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 (PrP
), 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.
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.
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.
The study is an observational study. It has registered retrospectively in https://clinicaltrials.gov/ and has been assigned an identification number NCT05746715.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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.
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