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  1. Lim SY, Lim KB, Hor JW, Tan AH
    Mov Disord, 2020 10;35(10):1884-1885.
    PMID: 33068479 DOI: 10.1002/mds.28274
  2. Tan AH, Hor JW, Chong CW, Lim SY
    JGH Open, 2021 Apr;5(4):414-419.
    PMID: 33860090 DOI: 10.1002/jgh3.12450
    The gut-brain axis is a hot topic in Parkinson's disease (PD). It has been postulated that gut pathogens and dysbiosis can contribute to peripheral inflammatory states or trigger downstream metabolic effects that exacerbate the neurodegenerative process in PD. Several preclinical and clinical studies have demonstrated disrupted intestinal permeability, intestinal inflammation, altered gut microbiome, and reduced fecal short-chain fatty acids in PD. In this regard, microbial-directed therapies such as probiotics are emerging as potential therapeutic options. Probiotic supplementation is postulated to confer a variety of health benefits due to the diverse functions of these live microorganisms, including inhibition of pathogen colonization, modulation/"normalization" of the microbiome and/or its function, immunomodulatory effects (e.g. reducing inflammation), and improved host epithelial barrier function. Interestingly, several PD animal model studies have demonstrated the potential neuroprotective effects of probiotics in reducing dopaminergic neuronal degeneration. Notably, two randomized placebo-controlled trials have provided class I evidence for probiotics as a treatment for constipation in PD. However, the effects of probiotics on other PD aspects, such as motor disability and cognitive function, and its long-term efficacy (including effects on PD drug absorption in the gut) have not been investigated adequately. Further targeted animal and human studies are also warranted to understand the mechanisms of actions of probiotics in PD and to tailor probiotic therapy based on individual host profiles to improve patient outcomes in this disabling disorder.
  3. Wong LW, Ong KS, Khoo JR, Goh CBS, Hor JW, Lee SM
    Expert Rev Gastroenterol Hepatol, 2020 Nov;14(11):1093-1105.
    PMID: 32755242 DOI: 10.1080/17474124.2020.1806711
    INTRODUCTION: Intestinal parasitic infection (IPI) is a global health concern among socioeconomically deprived communities in many developing countries. Many preventative strategies have been deployed to control IPI, however, there is a lack in standards on the techniques used to diagnose and monitor the prevalence of IPI.

    AREAS COVERED: The present article will review the diseases associated with IPI and discuss the current IPI control strategies such as the water, sanitation, and hygiene (WASH) interventions, community-led total sanitation (CLTS) approach, and regular anthelminthic treatments. For the first time, this review will also evaluate all currently practised diagnostic techniques for the detection of intestinal parasites and provide insights on future IPI control strategies.

    EXPERT OPINION: Advanced and improved diagnostic methods such as qPCR coupled with a high-resolution melting curve, aptamers, biosensors, and detection of extracellular vesicles can be used for detection of IPI. Vaccination against intestinal parasites can be made available to increase antibodies to interfere with the blood-feeding process by the parasites, which subsequently reduces the reproductive rates of the parasites. These methods collectively can serve as future management strategies for intestinal parasitic infections.

  4. Lim KB, Lim SY, Hor JW, Krishnan H, Mortadza F, Lim JL, et al.
    Parkinsonism Relat Disord, 2024 Apr 22;123:106980.
    PMID: 38657381 DOI: 10.1016/j.parkreldis.2024.106980
    BACKGROUND: Screening for orthostatic hypotension (OH) is integral in Parkinson's disease (PD) management, yet evidence-based guidelines on best practice methods for diagnosing OH in PD are lacking.

    METHODS: We investigated the frequency and correlates of OH, symptomatic OH, and neurogenic OH, in a large consecutively recruited PD cohort (n = 318), and compared the diagnostic performance of the sit-to-stand vs. the supine-to-stand blood pressure (BP) test. We evaluated the utility of continuous BP monitoring and tilt table testing in patients with postural symptoms or falls who were undetected to have OH with clinic-based BP measurements. Disease severity, fluid intake, orthostatic and overactive bladder symptoms, falls, comorbidities and medication history were evaluated.

    RESULTS: Patients' mean age was 66.1 ± 9.5years, with mean disease duration 7.8 ± 5.5years. OH frequency was 35.8 % based on the supine-to-stand test. OH in PD was significantly associated with older age, lower body mass index, longer disease duration, worse motor, cognitive and overactive bladder symptoms and functional disabilities, falls, and lower fluid intake. A similar profile was seen with asymptomatic OH. Three quarters of OH were neurogenic, with the majority also having supine hypertension. The sit-to-stand test had a sensitivity of only 0.39. One quarter of patients were additionally diagnosed with OH during continuous BP monitoring.

    CONCLUSIONS: The sit-to-stand test substantially underdiagnoses OH in PD, with the important practice implication that supine-to-stand measurements may be preferred. Screening for OH is warranted even in asymptomatic patients. Adequate fluid intake, treatment of urinary dysfunction and falls prevention are important strategies in managing PD patients with OH.

  5. Tan AH, Lim SY, Chong KK, A Manap MAA, Hor JW, Lim JL, et al.
    Neurology, 2021 02 02;96(5):e772-e782.
    PMID: 33046607 DOI: 10.1212/WNL.0000000000010998
    OBJECTIVE: To determine whether probiotics are effective for constipation, a common and often difficult-to-treat problem, in Parkinson disease (PD).

    METHODS: In this double-blind, randomized, placebo-controlled, single-center trial, 280 patients with PD were screened, and 72 eligible patients were block-randomized (1:1) to receive either multistrain probiotics capsules (n = 34) or identical-appearing placebo (n = 38), for 4 weeks. The primary endpoint was the change in the average number of spontaneous bowel movements (SBM) per week during the last 2 weeks of intervention compared with the 2-week preintervention phase, recorded by daily stool diary. Secondary outcome measures included changes in stool consistency, constipation severity score, and quality of life related to constipation. Satisfaction with intervention received was assessed. Change in levels of fecal calprotectin, a marker of intestinal inflammation, was an exploratory outcome.

    RESULTS: SBM increased by 1.0 ± 1.2 per week after treatment with probiotics and decreased by 0.3 ± 1.0 per week in the placebo group (mean difference 1.3, 95% confidence interval 0.8-1.8, p < 0.001). Significant improvements were also seen for secondary outcomes after correction for multiple comparisons, including stool consistency (p = 0.009) and quality of life related to constipation (p = 0.001). In the treatment group, 65.6% reported satisfaction with the intervention vs only 21.6% in the placebo group (p < 0.001). One patient (2.9%) in the treatment group withdrew due to a nonserious adverse event. Fecal calprotectin did not change significantly during the study.

    CONCLUSIONS: Multistrain probiotics treatment was effective for constipation in PD. Further studies are needed to investigate the long-term efficacy and safety of probiotics in PD, as well as their mechanisms of action.

    CLINICALTRIALSGOV IDENTIFIER: NCT03377322.

    CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for people with PD, multistrain probiotics significantly increased the average number of SBM per week.

  6. Hor JW, Lim SY, Khor ES, Chong KK, Song SL, Ibrahim NM, et al.
    J Mov Disord, 2021 Dec 24.
    PMID: 34937162 DOI: 10.14802/jmd.21085
    Objective: Converging evidence suggests that intestinal inflammation is involved in the pathogenesis of neurodegenerative diseases. Previous studies on fecal calprotectin in Parkinson's disease (PD) were limited by small sample sizes, and literature regarding intestinal inflammation in multiple system atrophy (MSA) is very scarce. We investigated the levels of fecal calprotectin, a marker of intestinal inflammation, in PD and MSA.

    Methods: We recruited 169 subjects (71 PD, 38 MSA, and 60 age-similar nonneurological controls). Clinico-demographic data were collected. PD and MSA were subtyped and the severity assessed using the MDS-UPDRS and UMSARS, respectively. Fecal calprotectin and blood immune markers were analyzed.

    Results: Compared to controls (median: 35.7 [IQR: 114.2] μg/g), fecal calprotectin was significantly elevated in PD (median: 95.6 [IQR: 162.1] μg/g, p = 0.003) and even higher in MSA (median: 129.5 [IQR: 373.8] μg/g, p = 0.002). A significant interaction effect with age was observed; between-group differences were significant only in older subjects (i.e., ≥ 61 years) and became more apparent with increasing age. A total of 28.9% of MSA and 18.3% of PD patients had highly abnormal fecal calprotectin levels (≥ 250 μg/g); however, this difference was only significant for MSA compared to controls. Fecal calprotectin correlated moderately with selected blood immune markers in PD, but not with clinical features of PD or MSA.

    Conclusions: Elevated fecal calprotectin suggests a role for intestinal inflammation in PD and MSA. A more complete understanding of gut immune alterations could open up new avenues of research and treatment for these debilitating diseases.

  7. Tay YW, Tan AH, Lim JL, Lohmann K, Ibrahim KA, Abdul Aziz Z, et al.
    Parkinsonism Relat Disord, 2023 Jun;111:105399.
    PMID: 37209484 DOI: 10.1016/j.parkreldis.2023.105399
    BACKGROUND: About 5-10% of Parkinson's disease (PD) cases are early onset (EOPD), with several genes implicated, including GBA1, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across populations and globally diverse studies are crucial to comprehensively understand the genetic architecture of PD. The ancestral diversity of Southeast Asians offers opportunities to uncover a rich PD genetics landscape, and identify common regional mutations and new pathogenic variants.

    OBJECTIVES: This study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort.

    METHODS: 161 index patients with PD onset ≤50 years were recruited from multiple centers across Malaysia. A two-step approach to genetic testing was used, combining a next-generation sequencing-based PD gene panel and multiplex ligation-dependent probe amplification (MLPA).

    RESULTS: Thirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA1, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic variants in GBA1 were identified in thirteen patients (8.1%), and were also commonly found in PRKN and PINK1 (11/161 = 6.8% and 6/161 = 3.7%, respectively). The overall detection rate was even higher in those with familial history (48.5%) or age of diagnosis ≤40 years (34.8%). PRKN exon 7 deletion and the PINK1 p.Leu347Pro variant appear to be common among Malay patients. Many novel variants were found across the PD-related genes.

    CONCLUSIONS: This study provides novel insights into the genetic architecture of EOPD in Southeast Asians, expands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations.

  8. Lim SY, Tan AH, Foo JN, Tan YJ, Chew EG, Annuar AA, et al.
    J Mov Disord, 2024 Jan 31.
    PMID: 38291878 DOI: 10.14802/jmd.24009
    Lysosomal dysfunction plays an important role in neurodegenerative diseases, including Parkinson's disease (PD) and possibly also Parkinson-plus syndromes such as progressive supranuclear palsy (PSP). This is exemplified by the involvement of the GBA1 gene, which results in a deficiency of the lysosomal enzyme glucocerebrosidase, and is currently the most frequently identified genetic factor underlying PD worldwide. Pathogenic variants in the SMPD1 gene are a recessive cause of Niemann-Pick disease type A and B. Here, we provide the first report on an association between a loss-of-function SMPD1 gene variant present in heterozygous state (p.Pro332Arg/p.P332R, which is known to result in reduced lysosomal acid sphingomyelinase activity), with PSP-Richardson syndrome in three unrelated patients of Chinese ancestry.
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