ORCID Profile
0000-0002-2869-0096
Current Organisations
King's College London
,
National University Health System
,
National University of Singapore
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 31-03-2021
DOI: 10.1002/ALZ.12332
Abstract: There is increasing evidence that phosphorylated tau (P‐tau181) is a specific biomarker for Alzheimer's disease (AD) pathology, but its potential utility in non‐White patient cohorts and patients with concomitant cerebrovascular disease (CeVD) is unknown. Single molecule array (Simoa) measurements of plasma P‐tau181, total tau, amyloid beta (Aβ)40 and Aβ42, as well as derived ratios were correlated with neuroimaging modalities indicating brain amyloid (Aβ+), hippoc al atrophy, and CeVD in a Singapore‐based cohort of non‐cognitively impaired (NCI n = 43), cognitively impaired no dementia (CIND n = 91), AD ( n = 44), and vascular dementia (VaD n = 22) subjects. P‐tau181/Aβ42 ratio showed the highest area under the curve (AUC) for Aβ+ (AUC = 0.889) and for discriminating between AD Aβ+ and VaD Aβ− subjects (AUC = 0.903). In addition, P‐tau181/Aβ42 ratio was associated with hippoc al atrophy. None of the biomarkers was associated with CeVD. Plasma P‐tau181/Aβ42 ratio may be a noninvasive means of identifying AD with elevated brain amyloid in populations with concomitant CeVD.
Publisher: MDPI AG
Date: 30-08-2022
Abstract: Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented in iduals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.BBRC.2018.04.075
Abstract: It has been known for decades that the regulation of sphingolipids (SLs) is essential for the proper function of many cellular processes. However, a complete understanding of these processes has been complicated by the structural ersity of these lipids. A well-characterized metabolic pathway is responsible for homeostatic maintenance of hundreds of distinct SL species. This pathway is perturbed in a number of pathological processes, resulting in derangement of the "sphingolipidome." Recently, advances in mass spectrometry (MS) techniques have made it possible to characterize the sphingolipidome in large-scale clinical studies, allowing for the identification of specific SL molecules that mediate pathological processes and/or may serve as biomarkers. This manuscript provides an overview of the functions of SLs, and reviews previous studies that have used MS techniques to identify changes to the sphingolipidome in non-metabolic diseases.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-06-2019
DOI: 10.1212/WNL.0000000000007818
Abstract: To assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity. We pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria (2) memory clinic patients and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs). Thirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10 95% confidence interval [CI] 1.11–3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95% CI 1.48–3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity. CAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.FREERADBIOMED.2021.10.019
Abstract: Ergothioneine (ET) is a dietary amino-thione with strong antioxidant and cytoprotective properties and has possible therapeutic potential for neurodegenerative and vascular diseases. Decreased blood concentrations of ET have been found in patients with mild cognitive impairment, but its status in neurodegenerative and vascular dementias is currently unclear. To address this, a cross-sectional study was conducted on 496 participants, consisting of 88 with no cognitive impairment (NCI), 201 with cognitive impairment, no dementia (CIND) as well as 207 with dementia, of whom 160 have Alzheimer's Disease (AD) and 47 have vascular dementia. All subjects underwent blood-draw, neuropsychological assessments, as well as neuroimaging assessments of cerebrovascular diseases (CeVD) and brain atrophy. Plasma ET as well as its metabolite l-hercynine were measured using high sensitivity liquid chromatography tandem-mass spectrometry (LC-MS/MS). Plasma ET concentrations were lowest in dementia (p < 0.001 vs. NCI and CIND), with intermediate levels in CIND (p < 0.001 vs. NCI). A significant increase in l-hercynine to ET ratio was also observed in dementia (p < 0.01 vs. NCI). In multivariate models adjusted for demographic and vascular risk factors, lower levels of ET were significantly associated with dementia both with or without CeVD, while ET associations with CIND were significant only in the presence of CeVD. Furthermore, lower ET levels were also associated with white matter hyperintensities and brain atrophy markers (reduced global cortical thickness and hippoc al volumes). The incremental decreases in ET levels along the CIND-dementia clinical continuum suggest that low levels of ET are associated with disease severity and could be a potential biomarker for cognitive impairment. Deficiency of ET may contribute towards neurodegeneration- and CeVD-associated cognitive impairments, possibly via the exacerbation of oxidative stress in these conditions.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.BBRC.2018.04.076
Abstract: Lipids comprise an exceptionally erse class of bioactive macromolecules. While quantitatively abundant lipid species serve fundamental roles in cell structure and energy metabolism, thousands of structurally-distinct, quantitatively minor species may serve as important regulators of cellular processes. Historically, a complete understanding of the biological roles of these lipids has been limited by a lack of sensitive, discriminating analytical techniques. The class of sphingolipids alone, for ex le, is known to consist of over 600 different confirmed species, but is likely to include tens of thousands of metabolites with potential biological significance. Advances in mass spectrometry (MS) have improved the throughput and discrimination of lipid analysis, allowing for the determination of detailed lipid profiles in large cohorts of clinical s les. Databases emerging from these studies will provide a rich resource for the identification of novel biomarkers and for the discovery of potential drug targets, analogous to that of existing genomics databases. In this review, we will provide an overview of the field of sphingolipidomics, and will discuss some of the challenges and considerations facing the generation of robust lipidomics databases.
Publisher: Wiley
Date: 2023
DOI: 10.1002/DAD2.12396
Abstract: Plasma neurofilament light chain (NfL) is a potential biomarker for neurodegeneration in Alzheimer's disease (AD), ischemic stroke, and non‐dementia cohorts with cerebral small vessel disease (CSVD). However, studies of AD in populations with high prevalence of concomitant CSVD to evaluate associations of brain atrophy, CSVD, and amyloid beta (Aβ) burden on plasma NfL are lacking. Associations were tested between plasma NfL and brain Aβ, medial temporal lobe atrophy (MTA) as well as neuroimaging features of CSVD, including white matter hyperintensities (WMH), lacunes, and cerebral microbleeds. We found that participants with either MTA (defined as MTA score ≥2 neurodegeneration [N]+WMH−) or WMH (cut‐off for log‐transformed WMH volume at 50th percentile N−WMH+) manifested increased plasma NfL levels. Participants with both pathologies (N+WMH+) showed the highest NfL compared to N+WMH−, N−WMH+, and N−WMH− in iduals. Plasma NfL has potential utility in stratifying in idual and combined contributions of AD pathology and CSVD to cognitive impairment.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2020
DOI: 10.1186/S13195-020-00694-3
Abstract: There has been ongoing research impetus to uncover novel blood-based diagnostic and prognostic biomarkers for Alzheimer’s disease (AD), vascular dementia (VaD), and related cerebrovascular disease (CEVD)-associated conditions within the spectrum of vascular cognitive impairment (VCI). Sphingosine-1-phosphates (S1Ps) are signaling lipids which act on the S1PR family of cognate G-protein-coupled receptors and have been shown to modulate neuroinflammation, a process known to be involved in both neurodegenerative and cerebrovascular diseases. However, the status of peripheral S1P in AD and VCI is at present unclear. We obtained baseline bloods from in iduals recruited into an ongoing longitudinal cohort study who had normal cognition ( N = 80) cognitive impairment, no dementia ( N = 160) AD ( N = 113) or VaD ( N = 31), along with neuroimaging assessments of cerebrovascular diseases. Plasma s les were processed for the measurements of major S1P species: d16:1, d17:1, d18:0, and d18:1, along with pro-inflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF). Furthermore, in vitro effects of S1Ps on cytokine expression were also studied in an astrocytoma cell line and in rodent primary astrocytes. Of the S1Ps species measured, only d16:1 S1P was significantly reduced in the plasma of VaD, but not AD, patients, while the d18:1 to d16:1 ratios were increased in all cognitive subgroups (CIND, AD, and VaD). Furthermore, d18:1 to d16:1 ratios correlated with levels of IL-6, IL-8, and TNF. In both primary astrocytes and an astroglial cell line, treatment with d16:1 or d18:1 S1P resulted in the upregulation of mRNA transcripts of pro-inflammatory cytokines, with d18:1 showing a stronger effect than d16:1. Interestingly, co-treatment assays showed that the addition of d16:1 reduced the extent of d18:1-mediated gene expression, indicating that d16:1 may function to “fine-tune” the pro-inflammatory effects of d18:1. Taken together, our data suggest that plasma d16:1 S1P may be useful as a diagnostic marker for VCI, while the d18:1 to d16:1 S1P ratio is an index of dysregulated S1P-mediated immunomodulation leading to chronic inflammation-associated neurodegeneration and cerebrovascular damage.
Publisher: Wiley
Date: 17-10-2018
DOI: 10.1111/BPA.12631
Publisher: Elsevier BV
Date: 03-2014
Publisher: Springer Science and Business Media LLC
Date: 08-09-2016
Publisher: Springer Science and Business Media LLC
Date: 17-02-2021
DOI: 10.1038/S41598-021-83601-6
Abstract: Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer’s disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood s les were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.
Publisher: BMJ
Date: 11-09-2021
Abstract: Discovery and development of clinically useful biomarkers for Alzheimer’s disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-β (Aβ) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring Aβ and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish Aβ and P-tau as blood-based biomarkers for AD, including validation with existing large s le sets, new independent cohorts from erse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of Aβ peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.NEUINT.2021.105251
Abstract: Inflammation is usually a tightly regulated process whose termination by mediators including Annexin A1 (AnxA1) results in the resolution of inflammatory responses. In neurodegenerative dementias, chronic neuroinflammation, along with accumulation of aggregated β-amyloid (Aβ) peptides and apoptosis, has long been recognized to be a pathological hallmark but it is unclear whether a failure of inflammation resolution contributes to this pathophysiological process. In this study, we measured AnxA1 immunoreactivities in postmortem neocortex (Brodmann areas BA9 and BA40) of well characterized Alzheimer's disease (AD), Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) patients as well as aged controls. Inactive cleaved AnxA1 was found to be elevated in AD and DLB in BA40. Levels of cleaved AnxA1 also positively correlated with amyloidogenic brain Aβ, anti-inflammatory markers such as IL10 and IL13, as well as with the pro-apoptotic marker cleaved caspase-3 in BA40. Our findings suggest that elevated cleaved AnxA1 in neurodegenerative dementias may reflect a failure of inflammation resolution in certain regions of the diseased brain, and also support a mechanistic link between AnxA1 and amyloid pathology, neuroinflammation and apoptosis.
Publisher: Wiley
Date: 23-01-2021
DOI: 10.1111/ENE.14704
Abstract: Various blood biomarkers reflecting brain amyloid‐β (Aβ) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort. Using the same cohort ( n = 68), the performances of the single‐molecule array (Simoa) Aβ40, Aβ42, Aβ42/Aβ40 and the lified plasmonic exosome (APEX) Aβ42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aβ+) participants. Compared to Simoa biomarkers, APEX‐Aβ42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre‐screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX‐Aβ42 and 48.6% for Simoa‐Aβ42/Aβ40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX‐Aβ42 pre‐screening does not increase the required number of initial participants. With its high diagnostic performance, APEX is an ideal candidate for Aβ+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aβ+ participants whilst halving recruitment costs.
Publisher: Wiley
Date: 18-07-2023
DOI: 10.1111/BPA.13190
Abstract: Docosahexaenoic acid (DHA) is an essential omega‐3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA‐containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated α‐synuclein‐containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post‐mortem s les from the parietal cortex of 25 DLB patients and 17 age‐matched controls were processed for phospholipidomics analyses using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA‐phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA‐phospholipid species were subsequently validated with further LC–MS/MS measurements. Of the DHA‐containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta‐amyloid (Aβ42) levels, whilst three also correlated with phosphorylated α‐synuclein (all p 0.05). Furthermore, five of these phospholipid species correlated with deficits of presynaptic Rab3A, postsynaptic neurogranin, or both (all p 0.05). Finally, we found altered immunoreactivities of brain lysolipid DHA transporter, MFSD2A, and the fatty acid binding protein FABP5 in DLB parietal cortex. In summary, we report alterations of specific DCP species in DLB, as well as their associations with markers of neuropathological burden and synaptopathology. These results support the potential role of DHA perturbations in DLB as well as therapeutic targets.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Joyce Ruifen Chong.