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Abstract Background Despite progress in stroke therapy (e.g., revascularisation interventions by thrombolysis and/or thrombectomy, organised stroke care), many stroke survivors will have impairment of neurological function. We aimed to compare the cost-effectiveness of an oral natural formulation, MLC601, versus placebo in functional recovery among subjects receiving standard of care after an ischemic stroke of intermediate severity assessed with NIH Stroke Scale at baseline (b-NIHSS 8–14). Methods A Markov cohort model with a 2-year time horizon was developed to simulate patients from a published randomised placebo-controlled clinical trial of MLC601 in their post-stroke functional recovery assessed by modified Rankin Score (mRS), from a health system perspective. Transition probabilities were derived from a multi-centre clinical trial in South East Asia. As cost and utility data were not collected in the trial, therefore we extracted them from the published literature. The main outcomes were incremental cost, incremental quality-adjusted life-year (QALY) gained, and incremental cost-effectiveness ratio (ICER). Besides base-case and sensitivity analyses, we performed subgroup analyses to explore the heterogeneity of patients with poor-prognosis factors (b-NIHSS 10–14, stroke onset to treatment time > 48 h, rehabilitation during first 3 month). All costs are expressed in 2022 Euro and USD, with an annual discount rate of 3% applied to costs and QALYs. Results Base-case analysis showed that MLC601 was cost-effective compared with placebo, with €5,080 saved and 0.45 QALY gained, resulting in an ICER of -€11,352.50 per QALY gained. Similarly, results from subgroup analyses indicated that the use of MLC601 was a dominant strategy in all subgroups with poor-prognosis factors. Sensitivity analyses revealed the results were robust. Conclusion Compared with placebo on top of standard stroke care, MLC601 was cost-effective in post-stroke functional recovery over two years. Due to the lack of cost and utility data from the study population, the results might not be generalizable to other settings. Further studies with country-specific data are needed to confirm the results of this study. Trial registration URL http://www.clinicaltrials.gov . Unique identifier NCT00554723 November 7, 2007.

Abstract JNK signaling is a critical regulator of inflammation and regeneration, but how it is controlled in specific tissue contexts remains unclear. Here we show that, in the Drosophila intestine, the TNF-type ligand, Eiger (Egr), is expressed exclusively by intestinal stem cells (ISCs) and enteroblasts (EBs), where it is induced by stress and during aging. Egr preferentially activates JNK signaling in a paracrine fashion in differentiated enterocytes (ECs) via its receptor, Grindelwald (Grnd). N-glycosylation genes (Alg3, Alg9) restrain this activation, and stress-induced downregulation of Alg3 and Alg9 correlates with JNK activation, suggesting a regulatory switch. JNK activity in ECs induces expression of the intermembrane protease Rhomboid (Rho), driving secretion of EGFR ligands Keren (Krn) and Spitz (Spi), which in turn activate EGFR signaling in progenitor cells (ISCs and EBs) to stimulate their growth and division, as well as to produce more Egr. This study uncovers an N-glycosylation-controlled, paracrine JNK-EGFR-JNK feedforward loop that sustains ISC proliferation during stress-induced gut regeneration.

Acute ischemic stroke (AIS) and traumatic brain injury (TBI) are two severe neurological events, both being major causes of death and prolonged impairment. Their incidence continues to rise due to the global increase in the number of people at risk, representing a significant burden on those remaining impaired, their families, and society. These molecular and cellular mechanisms of both stroke and TBI present similarities that can be targeted by treatments with a multimodal mode of action, such as traditional Chinese medicine. Therefore, we performed a detailed review of the preclinical and clinical development of MLC901 (NeuroAiDTMII), a natural multi-herbal formulation targeting several biological pathways at the origin of the clinical deficits. The endogenous neurobiological processes of self-repair initiated by the brain in response to the onset of brain injury are often insufficient to achieve complete recovery of impaired functions. This review of MLC901 and its parent formulation MLC601 confirms that it amplifies the natural self-repair process of brain tissue after AIS or TBI. Following AIS and TBI where "time is brain", many patients enter the post-acute phase with their functions still impaired, a period when "the brain needs time to repair itself". The treatment goal must be to accelerate recovery as much as possible. MLC901/601 demonstrated a significant reduction by 18 months of recovery time compared to a placebo, indicating strong potential for facilitating the improvement of health outcomes and the more efficient use of healthcare resources.

Abstract Background Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. Methods We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. Results We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p

Abstract Background Diagnostic performance of optical coherence tomography (OCT) to detect Alzheimer’s disease (AD) and mild cognitive impairment (MCI) remains limited. We assessed whether compensating the circumpapillary retinal nerve fiber layer (cpRNFL) thickness for multiple demographic and anatomical factors as well as the combination of macular layers improves the detection of MCI and AD. Methods This cross-sectional study of 62 AD (n = 92 eyes), 108 MCI (n = 158 eyes), and 55 cognitively normal control (n = 86 eyes) participants. Macular ganglion cell complex (mGCC) thickness was extracted. Circumpapillary retinal nerve fiber layer (cpRNFL) measurement was compensated for several ocular factors. Thickness measurements and their corresponding areas under the receiver operating characteristic curves (AUCs) were compared between the groups. The main outcome measure was OCT thickness measurements. Results Participants with MCI/AD showed significantly thinner measured and compensated cpRNFL, mGCC, and altered retinal vessel density (p

Poincaré inertio-gravity modes described by the shallow water equations in a rotating frame have nontrivial topology, providing a perspective on the origin of equatorially trapped Kelvin and Yanai waves. We investigate the topology of rotating shallow water equations and continuously stratified primitive equations with and without background shear flow. Continuously stratified fluids support waves that are analogous to the edge modes of weak three-dimensional topological insulators. Background shear flow not only breaks the Hermiticity and homogeneity of the system but also leads to instabilities. By introducing a gauge-invariant winding number, we show that singularities in the phase of the Poincaré waves of the unforced shallow-water equations and primitive equations persist in the presence of both horizontal and vertical shear flows. Thus, the bulk Poincaré bands have nontrivial topology and we expect and confirm the persistence of the equatorial waves in the presence of shear along the equator where the Coriolis parameter f changes signs.

Abstract There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

Abstract Age-related white matter lesion (WML) is considered a manifestation of sporadic cerebral small vessel disease and an important pathological substrate for dementia. Asia is notable for its large population with a looming dementia epidemic. Yet, the burden of WML and its associated risk factors across different Asian societies are unknown. Subjects from 9 Asian cities (Bangkok, Bandung, Beijing, Bengaluru, Hong Kong, Kaohsiung, Manila, Seoul, and Singapore) were recruited (n = 5701) and classified into (i) stroke/transient ischemic attack (TIA), (ii) Alzheimer’s disease (AD)/mild cognitive impairment (MCI), or (iii) control groups. Data on vascular risk factors and cognitive performance were collected. The severity of WML was visually rated on MRI or CT. The prevalence of moderate-to-severe WML was the highest in subjects with stroke/TIA (43.3%). Bandung Indonesia showed the highest prevalence of WML, adjusted for age, sex, education, disease groups, and imaging modality. Hypertension and hyperlipidemia were significant risk factors for WML, and WML was negatively associated with MMSE in all groups. WML is highly prevalent in Asia and is associated with increasing age, hypertension, hyperlipidemia, and worse cognitive performance. Concerted efforts to prevent WML will alleviate the huge dementia burden in the rapidly aging Asian societies.

IntroductionAlzheimer's disease (AD) and age-related eye diseases pose an increasing burden as the world's population ages. However, there is limited understanding on the association of AD/cognitive impairment, no dementia (CIND) with age-related eye diseases.MethodsIn this cross-sectional, memory clinic-based study of multiethnic Asians aged 50 and above, participants were diagnosed as AD (n = 216), cognitive impairment, no dementia (CIND) (n = 252), and no cognitive impairment (NCI) (n = 124) according to internationally accepted criteria. Retinal photographs were graded for the presence of age-related macular degeneration (AMD) and diabetic retinopathy (DR) using standard grading systems. Multivariable-adjusted logistic regression models were used to determine the associations between neurological diagnosis and odds of having eye diseases.ResultsOver half of the adults had at least one eye disease, with AMD being the most common (60.1%; n = 356), followed by DR (8.4%; n = 50). After controlling for age, sex, race, educational level, and marital status, persons with AD were more likely to have moderate DR or worse (OR = 2.95, 95% CI = 1.15–7.60) compared with NCI. In the fully adjusted model, the neurological diagnosis was not associated with AMD (OR = 0.75, 95% CI = 0.45–1.24).ConclusionPatients with AD have an increased odds of having moderate DR or worse, which suggests that these vulnerable individuals may benefit from specific social support and screening for eye diseases.

Despite recent progress with revascularisation interventions after acute ischemic stroke, many patients remain disabled after stroke. Using data from a multi-centre, randomised, double-blind, placebo-controlled trial of a neuro-repair treatment (NeuroAiD/MLC601) with a long-term follow-up, we analysed the savings in time to functional recovery, measured by a modified Rankin Scale (mRS) score of 0 or 1, in patients receiving a 3-month oral course of MLC601. Analysis of time to recovery was assessed by a log-rank test and hazard ratios (HRs) adjusted for prognosis factors. A total of 548 patients with baseline NIHSS scores 8–14, mRS scores ≥ 2 at day 10 post-stroke, and at least one mRS assessment on or after month 1 were included in the analysis (placebo = 261; MLC601 = 287). Time to functional recovery was significantly shortened for patients receiving MLC601 versus patients receiving placebo (log-rank test: p = 0.039). This result was confirmed by Cox regression adjusting for the main baseline prognostic factors (HR: 1.30 [0.99, 1.70]; p = 0.059) and was more pronounced in patients with additional poor prognosis factors. The Kaplan–Meier plot showed that approximately 40% cumulative incidence of functional recovery was achieved within 6 months after stroke onset in the MLC601 group versus 24 months in the placebo group. The main findings are that MLC601 reduced the time to achieve functional recovery, and a 40% functional recovery rate was achieved 18 months earlier compared to placebo.

Abstracts Background The retina and brain share many neuronal and vasculature characteristics. We investigated the retinal microvasculature in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) using optical coherence tomography angiography (OCTA). Methods In this cross-sectional study, 24 AD participants, 37 MCI participants, and 29 controls were diagnosed according to internationally accepted criteria. OCTA images of the superficial and deep capillary plexus (SCP, DCP) of the retinal microvasculature were obtained using a commercial OCTA system (Zeiss Cirrus HD-5000 with AngioPlex, Carl Zeiss Meditec, Dublin, CA). The main outcome measures were vessel density (VD) and fractal dimension (FD) in the SCP and DCP within a 2.5-mm ring around the fovea which were compared between groups. Perfusion density of large vessels and foveal avascular zone (FAZ) area were additional outcome parameters. Results Age, gender, and race did not differ among groups. However, there was a significant difference in diabetes status (P = 0.039) and systolic blood pressure (P = 0.008) among the groups. After adjusting for confounders, AD participants showed significantly decreased VD in SCP and DCP (P = 0.006 and P = 0.015, respectively) and decreased FD in SCP (P = 0.006), compared to controls. MCI participants showed significantly decreased VD and FD only in SCP (P = 0.006 and P 0.05) compared with controls. There was no difference in the OCTA variables between AD and MCI (P > 0.05). Perfusion density of large vessels and FAZ area did not differ significantly between groups (P > 0.05). Conclusions and relevance Eyes of patients with AD have significantly reduced macular VD in both plexuses whereas MCI participants only showed reduction in the superficial plexus. Changes in the retinal microvasculature and capillary network may offer a valuable insight on the brain in AD.

Histone H3 at lysine 27 (H3K27M) is often mutated in cancer but its role in tumour initiation is unclear. Here, the authors generated a transgenic model expressing H3.3K27M from the Fabp7 gene promoter, demonstrating that H3.3K27M can initiate diverse tumorigesis on its own, acting through a RAS/MYC transcriptomic programme.

Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.

Abstract Background Patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach. Methods We examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains. Results We demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition. Conclusions We demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Abstract Background Mixed vascular and neurodegenerative dementia, such as Alzheimer’s disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method. Methods We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects. Results The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance. Conclusions Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.

According to the network-based neurodegeneration hypothesis, neurodegenerative diseases target specific large-scale neural networks, such as the default mode network, and may propagate along the structural and functional connections within and between these brain networks. Cognitive impairment no dementia (CIND) represents an early prodromal stage but few studies have examined brain topological changes within and between brain structural and functional networks. To this end, we studied the structural networks [diffusion magnetic resonance imaging (MRI)] and functional networks (task-free functional MRI) in CIND (61 mild, 56 moderate) and healthy older adults (97 controls). Structurally, compared with controls, moderate CIND had lower global efficiency, and lower nodal centrality and nodal efficiency in the thalamus, somatomotor network, and higher-order cognitive networks. Mild CIND only had higher nodal degree centrality in dorsal parietal regions. Functional differences were more subtle, with both CIND groups showing lower nodal centrality and efficiency in temporal and somatomotor regions. Importantly, CIND generally had higher structural-functional connectome correlation than controls. The higher structural-functional topological similarity was undesirable as higher correlation was associated with poorer verbal memory, executive function, and visuoconstruction. Our findings highlighted the distinct and progressive changes in brain structural-functional networks at the prodromal stage of neurodegenerative diseases.

Aims: To examine the diagnostic utility of the National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network (NINDS-CSN) neuropsychological battery in memory clinics comparing controls with patients with no cognitive impairment (NCI), patients with cognitive impairment-no dementia (CIND) at varying severity levels (mild/moderate), and patients with dementia. Methods: A total of 405 participants with NCI, CIND or dementia were assessed with the NINDS-CSN battery. The discriminatory properties of all three protocols (5, 30 and 60 min) before and after education stratification (none/primary vs. secondary/above) were examined by receiver operating characteristic curves. Results: Overall, the shorter protocols are equivalent to the longer protocol in diagnosing dementia, regardless of education. To discriminate between nondementia groups, before education stratification, the 5-min protocol showed varied discriminatory properties between different diagnostic/severity groups. After stratification, the 5-min protocol was broadly equivalent to the longer protocols in lower-education groups [area under the curve (AUC) range: 0.77-0.87] but was less accurate in the higher-education groups (AUC range: 0.68-0.78). The 30- and 60-min protocol constantly showed moderate-to-excellent differentiating capacities regardless of education (AUC range: 0.80-0.90). Conclusion: The NINDS-CSN neuropsychological battery can be applied in memory clinics and effectively discriminate between cognitively intact individuals and those with cognitive impairments of varying severity. Furthermore, level of education should be taken into consideration when choosing protocols with different lengths for cognitive assessment.

OBJECTIVES:We aimed to examine changes in the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) scores within a one-year period after stroke/transient ischemic attack (TIA) in associating cognitive decline determined by a formal neuropsychological test battery. METHODS:Patients with ischemic stroke/TIA received MoCA and MMSE at baseline within 14 days after stroke/TIA, at 3-6 months and 1-year follow-ups. The scores of MoCA and MMSE were considered to have declined if there were a reduction of ≥2 points in the respective scores measured across two time points. The decline in neuropsychological diagnosis transitional status was defined by a category transition from no cognitive impairment or any cognitive impairment to a more severe cognitive impairment or dementia. RESULTS:275 patients with a mean age of 59.8 ± 11.6 years, and education of 7.7 ± 4.3 years completed all the assessments at baseline, 3-6 months and 1-year follow-ups. A decline in MoCA scores from 3-6 months to 1 year was associated with higher risk of decline in diagnosis transitional status (odd ratio = 3.21, p = 0.004) in the same time period whereas there was no association with a decline in MMSE scores. CONCLUSIONS:The decline in MoCA scores from 3-6 months to 1 year after stroke/TIA has three times higher risk for decline in the diagnosis transitional status. The decline of MoCA scores (reduction ≥ 2points) is associated with the decline in neuropsychological diagnosis transitional status.

Individuals with obstructive sleep apnea (OSA) experience sleep fragmentation and poor sleep quality that results in daytime sleepiness, which impairs performance during driving and leads to an increased risk for collisions. Not surprisingly, observational studies have shown that patients with OSA experience a two- to 10-fold higher risk for collision compared with healthy controls. Although treatment would clearly mitigate these risks, there is no current Canadian position on driving and OSA. This article, the first Canadian position statement addressing the issue, provides an overview of provincial regulations and proposes recommendations with regard to driving in patients with OSA.

Aim. This study sought to establish the discriminant validity of a rapid cognitive screen, that is, the National Institute of Neurological Disease and Stroke-Canadian Stroke Network (NINDS-CSN) 5-minute protocol, and compare its discriminant validity to the Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) in detecting cognitive impairment (CI) in PD patients. Methods. One hundred and one PD patients were recruited from a movement disorders clinic in Singapore and they received the NINDS-CSN 5-minute protocol, MoCA, and MMSE. No cognitive impairment (NCI) was defined as Clinical Dementia Rating (CDR) = 0 and CI was defined as CDR ≥ 0.5. Results. Area under the receiver operating characteristic curve of NINDS-CSN 5-minute protocol was statistically equivalent to MoCA and larger than MMSE (0.86 versus 0.90, P=0.07; 0.86 versus 0.76, P=0.03). The sensitivity of NINDS-CSN 5-minute protocol (

Alzheimer's Disease (AD) is the most common subtype of dementia. As the prevalence of dementia is projected to increase, the burden of the disease on society is expected to become increasingly significant. The link between eye pathology and neurodegenerative diseases has been established in multiple studies. In particular, optic nerve parameters associated with neuronal loss in AD include retinal ganglion cells (RGC). Retinal ganglion cells are similar to neurons in the cerebral cortex, and have been correlated to neurodegeneration in AD. Ocular imaging techniques such as optical coherence tomography (OCT) have provided a rapid and non-invasive method for quantifying optic nerve parameters in vivo . Spectral domain (SD)-OCT has shown good potential in the study of the optic nerve in AD as it enables more comprehensive assessment of RGCs. Earlier generation OCT techniques only assess the retinal nerve fibre layer, which consists of RGC axons. Spectral domain-OCT offers ultra-high scan speed and image resolution, enabling improved sampling of retinal layers. Retinal layers such as the ganglion cell-inner plexiform layer (GC-IPL), which contain the dendrites and nuclei of RGCs, can be assessed with SD-OCT. This article presents a review of literature associating eye pathology with AD, and explores the potential of SD-OCT in future AD studies. Spectral domain-OCT has the potential to draw more links between optic nerve pathology and neurodegeneration.

Objectives. The utility of informant AD8 for case finding of cognitive impairment at primary healthcare settings is unknown and therefore its feasibility and acceptability for targeted screening at a primary healthcare clinic should be investigated. Methods. The informants of older adult patients attending a primary healthcare clinic in Singapore were administered the AD8. Positive screening findings were provided to patients’ primary care physicians for referrals to specialist memory clinics. The acceptability of AD8 was evaluated by collecting feedbacks from the informants and primary care physicians. Results. 205 patients and their informants were recruited. However, 6 (2.9%) informants were uncontactable, while the majority of the remaining 199 patients with completed AD8 (96.5%, n=192) found it acceptable where 59 (29.6%) patients were deemed cognitively impaired (AD8 ≥ 2). Clinicians (100%, n=5) found the AD8 helpful in facilitating referrals to memory clinics. However, most referral recommendations (81.4%, n=48) were declined by patients and/or informant due to limited insight of implications of cognitive impairment. Conclusions. The AD8 can be easily administered and is well tolerated. It detected cognitive impairment in one-third of older adult patients and therefore may be useful for case finding of cognitive impairment in the primary healthcare.

Background: Recent advances in machine learning highlight the potential of Ai‐guided tools for early dementia prediction with major implications for timely clinical management. Yet, we still lack robust tools for predicting neurocognitive decline early in clinical practice. We have developed a predictive prognostic model based on Generalised Matrix Learning Vector Quantisation (GMLVQ) that combines multimodal biological and cognitive data to predict cognitive decline (Giorgio et al., 2020). Here we test the clinical validity of this model in predicting individualised cognitive trajectories on real‐world memory clinic data. Method: We trained our model (Fig.1) to classify sMCI (individuals with stable MCI diagnosis within a 3‐year period; n = 290) vs. pMCI (individuals who progressed from MCI to AD within a 3‐year period; n = 120). We tested the model (out‐of‐sample validation) on a) an asymptomatic sample (Berkley Ageing Cohort: BACS, n = 187 healthy controls), b) two clinical samples: National University of Singapore (NUS; AD: n = 32, non‐AD neurodegenerative disease: n = 15, MCI moderate: n = 42, MCI mild: n = 53, Control: n = 27); Quantitative MRI in NHS Memory Clinics; AD: n = 72, MCI: n = 50, Non‐AD: n = 30, Functional/attentional memory symptoms: n = 30, other cognitive disorders: n = 10). We trained and tested the model with baseline structural MRI (medial temporal grey matter density) and cognitive data (following data harmonization across training and test samples). Using a scalar projection method, we generated a prognostic index that indicates distance from the stable prototype and classifies individuals to Clinically Stable vs. Declining (slowly vs. rapidly). Result: Our trained model on ADNI data classified sMCI vs. pMCI with 79.87% class‐balanced cross‐validated accuracy (sensitivity = 83.33%, specificity = 76.52%). For the clinical NUS and QMIN‐MC samples, most AD patients were classified as rapidly progressive compared to MCI patients that were mostly classified as stable or slowly progressive (Fig.2). In contrast, for the BACS asymptomatic sample most individuals were classified as stable. Survival analysis on the NUS sample— for which longitudinal assessments (up to 6 years) are available— validated the model predictions, showing that patients with higher model‐derived prognostic index decline faster (Fig.3). Conclusion: Validating our AI‐guided tool for early dementia prediction in real‐world patient data provides evidence for its clinical utility. [ABSTRACT FROM AUTHOR]