-
Aging Cell Dec 2019Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing... (Review)
Review
Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.
Topics: Aging; Animals; Calcium; Cellular Senescence; Humans; Mitochondria; Oxidative Stress; Parkinson Disease; Substantia Nigra
PubMed: 31432604
DOI: 10.1111/acel.13031 -
Cell Jun 2019Defining cell types requires integrating diverse single-cell measurements from multiple experiments and biological contexts. To flexibly model single-cell datasets, we... (Comparative Study)
Comparative Study
Defining cell types requires integrating diverse single-cell measurements from multiple experiments and biological contexts. To flexibly model single-cell datasets, we developed LIGER, an algorithm that delineates shared and dataset-specific features of cell identity. We applied it to four diverse and challenging analyses of human and mouse brain cells. First, we defined region-specific and sexually dimorphic gene expression in the mouse bed nucleus of the stria terminalis. Second, we analyzed expression in the human substantia nigra, comparing cell states in specific donors and relating cell types to those in the mouse. Third, we integrated in situ and single-cell expression data to spatially locate fine subtypes of cells present in the mouse frontal cortex. Finally, we jointly defined mouse cortical cell types using single-cell RNA-seq and DNA methylation profiles, revealing putative mechanisms of cell-type-specific epigenomic regulation. Integrative analyses using LIGER promise to accelerate investigations of cell-type definition, gene regulation, and disease states.
Topics: Adolescent; Adult; Aged; Animals; DNA Methylation; Female; Gene Expression Regulation; Humans; Male; Mice; Middle Aged; Septal Nuclei; Sequence Analysis, RNA; Single-Cell Analysis; Substantia Nigra
PubMed: 31178122
DOI: 10.1016/j.cell.2019.05.006 -
Journal of Neurochemistry Oct 2016Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of... (Review)
Review
Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of patients with Parkinson's disease: The degeneration of dopaminergic neurons and the existence of protein aggregates consisting mainly of α-synuclein. Cultured cells offer many advantages over studying Parkinson's disease directly in patients or in animal models. At the same time, the choice of a specific cellular model entails the requirement to focus on one aspect of the disease while ignoring others. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types the aspects of Parkinson's disease they model along with technical advantages and disadvantages. It might also be helpful for researchers from other fields consulting literature on cellular models of Parkinson's disease. Important models for the study of dopaminergic neuron degeneration include Lund human mesencephalic cells and primary neurons, and a case is made for the use of non-dopaminergic cells to model pathogenesis of non-motor symptoms of Parkinson's disease. With regard to α-synuclein aggregates, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. Cellular models reproduce the two most salient changes of Parkinson's disease, the degeneration of dopaminergic neurons and the existence of α-synuclein aggregates. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types and treatments the aspects of Parkinson's disease they model along with technical advantages and disadvantages. Furthermore, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. This article is part of a special issue on Parkinson disease.
Topics: Animals; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra; alpha-Synuclein
PubMed: 27091001
DOI: 10.1111/jnc.13618 -
NeuroImage. Clinical 2023Differential diagnosis of essential tremor (ET) and Parkinson's disease (PD) can still be a challenge in clinical practice. These two tremor disorders may have different...
BACKGROUND
Differential diagnosis of essential tremor (ET) and Parkinson's disease (PD) can still be a challenge in clinical practice. These two tremor disorders may have different pathogenesis related to the substantia nigra (SN) and locus coeruleus (LC). Characterizing neuromelanin (NM) in these structures may help improve the differential diagnosis.
METHODS
Forty-three subjects with tremor-dominant PD (PD), 31 subjects with ET, and 30 age- and sex-matched healthy controls were included. All subjects were scanned with NM magnetic resonance imaging (NM-MRI). NM volume and contrast measures for the SN and contrast for the LC were evaluated. Logistic regression was used to calculate predicted probabilities by using the combination of SN and LC NM measures. The discriminative power of the NM measures in detecting subjects with PD from ET was assessed with a receiver operative characteristic curve, and the area under the curve (AUC) was calculated.
RESULTS
The NM contrast-to-noise ratio (CNR) of the LC, the NM volume, and CNR of the SN on the right and left sides were significantly lower in PD subjects than in ET subjects or healthy controls (all P < 0.05). Furthermore, when combining the best model constructed from the NM measures, the AUC reached 0.92 in differentiating PD from ET.
CONCLUSION
The NM volume and contrast measures of the SN and contrast for the LC provided a new perspective on the differential diagnosis of PD and ET, and the investigation of the underlying pathophysiology.
Topics: Humans; Parkinson Disease; Essential Tremor; Tremor; Locus Coeruleus; Magnetic Resonance Imaging; Substantia Nigra
PubMed: 37141646
DOI: 10.1016/j.nicl.2023.103420 -
PloS One 2021Alterations in the substantia nigra are strongly associated with Parkinson's disease. However, due to low contrast and partial volume effects present in typical MRI...
A robust method for the detection of small changes in relaxation parameters and free water content in the vicinity of the substantia nigra in Parkinson's disease patients.
Alterations in the substantia nigra are strongly associated with Parkinson's disease. However, due to low contrast and partial volume effects present in typical MRI images, the substantia nigra is not of sufficient size to obtain a reliable segmentation for region-of-interest based analysis. To combat this problem, the approach proposed here offers a method to investigate and reveal changes in quantitative MRI parameters in the vicinity of substantia nigra without any a priori delineation. This approach uses an alternative method of statistical, voxel-based analysis of quantitative maps and was tested on 18 patients and 15 healthy controls using a well-established, quantitative free water mapping protocol. It was possible to reveal the topology and the location of pathological changes in the substantia nigra and its vicinity. Moreover, a decrease in free water content, T1 and T2* in the vicinity of substantia nigra was indicated in the Parkinson's disease patients compared to the healthy controls. These findings reflect a disruption of grey matter and iron accumulation, which is known to lead to neurodegeneration. Consequently, the proposed method demonstrates an increased sensitivity for the detection of pathological changes-even in small regions-and can facilitate disease monitoring via quantitative MR parameters.
Topics: Aged; Aged, 80 and over; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Substantia Nigra; Water
PubMed: 33626092
DOI: 10.1371/journal.pone.0247552 -
Metabolic Brain Disease Jun 2021Parkinson's disease (PD) is a neurodegenerative disorder etiologically linked to the loss of substantia nigra (SN) dopaminergic neurons in the mid-brain. The... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder etiologically linked to the loss of substantia nigra (SN) dopaminergic neurons in the mid-brain. The etiopathology of sporadic PD is still unclear; however, the interaction of extrinsic and intrinsic factors may play a critical role in the onset and progression of the disease. Studies in animal models and human post-mortem tissue have identified distinct cellular and molecular changes in the diseased brain, suggesting complex interactions between different glial cell types and various molecular pathways. Small changes in the expression of specific genes in a single pathway or cell type possibly influence others at the cellular and system levels. These molecular and cellular signatures like neuroinflammation, oxidative stress, and autophagy have been observed in PD patients' brain tissue. While the etiopathology of PD is still poorly understood, the interplay between glial cells and molecular events may play a crucial role in disease onset and progression.
Topics: Disease Progression; Dopaminergic Neurons; Humans; Oxidative Stress; Parkinson Disease; Substantia Nigra
PubMed: 33599945
DOI: 10.1007/s11011-021-00689-5 -
Neurobiology of Aging Feb 2015Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson's disease. It is the case, however, that partial volume effects...
Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson's disease. It is the case, however, that partial volume effects from free water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free water is elevated in the substantia nigra for Parkinson's disease compared with control subjects. This hypothesis was tested between large cohorts of Parkinson's disease and control participants in a single-site study and validated against a multisite study using multiple scanners. The fractional volume of free water was increased in the posterior region of the substantia nigra in Parkinson's disease compared with control subjects in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water-corrected fractional anisotropy or free-water-corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinson's disease, and this was evidenced across both single-site and multi-site cohorts.
Topics: Aged; Anisotropy; Body Water; Cohort Studies; Diffusion Magnetic Resonance Imaging; Female; Humans; Male; Middle Aged; Parkinson Disease; Substantia Nigra
PubMed: 25467638
DOI: 10.1016/j.neurobiolaging.2014.10.029 -
AJNR. American Journal of Neuroradiology Mar 2018Free water in the posterior substantia nigra obtained from a bi-tensor diffusion MR imaging model has been shown to significantly increase over 1- and 4-year periods in...
BACKGROUND AND PURPOSE
Free water in the posterior substantia nigra obtained from a bi-tensor diffusion MR imaging model has been shown to significantly increase over 1- and 4-year periods in patients with early-stage idiopathic Parkinson disease compared with healthy controls, which suggests that posterior substantia nigra free water may be an idiopathic Parkinson disease progression biomarker. Due to the known temporal posterior-to-anterior substantia nigra degeneration in idiopathic Parkinson disease, we assessed longitudinal changes in free water in both the posterior and anterior substantia nigra in patients with later-stage idiopathic Parkinson disease and age-matched healthy controls for comparison.
MATERIALS AND METHODS
Nineteen subjects with idiopathic Parkinson disease and 19 age-matched healthy control subjects were assessed on the same 3T MR imaging scanner at baseline and after approximately 3 years.
RESULTS
Baseline mean idiopathic Parkinson disease duration was 7.1 years. Both anterior and posterior substantia nigra free water showed significant intergroup differences at baseline ( < .001 and = .014, respectively, idiopathic Parkinson disease versus healthy controls); however, only anterior substantia nigra free water showed significant longitudinal group × time interaction increases ( = .021, idiopathic Parkinson disease versus healthy controls). There were no significant longitudinal group × time interaction differences found for conventional diffusion tensor imaging or free water-corrected DTI assessments in either the anterior or posterior substantia nigra.
CONCLUSIONS
Results from this study provide further evidence supporting substantia nigra free water as a promising disease-progression biomarker in idiopathic Parkinson disease that may help to identify disease-modifying therapies if used in future clinical trials. Our novel finding of longitudinal increases in anterior but not posterior substantia nigra free water is potentially a result of the much longer disease duration of our cohort compared with previously studied cohorts and the known posterior-to-anterior substantia nigra degeneration that occurs over time in idiopathic Parkinson disease.
Topics: Aged; Biomarkers; Cohort Studies; Diffusion Tensor Imaging; Disease Progression; Female; Humans; Male; Middle Aged; Parkinson Disease; Substantia Nigra; Water
PubMed: 29419398
DOI: 10.3174/ajnr.A5545 -
European Neuropsychopharmacology : the... Mar 2023Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of... (Review)
Review
Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral functioning in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naïve patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased density of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABA receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers.
Topics: Humans; Schizophrenia; Dopamine; Corpus Striatum; Substantia Nigra; Receptors, GABA-A; RNA, Messenger
PubMed: 36640734
DOI: 10.1016/j.euroneuro.2022.12.008 -
ACS Chemical Neuroscience Aug 2019Crystals of TiO and CaO were detected in electron-beam exposed extracts of four substantia nigra specimens of Parkinson's disease donors. A likely precursor of the CaO...
Crystals of TiO and CaO were detected in electron-beam exposed extracts of four substantia nigra specimens of Parkinson's disease donors. A likely precursor of the CaO crystals is inflammatory calcium oxalate dihydrate, decomposing according to CaCO·2HO → CaO + CO + CO + 2HO. Crystals of hydrated iron oxide, earlier reported residents of the human brain, were also found.
Topics: Aged; Calcium Compounds; Calcium Oxalate; Ferric Compounds; Humans; Oxides; Parkinson Disease; Substantia Nigra; Titanium
PubMed: 31257859
DOI: 10.1021/acschemneuro.9b00318