Degeneration Of Substantia Nigra Research Articles

Near-Infrared Ratiometric Fluorescent Probe for Detecting Endogenous Cu2+ in the Brain.

Copper participates in a range of critical functions in the nervous system and human brain. Disturbances in brain copper content is strongly associated with neurological diseases. For example, changes in the level and distribution of copper are reported in neuroblastoma, Alzheimer's disease, and Lewy body disorders, such as Parkinson disease and dementia with Lewy bodies (DLB). There is a need for more sensitive techniques to measure intracellular copper levels to have a better understanding of the role of copper homeostasis in neuronal disorders. Here, we report a reaction-based near-infrared (NIR) ratiometric fluorescent probe CyCu1 for imaging Cu2+ in biological samples. High stability and selectivity of CyCu1 enabled the probe to be deployed as a sensor in a range of systems, including SH-SY5Y cells and neuroblastoma tumors. Furthermore, it can be used in plant cells, reporting on copper added to Arabidopsis roots. We also used CyCu1 to explore Cu2+ levels and distribution in post-mortem brain tissues from patients with DLB. We found significant decreases in Cu2+ content in the cytoplasm, neurons, and extraneuronal space in the degenerating substantia nigra in DLB compared with healthy age-matched control tissues. These findings enhance our understanding of Cu2+ dysregulation in Lewy body disorders. Our probe also shows promise as a photoacoustic imaging agent, with potential for applications in bimodal imaging.

Possible role of lncRNAs in amelioration of Parkinson’s disease symptoms by transplantation of dopaminergic cells

Long non-coding RNAs (lncRNAs) are biomarkers for diagnosis and treatment of Parkinson’s disease (PD). Since dopaminergic cell transplantation is a clinical method to treat PD, this study investigated the effects of dopaminergic cell therapy on the expression of some lncRNAs and genes related to PD. In this study, Twenty-eight rats were randomly assigned to four experimental groups. The control group (Sal group) received saline injections. The Par group was a PD rat model with 6-hydroxydopamine (6-OHDA) injection in right striatum (ST). PD animals were transplanted by undifferentiated P19 stem cells (Par-E group), and P19-derived dopaminergic cells (Par-N group). Cell transplant effects were evaluated using behavioral tests (cylinder, open field, and rotarod tests), and histological methods (H&E and Nissl staining, and immunohistochemistry). Moreover, the expression of lncRNAs MALAT1, MEG3, and SNHG1, alongside specific neuronal (synaptophysin) and dopaminergic (tyrosine hydroxylase) markers was evaluated by qRT-PCR. Behavioral and histopathological examinations revealed that cell transplantation partially compensated dopaminergic cell degeneration in ST and substantia nigra (SN) of PD rats. The expression of MALAT1, SNHG1, and MEG3 was decreased in the ST of the Par group, while MEG3 and SNHG1 gene expression was increased in PBMC relative to the Sal group. In PBMC of the Par-N group, all three lncRNAs showed a reduction in their expression. Conversely, MALAT1 and SNHG1 expression was increased in ST tissue, while MEG3 gene expression was decreased compared to the Sal group. In conclusion, dopaminergic cell transplantation could change the lncRNAs expression. Furthermore, it partially improves symptoms in PD rats.

Parkinson’s New Advancements in Diagnosis and Treatment: A Review

Parkinsonism Disease (PD) is a progressive neurological disorder. Although PD is associated with a variety of Non-motor symptoms (NMS) in virtually all patients including hyposmia, constipation, pain and sleep disturbances. It is age related disorder and affects more than 6 million population every year. It is associated with neuronal degeneration in substantia nigra and to lesser extent, in the globus pallidus, putamen and caudate nucleus. The degeneration of the neurons of the substantia nigra that send their axons to the corpus striatum results in reduction in the release of neurotransmitter dopamine with in corpus striatum. This leads to hypersensitivity of the dopamine receptors in the post synaptic neurons in the striatum. Individuals have characteristics signs and symptoms tremors, bradykinesia, postural instabilities, rigidity. Neither loss of sense nor muscle power is usually seen in such cases. Deep tendon, Superficial and Abdominal reflexes are well retained on evaluation. There has been various types of classification in Parkinsonism which are described later. Together with aging, genetics, environment and the role of biological sex as important factor in development of PD has been widely discussed in the past decade. Investigations in PD remains a challenge, recent studies included 7 Tesla MRI, PET and SPECT have proved to be confirmatory in diagnosis of PD. Parkinsonism disease treatment includes increasing the levels of dopamine in brain by giving its immediate precursor L-dopa which can easily cross blood brain barrier unlike dopamine. Evidence of slowing the process of degeneration has been seen with drug selegiline. Other than drugs surgical options include pallidotomy

Inosine monophosphate dehydrogenase intranuclear inclusions are markers of aging and neuronal stress in the human substantia nigra

We explored mechanisms involved in the age-dependent degeneration of human substantia nigra (SN) dopamine (DA) neurons. Owing to its important metabolic functions in post-mitotic neurons, we investigated the developmental and age-associated changes in the purine biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH). Tissue microarrays prepared from post-mortem samples of SN from 85 neurologically intact participants humans spanning the age spectrum were immunostained for IMPDH combined with other proteins. SN DA neurons contained two types of IMPDH structures: cytoplasmic IMPDH filaments and intranuclear IMPDH inclusions. The former were not age-restricted and may represent functional units involved in sustaining purine nucleotide supply in these highly metabolically active cells. The latter showed age-associated changes, including crystallization, features reminiscent of pathological inclusion bodies, and spatial associations with Marinesco bodies; structures previously associated with SN neuron dysfunction and death. We postulate dichotomous roles for these two subcellularly distinct IMPDH structures and propose a nucleus-based model for a novel mechanism of SN senescence that is independent of previously known neurodegeneration-associated proteins.

5 Midbrain Degeneration and Cognition in Parkinson’s Disease

Objective:Neuromelanin imaging is an emerging biomarker for PD as it captures degeneration of the midbrain, a process which is associated with the motor symptoms of the disease. Currently, it is unknown whether this degeneration also contributes to cognitive dysfunction in PD beyond dysfunction associated with fronto-subcortical systems, as quantitative examination of substantia nigra (SN) degeneration could not be studied until recently.In the current study, we examine whether neuromelanin signal is associated with broader cognitive dysfunction in PD patients with varying degrees of cognitive impairment: PD with normal cognition (PD-NC), PD with mild cognitive impairment (PD-MCI), and healthy controls (HC).Participants and Methods:11 PD-NC, 16 PD-MCI and 14 age and sex-matched healthy controls (HC) participated in the study. PD participants were diagnosed with MCI based on the Movement Disorders Society Task force, Level II assessment (comprehensive assessment). In addition, all participants underwent an MRI scan that included a T1-weighted sequence and a neuromelanin-sensitive (NM-MRI) sequence. Contrast-to-noise-ratio of the substantia nigra pars compacta (SNc) was calculated and a distribution-corrected z-score was used to identify the number of extrema voxels for each individual, suggestive of the number of voxels that have exhibited significant degeneration (extrema_count). An analysis of covariance (ANCOVA) was used to evaluate group differences between HC, PD-NC, and PD-MCI in the extrema_count accounting for age, sex, and education. A multiple regression for each cognitive variable with extrema_count as the dependent variable adjusting for age, sex, and education were conducted.Results:A significant main effect of group (F(2, 33) = 33.548 ; p < 0.001) indicated that PD-NC (21.55 ± 12.57) and PD-MCI (43.64 ± 32.84) patients exhibited significantly greater extrema_counts relative to HC (3.36 ± 3.61; both p < 0.001). Regression results indicated that higher extrema_counts were associated with worse cognitive performance across cognitive domains, including working memory (Digit Span Backward; R2 = .357, F(1,20) = 5.295, p = .032), (Hopkins Verbal Learning Test - Revised, Trials 1 to 3; R2 = .432, F(1,20) = 5.819, p = .026).Conclusions:PD patients (PD-NC and PD-MCI) exhibited decreased neuromelanin in the SNc relative to healthy controls, confirming the ability of the NM-MRI sequence to differentiate PD from HC. There was no significant difference in SNc neuromelanin levels between PD-NC patients and PD-MCI patients, however, this is likely due to the small sample size. In addition, significant SNc degeneration was associated with worse cognitive performances in tasks associated with working memory and executive functioning. These results warrant further examination of the role of SN in PD patients with differing levels of cognitive impairment.

Serum but not cerebrospinal fluid levels of allantoin are increased in de novo Parkinson’s disease

Oxidative stress supposedly plays a role in the pathogenesis of Parkinson’s disease (PD). Uric acid (UA), a powerful antioxidant, is lowered in PD while allantoin, the oxidation product of UA and known biomarker of oxidative stress, was not systematically studied in PD. We aim to compare serum and cerebrospinal fluid (CSF) levels of UA, allantoin, and allantoin/UA ratio in de novo PD patients and controls, and evaluate their associations with clinical severity and the degree of substantia nigra degeneration in PD. We measured serum and CSF levels of UA, allantoin, and allantoin/UA ratio in 86 PD patients (33 females, mean age 57.9 (SD 12.6) years; CSF levels were assessed in 51 patients) and in 40 controls (19 females, 56.7 (14.1) years). PD patients were examined using Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson Disease-Autonomic (SCOPA-AUT), the University of Pennsylvania Smell Identification Test (UPSIT), one-night video-polysomnography, and dopamine transporter single-photon emission computed tomography (DAT-SPECT). Serum allantoin and allantoin/UA ratio were significantly increased in the PD group compared to controls (p < 0.001 and p = 0.002, respectively). Allantoin/UA ratios in serum and CSF were positively associated with the SCOPA-AUT score (p = 0.005 and 0.031, respectively) and RBD presence (p = 0.044 and 0.028, respectively). In conclusion, serum allantoin and allantoin/UA ratio are elevated in patients with de novo PD. Allantoin/UA ratio in serum and CSF is associated with autonomic dysfunction and RBD presence, indicating that higher systemic oxidative stress occurs in PD patients with more diffuse neurodegenerative changes.

Monitoring Substantia Nigra Degeneration Using Free Water Imaging across Prodromal and Clinical Parkinson's Disease.

Substantia nigra (SN) free water has been suggested as a good surrogate marker in Parkinson's disease (PD). However, its usefulness for diagnosing prodromal PD (pPD) and monitoring disease progression warrants further validation. The aim was to investigate SN free water values across prodromal and clinical stages of PD. Four groups were enrolled in this study: 48 healthy controls (HC), 43 pPD patients, 50 de novo PD (dnPD) patients, and 49 medicated PD (mPD) patients. Based on diffusion tensor images, free water maps were calculated, and SN free water values were extracted from the anterior SN (ASN) and posterior SN (PSN). The SN free water values were compared among the four groups, and associations between free water and clinical symptoms were explored. The distinguishing power of PSN free water was evaluated using the receiver operating characteristic curve analysis. Follow-up was performed for 14 pPD patients. PSN free water in the pPD group was significantly higher than that in the HC group and significantly lower than that in the dnPD group. Surprisingly, the mPD group showed decreased PSN free water compared to the dnPD group. There was a positive correlation between motor symptoms and PSN free water in the pPD and dnPD groups. Longitudinal analysis showed a significant increase in PSN free water in pPD patients over time. The PSN free water increased from prodromal to early clinical stages, but the trend might be reversed in late disease stages. This biphasic trend should be considered when applying this marker in future studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diagnosing Parkinson's disease by combining neuromelanin and iron imaging features using an automated midbrain template approach

Background and purposeEarly diagnosis of Parkinson's disease (PD) is still a clinical challenge. Most previous studies using manual or semi-automated methods for segmenting the substantia nigra (SN) are time-consuming and, despite raters being well-trained, individual variation can be significant. In this study, we used a template-based, automatic, SN subregion segmentation pipeline to detect the neuromelanin (NM) and iron features in the SN and SN pars compacta (SNpc) derived from a single 3D magnetization transfer contrast (MTC) gradient echo (GRE) sequence in an attempt to develop a comprehensive imaging biomarker that could be used to diagnose PD. Materials and methodsA total of 100 PD patients and 100 age- and sex-matched healthy controls (HCs) were imaged on a 3T scanner. NM-based SN (SNNM) boundaries and iron-based SN (SNQSM) boundaries and their overlap region (representing the SNpc) were delineated automatically using a template-based SN subregion segmentation approach based on quantitative susceptibility mapping (QSM) and NM images derived from the same MTC-GRE sequence. All PD and HC subjects were evaluated for the nigrosome-1 (N1) sign by two raters independently. Receiver Operating Characteristic (ROC) analyses were performed to evaluate the utility of SNNM volume, SNQSM volume, SNpc volume and iron content with a variety of thresholds as well as the N1 sign in diagnosing PD. Correlation analyses were performed to study the relationship between these imaging measures and the clinical scales in PD. ResultsIn this study, we verified the value of the fully automatic template based midbrain deep gray matter mapping approach in differentiating PD patients from HCs. The automatic segmentation of the SN in PD patients led to satisfactory DICE similarity coefficients and volume ratio (VR) values of 0.81 and 1.17 for the SNNM, and 0.87 and 1.05 for the SNQSM, respectively. For the HC group, the average DICE similarity coefficients and VR values were 0.85 and 0.94 for the SNNM, and 0.87 and 0.96 for the SNQSM, respectively. The SNQSM volume tended to decrease with age for both the PD and HC groups but was more severe for the PD group. For diagnosing PD, the N1 sign performed reasonably well by itself (Area Under the Curve (AUC) = 0.783). However, combining the N1 sign with the other quantitative measures (SNNM volume, SNQSM volume, SNpc volume and iron content) resulted in an improved diagnosis of PD with an AUC as high as 0.947 (using an SN threshold of 50ppb and an NM threshold of 0.15). Finally, the SNQSM volume showed a negative correlation with the MDS-UPDRS III (R2 = 0.1, p = 0.036) and the Hoehn and Yahr scale (R2 = 0.04, p = 0.013) in PD patients. ConclusionIn summary, this fully automatic template based deep gray matter mapping approach performs well in the segmentation of the SN and its subregions for not only HCs but also PD patients with SN degeneration. The combination of the N1 sign with other quantitative measures (SNNM volume, SNQSM volume, SNpc volume and iron content) resulted in an AUC of 0.947 and provided a comprehensive set of imaging biomarkers that, potentially, could be used to diagnose PD clinically.

Association of Substantia Nigra Degeneration with Poor Neurological Recovery in Basal Ganglia Infarctions.

Association of Substantia Nigra Degeneration with Poor Neurological Recovery in Basal Ganglia Infarctions.

Increased Free Water in the Substantia Nigra in Asymptomatic LRRK2 G2019S Mutation Carriers.

The alteration of substantia nigra (SN) degeneration in populations at risk of Parkinson's disease (PD) is unclear. We investigated free water (FW) values in the posterior SN (pSN) in asymptomatic LRRK2 G2019S mutation carriers. We analyzed diffusion imaging data from 28 asymptomatic LRRK2 G2019S mutation carriers and 30 healthy controls (HCs), whereas 11 asymptomatic LRRK2 G2019S carriers and 11 HCs were followed up. FW values in the pSN were measured and compared between the groups. The relationship between longitudinal changes in FW in the pSN and dopamine transporter striatal binding ratio (SBR) was analyzed. FW values in the pSN were significantly elevated and kept increasing during follow-up in asymptomatic LRRK2 G2019S carriers. There was a negative correlation between FW changes in the left pSN and SBR changes in the left putamen. FW in the pSN has the potential to be a progression imaging marker of early dopaminergic degeneration in the population at risk of PD. © 2022 International Parkinson and Movement Disorder Society.

Chlorogenic Acid: a Polyphenol from Coffee Rendered Neuroprotection Against Rotenone-Induced Parkinson’s Disease by GLP-1 Secretion

Parkinson's disease (PD) is a chronic motor disorder, characterized by progressive loss of dopaminergic neurons. Numerous studies suggest that glucagon-like peptide-1 (GLP-1) secretagogue has a neuroprotective role in PD models. The present study evaluated potential of coffee bioactive compounds in terms of their ability to bind GPR-40/43 and tested the neuroprotective effect of best candidate on rotenone-induced PD mice acting via GLP-1 release. In silico molecular docking followed by binding free energy calculation revealed that chlorogenic acid (CGA) has a strong binding affinity for GPR-40/43 in comparison to other bioactive polyphenols. Molecular dynamics simulation studies revealed stable nature of GPR40-CGA and GPR43-CGA interaction and also provided information about the amino acid residues involved in binding. Subsequently, in vitro studies demonstrated that CGA-induced secretion of GLP-1 via enhancing cAMP levels in GLUTag cells. Furthermore, in vivo experiments utilizing rotenone-induced mouse model of PD revealed a significant rise in plasma GLP-1 after CGA administration (50mg/kg, orally for 13weeks) with concomitant increase in colonic GPR-40 and GPR-43 mRNA expression. CGA treatment also prevented rotenone-induced motor and cognitive impairments and significantly restored the rotenone-induced oxidative stress. Meanwhile, western blot results confirmed that CGA treatment downregulated rotenone-induced phosphorylated alpha-synuclein levels by upregulating PI3K/AKT signaling and inactivating GSK-3β through the release of GLP-1. CGA treatment ameliorated rotenone-induced dopaminergic nerve degeneration and alpha-synuclein accumulation in substantia nigra and augmented mean density of dopaminergic nerve fibers in striatum. These findings demonstrated novel biological function of CGA as a GLP-1 secretagogue. An increase in endogenous GLP-1 may render neuroprotection against a rotenone mouse model of PD and has the potential to be used as a neuroprotective agent in management of PD.

Differential Effects of Tau Stage, Lewy Body Pathology, and Substantia Nigra Degeneration on 18F-FDG PET Patterns in Clinical Alzheimer Disease.

Comorbid Lewy body (LB) pathology is common in Alzheimer disease (AD). The effect of LB copathology on 18F-FDG PET patterns in AD is yet to be studied. We analyzed associations of neuropathologically assessed tau pathology, LB pathology, and substantia nigra neuronal loss (SNnl) with antemortem 18F-FDG PET hypometabolism in patients with a clinical AD presentation. Methods: Twenty-one patients with autopsy-confirmed AD without LB neuropathologic changes (LBNC) (pure-AD), 24 with AD and LBNC copathology (AD-LB), and 7 with LBNC without fulfilling neuropathologic criteria for AD (pure-LB) were studied. Pathologic groups were compared regarding regional and voxelwise 18F-FDG PET patterns, the cingulate island sign ratio (CISr), and neuropathologic ratings of SNnl. Additional analyses assessed continuous associations of Braak tangle stage and SNnl with 18F-FDG PET patterns. Results: Pure-AD and AD-LB showed highly similar patterns of AD-typical temporoparietal hypometabolism and did not differ in CISr, regional 18F-FDG SUVR, or SNnl. By contrast, pure-LB showed the expected pattern of pronounced posterior-occipital hypometabolism typical for dementia with LB (DLB), and both CISr and SNnl were significantly higher compared with the AD groups. In continuous analyses, Braak tangle stage correlated significantly with more AD-like, and SNnl with more DLB-like, 18F-FDG PET patterns. Conclusion: In autopsy-confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional 18F-FDG PET pattern. A more DLB-like 18F-FDG PET pattern was observed in relation to SNnl, but advanced SNnl was mostly limited to relatively pure LB cases. AD pathology may have a dominant effect over LB pathology in determining the regional neurodegeneration phenotype.

Neurogenic effects of rotarod walking exercise in subventricular zone, subgranular zone, and substantia nigra in MPTP-induced Parkinson’s disease mice

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, and its incidence is predicted to increase worldwide. Striatal dopamine depletion caused by substantia nigra (SN) degeneration is a pathological hallmark of PD and is strongly associated with cardinal motor and non-motor symptoms. Previous studies have reported that exercise increases neuroplasticity and promotes neurorestoration by increasing neurotrophic factors and synaptic strength and stimulating neurogenesis in PD. In the present study, we found that rotarod walking exercise, a modality of motor skill learning training, improved locomotor disturbances and reduced nigrostriatal degeneration in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In addition, our exercise regimen improved MPTP-induced perturbation of adult neurogenesis in some areas of the brain, including the subventricular zone, subgranular zone, SN, and striatum. Moreover, rotarod walking activated the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and induced brain-derived neurotrophic factor (BDNF) expression in these regions. The results suggest that motor skill learning training using rotarod walking improves adult neurogenesis and restores motor performance by modulating the AMPK/BDNF pathway. Therefore, our findings provide evidence for neuroprotective effects and improved neuroplasticity in PD through motor skill learning training.

Increased Transferrin Sialylation Predicts Phenoconversion in Isolated REM Sleep Behavior Disorder.

BackgroundSialic acid–protein interactions are involved in regulating central nervous system immunity; therefore, derangements in sialylation could be involved in neurodegeneration.ObjectivesWe evaluate the differences in serum transferrin sialylation in prodromal and early‐stage Parkinson's disease (PD), its relation to substantia nigra degeneration, and the risk of phenoconversion to manifest disease.MethodsSixty treatment‐naive PD patients; 72 polysomnography‐confirmed isolated rapid eye movement sleep behavior disorder (iRBD) patients, that is, patients with prodromal synucleinopathy; and 46 healthy volunteers aged ≥45 years and drinking ≤60 standard drinks per month were included. The proportion of serum low‐sialylated, carbohydrate‐deficient transferrin (CDT) isoforms was assessed using high‐performance liquid chromatography, and the values were adjusted for alcohol intake (CDTadj). Dopamine transporter single‐photon emission computed tomography (DaT‐SPECT) imaging was performed. In iRBD, phenoconversion risk of DaT‐SPECT and CDTadj was evaluated using Cox regression adjusted for age and sex.ResultsMedian CDTadj was lower in PD (1.1 [interquartile range: 1.0–1.3]%) compared to controls (1.2 [1.1–1.6]%) (P = 0.001). In iRBD, median CDTadj was lower in subjects with abnormal (1.1 [0.9–1.3]%) than normal (1.3 [1.2–1.6]%) DaT‐SPECT (P = 0.005). After a median 44‐month follow‐up, 20% of iRBD patients progressed to a manifest disease. Although iRBD converters and nonconverters did not significantly differ in CDTadj levels (P = 0.189), low CDTadj increased the risk of phenoconversion with hazard ratio 3.2 (P = 0.045) but did not refine the phenoconversion risk associated with abnormal DaT‐SPECT yielding hazard ratio 15.8 (P < 0.001).ConclusionsDecreased serum CDTadj is associated with substantia nigra degeneration in synucleinopathies. iRBD patients with low CDTadj are more likely to phenoconvert to manifest disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Chapter 32 - From chronic stress and anxiety to neurodegeneration: Focus on neuromodulation of the axon initial segment

To adapt to the sustained demands of chronic stress, discrete brain circuits undergo structural and functional changes often resulting in anxiety disorders. In some individuals, anxiety disorders precede the development of motor symptoms of Parkinson's disease (PD) caused by degeneration of neurons in the substantia nigra (SN). Here, we present a circuit framework for probing a causal link between chronic stress, anxiety, and PD, which postulates a central role of abnormal neuromodulation of the SN's axon initial segment by brainstem inputs. It is grounded in findings demonstrating that the earliest PD pathologies occur in the stress-responsive, emotion regulation network of the brainstem, which provides the SN with dense aminergic and cholinergic innervation. SN's axon initial segment (AIS) has unique features that support the sustained and bidirectional propagation of activity in response to synaptic inputs. It is therefore, especially sensitive to circuit-mediated stress-induced imbalance of neuromodulation, and thus a plausible initiating site of neurodegeneration. This could explain why, although secondary to pathophysiologies in other brainstem nuclei, SN degeneration is the most extensive. Consequently, the cardinal symptom of PD, severe motor deficits, arise from degeneration of the nigrostriatal pathway rather than other brainstem nuclei. Understanding when and how circuit dysfunctions underlying anxiety can progress to neurodegeneration, raises the prospect of timed interventions for reversing, or at least impeding, the early pathophysiologies that lead to PD and possibly other neurodegenerative disorders.

Decoding the Role of Familial Parkinson's Disease-Related Genes in DNA Damage and Repair.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of midbrain substantia nigra pars compacta dopaminergic neurons and the formation of Lewy bodies. Over the years, researchers have gained extensive knowledge about dopaminergic neuron degeneration from the perspective of the environmental and disease-causing genetic factors; however, there is still no disease-modifying therapy. Aging has long been recognized as a major risk factor for PD; however, little is known about how aging contributes to the disease development. Genome instability is the main driving force behind aging, and has been poorly studied in patients with PD. Here, we summarize the evidence for nuclear DNA damage in PD. We also discuss the molecular mechanisms of nuclear DNA damage and repair in PD, especially from the perspective of familial PD-related mutant genes. Understanding the significance of DNA damage and repair may provide new potential intervention targets for treating PD.

Locus Coeruleus Degeneration Correlated with Levodopa Resistance in Parkinson’s Disease: A Retrospective Analysis

Background: The widely divergent responsiveness of Parkinson’s disease (PD) patients to levodopa is an important clinical issue because of its relationship with quality of life and disease prognosis. Preliminary animal experiments have suggested that degeneration of the locus coeruleus (LC) attenuates the efficacy of levodopa treatment.Objective: To explore the relationship between LC degeneration and levodopa responsiveness in PD patients in vivo.Methods: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a good indicator of LC and substantia nigra (SN) degeneration, and levodopa challenge tests were conducted in 57 PD patients. Responsiveness to levodopa was evaluated by the rates of change of the Unified Parkinson’s Disease Rating Scale Part III score and somatomotor network synchronization calculated from resting-state functional MRI before and after levodopa administration. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC) and levodopa responsiveness. Multiple linear regression analysis was conducted to rule out the potential influence of SN degeneration on levodopa responsiveness.Results: A significant positive correlation was found between CNRLC and the motor improvement after levodopa administration (R = 0.421, p = 0.004). CNRLC also correlated with improvement in somatomotor network synchronization (R = –0.323, p = 0.029). Furthermore, the relationship between CNRLC and levodopa responsiveness was independent of SN degeneration.Conclusion: LC degeneration might be an essential factor for levodopa resistance. LC evaluation using NM-MRI might be an alternative tool for predicting levodopa responsiveness and for helping to stratify patients into clinical trials aimed at improving the efficacy of levodopa.

White matter hyperintensities mediate the impact of amyloid ß on future freezing of gait in Parkinson's disease

BackgroundFreezing of gait (FOG) is a common symptom in Parkinson's Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid β deposition. However, there is a paucity of research on the concurrent impact of white matter damage. ObjectivesTo assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other. MethodsWe used baseline MRI and longitudinal gait data from 423 de novo PD patients from the Parkinson's Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid β were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid β on future FOG. ResultsSN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid β levels were significantly different between PD patients with and without future FOG (p < 0.008). Mediation analysis demonstrated an effect of CSF amyloid β levels on future FOG via WMH load, independent of SN atrophy and striatal DAT activity levels. ConclusionsAmyloid β might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology.

A Clinicopathologic Study of Movement Disorders in Frontotemporal Lobar Degeneration.

Despite the considerable overlap with atypical parkinsonism, a systematic characterization of the movement disorders associated with frontotemporal lobar degeneration (FTLD) is lacking. The aim of this study is to provide a detailed description of the phenomenology and neuropathologic correlations of movement disorders in FTLD. In this cohort study, movement disorder clinical data were retrospectively collected from medical records of consecutive patients with a postmortem diagnosis of FTLD from the Queen Square Brain Bank between January 2010 and December 2018. At postmortem, neurodegenerative pathologies were systematically evaluated following consensus criteria. Degeneration of the substantia nigra was assessed as a marker of presynaptic dopaminergic parkinsonism using semiquantitative methods. A total of 55 patients (35 men [64%]) were included with median (interquartile range) age at diagnosis of 58.8 (52.6-63.9) years and a disease duration of 9.6 (6.2-12.9) years. Movement disorders were present in 19 (35%) patients without differences among disease subtypes. The most common syndromes were parkinsonism (9 patients [16%]), usually as an additional late feature, and corticobasal syndrome (CBS, 7 patients [13%]), commonly as a presenting feature. Substantia nigra degeneration was present in 37 (67%) patients although it did not show a good clinical correlation with movement disorders. Those with Pick's disease showed milder substantia nigra degeneration and better response to levodopa. Movement disorders can present in all FTLD subtypes, more commonly as a late additional feature (parkinsonism) or as a presenting symptom (CBS). The underlying pathophysiology is complex and likely to involve structures outside the presynaptic striatonigral system. © 2020 International Parkinson and Movement Disorder Society.

Calcium, Bioenergetics, and Parkinson's Disease.

Degeneration of substantia nigra (SN) dopaminergic (DAergic) neurons is responsible for the core motor deficits of Parkinson’s disease (PD). These neurons are autonomous pacemakers that have large cytosolic Ca2+ oscillations that have been linked to basal mitochondrial oxidant stress and turnover. This review explores the origin of Ca2+ oscillations and their role in the control of mitochondrial respiration, bioenergetics, and mitochondrial oxidant stress.