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Fulltext Editorial: Genetic and molecular diversity in Parkinson's disease

Abdul Murad NA, Sulaiman SA, Ahmad-Annuar A, Mohamed Ibrahim N, Mohamed W, Md Rani SA, et al.

Front Aging Neurosci, 2022;14:1094914.
PMID: 36589546 DOI: 10.3389/fnagi.2022.1094914
A Molecular Approach to Epilepsy Management: from Current Therapeutic Methods to Preconditioning Efforts

Amini E, Rezaei M, Mohamed Ibrahim N, Golpich M, Ghasemi R, Mohamed Z, et al.

Mol Neurobiol, 2015 Aug;52(1):492-513.
PMID: 25195699 DOI: 10.1007/s12035-014-8876-5

Epilepsy is the most common and chronic neurological disorder characterized by recurrent unprovoked seizures. The key aim in treating patients with epilepsy is the suppression of seizures. An understanding of focal changes that are involved in epileptogenesis may therefore provide novel approaches for optimal treatment of the seizure. Although the actual pathogenesis of epilepsy is still uncertain, recently growing lines of evidence declare that microglia and astrocyte activation, oxidative stress and reactive oxygen species (ROS) production, mitochondria dysfunction, and damage of blood-brain barrier (BBB) are involved in its pathogenesis. Impaired GABAergic function in the brain is probably the most accepted hypothesis regarding the pathogenesis of epilepsy. Clinical neuroimaging of patients and experimental modeling have demonstrated that seizures may induce neuronal apoptosis. Apoptosis signaling pathways are involved in the pathogenesis of several types of epilepsy such as temporal lobe epilepsy (TLE). The quality of life of patients is seriously affected by treatment-related problems and also by unpredictability of epileptic seizures. Moreover, the available antiepileptic drugs (AED) are not significantly effective to prevent epileptogenesis. Thus, novel therapies that are proficient to control seizure in people who are suffering from epilepsy are needed. The preconditioning method promises to serve as an alternative therapeutic approach because this strategy has demonstrated the capability to curtail epileptogenesis. For this reason, understanding of molecular mechanisms underlying brain tolerance induced by preconditioning is crucial to delineate new neuroprotective ways against seizure damage and epileptogenesis. In this review, we summarize the work to date on the pathogenesis of epilepsy and discuss recent therapeutic strategies in the treatment of epilepsy. We will highlight that novel therapy targeting such as preconditioning process holds great promise. In addition, we will also highlight the role of gene reprogramming and mitochondrial biogenesis in the preconditioning-mediated neuroprotective events.
Fulltext MicroRNAs and Target Genes As Biomarkers for the Diagnosis of Early Onset of Parkinson Disease

Arshad AR, Sulaiman SA, Saperi AA, Jamal R, Mohamed Ibrahim N, Abdul Murad NA

Front Mol Neurosci, 2017;10:352.
PMID: 29163029 DOI: 10.3389/fnmol.2017.00352

Among the neurodegenerative disorders, Parkinson's disease (PD) ranks as the second most common disorder with a higher prevalence in individuals aged over 60 years old. Younger individuals may also be affected with PD which is known as early onset PD (EOPD). Despite similarities between the characteristics of EOPD and late onset PD (LODP), EOPD patients experience much longer disease manifestations and poorer quality of life. Although some individuals are more prone to have EOPD due to certain genetic alterations, the molecular mechanisms that differentiate between EOPD and LOPD remains unclear. Recent findings in PD patients revealed that there were differences in the genetic profiles of PD patients compared to healthy controls, as well as between EOPD and LOPD patients. There were variants identified that correlated with the decline of cognitive and motor symptoms as well as non-motor symptoms in PD. There were also specific microRNAs that correlated with PD progression, and since microRNAs have been shown to be involved in the maintenance of neuronal development, mitochondrial dysfunction and oxidative stress, there is a strong possibility that these microRNAs can be potentially used to differentiate between subsets of PD patients. PD is mainly diagnosed at the late stage, when almost majority of the dopaminergic neurons are lost. Therefore, identification of molecular biomarkers for early detection of PD is important. Given that miRNAs are crucial in controlling the gene expression, these regulatory microRNAs and their target genes could be used as biomarkers for early diagnosis of PD. In this article, we discussed the genes involved and their regulatory miRNAs, regarding their roles in PD progression, based on the findings of significantly altered microRNAs in EOPD studies. We also discussed the potential of these miRNAs as molecular biomarkers for early diagnosis.
Fulltext Aberrant Neurogliovascular Unit Dynamics in Cerebral Small Vessel Disease: A Rheological Clue to Vascular Parkinsonism

Che Mohd Nassir CMN, Damodaran T, Yusof SR, Norazit A, Chilla G, Huen I, et al.

Pharmaceutics, 2021 Aug 05;13(8).
PMID: 34452169 DOI: 10.3390/pharmaceutics13081207

The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood-brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU-a crossroad of the immune-vascular-nervous system-which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets.
Preconditioning as a potential strategy for the prevention of Parkinson's disease

Golpich M, Rahmani B, Mohamed Ibrahim N, Dargahi L, Mohamed Z, Raymond AA, et al.

Mol Neurobiol, 2015 Feb;51(1):313-30.
PMID: 24696268 DOI: 10.1007/s12035-014-8689-6

Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. A numerous of cellular processes including oxidative stress, mitochondrial dysfunction, and accumulation of α-synuclein aggregates are considered to contribute to the pathogenesis of Parkinson's disease. A further understanding of the cellular and molecular mechanisms involved in the pathophysiology of PD is crucial for developing effective diagnostic, preventative, and therapeutic strategies to cure this devastating disorder. Preconditioning (PC) is assumed as a natural adaptive process whereby a subthreshold stimulus can promote protection against a subsequent lethal stimulus in the brain as well as in other tissues that affords robust brain tolerance facing neurodegenerative insults. Multiple lines of evidence have demonstrated that preconditioning as a possible neuroprotective technique may reduce the neural deficits associated with neurodegenerative diseases such as PD. Throughout the last few decades, a lot of efforts have been made to discover the molecular determinants involved in preconditioning-induced protective responses; although, the accurate mechanisms underlying this "tolerance" phenomenon are not fully understood in PD. In this review, we will summarize pathophysiology and current therapeutic approaches in PD and discuss about preconditioning in PD as a potential neuroprotective strategy. Also the role of gene reprogramming and mitochondrial biogenesis involved in the preconditioning-mediated neuroprotective events will be highlighted. Preconditioning may represent a promising therapeutic weapon to combat neurodegeneration.
Fulltext Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment

Golpich M, Amini E, Mohamed Z, Azman Ali R, Mohamed Ibrahim N, Ahmadiani A

CNS Neurosci Ther, 2017 Jan;23(1):5-22.
PMID: 27873462 DOI: 10.1111/cns.12655

Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological-based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.
Fulltext The multifaceted impact of structured training program on persons with Parkinson disease and their adult caregiver: A protocol for a systematic review

Gopala Krishna Pillai S, Mohd Nordin NA, Mohamed Ibrahim N

Medicine (Baltimore), 2023 Jul 14;102(28):e33966.
PMID: 37443466 DOI: 10.1097/MD.0000000000033966

BACKGROUND: Training caregivers and persons with Parkinson Disease (PwPD) is crucial to provide them with adequate knowledge and care skills in preparation for the Parkinson disease (PD) progression. This review will systematically evaluate the effect of structured training programs on the mobility and quality of life (QoL) of PwPD. In addition, the effect of such training programs on the QoL, burden of caregiving, and knowledge of PD among adult caregivers of PwPD will also be evaluated.
METHODS: Systematic and comprehensive search of relevant studies will be conducted using electronic databases such as Cochrane Library, EBSCOhost, PubMed, SCOPUS, and Web of Science. The title, abstract, keywords, and full texts will be screened for eligibility. Studies to be selected are randomized controlled trials (RCT) from inception until April 2023. Studies based on structured PD training either in the form of training, education, program, multidisciplinary approach, or self-management targeted at both PwPD and their adult caregivers will be selected. Only full-text articles available in the English language will be included. Full-text articles will be inspected by 2 independent reviewers to produce the final set of articles that meet the eligibility criteria. A third reviewer will be engaged if no consensus is achieved between the first and second reviewers. Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) will be used to evaluate the quality of papers and inform the risk of bias.
RESULTS: This review will provide an outlook on the effects of structured PD training programs on mobility and QoL of PwPD. In addition, it will provide insight into the effects of such training on the caregivers' burden, knowledge of PD, and QoL.
CONCLUSION: This review findings may help clinicians and researchers to understand the effect of structured and comprehensive PD training programs for PwPD and their adult caregiver.
Fulltext LRRK2 G2385R and R1628P mutations are associated with an increased risk of Parkinson's disease in the Malaysian population

Gopalai AA, Lim SY, Chua JY, Tey S, Lim TT, Mohamed Ibrahim N, et al.

Biomed Res Int, 2014;2014:867321.
PMID: 25243190 DOI: 10.1155/2014/867321

The LRRK2 gene has been associated with both familial and sporadic forms of Parkinson's disease (PD). The G2019S variant is commonly found in North African Arab and Caucasian PD patients, but this locus is monomorphic in Asians. The G2385R and R1628P variants are associated with a higher risk of developing PD in certain Asian populations but have not been studied in the Malaysian population. Therefore, we screened the G2385R and R1628P variants in 1,202 Malaysian subjects consisting of 695 cases and 507 controls. The G2385R and R1628P variants were associated with a 2.2-fold (P = 0.019) and 1.2-fold (P = 0.054) increased risk of PD, respectively. Our data concur with other reported findings in Chinese, Taiwanese, Singaporean, and Korean studies.
Crosstalk between insulin and Toll-like receptor signaling pathways in the central nervous system

Hemmati F, Ghasemi R, Mohamed Ibrahim N, Dargahi L, Mohamed Z, Raymond AA, et al.

Mol Neurobiol, 2014 Dec;50(3):797-810.
PMID: 24464263 DOI: 10.1007/s12035-013-8631-3

Neuroinflammation is known as a key player in a variety of neurodegenerative and/or neurological diseases. Brain Toll-like receptors (TLRs) are leading elements in the initiation and progression of neuroinflammation and the development of different neuronal diseases. Furthermore, TLR activation is one of the most important elements in the induction of insulin resistance in different organs such as the central nervous system. Involvement of insulin signaling dysregulation and insulin resistance are also shown to contribute to the pathology of neurological diseases. Considering the important roles of TLRs in neuroinflammation and central insulin resistance and the effects of these processes in the initiation and progression of neurodegenerative and neurological diseases, here we are going to review current knowledge about the potential crosstalk between TLRs and insulin signaling pathways in neuroinflammatory disorders of the central nervous system.
Fulltext Automated Gait Analysis Based on a Marker-Free Pose Estimation Model

Hii CST, Gan KB, Zainal N, Mohamed Ibrahim N, Azmin S, Mat Desa SH, et al.

Sensors (Basel), 2023 Jul 18;23(14).
PMID: 37514783 DOI: 10.3390/s23146489

Gait analysis is an essential tool for detecting biomechanical irregularities, designing personalized rehabilitation plans, and enhancing athletic performance. Currently, gait assessment depends on either visual observation, which lacks consistency between raters and requires clinical expertise, or instrumented evaluation, which is costly, invasive, time-consuming, and requires specialized equipment and trained personnel. Markerless gait analysis using 2D pose estimation techniques has emerged as a potential solution, but it still requires significant computational resources and human involvement, making it challenging to use. This research proposes an automated method for temporal gait analysis that employs the MediaPipe Pose, a low-computational-resource pose estimation model. The study validated this approach against the Vicon motion capture system to evaluate its reliability. The findings reveal that this approach demonstrates good (ICC(2,1) > 0.75) to excellent (ICC(2,1) > 0.90) agreement in all temporal gait parameters except for double support time (right leg switched to left leg) and swing time (right), which only exhibit a moderate (ICC(2,1) > 0.50) agreement. Additionally, this approach produces temporal gait parameters with low mean absolute error. It will be useful in monitoring changes in gait and evaluating the effectiveness of interventions such as rehabilitation or training programs in the community.
Quantitative Gait and Balance Outcomes for Ataxia Trials: Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers

Ilg W, Milne S, Schmitz-Hübsch T, Alcock L, Beichert L, Bertini E, et al.

Cerebellum, 2023 Nov 13.
PMID: 37955812 DOI: 10.1007/s12311-023-01625-2

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.
Genetic Movement Disorders Commonly Seen in Asians

Jagota P, Lim SY, Pal PK, Lee JY, Kukkle PL, Fujioka S, et al.

Mov Disord Clin Pract, 2023 Jun;10(6):878-895.
PMID: 37332644 DOI: 10.1002/mdc3.13737

The increasing availability of molecular genetic testing has changed the landscape of both genetic research and clinical practice. Not only is the pace of discovery of novel disease-causing genes accelerating but also the phenotypic spectra associated with previously known genes are expanding. These advancements lead to the awareness that some genetic movement disorders may cluster in certain ethnic populations and genetic pleiotropy may result in unique clinical presentations in specific ethnic groups. Thus, the characteristics, genetics and risk factors of movement disorders may differ between populations. Recognition of a particular clinical phenotype, combined with information about the ethnic origin of patients could lead to early and correct diagnosis and assist the development of future personalized medicine for patients with these disorders. Here, the Movement Disorders in Asia Task Force sought to review genetic movement disorders that are commonly seen in Asia, including Wilson's disease, spinocerebellar ataxias (SCA) types 12, 31, and 36, Gerstmann-Sträussler-Scheinker disease, PLA2G6-related parkinsonism, adult-onset neuronal intranuclear inclusion disease (NIID), and paroxysmal kinesigenic dyskinesia. We also review common disorders seen worldwide with specific mutations or presentations that occur frequently in Asians.
The effects of intravenous infusion of autologous mesenchymal stromal cells in patients with subacute middle cerebral artery infarct: a phase 2 randomized controlled trial on safety, tolerability and efficacy

Law ZK, Tan HJ, Chin SP, Wong CY, Wan Yahya WNN, Muda AS, et al.

Cytotherapy, 2021 Sep;23(9):833-840.
PMID: 33992536 DOI: 10.1016/j.jcyt.2021.03.005

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are characterized by paracrine and immunomodulatory functions capable of changing the microenvironment of damaged brain tissue toward a more regenerative and less inflammatory milieu. The authors conducted a phase 2, single-center, assessor-blinded randomized controlled trial to investigate the safety and efficacy of intravenous autologous bone marrow-derived MSCs (BMMSCs) in patients with subacute middle cerebral artery (MCA) infarct.
METHODS: Patients aged 30-75 years who had severe ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 10-35) involving the MCA territory were recruited within 2 months of stroke onset. Using permuted block randomization, patients were assigned to receive 2 million BMMSCs per kilogram of body weight (treatment group) or standard medical care (control group). The primary outcomes were the NIHSS, modified Rankin Scale (mRS), Barthel Index (BI) and total infarct volume on brain magnetic resonance imaging (MRI) at 12 months. All outcome assessments were performed by blinded assessors. Per protocol, analyses were performed for between-group comparisons.
RESULTS: Seventeen patients were recruited. Nine were assigned to the treatment group, and eight were controls. All patients were severely disabled following their MCA infarct (median mRS = 4.0 [4.0-5.0], BI = 5.0 [5.0-25.0], NIHSS = 16.0 [11.5-21.0]). The baseline infarct volume on the MRI was larger in the treatment group (median, 71.7 [30.5-101.7] mL versus 26.7 [12.9-75.3] mL, P = 0.10). There were no between-group differences in median NIHSS score (7.0 versus 6.0, P = 0.96), mRS (2.0 versus 3.0, P = 0.38) or BI (95.0 versus 67.5, P = 0.33) at 12 months. At 12 months, there was significant improvement in absolute change in median infarct volume, but not in total infarct volume, from baseline in the treatment group (P = 0.027). No treatment-related adverse effects occurred in the BMMSC group.
CONCLUSIONS: Intravenous infusion of BMMSCs in patients with subacute MCA infarct was safe and well tolerated. Although there was no neurological recovery or functional outcome improvement at 12 months, there was improvement in absolute change in median infarct volume in the treatment group. Larger, well-designed studies are warranted to confirm this and the efficacy of BMMSCs in ischemic stroke.
Fulltext Frequency of Cognitive Impairment Among Malaysian Elderly Patients Following First Ischaemic Stroke-A Case Control Study

Mohamed Fuad Z, Mahadzir H, Syed Zakaria SZ, Mohamed Ibrahim N

Front Public Health, 2020;8:577940.
PMID: 33282811 DOI: 10.3389/fpubh.2020.577940

Background: Stroke is highly prevalent globally and is an important cause of cognitive impairment and dementia. Aims: We determined the frequency of post-stroke cognitive impairment (PSCI) at 1, 3, and 6 months among patients with first clinical ischemic stroke compared to risk and age-matched controls. Methods: This study involved 32 cases and 32 controls, and was conducted over 6 months. Cases were inpatients aged >60 with first clinical ischemic stroke. Controls were age-matched subjects without prior stroke. Montreal Cognitive Assessment (MoCA) was performed in all patients at 1, 3, and 6 month post stroke. A MoCA score of <26 was used for mild PSCI and <22 for moderate PSCI (post stroke dementia). Results: Post-stroke dementia was detected in 12 patients (37.5%) at 1st month, in 13 (40.6%) at 3rd month and 15 (48.4%) at 6th months. Mild PSCI was present in 7 patients (21.6%) at 1 month, 16 patients (50%) at 3 months, and 15 patients (48%) at 6 months. The odds ratio (OR) for post-stroke dementia was 3.2 (95%CI 0.98-10.68; p = 0.05) at 1 month; 3.69(95% CI 1.13-12.11; p = 0.031) at 3 months, and 4.88 (95% CI 1.49-15.99; p = 0.009) at 6 months. Years of education was an independent predictor for dementia (OR 0.60; p = 0.046). The OR for post-stroke dementia at 6th month was 7.23 with education level adjusted (95%CI 1.46-35.86, p = 0.015). Conclusion: The frequency of PSCI was high as early as 1 month after stroke. Stroke alone conferred a 7.2 times risk for post-stroke dementia compared to controls.
Fulltext Frequency of Spinocerebellar Ataxia type 1, 2, 3,6 and 7 and clinical profile of Spinocerebellar Ataxia type 3 in Malaysia

Mohamed Ibrahim N, Lau YH, Ariffin N, Md Desa SH, Azizan E, Chin LK, et al.

Cerebellum & ataxias, 2020;7:11.
PMID: 32922823 DOI: 10.1186/s40673-020-00120-2

Spinocerebellar ataxias (SCA) are highly heterogenous group of neurodegenerative diseases causing progressive cerebellar dysfunction. We report the first description of relative frequencies of the common SCA mutations and of phenotypic characteristics of SCA3 patients among Malaysians. Pooled data from adult Malaysian patients who had undergone genetic testing for SCA 1,2,3,6 and 7 at UKM Medical Centre and Institute for Medical Research from 2017 to 2020 were analysed. Fifteen patients with SCA 3 had detailed clinical phenotype evaluation using Inventory for Non -Ataxia Signs (INAS) and Ataxia Severity evaluation using the Scale for Assessment and Rating of Ataxia (SARA). Out of 152 adults patients who were tested for common SCA mutations, 64(42.1%) patients were tested positive for either SCA 1,2,3,6 or 7. Of the 64 positive cases, 44 (68.9%) patients were diagnosed with SCA 3 followed by SCA 2 in 13(20.3%) patients and SCA 1 in 5 (7.8%) patients. Our findings suggest that Malay race had the highest frequency of SCA (n = 34, 50%), followed by the Chinese (n = 16, 23.5%) and approximately 60 (93.8%) SCA patients had first degree family history. In conclusion, SCA 3 is the commonest SCA in Malaysia, followed by SCA 2 and SCA 1. It is important to develop a proper registry of SCA patients to further understand the true prevalence and local impact of the disease in Malaysia.
Earlier onset of motor complications in Parkinson's patients with comorbid diabetes mellitus

Mohamed Ibrahim N, Ramli R, Koya Kutty S, Shah SA

Mov Disord, 2018 12;33(12):1967-1968.
PMID: 30427552 DOI: 10.1002/mds.27526
An atypical course of a 71-year old man with right arm weakness and ataxia: Expert commentary

Mohamed Ibrahim N

Parkinsonism Relat Disord, 2022 Dec;105:157-158.
PMID: 36274018 DOI: 10.1016/j.parkreldis.2022.10.015
Fulltext Amelioration of Dystonic Opisthotonus in Pantothenate Kinase-Associated Neurodegeneration Syndrome with Absent "Eye-of-the-Tiger" Sign Following Bilateral Pallidal Deep Brain Stimulation

Mohd Fauzi NA, Mohamed Ibrahim N, Mohamed Mukari SA, Jegan T, Abdul Aziz Z

Mov Disord Clin Pract, 2019 Apr;6(4):332-334.
PMID: 31061845 DOI: 10.1002/mdc3.12748
Fulltext The Promise of the Zebrafish Model for Parkinson's Disease: Today's Science and Tomorrow's Treatment

Razali K, Othman N, Mohd Nasir MH, Doolaanea AA, Kumar J, Ibrahim WN, et al.

Front Genet, 2021;12:655550.
PMID: 33936174 DOI: 10.3389/fgene.2021.655550

The second most prevalent neurodegenerative disorder in the elderly is Parkinson's disease (PD). Its etiology is unclear and there are no available disease-modifying medicines. Therefore, more evidence is required concerning its pathogenesis. The use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the basis of most animal models of PD. MPTP is metabolized by monoamine oxidase B (MAO B) to MPP + and induces the loss of dopaminergic neurons in the substantia nigra in mammals. Zebrafish have been commonly used in developmental biology as a model organism, but owing to its perfect mix of properties, it is now emerging as a model for human diseases. Zebrafish (Danio rerio) are cheap and easy to sustain, evolve rapidly, breed transparent embryos in large amounts, and are readily manipulated by different methods, particularly genetic ones. Furthermore, zebrafish are vertebrate species and mammalian findings obtained from zebrafish may be more applicable than those derived from genetic models of invertebrates such as Drosophila melanogaster and Caenorhabditis elegans. The resemblance cannot be taken for granted, however. The goal of the present review article is to highlight the promise of zebrafish as a PD animal model. As its aminergic structures, MPTP mode of action, and PINK1 roles mimic those of mammalians, zebrafish seems to be a viable model for studying PD. The roles of zebrafish MAO, however, vary from those of the two types of MAO present in mammals. The benefits unique to zebrafish, such as the ability to perform large-scale genetic or drug screens, should be exploited in future experiments utilizing zebrafish PD models.
Fulltext Apolipoprotein Eε4: A Biomarker for Executive Dysfunction among Parkinson's Disease Patients with Mild Cognitive Impairment

Samat NA, Abdul Murad NA, Mohamad K, Abdul Razak MR, Mohamed Ibrahim N

Front Neurosci, 2017;11:712.
PMID: 29326545 DOI: 10.3389/fnins.2017.00712

Background: Cognitive impairment is prevalent in Parkinson's disease (PD), affecting 15-20% of patients at diagnosis. α-synuclein expression and genetic polymorphisms of Apolipoprotein E (ApoE) have been associated with the presence of cognitive impairment in PD although data have been inconsistent. Objectives: To determine the prevalence of cognitive impairment in patients with PD using Montreal Cognitive Assessment (MoCA), Comprehensive Trail Making Test (CTMT) and Parkinson's disease-cognitive rating scale (PDCRS), and its association with plasma α-synuclein and ApoE genetic polymorphisms. Methods: This was across-sectional study involving 46 PD patients. Patients were evaluated using Montreal cognitive assessment test (MoCA), and detailed neuropsychological tests. The Parkinson's disease cognitive rating scale (PDCRS) was used for cognitive function and comprehensive trail making test (CTMT) for executive function. Blood was drawn for plasma α-synuclein measurements and ApoE genetic analysis. ApoE polymorphism was detected using MutaGELAPoE from ImmunDiagnostik. Plasma α-synuclein was detected using the ELISA Technique (USCN Life Science Inc.) according to the standard protocol. Results: Based on MoCA, 26 (56.5%) patients had mild cognitive impairment (PD-MCI) and 20 (43.5%) had normal cognition (PD-NC). Based on the PDCRS, 18 (39.1%) had normal cognition (PDCRS-NC), 17 (37%) had mild cognitive impairment (PDCRS-MCI), and 11 (23.9%) had dementia (PDCRS-PDD). In the PDCRS-MCI group, 5 (25%) patients were from PD-NC group and all PDCRS-PDD patients were from PD-MCI group. CTMT scores were significantly different between patients with MCI and normal cognition on MoCA (p = 0.003). Twenty one patients (72.4%) with executive dysfunction were from the PD-MCI group; 17 (77.3%) with severe executive dysfunction and 4 (57.1%) had mild to moderate executive dysfunction. There were no differences in the plasma α-synuclein concentration between the presence or types of cognitive impairment based on MoCA, PDCRS, and CTMT. TheApoEe4 allele carrier frequency was significantly higher in patients with executive dysfunction (p = 0.014). Conclusion: MCI was prevalent in our PD population. PDCRS appeared to be more discriminatory in detecting MCI and PDD than MoCA. Plasma α-synuclein level was not associated with presence nor type of cognitive impairment, but the ApoEe4 allele carrier status was significantly associated with executive dysfunction in PD.

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