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.
Background and purpose
Subtle executive dysfunction is common in people newly diagnosed with Parkinson disease (PD), even when general cognitive abilities are intact. This study examined the Short ...Weekly Calendar Planning Activity (WCPA‐10)'s known‐group construct validity, comparing persons with PD to healthy controls (HCs) and nonmanifesting carriers of LRRK2 and GBA gene mutations to HCs. Additionally, convergent and ecological validity was examined.
Methods
The study included 73 participants: 22 with idiopathic PD (iPD) who do not carry any of the founder GBA mutations or LRRK2‐G2019S, 29 nonmanifesting carriers of the G2019S‐LRRK2 (n = 14) and GBA (n = 15) mutations, and 22 HCs. Known‐group validity was determined using the WCPA‐10, convergent validity by also using the Montreal Cognitive Assessment (MoCA) and Color Trails Test (CTT), and ecological validity by using the WCPA‐10, Schwab and England Activities of Daily Living Scale (SE ADL), and Physical Activity Scale for the Elderly (PASE).
Results
Known‐group validity of the WCPA‐10 was established for the iPD group only; they followed fewer rules (p = 0.020), were slower (p = 0.003) and less efficient (p = 0.001), used more strategies (p = 0.017) on the WCPA‐10, and achieved significantly lower CTT scores (p < 0.001) than the HCs. The nonmanifesting carriers and HCs were similar on all cognitive tests. Convergent and ecological validity of the WCPA‐10 were partially established, with few correlations between WCPA‐10 outcome measures and the MoCA (r = 0.50, r = 0.41), CTT‐2 (r = 0.43), SE ADL (r = 0.41), and PASE (r = 0.54, r = 0.46, r = 0.31).
Conclusions
This study affirms the known‐group validity for most (four) WCPA‐10 scores and partially confirms its convergent and ecological validity for PD.
Abstract Objective Mutations in the GBA gene are associated with Parkinson's disease (PD). A definite description of the clinical characteristics of PD patients who are compound heterozygotes or ...homozygotes for mutations in the GBA gene (GD-PD) requires further elucidation. Methods We assessed motor, cognitive, olfactory and autonomic functions as well as demographic data and medical history in a cohort of Ashkenazi Jewish PD patients who were screened for seven common mutations in the GBA gene. We then compared three groups of patients (matched for age and disease duration) who were distinguished by their GBA mutation status, idiopathic PD (iPD), GBA heterozygote PD ( GBA -PD) and GD-PD. Results Out of a total of 1050 AJ PD patients screened, 12 were found to be either homozygotes or compound heterozygotes for mutations in the GBA gene. These patients had an earlier age of onset, more severe motor impairment, poorer cognition and lower olfactory scores. They also had a higher prevalence of REM sleep behavior disorder and higher frequencies of hallucinations compared to both GBA -PD and iPD. Conclusions The severity of PD phenotype is related to the burden of GBA mutations with GD-PD patients manifesting a more severe phenotype.
Mutations in the glucocerebrosidase (GBA) gene are a risk factor for the development of dementia with Lewy bodies (DLB). These mutations are common among Ashkenazi Jews (AJ) and appear to have an ...effect on the natural history of the disease.
To evaluate the clinical and genetic characteristics of an AJ cohort of patients diagnosed with DLB, assess the association of phenotype of DLB with GBA mutations, and explore the effects of these mutations on the clinical course of the disease.
Thirty-five consecutively recruited AJ patients with newly diagnosed clinically probable or possible DLB underwent genotyping for the 7 known AJ GBA mutations and the LRRK2 G2019S mutation. Two patients with the LRRK2 G2019S mutation were excluded from the final analysis. Data were collected from July 1, 2013, to July 31, 2015.
Assessment of clinical markers included the following standardized scales: Autonomic Scale for Outcomes in Parkinson's Disease (SCOPA-AUT), REM (Rapid Eye Movement) Sleep Behavior Disorder Single-Question Screen, Geriatric Depression Scale, and Montreal Cognitive Assessment. Motor symptoms were assessed with the Unified Parkinson's Disease Rating Scale motor part III. A subset of 15 patients also underwent assessment with the Color Trail Making Test, FAS verbal fluency, Digit Span, Hooper Visual Organization Test, and Stroop test.
Among the 35 patients with DLB (23 men 66% and 12 women 34%; mean SD, 69.6 8.2 years), 11 (31%) were carriers of mutations in the GBA gene. Among the 33 patients undergoing further analysis, the GBA mutation carriers were younger at symptom onset (mean SD age, 65.7 11.7 vs 72.1 5.1 years; P = .03), had more frequent visual hallucinations that did not achieve significance (9 of 11 82% compared with 12 of 22 55%; P = .052), and had higher scores on the RBD questionnaire (mean SD, 7.8 2.2 vs 5.1 3.3; P = .03). After adjusting for age and duration of symptoms, testing revealed that GBA mutation carriers had poorer cognition as assessed by the Montreal Cognitive Assessment Battery (mean SD score, 18.75 5.99 vs 23.23 3.16; P = .03), lower scores on tests of verbal fluency (adjusted z scores, 0.50 vs -2.02; P = .02), worse scores on tests of visuospatial function (adjusted t scores, 68.55 vs 79.57; P = .046), and higher mean (SD) scores on the Unified Parkinson's Disease Rating Scale motor part III (36.72 10.62 vs 25.72 10.32; P = .03).
One in 3 AJ patients diagnosed with DLB were carriers of a GBA mutation, making it the most common genetic mutation identified in association with this disease and with any dementia disorder. Mutations in the GBA gene were associated with more severe motor and cognitive dysfunction, supporting a specific contribution of the GBA gene or lysosome function to this clinical syndrome.
ABSTRACT
Background: The G2019S mutation in the LRRK2 gene generates a milder PD phenotype compared with GBA‐PD; however, genetic based survival studies are lacking.
Objectives: To compare mortality ...rates between LRRK2‐PD, GBA‐PD, and idiopathic PD patients (iPD).
Methods: Patients were screened for the G2019S mutation in the LRRK2 gene and the seven common GBA mutations among Ashkenazi Jews, classified as mild and severe (mGBA, sGBA). Motor symptoms onset and date of death were ascertained, with mortality rates calculated for each group of patients.
Results: Overall, 380 of 1,086 idiopathic PD patients, 49 of 159 LRRK2‐PD, 56 of 148 mGBA‐PD, and 13 of 49 sGBA‐PD participants died by the time of analysis. LRRK2‐PD tended to have longer survival compared to idiopathic PD whereas GBA status did not affect mortality. Genetic status did not predict mortality in a multivariate analysis.
Conclusion: Survival of patients with PD does not seem to be related to GBA status, whereas LRRK2 might confer higher survival rates.
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