Fatin Zahra Zailan

Background Statins are the most prevalent treatment for dyslipidaemia, but cognitive side effects are disputed. This study examines the impact of statins on cognition within a prospective study specifically designed to examine cognitive outcomes and underlying pathobiology. Objective To evaluate the association between statin-use on cognitive impairment and voxel-wise and network-based grey matter atrophy. Design Cross-sectional cognitive and neuroimaging data obtained from a prospective cohort study. Setting Community-based, Southeast Asian cohort. Participants Participants(n=1170) from the BIOCIS cohort were classified as Cognitively Normal(CN) or Mild Cognitive Impairment(MCI). Participants were categorized into normal cholesterol no statins(S-C-), normal cholesterol with statins(S+C-), and high cholesterol no statins(S-C+). Exposures Neuropsychological test battery, Magnetic Resonance Imaging, Apolipoprotein E4 genotyping Main Outcome(s) and Measure(s) Montreal Cognitive Assessment (MoCA) and z-scores across episodic memory, executive function, processing speed, visuospatial, and language domains were employed to evaluate cognitive performance and voxel-based and functional network-based grey matter atrophy. Results 1170 participants (age=61.6±10.3, 63% female), comprising 558 CN and 612 MCI, were included. Among CN, S+C- performed significantly worse than S-C- on MoCA (Cohen’s đ=-0.386, p=0.014), episodic memory (đ=-0.374, pConclusions Statin use and duration was significantly associated with impairment across cognitive domains in CN and MCI participants. Impairment in cognitive function among statin users was correlated to voxel-based and network-based grey matter atrophy in brain regions crucial for cognition. Prospective longitudinal studies need to confirm the adverse cognitive effects of statins and facilitate appropriate clinical use.

Background: Behavioral and psychological symptoms are one of the earliest observable changes when a person experiences cognitive decline. These symptoms are common and are known as Neuropsychiatric symptoms(NPS), which increases risk of progression to dementia. The prevalence of NPS was compared in a cohort of Southeast Asian adults with Subjective Cognitive Decline(SCD) and Mild Cognitive Impairment(MCI).Method: This study utilized cross‐sectional data from the Biomarkers and Cognition Study, Singapore(BIOCIS). From February to December 2022, participants who met criteria for SCD and MCI in accordance with NIA‐AA’s criteria were classified into two groups, NPS and without‐NPS, based on clinical cut‐offs of Depression Anxiety Stress Scales(DASS) scores. Self‐reported questionnaires assessed behavioral symptoms ‐ Mild Behavioral Impairment‐Checklist(MBI‐C); Dementia‐Quality of Life Instrument(Dem‐QOL); International Physical Activity Questionnaire(IPAQ); and Pittsburgh Sleep Quality Index(PSQI). Group comparisons of data were applied separately using univariate analyses. A Receiver Operating Characteristic analysis was conducted to test the diagnostic performance of MBI‐C total, MBI‐C‐subdomains, and PSQI in distinguishing participants with NPS and without‐NPS.Result: 488 participants (μ age = 62.7±9.64,42.2% males) were analyzed. 133(27.25%) reported significant NPS symptoms. Participants with NPS reported significantly more symptoms on MBI‐C‐total(p<.001); interest(p<.001); mood(p<.001); control(p<.001), social(p<.001), and beliefs(p<.001) subdomains; poorer sleep(p<.001) and lower quality of life(p<.001) compared to participants without‐NPS(Table 1). MBI‐C‐total, MBI‐C‐mood and MBI‐C‐control subdomains were effective in discriminating between participants with and without NPS, with an acceptable Area Under the Curve: .782(.732‐.833) for MBI‐C‐total, .753(.699‐.807) for MBI‐C‐mood, and .753(.699‐.807) for MBI‐C‐control(Figure 1 and Table 2).Conclusion: In a prodromal cohort of southeast Asians, participants with NPS reported significantly worse scores on MBI‐C‐total and subdomains, specifically ‐ decreased motivation, emotional dysregulation, impulse control, social inappropriateness, abnormal perceptions, as well as poorer sleep quality and a lower quality of life compared to participants without‐NPS. The results are keeping with the strong evidence that behavioral changes are among the first symptoms noticeable to the person themselves as they begin to experience cognitive decline. The self‐reported questionnaires used are easily administered and brief, which has important real‐world relevance for early diagnoses of, and timely intervention for prodromal dementia. Further studies of BIOCIS is on‐going to investigate the impact of NPS on cognitive decline.

Background: White matter(WM) fibres have been shown to be vulnerable to amyloid‐beta and cerebrovascular disease(CVD) (Vipin et al.,2019; Croall et al.,2017; Salthouse et al.,2011). Indeed, fractional anisotropy(FA) of corpus callosum genu has been shown to capture variability in systemic vascular health and CVD (Vemuri et al., 2018). WM alterations are also associated with memory and executive function decline(Salthouse 2011). Additionally, the CAIDE risk score estimates future dementia risk based on vascular, demographic and genetic risk factors(Kivipelto et al.,2006). However, given the high CVD load among Asians, the combined influence of such risk factors and amyloid‐beta on WM microstructure and cognition in an Asian cohort needs further exploration. Thus, we examined WM FA between low, medium and high CVD‐amyloid pathology and association with cognition in a pre‐dementia Asian cohort. We hypothesized that derogatory WM FA reduction would be greatest in the high CVD‐amyloid group and relate to worse cognition.Method: In a community cohort of 78 pre‐dementia subjects having undergone diffusion tensor imaging (mean age:55.37 years; mean education:14.72 years), neuropsychological assessments, CAIDE derivation (CVD risk) and oligomeric amyloid‐beta from the Dementia Research Centre (Singapore), we identified low CVD‐amyloid pathology (A‐C‐,n = 24), intermediate CVD‐amyloid (A±C±,n = 46) pathology and high CVD‐amyloid (A+C+,n = 8). TRActs Constrained by UnderLying Anatomy, FreeSurfer, was used to reconstruct major white matter tracts and fibre‐based FA, a measure of white matter tract overall health, was derived.Result: Increasing CVD‐amyloid pathology related to worsening white matter microstructure with A+C+ subjects showing lowest FA in the corpus callosum genu compared to the A‐C‐ group (Fig. 1). Furthermore, higher FA in the corpus callosum splenium related to better executive function/ working memory performance (indexed using the digit span backwards test) in the A‐C‐ group (Fig. 2). In the A±C± group, presence of either amyloid or CVD pathology related to reduced executive function performance.Conclusion: In this community cohort of pre‐dementia older adults, we illustrate associations between presence of amyloid and CVD pathology and WM microstructure and cognitive disruption, especially in fibre tracts related to vascular disease and cognitive resilience. Early interventions targeting amyloid and vascular risk factors could encourage neuroplasticity, providing a window for recovery in cognitive performance.

Background: Our previous work has shown increased presence of early behavioural impairment in Asian than Western cohorts(Soo et al.,2021). Such impairments include mild behavioural changes, sleep disruptions and higher depression, anxiety and stress, in turn representing an at‐risk state which may predict later development of dementia(Müller‐Spahn,2003;Soo et al.,2021). Additionally, growing evidence illustrates that cerebrovascular changes are a key component in the pathological sequelae and may be detectable years before clinical presentation of dementia (de la Torre,2018). However, the influence of cerebral perfusion on behaviour, especially in pre‐dementia stages remains to be elucidated. Thus, we examined the association between regional grey matter perfusion and behaviour in cognitively normal(CN) and subjects with mild cognitive impairment(MCI) or subjective cognitive decline(SCD). We hypothesized that grey matter perfusion deficits would be related to behaviour impairment even in early stages of SCD/MCI.Method: We studied 35 CN and 248 pre‐dementia (MCI/SCD) from a community‐based research cohort from the Dementia Research Centre (Singapore) with neuroimaging, neuropsychological and behavioural assessments(Table 1). We investigated the association between regional grey matter perfusion across 31 regions of interest spanning frontal, parietal, temporal and occipital lobes using 2D pulsed Arterial Spin Labelling and performance on the mild behaviour impairment‐checklist(MBI‐C), Pittsburgh Sleep Quality Index(PSQI) and Depression, Anxiety and Stress Scale(DASS). These associations were examined in CN and MCI/SCD groups separately and respective Pearson’s correlation matrices were derived.Result: Overall, greater behavioural impairment on the MBI‐C, DASS and PSQI was associated with hypoperfusion across multiple grey matter regions. This association was stronger in CN than in the pre‐dementia group. Specifically, among CN, hypoperfusion in the frontal, parietal and occipital lobes related most strongly to greater behavioural impairment, especially MBI‐C and DASS depression(Fig.1). In the MCI+SCD group, only hypoperfusion in the frontal and temporo‐occipital regions related to worse behavioural impairment across the MBI, PSQI and DASS(Fig.2).Conclusion: In this study, we illustrate differential associations between cerebral hypoperfusion and behavioural impairment in CN and MCI/SCD groups, with CN individuals showing more widespread and stronger associations between behavioural impairment and hypoperfusion across the brain. In SCD/MCI, hypoperfusion in frontal and temporo‐occipital regions were associated with behavioural impairment.

Background: Gait speed has been found to be associated with cognitive function (Liu, 2022) with slower walking speed related to poorer cognition (Hoogendijik, 2020). Slower gait speed was found to be associated with poorer global cognitive function, verbal memory and executive function (Watson, 2010). Additionally, APOE E4 carriers with slow gait speed have been found to perform worse on the MMSE than APOE E4 carriers without slow gait and APOE E4 non‐carriers with slow gait (Sakurai, 2017).We aim to evaluate the moderating effects of APOE E4 status on gait speed and cognition in a pre‐dementia community population in Singapore.Method: We recruited 534 participants from the community who completed a detailed neuropsychological assessment and APOE genotyping. To test for the moderating effects of APOE E4 with gait speed and cognition, we performed a multiple generalized linear model controlling for covariates of age, sex and education.Result: The cohort included 186 subjects with subjective cognitive decline and 348 mild cognitive impairment subjects from Dementia Research Centre (Singapore). Mean age of the cohort was 62.55, SD = 9.55, mean education years was 13.97, SD = 3.45 and majority were women (57.1%). The presence of slow gait speed among our cohort was 4.7% and there were 12.6% APOE E4 carriers. There were no significant differences in walking gait between APOE E4 carriers and non‐carriers (p = 0.235). APOE E4 moderated the effect of slow gait speed on executive function. APOE E4 non‐carrier interacted with slow gait speed, resulting in worse performance on the trail making task B (β = 71.97, p = 0.003), digit span backwards (β = ‐2.23, p = 0.037), and colour trails 2 (β = 64.01, p<0.001).Conclusion: APOE E4 status moderates the effect of slow gait speed on executive function. APOE E4 non‐carriers with slow gait speed are at risk for poorer executive function.

Background: MicroRNAs(miRNAs) form the most intensively characterised branch of non‐coding RNAs, with universal expression in a repertoire of biofluids and active regulatory roles in multiple biological pathways(Blount, Coursey, and Kocerha 2022). Therefore, any perturbance in miRNA expression produces pronounced biological effects, due to its pleiotropic nature(Blount, Coursey, and Kocerha 2022). A variety of miRNAs have been investigated in multiple dementia syndromes (Blount, Coursey, and Kocerha 2022). However, what remains to be evaluated is differential miRNA expression in dementia classified using the more toxic oligomeric amyloid beta(OAβ) as well as based on burden of cerebrovascular disease(CVD).Method: A cross‐sectional pilot study was conducted in a cohort of 24 research participants(Table 1), stratified on the basis of their plasma OAβ levels [Multimer Detection System based plasma OAβ analysis(PeopleBio Inc, South Korea)](Dominguez et al. 2022). T3 ‐ based MRI data was evaluated for CVD status ‐ White Matter Hyperintensity load, was scored using the Fazekas scale(Table 1). Blood plasma‐based expression profiling of 376 miRNAs was conducted using the ID3EAL™ PanoramiR miRNA Knowledge Panel(MiRXES Pte Ltd, Singapore) and normalised miRNA expression was defined via the delta‐delta(d) Ct method. MiRNA target interaction analyses was conducted using miRTarBase 9.0, revealing potential reactome pathways of interest(Huang et al. 2022).Result: Mean age and MoCA scores are 60.05 and 25.42 respectively (Table 1). 10 miRNAs(upregulated : hsa‐miR‐42, hsa‐miR‐378c, hsa‐miR‐938; downregulated: hsa‐miR‐545‐3p, hsa‐miR‐449c‐5p, hsa‐miR‐657, hsa‐miR‐23c, hsa‐miR‐888‐5p, hsa‐miR‐599, hsa‐let‐7d‐5p) were significantly differentially expressed in OAβ positivity(Table 2). 6 miRNAs(upregulated: hsa‐miR‐513c‐5p, hsa‐miR‐592; downregulated: hsa‐miR‐98‐5p, hsa‐miR‐744‐5p, hsa‐let‐7d‐5p, hsa‐miR‐517‐5p were significantly differentially expressed in CVD(Table 2). Reactome pathways demonstrating putative biological relevance are the FOXO/p53 mediated transcriptional regulation (metabolism/senescence/neuronal genes),Caspase mediated inflammatory activation, Insulin/IGF‐1/PI3K/Akt/GSK3β mediated metabolic signalling, IL‐4/IL‐13 mediated immune(inflammatory) signalling, Nervous System/Axonal Development and WNT Signalling(Table 2).Conclusion: Findings from this cross‐sectional pilot study, have revealed 16 miRNAs to be promising biomarker candidates within the OAβ positivity and CVD burden setting. Longitudinal study with larger sample size is on‐going to confirm and validate these findings.The authors wish to express their sincere gratitude to MiRXES Pte Ltd for their technical expertise and efforts towards the miRNA expression profiling and associated analyses.

Background: Oligomeric amyloid‐β(OAβ) accumulation within brain tissue has been shown to be associated with major AD neuropathological features including tau pathology, synaptic loss, inflammation and oxidative damage; as well as cognitive impairment in dementia cohorts (Celine.E.N et.al.,2018). However, association of OAβ with functional connectivity (FC) and cardiovascular risk factors is not clearly known in the pre‐dementia stage. We aimed to examine association of FC with OAβ and other dementia risk factors in a pre‐dementia cohort to understand the underlying mechanisms related to OAβ.Methods: We included 98 age and sex matched participants and classified them into OAβ+(28) and OAβ‐(70) subgroups using a OAβ cut‐off ratio of ≥ 0.9 (MDS‐ OAβ Test Kit, PeopleBio Inc, South Korea). Participants completed resting‐state functional MRI, clinical and lifestyle history questionnaires, blood, and neuropsychological assessments for global cognition on Montreal cognitive assessment and Visual Cognitive Assessment at Dementia Research Centre (Singapore). The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score was computed, and independent sample or chi‐squared analysis were performed to evaluate group‐level participant characteristics. Region‐of‐interest based FC analysis for 19 seeds from executive control (ECN), default‐mode, salience and dorsal‐attention networks (DAN) was performed to examine the network‐based FC differences in OAβ+ and OAβ‐ groups in association with CAIDE using ANCOVA model.Results: Mean age of OAβ+ and OAβ‐ were 62.04±8.84, and 62.05±8.07 (Table‐1). No significant FC differences were observed between OAβ+ vs OAβ‐ subjects. There were no significant FC differences related to CAIDE score in OAβ+ and OAβ‐ groups. Nonetheless, the OAβ*CAIDE interaction showed significant FC changes. The OAβ+*CAIDE interaction analyses showed reduced FC within ECN and DAN (Figure‐1a). Whereas OAβ‐*CAIDE interaction showed reduced FC only within ECN (Figure‐1b). Furthermore, OAβ interaction with apolipoprotein‐ε4 (OAβ*APOE4) was found to further influence FC trends in ECN and DAN (Figure‐1c,1d).Conclusion: While no FC differences were observed between OAβ+ vs OAβ‐ subjects, the interaction between CAIDE and APOE4 moderated FC changes within the ECN and DAN. These observations in a pre‐dementia cohort suggest that the presence of cerebrovascular risk factors may result in differential FC dysfunction in ECN and DAN depending on APOE4 status.

Background: Oligomeric Amyloid Beta (OAβ), is representative of a soluble, neurotoxic and pathogenic form of Aβ, which has been found to function as upstream drivers of Alzheimer’s Disease pathology (Tolar et al., 2021). It serves as a contributory factor towards the formation of cortical Aβ plaques and neurofibrillary Tau tangles, and has been found to induce oxidative stress, synaptic toxicity and neuroinflammation (Tolar et al., 2021). The pathology culminates in neuronal dysfunction/death and resultant neurodegeneration which has been found to manifest clinically as symptoms of cognitive decline. OAβ has been found to correlate with the severity of cognitive performance, as well as brain volume reduction (An et al., 2017, Wang et al., 2017, Meng et al., 2019, Youn et al., 2019, Babapour Mofrad et al., 2021). Nevertheless, its effect on language neutral cognitive tests ‐ the novel Visual Cognitive Assessment Test (VCAT) developed and validated by our team of neurologist and neuropsychologists; remains to be evaluated (Kandiah et al., 2016, Lim et al., 2018, Low et al., 2020).Methods: A cross‐sectional pilot study was conducted in a cohort of 63 patients, clinically diagnosed with mild cognitive impairment (MCI). The patients underwent cognitive evaluation tests, Multimer Detection System (MDS) based plasma OAβ analysis and MRI based cortical grey matter evaluations (Wang et al., 2017, Youn et al., 2019, Pyun et al., 2021, Vipin et al., 2021). Pearson’s correlation evaluated associations between plasma OAβ, cognitive scores [Mini‐Mental State Examination (MMSE), VCAT] and brain volume measures [Grey Matter Volume (GMV) / Intracranial Volume (ICV)].Results: Increasing plasma OAβ expression associated with decreasing, VCAT scores (r = ‐0.291, 95% CI = ‐0.504 to ‐0.044, p = 0.022) and MMSE scores (r = ‐0.272, 95% CI = ‐0.489 to ‐0.024, p = 0.032), in MCI patients (Figure 1A, B). Additionally increasing plasma OAβ expression also associated with decreasing and GMV/ ICV ratio (r = ‐0.264, 95% CI = ‐0.489 to ‐0.007, p = 0.045), in MCI patients (Figure 1C).Conclusion: Findings from this study, emphasise on the promising clinical utility of plasma OAβ as a biomarker. Future longitudinal studies will validate these associations across the Alzheimer’s disease spectrum.