Abstract
MRI was suggested as a promising method for the diagnosis and assessment of Parkinson’s Disease (PD). We aimed to assess the sensitivity of neuromelanin-MRI and T
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* with radiomics analysis ...for detecting PD, identifying individuals at risk, and evaluating genotype-related differences. Patients with PD and non-manifesting (NM) participants NM-carriers (NMC) and NM-non-carriers (NMNC), underwent MRI and DAT-SPECT. Imaging-based metrics included 48 neuromelanin and T
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* radiomics features and DAT-SPECT specific-binding-ratios (SBR), were extracted from several brain regions. Imaging values were assessed for their correlations with age, differences between groups, and correlations with the MDS-likelihood-ratio (LR) score. Several machine learning classifiers were evaluated for group classification. A total of 127 participants were included: 46 patients with PD (62.3 ± 10.0 years) 15:LRRK2-PD, 16:GBA-PD, and 15:idiopathic-PD (iPD), 47 NMC (51.5 ± 8.3 years) 24:LRRK2-NMC and 23:GBA-NMC, and 34 NMNC (53.5 ± 10.6 years). No significant correlations were detected between imaging parameters and age. Thirteen MRI-based parameters and radiomics features demonstrated significant differences between PD and NMNC groups. Support-Vector-Machine (SVM) classifier achieved the highest performance (AUC = 0.77). Significant correlations were detected between LR scores and two radiomic features. The classifier successfully identified two out of three NMC who converted to PD. Genotype-related differences were detected based on radiomic features. SBR values showed high sensitivity in all analyses. In conclusion, neuromelanin and T
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* MRI demonstrated differences between groups and can be used for the assessment of individuals at-risk in cases when DAT-SPECT can’t be performed. Combining neuromelanin and T
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*-MRI provides insights into the pathophysiology underlying PD, and suggests that iron accumulation precedes neuromelanin depletion during the prodromal phase.
The effects of one genetic factor upon Parkinson's disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the 'missing heritability' of PD ...and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson's Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65-1.95, p = 2.7 × 10
). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.
Introduction: The
GBA‐N370S mutation is one of the most frequent risk factors for dementia with Lewy bodies (DLB) and Parkinson's disease (PD). We looked for genetic variations that contribute to the ...outcome in N370S‐carriers, whether PD or DLB.
Methods
Whole‐genome sequencing of 95 Ashkenazi‐N370S‐carriers affected with either DLB (n = 19) or PD (n = 76) was performed, and 564 genes related to dementia and PD analyzed.
Results
We identified enrichment of linked alleles in PINK1 locus in DLB patients (false discovery rate P = .0412). Haplotype analysis delineated 1.8 Mb interval encompassing 29 genes and 87 unique variants, of them, KIF17‐R869C received the highest functional prediction score (Combined Annotation Dependent Depletion = 34). Its frequency was significantly higher in 26 DLB‐N370S‐carriers compared to 140 PD‐N370S‐carriers (odds ratio OR = 33.4 P = .001, and OR = 70.2 when only heterozygotes were included).
Discussion
Because KIF17 was shown to be important for learning and memory in mice, our data further suggest, for the first time, its involvement in DLB, and possibly in human dementia.
Between 10 and 15% of Parkinson disease (PD) cases can be traced to a genetically identified causative mutation which currently number over 40. This enables the study of both "at risk" populations ...for future development of PD and a unique sub-group of genetically determined patient population. Structural and functional magnetic imaging has the potential of assisting diagnosis, early detection and disease progression as it is relatively cheap and easy to implement. However, the large variety of imaging options and different analytical approaches hamper the pursuit of a unified imaging biomarker. This chapter details the current imaging options and summarizes the findings among both genetically determined patients with PD and their non-manifesting first degree relatives, speculating on possible compensational mechanisms while mapping future directions in order to better utilize MRI in the research of genetic PD.
The mechanisms underlying cognitive disturbances in Parkinson's disease (PD) are poorly understood but likely to depend on the ongoing degenerative processes affecting structural and functional ...connectivity (FC). This pilot study examined patterns of FC alterations during a cognitive task using EEG and structural characteristics of white matter (WM) pathways connecting these activated regions in early-stage PD. Eleven PD patients and nine healthy controls (HCs) underwent EEG recording during an auditory oddball task and MRI scans. Source localization was performed and Gaussian mixture model was fitted to identify brain regions with high power during task performance. These areas served as seed regions for connectivity analysis. FC among these regions was assessed by measures of magnitude squared coherence (MSC), and phase-locking value (PLV), while structural connectivity was evaluated using fiber tracking based on diffusion tensor imaging (DTI). The paracentral lobule (PL), superior parietal lobule (SPL), superior and middle frontal gyrus (SMFG), parahippocampal gyrus, superior and middle temporal gyri (STG, MTG) demonstrated increased activation during task performance. Compared to HCs, PD showed lower FC between SMFG and PL and between SMFG and SPL in MSC (p = 0.012 and p = 0.036 respectively). No significant differences between the groups were observed in PLV and the measured DTI metrics along WM tracts. These findings demonstrate that in early PD, cognitive performance changes might be attributed to FC alterations, suggesting that FC is affected early on in the degenerative process, whereas structural damage is more prominent in advanced stages as a result of the disease burden accumulation.
Mutations in the glucocerebrosidase (GBA) gene are divided into mild and severe (mGBA, sGBA) based on their contribution to the phenotype of Gaucher disease (GD) among homozygotes. We conducted a ...longitudinal analysis of Parkinson's disease (PD) patients carrying mutations in the GBA gene to better characterize genotype-phenotype correlations.
Patients underwent a comprehensive assessment of medical, neurological, cognitive and non-motor functions. Data from these patients was explored to evaluate differences in disease phenotype based on genotype.
A total of 355 PD patients participated in this study; 152 idiopathic PD patients, 139 mGBA, 48 sGBA and 16 GD-PD. Groups were similar in age, sex, years of education and age of onset. Both sGBA and GD-PD had higher Unified Parkinson Disease Rating Scale (UPDRS) scores (p = 0.041), higher frequencies of REM sleep behavior disorder (RBD) (p = 0.022) and hallucinations (p < 0.0001) compared to the other groups of patients. sGBA experienced more non-motor symptoms (p < 0.0001), depression (p < 0.001) and worse hyposmia (p = 0.010). Trail making test was significantly longer in GD-PD followed by sGBA, mGBA and iPD (p = 0.005).
Motor, cognitive, olfactory and psychiatric symptoms are more severe in sGBA and GD-PD compared to mGBA and iPD, reinforcing the notion that the severity of the PD phenotype is related to the severity of the mutation in the GBA gene.
•Mutations in the GBA gene identified as the strongest genetic risk factor for developing Parkinson's disease (PD).•GBA-PD is associated with worse motor and non-motor phenotype.•We compared GBA-PD phenotype between severe and mild mutations.•Severe GBA-PD was associated with worse PD phenotype while mild GBA-PD did not differ from idiopathic PD.•The severity of the GBA mutation has important impact on PD phenotype.
Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 OMIM 609007) mutation. Knowledge about such ...progression will aid clinical trials.
To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation.
A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis.
Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores.
Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 0.192 points per year) was less than among those without the mutation (1.056 0.187 points per year; difference, -0.367 0.149 points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 0.090 points per year) and those without the mutation (-0.192 0.102 points per year) did not reach statistical significance (difference, 0.097 0.055 points per year; P = .08).
Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.
The clock drawing test (CDT) is a neuropsychological test for the screening of global cognitive functioning. The test requires use of multiple cognitive domains including executive functions, ...visuospatial abilities and semantic memory and can be a suitable tool for screening cognitive decline in participants in the early stages of Parkinson's Disease (PD). Behavioral performance on the CDT has been studied in depth, however, neural activation during real-time performance has not been extensively investigated. In this study we explored changes in prefrontal cortex (PFC) activation during the performance of CDT in participants with PD compared to healthy controls (HC) and assessed the correlations between PFC activation and CDT performance.
The study included 60 participants, 29 PD and 31 HC participants whom performed a digital CDT (DCTclock) in conjunction with a Functional Near-Infrared Spectroscopy (fNIRS) system measuring neural activation in the PFC.
HbO2 signals derived from the fNIRS during the CDT revealed that PD participants showed more moderate slopes than the HC in the right hemisphere in the command (p = 0.042) and copy task (p = 0.009). Better score on the measurement of information processing correlated with steeper right hemisphere HbO2 slope in the copy task in the PD group (p = 0.003).
Our results reflect slower PFC activation in participants with PD which correlates with behavioral measures. In addition, the findings of the study indicate the importance of performing the CDT copy task condition that detect early cognitive decline in participants with PD.
•Right but not left PFC activation during the CDT was different between PD and HC.•HbO2 slopes in the right PFC measured with fNIRS depict early cognitive changes in PD.•Steeper right PFC HbO2 slope are related to greater information processing among PD.
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