Identification of an early-stage Parkinson's disease neuromarker using event-related potentials, brain network analytics and machine-learning.

OBJECTIVE: The purpose of this study is to explore the possibility of developing a biomarker that can discriminate early-stage Parkinson's disease from healthy brain function using electroencephalography (EEG) event-related potentials (ERPs) in combination with Brain Network Analytics (BNA) technology and machine learning (ML) algorithms. BACKGROUND: Currently, diagnosis of PD depends mainly on motor signs and symptoms. However, there is need for biomarkers that detect PD at an earlier stage to allow intervention and monitoring of potential disease-modifying therapies. Cognitive impairment may appear before motor symptoms, and it tends to worsen with disease progression. While ERPs obtained during cognitive tasks performance represent processing stages of cognitive brain functions, they have not yet been established as sensitive or specific markers for early-stage PD. METHODS: Nineteen PD patients (disease duration of ≤2 years) and 30 healthy controls (HC) underwent EEG recording while performing visual Go/No-Go and auditory Oddball cognitive tasks. ERPs were analyzed by the BNA technology, and a ML algorithm identified a combination of features that distinguish early PD from HC. We used a logistic regression classifier with a 10-fold cross-validation. RESULTS: The ML algorithm identified a neuromarker comprising 15 BNA features that discriminated early PD patients from HC. The area-under-the-curve of the receiver-operating characteristic curve was 0.79. Sensitivity and specificity were 0.74 and 0.73, respectively. The five most important features could be classified into three cognitive functions: early sensory processing (P50 amplitude, N100 latency), filtering of information (P200 amplitude and topographic similarity), and response-locked activity (P-200 topographic similarity preceding the motor response in the visual Go/No-Go task). CONCLUSIONS: This pilot study found that BNA can identify patients with early PD using an advanced analysis of ERPs. These results need to be validated in a larger PD patient sample and assessed for people with premotor phase of PD.

Deep Brain Stimulation Can Differentiate Subregions of the Human Subthalamic Nucleus Area by EEG Biomarkers.

Introduction: Precise lead localization is crucial for an optimal clinical outcome of subthalamic nucleus (STN) deep brain stimulation (DBS) treatment in patients with Parkinson's disease (PD). Currently, anatomical measures, as well as invasive intraoperative electrophysiological recordings, are used to locate DBS electrodes. The objective of this study was to find an alternative electrophysiology tool for STN DBS lead localization. Methods: Sixty-one postoperative electrophysiology recording sessions were obtained from 17 DBS-treated patients with PD. An intraoperative physiological method automatically detected STN borders and subregions. Postoperative EEG cortical activity was measured, while STN low frequency stimulation (LFS) was applied to different areas inside and outside the STN. Machine learning models were used to differentiate stimulation locations, based on EEG analysis of engineered features. Results: A machine learning algorithm identified the top 25 evoked response potentials (ERPs), engineered features that can differentiate inside and outside STN stimulation locations as well as within STN stimulation locations. Evoked responses in the medial and ipsilateral fronto-central areas were found to be most significant for predicting the location of STN stimulation. Two-class linear support vector machine (SVM) predicted the inside (dorso-lateral region, DLR, and ventro-medial region, VMR) vs. outside [zona incerta, ZI, STN stimulation classification with an accuracy of 0.98 and 0.82 for ZI vs. VMR and ZI vs. DLR, respectively, and an accuracy of 0.77 for the within STN (DLR vs. VMR)]. Multiclass linear SVM predicted all areas with an accuracy of 0.82 for the outside and within STN stimulation locations (ZI vs. DLR vs. VMR). Conclusions: Electroencephalogram biomarkers can use low-frequency STN stimulation to localize STN DBS electrodes to ZI, DLR, and VMR STN subregions. These models can be used for both intraoperative electrode localization and postoperative stimulation programming sessions, and have a potential to improve STN DBS clinical outcomes.

Botulinum Injections for Idiopathic Cervical Dystonia: a Longitudinal Study.

Botulinum toxin (BT) injections into the cervical muscles are an effective and commonly practiced treatment approach for cervical dystonia. In this retrospective longitudinal study, we collected data from the Sheba electronic medical records on consecutive patients with idiopathic cervical dystonia (ICD), treated regularly with periodic BT injections between the years 2008-2020. All treatment visits were analyzed regarding type of toxin, dose injected, and clinical outcomes. The vast majority of patients were treated with abobotulinum toxin A. Sixty-four ICD patients (51 (79.7%) females, onset at age 45.8 ± 13.7 years) were treated over 17.1 ± 13.9 (range 3 to 49) visits per patient; BT treatment efficacy increased gradually from initial treatment sessions to visit 13, when it achieved a steady state. While the subjective report of percentage improvement and its duration were around 78.9 ± 17.1% for 2.8 ± 1.0 months, respectively, the dose of BT increased significantly over the years (p = 0.006). Side effects (SE) were not rare, and commonly recurred after subsequent sessions and were usually mild and short-lasting, with dysphagia being the most common (~17.5%), followed by neck/arm weakness (11.9%) and cervical pain (8.9%). Repeated injections of BT for ICD remain beneficial for patients over several years of therapy, and despite mild SE, patients tend to adhere to a 3-4 months interval schedule.

Overconfidence in visual perception in parkinson's disease.

Increased dependence on visual cues in Parkinson's disease (PD) can unbalance the perception-action loop, impair multisensory integration, and affect everyday function of PD patients. It is currently unknown why PD patients seem to be more reliant on their visual cues. We hypothesized that PD patients may be overconfident in the reliability (precision) of their visual cues. In this study we tested coherent visual motion perception in PD, and probed subjective (self-reported) confidence in their visual motion perception. Twenty patients with idiopathic PD, 21 healthy aged-matched controls and 20 healthy young adult participants were presented with visual stimuli of moving dots (random dot kinematograms). They were asked to report: (1) whether the aggregate motion of dots was to the left or to the right, and (2) how confident they were that their perceptual discrimination was correct. Visual motion discrimination thresholds were similar (unimpaired) in PD compared to the other groups. By contrast, PD patients were significantly overconfident in their visual perceptual decisions (p = .002 and p < .001 vs. the age-matched and young adult groups, respectively). These results suggest intact visual motion perception, but overestimation of visual cue reliability, in PD. Overconfidence in visual (vs. other, e.g., somatosensory) cues could underlie increased visual dependence and impaired multisensory/sensorimotor integration in PD. It could thereby contribute to gait and balance impairments, and affect everyday activities, such as driving. Future work should investigate and compare PD confidence in somatosensory function. A better understanding of altered sensory reliance might open up new avenues to treat debilitating PD symptoms.

Self-motion perception in Parkinson's disease.

Parkinson's disease (PD), best characterized by its classic motor symptoms, also manifests non-motor symptoms including perceptual impairments. Normal motor and perceptual brain functions interact continuously in an action-perception loop; hence, perceptual and motor dysfunction in PD are likely also intertwined. A vital skill in order to maintain balance, and to move around in the environment is the ability to perceive one's own motion in space (self-motion perception). Self-motion perception is a complex brain process, that requires the integration of information from visual (optic flow), vestibular (gravito-inertial), and somatosensory senses. Yet, not much is known about self-motion perception or multisensory integration in PD. In this review, we highlight the need to better study these important functions in PD. We review perceptual deficits in underlying functions required for adept self-motion perception (visual, vestibular and somatosensory, as well as multisensory integration) and address how these might affect self-motion perception and motor function in PD. We propose that dysfunction of central brain mechanisms, implicated in impaired visual, vestibular and somatosensory function, likely impact self-motion perception in PD. Recent evidence suggests that visual and multisensory integration mechanisms of self-motion perception are indeed impaired in PD. This can affect motor control, gait and balance. Future research is needed to better investigate this important topic. A better understanding of self-motion perception and multisensory integration in PD may aid diagnosis and subtyping and may open new avenues for novel therapies to treat debilitating motor symptoms, including gait and balance impairment, using sensory augmentation devices or sensory retraining.

At the Epicenter of COVID-19-the Tragic Failure of the Global Supply Chain for Medical Supplies.

The tragic failure of the global supply chain in the face of the current coronavirus outbreak has caused acute shortages of essential frontline medical devices and personal protective equipment, crushing fear among frontline health workers and causing fundamental concerns about the sustainability of the health system. Much more coordination, integration, and management of global supply chains will be needed to mitigate the impact of the pandemics. This article describes the pressing need to revisit the governance and resilience of the supply chains that amplified the crisis at pandemic scale. We propose a model that profiles critical stockpiles and improves production efficiency through new technologies such as advanced analytics and blockchain. A new governance system that supports intervention by public-health authorities during critical emergencies is central to our recommendation, both in the face of the current crisis and to be better prepared for potential future crises. These reinforcements offer the potential to minimize the compromise of our healthcare workers and health systems due to infection exposure and build capacity toward preparedness and action for a future outbreak.

Visual self-motion cues are impaired yet overweighted during visual-vestibular integration in Parkinson's disease.

Parkinson's disease is prototypically a movement disorder. Although perceptual and motor functions are highly interdependent, much less is known about perceptual deficits in Parkinson's disease, which are less observable by nature, and might go unnoticed if not tested directly. It is therefore imperative to seek and identify these, to fully understand the challenges facing patients with Parkinson's disease. Also, perceptual deficits may be related to motor symptoms. Posture, gait and balance, affected in Parkinson's disease, rely on veridical perception of one's own motion (self-motion) in space. Yet it is not known whether self-motion perception is impaired in Parkinson's disease. Using a well-established multisensory paradigm of heading discrimination (that has not been previously applied to Parkinson's disease), we tested unisensory visual and vestibular self-motion perception, as well as multisensory integration of visual and vestibular cues, in 19 Parkinson's disease, 23 healthy age-matched and 20 healthy young-adult participants. After experiencing vestibular (on a motion platform), visual (optic flow) or multisensory (combined visual-vestibular) self-motion stimuli at various headings, participants reported whether their perceived heading was to the right or left of straight ahead. Parkinson's disease participants and age-matched controls were tested twice (Parkinson's disease participants on and off medication). Parkinson's disease participants demonstrated significantly impaired visual self-motion perception compared with age-matched controls on both visits, irrespective of medication status. Young controls performed slightly (but not significantly) better than age-matched controls and significantly better than the Parkinson's disease group. The visual self-motion perception impairment in Parkinson's disease correlated significantly with clinical disease severity. By contrast, vestibular performance was unimpaired in Parkinson's disease. Remarkably, despite impaired visual self-motion perception, Parkinson's disease participants significantly overweighted the visual cues during multisensory (visual-vestibular ) integration (compared with Bayesian predictions of optimal integration) and significantly more than controls. These findings indicate that self-motion perception in Parkinson's disease is affected by impaired visual cues and by suboptimal visual-vestibular integration (overweighting of visual cues). Notably, vestibular self-motion perception was unimpaired. Thus, visual self-motion perception is specifically impaired in early-stage Parkinson's disease. This can impact Parkinson's disease diagnosis and subtyping. Overweighting of visual cues could reflect a general multisensory integration deficit in Parkinson's disease, or specific overestimation of visual cue reliability. Finally, impaired self-motion perception in Parkinson's disease may contribute to impaired balance and gait control. Future investigation into this connection might open up new avenues of alternative therapies to better treat these difficult symptoms.

The Montreal Cognitive Assessment: Is It Suitable for Identifying Mild Cognitive Impairment in Parkinson's Disease?

BACKGROUND: Administering an abbreviated global cognitive test, such as the Montreal Cognitive Assessment (MoCA), is necessary for the recommended first-level diagnostic criteria for mild cognitive impairment (MCI) in Parkinson's disease (PD). Level II requires administering cognitive functioning neuropsychological tests. The MoCA's suitability for identifying PD-MCI is questionable and, despite the importance of cognitive deficits reflected through daily functioning in identifying PD-MCI, knowledge about it is scarce. OBJECTIVES: To explore neuropsychological test scores of patients with PD who were categorized based on their MoCA scores and to analyze correlations between this categorization and patients' self-reports about daily functional-related cognitive abilities. METHODS: A total of 78 patients aged 42 to 78 years participated: 46 with low MoCA scores (22-25) and 32 with high MoCA scores (26-30). Medical assessments and level II neuropsychological assessment tools were administered along with standardized self-report questionnaires about daily functioning that reflects patients' cognitive abilities. RESULTS: A high percentage of the low MoCA group obtained neuropsychological test scores within the normal range; a notable number in the high MoCA group were identified with MCI-level scores on various neuropsychological tests. Suspected PD-MCI according to the level I criteria did not correspond well with the level II criteria. Positive correlations were found among the 3 self-report questionnaires. CONCLUSIONS: These results support the ongoing discussion of the complexity of capturing PD-MCI. Considering the neuropsychological tests results, assessments that reflect cognitive encounters in real life daily confrontations are warranted among people diagnosed with PD who are at risk for cognitive decline.

Chronic Neurology in COVID-19 Era: Clinical Considerations and Recommendations From the REPROGRAM Consortium.

With the rapid pace and scale of the emerging coronavirus 2019 (COVID-19) pandemic, a growing body of evidence has shown a strong association of COVID-19 with pre- and post- neurological complications. This has necessitated the need to incorporate targeted neurological care for this subgroup of patients which warrants further reorganization of services, healthcare workforce, and ongoing management of chronic neurological cases. The social distancing and the shutdown imposed by several nations in the midst of COVID-19 have severely impacted the ongoing care, access and support of patients with chronic neurological conditions such as Multiple Sclerosis, Epilepsy, Neuromuscular Disorders, Migraine, Dementia, and Parkinson disease. There is a pressing need for governing bodies including national and international professional associations, health ministries and health institutions to harmonize policies, guidelines, and recommendations relating to the management of chronic neurological conditions. These harmonized guidelines should ensure patient continuity across the spectrum of hospital and community care including the well-being, safety, and mental health of the patients, their care partners and the health professionals involved. This article provides an in-depth analysis of the impact of COVID-19 on chronic neurological conditions and specific recommendations to minimize the potential harm to those at high risk.

Age at Onset of Parkinson's Disease Among Ashkenazi Jewish Patients: Contribution of Environmental Factors, LRRK2 p.G2019S and GBA p.N370S Mutations.

BACKGROUND: Both genetic and environmental factors contribute to Parkinson's disease (PD) risk. OBJECTIVE: We investigated the potential association of several relevant variables with PD age at onset (AAO), focusing on LRRK2 p.G2019S and GBA p.N370S mutations. METHODS: Ashkenazi Jewish (AJ) PD patients, screened for LRRK2 and GBA mutations, underwent an interview regarding exposure to the following environmental and lifestyle factors: cigarette smoking, consumption of coffee, tea and alcohol, head injury and rural living. Multivariate linear regression (adjusted for sex) was used to examine the association with AAO, and models included LRRK2 p.G2019S and GBA p.N370S mutation status (carrier/non-carriers), single environmental variable and their interactions terms, as independent variables. RESULTS: 225 Israeli AJ PD patients were enrolled: 65 LRRK2 p.G2019S mutation carriers, 60 GBA p.N370S carriers and 100 non-carries of these mutations. In the dichotomized exposure/non-exposure analyses, positive LRRK2 p.G2019S status was associated with younger AAO in all models, at nominal or near significant levels (p = 0.033-0.082). Smoking was associated with older AAO (p = 0.032), and the interaction between GBA p.N370S and history of head injury was associated with younger AAO (p = 0.049), both at nominal significance. There was no indication of a consistent main effect for GBA p.N370S status or significant LRRK2 p.G2019S-environmental factor interaction. In the dose-dependent analyses, increased coffee and tea consumption levels were associated with older AAO (p = 0.001 and p = 0.002, respectively). CONCLUSIONS: Our results suggest that genetic and environmental factors may affect AAO in PD patients, but validation in additional samples is required.

Smartphone Based Timed Up and Go Test Can Identify Postural Instability in Parkinson's Disease.

BACKGROUND: There is a need for standardized and objective methods to measure postural instability (PI) and gait dysfunction in Parkinson's disease (PD) patients. Recent technological advances in wearable devices, including standard smartphones, may provide such measurements. OBJECTIVES: To test the feasibility of smartphones to detect PI during the Timed Up and Go (TUG) test. METHODS: Ambulatory PD patients, divided by item 30 (postural stability) of the motor Unified Parkinson's Disease Rating Scale (UPDRS) to those with a normal (score = 0, PD-NPT) and an abnormal (score ≥ 1, PD-APT) test and a group of healthy controls (HC) performed a 10-meter TUG while motion sensor data was recorded from a smartphone attached to their sternum using the EncephaLog application. RESULTS: In this observational study, 44 PD patients (21 PD-NPT and 23 PD-APT) and 22 HC similar in age and gender distribution were assessed. PD-APT differed significantly in all gait parameters when compared to PD-NPT and HC. Significant difference between PD-NPT and HC included only turning time (P < 0.006) and step-to-step correlation (P < 0.05). CONCLUSIONS: While high correlations were found between EncephaLog gait parameters and axial UPDRS items, the pull test was least correlated with EncephaLog measures. Motion sensor data from a smartphone can detect differences in gait and balance measures between PD with and without PI and HC.

Psychiatric Patients on Neuroleptics: Evaluation of Parkinsonism and Quantified Assessment of Gait.

OBJECTIVES: We aimed to characterize parkinsonian features and gait performance of psychiatric patients on neuroleptics (PPN) and to compare them to Parkinson's disease (PD) and healthy controls (HC). METHODS: Hospitalized PPN (n = 27) were recruited, examined, and rated for parkinsonian signs according to the motor part of the Movement Disorders Society Unified Parkinson's Disease Rating Scale and performed a 10-m "timed-up-and-go" (TUG) test with a smartphone-based motion capture system attached to their sternum. Gait parameters and mUPDRS scores were compared to those of consecutive age-matched PD patients (n = 18) and HC (n = 27). RESULTS: Psychiatric patients on neuroleptics exhibited parkinsonism (mUPDRS score range: 8-44) but less than that of PD patients (18.2 ± 9.2 vs 29.8 ± 10.3, P = 0.001). TUG times were slower for PPN and PD versus HC (total: 30.6 ± 7.6 seconds vs 30.0 ± 7.3 seconds vs 20.0 ± 3.2 seconds, straight walking: 10.6 ± 2.7 seconds vs 10.6 ± 2.4 seconds vs 6.8 ± 1.2 seconds) (P < 0.001), and cadence and step length were similar among PPN and PD and different from HC as well. Although their gait speed was slower than HC but similar to PD, PPN had lower mediolateral sway (4.3 ± 1.1 cm vs 6.7 ± 2.9 cm vs 6.9 ± 2.9 cm, respectively, P < 0.001) than both. CONCLUSIONS: Parkinsonism is very common in hospitalized PPN, but usually milder than that of PD. It seems that wearable sensor-based technology for assessing gait and balance may present a more sensitive and quantitative tool to detect clinical aspects of neuroleptic-induced parkinsonism than standard clinical ratings.

Decreasing battery life in subthalamic deep brain stimulation for Parkinson's disease with repeated replacements: Just a matter of energy delivered?

BACKGROUND: People with Parkinson's disease (PD) treated with deep brain stimulation (DBS) with non-rechargeable implantable pulse generators (IPGs) require elective IPG replacement operations involving surgical and anesthesiologic risk. Life expectancy and the number of replacements per patient with DBS are increasing. OBJECTIVE: To determine whether IPG longevity is influenced by stimulation parameters alone or whether there is an independent effect of the number of battery replacements and IPG model. METHODS: PD patients treated with bilateral subthalamic DBS were included if there was at least one IPG replacement due to battery end of life. Fifty-five patients had one or two IPG replacements and seven had three or four replacements, (80 Kinetra® and 23 Activa-PC®). We calculated longevity corrected for total electrical energy delivered (TEED) and tested for the effect of IPG model and number of previous battery replacements on this measure. RESULTS: TEED-corrected IPG longevity for the 1st implanted IPG was 51.3 months for Kinetra® and 35.6 months for Activa-PC®, which dropped by 5.9 months and 2.8 months, respectively with each subsequent IPG replacement (p < 10-6 for IPG model and p < 10-3 for IPG number). CONCLUSIONS: Activa-PC® has shorter battery longevity than the older Kinetra®, battery longevity reduces with repeated IPG replacements and these findings are independent of TEED. Battery longevity should be considered both in clinical decisions and in the design of new DBS systems. Clinicians need accessible, reliable and user-friendly tools to provide online estimated battery consumption and end of life. Furthermore, this study supports the consideration of using rechargeable IPGs in PD.

Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease.

BACKGROUND: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered. METHODS: GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used. RESULTS: Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9-3.8, p < 0.0001). CONCLUSION: Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.

Intersegmental coordination patterns are differently affected in Parkinson's disease and cerebellar ataxia.

The law of intersegmental coordination (Borghese et al. 1996) may be altered in pathological conditions. Here we investigated the contribution of the basal ganglia (BG) and the cerebellum to lower limb intersegmental coordination by inspecting the plane's orientation and other parameters pertinent to this law in patients with idiopathic Parkinson's disease (PD) or cerebellar ataxia (CA). We also applied a mathematical model that successfully accounts for the intersegmental law of coordination observed in control subjects (Barliya et al. 2009). In the present study, we compared the planarity index (PI), covariation plane (CVP) orientation, and CVP orientation predicted by the model in 11 PD patients, 8 CA patients, and two groups of healthy subjects matched for age, height, weight, and gender to each patient group (Ctrl_PD and Ctrl_CA). Controls were instructed to alter their gait speed to match those of their respective patient group. PD patients were examined after overnight withdrawal of anti-parkinsonian medications (PD-off-med) and then on medication (PD-on-med). PI was above 96% in all gait conditions in all groups suggesting that the law of intersegmental coordination is preserved in both BG and cerebellar pathology. However, the measured and predicted CVP orientations rotated in PD-on-med and PD-off-med compared with Ctrl_PD and in CA vs. Ctrl_CA. These rotations caused by PD and CA were in opposite directions suggesting differences in the roles of the BG and cerebellum in intersegmental coordination during human locomotion. NEW & NOTEWORTHY Kinematic and muscular synergies may have a role in overcoming motor redundancies, which may be reflected in intersegmental covariation. Basal ganglia and cerebellar networks were suggested to be involved in crafting and modulating synergies. We thus compared intersegmental coordination in Parkinson's disease and cerebellar disease patients and found opposite effects in some aspects. Further research integrating muscle activities as well as biomechanical and neural control modeling are needed to account for these findings.

Carriers of both GBA and LRRK2 mutations, compared to carriers of either, in Parkinson's disease: Risk estimates and genotype-phenotype correlations.

INTRODUCTION: The clinical characteristics of Parkinson's disease (PD) associated with both the LRRK2 p.G2019S mutation and a GBA variant (LRRK2-GBA-PD) have not yet been determined. METHODS: In this retrospective observational study of Ashkenazi-Jewish (AJ) PD patients, we describe the clinical course and characteristics of LRRK2-GBA-PD and estimate the risk to develop PD for the double mutation carriers. Odds ratios (OR) were estimated using published data on frequencies of GBA and LRRK2 mutations. Demographic and clinical data was retrieved from medical records and from rating at last visit. RESULTS: Our analysis included 236 PD patients, divided into four groups: LRRK2-PD (n = 66), GBA-PD (n = 78), GBA-LRRK2-PD (n = 12) and mutation-negative PD (MNPD, n = 80 randomly selected). The estimated ORs in different models for GBA-LRRK2 PD were 15-28 (95% CI 6.7-72.0, p < 0.0001), compared to AJ controls. Using logistic regression (while controlling for sex, age at onset and PD duration), we found that probable REM-sleep behavior disorder (RBD) was significantly more common for GBA-PD than for LRRK2-PD, while none of the GBA-LRRK2-PD patients reported RBD. Dementia was significantly more common for GBA-PD than for the LRRK2-PD and MNPD. Psychosis was the most common for GBA-PD and least common for LRRK2-GBA-PD. CONCLUSIONS: While GBA-PD is characterized by higher rates of dementia, probable RBD and psychosis, it seems that compared to the other groups, these features are less common for LRRK2-GBA-PD. This may imply to a possible protective effect of LRRK2 p.G2019S mutation among GBA variant carriers.

Acquired premature ejaculation in Parkinson's disease and possible mechanisms.

Premature ejaculation (PE) has been reported in 40.6-51.5% of men affected by Parkinson's disease (PD), however, this non-motor sexual complaint has not been studied in detail. We describe eight PD patients who asked for a sexological consultation between 2008 and 2014 because of a new-onset of PE. They were diagnosed with acquired PE (APE) according to the DSM-V criteria and the International Society for Sexual Medicine (ISSM) committee. Patients' demographic, medical and sexual related data were retrieved and studied. The average age of onset of PD was 53.3 ± 12.7 years (range 38-77 years) and the sexual problem appeared 4.0 ± 3.1 years later. The mean intravaginal ejaculation latency (IELT) before APE onset was 7.3 (range 2-20) min. Interestingly, the ejaculatory disorder appeared abruptly, characterized by a dramatically shortened IELT in all patients, while in three of the cases ejaculation occurred before vaginal penetration, hampering sexual intercourse. Some patients had 2 additional sexual problems, (four with erectile dysfunctions, five with libido changes: increased desire in four and reduced in one). In this case series of PD patients with APE, the ejaculatory dysfunction developed when patients were on antiparkinsonian medications, suggesting a possible medication effect.

The impact of early versus late levodopa administration.

Long-term levodopa therapy in patients with Parkinson's disease (PD) is associated with motor complications including motor fluctuations (MF) and levodopa-induced dyskinesias (LID). The time to appearance of MF and LID is apparently related to both the timing and the duration of levodopa therapy, but is highly variable. We performed a retrospective analysis of all levodopa-treated PD patients to explore the effect of time from PD onset to levodopa initiation on time to MF or LID. We used a Cox multivariate regression model after stratifying patients into four quartiles, according to the time to levodopa initiation. Data from 170 PD patients (117 males, age at onset: 65.1 ± 11.6 years, time to levodopa treatment: 23.8 ± 28.4 months) was included in the analysis. Early levodopa administration was associated with a shorter time from diagnosis to both MF (p < 0.001) and LID (p = 0.001). The hazard ratio to develop MF and LID from the time of PD diagnosis was 2.48 (p < 0.001) and 2.71 (p = 0.002), respectively. In our population, we found that delaying levodopa administration was associated with a longer time to the appearance of motor complications after diagnosis. While disease duration is the most important determinant of the onset of motor complications, delaying levodopa could prolong the 'complication-free' period.

The LRRK2 G2019S mutation status does not affect the outcome of subthalamic stimulation in patients with Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for advanced Parkinson's disease (PD). The most common genetic mutation associated with PD identified to date is the G2019S mutation of the LRRK2 gene, which is highly prevalent in the Ashkenazi Jewish population. The effect of STN-DBS surgery in patients carrying this mutation has not been systematically studied. We therefore performed a case-control study to evaluate the impact of the G2019S mutation status on the outcomes of bilateral STN-DBS. METHODS: The study sample included 39 Jewish PD patients with bilateral STN-DBS. Thirteen patients (5 females) were G2019S mutation heterozygous. The control group consisted of 26 PD patients with bilateral STN-DBS, negative for the mutation, matched (2:1) for gender, age at PD onset, and disease duration at surgery. Clinical data including the Unified PD Rating Scale scores (UPDRS), levodopa equivalent daily dose (LEDD), and clinical global impression of change (CGIC) concerning both motor and neuropsychiatric outcome- were available at 3 time points (preoperative baseline, 6-12 months and 3 years postoperatively). RESULTS: Implementing a linear mixed model, a significant improvement (p < 0.05) was found for the whole group concerning reduction in motor UPRDS (off state) and LEDD pre- vs. postoperatively, as expected. No difference in clinical outcome was found between carriers and matched non-carriers at baseline or at postoperative follow-up (up to 3 years). CONCLUSIONS: In our study, STN-DBS outcomes were not influenced by the LRRK2 G2019S mutation, and thus knowledge of carrier status may not be relevant to the considerations of patient selection for surgery.

Subthalamic nucleus deep brain stimulation does not improve visuo-motor impairment in Parkinson's disease.

OBJECTIVE: To evaluate how bilateral subthalamic nucleus deep brain stimulation (STN-DBS) affects visuo-motor coordination (VMC) in patients with Parkinson's disease (PD). BACKGROUND: VMC involves multi-sensory integration, motor planning, executive function and attention. VMC deficits are well-described in PD. STN-DBS conveys marked motor benefit in PD, but pyscho-cognitive complications are recognized and the effect on VMC is not known. METHODS: Thirteen PD patients with bilateral STN-DBS underwent neurological, cognitive, and mood assessment before VMC testing with optimal DBS stimulation parameters ('on-stimulation') and then, on the same day without any medication changes, after DBS silencing and establishing motor function deterioration ('off-stimulation'). Twelve age-matched healthy controls performed 2 successive VMC testing sessions, with a break of similar duration to that of the PD group. The computer cursor was controlled with a dome-shaped 'mouse' hidden from view that minimized tremor effects. Movement duration, hand velocity, tracking continuity, directional control variables, and feedback utilization variables were measured. MANOVA was performed on (1) clinically measured motor function, (2) VMC performance and (3) mood and attention, looking for main and interaction effects of: (1) group (controls/PD), (2) test-order (controls: first/second, PD: on-stimulation/off-stimulation), (3) path (sine/square/circle) and (4) hand (dominant/non-dominant). RESULTS: Unified PD Rating Scale (UPDRS) Part III worsened off-stimulation versus on-stimulation (mean: 42.3 versus 21.6, p = 0.02), as did finger tapping (p = 0.02), posture-gait (p = 0.01), upper limb function (p<0.001) and backwards digit span (p = 0.02). Stimulation state did not affect mood. PD patients performed worse in non-velocity related VMC variables than controls (F(5,18) = 8.5, p<0.001). In the control group there were significant main effects of hand (dominant/non-dominant), path (sine/square/circle) and test-order (Test_1/Test_2). In the PD group, hand and path effects, but no test-order (on-stimulation/off-stimulation), were found. CONCLUSIONS: 'Low-level' clinically-measured motor function responds to STN-DBS but 'high-level' motor and cognitive functions relating to VMC may be unresponsive to STN-DBS.