's disease (PD) is associated with mutations in LRRK2, GBA, and SMPD1 genes. We describe the clinical characteristics of PD patients related to their carrier status of the Ashkenazi founder mutations in the aforementioned genes. METHODS: Ashkenazi PD patients (n = 270) were recruited following informed consent, and tested for the founder Ashkenazi mutations in the above genes. Clinical characteristics were compared between carriers and noncarriers. Homozygotes for mutations in GBA or LRRK2, and those who carried mutations in two causative genes were excluded from the analysis. RESULTS: Five (1.85%), 54 (20%), and 22 (8.1%) PD patients carried mutations in SMPD1, GBA or LRRK2, respectively. By post hoc Bonferroni analysis, GBA carriers were singled at a significantly earlier age at diagnosis compared to noncarriers (58.06 ± 10.84 and 62.65 ± 10.86 years, respectively; p = 0.036), and due to bilateral manifestation at diagnosis compared to all other PD groups (n = 8, 15.7% compared to n = 2, 1.1%, respectively; p < 0.001). Other clinical manifestations were comparable between groups. CONCLUSION: Although only GBA mutation carriers, compared to noncarriers, reached statistical significance regarding age at diagnosis, it appears that LRRK2 and SMPD1 mutation carriers may reach significance with larger group numbers.

Closed-loop auditory feedback for the improvement of gait in patients with Parkinson's disease.

OBJECTIVE: To study the effects of closed-loop auditory feedback cues, corresponding to patient self-motion, on the walking abilities of patients with Parkinson's disease, in comparison to the effects of open-loop (metronome-like) auditory cues. METHODS: Sixteen patients on their regular medication schedule participated. A device which translates patient steps into a clicking cue sounded by earphones provides auditory feedback for gait pattern correction. Walking speed and stride length are measured. Device-on performance is compared to device-off performance and to baseline performance, and short-term residual performance following 15 min rest is compared to baseline performance. RESULTS: Device-on performance was found to represent, on average, 10.72%±19.53% improvement in walking speed and 6.77%±6.57% improvement in stride length with respect to device-off performance, and an average improvement of 12.37%±18.37% in walking speed and 4.30%±3.64% in stride length with respect to baseline performance, with 87.5% and 81.25% of the patients improving their walking speed and stride length, respectively. Average short-term residual performance showed 9.09%±6.34% improvement in walking speed and 6.52%±4.36% improvement in stride length, compared to baseline performance, with 85.71% of the patients improving in both walking speed and stride length. CONCLUSIONS: Closed-loop auditory feedback improves walking speed and stride length in patients with Parkinson's disease. Improvement in walking speed is more pronounced than improvement in stride length. Yet, in contrast to previously studied open-loop auditory cues, training with closed-loop auditory feedback results in non-negligible on-line improvement in stride length. Moreover, in contrast to previously reported results of open-loop auditory cuing, training with closed-loop auditory feedback has residual effects, which suggest the examination of this approach in a comprehensive therapy program.