Cause Of Parkinsonism Research Articles

Neurophysiological mechanisms of gait disturbance in advanced Parkinson's disease patients

This review considers pathophysiological mechanisms of posture-gait disturbances in Parkinson's disease (PD). Clinical studies have shown that posture-gait disturbance attributes to the dysfunction of the whole neuraxis in addition to the musculoskeletal system. The cerebral cortex, basal ganglia (BG), cerebellum, brainstem, and spinal cord temporally and spatially integrate and coordinate multisensory feedback and efferent copies of the motor command. Therefore, the extensive repertoire of voluntary movements can be coupled with anticipatory and reactive postural adjustments to provide the framework for supporting and stabilizing the goal-directed gait activity. Redundancies in the system allow adaptation and compensation through reward-oriented and error-based learning processes implemented through the BG and cerebellar pathways, respectively. However, the impairment of these systems in PD may considerably compromise the capacity to adapt and lead to maladaptive changes impairing posture-gait control. When these impairments occur, the risk of falls can significantly increase, and interventions are required to reduce morbidity. The damage in dopamine (DA) neurons is the primary cause of PD. Insufficient DA supply in the striatum disturbs the operation of intrinsic networks in the BG. This also pathologically increases GABAergic BG output to the cerebral cortex and brainstem, resulting in functional disconnection of other structures from the BG. The disconnection makes PD patients disable to achieve habitually acquired automatized gait control. Moreover, Lewy body degeneration in most brain areas, particularly in cholinergic and other monoaminergic systems vulnerable to neurodegeneration, further disturbs posture-gait control and alters non-motor symptoms of PD.

Magnetic resonance and dopamine transporter imaging for the diagnosis of Parkinson´s disease: a narrative review.

the diagnosis of Parkinson's disease (PD) can be challenging, especially in the early stages, albeit its updated and validated clinical criteria. Recent developments on neuroimaging in PD, altogether with its consolidated role of excluding secondary and other neurodegenerative causes of parkinsonism, provide more confidence in the diagnosis across the different stages of the disease. This review highlights current knowledge and major recent advances in magnetic resonance and dopamine transporter imaging in aiding PD diagnosis. This study aims to review current knowledge about the role of magnetic resonance imaging and neuroimaging of the dopamine transporter in diagnosing Parkinson's disease. We performed a non-systematic literature review through the PubMed database, using the keywords "Parkinson", "magnetic resonance imaging", "diffusion tensor", "diffusion-weighted", "neuromelanin", "nigrosome-1", "single-photon emission computed tomography", "dopamine transporter imaging". The search was restricted to articles written in English, published between January 2010 and February 2022. The diagnosis of Parkinson's disease remains a clinical diagnosis. However, new neuroimaging biomarkers hold promise for increased diagnostic accuracy, especially in earlier stages of the disease. Future validation of new imaging biomarkers bring the expectation of an increased neuroimaging role in the diagnosis of PD in the following years.

A Review and Case Study of the Action of Chlorpromazine on Dopaminergic Pathways and its Associated Extrapyramidal Disturbances

Abstract: As a first-line antipsychotic, Chlorpromazine is an excellent blocking agent of the D2 receptor. Dopamine pathways are predominantly affected by the use of this medicine in schizophrenia therapy, leading to the development of drug-induced Parkinsonism (DIP). Extrapyramidal symptoms (EPS) include motor rigidity, tremors, restlessness, dystonia, stumbling, nervousness, improper posture, Tardive dyskinesia, Akathisia, and many other side effects. In seniors over 70 suffering from schizophrenia, DIP has become very common and is the second most common cause of Parkinsonism behind Parkinson's disease (PD). A concise review of the actual mechanism of blockade by chlorpromazine is presented in this article, with a particular focus on EPS and other adverse effects. Keywords: Drug-induced Parkinsonism, Extrapyramidal symptoms, Schizophrenia, Tardive dyskinesia, Chlorpromazine.

Resilin, an insect-derived elastomeric protein, protects dopaminergic neurons in Parkinson disease models

Parkinson disease (PD) is a prevalent neurodegenerative disorder that is characterized by motor and behavioral disturbances, including resting tremors, rigidity, bradykinesia, and postural instability. The primary cause of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region that subsequently reduces the dopamine content in the striatum (ST); this is a promising therapeutic target for PD. Resilin is an elastomeric protein with high strain, low stiffness, and high resilience that is found in insect cuticles. However, scant evidence supports the application of resilin in neurodegenerative diseases, including PD. Herein, we investigated the protective effects of resilin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mouse models and explored the mechanisms underlying its action. Resilin significantly and concentration-dependently reduced 1-methyl-4-phenylpyridinium+ (MPP+)-induced apoptotic neurotoxicity in differentiated PC12 and SH-SY5Y cells. Moreover, resilin prevented dopamine depletion in ST, and immunohistochemical findings indicated that resilin protects against dopaminergic neuronal loss induced by MPTP in the SNpc and ST. Behavioral studies using pole and rotarod tests showed significantly improved PD-related motor impairment in mice treated with resilin. We then explored the molecular mechanisms underlying the apoptosis of dopaminergic neurons using protein arrays and discovered that resilin inhibits dopaminergic neuronal death through the apoptosis signaling factors cytochrome c and caspases-9 and −3 in the SNpc. Thus, resilin has potential in treating PD by controlling apoptosis signals.

Ca2+ Dyshomeostasis Links Risk Factors to Neurodegeneration in Parkinson's Disease.

Parkinson’s disease (PD), a common neurodegenerative disease characterized by motor dysfunction, results from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although the precise causes of PD are still unknown, several risk factors for PD have been determined, including aging, genetic mutations, environmental factors, and gender. Currently, the molecular mechanisms underlying risk factor-related neurodegeneration in PD remain elusive. Endoplasmic reticulum stress, excessive reactive oxygen species production, and impaired autophagy have been implicated in neuronal death in the SNc in PD. Considering that these pathological processes are tightly associated with intracellular Ca2+, it is reasonable to hypothesize that dysregulation of Ca2+ handling may mediate risk factors-related PD pathogenesis. We review the recent findings on how risk factors cause Ca2+ dyshomeostasis and how aberrant Ca2+ handling triggers dopaminergic neurodegeneration in the SNc in PD, thus putting forward the possibility that manipulation of specific Ca2+ handling proteins and subcellular Ca2+ homeostasis may lead to new promising strategies for PD treatment.

Effects of Cannabidiol on Parkinson's Disease in a Transgenic Mouse Model by Gut-Brain Metabolic Analysis.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by a disorder of the dopaminergic system in the midbrain, causing classical PD motor symptoms. The therapeutic effect of cannabidiol (CBD) on PD has been a research frontier in recent years. However, the pathogenesis of PD and the therapeutic mechanism of cannabinoid remain unclear. To further study the causes of PD and the effect of CBD on PD, we exposed the PD transgenic mouse model to CBD and then estimated the motorial and postural coordination through a modified swim test. Afterwards, the mechanism was investigated via the histopathology of substantia nigra and the gut-brain metabolic analysis in the approach of UHPLC-TOF-MS. The results showed that CBD significantly improved motor deficits of PD model and protected the substantia nigra area. The metabolic function of fatty acid biosynthesis, arginine biosynthesis/metabolism, butanoate (ketone body) metabolism, β-alanine metabolism, and pantothenate/CoA biosynthesis was highlighted in the pathological and therapeutic process along the gut-brain axis. In conclusion, CBD could attenuate PD via the neuroprotective effect on the midbrain. The attenuation of the central nervous system in turn improved motor performance of PD, which might be partially induced by the metabolic interaction between the gut-brain. In view of gut-brain metabolomics, the mechanism of PD pathogenesis and the effect of CBD on PD are highly related to the biosynthesis and metabolism of energy and essential substance.

Parkinson Disease: Epidemiology, Pathology, and Clinical Diagnosis

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. PD predominantly affects elderly people, and most countries are now facing a marked demographic change, with a progressively larger proportion of the population reaching old age. Thus, PD is expected to cause an increasing social and economic burden on society in the near future. The causes of PD are still mostly unknown. There has been a substantial progress in our understanding of the genetic basis of PD in the past 15 years; however, these mutations explain only a small fraction of all PD cases and other non-genetic factors may play a role. This review covers the epidemiology, pathology, and clinical diagnosis of PD. Figures show age-specific incidence of PD, age-specific prevalence of PD, PD risks for exposures reported in high-quality studies, PD and atypical parkinsonism clinical features, and neuroimaging alterations in PD and atypical parkinsonism. Tables list factors associated with increased or decreased risk of PD, Braak staging scheme of α-synuclein pathology in PD, United Kingdom Parkinson’s Disease Society Brain Bank clinical diagnostic for PD, National Institute of Neurological Disorders and Stroke diagnostic criteria for PD, differential diagnosis of parkinsonian syndromes, and “atypical” atypical parkinsonism.

Parkinson Disease: Epidemiology, Pathology, and Clinical Diagnosis

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. PD predominantly affects elderly people, and most countries are now facing a marked demographic change, with a progressively larger proportion of the population reaching old age. Thus, PD is expected to cause an increasing social and economic burden on society in the near future. The causes of PD are still mostly unknown. There has been a substantial progress in our understanding of the genetic basis of PD in the past 15 years; however, these mutations explain only a small fraction of all PD cases and other non-genetic factors may play a role. This review covers the epidemiology, pathology, and clinical diagnosis of PD. Figures show age-specific incidence of PD, age-specific prevalence of PD, PD risks for exposures reported in high-quality studies, PD and atypical parkinsonism clinical features, and neuroimaging alterations in PD and atypical parkinsonism. Tables list factors associated with increased or decreased risk of PD, Braak staging scheme of α-synuclein pathology in PD, United Kingdom Parkinson’s Disease Society Brain Bank clinical diagnostic for PD, National Institute of Neurological Disorders and Stroke diagnostic criteria for PD, differential diagnosis of parkinsonian syndromes, and “atypical” atypical parkinsonism.

Parkinson's Disease: A Current Perspectives on Parkinson's Disease and Key Bioactive Natural Compounds as Future Potential Drug Candidates.

Parkinson's disease (PD) is one of the most common types of neurological disorder prevailing worldwide and is rapidly increasing in the elderly population across the globe. The cause of PD is still unknown, but a number of genetic as well as environmental factors contributing to the pathogenesis of Parkinson's disease have been identified. The hallmark of PD includes dopamine deficiency (neurotransmitter imbalance) due to the gradual loss of dopaminergic nerves in the substantia nigra in the midbrain. Studying the mutation of associated genes is particularly informative in understanding the fundamental molecular and pathogenic changes in PD. Intracellular accumulation of misfolded or degraded protein due to mutated genes leading to the manifestation of mitochondrial dysfunction, oxidative stress followed by multifaceted patho-physiologic symptoms. Other studies include the appearance of both motor and non-motor responses like resting tremor, muscle stiffness, slow movement and anxiety, anaemia, constipation, rapid eye movement sleep behaviour disorder. Many bioactive natural compounds have shown positive pharmacological results in treating a number of extensive disease models of PD. Despite the availability of end number of potent medicinal plants around the world, limited research has been done associated with various neurological disorders, including PD. The currently available dopamine-based drug treatments have several side-effects, further, not effective enough to combat PD completely. Therefore, various plant-based compounds with medicinal benefits have grabbed lots of attention of researchers to deal with various life-threatening neurodegenerative disorders like PD. On the basis of literature available till date, here, we have discussed and addressed the molecular basis, current scenario, and the best possible treatment of PD for the future with minimal or no side-effects using various key bioactive compounds from natural origin/medicinal plants.

Analiza polimorfizma rs34637584 u genu LRRK2 kod bolesnika sa Parkinsonovom bolešću

Introduction: Parkinson's disease (PD) belongs to neurodegenerative diseases, and since the prevalence is 1% to 2% in people older than 65 years and over 4% in people older than 85 years, it is the second most common disease in this group. The cause of PD is the death of dopaminergic neurons in the CNS, primarily in the basal ganglia and the substantia nigra. The LRRK2/PARK8 gene is located on the short arm of chromosome 12. There are many variants in this gene associated with PD, and the most common of which is mutation c.6055G>A (p.Gly2019Ser), also referred to as rs34637584. Aim: The aim of this study was to determine the frequency of the c.6055G>A (rs34637584) mutation in the LRRK2 gene in a group of patients with PD from Serbia. Material and methods: The study included a group of 127 patients with PD from tertiary healthcare institutions in Serbia, as well as an appropriate control group without neurological diseases. Molecular genetic analysis was performed by real-time PCR, using a commercial TaqMan assay. Results: Mutation c.6055G>A ie. rs34637584 variant was detected in 1 of 127 examinees with PD (0.7%). That patient was without a previous family history of PD. This mutation was not found in the control group. Conclusion: The results obtained align with findings of previous studies for the European, especially the southern European population. If these results would be confirmed in a larger patient sample, testing of LRRK2 mutation c.6055G>A (rs34637584) should become part of the PD test protocol.

Reduction of tyrosine hydroxylase expression and increase of α-synuclein in the substantia nigra in a rat model of benign prostatic hyperplasia

Parkinson's disease (PD) occurs when dopaminergic cells in the substantia nigra (SN) region are destroyed; however, the cause of the destruction of dopamine cells has not yet been determined. This study was performed to investigate whether changes in the hormones that cause benign prostatic hyperplasia (BPH) are related to pathological changes in PD. The pathological findings were examined by observing the lesion sites related to PD in a BPH rat model. BPH was induced in rats by subcutaneous injection of testosterone propionate for 4 weeks after castration. To investigate the changes in the SN regions, tyrosine hydroxylase (TH) and α-synuclein (α-syn) expression were analyzed by western blotting. TH expression, expressed in dopaminergic cells and used as a dopaminergic cell detection marker, decreased, whereas α-syn expression increased at the SN site. These results are quite similar to the pathological changes observed in patients with PD and Parkinsonism animal models. Our results showed an increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in the SN regions in the BPH group. Additionally, a decreased expression of B-cell lymphoma protein 2 and an increased expression of B-cell lymphoma protein 2-associated X, suggesting increased apoptosis, were observed in the BPH group. These results suggest that the pathological changes associated with PD may be caused by BPH or factors related to BPH. Thus, this study has presented a new avenue for an approach related to hormonal changes as a method to determine the cause of PD, for which the exact cause is not yet known.

Cognitive and Behavior Deficits in Parkinson’s Disease with Alteration of FDG-PET Irrespective of Age

Significant progress has been made in our understanding of the neurobiology of Parkinson’s disease (PD). Post-mortem studies are an important step and could help to comprehend not only the progression of motor symptoms, but also the involvement of other clinical domains, including cognition, behavior and impulse control disorders (ICDs). The correlation of neuropathological extension of the disease with the clinical stages remains challenging. Molecular imaging, including positron emission tomography (PET) and single photon computed tomography (SPECT), could allow for bridging the gap by providing in vivo evidence of disease extension. In the last decade, we have observed a plethora of reports describing improvements in the sensitivity of neuroimaging techniques. These data contribute to increasing the accuracy of PD diagnosis, differentiating PD from other causes of parkinsonism and also obtaining a surrogate marker of disease progression. FDG-PET has been used to measure cerebral metabolic rates of glucose, a proxy for neuronal activity, in PD. Many studies have shown that this technique could be used in early PD, where reduced metabolic activity correlates with disease progression and could predict histopathological diagnosis. The aim of this work is to report two particular cases of PD in which the assessment of brain metabolic activity (from FDG-PET) has been combined with clinical aspects of non-motor symptoms. Integration of information on neuropsychological and metabolic imaging allows us to improve the treatment of PD patients irrespective of age.

The global Parkinson's Genetics Program (GP2): The Monogenic Hub 500-genomes pilot project

The Global Parkinson's Genetics Program (GP2) is an international collaborative program that focuses on improving our understanding of the role of genetics in Parkinson's disease (PD) and on making this knowledge globally available and actionable. The “Monogenic Hub” aims to perform both short and long-read whole-genome sequencing (WGS) for a total of 10.000 PD patients starting with a 500-genomes pilot project, with the goal of identifying novel monogenic causes of PD.

LRRK2 is required for CD38-mediated NAADP-Ca2+ signaling and the downstream activation of TFEB (transcription factor EB) in immune cells

ABSTRACT CD38 is a cell surface receptor capable of generating calcium-mobilizing second messengers. It has been implicated in host defense and cancer biology, but signaling mechanisms downstream of CD38 remain unclear. Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common genetic cause of Parkinson disease; it is also a risk factor for Crohn disease, leprosy, and certain types of cancers. The pathogenesis of these diseases involves inflammation and macroautophagy/autophagy, processes both CD38 and LRRK2 are implicated in. Here, we mechanistically and functionally link CD38 and LRRK2 as upstream activators of TFEB (transcription factor EB), a host defense transcription factor and the master transcriptional regulator of the autophagy/lysosome machinery. In B-lymphocytes and macrophages, we show that CD38 and LRRK2 exist in a complex on the plasma membrane. Ligation of CD38 with the monoclonal antibody clone 90 results in internalization of the CD38-LRRK2 complex and its targeting to the endolysosomal system. This generates an NAADP-dependent calcium signal, which requires LRRK2 kinase activity, and results in the downstream activation of TFEB. lrrk2 KO macrophages accordingly have TFEB activation defects following CD38 or LPS stimulation and fail to switch to glycolytic metabolism after LPS treatment. In overexpression models, the pathogenic LRRK2G2019S mutant promotes hyperactivation of TFEB even in the absence of CD38, both by stabilizing TFEB and promoting its nuclear translocation via aberrant calcium signaling. In sum, we have identified a physiological CD38-LRRK2-TFEB signaling axis in immune cells. The common pathogenic mutant, LRRK2G2019S, appears to hijack this pathway. Abbreviations:ADPR: ADP-ribose; AMPK: AMP-activated protein kinase; BMDM: bone marrow-derived macrophage; cADPR: cyclic-ADP-ribose; COR: C-terminal of ROC; CTSD: cathepsin D; ECAR: extracellular acidification rate; EDTA: ethylenediaminetetraacetic acid; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GPN: Gly-Phe β-naphthylamide; GSK3B/GSK3β: glycogen synthase kinase 3 beta; GTP: guanosine triphosphate; KD: knockdown; LAMP1: lysosomal-associated membrane protein 1; LRR: leucine rich repeat; LRRK2: leucine rich repeat kinase 2; mAb: monoclonal antibody; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; MCOLN1: mucolipin 1; MFI: mean fluorescence intensity; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NAADP: nicotinic acid adenine dinucleotide phosphate; NAD: nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; PD: Parkinson disease; PPP3CB: protein phosphatase 3, catalytic subunit, beta isoform; q-RT-PCR: quantitative reverse transcription polymerase chain reaction; ROC: Ras of complex; siRNA: small interfering RNA; SQSTM1/p62: sequestome 1; TFEB: transcription factor EB; TPCN: two pore channel; TRPM2: transient receptor potential cation channel, subfamily M, member 2; ZKSCAN3: zinc finger with KRAB and SCAN domains 3

In-silico Prediction of the Beta-carboline Alkaloids Harmine and Harmaline as Potent Drug Candidates for the Treatment of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease manifested by core symptoms of loss of motor control and postural instability. Loss of dopaminergic neurons is the cause of PD, thus enhancing dopamine level by pharmacological treatment is one of the key treatment strategies for PD. However, the limitations of current treatment strategies open the possibility of novel drug candidates for the treatment of PD. To investigate the anti-PD potential of Harmine and Harmaline. We aim to evaluate the therapeutic potential of Harmine and Harmaline by in-silico approaches; molecular docking, pharmacokinetic and Prediction of Activity Spectra for Substances (PASS) analysis were used for evaluating the therapeutic potential of Harmine and Harmaline and standard drug levodopa (L-DOPA). Auto dock vina was used for molecular docking of all three compounds against D2- and D3- dopamine receptors. The pharmacokinetics (PKs) and toxicity profile were predicted by pkCSM, and the pharmacological activity was predicted by PASS analysis. Molecular docking showed a higher binding affinity of Harmine and Harmaline as compared to L-DOPA, and these results were supported by in-silico pharmacokinetic and toxicity profiling. Moreover, PASS analysis showed anti-PD activity of Harmine and Harmaline. Harmine and Harmaline exhibit higher binding affinity towards D2- and D3- dopamine receptors compared to L-DOPA, and PKs and toxicity profile support their potential as drug candidates for PD therapy.

Neuroprotective Effect of Intrastriatal Caffeic Acid Phenethyl Ester Treatment in 6-OH Dopamine Model of Parkinson's Disease in Rats.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the main cause of PD is still not known. Until now, no cure for Parkinson's disease is yet in sight. Caffeic acid phenethyl ester (CAPE) is a polyphenolic component of the propolis, which can be derived from honeybee hive propolis. We aimed to determine the effect of intrastriatal CAPE administration as a neuroprotective agent on 6-hydroxydopamine (6-OHDA)-induced PD model. Adult male Wistar rats weighing 280–320 g were used. The PD model was induced with unilateral intrastriatal 6-OHDA injection. Treatment groups received 20 μmol/5 μL/4 day and 80 μmol/5 μL/4 day CAPE 24 h after 6-OHDA injection. Eight days after 6-OHDA application, behavioral studies (adhesive tape removal test, open-field test, cylinder test, and apomorphine-induced asymmetric rotational behavior) were performed once more to compare the effects of CAPE on behavior tests. Striatal histological verifications, immunohistochemistry, and stereological quantitation were performed. Our results for the first time showed that, besides improving the motor performance, CAPE treatment also prevents 6-OHDA-induced loss of TH-positive neurons. From our results, CAPE may be a promising clinical agent in the treatment of PD.

Corrective effects of benzodiazepine derivative – diazepinone on purine and lipid metabolism in the liver of rats with Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The cause of PD is not fully understood, and effective treatments still do not exist. It is believed that oxidative stress, mitochondrial dysfunction, and impaired lipid metabolism may underlie the pathogenesis of PD. Bile contains the breakdown products of various compounds that form in hepatocytes. This study aimed to evaluate the effect of a new benzodiazepine derivative - diazepinone (DP) on purine and lipid metabolism in the liver of rats with PD caused by rotenone (ROT) by studying the composition of bile. The concentration of ATP, ADP, AMP, xanthine, hypoxanthine, phospholipids (PL), cholesterol (CHOL), cholesterol esters (ECHOL), free fatty acids (FFA), and triglycerides (TG) was quantified in bile samples by thin-layer chromatography. Our findings suggested that the ratio of AMP/ ATP in bile increased almost threefold under the influence of ROT, and with DP, it exceeded the norm by only 1.6 times. ROT also increased the content of xanthine and hypoxanthine by 28.6% and 66.7%, respectively. DP did not affect the increased xanthine content relative to control but significantly reduced the level of hypoxanthine (up to 22.2%, above normal). In addition, ROT reduced the content of bile PL, CHOL, ECHOL, TG by 23.9%, 38.6%, 47.5%, 39.2 %, respectively. Under the influence of the DP, all the above indicators returned to the level of control. Thus, diazepinone improves both the metabolism of purines and lipids in the liver of rats with ROT-simulated PD. This drug may become a therapeutic agent for treating PD and possibly other neurodegenerative diseases in the future.

The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

Review on Parkinson’s Disease, a Neurodegenerative Disorder and The Role of Ceruloplasmin Protein in It

Parkinson’s disease (PD), a neurodegenerative disease is becoming major health concern mainly for elder people of age over 60 years. The main cause of PD is permanent loss/death of dopaminergic nerve cells present in brain part called substantia nigra, which is responsible for dopamine synthesis. MAO-B, monoamine oxidase B, regulates dopamine metabolism and increased activity of MAO-B causes dopamine degradation which in turn promotes the accumulation of glutamate and oxidative stress with free radical liberation. Several factors like oxidative stress, free radical formation, increased cholesterol, mitochondrial dysfunction, nitric oxide toxicity, signal-mediated apoptosis, head trauma, and environmental toxins and gene mutations like VPS35, SNCA, EIF4G1, GBA, CHCHD, LRRK2, PINK1, DNAJC13 and SOD2 are associated with PD. Symptoms of PD include bradykinesia, muscle rigidity, resting tremors, postural instability and shuffling gait, constipation, sleep problems, fatigue, apathy, loss of smell and taste, excessive sweating, frequent nightmares, dream enacting behaviour, anxiety, depression, daytime drowsiness. In PD, low levels of ceruloplasmin were observed in people with early onset of PD. Ceruloplasmin, a ferroxidase enzyme which is synthesized in liver parenchymal cell, regulates iron metabolism and lower level of which causes iron accumulation in brain which is responsible for the early onset of PD. Levodopa-based preparations, Dopamine agonists, Catechol-o-methyltransferase (COMT) inhibitors, MOA-B inhibitors, Adjunctive therapy, Antiglutamatergics drugs are currently used for the treatment of PD.

Does antiretroviral therapy alter the course of Parkinson's disease in people living with HIV?

South Africa has the world's largest antiretroviral programme which has resulted in an increase in life expectancy in persons living with HIV. Parkinson's disease (PD) is an age-related neurodegenerative disorder. No data has been published in this setting with regards to the interaction between PD and people infected with HIV. This was a retrospective study which matched two HIV non-infected PD patients to one HIV-infected patient with PD. Patients with secondary causes of Parkinsonism were excluded. Demographic, clinical and laboratory data were extracted from the charts. Hoehn and Yahr scale was used to assess PD severity. Twenty PD patients were recruited from 1 January 2008 to 31 October 2020 and were diagnosed with HIV for a median of 72 months. The median age at onset of PD was 52 years. All patients were on antiretroviral therapy. There were no statistically significant differences in the levodopa equivalent daily dose, clinical phenotype, impulse control disorders (ICDs) and frequency of a positive family history between the two groups. HIV-infected patients had a higher frequency of dopamine dysregulation syndrome. At the end of follow-up, 3 (15%) PLH-PD had moderate to severe PD compared to 16 (40%) of PD controls. The OR of having moderate to severe PD in HIV non-infected PD patients was 4. Persons living with HIV and Parkinson's disease present with PD symptoms at a younger age, progress slower to a severe stage and respond well to dopaminergic replacement therapy.