RESUMO
Patients with Parkinson's Disease (PD) experience REM sleep behavior disorder (RBD) more frequently than healthy controls. RBD is associated with torpid disease evolution. To test the hypothesis that differential genetic signatures might contribute to the torpid disease evolution in PD patients with RBD we compared the rate of genetic mutations in PD patients with or without probable RBD. Patients with a clinical diagnosis of PD in the Parkinson's Progression Markers Initiative (PPMI) database entered the study. We excluded those with missing data, dementia, psychiatric conditions, or a diagnosis change over the first five years from the initial PD diagnosis. Probable RBD (pRBD) was confirmed by a REM Sleep Behavior Disorder Screening Questionnaire score > 5 points. Logistic regression and Machine Learning (ML) algorithms were used to relate Single Nucleotide Polymorphism (SNPs) in PD-related genes with pRBD. We included 330 PD patients fulfilling all inclusion and exclusion criteria. The final logistic multivariate model revealed that the following SNPs increased the risk of pRBD: GBA_N370S_rs76763715 (OR, 95% CI: 3.38, 1.45-7.93), SNCA_A53T_rs104893877 (8.21, 2.26-36.34), ANK2. CAMK2D_rs78738012 (2.12, 1.08-4.10), and ZNF184_rs9468199 (1.89, 1.08-3.33). Conversely, SNP COQ7. SYT17_rs11343 reduced pRBD risk (0.36, 0.15-0.78). The ML algorithms led to similar results. The predictive models were highly specific (95-99%) but lacked sensitivity (9-39%). We found a distinctive genetic signature for pRBD in PD. The high specificity and low sensitivity of the predictive models suggest that genetic mutations are necessary but not sufficient to develop pRBD in PD. Additional investigations are needed.
RESUMO
The genetic basis of Neurogenic Orthostatic Hypotension (NOH) in Parkinson's disease (PD) has been inadequately explored. In a cross-sectional study, we examined the association between NOH and PD-related single-nucleotide polymorphisms (SNPs) and mapped their effects on gene expression and metabolic and signaling pathways. Patients with PD, free from pathological conditions associated with OH, and not taking OH-associated medications were included. NOH was defined as per international guidelines. Logistic regression was used to relate SNPs to NOH. Linkage-disequilibrium analysis, expression quantitative trait loci, and enrichment analysis were used to assess the effects on gene expression and metabolic/signaling pathways. We included 304 PD patients in the study, 35 of whom had NOH (11.5%). NOH was more frequent in patients with SNPs in SNCA, TMEM175, FAM47E-STBD1, CCDC62, SCN3A, MIR4696, SH3GL2, and LZTS3/DDRGK1 and less frequent in those with SNPs in ITGA8, IP6K2, SIPA1L2, NDUFAF2. These SNPs affected gene expression associated with the significant hierarchical central structures of the autonomic nervous system. They influenced several metabolic/signaling pathways, most notably IP3/Ca++ signaling, the PKA-CREB pathway, and the metabolism of fatty acids. These findings provide new insights into the pathophysiology of NOH in PD and may provide targets for future therapies.
RESUMO
Parkinson's disease (PD) is an extrapyramidal disorder characterized by neuronal degeneration in several regions of the peripheral and central nervous systems. It is the second most frequent neurodegenerative disease after Alzheimer's. It has become a major health problem, affecting 1% of the world population over 60 years old and 3% of people beyond 80 years. The main histological findings are intracellular Lewy bodies composed of misfolded α-synuclein protein aggregates and loss of dopaminergic neurons in the central nervous system. Neuroinflammation, apoptosis, mitochondrial dysfunction, altered calcium homeostasis, abnormal protein degradation, and synaptic pathobiology have been put forward as mechanisms leading to cell death, α-synuclein deposition, or both. A progressive loss of dopaminergic neurons in the substantia nigra late in the neurodegeneration leads to developing motor symptoms like bradykinesia, tremor, and rigidity. The renin-angiotensin system (RAS), which is involved in regulating blood pressure and body fluid balance, also plays other important functions in the brain. The RAS is involved in the autocrine and paracrine regulation of the nigrostriatal dopaminergic synapses. Dopamine depletion, as in PD, increases angiotensin II expression, which stimulates or inhibits dopamine synthesis and is released via AT1 or AT2 receptors. Furthermore, angiotensin II AT1 receptors inhibit D1 receptor activation allosterically. Therefore, the RAS may have an important modulating role in the flow of information from the brain cortex to the basal ganglia. High angiotensin II levels might even aggravate neurodegeneration, activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which leads to increased reactive oxygen species production.
RESUMO
INTRODUCTION: We explored the potential clinical effects of angiotensin-II AT1 receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) in patients from the Parkinson's Progress Marker Initiative (PPMI) study database. METHODS: We included 423 newly diagnosed PD patients, free from antiparkinsonian treatment, from the PPMI. We compared the proportion of patients starting on l-DOPA during the first year of follow-up, and the changes in MDS-UPDRS total score and sub-scores during the first five follow-up years for patients exposed or not to ARBs or ACEIs. RESULTS: Treatment with ARBs did not affect the proportion of patients on l-DOPA during the first year (adjusted OR, 95% CI = 0.26, 0.03-2.18, N.S.) while reduced MDS-UPDRS total score (0.85, 0.76-0.95, p < 0.01). Patients treated with ACEIs experienced no changes in either measure. CONCLUSIONS: These results show potential signals for a beneficial effect with ARBs. Further clinical trials are warranted.
