PROGRAMME

Paramedic on the Frontline: Rapid Stroke Recognition and Safe Handover

Stroke is a time-critical emergency in which early recognition, decisive prehospital action, and a safe, structured handover can directly influence patient outcomes. In the frontline setting, paramedics play a pivotal role in identifying stroke signs, differentiating stroke from common mimics, initiating appropriate pre-notification, and preparing the patient for rapid transfer to definitive care. This lecture will examine the paramedic’s contribution across the stroke pathway, from first clinical contact to hospital handover, with emphasis on practical strategies that support speed without compromising safety.

The talk will highlight key considerations in rapid stroke recognition, including focused assessment, scene prioritisation, and clinical decision-making in dynamic environments. It will also address safe handover principles, including concise communication, relevant clinical information transfer, and coordination with receiving teams to reduce delays and support continuity of care. Drawing from frontline experience, the lecture will reinforce how disciplined assessment, teamwork, and system-aware practice can improve the quality of prehospital stroke care.

Brief outline:
- The paramedic’s role in the acute stroke pathway.
- Rapid stroke recognition in the field.
- Common stroke mimics and prehospital decision-making.
- Scene management, transport prioritisation, and pre-notification.
- Safe, structured handover to the receiving hospital team.
- Practical lessons for improving speed, safety, and patient outcomes.

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Understanding Biological Ageing-Related Biomarkers in Neurodegenerative Diseases

Introduction: Aging is the strongest risk factor for Alzheimer's disease (AD) characterized by amyloid-β (Aβ) plaques and tau tangles in the brain. We aim to compare biological aging-related biomarkers among AD, non-neurodegenerative control (NDC) and non-AD neurodegenerative (Non-AD) individuals to evaluate their clinical utility.

Methods: We included 137 participants (37 NDC, 67 AD, 33 Non-AD) from the University College London (UCL) Dementia Research Centre and measured matrix metallopeptidase 10 (MMP-10), osteopontin (OPN), neurofilament-light, and glial fibrillary acidic protein in cerebrospinal fluid (CSF) in addition to Aβ/pTau and clinical parameters.

Results: Elevated MMP-10 associated with poorer cognition and later onset specifically in AD, whereas elevated OPN associated with Aβ and tau pathology. MMP-10 and OPN levels improved the differentiation of AD from NDC, and AD from Non-AD, respectively.

Discussion: Our study provides evidence on potential clinical utility of CSF MMP-10 and OPN in diagnosis and supports taking biological aging into consideration in AD research.

How Neurodegenerative and Cerebrovascular Diseases Relate to Brain Functional Connectivity, Cognition and Behaviour: Evidence from Neuroimaging

Cerebrovascular disease and neurodegenerative diseases such as Alzheimer’s disease are among the leading causes of cognitive impairment and dementia in older adults. Resting-state functional magnetic resonance imaging offers a powerful tool for elucidating the brain functional changes associated with these diseases and their impact on cognition and behaviour. In this talk, I will present a series of studies examining how multiple diseases, including Alzheimer’s disease, cerebrovascular disease and behavioural-variant frontotemporal dementia, relate to brain functional connectivity as well as cognition and behaviour, providing insights into the role of large-scale network dysfunction in neurodegenerative and cerebrovascular diseases.

Brain Age Gap in the Memory Clinic: From Validation to Application

Brain age gap, defined as the difference between predicted brain age and chronological age, has emerged as a potential marker of brain health and accelerated ageing. This talk will present work examining the utility of brain age gap across local clinical populations, including validation within a Singaporean memory clinic cohort and its associations with cognitive and mental health outcomes.

Findings from longitudinal and cross-sectional studies suggest that brain age gap may provide clinically relevant insight into cognitive decline, neurodegenerative risk, and interactions with psychological factors. Together, these studies highlight the potential of brain age gap as a scalable biomarker for understanding variation in brain health across ageing populations.

Citation of Additional Authors: Elenor Morgenroth, Kymberly Goh Kai Xuan, Elaine Teo Yi Li, Jayne Tan Yi, Seyed Ehsan Saffari, Nicole Isabella Tan Yi Zhen, , Ng Kok Pin, Chiew Hui Jin, Ting Kang Seng Simon, Seyed Shahul Hameed Wahab, Jinesh Mukesh Shah, Adeline Ng Su Lyn

Imaging Blood–Brain Barrier Dysfunction Across Ageing and Small Vessel Disease: From Mechanisms to Therapeutic Implications

This talk will explore the role of blood brain barrier dysfunction in brain aging and cerebral small vessel disease, highlighting its importance as an early and potentially modifiable contributor to cognitive decline and dementia. Focusing particularly on Asian populations, the presentation will examine how advances in non-invasive neuroimaging are transforming our ability to detect and characterise vascular and neurodegenerative changes in vivo.

Drawing on multimodal MRI, including advanced structural imaging and novel techniques for assessing blood–brain barrier integrity, this talk will demonstrate how neuroimaging can be integrated with fluid biomarkers and cognitive profiling to provide a more comprehensive understanding of disease mechanisms. Particular attention will be given to the interplay between vascular dysfunction, cerebral amyloid angiopathy, and neurodegeneration, including the implications of these processes for emerging anti-amyloid therapies.

By bridging mechanistic insights with clinical application, this talk will highlight how innovative imaging approaches can improve disease phenotyping, inform patient stratification, and support the development of precision therapeutics in ageing and dementia.

Transcriptomic Architecture of MRI-Derived Brain Ageing

MRI-derived brain age gap (BAG) quantifies how old a brain appears relative to chronological age and is increasingly used as a marker of brain health, with links to cognitive decline, neuropsychiatric disease, and mortality. In this lecture, I will outline how BAG can be used as a biologically meaningful phenotype and how genetic and transcriptomic data help explain individual differences in brain ageing.

Drawing on large population studies, I will describe an integrative framework that connects genetic variation to BAG through predicted gene expression and RNA splicing across brain and peripheral tissues. A central finding is that BAG-related molecular signals are highly reproducible and organised by tissue type, with splicing-based effects showing stronger consistency and causal support than conventional gene expression signals.

Rather than reflecting a diffuse polygenic process, the transcriptomic architecture of BAG is shaped by a small number of dominant regulatory hubs. Evidence from causal inference analyses supports isoform-level regulation as a key mechanism linking genetic variation to brain ageing, while additional neuronal, metabolic, immune, and vascular pathways likely reflect downstream or correlated biology. Focusing on the 17q21.31 locus, I will illustrate how a coordinated switch in RNA splicing can account for many local genetic–transcriptomic associations with BAG, providing insight into how genetic risk translates into brain-wide ageing patterns.

Citation of Additional Authors (if any): Qiaoyang Sun, Ling Ling Chan, Eng-King Tan

Lunch Break

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Therapeutic Approaches for Repeat Expansion Diseases

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene. This generates neurotoxic species, including mutant polyglutamine (polyQ)-containing Huntingtin protein and expanded CAG RNA transcripts. Our group previously identified a peptide, RP001, that binds mutant CAG transcripts and suppresses polyQ toxicity in vitro and in vivo. In this study, we report RP001v63, a rationally engineered variant with enhanced bioactivity and stability. RP001v63reduces soluble mutant Htt, suppresses CAG RNA foci and Htt aggregation in cellular and animal HD models. Intranasal nose-to-brain delivery of RP001v63 successfully reaches the striatum—the most affected region—in R6/2 HD mice, alleviates locomotor deficits, and restores transcriptional abnormalities in apoptosis pathway (RNA-seq). In summary, this work presents a peptide biologics against triplet repeat disorders and a non-invasive brain-targeting therapeutic approach for ameliorating HD neurodegeneration.

Therapeutic Targeting of NOTCH2NLC-polyG in NOTCH2NLC-Related GGC Repeat Expansion Disorders (NRED)

NOTCH2NLC-related GGC repeat expansion disorders (NRED), including neuronal intranuclear inclusion disease, are progressive neurodegenerative conditions with no disease-modifying therapies. These disorders are caused by expanded GGC repeats in NOTCH2NLC, yet the mechanisms linking repeat expansion to neurodegeneration remain incompletely defined. Here, we establish and characterize a human disease-relevant model to investigate NRED pathogenesis and therapeutic targeting. We demonstrate that GGC repeat expansions drive the production of toxic polyglycine (polyG) proteins via repeat-associated non-AUG (RAN) translation, resulting in protein aggregation and cellular dysfunction. These findings provide mechanistic insight into how repeat expansions contribute to neuronal vulnerability.
To advance therapeutic development, we evaluated NOTCH2NLC mRNA-binding peptides in our in vitro models. Treatment reduced polyG aggregation and partially rescued disease-associated phenotypes, supporting the feasibility of targeting repeat-containing transcripts to mitigate downstream toxicity. Collectively, this work identifies NOTCH2NLC-polyG as a tractable therapeutic target and supports RNA-targeting strategies as a promising approach for NRED. These findings provide a translational framework bridging disease mechanism to therapeutic intervention, with potential relevance for a broader class of repeat expansion disorders.

Novel Tau11i Species Exhibits Pathological Properties and Is Elevated in Blood Plasma from Alzheimer's Disease Patients

A novel Tau11i isoform was previously found to be enriched in Alzheimer’s disease (AD) brains. Further characterization showed that the 19-amino acid peptide encoded by retained intron 11 facilitates the formation of high-molecular-weight heterodimers and phase-separated liquid droplets, as well as enhances heparin-induced beta-sheet aggregation and cellular seeding of Tau11i. Compared to full-length Tau441 isoform, expression of Tau11i in human neurons caused significant transcriptional changes that recapitulated single-cell molecular signatures of neurofibrillary tangle (NFT)-free excitatory AD neurons in the prefrontal cortex. These data suggest that Tau11i contribute to AD pathology by inducing pathological aggregation and transcriptional dysregulation that resembles the molecular signatures of NFT-free AD neurons. Importantly, Tau11i was detected in human plasma. Preliminary results indicate that Tau11i levels are elevated in blood plasma from AD patients as compared to healthy controls.

Mechanisms of Membrane Potential Regulation as a Strategy Against Excitotoxicity in Vascular Dementia

Vascular dementia (VaD) is an age-related, heterogeneous clinical syndrome affecting cognitive and psychomotor functions. In VaD, impaired circulation deprives oxygen and nutrient supply to the brain, causing neuronal death. During the process, increased level of extracellular excitatory neurotransmitter glutamate activates glutamate receptors such as N-methyl-D-aspartate receptor (NMDA receptor). Excessive calcium influx via NMDA receptors triggers multiple mechanisms of cellular death known as excitotoxicity. Many high-affinity NMDA receptor antagonists have failed in clinical trials because they indiscriminately block both pathological excitotoxicity and essential physiological neuronal signalings. Under resting state, NMDA receptor is blocked by physiological magnesium which can be removed by membrane depolarization under conditions of hypoxia/ischemia. Thus, managing membrane potential provides a unique way to regulate NMDA receptor activity under pathological conditions without affect healthy neurons for physiological functions. In this talk, I will also share our research to regulate membrane potential in neurons under chronic hypoxia. This marks a novel therapeutic approach to manage VaD.

Tea Break

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Precision Modelling of Blood–Brain Barrier Dysfunction in

Vascular Dementia: Therapeutic Insights from an Asian-Specific NOTCH3 Mutation

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of vascular dementia caused by mutations in NOTCH3, leading to progressive vascular dysfunction and cognitive decline. An Asian-specific NOTCH3 variant is carried by approximately 1% of the Singaporean Chinese population, yet its impact on blood–brain barrier (BBB) function remains poorly understood.

Here, we established patient-derived induced pluripotent stem cell (iPSC)–based BBB models to investigate CADASIL vascular pathogenesis. Patient peripheral blood mononuclear cells were reprogrammed into iPSCs, and the mutation was corrected using CRISPR–Cas9 to generate isogenic controls. Mutant and corrected iPSCs were differentiated into endothelial cells, pericytes, and astrocytes, followed by transcriptomic and functional analyses and integration into a 3D BBB-like microtissue model.

Mutant endothelial cells and astrocytes exhibited dysregulated extracellular matrix, angiogenic, and inflammatory pathways, with impaired angiogenesis and reduced barrier integrity. Correspondingly, 3D mutant BBB microtissues displayed disorganized vasculature, increased permeability, and a pro-inflammatory secretory profile. These findings highlight the multicellular consequences of this NOTCH3 variant and demonstrate the utility of precision BBB modeling for identifying therapeutic targets in CADASIL.

Reconceptualising FTD/ALS: The Emerging Role of SFPQ

Age-related neurodegenerative diseases such as front-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exist on a spectrum and remain largely untreatable due to an incomplete understanding of their underlying cellular and molecular mechanisms. Our laboratory focuses on elucidating the pathogenic processes driving neuronal degeneration in FTD/ALS using patient-derived human stem cell models. Over the past two decades, we have developed and refined methods to generate induced pluripotent stem cells from patients and differentiate them into disease-relevant neural cell types, including region-specific neurons and glia. These systems allow us to examine the sequence of molecular events that occur within specific cell populations during disease progression. In this presentation, I will highlight key contributions from our laboratory toward understanding the mechanisms underlying neuronal degeneration in FTD/ALS. Specifically, we investigate cell type-specific processes implicated in disease pathogenesis: aberrant intron retention, mislocalisation of the RNA-binding protein SFPQ, and the reactive transformation of astrocytes. By dissecting how these events arise, when they occur, and in which cell types they manifest, our work aims to define critical drivers of neurodegeneration. Together, these studies provide insight into the cellular and molecular origins of FTD/ALS and identify potential targets for therapeutic intervention, with the ultimate goal of developing effective treatments for patients with neurodegenerative disease.

Panel Discussion: Advanced Biomarker and Therapeutics in Neurocognitive Disorders

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End of Seminar

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