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Using a grounded theory research design, this paper examined the collaborative learning experiences of secondary school students in Singapore. The core phenomenon that emerged was the need for social interactions in collaborative learning, both in classroom and online settings. Educators often take for granted that effective collaborative learning will occur naturally once students are assigned to work in groups. In examining students' dissatisfaction when working in groups, this study highlighted the importance of surfacing these hidden assumptions for careful scrutiny. The key factors identified were centered on the need to address social challenges within collaborative learning. These included a pragmatic, results-oriented approach with limited interpersonal engagement used by students that can compromise collaborative learning outcomes. Having a deeper understanding of the challenges that resulted from limited social interactions provides educators with insights when designing classroom and online learning activities. This paper contributes to the understanding of groups' active learning to inform pedagogical practices for educators engaged in designing better collaborative learning experiences. Educators and curriculum designers need to be aware of the social drawbacks in collaborative learning in order to design a more socially engaging learning environment.

Background and purpose: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. Methods: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self‐reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube‐transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex‐stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. Results: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. Conclusions: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We tested associations between two retinal measures (optic disc pallor, peripapillary retinal nerve fiber layer [pRNFL] thickness) and four magnetic resonance imaging markers of cerebral small vessel disease (SVD; lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces [ePVSs]). METHODS: We used PallorMetrics to quantify optic disc pallor from fundus photographs, and pRNFL thickness from optical coherence tomography scans. Linear and logistic regression assessed relationships between retinal measures and SVD markers. Participants (N = 108, mean age 51.6) were from the PREVENT Dementia study. RESULTS: Global optic disc pallor was linked to ePVSs in the basal ganglia in both left (β = 0.12, standard error [SE] = 0.05, P < 0.05) and right eyes (β = 0.13, SE = 0.05, P < 0.05). Associations were also noted in different disc sectors. No pRNFL associations with SVD markers were found. DISCUSSION: Optic disc pallor correlated with ePVSs in the basal ganglia, suggesting retinal examination may be a useful method to study brain health changes related to SVD. Highlights: Optic disc pallor is linked to enlarged perivascular spaces in basal ganglia.There is no association between peripapillary retinal nerve fiber layer thickness and cerebral small vessel disease markers.Optic disc examination could provide insights into brain health.The sample included 108 midlife adults from the PREVENT Dementia study. [ABSTRACT FROM AUTHOR]

All gammaretroviruses, including murine leukemia viruses (MuLVs), feline leukemia viruses, and gibbon-ape leukemia virus, encode an alternate, glycosylated form of Gag polyprotein (glyco-Gag or gPr80gag) in addition to the polyprotein precursor of the viral capsid proteins (Pr65gag). gPr80gag is translated from an upstream in-frame CUG initiation codon, in contrast to the AUG codon used for Pr65gag. The role of glyco-Gag in MuLV replication has been unclear, since gPr80gag-negative Moloney MuLV (M-MuLV) mutants are replication competent in vitro and pathogenic in vivo. However, reversion to the wild type is frequently observed in vivo. In these experiments, in vivo inoculation of a gPr80gag mutant, Ab-X-M-MuLV, showed substantially lower (2 log) initial infectivity in newborn NIH Swiss mice than that of wild-type virus, and revertants to the wild type could be detected by PCR cloning and DNA sequencing as early as 15 days postinfection. Atomic force microscopy of Ab-X-M-MuLV-infected producer cells or of the PA317 amphotropic MuLV-based vector packaging line (also gPr80gag negative) revealed the presence of tube-like viral structures on the cell surface. In contrast, wild-type virus-infected cells showed the typical spherical, 145-nm particles observed previously. Expression of gPr80gag in PA317 cells converted the tube-like structures to typical spherical particles. PA317 cells expressing gPr80gag produced 5- to 10-fold more infectious vector or viral particles as well. Metabolic labeling studies indicated that this reflected enhanced virus particle release rather than increased viral protein synthesis. These results indicate that gPr80gag is important for M-MuLV replication in vivo and in vitro and that the protein may be involved in a late step in viral budding or release.

Background: The APOE ε4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease (AD). However, the mechanisms by which APOE ε4 is associated with neurodegeneration are still poorly understood. Here, we applied the NODDI to characterise the effects of APOE ε4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Method: Data from 1954 participants were included from the PREVENT‐Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non‐carriers, 757 APOE ε4 carriers). T1 MRIs were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index (ODI) maps from diffusion MRI. Primary analyses were focused on the (a) main effects of APOE ε4, and the (b) interactions of APOE ε4 with age and education on lobar and vertex‐wise ODI and implemented using Permutation Analysis of Linear Models. Result: APOE ε4 carriers and non‐carriers did not differ in terms of lobar ODI. However, there were APOE ε4 × age interactions in the temporo‐parietal and frontal lobes (TFCE p FWE < 0.05), indicating steeper age‐dependent ODI changes in APOE ε4 (Figure 1). Lobar analyses revealed decreased temporal ODI in APOE ε4 carriers after age = 60 (Figure 2). There was a three‐way interaction of APOE ε4 x age x education; steeper age‐related ODI declines among APOE ε4 carriers with lower years of education (Figure 3, TFCE p FWE < 0.05). There were no significant main effects or interactions of APOE ε4 on cortical thickness. Conclusion: We found novel evidence that APOE ε4 worsened age‐related ODI decreases in brain regions typically associated with atrophy patterns of AD. This finding also suggests that APOE ε4 may hasten the onset age of dementia by accelerating age‐dependent reductions in cortical ODI, although additional studies are needed to verify this hypothesis. These findings were independent of cortical thickness. While conclusions are limited due to the cross‐sectional design, our findings imply that APOE ε4 related changes in ODI may precede macroscopically visible changes in cortical atrophy and may be a more sensitive marker of incipient AD. [ABSTRACT FROM AUTHOR]

Introduction: Artificial intelligence (AI) and neuroimaging offer new opportunities for diagnosis and prognosis of dementia. Methods: We systematically reviewed studies reporting AI for neuroimaging in diagnosis and/or prognosis of cognitive neurodegenerative diseases. Results: A total of 255 studies were identified. Most studies relied on the Alzheimer's Disease Neuroimaging Initiative dataset. Algorithmic classifiers were the most commonly used AI method (48%) and discriminative models performed best for differentiating Alzheimer's disease from controls. The accuracy of algorithms varied with the patient cohort, imaging modalities, and stratifiers used. Few studies performed validation in an independent cohort. Discussion: The literature has several methodological limitations including lack of sufficient algorithm development descriptions and standard definitions. We make recommendations to improve model validation including addressing key clinical questions, providing sufficient description of AI methods and validating findings in independent datasets. Collaborative approaches between experts in AI and medicine will help achieve the promising potential of AI tools in practice. Highlights: There has been a rapid expansion in the use of machine learning for diagnosis and prognosis in neurodegenerative diseaseMost studies (71%) relied on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with no other individual dataset used more than five timesThere has been a recent rise in the use of more complex discriminative models (e.g., neural networks) that performed better than other classifiers for classification of AD vs healthy controlsWe make recommendations to address methodological considerations, addressing key clinical questions, and validationWe also make recommendations for the field more broadly to standardize outcome measures, address gaps in the literature, and monitor sources of bias [ABSTRACT FROM AUTHOR]

Background: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD.Methods: Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen.Results: At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory.Conclusion: Higher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score's potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk. [ABSTRACT FROM AUTHOR]

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm resulting from an acquired driver mutation in the JAK2 gene of hematopoietic stem and progenitor cells resulting in the overproduction of mature erythrocytes and abnormally high hematocrit, in turn leading to thromboembolic complications. Therapeutic phlebotomy is the most common treatment to reduce the hematocrit levels and consequently decrease thromboembolic risk. Here we demonstrate that, by using the iron restrictive properties of the antisense oligonucleotides against Tmprss6 mRNA, we can increase hepcidin to achieve effects equivalent to therapeutic phlebotomy. We provide evidence that this less invasive approach could represent an additional therapeutic tool for the treatment of PV patients. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMHs) are a highly prevalent MRI marker of cerebral small vessel disease (SVD), which predict stroke and dementia risk, and are being increasingly used as a surrogate marker in clinical trials. However, the influence of study population selection on WMH progression rate has not been studied and the effect of individual patient factors for WMH growth are not fully understood.Methods: We performed a systematic review and meta-analysis of the literature on progression of WMHs in longitudinal studies to determine rates of WMH growth, and how these varied according to population characteristics and cardiovascular risk factors. We used these data to calculate necessary sample sizes for clinical trials using WMH as an endpoint.Results: WMH growth rate was highest in SVD (2.50cc/year), intermediate in unselected stroke patients (1.29cc/year) and lower in patients with non-stroke cardiovascular disease, and with cognitive impairment. Age was significantly associated with progression (correlation coefficient 0.15cc/year, 95% CI 0.02 to 0.28cc/year) as was baseline lesion volume (0.6cc/year, 95% CI 0.13 to 1.06 cc/year). Both hypertension (OR 1.72, 95% CI 1.19 to 2.46) and current smoking (OR 1.48, 95% CI 1.02 to 2.16) were associated with WMH growth. Sample sizes for a clinical trial varied greatly with patient population selection and baseline lesion volume; estimates are provided.Conclusions: WMH progression varies markedly according to the characteristics of the population being studied and this will have a major impact on sample sizes required in a clinical trial. Our sample size estimates provide data for planning clinical trials using WMH as an outcome measure.Prospero Registration Number: CRD42020191781. [ABSTRACT FROM AUTHOR]

Background: The Mediterranean diet (MedDiet) has been associated with better cardiometabolic and brain health. Research has suggested differences in these associations between men and women, with men typically reported to benefit more from higher MedDiet adherence. However there remains a lack of research in this area in non‐Mediterranean countries. This study aimed to explore cross‐sectional associations between MedDiet adherence in the PREVENT Dementia cohort (UK and Ireland), stratified by sex. Method: After deriving scores to quantify adherence to the MedDiet (MEDAS, MEDAS continuous and Pyramid), we used linear regression and linear mixed effects models to test for associations between the MedDiet scores, cardiometabolic health (blood pressure, BMI, glycemia, cholesterol, triglycerides) and brain health (white matter hyperintensity volume (WMHV), cortical thickness, hippocampal subfield volumes, cognition). Propensity scores were calculated to strengthen causality inferences from the data, and used as covariates along with total energy intake and Western diet scores. Result: We included 533 participants, mean age 51.25 (±5.40) years, majority women (60.0%). Higher MedDiet scores (MEDAS data presented) were associated with lower blood pressure (systolic ß: ‐1.16, p:0.009; diastolic ß: ‐1.00, p<0.001) and BMI (ß: ‐0.53, p<0.001). There were significant interactions between MedDiet and sex for diastolic blood pressure and hip‐to‐waist ratio. When stratified by sex, women had significant positive associations between MedDiet scores and blood pressure (systolic ß: ‐1.45, p: 0.006; diastolic ß: ‐1.29, p<0.001), BMI (ß: ‐0.51, p: 0.02) and glycemia (Pyramid only: ß: ‐0.11, p: 0.02), whereas men only had a significant association with BMI (ß: ‐0.45, p: 0.02) (Figure 1). There were no significant associations between dietary scores and any markers of brain health. An exploratory path analysis found a significant mediation between the Pyramid MedDiet score, pulse pressure and WMHV (Figure 2), which was only seen in women. Conclusion: There were significant associations between higher MedDiet scores and better cardiometabolic health, particularly for women. There were no direct associations with brain health outcomes, however a path analysis suggested a mediating effect of pulse pressure between the MedDiet and WMHV. Sex‐stratified nutritional guidelines to support better cardiometabolic health, may lead to better brain health and warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: The long‐term consequences of mild traumatic brain injury (mTBI) are poorly understood. Prior studies have shown that a history of mTBI is associated with a 2 fold increase of dementia diagnosis. However, the precise mechanisms for increased dementia risk which could start in mid‐life remain unclear. TBI can cause varying degrees of damage to different regions of the brain, and as a result, may affect distinct subdomains of cognitive function in distinct ways. This study investigated cognitive performance and brain volume among individuals at risk of Alzheimer's Disease (AD) in mid‐life with a history of self‐reported mTBI. Method: 578 participants (118 no head injury, 116 single mTBI & 344 repeated mTBI) aged 40‐60 years participating in the PREVENT study, a large cohort study examining the risk of AD in mid‐life, underwent structural 3T MRI and neuropsychometric evaluation (ACE‐III and COGNITO) at baseline. Self‐reported, cross‐sectional data on head injury were collected through the Brain Injury Screening Questionnaire (BISQ). FSL (version 6.0.1) was used to calculate brain volume (correcting for head size). Comparisons between participants with no history of head injury and single or repeated mTBI were done using a one‐way ANOVA. Result: There was no statistically significant difference in total brain volume between participants with or without a history of mTBI (F(2,576) = 1.24, p = 0.29). There was also no significant difference between self‐reported mTBI and ACE‐III total scores F(2,579) = 0.0112, p = 0.99) or performance on memory (p = 0.87), language (p = 0.24), visuospatial abilities (p = 0.61) and attention (p = 0.14) in the COGNITO battery. Conclusion: We found no evidence that a history of mTBI (single or repeated) is associated with cognitive impairment in this cohort. Future longitudinal studies are necessary to further evaluate self‐reported mTBI and how the aging process might interact with cognitive outcome post‐injury. Future analysis of covariates such as lower socioeconomic status, gender, physical health and history of alcohol/drug use, that are known to impact cognitive performance and are related to greater rates of TBI, will be studied to determine the influence of a history of mTBI on dementia risk. [ABSTRACT FROM AUTHOR]

Background: Carriership of the apolipoprotein ε4 (APOE4) allele confers a heightened risk for the development of Alzheimer's disease (AD). Cerebral blood flow (CBF) is decreased in prodromal and established AD, however findings in the preclinical stage are mixed, with some studies reporting increases. CBF can be impacted by many factors including the haematocrit. We investigated in a cohort at risk of developing AD how haematological variables relate to CBF and if this relationship is differentially moderated by APOE4. Method: 375 participants from the PREVENT‐Dementia study underwent arterial spin labelling (ASL) and structural 3Tesla MRI. ASL data were analysed using BASIL/FSL and structural scans with SPM12. CBF maps were corrected for partial volume effects. A vascular territory mask with nine territories, the middle, proximal and distal branches of the anterior, middle and posterior cerebral arteries (ACA, MCA, PCA) was used for region‐of‐interest analysis and registered to the native ASL space. Regional gray matter (GM) CBF values were harmonised using COMBAT. Linear regression was used to examine differences between APOE4 carriers and non‐carriers controlling for age, sex and years of education. Associations between haematological properties and CBF were examined with Pearson's correlations. Differential relationships between CBF, haematocrit, and measures of red blood cell size and shape (distribution width (RDW) and mean corpuscular volume (MCV)) were investigated by including interaction terms of APOE4 and haematological variables in the models. Result: APOE4 carriers had significantly higher CBF in the proximal MCA (t = 2.54, p = 0.01). Across all subjects, RDW and MCV were not associated with GM CBF, though several significant interactions were observed between APOE4 and RDW in predicting CBF (Figure 1). Haematocrit was associated with GM CBF (ρ = ‐0.19, p < 0.01). No significant interactions were seen between APOE4 and haematocrit or MCV in predicting CBF. Conclusion: The variability of the size and shapes of erythrocytes was differentially associated with CBF between APOE4 carriers and non‐carriers suggesting a different response to morphological erythrocyte alterations. This could further relate to underlying factors such as inflammation, which is associated with a higher RDW. Such associations should be examined in further studies. [ABSTRACT FROM AUTHOR]

Background: Cerebral microbleeds (CMB) are predictive of increased risk of dementia and stroke. Although commonly regarded as vascular markers, CMB can also stem from non‐vascular aetiologies like head injuries or traumatic brain injury (TBI), although these are often overlooked. Therefore, this study examines CMB in relation to TBI, and their differential causes (i.e., risk factors) and consequences (i.e., clinical outcomes). Method: In 605 healthy middle‐aged adults (aged 40‐59), CMB were rated on 3T susceptibility weighted imaging (SWI) MRI. TBI was assessed using the Brain Injury Screening Questionnaire (BISQ). TBI+ was defined as at least one blow to the head resulting in loss of consciousness (36.0%; n = 217). Memory was assessed using the COGNITO battery. Interaction analyses examined TBI*CMB interactions on hypertension, gait, and memory. Dominance analysis examined the relative contribution of TBI and vascular risk factors on predicting gait disturbances and memory. All models adjusted for sex, age, education, and study site. Result: TBI was related to higher CMB count (t = 2.06, p =.039), and were more common in males (48.3%) than females (28.0%) (Χ2 = 28.91, p<.001). Number of TBI events related to poorer memory (t = ‐2.62, p =.009) and gait disturbances (t = 3.54, p<.001). Interaction analyses demonstrated that hypertension (t = ‐2.26, p =.024), memory (t = 2.70, p =.007) and gait (t = ‐2.29, p =.023) were less closely related to CMB in individuals with greater number of TBI events, relative to those with fewer TBIs. Regionally, these interactions were significant for lobar CMB, but not deep subcortical CMB. Within the TBI+ group, dominance analysis demonstrated that number of TBI events outperformed vascular risk factors in predicting gait disturbances (Contribution to R2: TBI = 52.9%, vascular risk = 32.6%) and memory (TBI = 28.7%, vascular risk = 1.2%). Conclusion: CMB appeared to differ aetiologically and clinically in those with and without TBI. In individuals with TBI, TBI itself was the dominant driver of clinical deficits. When compared to CMB of presumed vascular origins cross‐sectionally, TBI‐related CMB may appear to be less detrimental. However, longitudinal analysis is required to determine how TBI‐related CMB differ in clinical trajectory and downstream pathologies. This study highlights the importance of differentiating between CMB of vascular origins vs. TBI in both research and clinically to aid prognosis and treatment decisions. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer's disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40–59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+. [ABSTRACT FROM AUTHOR]

Introduction: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging.Methods: Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer's disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195.Results: Global [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66-0.76, t=3.90-5.58, FDR-corrected p (pFDR)=<0.001-0.002) and orbitofrontal cortex (β=0.51-0.57, t=3.53-4.30, pFDR=0.001-0.004).Conclusion: Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD. [ABSTRACT FROM AUTHOR]

Background: First‐degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Identifying preclinical brain changes would facilitate both early quantifiable longitudinal disease monitoring and interventional trials. However, the literature of imaging changes in FH+ remains highly controversial. We aim to investigate "estimated years to onset of dementia" (EYOD) as a surrogate marker of preclinical progression and assessed whether FH+ approaching the parental age of dementia onset would express more severe patterns of longitudinal brain changes. Method: 89 FH+ persons underwent serial 3T‐MRI with T1‐MPRAGE, DWI and ASL (mean interval: 2 years). The longitudinal Freesurfer pipeline was used to segment hippocampal subfields and early‐AD regions. Partial‐volume corrected ASL data and DWI data were processed with FSL‐BASIL4 and DTI‐TK5. Small vessel disease was indexed with white matter hyperintensities (WMHs) (Figure 1). We applied linear mixed effects models to predict MRI changes relative to EYOD, accounting for age, gender, education and time from baseline. Secondary analyses examined the interaction of APOE‐ε4+ on proximity‐related brain changes. Result: A shorter EYOD was associated with progressive decrease in FA, increase in MD/RD and atrophy of the fusiform gyrus over time (Figure 2). Interaction analyses revealed that APOE‐ε4+ carriers showed significant longitudinal atrophy of the hippocampal subfields with shorter EYOD. In contrast, cortical perfusion increased before plateauing ∼10 years before estimated onset. There were no associations of EYOD with mean cortical thickness or WMHs (See Figure 3 for a summary of main findings). Conclusion: Our findings represent the first extensive characterisation of longitudinal brain changes associated with proximity to dementia in FH+. Individuals who are approaching their parental age of dementia onset may be showing incipient brain abnormalities, particularly amongst APOE‐ε4 carriers. The specificity our findings in early‐AD regions also confer support to biological validity of EYOD as a stage marker of preclinical progression. Further ongoing clinical follow‐up of our sample would provide critical validation of these findings. [ABSTRACT FROM AUTHOR]

Background: Subclinical brain changes in Alzheimer's disease (AD) are detectable many years before symptom onset. While cerebral small vessel disease (SVD) has been well‐established as a key pathology in AD, whether genetic predisposition to AD influences markers of SVD in midlife remains unclear. In this study, we compare the longitudinal change in SVD burden between cognitively healthy middle‐aged adults with and without genetic predisposition to AD, and their effect on cognitive decline. Method: 151 cognitively‐normal participants (age 52.0 ± 5.5; PREVENT‐Dementia study) underwent 3T MRI and cognitive assessment at baseline and two‐year follow‐up. Genetic predisposition to AD was assessed by family history of parental dementia (FH) and APOE4 carriership. White matter hyperintensity (WMH) volumes were segmented and manually corrected on FLAIR MRI and cerebral microbleeds (CMB) on susceptibility‐weighted imaging (Figure 1). WMH volume was adjusted for total intracranial volume and inverse‐normal transformed. SVD progression was compared between groups using ANCOVA and linear mixed modelling in R controlling for sex, age, and education. Result: Cross‐sectionally, WMH and CMB did not differ by FH or APOE4 status. However, longitudinal data showed greater WMH progression in FH+ subjects (t=3.94, p<.001) and APOE4+ (t=2.09, p=.038) (Figure 2). The effect of FH on WMH progression was stronger for periventricular WMH (t=3.65, p<.001; deep WMH: t=2.13, p=.035), while APOE4+ subjects displayed greater progression of deep (t=3.30, p=.001), but not periventricular WMH (t=1.17, p=.243). CMB progression did not differ by FH or APOE4 status. Significant three‐way interaction indicated that longitudinal decline in processing speed was associated with global and deep WMH progression in FH+ but not FH‐ subjects (global: t=2.05, p=.042; deep: t=2.90, p=.004; periventricular: t=0.87, p=.384) (Figure 3), while no effect was observed regarding APOE4 carriership. Conclusion: Cognitively‐healthy individuals with a genetic predisposition to AD displayed greater WMH progression in midlife. WMH progression was associated with longitudinal decline in processing speed in those with FH of parental dementia, but not in those without FH. Taken together, findings suggest that WMH progression is evident decades before dementia might occur, and may be of clinical relevance in predicting cognitive decline particularly in individuals at increased inherited risk of AD. [ABSTRACT FROM AUTHOR]

Background: Hypertension and white matter hyperintensity(WMH) burden are major risk‐factors for Alzheimer's disease[Pantoni et al.,2010;Sweeney et al.,2018]. Prior studies show variable grey matter alterations, involving both negative and positive associations, independently related to WMH and hypertension in early stages of late‐onset AD[Vipin et al.,2018;Foster‐Dingley et al.,2015;Tuladhar et al.,2015;Den Heijer et al.,2003]. However, the effect of incremental WMH load and concomitant hypertension on brain structure in young‐onset mild cognitive impairment(MCI) remains to be elucidated. Such investigations may provide better insight into relationships between WMH, hypertension and dementia risk. We thus examine the influence of increasing WMH load on grey matter volume(GMV) as well as on the association between blood pressure(BP) and GMV in young‐onset MCI. We hypothesize that WMH burden and BP will have derogatory effects on GMV, especially under high WMH conditions. Method: T1‐MRI data from 78 MCI subjects(<65years) from the Singapore‐YouNg‐Dementia‐Cohort was studied. WMH load was divided into low(0.00‐1.49ml), medium(1.50‐4.99ml) and high(>5.00ml). Voxel‐based morphometry(VBM) assessed whole‐brain voxel‐wise changes related to increasing WMH load between hypertensive(systolic‐BP>130mmHg)[Whelton et al.,2017] and non‐hypertensive subjects. Pearson's correlation analysis tested associations between GMV from key Executive‐Control‐Network(ECN) and Default‐Mode‐Network(DMN) regions‐of‐interest(ROI)[Shirer et al.,2012] and vascular risk‐factors. Result: Whole‐brain VBM revealed less GMV reduction in hypertensive compared to non‐hypertensive subjects in frontal and temporal regions at low‐WMH load, with more pronounced effects at medium‐WMH load (Fig.1;uncorrected‐p<0.001, cluster‐size‐threshold:p<0.05). However, at high‐WMH load, hypertensive and non‐hypertensive subjects showed no differences in GMV. Additionally, at low‐WMH load, average and ROI‐specific DMN(bilateral posterior‐cingulate‐cortex, precuneus;p<0.05) and ECN(left[p<0.05] and right[p<0.10] posterior‐parietal‐cortex) GMV related positively to WMH but showed no association at medium‐WMH load. Importantly, only high‐WMH load was associated with lower ECN(p<0.05) and DMN(p<0.10) GMV(Fig.2). These associations remained regardless of hypertension status. Additionally, high systolic‐BP related to lower GMV at high‐WMH load only(Fig.3). Conclusion: Our findings indicate that in young‐onset MCI, the relationship between WMH and GMV is determined by WMH load rather than hypertension status. WMH load also influences the relationship between systolic BP and GMV in young‐onset MCI. Importantly, our results suggest that WMH and hypertension influence GMV via different mechanisms and BP recommendations for dementia prevention may be different in MCI with and without WMH. [ABSTRACT FROM AUTHOR]