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Molecular Neurodegeneration Nov 2017Parkinson's disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain.... (Review)
Review
Parkinson's disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, is thought to play an important role in dopaminergic neurotoxicity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are multi-subunit enzymatic complexes that generate reactive oxygen species as their primary function. Increased immunoreactivities for the NADPH oxidases catalytic subunits Nox1, Nox2 and Nox4 have been reported in the brain of PD patients. Furthermore, knockout or genetic inactivation of NADPH oxidases exert a neuroprotective effect and reduce detrimental aspects of pathology in experimental models of the disease. However, the connections between NADPH oxidases and the biological processes believed to contribute to neuronal death are not well known. This review provides a comprehensive summary of our current understanding about expression and physiological function of NADPH oxidases in neurons, microglia and astrocytes and their pathophysiological roles in PD. It summarizes the findings supporting the role of both microglial and neuronal NADPH oxidases in cellular disturbances associated with PD such as neuroinflammation, alpha-synuclein accumulation, mitochondrial and synaptic dysfunction or disruption of the autophagy-lysosome system. Furthermore, this review highlights different steps that are essential for NADPH oxidases enzymatic activity and pinpoints major obstacles to overcome for the development of effective NADPH oxidases inhibitors for PD.
Topics: Animals; Humans; NADPH Oxidases; Parkinson Disease
PubMed: 29132391
DOI: 10.1186/s13024-017-0225-5 -
Frontiers in Neurology 2017Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with... (Review)
Review
BACKGROUND
Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex.
METHODS
We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed.
RESULTS
The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 μm (95% CI, -6.23 to -4.73; < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 µm (95% CI, -4.03 to 6.26; = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients.
CONCLUSION
The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected.
PubMed: 28596752
DOI: 10.3389/fneur.2017.00206 -
PloS One 2016Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as... (Review)
Review
IMPORTANCE
Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD).
OBJECTIVE
To systematically review studies investigating epigenetic marks in AD or PD.
METHODS
Eleven bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, Scopus, PubMed, Cinahl (EBSCOhost), Cochrane Central, ProQuest, Lilacs, Scielo and Google Scholar) were searched until July 11th 2016 to identify relevant articles. We included all randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined associations between epigenetic marks and ND. Two independent reviewers, with a third reviewer available for disagreements, performed the abstract and full text selection. Data was extracted using a pre-designed data collection form.
RESULTS
Of 6,927 searched references, 73 unique case-control studies met our inclusion criteria. Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PD outcomes). There was no consistent association between global DNA methylation pattern and any ND. Studies reported epigenetic regulation of 31 genes (including cell communication, apoptosis, and neurogenesis genes in blood and brain tissue) in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistently reported associations. Methylation of α-synuclein gene (SNCA) was also found to be associated with PD. Seven studies reported histone protein alterations in AD and PD.
CONCLUSION
Many studies have investigated epigenetics and ND. Further research should include larger cohort or longitudinal studies, in order to identify clinically significant epigenetic changes. Identifying relevant epigenetic changes could lead to interventional strategies in ND.
Topics: Alzheimer Disease; Bias; Cross-Sectional Studies; DNA Methylation; Epigenesis, Genetic; Genome, Human; Histone Code; Histones; Humans; Inflammation; Neurodegenerative Diseases; Parkinson Disease; Randomized Controlled Trials as Topic
PubMed: 27973581
DOI: 10.1371/journal.pone.0167201 -
Frontiers in Molecular Neuroscience 2016Growing evidence suggests that increased levels of α-synuclein might contribute to the pathogenesis of Parkinson's disease (PD) and therefore, it is crucial to... (Review)
Review
Growing evidence suggests that increased levels of α-synuclein might contribute to the pathogenesis of Parkinson's disease (PD) and therefore, it is crucial to understand the mechanisms underlying α-synuclein expression. Recently, microRNAs (miRNAs) have emerged as key regulators of gene expression involved in several diseases such as PD and other neurodegenerative disorders. A systematic literature search was performed here to identify microRNAs that directly or indirectly impact in α-synuclein expression/accumulation and describe its mechanism of action. A total of 27 studies were incorporated in the review article showing evidences that six microRNAs directly bind and regulate α-synuclein expression while several miRNAs impact on α-synuclein expression indirectly by targeting other genes. In turn, α-synuclein overexpression also impacts miRNAs expression, indicating the complex network between miRNAs and α-synuclein. From the current knowledge on the central role of α-synuclein in PD pathogenesis/progression, miRNAs are likely to play a crucial role at different stages of PD and might potentially be considered as new PD therapeutic approaches.
PubMed: 27917109
DOI: 10.3389/fnmol.2016.00128 -
Neuropsychology Review Dec 2015Many patients with Parkinson's disease (PD) will develop cognitive impairment. Cross-sectional studies have shown that certain protein levels are altered in the... (Review)
Review
Many patients with Parkinson's disease (PD) will develop cognitive impairment. Cross-sectional studies have shown that certain protein levels are altered in the cerebrospinal fluid (CSF) of PD patients with dementia and are thought to represent potential biomarkers of underlying pathogenesis. Recent studies suggest that CSF biomarker levels may be predictive of future risk of cognitive decline in non-demented PD patients. However, the strength of this evidence and difference between specific CSF biomarkers is not well delineated. We therefore performed a systematic review to assess if levels of specific CSF protein biomarkers are predictive of progression to cognitive impairment. Nine articles were identified that met inclusion criteria for the review. Findings from the review suggest a convergence of evidence that a low baseline Aβ42 in the CSF of non-demented PD patients predicts development of cognitive impairment over time. Conversely, there is limited evidence that CSF levels of tau, either total tau or phosphorylated tau, is a useful predictive biomarker. There are mixed results for other CSF biomarkers such as α-synuclein, Neurofilament light chain, and Heart fatty acid-binding protein. Overall the results of this review show that certain CSF biomarkers have better predictive ability to identify PD patients who are at risk for developing cognitive impairment. Given the interest in developing disease-modifying therapies, identifying this group will be important for clinical trials as initiation of therapy prior to the onset of cognitive decline is likely to be more efficacious.
Topics: Biomarkers; Cognition; Cognition Disorders; Humans; Parkinson Disease; Prognosis
PubMed: 26626621
DOI: 10.1007/s11065-015-9307-8 -
Functional Neurology 2015The hallmark of dementia with Lewy bodies (DLB) is the “Lewy body”, an abnormal aggregation of alpha-synuclein found in some areas of the brain. The brain is the... (Review)
Review
The hallmark of dementia with Lewy bodies (DLB) is the “Lewy body”, an abnormal aggregation of alpha-synuclein found in some areas of the brain. The brain is the organ/system that is most vulnerable to this oxidative damage, and reactive oxygen species can cause neurodegenerative diseases. Different models of mitochondrial deregulation have been compared in DLB. The results are consistent with the hypothesis that alpha-synuclein affects the mitochondria themselves, increasing their sensitivity or leading to cell death through protective (neurosin) and accelerating (cytochrome c) factors. This systematic review suggests that mitochondria play an important role in neurodegeneration and a crucial role in the formation of Lewy bodies. DLB is a disease characterized by abnormal accumulation of alpha-synuclein that could result in the release of cytochrome c and subsequent activation of the apoptotic cascade.
Topics: Brain; Humans; Lewy Body Disease; Mitochondria; Mutation; alpha-Synuclein
PubMed: 26346695
DOI: 10.11138/fneur/2015.30.3.151 -
Revista de Neurologia Jul 2015Cognitive impairment may appear at the earliest stages in Parkinson's disease (PD). To assess the prevalence of mild cognitive impairment (MCI) and its different... (Review)
Review
INTRODUCTION
Cognitive impairment may appear at the earliest stages in Parkinson's disease (PD). To assess the prevalence of mild cognitive impairment (MCI) and its different subtypes, as transitional stage, is complicated by the lack of consensus diagnostic criteria.
AIM
To review MCI in PD (MCI-PD), diagnostic criteria and predictive factors of conversion to dementia.
PATIENTS AND METHODS
Systematic review of articles published in Medline (PubMed) using the combination of keywords 'mild cognitive impairment' and 'Parkinson's disease'.
RESULTS
MCI-PD diagnostic criteria published by the Movement Disorders Society are an interesting tool for the diagnosis, in spite they are not validated. Its implementation has the following limitations: 1) the heterogeneity of cognitive deficits described in PD; 2) a variable evolution of cognitive symptoms in PD which difficult the identification of dementia predictors; 3) selection of the more appropriate neuropsychological tests and cut-off points; 4) patient characteristics, disease stage and type of antiparkinsonian treatment.
CONCLUSIONS
Neuropsychological subtypes, neuroimaging, biomarkers or limitation in some instrumental activities seem to be very sensitive for detecting patients with MCI-PD and increased risk of conversion to dementia.
Topics: Amyloid beta-Peptides; Atrophy; Attention; Biomarkers; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Disease Progression; Executive Function; Humans; Language Disorders; Longitudinal Studies; Memory Disorders; Neuroimaging; Neuropsychological Tests; Parkinson Disease; Peptide Fragments; Prevalence; Quality of Life; Research Design; Risk Factors; Severity of Illness Index; Symptom Assessment; alpha-Synuclein
PubMed: 26108904
DOI: No ID Found