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.
Objective T1-weighted MRI images are commonly used for volumetric assessment of brain structures. Magnetization prepared 2 rapid gradient echo (MP2RAGE) sequence offers superior gray (GM) and white ...matter (WM) contrast. This study aimed to quantitatively assess the agreement of whole brain tissue and deep GM (DGM) volumes obtained from MP2RAGE compared to the widely used MP-RAGE sequence. Methods Twenty-nine healthy participants were included in this study. All subjects underwent a 3T MRI scan acquiring high-resolution 3D MP-RAGE and MP2RAGE images. Twelve participants were re-scanned after one year. The whole brain, as well as DGM segmentation, was performed using CAT12, volBrain, and FSL-FAST automatic segmentation tools based on the acquired images. Finally, contrast-to-noise ratio between WM and GM (CNR.sub.WG ), the agreement between the obtained tissue volumes, as well as scan-rescan variability of both sequences were explored. Results Significantly higher CNR.sub.WG was detected in MP2RAGE vs. MP-RAGE (Mean ± SD = 0.97 ± 0.04 vs. 0.8 ± 0.1 respectively; p<0.0001). Significantly higher total brain GM, and lower cerebrospinal fluid volumes were obtained from MP2RAGE vs. MP-RAGE based on all segmentation methods (p<0.05 in all cases). Whole-brain voxel-wise comparisons revealed higher GM tissue probability in the thalamus, putamen, caudate, lingual gyrus, and precentral gyrus based on MP2RAGE compared with MP-RAGE. Moreover, significantly higher WM probability was observed in the cerebellum, corpus callosum, and frontal-and-temporal regions in MP2RAGE vs. MP-RAGE. Finally, MP2RAGE showed a higher mean percentage of change in total brain GM compared to MP-RAGE. On the other hand, MP-RAGE demonstrated a higher overtime percentage of change in WM and DGM volumes compared to MP2RAGE. Conclusions Due to its higher CNR, MP2RAGE resulted in reproducible brain tissue segmentation, and thus is a recommended method for volumetric imaging biomarkers for the monitoring of neurological diseases.
Parkinson’s disease (PD) is a complex neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rigidity, and resting tremor. While the majority of PD cases are sporadic, ...approximately 15–20% of cases have a genetic component. Advances in neuroimaging techniques have provided valuable insights into the pathophysiology of PD, including the different genetic forms of the disease. This literature review aims to summarize the current state of knowledge regarding neuroimaging findings in genetic PD, focusing on the most prevalent known genetic forms: mutations in the GBA1, LRRK2, and Parkin genes. In this review, we will highlight the contributions of various neuroimaging modalities, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI), in elucidating the underlying pathophysiological mechanisms and potentially identifying candidate biomarkers for genetic forms of PD.
Healthy walking is characterized by pronounced arm swing and axial rotation. Aging effects on gait speed, stride length and stride time variability have been previously reported, however, less is ...known about aging effects on arm swing and axial rotation and their relationship to age-associated gait changes during usual walking and during more challenging conditions like dual tasking. Sixty healthy adults between the ages of 30-77 were included in this study designed to address this gap. Lightweight body fixed sensors were placed on each wrist and lower back. Participants walked under 3 walking conditions each of 1 minute: 1) comfortable speed, 2) walking while serially subtracting 3's (Dual Task), 3) walking at fast speed. Aging effects on arm swing amplitude, range, symmetry, jerk and axial rotation amplitude and jerk were compared between decades of age (30-40; 41-50; 51-60; 61-77 years). As expected, older adults walked slower (p = 0.03) and with increased stride variability (p = 0.02). Arm swing amplitude decreased with age under all conditions (p = 0.04). In the oldest group, arm swing decreased during dual task and increased during the fast walking condition (p<0.0001). Similarly, arm swing asymmetry increased during the dual task in the older groups (p<0.004), but not in the younger groups (p = 0.67). Significant differences between groups and within conditions were observed in arm swing jerk (p<0.02), axial rotation amplitude (p<0.02) and axial jerk (p<0.001). Gait speed, arm swing amplitude of the dominant arm, arm swing asymmetry and axial rotation jerk were all independent predictors of age in a multivariate model. These findings suggest that the effects of gait speed and dual tasking on arm swing and axial rotation during walking are altered among healthy older adults. Follow-up work is needed to examine if these effects contribute to reduced stability in aging.
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.
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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