Associate Professor Christopher Chen Li Hsian

Appointment(s)

Associate Professor, Department of Pharmacology, National University of Singapore
Director, Memory Aging & Cognition Centre, National University Health System
Visiting Senior Consultant, Department of Psychological Medicine, National University Hospital

Degree(s)

FRCP, Medicine, Royal College of Physicians, Edinburgh (2003) 
FAMS, Neurology, Academy of Medicine, Singapore (1998) 
MRCP, Medicine, Royal College of Physicians, UK (1988)
BMBCh, Clinical Medicine, University of Oxford (1985) 
BA, Natural Sciences, University of Cambridge (1982)

Biography

Associate Professor Christopher Chen studied for the Medical and Natural Science Tripos at Fitzwilliam College, Cambridge University, and received his clinical training at the University of Oxford. He began his research career in neuroscience translational research as the Janssen Junior Research Fellow at Worcester College, Oxford University and Visiting Research Fellow at the Institute of Neurology, London.

Since returning to Singapore in 1995, he has developed a comprehensive multi-disciplinary dementia programme and encouraged collaborative research in the Asia-Pacific region and beyond. In particular, as the Director of the Memory Aging and Cognition Centre (MACC), he focuses on studying biomarkers of cognitive impairment and dementia due to cerebrovascular and neurodegenerative disease. This has resulted in productive collaborations with the Singapore Eye Research Institute (SERI) on the importance of retinal imaging in dementia and stroke, and with the Cardiovascular Research Institute (CVRI) NUHS, through successful competitive grant applications which has led to high impact publications.

His major research and clinical interests are in neurochemistry, molecular biology and treatment of stroke and dementia. He has published over 450 peer-reviewed papers and book chapters, served on several editorial boards, trial steering committees and data safety monitoring boards.

He has also developed an international reputation for academically driven as well as industry sponsored clinical trials. His aim is to develop synergies with basic neuroscience research and to translate novel scientific findings into therapeutic possibilities as well as to provide clinical insights for disease specific laboratory research.

He has supervised many post-graduate students (31 PhD students, 26 local and overseas fellows) and plans to continue nurturing emerging academics and clinicians as the current co-chair of the World Stroke Organisation’s Future Leaders Program as well as being a board member of the College of Clinician-Scientists, Academy of Medicine, Singapore.

Research Areas/Research Interest

In my initial application for the CSI Category A award in 2005, I stated that I intended to develop upon the theme of ‘Translational Research and Clinical Trials in Stroke and Dementia’ so as to lead a productive and integrated research programme.

In many important respects, we have made much progress in achieving this aim by the establishment of a) the NUHS Dementia Translational Programme in 2008, b) the award of a National Research Foundation Competitive Research Programme grant focusing on intracranial disease and stroke in 2009 and c) the award of an NMRC Centre Grant for the Memory Aging and Cognition Centre to investigate the interaction between cerebrovascular and neurogenerative disease in 2010.

Hence, for my successful renewal application (awarded in 2012) , my aim would be to deepen existing collaborations and to develop new ones so as to benefit Neuroscience research in Singapore and provide a basis for the training of young clinicians / scientists keen on pursuing and developing a research career. The revised theme is ‘Translational Research and Clinical Trials in Post-Stroke Cognitive Impairment : Biomarkers and Clinical Trials’ which combines my research interests in dementia and stroke.

Dementia
Neurochemistry Our work and that from other groups has shown that alterations in receptor density as well as common genetic variation in a variety of neurochemical systems have an influence on the development of a number of de novo symptoms in AD.
I aim to continue investigation of the neurochemical basis of dementia with an emphasis on the second messenger systems involved. The correlation of particular neurochemical parameters to clinical symptoms provides a basis for further studies into rational treatment with drugs and in vivo screening for patients at risk of developing behavioral and cognitive symptoms.
Our research may therefore have applications for the treatment of dementia symptoms.
Neuroimaging Functional neuroimaging studies using PET, SPECT and fMRI may be useful to further characterize the effects of neurotranmitters on the response of neural circuits underlying the symptomology of and susceptibility to dementia. Newly developed Arterial Spin Labelling (ASL) MRI techniques may offer non-invasive means of measuring the relationship between perfusion and cognitive function in dementia as well as provide a novel biomarker for clinical trials. The animal imaging facility of the BMRC Bioimaging group provides an opportunity to study animal models of dementia.

Studies utilising BOLD functional magnetic resonance imaging have demonstrated genetically driven variation in the response of brain regions underlying human emotional behavior. I intend to develop fMRI studies on patients with dementia with the help of colleagues in Singapore (A Qiu, A Chen, M Chee).

PET ligands are available for several of the receptors we have investigated in post-mortem brains and I hope to initiate collaborations with colleagues in Singapore (D Townsend) on using PET to perform in vivo screening for dementia patients and patients at risk of developing dementia, as well as an outcome measure in clinical trials of drugs targeted at these receptors.
Arterial Spin Labelling (ASL) MRI techniques (A Qiu, KH Chuang) will be utilized to investigate the relationship between perfusion and cognitive function in dementia, particularly in patients with intracranial atherosclerosis as part of the Stroke CRP.
I am collaborating with my colleagues (BS Wong, KH Chuang, M Lai) to utilize advanced MRI techniques to investigate pathophysiology and effects of treatment in transgenic mouse models of Alzheimers Disease.
Genetics We are collecting a large, well annotated Dementia / Cognitive Impairment DNA Bank. Our future plans are to collaborate with GIS (JJ Liu, M Hayden) on genome wide screens for new cognitive impairment genes and haplotypes.
Neuroscience Our group has established links with other neuroscientists in Singapore and overseas and our aim would be to deepen & broaden our collaborations. We are collaborating with colleagues in NUS on animal models of dementia with colleagues from NUS (Dr BS Wong) and SBIC (KH Chuang) and will be collaborating with Dr N Sze from NTU on his studies of the proteonomics of dementia.
Dementia Research Network In collaboration with the Singapore Clinical Research Institute and colleagues from NUHS, KTPH and SGH, we have set up a national Dementia Research Network which has a shared database and plans to perform joint clinical research projects including computerized dementia screening programmes, clinical trials and observational studies.
Industry A novel and potentially vital development are collaborations with industry. Together with TY Wong and C Cheung from SERI, we have recently been awarded a Glaxo Smith Kline Academic Center of Excellence grant to investigate retinal biomarkers for dementia. Furthermore, I am the PI of a novel experimental medicine study to develop improved imaging methods for the evaluation of dementia treatments from Merck.

Stroke
We intend to pursue our studies on the pathogenesis of as well as biomarkers for stroke in collaboration with various institutions in a number of areas.

Neurochemistry.
We aim to identify novel biomarkers for stroke suitable for diagnostic or prognostic purposes (as part of the Stroke CRP) as well as continuing with the very promising area of cysteine and hydrogen sulphide neurotoxicity (Prof P Wong & B Halliwell, NUS) so as to identify new therapeutic targets.

Neuroimaging
As part of the Stroke CRP (B Chan, V Sharma & KH Chuang), we plan to investigate other modalities such as diffusion tensor imaging and ASL, in line with our long term strategy of developing bioimaging as an outcome measure and to better understand pathophysiology.
Other Biomarkers We are investigating the association of retinal microvascular signs in acute stroke with stroke subtype & prognosis (TY Wong, MC Wong, HM Chang, D de Silva) and also utilizing proteonomics (N Sze), lipodomics (M Wenk) and metabolomics (CN Ong) for biomarker discovery in stroke.

Genetics In addition to our ongoing work with the GIS on haplotype-based case control association analysis of homocysteine metabolism candidate genes (JJ Liu), we plan to extend this work to other candidate genes, intracranial disease and cognitive impairment (B Chan, V Sharma, R Seet and P Wong).

Clinical Trials
A major goal is to developing a regional Neuroscience clinical trials network with a coordinating centre based in Singapore for larger scale trials as well as sophisticated Phase II studies utilising biomarkers such as neuroimaging, neurochemistry and molecular biology so as to:
Accelerate clinical evaluation of the best scientific ideas and approaches for treatment and prevention of diseases affecting the brain & nervous system
Study a broader range of clinically relevant questions.
Create a more effective and efficient neuroscience clinical trials system.
Enhance collaborations between academia, industry, and other agencies in developing promising therapeutic and preventive approaches.
Make access to clinical trials a realistic possibility for many more patients with diseases affecting the brain and nervous system.
Achieve better short-term assessment of promising strategies by developing and validating molecular and imaging biomarkers.
Singapores society reflects the diversity of Asia but combines this with excellent infrastructure for medical care and clinical trials. Whilst Singapores own population is only 5 million, availability of medical care is not limited by geographical or economic barriers. Hence, there exists a readily accessible pool of patients. The most common neurological disorders would include stroke and dementia. Many well trained Singaporean neuro-clinicians are or have been actively engaged in clinical trials. Nevertheless, it is clear that we are not fully utilizing our potential. There remains a great need to nurture new investigators and to enhance our ability to perform more sophisticated and innovative studies, which would be greatly facilitated by the formation of a Neuroscience Clinical Trials network especially if core staff and resources could have a shared location in the SCRI.

Furthermore, Singapore is already a regional center for clinical trial organization and leadership. In particular, the first regionally designed acute stroke trial was organized between the NNI, Chinese University of Hong Kong and CTERU in 2001 (Lancet Neurology 6 (2007) 407-13). A further regional acute stroke trial utilizing advanced surrogate outcomes (multiple emboli detection & diffusion weighted imaging) has also been completed (Lancet Neurology 9 (2010) 489-97). The innovative CHIMES study of stroke recovery is nearly 2/3 complete and has sites from 5 countries (International Journal of Stroke 4 (2009) 54-60) Thus, there is potential for a Neuroscience Clinical Trial network for the Asia-Pacific region to be established in Singapore by collaboration between sites in Singapore and across the region with the support of the SCRI. By investing in, restructuring, and increasing the capacity of our neuroscience clinical trials program, we would enable Singapore to take a leading role in clinical trials and thus further the development of the biomedical sciences by improving the visibility of Singapore and the regions neuroscience capabilities to pharmaceutical / biomedical enterprises; coordinating existing clinical trial centres, and development of new centres of excellence; more efficiently convert recent scientific discoveries into effective interventions and increase patient access to clinical trials.

In the first instance, I intend to further develop the SCRI supported dementia research network into a regional dementia network with the support of SCRI (J Rush, S Lim, SB Tan) and the Asian Society Against Dementia of which I am the Secretary-General, which will be based in Singapore.

Mentoring and training of junior scientists
I aim to continue to continue to foster an academic, research orientated environment within our clinical and research programmes through a commitment to sub-speciality development, the practice and development of evidence based medicine and a close relationship between basic, translational and clinical research.

We plan to increase the numbers of clinical and research fellows, especially those reading for higher degrees, through the existing programme grants. In addition, the MACC has a pilot grants scheme which will be utilized to encourage junior researchers to plan and execute their initial research projects.

Selected Publications

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer’s disease but not Lewy Body Dementias. Journal of Neuroinflammation 20, 111 (2023) IF=9.3

Chai YL…Chen CP, Aarsland D, Lai MKP.

Association of plasma GFAP with elevated brain amyloid is dependent on severity of white matter lesions in an Asian cognitively impaired cohort. Alzheimers Dement (Amst). (2024) Apr 11;16(2): e12576. IF=5.3

Chong JR, Chai YL, Yam ATY, Hilal S, Vrooman H, Venketasubramanian N, Blennow K, Zetterberg H, Ashton NJ, Chen CP, Lai MKP.

Elevated Soluble TNF-Receptor 1 in the Serum of Predementia Subjects with Cerebral Small Vessel Disease. Biomolecules. (2023) 525 IF=5.5

Salai KHT, Wu LY, Chong JR, Chai YL, Gyanwali B, Robert C, Hilal S, Venketasubramanian N, Dawe GS, Chen CP, Lai MKP.

Lipidomics profiling reveals distinct patterns of plasma sphingolipid alterations in Alzheimer’s disease and vascular dementia. Alzheimer's Research & Therapy 15 (2023) 214 IF=9

Chua XY, Torta F, Chong JR, Venketasubramanian N, Hilal S, Wenk MR, ...Chen CP, Arumugam TV, Herr DR, Lai MKP.

Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics. Antioxidants 11 (2022) 1717 IF=7

Wu LY, Kan CN, Cheah IK, Chong JR, Xu X, Vrooman H, Hilal S, Venketasubramanian N, Chen CP, Halliwell B, Lai MKP.

Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia. Free Radical Biology and Medicine 177 (2021) 201-211 IF=7.4

Wu LY, Cheah IK, Chong JR, Chai YL, Tan JY, Hilal S, Vrooman H, Chen CP, Halliwell B, Lai MKP.

Plasma P-tau181 to Aβ42 ratio associates with brain amyloid burden and hippocampal atrophy in an Asian cohort of Alzheimer’s disease patients with concomitant cerebrovascular disease. Alzheimer's & Dementia 17 (2021) 1649-1662 IF=14

Chong JR, Ashton NJ, Karikari TK, Tanaka T, Saridin FN, Reilhac Am Robins EG, Nai YH, Vrooman H, Hilal S, Zetterberg H, Blennow K, Lai MKP, Chen C.

Lysosomal cathepsin D is upregulated in Alzheimer’s disease neocortex and may be a marker for neurofibrillary degeneration. Brain Pathology 29 (2019) 63-74 IF=6.4

Chai YL, Chong JR, Weng JJ, Howlett D, Halsey A, Lee JH, Attems J, Aarsland D, Francis PT, Chen CP, Lai MK.

The brain lipidomes of subcortical ischemic vascular dementia and mixed dementia Neurobiology of Aging 35 (2014) 2369-2381 IF=4.2

Lam SM, Wang Y, Duan X, Wenk MR, Kalaria RN, Chen CP, Lai MK, Shui GH.

Interethnic differences in neuroimaging markers and cognition in Asians, a population-based study. Sci Rep. (2020);10(1):2655. IF=4.6

LCK Wong, MYZ Wong, CS Tan, H Vrooman, N Venketasubramanian, CY Cheng, C Chen, S Hilal.

Prevalence and Risk Factors for Cognitive Impairment and Dementia in Indians: A Multiethnic Perspective from a Singaporean Study. J Alzheimers Dis. (2019);71(1):341-351. IF=4

MYZ Wong, CS Tan, N Venketasubramanian, C Chen, MK Ikram, CY Cheng, S Hilal.

Prevalence of cognitive impairment and dementia in Malays – Epidemiology of Dementia in Singapore Study Current Alzheimer Research 14 (2017) 620-27 IF=2.1

S Hilal, CS Tan, X Xin, SM Amin, TY Wong, C Chen, N Venketasubramanian, MK Ikram.

Prevalence of and risk factors for cognitive impairment and dementia in Chinese: The Epidemiology of Dementia in Singapore (EDIS) Study J Neurology Neurosurgery & Psychiatry 84 (2013) 686-92 IF=11.1

S Hilal, MK Ikram, M Saini, JA Catindig, CS Tan, YH Dong, L Lim, A Qui, TY Wong, C Chen, N Venketasubramanian.

Epidemiology of Dementia in Asia: Insights on Prevalence, Trends and Novel Risk Factors J of Neurological Sciences 321 (2012) 6-11 IF=4.4

JA Catindig, N Venketasubramanian, MK Ikram, C Chen

The prognostic effects of post stroke cognitive impairment no dementia and domain specific cognitive impairments in non-disabled ischemic stroke patients Stroke 42 (2011) 883-8 IF=8.4

K Narasimhalu, S Ang, DA De Silva, MC Wong, HM Chang, KS Chia, AP Auchus, C Chen

Inter-Ethnic Differences In Dementia Epidemiology – Global And Asia-Pacific Perspectives Dement Geriatr Cogn Disord 30 (2010) 492-8 IF=2.4

N Venketasubramanian, S Sahadevan , EH Kua , CPL Chen, TP Ng.

Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort. Neurology 73 (2009) 1866-1872 IF=10.1

K Narasimhalu, S Ang, DA De Silva, MC Wong, HM Chang, KS Chia, AP Auchus, C Chen.

Lecanemab in Early Alzheimer's Disease. N Eng J Med. 388 (2023) Jan 5;388(1):9-21 IF=158.5

van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, et al.

The SINgapore GERiatric intervention study to reduce cognitive decline and physical frailty (SINGER): Study Design and

Xu X, Chew KA, Wong ZX, Phua AKS, Chong EJY, Teo CKL, Sathe N, Chooi YC, Chia WPF, Henry CJ, Chew E, Wang M, Maier AB, Kandiah N, Chen CL-H

Alzheimer’s disease THErapy with NEuroaid (ATHENE): A randomized double-blind delayed-start trial. Journal of the American Medical Directors Association 23 (2022) 379-86 IF=7.6

Chen CLH, Lu Q, Moorakonda RB, Kandiah N, Tan BY, Villaraza SG, Cano J, Venketasubramaniam N.

NEURoaid II (MLC901) in cognitively Impaired not demenTEd patientS (NEURITES): a pilot double blind, placebo-controlled randomized Trial. Alzheimer's & Dementia: Translational Research & Clinical Interventions 7 (2021) e12141 IF=4.8

Chen CLH, Nguyen TH, Marasigan S, Lee CF, Lu Q, Kandiah N, de Silva D, Chong E, Venketasubramanian N.

B Vitamins and Cognition in subjects with small vessel disease: An extension study of VITATOPS, A Randomised, Placebo-Controlled Trial. J Neurol Sci 379 (2017) 124-126 IF=4.4

SKS Ting, A Earnest, H Lid, S Hameed, HM Chang, CLH Chen, EK Tan.

CHInese Medicine NeuroAiD Efficacy on Stroke recovery – Extension Study (CHIMES-E: A multicenter study of long-term efficacy Cerebrovascular Diseases 39 (2015) 309-18 IF=2.9

N Venketasubramanian, SHY Young, SS Tay, T Umapathi, AY Lao, HH Gan, AC Baroque II, , JC Navarro, HM Chang, JM Advincula, S Muengtaweepongsa, BPL Chan, CL Chua, N Wijekoon, HA de Silva, JHB Hiyadan, NC Suwanwela, KSL Wong, N Poungvarin, GB Eow, CF Lee, CLH Chen.

Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. Lancet. 385 (2015) 617-28 IF=168.9

Bath PMW, Woodhouse L, Scutt P, Krishnan K, Wardlaw JM, Bereczki D, Sprigg N, Berge E, Beridze M, Caso V, Chen C, Christensen H, Collins R, El Etribi A, Laska AC, Lees KR, Ozturk S, Phillips S, Pocock S, de Silva HA, Szatmari S, Utton S

Chinese Medicine Neuroaid Efficacy on Stroke Recovery A Double-Blind, Placebo-Controlled, Randomized Study Stroke 44 (2013) 2093-2100 IF=8.4

CLH Chen, SHY Young, HH Gan, R Singh, AY Lao, AC Baroque II, HM Chang, JHB Hiyadan, CL Chua, JM Advincula, S Muengtaweepongsa, BPL Chan, HA de Silva, S Towanabut, NC Suwanwela, N Poungvarin, S Chankrachang, KSL Wong, GB Eow, JC Navarro, N Venketasubramanian, CF Lee, M-G Bousser

Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial

Wong KSL, Chen C, Fu J, Chang HM, Suwanwela NC, Huang YN, Han Z, Tan KS, Ratanakorn D, Chollate P, Zhao Y, Koh A, Hao Q, Markus HS

CT-based volumetric measures obtained through deep learning: Association with biomarkers of neurodegeneration. Alzheimers Dement. (2024) Jan;20(1):629-640. IF=14

Srikrishna M, Ashton NJ, Moscoso A, Pereira JB, Heckemann RA, van Westen D, Volpe G, Simrén J, Zettergren A, Kern S, Wahlund LO, Gyanwali B, Hilal S, Ruifen JC, Zetterberg H, Blennow K, Westman E, Chen C, Skoog I, Schöll M.

Associations of blood cardiovascular biomarkers with brain free water and its relationship to cognitive decline: A diffusion-MRI study, Neurology (2023) Jul 11;101(2):e151-e163 IF=10.1

Ji F…Chen C, Lai MKP, Zhou JH.

Retinal parameters, cortical cerebral microinfarcts and their interaction with functional cognitive impairment. International Journal of Stroke (2023) Jan;18(1):70-77 IF=6.7

Hilal S, Cheung CY, Wong TY, Schmetterer L, Chen C.

A deep learning model for detection of Alzheimer's disease based on retinal photographs: a retrospective, multicentre case-control study. Lancet Digital Health (2022) Nov;4(11):e806-e815. IF=30.8

Cheung CY, Ran AR, Wang S, Chan VTT, Sham K, Hilal S, Venketasubramanian N, Cheng CY, Sabanayagam C, Tham YC, Schmetterer L, McKay GJ, Williams MA, Wong A, Au LWC, Lu Z, Yam JC, Tham CC, Chen JJ, Dumitrascu OM, Heng PA, Kwok TCY, Mok VCT, Milea D, Chen CL, Wong TY.

Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer’s disease. Brain 140 (2017) 3012-3022 IF=14.5

Chong, JSX, Liu, S, Loke YM, Hilal S, Ikram Mohammad, Xu X, Tan BY, Venketasubramanian N, Chen C, Zhou J.

Association between subclinical cardiac biomarkers and clinically manifest cardiac diseases with cortical cerebral microinfarcts. JAMA Neurology 74 (2017) 403-1 IF=29

S Hilal, YL Chai, S van Veluw, MA Shaik, MK Ikram, N Venketasubramanian, AM Richards, GJ Biessels, C Chen.

Cerebral Microbleeds and Neuropsychiatric Symptoms in an Elderly Asian Cohort. J Neurol Neurosurgery & Psychiatry 88 (2017) 7-11 IF=11.1

X Xu, QL Chan, S Hilal, WK Goh, M K Ikram, N Venketasubramanian, T Y Wong, CY Cheng, CL-H Chen.

Detection, risk factors, and functional consequences of cerebral microinfarcts. Lancet Neurology 16 (2017) 730-40 IF=48

SJ van Veluw, AY Shih, EE. Smith, C Chen, JA Schneider, JM Wardlaw, SM Greenberg, GJ Biessels.