Cause Of Parkinsonism Research Articles

G67(P) Childhood parkinsonism: a rare complication of hypoxic brain injury

<h3>Case report</h3> Child A is a 13-year old boy with a history of poor adherence to his asthma treatment. He was admitted to hospital with an acute severe exacerbation of asthma, which needed escalation of treatment to intravenous bronchodilators. Despite intensive treatment, he went on to have a cardio-respiratory arrest, necessitating five minutes of cardiopulmonary resuscitation and adrenaline prior to return of his circulation. Child A spent a week on PICU, after which he underwent neurological rehabilitation on the ward, involving a multidisciplinary team. MRI of his brain confirmed severe hypoxic brain injury with infarction within the basal ganglia and occipital lobe (Figure 1). Similar to other children with acquired brain injury, he demonstrated 4-limb spasticity, as well as dystonic posturing. In addition to this, he also displayed Parkinsonian features, which is a rare complication of brain injury. He had a resting tremor, bradykinesia, rigidity and a shuffling gait, with difficulty in turning around. He displayed hypomimic facies, along with a monotonous speech. The above symptoms responded well to co-careldopa. <h3>Discussion</h3> Poor compliance with asthma medication in children remains a significant problem with major health implications. Our case sustained a severe brain injury as a result of this. Unlike in adults where Parkinsonism is common, this condition is rare in children and easy to miss. The commonest cause of Parkinsonism is the loss of dopaminergic neurones in the substantia niagra of the basal ganglia. Child A’s symptoms resolved with co-careldopa which increases dopamine levels in the brain. We have not come across a similar paediatric case during our literature review. Paediatricians need to be vigilant to identify Parkinsonian features in children with brain injury. These typical signs become apparent to the clinician who is clearly looking out for them. Making this diagnosis correctly is important so that we can prescribe a specific anti-Parkinsonian medication, rather than make the child go through repeated failed trials with incorrect drugs. There are different classes of medication for Parkinsonism and treatment choices are largely based on data from adults. Recognising this movement disorder is hence vital to support the rehabilitation process and optimise recovery.

DJ-1-dependent protective activity of DJ-1-binding compound no. 23 against neuronal cell death in MPTP-treated mouse model of Parkinson's disease

Parkinson's disease (PD) is caused by dopaminergic cell death in the substantia nigra, leading to a reduced level of dopamine in the striatum. Oxidative stress is one of the causes of PD. Since symptomatic PD therapies are used, identification of compounds or proteins that inhibit oxidative stress-induced neuronal cell death is necessary. DJ-1 is a causative gene product of familial PD and plays a role in anti-oxidative stress reaction. We have identified various DJ-1-binding compounds, including compound-23, that restored neuronal cell death and locomotion defects observed in neurotoxin-induced PD models. In this study, wild-type and DJ-1-knockout mice were injected intraperitoneally with 1 mg/kg of compound-23 and then with 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 1 h after injection. Five days after administration, the effects of compound-23 on MPTP-induced locomotion deficits, on dopaminergic cell death and on brain dopamine levels were analyzed by rotor rod tests, by staining cells with an anti-TH antibody and by an HPLC, respectively. The results showed that compound-23 inhibited MPTP-induced reduction of retention time on the rotor rod bar, neuronal cell death in the substantia nigra and striatum and dopamine content in wild-type mice but not in DJ-1-knockout mice, indicating a DJ-1-dependent effect of compound-23.

New roles of glycosaminoglycans in α-synuclein aggregation in a cellular model of Parkinson disease.

The causes of Parkinson disease (PD) remain mysterious, although some evidence supports mitochondrial dysfunctions and α-synuclein accumulation in Lewy bodies as major events. The abnormal accumulation of α-synuclein has been associated with a deficiency in the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Cathepsin D (cathD), the major lysosomal protease responsible of α-synuclein degradation was described to be up-regulated in PD model. As glycosaminoglycans (GAGs) regulate cathD activity, and have been recently suggested to participate in PD physiopathology, we investigated their role in α-synuclein accumulation by their intracellular regulation of cathD activity. In a classical neuroblastoma cell model of PD induced by MPP+, the genetic expression of GAGs-biosynthetic enzymes was modified, leading to an increase of GAGs amounts whereas intracellular level of α-synuclein increased. The absence of sulfated GAGs increased intracellular cathD activity and limited α-synuclein accumulation. GAGs effects on cathD further suggested that specific sequences or sulfation patterns could be responsible for this regulation. The present study identifies, for the first time, GAGs as new regulators of the lysosome degradation pathway, regulating cathD activity and affecting two main biological processes, α-synuclein aggregation and apoptosis. Finally, this opens new insights into intracellular GAGs functions and new fields of investigation for glycobiological approaches in PD and neurobiology.

Knowledge and Attitudes of Parkinson's Disease in Rural and Urban Mukono District, Uganda: A Cross-Sectional, Community-Based Study.

Background. Parkinson's disease (PD) negatively affects the quality of life. There is limited information on PD published from Africa. Lack of adequate knowledge poses a barrier in the provision of appropriate treatment and care for individuals with PD. Methods. A cross-sectional survey was conducted in urban and rural Mukono district, central Uganda. Through the systematic sampling method, data were gathered from 377 adult participants, interviewed on selected aspects of PD knowledge and attitudes. Results. Of the 377 participants, 47% were from urban settings and 68% (260/377) were women with a median age (IQR) of 34 (26–48) years. Half of the study respondents did not know the body part involved in or apparent cause of PD. Nearly 1/3 of individuals believed that PD is a form of insanity and 17% believed that PD is contagious. Rural dwellers were more likely to have incorrect knowledge regarding selected aspects of PD. Conclusions. Understanding the cause of PD is very limited in our setting. Some beliefs about PD aetiology may potentially worsen stigma and social isolation. This study highlights the need for increasing PD awareness in our settings. Public health approaches that improve knowledge are urgently needed to promote care access and community response to Parkinson's disease.

Evaluating rehabilitation interventions in Parkinson's disease with functional MRI: a promising neuroprotective strategy.

Evaluating rehabilitation interventions in Parkinson's disease with functional MRI: a promising neuroprotective strategy.

Methcathinone "Kitchen Chemistry" and Permanent Neurological Damage.

Methcathinone abuse is a significant cause of parkinsonism among young patients in the Eastern European countries. The drug is synthesized from over-the-counter cold remedies containing ephedrine or pseudoephedrine. The final mixture contains a high concentration of manganese if potassium permanganate is used as the oxidant agent. Though manganese is an essential trace element and its homeostasis is well maintained, exposure to a high level of manganese is neurotoxic. The use of manganese-contaminated methcathinone may cause permanent neurological damage and severe disability. Drug users develop a distinctive extrapyramidal syndrome that resembles classic manganese intoxication. Methcathinone could have additive neurotoxic effect to the progression of parkinsonism. The most prevalent symptoms are symmetrical bradykinesia, dystonias, and early postural, gait, and speech impairment. After cessation of exposure, the syndrome is generally irreversible and can even progress.

Chapter 13 - Extrapyramidal system neurotoxicity: animal models

The central nervous system's extrapyramidal system provides involuntary motor control to the muscles of the head, neck, and limbs. Toxicants that affect the extrapyramidal system are generally clinically characterized by impaired motor control, which is usually the result of basal ganglionic dysfunction. A variety of extrapyramidal syndromes are recognized in humans and include Parkinson's disease, secondary parkinsonism, other degenerative diseases of the basal ganglia, and clinical syndromes that result in dystonia, dyskinesia, essential tremor, and other forms of tremor and chorea. This chapter briefly reviews the anatomy of the extrapyramidal system and discusses several naturally occurring and experimental models that target the mammalian (nonhuman) extrapyramidal system. Topics discussed include extrapyramidal syndromes associated with antipsychotic drugs, carbon monoxide, reserpine, cyanide, rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and manganese. In most cases, animals are used as experimental models to improve our understanding of the toxicity and pathogenesis of these agents. Another agent discussed in this chapter, yellowstar thistle poisoning in horses, however, represents an important spontaneous cause of parkinsonism that naturally occurs in animals. The central focus of the chapter is on animal models, especially the concordance between clinical signs, neurochemical changes, and neuropathology between animals and people.

The causative gene of Parkinsonism and its medical treatment strategy

Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The neurodegenerative condition of Parkinson's disease (PD) is the most common cause of parkinsonism. PD is classified as sporadic PD and familial PD. Whereas idiopathic PD is caused by a number of complex factors, familial PD is a result of mutations in PD-associated genes. Unraveling the mechanisms surrounding familial PD will offer pivotal clues in understanding etiology of not only familial PD but also sporadic PD. We have demonstrated neuroprotective effects with particular focus on DJ-1. On the other hand, idiopathic basal ganglia calcification, also known as Fahr disease (FD) is another condition characterized by parkinsonism. In 2012, solute carrier family 20A2 (SLC20A2) was identified as the causative gene for familial FD. Our analysis of patient samples revealed a novel mutation in SLC20A2. Type-III sodium-dependent phosphate transporter 2 (PiT-2), the protein encoded by SLC20A2, plays an important role in phosphate homeostasis. However, PiT-2's role in the pathology of FD remains largely unclear. We have established induced pluripotent stem (iPS) cells from FD patients and are investigating their usefulness in drug development. Here, we present some of our latest research findings.

Dopamine transporter imaging as a diagnostic tool for parkinsonism and related disorders in clinical practice.

Accurate diagnosis of Parkinson disease (PD) and other degenerative parkinsonian syndromes is important for management and prognostic purposes. Diagnosis can be challenging in early disease and in atypical cases. We reviewed the literature on the application of dopamine transporter single-photon emission computed tomography (DAT-SPECT) in degenerative parkinsonism and related disorders as a diagnostic tool. The use of DAT-SPECT shows some utility in the early diagnosis of PD and differentiation from other non-degenerative parkinsonian disorders (i.e. essential tremor, dystonic tremor, drug-induced and in most cases of psychogenic parkinsonism), since it can accurately detect the presynaptic dopaminergic deficit. The test has been shown to have high sensitivity/specificity by multiple studies. DAT imaging may also have some prognostic value for disease progression. However, it has limited value in differentiating among degenerative causes of parkinsonism. DAT imaging has some limitations. In most studies, true test accuracy is unknown since the gold standard is clinical diagnosis by a movement disorders neurologist. Therefore, the sensitivity of the test cannot exceed that of the clinical diagnosis. In addition, false negative scans occur and highlight the need for clinical follow-up. Clinical assessment remains the most important aspect in evaluating these patients. DAT-SPECT is a sensitive modality to detect nigrostriatal degeneration. In spite of increasing data using this technique, however, more long-term clinical studies are required to determine how DAT-SPECT scan can guide decision-making.

Neuroimaging in Parkinson disease: from research setting to clinical practice.

Over the past three decades, neuroimaging studies-including structural, functional and molecular modalities-have provided invaluable insights into the mechanisms underlying Parkinson disease (PD). Observations from multimodal neuroimaging techniques have indicated changes in brain structure and metabolic activity, and an array of neurochemical changes that affect receptor sites and neurotransmitter systems. Characterization of the neurobiological alterations that lead to phenotypic heterogeneity in patients with PD has considerably aided the in vivo investigation of aetiology and pathophysiology, and the identification of novel targets for pharmacological or surgical treatments, including cell therapy. Although PD is now considered to be very complex, no neuroimaging modalities are specifically recommended for routine use in clinical practice. However, conventional MRI and dopamine transporter imaging are commonly used as adjuvant tools in the differential diagnosis between PD and nondegenerative causes of parkinsonism. First-line neuroimaging tools that could have an impact on patient prognosis and treatment strategies remain elusive. This Review discusses the lessons learnt from decades of neuroimaging research in PD, and the promising new approaches with potential applicability to clinical practice.

Phosphatases of α-synuclein, LRRK2, and tau: important players in the phosphorylation-dependent pathology of Parkinsonism.

An important challenge in the field of Parkinson’s disease (PD) is to develop disease modifying therapies capable of stalling or even halting disease progression. Coupled to this challenge is the need to identify disease biomarkers, in order to identify pre-symptomatic hallmarks of disease and monitor disease progression. The answer to these challenges lies in the elucidation of the molecular causes underlying PD, for which important leads are disease genes identified in studies investigating the underlying genetic causes of PD. LRRK2 and α-syn have been both linked to familial forms of PD as well as associated to sporadic PD. Another gene, microtubule associated protein tau (MAPT), has been genetically linked to a dominant form of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and genome-wide association studies report a strong association between MAPT and sporadic PD. Interestingly, LRRK2, α-syn, and tau are all phosphorylated proteins, and their phosphorylation patterns are linked to disease. In this review, we provide an overview of the evidence linking LRRK2, α-syn, and tau phosphorylation to PD pathology and focus on studies which have identified phosphatases responsible for dephosphorylation of pathology-related phosphorylations. We also discuss how the LRRK2, α-syn, and tau phosphatases may point to separate or cross-talking pathological pathways in PD. Finally, we will discuss how the study of phosphatases of dominant Parkinsonism proteins opens perspectives for targeting pathological phosphorylation events.

Analysis of Parkinson's disease pathophysiology using an integrated genomics-bioinformatics approach

The pathogenesis and pathophysiology of a disease determine how it should be diagnosed and treated. Yet, understanding the cause and mechanisms of progression often requires intensive human efforts, especially for diseases with complex etiology. The latest genomic technology coupled with advanced, large-scale data analysis in the field known as bioinformatics has promised a high-throughput approach that can quickly identify disease-affected genes and pathways by examining tissue samples collected from patients and control subjects. Furthermore, significant biological themes indicative of genomic events can be recognized on the basis of affected genes. However, given identified biological themes, it is not clear how to organize genomic events to arrive at a coherent pathophysiological explanation about the disease. To address this important issue, we have developed an innovative method named “Expression Data Up-Stream Analysis” (EDUSA) that can perform a bioinformatics analysis to identify and rank upstream processes effectively. We applied it to Parkinson's disease (PD) using a genomic data set available at a public data repository known as Gene Expression Omnibus (GEO). In this study, disease-affected genes were identified using GEO2R software, and disease-pertinent processes were identified using EASE software. Then the EDUSA program was used to determine the upstream versus downstream hierarchy of the processes. The results confirmed the current misfolded protein theory about the pathogenesis of PD, and provided new insights as well. Particularly, our program discovered that RNA (ribonucleic acid) metabolism pathology was a potential cause of PD, which in fact, is an emerging theory of neurodegenerative disorders. In addition, it was found that the dysfunction of the transport system seemed to occur in the early phase of neurodegeneration, whereas mitochondrial dysfunction appeared at a later stage. Using this methodology, we have demonstrated how to determine the stages of disease development with single-point data collection.

Woman With X-Linked Recessive Dystonia-Parkinsonism

Despite recessive inheritance, X-linked dystonia-parkinsonism (Lubag disease) has also been described in women presenting with a late-onset isolated parkinsonian syndrome. Interestingly, unlike in other populations, there is a slight female predominance in the prevalence of parkinsonism in the Philippines. In a Filipino woman with suspected Parkinson disease, we confirmed the presence of all changes specific for X-linked dystonia-parkinsonism in genomic DNA. Subsequently, we analyzed complementary DNA and evaluated the methylation status of the androgen receptor gene. Owing to extremely skewed (98%:2%) X-chromosome inactivation, the patient expressed almost solely the mutated allele in a disease-specific change, rendering her molecularly comparable with a hemizygously affected man. Skewed X-chromosome inactivation is the likely cause of parkinsonism in this heterozygous mutation carrier. Because women carriers of the genetic changes specific for X-linked dystonia-parkinsonism are common in the Philippines, the epigenetic factor of nonrandom X-chromosome inactivation may contribute to the skewing of the sex prevalence of parkinsonism toward women in this country, warranting further investigation.

Genetic analysis of SNCA coding mutation in Chinese Han patients with Parkinson disease.

Parkinson disease (PD) is the second most common progressive neurodegenerative disorder. It is characterized by selective loss of dopamine-producing neurons and aggregation of alpha-synuclein (SNCA) in neurons of particular brain regions. At least 20 loci and 15 disease-causing genes have been identified. Rare missense or multiplication mutations in the SNCA gene have been reported to be involved in some familial and sporadic cases of PD. More recently, two novel pathogenic missense mutations (p.H50Q and p.G51D) were identified in the SNCA gene. To evaluate whether mutation(s) in the coding region of SNCA gene is related to PD in Chinese population, we investigated the SNCA gene in 502 PD patients of Chinese Han ethnicity from Mainland China. No pathogenic mutation was identified in the coding region of the gene. A known G to A transition (c.306 + 66G>A, rs10005233) in the intron 4, which does not potentially change splicing, was identified. Our data indicate that mutations in the coding region of the SNCA gene are not likely to be a common cause of PD in Chinese population.

Arsenite Stress Down-regulates Phosphorylation and 14-3-3 Binding of Leucine-rich Repeat Kinase 2 (LRRK2), Promoting Self-association and Cellular Redistribution

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson disease, but the mechanisms whereby LRRK2 is regulated are unknown. Phosphorylation of LRRK2 at Ser(910)/Ser(935) mediates interaction with 14-3-3. Pharmacological inhibition of its kinase activity abolishes Ser(910)/Ser(935) phosphorylation and 14-3-3 binding, and this effect is also mimicked by pathogenic mutations. However, physiological situations where dephosphorylation occurs have not been defined. Here, we show that arsenite or H2O2-induced stresses promote loss of Ser(910)/Ser(935) phosphorylation, which is reversed by phosphatase inhibition. Arsenite-induced dephosphorylation is accompanied by loss of 14-3-3 binding and is observed in wild type, G2019S, and kinase-dead D2017A LRRK2. Arsenite stress stimulates LRRK2 self-association and association with protein phosphatase 1α, decreases kinase activity and GTP binding in vitro, and induces translocation of LRRK2 to centrosomes. Our data indicate that signaling events induced by arsenite and oxidative stress may regulate LRRK2 function.

Postencephalitic Parkinsonism in a Patient with Mumps Infection: A Case Report

In 1917, Von Economo described a disease named Encephalitis Lethargica which affected a large number of patients across the world in an epidemic between 1916 and 1927. It's spread paralleled with the spread of the pandemic influenza, but Von Economo and the contemporary authors did not believe it to be a post-influenzal sequela. Now parkinsonism is a well-known complication of acute infectious encephalitis. There are many potential infectious causes of parkinsonism reported in literature. In India, postencephalitic parkinsonism is commonly due to Japanese Encephalitis. Neurologic manifestations reported in Mumps include meningitis, encephalitis, deafness, facial neuritis, cerebellar ataxia, hydrocephalus, transverse myelitis and polyradiculitis. We describe a case of young girl who had Mumps parotitis and encephalitis and then subsequently developed parkinsonism as a sequela. Mumps was confirmed by positive serology and basal ganglia lesions were demonstrated by magnetic resonance imaging of the brain. To the best of our knowledge, this is the first case of postencephalitic parkinsonism following Mumps infection from India.

Parkinsonism and inborn errors of metabolism.

Parkinsonism is a frequent neurological syndrome in adulthood but is very rare in childhood. Early forms of Parkinsonism have many distinctive features as compared to Parkinsonism in adults. In fact, rather than Parkinsonism, the general concept "hypokinetic-rigid syndrome" (HRS) is more accurate in children. In general, the terms "dystonia-parkinsonism", "parkinsonism-plus", or "parkinsonism-like" are preferred to designate these forms of paediatric HRS. Inborn errors of metabolism (IEM) constitute an important group amongst the genetic causes of Parkinsonism at any age. The main IEM causing Parkinsonism are metal-storage diseases, neurotransmitter defects, lysosomal storage disorders and energy metabolism defects. IEM should not be neglected as many of them represent treatable causes of Parkinsonism. Here we review IEMs causing this neurological syndrome and propose diagnostic approaches depending on the age of onset and the associated clinical and neuroimaging features.

Differentiating drug-induced parkinsonism from Parkinson's disease: an update on non-motor symptoms and investigations.

Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management and prognosis. However, differentiating between these conditions can be challenging on a clinical ground, especially in the early stages. We therefore performed a review to ascertain whether assessment of non-motor symptoms, or use of ancillary investigations, namely dopamine transporter imaging, transcranial sonography of the substantia nigra, and scintigraphy for myocardial sympathetic innervation, can be recommended to distinguish between these conditions. Among non-motor symptoms, there is evidence that hyposmia can differentiate between patients with "pure" drug-induced parkinsonism and those with degenerative parkinsonism unmasked by an anti-dopaminergic drug. However, several issues, including smoking history and cognitive functions, can influence smell function assessment. Higher diagnostic accuracy has been demonstrated for dopamine transporter imaging. Finally, preliminary evidence exists for sympathetic cardiac scintigraphy to predict dopaminergic pathway abnormalities and to differentiate between drug-induced parkinsonism and Parkinson's disease. Imaging of the dopaminergic pathway seems to be the only, reasonably available, technique to aid the differential diagnosis between drug-induced parkinsonism and Parkinson's disease.

Deep brain stimulation: a mysterious success or a clue to help localize the causes of Parkinsonism?

Deep brain stimulation: a mysterious success or a clue to help localize the causes of Parkinsonism?

Lack of C9orf72 Repeat Expansion in Taiwanese Patients with Mixed Neurodegenerative Disorders

Background: The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is recognized as the most common genetic cause of frontotemporal dementia (FTD). There are overlapping clinical and pathological characteristics between FTD and Parkinsonism syndrome, and some FTD patients may present with Parkinsonism. The aim of this study was to analyze the hexanucleotide repeat numbers of C9orf72 gene in a mixed Taiwanese cohort with FTD, Parkinsonism syndrome, Parkinson’s disease (PD), and Alzheimer’s dementia (AD).Method: The number of hexanucleotide repeats was estimated in a total of 482 patients with mixed neurodegenerative disorders and 485 control subjects, using a two-step repeat-primed polymerase chain reaction-based genotyping strategy. The individual groups of patients included patients with Parkinsonism syndrome (n = 95), familial PD (n = 109), young-onset PD (n = 201), FTD (n = 9), sporadic AD (n = 61), and early-onset AD (n = 7).Results: We did not identify any pathogenic repeats (>30 repeats) of C9orf72 in either the patients or control subjects. However, we found one young-onset PD patient and one control subject that each had an intermediate number of repeats (25 and 21 repeats, respectively). The clinical phenotype of the young-onset PD in this patient was similar to typical idiopathic PD without additional features, and the patient responded well to levodopa treatment.Conclusion: The repeat expansion in C9orf72 is not a common cause of PD, Parkinsonism syndrome, or dementia in our population. Further studies are needed to investigate the clinical and biological significance of intermediate repeats in C9orf72.