REVIEW ARTICLEParkinson's disease
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Comparison of quantitative REM without atonia parameters in isolated REM sleep behavior disorder and early untreated Parkinson's disease
2024, Sleep MedicineTo analyze REM sleep without atonia (RWA) metrics in patients with isolated REM sleep behavior disorder (iRBD), Parkinson's disease (PD) and healthy subjects and compare them in terms of degree of presumed brainstem damage.
Forty-nine iRBD patients, 62 PD patients and 38 healthy controls were included into the analysis. Detailed polysomnographic and clinical data including motor, olfactory, autonomic, and cognitive assessment were obtained in all participants and subsequently compared within groups without RBD (i.e., healthy controls, PD-RBD-) and with RBD (i.e., iRBD, PD-RBD+). SINBAR criteria were used to score RWA.
Twenty-one PD patients (33.8 %) had RBD. When comparing PD-RBD-patients and controls, RWA tonic (p = 0.001) and RWA mixed (p = 0.03) were higher in PD-RBD-group. PD-RBD-patients had worse olfactory function than controls (p < 0.001); no significant difference in autonomic or cognitive function was registered. There were no significant differences in RWA parameters when comparing iRBD and PD-RBD + groups. iRBD patients had better olfactory function than PD-RBD+ (p = 0.006); no significant difference in autonomic or cognitive function was registered. PD-RBD + had worse autonomic (p = 0.006) and olfactory (p = 0.001) but not motor and cognitive function compared to PD-RBD-.
Untreated de-novo PD patients without RBD have increased RWA metrics compared to healthy subjects indicating subclinical degeneration of brainstem nuclei responsible for RWA. iRBD patients do not differ in RWA metrics from untreated de-novo PD patients with premotor RBD suggesting a similar level of brainstem degeneration caudal to substantia nigra in both groups. Groups with RBD are associated with autonomic dysfunction.
6-hydroxydopamine affects multiple pathways to induce cytotoxicity in differentiated LUHMES dopaminergic neurons
2023, Neurochemistry InternationalThe debilitating effects of Parkinson's disease (PD) progress over time and are pathophysiologically characterized by the formation of Lewy bodies due to the accumulation of α-synuclein aggregates resulting in the death of dopaminergic neurons. In the present study, we determined cell death pathways activated by acute exposure to 6-hydroxydopamine (6-OHDA) in differentiated LUHMES cells empirically followed by a 24 h toxin free interval, henceforth termed as washout/recovery period. Acute 6-OHDA exposure led to morphological changes in LUHMES cells and resulted in significant loss of neurite length and neurite thickness. Generation of reactive oxygen species and loss of mitochondrial membrane potential in the neuronal processes were persistent even after the recovery period. Our results show that 6-OHDA exposure leads to significant reduction in expression of mitochondrial OXPHOS complexes I, II, and IV and activation of caspase mediated apoptotic cell death cascade as observed by enhanced protein expression of cleaved-PARP-1 and cleaved-Caspase-3. Immunofluorescence microscopy approach confirmed that cell death occurs independent of the AIF translocation to the nucleus. Our experimental model, led to a ∼5-fold lower α-synuclein monomer expression and, interestingly, resulted in loss of protein ubiquitination in whole cell lysates. Altogether, this work provides evidence of multiple pathways targeted by 6-OHDA in differentiated LUHMES cells and expands research avenues for addressing the knowledge gap regarding the effect of 6-OHDA in the ubiquitin proteasome system for PD therapies.
Neuromelanin: Its role in the pathogenesis of idiopathic Parkinson's disease and potential as a therapeutic target
2023, Parkinsonism and Related DisordersParkinson's disease is an increasingly prevalent condition that involves the marked loss of dopaminergic neurons in the substantia nigra pars compacta. These neurons pigmented with neuromelanin along with other regions of the brain are almost exclusively victims of neurodegeneration in the disease. The link between neuromelanin and Parkinson's disease has been widely studied for decades. While many studies have outlined the pigment's neuroprotective function as a potent free radical scavenger, antioxidant, and ion-chelator, it has also been observed to play a role in cell death due to mitochondrial dysfunction and oxidative stress, especially in the parkinsonian disease state. This is due to the damaging effects of neuromelanin precursors, neuromelanin-related ion dysregulation and intra- and extraneuronal neuromelanin accumulation. Current and emerging therapeutic endeavours guided by these pathological processes may include antioxidant therapy, proteostasis enhancement, ion chelation and neuromelanin-targeted immunotherapy to prevent the accumulation, formation and effects of neuromelanin and oxidative neuromelanin precursors. Some of these therapeutic strategies are already in nascent stages, while others have produced mixed results in clinical trials. This review aims to provide an update on how neuromelanin and neuromelanin-related substances may be linked to the pathogenesis of Parkinson's disease and how future therapeutic strategies may be able to hamper or prevent neuromelanin-related pathological processes and ultimately modify disease progression in Parkinson's.
Impact of age on the rotenone-induced sporadic Parkinson's disease model using Drosophila melanogaster
2023, Neuroscience LettersRotenone, a naturally occurring toxin, has been used to induce sporadic Parkinson's disease (PD) in Drosophila melanogaster for decades. However, the age of flies varies considerably between studies in this model. To investigate the impact of age on the rotenone-induced PD model, we collected male flies at the age of 1, 5, 7, and 10 days post-eclosion, respectively. Then, flies were immediately exposed to a feeding medium supplemented with 250 μM rotenone for seven days. The motor ability of Drosophila was detected by negative geotaxis assay, and the number of dopamine (DA) neurons and tyrosine hydroxylase (TH) expression levels were evaluated. The results showed that both the motor deficits and mortality increased with age. The flies older than five days showed typical PD features, including the loss of DA neurons, decreased TH expression levels, and decreased locomotive ability. However, 1-day-old flies displayed an unstable motor deficit and little TH expression changes after seven days of rotenone exposure. Lastly, after 7 days of exposure to rotenone, the death rate of flies rapidly increased with increasing starting age. The death rates of 1-, 5-, 7-, and 10-days old flies were 10.0%, 22.8%, 41.5%, and 50.4%, respectively. The findings of this study suggest that age is a crucial factor impacting the Drosophila PD model. This information provides a reference for the age selection to use this model for future studies.
MSC based gene delivery methods and strategies improve the therapeutic efficacy of neurological diseases
2023, Bioactive MaterialsMesenchymal stem cells (MSCs) are promising seed cells for neural regeneration therapy owing to their plasticity and accessibility. They possess several inherent characteristics advantageous for the transplantation-based treatment of neurological disorders, including neural differentiation, immunosuppression, neurotrophy, and safety. However, the therapeutic efficacy of MSCs alone remains unsatisfactory in most cases. To improve some of their abilities, many studies have employed genetic engineering to transfer key genes into MSCs. Both viral and nonviral methods can be used to overexpress therapeutic proteins that complement the inherent properties. However, to date, different modes of gene transfer have specific drawbacks and advantages. In addition, MSCs can be functionalized through targeted gene modification to facilitate neural repair by promoting neural differentiation, enhancing neurotrophic and neuroprotective functions, and increasing survival and homing abilities. The methods of gene transfer and selection of delivered genes still need to be optimized for improved therapeutic and targeting efficacies while minimizing the loss of MSC function. In this review, we focus on gene transport technologies for engineering MSCs and the application of strategies for selecting optimal delivery genes. Further, we describe the prospects and challenges of their application in animal models of different neurological lesions to broaden treatment alternatives for neurological diseases.
Specific Challenges in Geriatric Cirrhosis and Hepatic Encephalopathy
2022, Clinical Gastroenterology and HepatologyAs the world’s population ages, diseases predominantly found in the elderly now overlap with diseases that were thought to be the purview of younger patients. This includes chronic liver disease, which affects more than 2 billion people worldwide. Owing to the obesity epidemic (and associated metabolic diseases), nonalcoholic fatty liver disease has become the most common cause of chronic liver disease and cirrhosis. A major complication of cirrhosis is hepatic encephalopathy (HE), which becomes challenging to diagnose in elderly patients. HE is usually included in the differential diagnosis of acute delirium but not of reversible dementias. To illustrate this point, we present 2 cases of older patients that were misdiagnosed as having dementia and Parkinson’s disease or a parkinsonian syndrome but had contributions from cirrhosis. Both cognitive impairment and tremor resolved with treatment of HE.