Cause Of Parkinsonism Research Articles

Neuroprotective strategies to prevent and treat Parkinson's disease based on its pathophysiological mechanism.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease after Alzheimer's disease. PD exhibits clinical symptoms that include tremors, rigidity, and bradykinesia. Many drugs are available to treat PD, such as, L-dopa, COMT inhibitor, MAO-B inhibitor, and dopamine agonists, but these drugs simply compensate for dopamine loss in PD, and therefore, cannot completely suppress its symptoms or progression. Although the causes of PD are not clearly understood, common pathophysiological pathways, such as, oxidative stress, mitochondrial dysfunction, and neuroinflammation are considered to be etiological factors, and thus, many treatments and interventions have been developed to target these pathophysiological factors. This review describes the neuroprotective strategies devised based on current understanding of the pathophysiological mechanisms of PD.

Olfactory Dysfunction as an Early Biomarker in Parkinson's Disease.

Olfactory dysfunction is common in Parkinson's disease (PD) and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histologic hallmark of PD, in the olfactory bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification, discrimination, detection, and recognition thresholds, memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations. The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD. Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of "pre-motor" PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis.

Vestibulo-ocular reflex abnormality in Parkinson's disease detected by video head impulse test.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by dopaminergic neuronal loss. The underlying cause of PD is unknown. To assess the clinical relevance of vestibular-ocular reflex (VOR) gain in patients with PD, especially those in the early stages. Sixty-three PD patients and 56 control healthy individuals were enrolled in this study between Mar 2015 and Aug 2015. VOR gains were determined by video head impulse test (vHIT) device. Statistical analysis was performed to assess the difference in VOR gains between PD patients and normal people. The relationship of VOR gain with age, duration and severity of disease was also assessed. In the control group, average VOR gain was 0.98±0.09 on the left side and 0.99±0.16 on the right side. No statistically significant difference was observed between the two sides in the control group (P>0.05). In the PD group, average VOR gain was 1.20±0.22 on the left side and 1.23±0.23 on the right side. No statistically significant difference was observed between the two sides in the PD group (P>0.05). There was a significant difference in VOR gain between the PD (both in early and mid-late stages) and the control group (P<0.05). A weak correlation was observed between VOR gain and the motor Unified Parkinson Disease Rating Scale score. No correlation of VOR gain with age, duration of disease or the Hoehn and Yahr Scale score was observed. VOR gains in PD patients were found to be higher than normal, especially in the early stages of the disease. vHIT is a potential tool to determine the VOR gain in PD patients and may help detect PD at an early stage.

Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson's Disease Induced by MPTP.

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. β-caryophyllene (BCP) is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R). Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD.

Non-motor features of Parkinson disease.

Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD.

Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease

Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the cause of PD remains elusive, mitochondrial dysfunction and severe oxidative stress are strongly implicated in the cell death that characterizes the disease. Under oxidative stress, the master regulator of cellular redox status, nuclear factor erythroid 2 related factor 2 (Nrf2), is responsible for activating the transcription of several cytoprotective enzymes, namely glutathione peroxidase (GPx) and heme oxygenase-1 (HO-1). Nrf2 is a promising target to limit reactive oxygen species (ROS)-mediated damage in PD.Here, we show that tauroursodeoxycholic acid (TUDCA) prevents both 1-methyl-4-phenylpyridinium (MPP+)- and α-synuclein-induced oxidative stress, through Nrf2 activation, in SH-SY5Y cells. Additionally, we used C57BL/6 male mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to elucidate the effect of TUDCA in this in vivo model of PD. In vivo, TUDCA treatment increases the expression of Nrf2, Nrf2 stabilizer DJ-1, and Nrf2 downstream target antioxidant enzymes HO-1 and GPx. Moreover, we found that TUDCA enhances GPx activity in the brain.Altogether, our results suggest that TUDCA is a promising agent to limit ROS-mediated damage, in different models of PD acting, at least in part, through modulation of the Nrf2 signaling pathway. Therefore, TUDCA should be considered a promising therapeutic agent to be implemented in PD.

Clinical Application of Brain MRI in the Diagnostic Work-up of Parkinsonism.

Background: Differentiating Parkinson’s disease and atypical parkinsonism on clinical parameters is challenging, especially in early disease courses. This is due to large overlap in symptoms and because the so called red flags, i.e. symptoms indicating atypical parkinsonism, have not (fully) developed. Brain MRI can aid to improve the accuracy and confidence about the diagnosis.Objective and Methods: In the current paper, we discuss when brain MRI should be performed in the diagnostic work-up of parkinsonism, our preferred brain MRI scanning protocol, and the diagnostic value of specific abnormalities.Results and Conclusions: The main purpose of brain MRI is to assess cerebrovascular damage, and to exclude other possible – and sometimes treatable – causes of parkinsonism, such as normal pressure hydrocephalus. Furthermore, brain MRI can support the possible or probable diagnosis of a specific form of atypical parkinsonism.

Beliefs, knowledge and attitudes towards Parkinson's disease among a Xhosa speaking black population in South Africa: A cross-sectional study

IntroductionMany patients with Parkinson's disease (PD) in sub-Saharan Africa (SSA) are thought to be undiagnosed and untreated, leading to poor health outcomes. Increasing rates of diagnosis and treatment, with consequent improvements in the quality of life of people with PD in SSA requires an understanding of how PD is perceived and conceptualized within communities. MethodsA cross-sectional survey was conducted among a group of Xhosa speaking black South Africans. The survey involved the administration of questionnaires on beliefs, knowledge and attitudes about PD to the public, people with PD (PwPD) and traditional healers (THs). Results18% of the participants could identify PD through its symptoms. Mental illness, other diseases, stress, expressing strong emotions, consumption of certain foods or drinks and witchcraft were identified as possible causes of PD. PwPD and THs had a greater knowledge of PD than the public and greater age was a significant predictor of greater knowledge. The public and THs had a greater degree of concern about a range of symptoms of PD compared to PwPD. ConclusionThere is a striking lack of knowledge about PD amongst black South Africans. Almost half the members of the general public interviewed felt that PwPD should not live amongst their community, and a third considered that witchcraft could be a cause of PD. Finding ways to effectively educate members of a community about PD would make it easier for PwPD to adapt to their condition within their communities.

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

Mutations in the mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) cause Parkinson's disease (PD), likely by disrupting PINK1's kinase activity. Although the mechanism(s) underlying how this loss of activity causes degeneration remains unclear, increasing PINK1 activity may therapeutically benefit some forms of PD. However, we must first learn whether restoring PINK1 function prevents degeneration in patients harboring PINK1 mutations, or whether boosting PINK1 function can offer protection in more common causes of PD. To test these hypotheses in preclinical rodent models of PD, we used kinetin triphosphate, a small-molecule that activates both wild-type and mutant forms of PINK1, which affects mitochondrial function and protects neural cells in culture. We chronically fed kinetin, the precursor of kinetin triphosphate, to PINK1-null rats in which PINK1 was reintroduced into their midbrain, and also to rodent models overexpressing α-synuclein. The highest tolerated dose of oral kinetin increased brain levels of kinetin for up to 6 months, without adversely affecting the survival of nigrostriatal dopamine neurons. However, there was no degeneration of midbrain dopamine neurons lacking PINK1, which precluded an assessment of neuroprotection and raised questions about the robustness of the PINK1 KO rat model of PD. In two rodent models of α-synuclein-induced toxicity, boosting PINK1 activity with oral kinetin provided no protective effects. Our results suggest that oral kinetin is unlikely to protect against α-synuclein toxicity, and thus fail to provide evidence that kinetin will protect in sporadic models of PD. Kinetin may protect in cases of PINK1 deficiency, but this possibility requires a more robust PINK1 KO model that can be validated by proof-of-principle genetic correction in adult animals.

Beyond Mitophagy: The Diversity and Complexity of Parkin Function.

Parkin is an E3 ubiquitin ligase that mediates mitochondrial autophagy, or mitophagy, in multiple cell types. Although discovered in the context of Parkinson disease, Parkin is also an important regulator of mitophagy in the heart. In addition, while most current work is focused on the role of Parkin in mitophagy, accumulating evidence suggests that Parkin also impacts cellular physiology and function through additional processes. This Viewpoint discusses current controversies on the functional role of Parkin-mediated mitophagy and emerging evidence that Parkin regulates several additional pathways. Ubiquitylation is a post-translational modification that involves covalently attaching ubiquitin to target proteins.1 The process of ubquitylation requires a series of events including ubiquitin activation, conjugation, and ligation, catalyzed by E1, E2, and E3 enzymes, respectively. Parkin is one of >500 E3 ubiquitin ligases encoded by the human genome that selectively bestows ubiquitin molecules onto particular proteins. One of Parkin’s most widely appreciated roles is the ubiquitylation of proteins on the membrane of damaged mitochondria to designate them for clearance via mitophagy. Mitophagy is a selective form of macroautophagy that traffics damaged mitochondria to lysosomes for degradation and serves as a critical mechanism in maintaining the health of the mitochondrial collective in a cell. Although it is clear that mutations that impair Parkin’s E3 ligase function contribute to the attrition of dopaminergic neurons through cell death in Parkinson disease,2 the underlying mechanisms are still not fully understood and there is no direct evidence that a defect in mitophagy is the underlying cause of Parkinson disease. The assumption that faulty mitophagy is responsible for Parkinson disease stems from observations that defects in mitochondrial morphology and function are key features of Parkinson disease2 and that loss of Parkin in Drosophila leads to mitochondrial dysfunction and muscle degeneration.3 When combined with the seminal work …

TMEM230 in Parkinson's disease

A study on familial Parkinson disease (PD) described 4 variants in the gene TMEM230 (Chr. 20p13) as the cause of PD. The aim of this study was to test if variants in the TMEM230 gene are associated with PD in 2 independent American European data sets. No variants in the TMEM230 region were found associated with PD, age at onset, or cerebrospinal fluid α-synuclein levels.

Pathologic correlates of supranuclear gaze palsy with parkinsonism

IntroductionSupranuclear gaze palsy (SGP) is a classic clinical feature of progressive supranuclear palsy (PSP) but is not specific for this diagnosis and has been reported to occur in several other neurodegenerative parkinsonian conditions. Our objective was to evaluate the association between SGP and autopsy-proven diagnoses in a large population of patients with parkinsonism referred to a tertiary movement disorders clinic. MethodsWe reviewed clinical and autopsy data maintained in an electronic medical record from all patients seen in the Movement Disorders Clinic at Washington University, St. Louis between 1996 and 2015. All patients with parkinsonism from this population who had subsequent autopsy confirmation of diagnosis underwent further analysis. Results221 unique parkinsonian patients had autopsy-proven diagnoses, 27 of whom had SGP documented at some point during their illness. Major diagnoses associated with SGP were: PSP (9 patients), Parkinson disease (PD) (10 patients), multiple system atrophy (2 patients), corticobasal degeneration (2 patients), Creutzfeld-Jakob disease (1 patient) and Huntington disease (1 patient). In none of the diagnostic groups was the age of onset or disease duration significantly different between cases with SGP and those without SGP. In the PD patients, the UPDRS motor score differed significantly between groups (p = 0.01) with the PD/SGP patients having greater motor deficit than those without SGP. ConclusionAlthough a common feature of PSP, SGP is not diagnostic for this condition and can be associated with other neurodegenerative causes of parkinsonism including PD.

Tremor analysis separates Parkinson's disease and dopamine receptor blockers induced parkinsonism.

Parkinson's disease, the most common cause of parkinsonism is often difficult to distinguish from its second most common etiology due to exposure to dopamine receptor blocking agents such as antiemetics and neuroleptics. Dual axis accelerometry was used to quantify tremor in 158 patients with parkinsonism; 62 had Parkinson's disease and 96 were clinically diagnosed with dopamine receptor blocking agent-induced parkinsonism. Tremor was measured while subjects rested arms (resting tremor), outstretched arms in front (postural tremor), and reached a target (kinetic tremor). Cycle-by-cycle analysis was performed to measure cycle duration, oscillation amplitude, and inter-cycle variations in the frequency. Patients with dopamine receptor blocker induced parkinsonism had lower resting and postural tremor amplitude. There was a substantial increase of kinetic tremor amplitude in both disorders. Postural and resting tremor in subjects with dopamine receptor blocking agent-induced parkinsonism was prominent in the abduction-adduction plane. In contrast, the Parkinson's disease tremor had equal amplitude in all three planes of motion. Tremor frequency was comparable in both groups. Remarkable variability in the width of the oscillatory cycles suggested irregularity in the oscillatory waveforms in both subtypes of parkinsonism. Quantitative tremor analysis can distinguish Parkinson's disease from dopamine receptor blocking agent-induced parkinsonism.

Candidate novel long noncoding RNAs, MicroRNAs and putative drugs for Parkinson's disease using a robust and efficient genome-wide association study

Parkinson's disease (PD) is a neurodegenerative disorder with serious symptoms of which, are not clearly demonstrated at the beginning stages of the disease, making treatment challenging. Understanding the genetic causes of PD can be useful for determining its mechanisms and proposing treatments and preventive methods. For different populations with different genetic backgrounds and lifestyles, genome-wide association studies (GWASs) represent a crucial approach for genetic analysis. In this study, a robust and efficient GWAS without dimensionality reduction applied to evaluate heritability and genetic causes of PD in the German and US populations. The results show higher rate of PD heritability in the German population. Moreover, 25 significant SNPs have been determined, as well as five newly identified candidate genes associated with PD and some potential drug candidates. Analysis also reveals various long noncoding RNAs (lncRNAs), microRNAs and transcription-factor binding sites (TFBSs) with potential in the prevention and treatment of PD.

Epidemiology of Parkinson's disease.

Parkinson's disease (PD) affects 1-2 per 1000 of the population at any time. PD prevalence is increasing with age and PD affects 1% of the population above 60years. The main neuropathological finding is α-synuclein-containing Lewy bodies and loss of dopaminergic neurons in the substantia nigra, manifesting as reduced facilitation of voluntary movements. With progression of PD, Lewy body pathology spreads to neocortical and cortical regions. PD is regarded as a movement disorder with three cardinal signs: tremor, rigidity and bradykinesia. A recent revision of the diagnostic criteria excludes postural instability as a fourth hallmark and defines supportive criteria, absolute exclusion criteria and red flags. Non-motor symptoms in PD have gained increasing attention and both motor and non-motor signs are now included among the supportive criteria. The cause of PD is unknown in most cases. Genetic risk factors have been identified, including monogenetic causes that are rare in unselected populations. Some genetic factor can be identified in 5-10% of the patients. Several environmental factors are associated with increased risk of PD. Autopsy studies show that the clinical diagnosis of PD is not confirmed at autopsy in a significant proportion of patients. Revised diagnostic criteria are expected to improve the clinician´s accuracy in diagnosing PD. Increasing knowledge on genetic and environmental risk factors of PD will probably elucidate the cause of this disease within the near future.

Pyrazinamide Induced Parkinsonism

“Parkinsonism” refers to a syndrome characterized by the presence of tremor, rigidity and bradykinesia. In addition there is loss of postural reflexes as well as freezing. Drugs rank the second in the causes of parkinsonism. As it is reversible, drug-induced parkinsonism (Rabbit syndrome) should be borne in mind and suspected in any patient receiving drug treatment. We report a case of drug induced parkinsonism, evidently due to pyrazinamide. To the best of our knowledge, this is the first case to be reported in our country.J MEDICINE January 2017; 18 (1) : 42-43

RIC3 variants are not associated with Parkinson's disease in French-Canadians and French

Variants in the RIC3 gene have recently been suggested as a novel cause of Parkinson's disease (PD). Herein, the entire RIC3 gene was sequenced in a French-Canadian and French sample series of 535 PD patients and 527 unaffected controls. The effect of single variants and the combined effect of variants were calculated. Sequence Kernel association tests (SKAT, SKAT-O) were done on the entire gene level, and on the different domains and exons of RIC3. A total of 28 common and rare variants were identified in patients and controls. No significant association was found between any variant and haplotype in RIC3 and PD, and there was no over-representation of RIC3 variants at the entire gene, domain, or exon levels in patients versus controls. Our results do not support a role for RIC3 mutations as a common cause of PD in the French-Canadian and French populations.

Genetic analysis of CHCHD2 and CHCHD10 in Italian patients with Parkinson's disease

In recent years, CHCHD2 and CHCHD10 mutations were reported to be associated with a broad spectrum of neurodegenerative diseases, including Parkinson's disease (PD), although with conflicting results in different populations. The present study aimed to evaluate CHCHD2 and CHCHD10 coding variants in Italian patients with PD. All the coding regions and flanking intronic splice sites of CHCHD2 and CHCHD10 were sequenced. None of our 119 PD cases carried CHCHD2 mutations, whereas 1 sporadic PD patient showed the Pro34Ser substitution in CHCHD10. Our data suggest that CHCHD2 and CHCDH10 mutations are not a relevant cause of PD in Italian population.

Neurological Deficits After Long-term Pyrethroid Exposure

Pyrethroid pesticides have been suggested to be a cause of Parkinson disease and other neurodegenerative diseases. To investigate this, a cross-sectional study was conducted among 120 Bolivian public health vector program spray men, primarily exposed to pyrethroids. Pesticide exposure and central nervous system (CNS) symptoms were determined by a structured interview, whereas neuromotor and neurocognitive performance was assessed using the computerized Behavioral Assessment and Research System and CATSYS system. Individuals exposed to higher levels reported significantly more CNS symptoms (adjusted odds ratio per quintile of cumulative exposure = 2.01 [1.22-3.31]). There was no association seen between pyrethroid exposure and neuromotor performance. Higher spraying intensity was associated with significantly worse neurocognitive performance in structural equation models (adjusted β per quintile = −0.405 [−0.660 to −0.150]), and workers only exposed to pyrethroids performed worse than workers also exposed to other pesticides (adjusted β = −1.344 [−2.224 to −0.464]). Chronic pyrethroid exposure may cause deterioration in neurocognitive performance, and exposure control is recommended.

MicroRNAs in Parkinson's disease and emerging therapeutic targets

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons. Oxidative stress is also recognized as one of the main causes of PD, and excessive reactive oxygen species (ROS) and reactive nitrogen species can lead to dopaminergic neuron vulnerability and eventual death. MicroRNAs control a range of physiological and pathological functions, and may serve as potential targets for intervention against PD to mitigate damage to the brain. Several studies have demonstrated that microRNAs can regulate oxidative stress and prevent ROS-mediated damage to dopaminergic neurons, suggesting that specific microRNAs may be putative targets for novel therapeutic strategies in PD. Recent human and animal studies have identified a large number of dysregulated microRNAs in PD brain tissue samples, many of which were downregulated. The dysregulated microRNAs affect downstream targets such as SNCA, PARK2, LRRK2, TNFSF13B, LTA, SLC5A3, PSMB2, GSR, GBA, LAMP-2A, HSC. Apart from one study, none of the studies reviewed had used agomirs or antagomirs to reverse the levels of downregulated or upregulated microRNAs, respectively, in mouse models of PD or with isolated human or mouse dopaminergic cells. Further large-scale studies of brain tissue samples collected with short postmortem interval from human PD patients are warranted to provide more information on the microRNA profiles in different brain regions and to test for gender differences.