Ilana Schlesinger

Detection of Alzheimer’s and Parkinson’s disease from exhaled breath using nanomaterial-based sensors

AIM To study the feasibility of a novel method in nanomedicine that is based on breath testing for identifying Alzheimers disease (AD) and Parkinsons disease (PD), as representative examples of neurodegenerative conditions. PATIENTS & METHODS Alveolar breath was collected from 57 volunteers (AD patients, PD patients and healthy controls) and analyzed using combinations of nanomaterial-based sensors (organically functionalized carbon nanotubes and gold nanoparticles). Discriminant factor analysis was applied to detect statistically significant differences between study groups and classification success was estimated using cross-validation. The pattern identification was supported by chemical analysis of the breath samples using gas chromatography combined with mass spectrometry. RESULTS The combinations of sensors could clearly distinguish AD from healthy states, PD from healthy states, and AD from PD states, with a classification accuracy of 85, 78 and 84%, respectively. Gas chromatography combined with mass spectrometry analysis showed statistically significant differences in the average abundance of several volatile organic compounds in the breath of AD, PD and healthy subjects, thus supporting the breath prints observed with the sensors. CONCLUSION The breath prints that were identified with combinations of nanomaterial-based sensors have future potential as cost-effective, fast and reliable biomarkers for AD and PD.

Uric acid in Parkinson's disease.

Recent studies have provided evidence that uric acid may play a role in the development and progression of Parkinsons disease (PD). Uric acid is a natural antioxidant that may reduce oxidative stress, a mechanism thought to play a role in the pathogenesis of PD. Higher levels of serum urate (SU) may have a neuroprotective effect. High SU levels reduced the risk of developing PD and correlated with slower PD progression. Among PD patients SU levels were lower as compared with controls. The manipulation of SU levels holds promise in the treatment of PD. It is possible that a high purine diet in patients with PD may slow progression of the disease. Milk and meat consumption as well as exercise modify the risk of developing PD possibly through their influence on SU levels. In this article, we review the association between PD and SU levels and its implication on the management of PD.

MRI Guided Focused Ultrasound Thalamotomy for Moderate-to-Severe Tremor in Parkinson’s Disease

Background. Thalamotomy is effective in alleviating tremor in Parkinsons disease (PD). Methods. Seven PD patients, mean age 59.4 ± 9.8 years (range, 46–74) with a mean disease duration of 5.4 ± 2.8 years (range, 2–10) suffering from severe refractory tremor, underwent ventral intermediate nucleus thalamotomy using MRI guided focused ultrasound (MRgFUS), an innovative technology that enables noninvasive surgery. Results. Tremor stopped in the contralateral upper extremity in all patients immediately following treatment. Total UPDRS decreased from 37.4 ± 12.2 to 18.8 ± 11.1 (p = 0.007) and PDQ-39 decreased from 42.3 ± 16.4 to 21.6 ± 10.8 (p = 0.008) following MRgFUS. These effects were sustained (mean follow-up 7.3 months). Adverse events during MRgFUS included headache (n = 3), dizziness (n = 2), vertigo (n = 4), and lip paresthesia (n = 1) and following MRgFUS were hypogeusia (n = 1), unsteady feeling when walking (n = 1, resolved), and disturbance when walking tandem (n = 1, resolved). Conclusions. Thalamotomy using MRgFUS is safe and effective in PD patients. Large randomized studies are needed to assess prolonged efficacy and safety.

Parkinson's disease tremor is diminished with relaxation guided imagery.

Patients with Parkinsons disease (PD) may have pronounced tremor that exacerbates during stress. To determine whether PD tremor improves with relaxation guided imagery (RGI) and relaxing music. Twenty patients with PD with moderate to severe tremor participated in sessions where relaxation techniques were implemented. Tremor was objectively monitored using an accelerometer. RGI dramatically decreased tremor in all 20 patients (baseline 270.38 ± 85.82 vs. RGI 35.57 ± 43.90 movements per minute P < 0.0001). In 15 patients, RGI completely abolished tremor for 1–13 min. Average tremor activity remained significantly bellow baseline both 15 min and 30 min after RGI was discontinued (P < 0.001). Patients reported improvement lasting 2–14 hours (mean 6.8 ± 3.8). Relaxing music significantly reduced tremor but to a lesser degree than RGI (220.04 ± 106.53 movements per minute P = 0.01). Self‐relaxation had no significant effect on tremor. RGI can supplement conventional medical treatments for tremor in patients with PD on best medical treatment.

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 Parkinsons 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 Parkinsons 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.

Paradoxical kinesia at war

Paradoxical kinesia is the sudden transient ability of a patient with Parkinsons disease to perform a task he was previously unable to perform, usually when facing an immediate threat. The sensory cues governing this behavior and the prevalence in real life situations are unknown. The objective of this study was to determine the occurrence of paradoxical kinesia in Parkinsons disease (PD) patients whose residential area was suddenly a war zone, under a life threatening missile attack, necessitating immediate evacuation. Fifty PD patients were interviewed during and immediately following the war. Only two patients experienced paradoxical kinesia, one war related and the other historical, both in response to visual cues. In contrast, an auditory stimulus in the form of a frightening loud siren, warning patients of an imminent missile attack, did not induce paradoxical kinesia. When questioned about their general function during wartime, patients reported significant increases in OFF time (P < 0.01), dyskinesia (P < 0.009), anxiety (P < 0.002), and depression (P < 0.01) as compared with their performance before the war. Paradoxical kinesia is uncommon, even in the face of danger. Visual, but not auditory, triggers appear to be needed to prompt its occurrence.

The contribution of Niemann-Pick SMPD1 mutations to Parkinson disease in Ashkenazi Jews

INTRODUCTION Parkinson disease is noted for its association with mutations in GBA and the p.G2019S mutation in LRRK2. This study aimed to evaluate the frequency of Ashkenazi founder mutations in sphingomyelin phosphodiesterase 1 (SMPD1) in Ashkenazi patients diagnosed with Parkinsons disease (PD); and their impact on PD phenotypic expression. SMPD1 underlies the lysosomal storage disease - Niemann-Pick. METHODS A case (n = 287) control (n = 400) study was undertaken. All patients underwent a physical, neurobehavioral and neurologic examination that incorporated the Unified Parkinsons Disease Rating Scale. Three founder SMPD1 Ashkenazi mutations (c.996delC (fsP330), p.L302P and p.R496L) were investigated in patients and controls, previously evaluated for carriage of founder mutations in GBA and the p.G2019S mutation in LRRK2. RESULTS Nine (3.1%) PD patients compared to two (0.5%) individuals from the control group were found to carry one of the three Ashkenazi SMPD1 founder mutations (p = 0.007). The overall clinical characteristics of PD patients carrying SMPD1 mutations were similar to those of PD patients with no mutations in SMPD1, GBA and LRRK2 (n = 189). CONCLUSION We maintain that disruptive mutations in SMPD1 constitute a risk factor for PD.

Automatic assessment of Parkinson's Disease from natural hands movements using 3D depth sensor

Parkinsons Disease (PD) is a degenerative disease of the central nervous system with a profound effect on the motor system. Symptoms include slowness of movement, rigidity of motion and in some patients, tremor. The severity of the disease is quantified using the Unified Parkinson Disease Rating Scale (UPDRS) which is a subjective scale performed and scored by physicians. In this work, we present an automated, objective quantitative analysis of four UPDRS motor examinations of Hand Movement and Finger Taps. For this purpose, a non-invasive system for recording and analysis of fine motor skills of hands was developed. The system is based on a simple low-cost depth acquisition sensor, similar to the second generation of Microsofts Kinect sensor, and novel recursive self-correcting hand tracking algorithm. The system allows patients to perform test tasks in a natural and unhindered manner. The evaluation of the system was carried out on PD patients and controls. Machine Learning based classification was performed on the acquired data, followed by a decision making scheme.

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 Parkinsons disease or other neurodegenerative parkinsonisms. Directions for future research are also discussed.

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

Background/Aim: Parkinsons 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.