Mild cognitive impairment among LRRK2 and GBA1 patients with Parkinson's disease.

BACKGROUND: Mild cognitive impairment (MCI) is common in Parkinson's disease (PD). We aimed to assess the incidence of MCI among patients with PD, carriers of mutations in LRRK2 and GBA1 genes, based on the movement disorder society (MDS) criteria for the diagnosis of MCI in early-stage PD. METHODS: Patients with PD were included if they scored ≤2 on the Hoehn and Yahr and ≤6 years since motor symptom onset. A group of age and gender matched healthy adults served as controls. A neuropsychological cognitive battery was used covering five cognitive domains (executive functions, working memory, memory, visuospatial and language). MCI was explored while applying two methods (level I and II). Frequency of MCI was assessed in comparison between groups. RESULTS: 70 patients with idiopathic PD (iPD) (68 % males), 42 patients with LRRK2-PD (61 % males), 83 patients with GBA1-PD (63 % males) and 132 age and gender matched controls (61 % males), participated in this study. PD groups were similar in clinical characteristics. Level I criteria were positive in 57.5 % of iPD, 43 % of LRRK2-PD and 63.4 % of the GBA1-PD (p = 0.071). Level II criteria was met by 39 % of iPD, 14 % LRRK2-PD and 41 % of GBA1-PD (p < 0.001), when using a 2 standard-deviation (SD) threshold. GBA1-PD and iPD showed impairments on multiple domains even in the more conservative 2 SD, reflecting MCI. CONCLUSIONS: The majority of our PD cohort was classified as MCI when assessed with strict criteria. GBA1-PD and iPD showed a more widespread pattern of MCI compared with LRRK2-PD.

The natural history study of preclinical genetic Creutzfeldt-Jakob Disease (CJD): a prospective longitudinal study protocol.

BACKGROUND: Creutzfeldt-Jakob Disease (CJD) is the most common prion disease in humans causing a rapidly progressive neurological decline and dementia and is invariably fatal. The familial forms (genetic CJD, gCJD) are caused by mutations in the PRNP gene encoding for the prion protein (PrP). In Israel, there is a large cluster of gCJD cases, carriers of an E200K mutation in the PRNP gene, and therefore the largest population of at-risk individuals in the world. The mutation is not necessarily sufficient for the formation and accumulation of the pathological prion protein (PrPsc), suggesting that other, genetic and non-genetic factors affect the age at symptoms onset. Here we present the protocol of a cross-sectional and longitudinal natural history study of gCJD patients and first-degree relatives of gCJD patients, aiming to identify biological markers of preclinical CJD and risk factors for phenoconversion. METHODS: The study has two groups: Patients diagnosed with gCJD, and first-degree healthy relatives (HR) (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. At baseline, and at the end of every year, healthy participants are invited for an "in-depth" visit, which includes a clinical evaluation, blood and urine collection, gait assessment, brain MRI, lumbar puncture (LP), and Polysomnography (PSG). At 6 months from baseline, and then halfway through each year, participants are invited for a "brief" visit, which includes a clinical evaluation, short cognitive assessment, and blood and urine collection. gCJD patients will be invited for one "in-depth" visit, similar to the baseline visit of healthy relatives. DISCUSSION: This continuous follow-up of the participants and the frequent assessments will allow early identification and diagnosis in case of conversion into disease. The knowledge generated from this study is likely to advance the understanding of the underlying clinicopathological processes that occur at the very beginning of CJD, as well as potential genetic and environmental risk factors for the development of the disease, therefore advancing the development of safe and efficient interventions. TRIAL REGISTRATION: The study is an observational study. It has registered retrospectively in https://clinicaltrials.gov/ and has been assigned an identification number NCT05746715.

The Influence of GBA and LRRK2 on Mood Disorders in Parkinson's Disease.

Background: Mood disorders have emerged as major non-motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the LRRK2 and GBA genes are common among Ashkenazi Jews, with more severe phenotype reported for GBA-PD. Objective: To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood-related medications, phenotype, and genetic status. Methods: Participants were genotyped for mutations in the LRRK2 and GBA genes. State of depression, anxiety and non-motor features were evaluated using validated questionnaires. History of mood disorders prior to diagnosis of PD and use of mood-related medications were assessed. Results: The study included 105 idiopathic PD (iPD), 55 LRRK2-PD and 94 GBA-PD. Scores on mood related questionnaires and frequency of depression and anxiety before diagnosis were similar between the groups (p>0.05). However, more GBA-PD patients used mood related medications before PD diagnosis than LRRK2-PD and iPD (16.5% vs 7.1% and 8.2%, p=0.044). LRRK2-PD and GBA-PD receiving mood-related medications at time of assessment had worse motor and non-motor phenotype compared to those that did not (p<0.05). LRRK2-PD receiving mood related-medications at time of assessment, scored higher on mood-related questionnaires compared to LRRK2-PD not receiving such medications (p<0.04). Conclusions: Prodromal GBA-PD are more frequently treated with mood related-medications despite equal rates of reported mood-related disorders, while LRRK2-PD with mood-related disorders experience high rates of anxiety and depression despite treatment, attesting to the need of more precise assessment and treatment of these genetic subgroups.

Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers.

Non-manifesting carriers (NMCs) of Parkinson's disease (PD)-related mutations such as LRRK2 and GBA are at an increased risk for developing PD. Dopamine transporter (DaT)-spectral positron emission computed tomography is widely used for capturing functional nigrostriatal dopaminergic activity. However, it does not reflect other ongoing neuronal processes; especially in the prodromal stages of the disease. Resting-state fMRI (rs-fMRI) has been proposed as a mode for assessing functional alterations associated with PD, but its relation to dopaminergic deficiency remains unclear. We aimed to study the association between presynaptic striatal dopamine uptake and functional connectivity (FC) patterns among healthy first-degree relatives of PD patients with mutations in LRRK2 and GBA genes. N = 85 healthy first-degree subjects were enrolled and genotyped. All participants underwent DaT and rs-fMRI scans, as well as a comprehensive clinical assessment battery. Between-group differences in FC within striatal regions were investigated and compared with striatal binding ratios (SBR). N = 26 GBA-NMCs, N = 25 LRRK2-NMCs, and N = 34 age-matched nonmanifesting noncarriers (NM-NCs) were included in each study group based on genetic status. While genetically-defined groups were similar across clinical measures, LRRK2-NMCs demonstrated lower SBR in the right putamen compared with NM-NCs, and higher right putamen FC compared to GBA-NMCs. In this group, higher striatal FC was associated with increased risk for PD. The observed differential SBR and FC patterns among LRRK2-NMCs and GBA-NMCs indicate that DaTscan and FC assessments might offer a more sensitive prediction of the risk for PD in the pre-clinical stages of the disease.

Glucocerebrosidase Activity is not Associated with Parkinson's Disease Risk or Severity.

BACKGROUND: Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD). OBJECTIVE: To explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in the GBA and LRRK2 genes. METHODS: Participants were genotyped for the G2019S-LRRK2 and nine GBA mutations common in Ashkenazi Jews. Performance-based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected. RESULTS: One hundred and seventy PD patients (102 GBA-PD, 38 LRRK2-PD, and 30 idiopathic PD) and 221 non-manifesting carriers (NMC) (129 GBA-NMC, 45 LRRK2-NMC, 15 GBA-LRRK2-NMC, and 32 healthy controls) participated in this study. GCase activity was lower among GBA-PD (3.15 ± 0.85 µmol/L/h), GBA-NMC (3.23 ± 0.91 µmol/L/h), and GBA-LRRK2-NMC (3.20 ± 0.93 µmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype. CONCLUSIONS: Low GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Quantification of Daily-Living Gait Quantity and Quality Using a Wrist-Worn Accelerometer in Huntington's Disease.

Background: Huntington's disease (HD) leads to altered gait patterns and reduced daily-living physical activity. Accurate measurement of daily-living walking that takes into account involuntary movements (e.g. chorea) is needed. Objective: To evaluate daily-living gait quantity and quality in HD, taking into account irregular movements. Methods: Forty-two individuals with HD and fourteen age-matched non-HD peers completed clinic-based assessments and a standardized laboratory-based circuit of functional activities, wearing inertial measurement units on the wrists, legs, and trunk. These activities were used to train and test an algorithm for the automated detection of walking. Subsequently, 29 HD participants and 22 age-matched non-HD peers wore a tri-axial accelerometer on their non-dominant wrist for 7 days. Measures included gait quantity (e.g., steps per day), gait quality (e.g., regularity) metrics, and percentage of walking bouts with irregular movements. Results: Measures of daily-living gait quantity including step counts, walking time and bouts per day were similar in HD participants and non-HD peers (p > 0.05). HD participants with higher clinician-rated upper body chorea had a greater percentage of walking bouts with irregular movements compared to those with lower chorea (p = 0.060) and non-HD peers (p < 0.001). Even after accounting for irregular movements, within-bout walking consistency was lower in HD participants compared to non-HD peers (p < 0.001), while across-bout variability of these measures was higher (p < 0.001). Many of the daily-living measures were associated with disease-specific measures of motor function. Conclusions: Results suggest that a wrist-worn accelerometer can be used to evaluate the quantity and quality of daily-living gait in people with HD, while accounting for the influence of irregular (choreic-like) movements, and that gait features related to within- and across-bout consistency markedly differ in individuals with HD and non-HD peers.

Mutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers.

BACKGROUND: Inflammation is an integral part of neurodegeneration including in Parkinson's disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA-PD and LRRK2-PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. OBJECTIVE: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. METHODS: The following cytokines were assessed from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ. A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. RESULTS: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK2-PD, 77 GBA-PD, 3 homozygote GBA-PD, 3 GBA-LRRK2-PD, 67 LRRK2-NMC, 105 GBA-NMC, 14 LRRK2-GBA-NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. CONCLUSION: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers.

Biochemical markers for severity and risk in GBA and LRRK2 Parkinson's disease.

BACKGROUND: The phenotype of Parkinson's disease (PD) is variable with mutations in genes such as LRRK2 and GBA explaining part of this heterogeneity. Additional genetic and environmental factors contribute to disease variability. OBJECTIVE: To assess the association between biochemical markers, PD severity and probability score for prodromal PD, among GBA and LRRK2 mutation carriers. METHODS: Levels of uric acid, vitamin D, C-reactive protein, microalbumin/creatinine ratio (ACR), white blood count (WBC), hemoglobin, platelets, neutrophil/lymphocyte ratio and estimated glomerular filtration rate (eGFR) were assessed from patients with PD and non-manifesting carriers (NMC) of mutations in GBA and LRRK2, together with disease related questionnaires enabling the construction of the MDS prodromal probability score. RESULT: A total of 241 patients with PD: 105 idiopathic PD (iPD), 49 LRRK2-PD and 87 GBA-PD and 412 non-manifesting subjects; 74 LRRK2-NMC, 118 GBA-NMC and 220 non-manifesting non-carriers (NMNC), participated in this study. No significant differences in biochemical measures were detected among patients with PD or non-manifesting carriers. Among GBA-PD patients, worse motor performance was associated with ACR (B = 4.68, 95% CI (1.779-7.559); p = 0.002). The probability score for prodromal PD among all non-manifesting participants was associated with eGFR; NMNC (B = - 0.531 95% CI (- 0.879 to - 0.182); p < 0.001, LRRK2-NMC (B = - 1.014 95% CI (- 1.663 to - 0.366); p < 0.001) and GBA-NMC (B = - 0.686 95% CI (1.300 to - 0.071); p = 0.029). CONCLUSION: Sub-clinical renal impairment is associated with increased likelihood for prodromal PD regardless of genetic status. While the mechanism behind this finding needs further elucidation, it suggests that kidney function might play a role in PD pathogenesis.

Low cerebrospinal fluid volume and the risk for post-lumbar puncture headaches.

BACKGROUND: Cerebrospinal fluid (CSF) is essential for the medical workup of patients with neurological conditions and for disease-modifying clinical trials. Post- lumbar puncture (LP) headache is influenced by both operator and patient-related factors, including needle type and gauge, age, and gender. OBJECTIVES: We aimed to assess whether CSF volume measured based on pre-procedural brain MRI is associated with the risk of developing a post-LP headache. METHODS: In total, n = 117 participants (n = 58 Parkinson's disease patients, and n = 59 healthy controls) underwent an LP and CSF collection. Of those, n = 89 underwent MRI scans prior to the LP procedure acquiring high-resolution 3D magnetization-prepared rapid gradient echo (MP-RAGE) T1-weighted images using a 3 T MR scanner. Clinical and behavioral assessments were performed for all participants, and CSF was assessed for content. The T1-weighted images were segmented producing gray matter, white matter, and CSF probability maps. RESULTS: Thirteen participants (11.1%) experienced post-LP headache. They were younger (p = .033) and had lower CSF volumes (p = .040) compared to participants that did not develop a post LP headache. CONCLUSIONS: The results of this pilot study suggest that low CSF volumes might increase the risk for the occurrence of post-LP adverse events and should be taken into consideration when planning LP's.

Metabolic syndrome does not influence the phenotype of LRRK2 and GBA related Parkinson's disease.

In order toevaluate the influence of the metabolic syndrome (MS) (obesity, hypertension, elevated triglycerides, reduced levels of HDL cholesterol and glucose impairment) on the phenotype of LRRK2 and GBA Parkinson's disease (PD), and on the prevalence of prodromal features among individuals at risk, we collected, laboratory test results, blood pressure, demographic, cognitive, motor, olfactory and affective information enabling the assessment of each component of MS and the construction of the MDS prodromal probability score. The number of metabolic components and their levels were compared between participants who were separated based on disease state and genetic status. One hundred and four idiopathic PD, 40 LRRK2-PD, 70 GBA-PD, 196 healthy non-carriers, 55 LRRK2-NMC and 97 GBA-NMC participated in this study. PD groups and non manifesting carriers (NMC) did not differ in the number of metabolic components (p = 0.101, p = 0.685, respectively). LRRK2-PD had higher levels of triglycerides (p = 0.015) and higher rates of prediabetes (p = 0.004), while LRRK2-NMC had higher triglyceride levels (p = 0.014). NMC with probability rates for prodromal PD above 50% had higher frequencies of hypertriglyceridemia and prediabetes (p < 0.005, p = 0.023 respectively). While elevated triglycerides and prediabetes were more frequent among LRRK2 carriers, MS does not seem to influence GBA and LRRK2-PD phenotype.

A Possible Modifying Effect of the G2019S Mutation in the LRRK2 Gene on GBA Parkinson's Disease.

BACKGROUND: The phenotype of Parkinson's disease (PD) is milder among patients with LRRK2-PD and more severe among patients with GBA-PD; however, whether an additive phenotypical effect occurs among dual-mutation carriers requires validation. OBJECTIVE: The objective of this study was to explore the phenotypic expression of patients with PD who carry mutations in both genes compared with a single-mutation presentation. METHODS: Patients with PD were genotyped for the G2019S-LRRK2 mutation and 9 mutations in the GBA gene. Subjects were classified into 5 groups: idiopathic PD, mild GBA-PD, severe GBA-PD, LRRK2-PD, and LRRK2+GBA-PD. Clinical symptoms were evaluated using performance-based measures. RESULTS: A total of 1090 patients with idiopathic PD, 155 patients with LRRK2-PD, 155 patients with mild GBA-PD, 56 patients with severe GBA-PD, and 27 patients with LRRK2+GBA-PD participated in this study. The patients with LRRK2-PD and LRRK2+GBA-PD exhibited lower scores on total Unified Parkinson's Disease Rating Scale (P < 0.01) and better olfaction (P < 0.01) compared with GBA-PD. CONCLUSIONS: Patients with LRRK2+GBA-PD were symptomatically similar to patients with LRRK2-PD, suggesting a dominant effect of LRRK2 over GBA in the phenotypic presentation. © 2020 International Parkinson and Movement Disorder Society.

Safety in the epilepsy monitoring unit: A retrospective study of 524 consecutive admissions.

The yield of monitoring patients at an epilepsy monitoring unit (EMU) depends on the recording of paroxysmal events in a timely fashion, however, increasing the risk of safety adverse events (AEs). We aimed to retrospectively study the frequency and risk factors for AE occurrences in all consecutive admissions to an adult EMU in a tertiary medical center. We also compared our findings with published data from other centers. Between January 2011 and June 2014, there were 524 consecutive admissions to the adult EMU at the Tel Aviv Sourasky Medical Center. Adverse events were recorded in 47 (9.0%) admissions. The most common AE was 4-hour seizure cluster (58.7% of AEs) and, in decreasing frequency, AEs related to antiepileptic drugs (AEDs, 11.1%), falls and traumatic injuries (9.5%), intravenous line complications (9.5%), electrode-related (4.8%), status epilepticus (SE, 3.2%), and cardiac (1.6%) and psychiatric (1.6%) complications. There were significantly more AEs among patients with a younger age at disease onset (p=0.005), a history of temporal lobe epilepsy (p=0.046), a history of focal seizures with altered consciousness (p=0.008), a history of SE (p=0.022), use of a vagal nerve stimulator (p=0.039), and intellectual disability (p=0.016) and when the indication for EMU monitoring was noninvasive or invasive presurgical evaluation (p=0.001). Adverse events occurred more frequently when patients had more events in the EMU (p=0.001) and among those administered carbamazepine (p=0.037), levetiracetam (p=0.004), clobazam (p=0.008), and sulthiame (p=0.016). Patients with a history of psychogenic nonepileptic seizures (PNESs) had significantly fewer AEs (p=0.013). Adverse events were not associated with the age, gender, duration of hospitalization or monitoring, AED withdrawal and renewal, seizure frequency by history, presence of major psychiatric comorbidities, abnormal neurological exam, or the presence of a lesion as on brain magnetic resonance imaging. In conclusion, this study reveals that AEs are not unusual in the EMU and that seizure clustering is the most common among them. Adverse events occur more frequently in patients with more severe epilepsy and intellectual disability and in patients undergoing presurgical evaluations and less frequently in patients with PNESs.