Marker Of Cerebrovascular Disease Research Articles

White matter hyperintensity shape is related to long-term progression of cerebrovascular disease in community-dwelling older adults

White matter hyperintensity (WMH) shape is associated with long-term dementia risk in community-dwelling older adults, however, the underlying structural correlates of this association are unknown. We therefore aimed to investigate the association between baseline WMH shape and cerebrovascular disease progression over time in community-dwelling older adults. The association of WMH shape and cerebrovascular disease markers was investigated using linear and logistic regression models in the Age, Gene/Environment Susceptibility-Reykjavik (AGES) study (n = 2297; average time to follow-up: 5.2 years). A more irregular shape of periventricular/confluent WMH at baseline was associated with a larger increase in WMH volume, and with occurrence of new subcortical infarcts, new microbleeds, new enlarged perivascular spaces, and new cerebellar infarcts at the 5.2-year follow-up (all p < 0.05). Furthermore, less elongated and more irregularly shaped deep WMHs were associated with a larger increase in WMH volume, and new cortical infarcts at follow-up (p < 0.05). A less elongated shape of deep WMH was associated with new microbleeds at follow-up (p < 0.05). Our findings show that WMH shape may be indicative of the type of cerebrovascular disease marker progression. This underlines the significance of WMH shape to aid in the assessment of cerebrovascular disease progression.

ASSOCIATIONS OF MEAN COGNITIVE PERFORMANCE AND INTRAINDIVIDUAL VARIABILITY WITH WHITE MATTER LESIONS

Abstract White matter lesions (WMLs) are magnetic resonance imaging markers of small vessel cerebrovascular disease and have been associated with Alzheimer’s disease and related dementias. Intraindividual variability (IIV), often measured as variability in performance across neuropsychological tests at a single time point, has emerged as a sensitive marker of early cognitive difficulties that may have utility beyond measures of mean neuropsychological performance (MP). However, the associations of IIV with neuroimaging variables remains understudied. This study included 70 older adults without dementia (mean age=68.57) who completed a comprehensive neuropsychological battery and underwent MRI brain scans. WMLs were adjusted for estimated total intracranial volume and transformed to reduce skew. Linear regression models examined the associations of IIV, MP, and WMLs both across and within the cognitive domains of memory, attention/processing speed, and executive function. Covariates included age, sex, and education. IIV showed no significant association with WMLs, neither within nor across the domains examined (all p’s&amp;gt;.05). In the domains of memory (B=-.035, p=.025), executive function (B=-.039, p=.018), and in global cognition (B=-.065, p=.003) lower MP was associated with more WMLs. In the attention/processing speed domain, MP was not significantly associated with WMLs (all p’s &amp;gt;.05). The present study only examined cross-sectional data, so future studies should re-evaluate the associations with IIV, MP, and WMLs longitudinally. While the small sample size may limit the generalizability of this study, these findings suggest that measures of MP may better reflect WMLs relative to measures of IIV.

Additive effects of cerebrovascular disease functional connectome phenotype and plasma p-tau181 on longitudinal neurodegeneration and cognitive outcomes.

We investigated the effects of multiple cerebrovascular disease (CeVD) neuroimaging markers on brain functional connectivity (FC), and how such CeVD-related FC changes interact with plasma phosphorylated tau (p-tau)181 (an Alzheimer's disease [AD] marker) to influence downstream neurodegeneration and cognitive changes. Multivariate associations among four CeVD markers and whole-brain FC in 529 participants across the dementia spectrum were examined using partial least squares correlation. Interactive effects of CeVD-related FC patterns and p-tau181 on longitudinal gray matter volume (GMV) and cognitive changes were investigated using linear mixed-effects models. We identified a brain FC phenotype associated with high CeVD burden across all markers. Further, expression of this general CeVD-related FC phenotype and p-tau181 contributed additively, but not synergistically, to baseline and longitudinal GMV and cognitive changes. Our findings suggest that CeVD exerts global effects on the brain connectome and highlight the additive nature of AD and CeVD on neurodegeneration and cognition. Effects of multiple cerebrovascular disease (CeVD) markers on functional connectivity were studied. A global network phenotype linked to high burden across CeVD markers was identified. CeVD phenotype and plasma phosphorylated tau 181 contributed additively to downstream outcomes.

Enhancing cognitive performance prediction by white matter hyperintensity connectivity assessment.

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables us to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (i) LNM-informed markers surpass WMH volumes in predicting cognitive performance; and (ii) WMH contributing to cognitive impairment map to specific brain networks. We analysed cross-sectional data of 3485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in four cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based grey and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in grey and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

SDMA as a marker and mediator in cerebrovascular disease.

Symmetric dimethylarginine (SDMA) is a methylated derivative of arginine, generated by all cells as a by-product of cellular metabolism and eliminated via the kidney. For many years SDMA has been considered inert and of little biological significance. However, a growing body of evidence now suggests this view is outdated and that circulating SDMA levels may, in fact, be intricately linked to endothelial dysfunction and vascular risk. In this review, we specifically examine SDMA within the context of cerebrovascular disease, with a particular focus on ischaemic stroke. We first discuss pre-clinical evidence supporting the notion that SDMA has effects on nitric oxide signalling, inflammation, oxidative stress, and HDL function. We then appraise the most recent clinical studies that explore the relationship between circulating SDMA and cerebrovascular risk factors, such as chronic kidney disease, hypertension, atrial fibrillation, and atherosclerosis, exploring whether any associations may arise due to the existence of shared risk factors. Finally, we consider the evidence that elevated circulating SDMA is linked to poor outcomes following ischaemic and haemorrhagic stroke. We draw upon pre-clinical insights into SDMA function to speculate how SDMA may not only be a marker of cerebrovascular disease but could also directly influence cerebrovascular pathology, and we highlight the pressing need for more mechanistic pre-clinical studies alongside adequately powered, longitudinal clinical studies to fully evaluate SDMA as a marker/mediator of disease.

Interactive effect of diabetes mellitus and subclinical MRI markers of cerebrovascular disease on cognitive decline and incident dementia: a memory-clinic study

BackgroundCognitive impairment is an increasingly recognized comorbidity of diabetes, yet the mechanisms underlying this association remain poorly understood. This knowledge gap has contributed to conflicting findings regarding the impact of diabetes on long-term cognitive outcomes in older adults. The presence of cerebrovascular disease (CeVD) may potentially modify this relationship. However, interactive effect between diabetes and subclinical MRI markers of CeVD on cognitive trajectories and incident dementia remains unexplored.MethodsA total of 654 participants underwent brain MRI at baseline, from whom 614 with at least one follow-up were selected for longitudinal analysis. Cognitive tests were performed annually up to 5 years. CeVD markers of interest were lacunes, white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), cortical microinfarcts (CMIs), intracranial stenosis (ICS), and cortical infarcts. Blood-based Alzheimer biomarkers, including p-tau181 and p-tau181/Aβ42 ratio, were used as indicators of Alzheimer pathology.ResultsAt baseline, diabetes was associated with lower cognitive performance and higher burden of CeVD, but not p-tau181 or p-tau181/Aβ42 ratio. Longitudinally, we found an interactive effect of diabetes and WMHs, rather than an independent effect of diabetes, on cognitive decline and dementia risk. Subgroup analyses showed association of diabetes with cognitive outcomes was stronger in participants with high WMHs load but non-significant in those with low WMHs load. Moreover, these associations remained unchanged after adjusting for blood-based Alzheimer biomarkers.ConclusionsThe effect of diabetes on cognitive decline is contingent upon the presence of WMHs and independent of Alzheimer’s pathology. This finding raises the possibility of utilizing WMHs as an imaging biomarker to identify diabetic subgroup at greater risk of developing cognitive impairment. Furthermore, therapeutic interventions targeting WMHs may prevent cognitive deterioration in older adults with diabetes.

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

B.3 Neuroimaging markers of cerebrovascular disease and cognition in adults with moderate-great complexity congenital heart disease

Background: Adults with congenital heart disease (ACHD) are at risk for stroke and dementia. We report baseline and Year 1 results from an ongoing study assessing brain health in people with moderate- and great-complexity ACHD. Methods: Participants aged ≥18 undergo baseline and Year-3 brain MRI/MRA and annual cognitive assessment (MoCA, NIH Toolbox-Cognitive Battery (NIH-TB)). Results: Of 93 participants to date, 79 (85%) have completed Year 1 follow-up. At baseline, the great-complexity group had lower MoCA (26.32 vs. 27.38; p=0.04) and NIH-TB scores (total composite 45.63 vs. 52.80; p=0.002) than the moderate-complexity group. Year-1 testing showed numerical improvements across cognitive batteries in both groups. More participants with great-complexity ACHD had white matter hyperintensities (WMH; 72% vs. 55%; p=0.21) and cerebral microbleeds (CMBs; 72% vs. 54%; p=0.17) on baseline neuroimaging, but differences were not significant. Conclusions: Baseline neuroimaging shows a greater-than-expected burden for age of CMB and WMH in the context of previous cardiac surgery. Baseline cognitive performance was worse with great-complexity ACHD. Improved cognitive battery performance across both subgroups at Year-1 suggests a practice effect. Repeat neuroimaging will be performed in Year-3 and cognitive performance is reassessed annually.

A pathway linking pulse pressure to dementia in adults with Down syndrome.

Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer's Disease - Down Syndrome study (n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.

Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10years: 0.18mm, 0.11mm, and 0.12mm), male sex (WA: 0.24mm, 0.13mm, and 0.21mm), and TCV (WA: for one TCV standard deviation: 0.24mm, 0.29mm, and 0.18mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39mm and 0.73mm) and negative correlation with BA diameters (WA: -0.88mm and -1.73mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

Cerebrovascular features of Alzheimer’s disease in adults with Down syndrome

AbstractBackgroundCerebrovascular disease contributes to clinical onset and course of Alzheimer’s disease (AD) but it is unclear if it is related directly to AD pathogenesis. In late onset AD, MRI markers of small vessel cerebrovascular disease relate to AD diagnosis, genetic risk for AD, and severity of AD symptoms, but it is not possible to determine whether these associations reflect comorbidity due to risk factor exposure or whether they represent a core feature of AD. We have been studying cerebrovascular features of Alzheimer’s disease in adults with Down syndrome, who are at genetic risk for developing AD but have very low prevalence of classical vascular risk factors.MethodIn the context of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS), a US‐based multisite observational study of the clinical, biomarker, and pathological features of AD in adults with Down syndrome, our laboratory has analyzed high‐resolution, harmonized MRI scans for markers of cerebrovascular disease, including white matter hyperintensities (WMH), enlarged perivascular spaces, microbleeds, and infarcts, in adults with Down syndrome across the adult lifespan. We tested the association of these markers with age, AD‐related clinical diagnoses, proteomic profiles of vascular function and inflammation, and AD‐related biofluidic biomarker concentrations.ResultOur studies show that MRI‐derived markers of cerebrovascular disease are prevalent in adults with Down syndrome and increase in severity across AD‐associated clinical diagnoses. Age analyses suggest that there is an inflection of these markers at around age 40, when other pathological features also begin to emerge. Proteomic correlates of these cerebrovascular disease markers suggest an association with inflammatory processes in presymptomatic and neurodegenerative processes in symptomatic adults with Down syndrome. Finally, markers of cerebrovascular disease are particularly associated with plasma phosphorylated tau concentrations in adults with Down syndrome.ConclusionOur work shows that MRI‐derived markers of cerebrovascular disease are prevalent, related to AD symptoms, temporally track with AD pathology, relate to inflammation and neurodegeneration markers, and associate with markers of tau pathology. Without the confound of exposure to peripheral vascular risk factors, these observations suggest that cerebrovascular disease represents a “core feature” of AD that contributes both to symptoms and to disease pathogenesis.

Antemortem visit‐to‐visit blood pressure variability and postmortem cerebrovascular disease lesion burden in older adults without dementia

AbstractBackgroundBlood pressure management is an accessible therapeutic target for dementia prevention. Beyond the current focus of managing mean levels, there is a burgeoning interest in understanding the variability in blood pressure levels. Emerging research suggests elevated blood pressure variability is associated with increased risk for Alzheimer’s dementia and cerebrovascular disease, including white matter hyperintensities on MRI (e.g., Fazekas score), but relationships with white matter lesions and overall cerebrovascular pathology at autopsy remain understudied. The aim of the current study was to determine whether antemortem blood pressure variability predicts cerebrovascular pathology in older adults without clinical dementia.Method1866 older adults from the National Alzheimer’s Coordinating Center study underwent repeated approximately annual blood pressure measurement and autopsy and were free of clinical dementia at study baseline. Visit‐to‐visit blood pressure variability was calculated as variability independent of mean using at least 3 (median 5, range 3 ‐ 15) annual blood pressure measurements. White matter rarefaction was scored as none vs mild/moderate vs severe. An index of overall cerebrovascular lesion burden (range 0‐7) was calculated as the sum of severity (0‐2) of atherosclerosis in the Circle of Willis and arteriolosclerosis, and the presence/absence (0‐1) of microinfarcts, infarcts and lacunes, and microbleeds and hemorrhages. Linear and multinomial logistic regression models examined relationships between blood pressure variability, white matter rarefaction severity, and overall cerebrovascular lesion burden, controlling for age, sex, mean blood pressure, antihypertensive use, and Hachinski Ischemic Score, among other variables.ResultElevated blood pressure variability predicted increased severity of white matter rarefaction (OR of mild/moderate [vs none] = 1.21 [1.06, 1.33], p = .004; OR of severe [vs none] = 1.30 [1.07, 1.46], p = .008), and greater overall cerebrovascular lesion burden (ß = .12 [.11, .42]; p &lt; .0001).ConclusionElevated blood pressure variability is related to postmortem cerebrovascular lesion burden, including increased severity of white matter rarefaction, in older adults without clinical dementia, independent of mean blood pressure. Findings are consistent with studies using MRI‐based markers of cerebrovascular disease and may help improve blood pressure as a risk indicator for dementia and cerebrovascular disease.

White matter hyperintensity burden does not differentiate SuperAgers from average cognitive agers

AbstractBackgroundThe amount of white matter hyperintensity (WMH) found on T2‐weighted imaging has shown a strong relationship with age and is thought to be a marker of ischemia‐associated demyelination or secondary axonal degeneration associated with neurodegenerative disease. Previous healthy older aging studies have shown increased WMH are associated with poorer episodic memory performance and decreased volume of medial temporal lobe regions. Here, we examine if lower WMH are associated with a phenotype of successful cognitive aging, SuperAging. SuperAgers are participants over the age 80 with episodic memory at least as good as that of average middle‐aged adults.MethodWe quantified the WMH volume from T2‐FLAIR imaging with a pre‐trained Bayesian 3D U‐Net convolutional neural network in SuperAgers and cognitively healthy elderly controls (EC) of a similar age and education. All participants underwent the ADNI‐3 FLAIR on the same 3T Prisma MRI. WMH volume was square root transformed to account for the skewed distribution. A 2‐tail independent samples t‐test evaluated the difference in WMH volume between SuperAgers and EC. Additionally, we examined if there were differences within SA and EC groups by sex.Result46 SuperAgers (average age 86.3 ± 1.86; average years of education 16.9 ± 1.9) and 25 EC (average age 87.1 ± 5.17; average years of education 17.1 ± 3.1) met criteria and were included in the study. There was no significant difference in the volume of WMH between SuperAgers and ECs (t = 1.01, p = 0.32). Further, there was no significant difference in WMH by sex within the SuperAging group (t = 0.10, p = 0.92) or EC group (t = 0.82, p = 0.42).ConclusionResistance to the development of WMH, a cross‐sectional marker of cerebrovascular disease and demyelination, does not appear to be a strong discriminating factor in 80+ year‐olds with superior memory function compared to cognitively average agers. Future analyses will include longitudinal changes in WMH and examining regional WMH. Cognitive aging is associated with several underlying brain‐based etiologies, and SuperAging may be better explained by a more sophisticated multi‐modal approach.

Relationship between a novel virtual reality test of mild functional difficulties and cerebrovascular disease

AbstractBackgroundIt is well known that mild cognitive impairment (MCI) is associated with subtle functional decline. However, standardized and cost‐effective methods for the objective quantification of mild functional difficulties are lacking. Here we report preliminary validity data for a novel, non‐immersive virtual‐reality task (Virtual Kitchen Challenge [VKC]) against brain markers of cerebrovascular disease and in contrast to a conventional, self‐report measure of function.MethodTwenty (n = 14 healthy control, n = 6 MCI) community‐dwelling older adults aged 60+ completed neuropsychological testing, including the Functional Activities Questionnaire (FAQ), and the VKC, which requires completion of simulated breakfast and lunch tasks on a touch‐screen computer. White matter hyperintensity (WMH) volumes from Fluid Attenuation Inversion Recovery (FLAIR) MRI sequences were derived using the UBO detector, a cluster‐based WMH extraction pipeline based on k‐nearest neighbors (k‐NN) algorithm. WMH volumes were calculated in SPM’s DARTEL space, precluding the need to adjust for intracranial volume (ICV).ResultMCI participants reported significantly more functional difficulties than healthy controls (FAQ U = 76.50 p = .002) and obtained marginally slower completion times on the VKC (U = 60.00, p = .138). VKC completion time was moderately associated with age (r = .441, p = .059) but relations with sex, race, and IQ were weak and not significant (all rs&lt;.195). VKC completion time significantly and strongly correlated with all WMH measures, even after controlling for age, sex, race, and IQ (total WMH r = .649, p = .031; deep WMH r = .615, p = .044; periventricular WMH r = .623, p = .041). By contrast, FAQ was not associated with WMH (rs&lt;.2, p&gt;.05 for all) or VKC completion time (r&lt;.1, p&gt;05) after controlling for age, sex, race, and IQ.ConclusionOur naturalistic, performance‐based measure of function (VKC) was not associated with race, sex, or premorbid IQ, but was strongly associated with neuroimaging markers of cerebrovascular disease (WMH). By contrast, a conventional self‐report measure of everyday functioning (FAQ) was not associated with neuroimaging measures (WMH). These results offer preliminary support for the VKC as a valid measure of early, subtle functional difficulties associated with cerebrovascular pathology that is not vulnerable to bias associated with race, sex, or premorbid IQ.

What time window do AD trajectories depart from normal? Estimating age‐related trajectories to chart preclinical phase of Alzheimer’s disease and select trial‐ready cohorts

AbstractBackgroundThe preclinical phase of Alzheimer’s disease (AD), where pathology slowly accumulates years before cognitive impairment becomes apparent, could offer a treatment window with the greatest potential to preserve cognitive function before downstream pathological processes gather momentum. Characterizing when biomarker trajectories deviate from normal ageing, and the heterogeneity therein, could facilitate targeted trial recruitment and improved biomarker‐based evidence of disease modification. However, reliably identifying early abnormal changes can be challenging due to various confounds, such as age and vascular factors, as well as disease heterogeneity.MethodData from the following cohorts were analysed: (1) individuals at risk for, or affected by, autosomal dominant AD (ADAD), including the Dominantly Inherited Alzheimer Network; (2) Insight 46, a neuroimaging substudy of the MRC National Survey of Heath and Development; (3) pre‐randomization study data from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4); and (4) the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression assessed differences between at‐risk groups (biomarker‐ or mutation‐positive) and normal ageing. Longitudinal changepoint models estimated when atrophy rates deviate from normal ageing trajectories. Normative modelling, based on large reference datasets, identified outliers of regional atrophy assessed within‐group heterogeneity at the individual level. Data‐driven disease progression models (DPMs) were used to estimate quantitative signatures of AD, including imaging biomarkers.ResultDPMs reveal that amyloid markers deviate first in ADAD, roughly ten years before neurodegenerative markers. Changepoint models indicate that atrophy rates in ADAD become abnormal 3‐8 years before expected symptom onset, with longitudinal tau PET data suggesting a similar trend. While cross‐sectional volumetric measures showed no evidence of association with amyloid markers, atrophy rates were independently related to both amyloid positivity and markers of cerebrovascular disease, indicating similar, additive effects. Both DPMs and normative modelling found evidence of heterogeneity within imaging biomarkers in ADNI and A4, which explained variability in cognitive decline observed in at‐risk participants.ConclusionBiomarker data from preclinical AD suggests a long temporal gap between amyloidosis and subsequent changes. This represents a treatment opportunity to remove amyloid while minimising irreversible damage. There is evidence of heterogeneity within the biomarker trajectories, which could impact the ability to detect disease modification.

Relationship between a novel virtual reality test of mild functional difficulties and cerebrovascular disease

AbstractBackgroundIt is well known that mild cognitive impairment (MCI) is associated with subtle functional decline. However, standardized and cost‐effective methods for the objective quantification of mild functional difficulties are lacking. Here we report preliminary validity data for a novel, non‐immersive virtual‐reality task (Virtual Kitchen Challenge [VKC]) against brain markers of cerebrovascular disease and in contrast to a conventional, self‐report measure of function.MethodTwenty (n = 14 healthy control, n = 6 MCI) community‐dwelling older adults aged 60+ completed neuropsychological testing, including the Functional Activities Questionnaire (FAQ), and the VKC, which requires completion of simulated breakfast and lunch tasks on a touch‐screen computer. White matter hyperintensity (WMH) volumes from Fluid Attenuation Inversion Recovery (FLAIR) MRI sequences were derived using the UBO detector, a cluster‐based WMH extraction pipeline based on k‐nearest neighbors (k‐NN) algorithm. WMH volumes were calculated in SPM’s DARTEL space, precluding the need to adjust for intracranial volume (ICV).ResultMCI participants reported significantly more functional difficulties than healthy controls (FAQ U = 76.50 p = .002) and obtained marginally slower completion times on the VKC (U = 60.00, p = .138). VKC completion time was moderately associated with age (r = .441, p = .059) but relations with sex, race, and IQ were weak and not significant (all rs&lt;.195). VKC completion time significantly and strongly correlated with all WMH measures, even after controlling for age, sex, race, and IQ (total WMH r = .649, p = .031; deep WMH r = .615, p = .044; periventricular WMH r = .623, p = .041). By contrast, FAQ was not associated with WMH (rs&lt;.2, p&gt;.05 for all) or VKC completion time (r&lt;.1, p&gt;05) after controlling for age, sex, race, and IQ.ConclusionOur naturalistic, performance‐based measure of function (VKC) was not associated with race, sex, or premorbid IQ, but was strongly associated with neuroimaging markers of cerebrovascular disease (WMH). By contrast, a conventional self‐report measure of everyday functioning (FAQ) was not associated with neuroimaging measures (WMH). These results offer preliminary support for the VKC as a valid measure of early, subtle functional difficulties associated with cerebrovascular pathology that is not vulnerable to bias associated with race, sex, or premorbid IQ.

White matter hyperintensity burden does not differentiate SuperAgers from average cognitive agers

AbstractBackgroundThe amount of white matter hyperintensity (WMH) found on T2‐weighted imaging has shown a strong relationship with age and is thought to be a marker of ischemia‐associated demyelination or secondary axonal degeneration associated with neurodegenerative disease. Previous healthy older aging studies have shown increased WMH are associated with poorer episodic memory performance and decreased volume of medial temporal lobe regions. Here, we examine if lower WMH are associated with a phenotype of successful cognitive aging, SuperAging. SuperAgers are participants over the age 80 with episodic memory at least as good as that of average middle‐aged adults.MethodWe quantified the WMH volume from T2‐FLAIR imaging with a pre‐trained Bayesian 3D U‐Net convolutional neural network in SuperAgers and cognitively healthy elderly controls (EC) of a similar age and education. All participants underwent the ADNI‐3 FLAIR on the same 3T Prisma MRI. WMH volume was square root transformed to account for the skewed distribution. A 2‐tail independent samples t‐test evaluated the difference in WMH volume between SuperAgers and EC. Additionally, we examined if there were differences within SA and EC groups by sex.Result46 SuperAgers (average age 86.3 ± 1.86; average years of education 16.9 ± 1.9) and 25 EC (average age 87.1 ± 5.17; average years of education 17.1 ± 3.1) met criteria and were included in the study. There was no significant difference in the volume of WMH between SuperAgers and ECs (t = 1.01, p = 0.32). Further, there was no significant difference in WMH by sex within the SuperAging group (t = 0.10, p = 0.92) or EC group (t = 0.82, p = 0.42).ConclusionResistance to the development of WMH, a cross‐sectional marker of cerebrovascular disease and demyelination, does not appear to be a strong discriminating factor in 80+ year‐olds with superior memory function compared to cognitively average agers. Future analyses will include longitudinal changes in WMH and examining regional WMH. Cognitive aging is associated with several underlying brain‐based etiologies, and SuperAging may be better explained by a more sophisticated multi‐modal approach.

Effects of cerebrovascular disease on tau progression and cognitive decline in Alzheimer’s disease

AbstractBackgroundRecent post‐mortem studies suggest that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and clinical progression. In particular, cerebral amyloid angiopathy is highly common in AD and has been linked to faster cognitive decline. Yet, in‐vivo evidence on the contribution of cerebrovascular disease to pathobiological and/or clinical AD progression is rare. Thus, we assessed in‐vivo, whether i) higher cerebrovascular burden is associated with accelerated progression of primary AD pathology and ii) whether cerebrovascular burden synergistically accelerates AD‐related cognitive decline.MethodWe included n = 256 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) across the AD spectrum with longitudinal 18F‐flortaucipir tau‐PET (follow‐up∼2.30±1.32 years), 18F‐florbetapir or 18F‐florbetaben Aß‐PET transformed to centiloid (A7: n = 85 Cognitively normal (CN); Aß+: n = 83 CN, n = 57 Mild Cognitive Impairment, n = 31 Dementia). We focused on global white matter hyperintensity (WMH) volume adjusted to intracranial volume and microhemorrhage (MCH) count as well‐established cerebrovascular disease markers. Cognition was probed through the AD Assessment Scale Cognition 13‐item scale (ADAS‐13). Subject‐specific annual changes in tau‐PET and cognition were calculated via linear mixed models, including random slope and intercept. To enhance reproducibility of our findings, statistical analyses were pre‐specified at AsPredicted.org. All statistical models were controlled for age, sex and APOE.ResultUsing linear regression, we found no main effect of cerebrovascular disease markers on baseline amyloid‐PET or tau‐PET (ps&gt;0.05). Further, higher cerebrovascular burden was not associated with faster Aß‐related tau‐PET SUVR increase (Fig. 1A+B). In contrast, higher cerebrovascular burden was associated with accelerated cognitive decline. Specifically, interaction models revealed that a higher MCH count was associated with faster cognitive decline at higher tau levels (Fig. 1C), while higher white matter hyperintensity burden was associated with faster cognitive decline at lower tau levels (Fig. 1D).ConclusionWe found no effect of cerebrovascular disease on primary AD pathology. In contrast, cerebrovascular disease was linked to accelerated tau‐associated cognitive decline. This suggests that cerebrovascular disease may not modulate pathobiological AD trajectories but rather add synergistically to AD symptom severity. This has important therapeutic implications, as treating cerebrovascular disease in addition to primary AD pathology (e.g. amyloid) may yield largest clinical efficacy.

Effects of cerebrovascular disease on tau progression and cognitive decline in Alzheimer’s disease

AbstractBackgroundRecent post‐mortem studies suggest that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and clinical progression. In particular, cerebral amyloid angiopathy is highly common in AD and has been linked to faster cognitive decline. Yet, in‐vivo evidence on the contribution of cerebrovascular disease to pathobiological and/or clinical AD progression is rare. Thus, we assessed in‐vivo, whether i) higher cerebrovascular burden is associated with accelerated progression of primary AD pathology and ii) whether cerebrovascular burden synergistically accelerates AD‐related cognitive decline.MethodWe included n = 256 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) across the AD spectrum with longitudinal 18F‐flortaucipir tau‐PET (follow‐up∼2.30±1.32 years), 18F‐florbetapir or 18F‐florbetaben Aβ‐PET transformed to centiloid (Aβ–: n = 85 Cognitively normal (CN); Aβ+: n = 83 CN, n = 57 Mild Cognitive Impairment, n = 31 Dementia). We focused on global white matter hyperintensity (WMH) volume adjusted to intracranial volume and microhemorrhage (MCH) count as well‐established cerebrovascular disease markers. Cognition was probed through the AD Assessment Scale Cognition 13‐item scale (ADAS‐13). Subject‐specific annual changes in tau‐PET and cognition were calculated via linear mixed models, including random slope and intercept. To enhance reproducibility of our findings, statistical analyses were pre‐specified at AsPredicted.org. All statistical models were controlled for age, sex and APOE.ResultUsing linear regression, we found no main effect of cerebrovascular disease markers on baseline amyloid‐PET or tau‐PET (ps&gt;0.05). Further, higher cerebrovascular burden was not associated with faster Aβ‐related tau‐PET SUVR increase (Fig. 1A+B). In contrast, higher cerebrovascular burden was associated with accelerated cognitive decline. Specifically, interaction models revealed that a higher MCH count was associated with faster cognitive decline at higher tau levels (Fig. 1C), while higher white matter hyperintensity burden was associated with faster cognitive decline at lower tau levels (Fig. 1D).ConclusionWe found no effect of cerebrovascular disease on primary AD pathology. In contrast, cerebrovascular disease was linked to accelerated tau‐associated cognitive decline. This suggests that cerebrovascular disease may not modulate pathobiological AD trajectories but rather add synergistically to AD symptom severity. This has important therapeutic implications, as treating cerebrovascular disease in addition to primary AD pathology (e.g. amyloid) may yield largest clinical efficacy.

Sleep apnea‐related hypoxemia, not sleep fragmentation, is associated with white matter hyperintensities in older adults

AbstractBackgroundSleep apnea is a type of sleep‐disordered breathing that increases risk for Alzheimer’s disease‐related pathology potentially through cerebrovascular pathology, likely exacerbated by two features of sleep apnea: intermittent hypoxia and sleep fragmentation. White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase in aging and in AD. Here, we tested the hypothesis that apnea‐related hypoxemia severity, and not sleep fragmentation, are associated with WMH volume in older adults.MethodsThirty‐two older adults (73.4±5.3 years, 19 female, AHI = 15.2±18.9) were evaluated with overnight polysomnography (PSG). Apnea severity was quantified using the Apnea‐Hypopnea Index (AHI), Respiratory Disturbance Index (RDI), and blood oxygen desaturation (Oxygen Desaturation Index (ODI), duration, frequency of ≥4% desaturations, and desaturation nadir) stratified by sleep stages. T1‐MPRAGE and T2‐FLAIR scans were acquired using a 3T Siemens scanner. Total WMH volumes were derived using a semi‐automated algorithm. Overnight memory retention was assessed using the change in the lure discrimination index (LDI) for the emotional version of the Mnemonic Discrimination Task.ResultsTraditional measures of apnea severity and sleep fragmentation were not significantly associated with global WMH volume. However, both max duration of oxygen desaturation events (r = 0.44, p = 0.011) and max oxygen desaturation percentage (in rapid‐eye movement (REM) and in total sleep: r = 0.48, p = 0.005, and r = 0.44, p = 0.01), were significantly associated with total WMH volume. Similar relationships were found with time spent below 90% and 80% oxygen saturation (Kendall’s tau = 0.33, p = 0.02 and tau = 0.275, p = 0.03). These relationships survived adjustment for sex, age, and hyperlipidemia and/or hypertension medication at time of PSG. Global WMH volume was also negatively associated with overnight memory retention (r = ‐0.38, p = 0.03).ConclusionsThese findings suggest that hypoxemia severity, compared to sleep fragmentation, are more strongly associated with global WMH volume. As WMH volume was associated with overnight memory retention, this may suggest a pathway in which OSA increases WMH, which is subsequently associated with tau burden, worsening sleep‐dependent memory.