Marker Of Cerebrovascular Disease Research Articles

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 < .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<.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<.2, p>.05 for all) or VKC completion time (r<.1, p>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<.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<.2, p>.05 for all) or VKC completion time (r<.1, p>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>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>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.

Cerebrovascular disease is associated with memory function in the Health and Aging in Africa Longitudinal Study of an INDEPTH community in rural South Africa

AbstractBackgroundHealth and Aging in Africa Longitudinal Study of an INDEPTH community in South Africa (HAALSI) is a sister study to the US‐based Health and Retirement Study. The purpose of HAALSI is to characterize the social, economic, biological, physical, and mental health factors in a population‐representative cohort of older adults in a rural community in Agincourt, South Africa. Beginning in 2020, as part of an Alzheimer’s disease and related disorders (ADRD) substudy, we conducted neuropsychological evaluations and structural magnetic resonance imaging (MRI) in a subset of HAALSI participants. Here, we report preliminary observations on the relationship of white matter hyperintensity (WMH) volume, a marker of small vessel cerebrovascular disease, and hippocampal volume, a marker of neurodegeneration, on memory function in a group of substudy participants.MethodNinety‐nine HAALSI ADRD participants with available MRI scans and neuropsychological outcomes at time of analysis (mean ± SD; age = 70.3 ± 10.9, 87% with no formal education or some primary education) were included in these analyses. Participants received research‐grade, harmonized 1.5T MRI scanning at a private hospital and were evaluated with a battery of neuropsychological tests. Using in‐house developed software and FreeSurfer, respectively, we derived total WMH volume and total hippocampal volume. We examined the association of these variables with memory function, operationalized as the delayed recall score of the Logical Memory Test, adapted for context.ResultAdjusting for education level, increased WMH volume was associated with poorer performance on the Logical Memory Test (standardized β = ‐0.21, p<0.05) but hippocampal volume was not (standardized β = 0.09, p = 0.41). Associations of these MRI markers with memory function did not interact with education level.ConclusionIn these preliminary analyses of older adults in a rural South African community, markers of small vessel cerebrovascular disease but not neurodegeneration are associated with poorer cognitive outcomes. Future work will examine the pathways that give rise to cognitive impairment and dementia in this rural South African population and track cognitive trajectories over time.

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.

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.MethodThirty‐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.ResultTraditional 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).ConclusionThese 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.

Plasma Alzheimer biomarker correlates of cerebrovascular disease in adults with Down syndrome

AbstractBackgroundBy age 40 over 90% of adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology and most progress to dementia. Despite having fewer systemic vascular risk factors than neurotypical adults, recent studies demonstrate evidence of significant cerebrovascular disease in individuals with DS that track with the clinical progression of AD, suggesting a role for cerebrovascular disease that is not attributable solely to exposure to vascular risk factors. In the current study, we examined the codependency between white matter hyperintensity (WMH) volume, a marker of small vessel cerebrovascular disease, and AD pathophysiology, indexed with plasma AD biomarkers, in adults with DS.MethodOne hundred eighty‐seven participants from the Alzheimer Biomarkers Consortium – Down Syndrome (mean[SD] = 45.1[9.4] years) with available MRI and plasma biomarker data were included in the study. Whole‐brain WMH volumes were derived from T2‐weighted FLAIR MRI scans with in‐house software and plasma p‐tau217, Aβ42/Aβ40, and neurofilament light (NfL) concentrations were measured with SIMOA assays. Separate general linear models tested the association of WMH volume with each of the three biomarker concentrations; subsequent models were stratified by age, based on the median (46 years old).ResultHigher WMH volume was associated with increased p‐tau217 and NfL concentrations but not with Aβ. In stratified analyses, the association between WMH and NfL concentration was stronger in younger adults than in older adults whereas the association between WMH and p‐tau217 concentration was stronger in older adults than in younger adults.ConclusionOur findings suggest a co‐dependency of cerebrovascular disease with tau pathology and neurodegeneration in adults with Down syndrome. Cerebrovascular disease may promote neurodegenerative changes in early adulthood and tau changes in later adulthood. The additional or alternative possibility that tau and neurodegeneration promote white matter changes cannot be ruled out in these cross sectional analyses. Future work will address the relative temporal emergence of these markers in adults with DS.

Investigating associations of multiple common infections with brain structure and white matter lesions: findings from prospective neuroimaging studies

AbstractBackgroundEvidence for a role of common infections in neurodegenerative and cerebrovascular diseases is conflicting, and the extent to which pathogen exposure associates with subclinical imaging markers of these diseases is unclear. We aimed to investigate associations between a panel of serological measures characterising exposure to common pathogens – selected based on their relevance to public health – and brain volume, hippocampal volume, and white matter lesions in two population‐based cohorts in the UK.MethodSerology and imaging data were available for 1371 participants across two studies: the UK Biobank (N = 935, mean age(SD)[years] = 55.3(7.7) at serology; 63.8(7.7) at imaging) and the Medical Research Council National Survey of Health and Development [N = 436, mean age(SD) [years] = 63.3(1.1) years at serology; 70.7(0.7) years at imaging). Serology measures included a) serostatuses of 17 pathogens, b) total proportion of 17 pathogens exposed to, and c) total proportion of 11 neurotropic pathogens exposed to (Table 1). Associations between serology measures and outcomes (brain volume, hippocampal volume, and white matter lesion volume) were tested using linear regression. Regression models included adjustments for total intracranial volume and clinic information (basic models), and age, sex, ethnicity, education, socioeconomic position and lifestyle factors (Figure 1). Findings across cohorts were meta‐analysed using random‐effects models. The present study will be expanded to include an additional cohort (Southall and Brent Revisited,N≤1200) to add more precision for identifying associations.ResultSeropositivity to seven pathogens associated with an outcome in basic models, and four in fully‐adjusted models: seropositivity to JC virus was associated with smaller brain volumes, Epstein‐Barr virus with larger brain volumes, Merkel cell virus with larger hippocampal volumes and fewer white matter lesions, and C.trachomatis with fewer white matter lesions (Figure 2). Neurotropic pathogen burden scores associated with smaller hippocampal volumes in basic models, but no associations were seen for either pathogen burden score in fully‐adjusted models.ConclusionWe found some evidence of both positive and negative associations between common infections and imaging markers of subclinical cerebrovascular disease and neurodegeneration, with no evidence of relationships with pathogen burden. This work highlights key relationships for further investigation, which may reveal novel pathways associated with brain structure and cerebrovascular pathology.

Ante‐mortem cognitive trajectories of older adults with cerebrovascular disease across Aβ and tau biomarker profiles determined at autopsy in the National Alzheimer’s Coordinating Center database

AbstractBackgroundAlzheimer’s disease (AD) is characterised biologically by beta‐amyloid (Aβ) plaques and tau tangles, but autopsy studies reveal that most older adults also present with cerebrovascular disease (CVD) markers. Effects of biological AD on cognition in the context of concurrent CVD remain unclear. In older adults with CVD pathology, this study sought to determine ante‐mortem cognitive trajectories associated with Aβ/tau positivity or negativity (+/−) at autopsy.MethodParticipants aged 65‐95 classified as cognitively unimpaired at baseline from the National Alzheimer’s Coordinating Center database, with ≥1 follow‐up between 2005‐2015, and available autopsy/APOE data were included (N = 924). Autopsy indicated that all participants had at least one of six CVD pathology markers. Participants were classified into four groups (A−T−, A+T−, A−T+, A+T+) based on semiquantitative Consortium to Establish a Registry for Alzheimer’s Disease neuritic plaque staging and Braak staging. Linear mixed models including group × time interactions assessed rate of change in Preclinical Alzheimer’s Cognitive Composite scores, episodic memory, and executive function. Interactions between age, sex, APOE ε4 × time and the interval between death/the final study visit were included as covariates.ResultA+T+ adults demonstrated significantly faster cognitive decline on all outcomes in the ∼10 years preceding death compared to A−T−, A+T−, and A−T+ adults (Table 1, Figure 1, d = 0.15 – 0.39). At final visit prior to death, a greater proportion of A+T+ adults (36%) received a dementia diagnosis compared to A−T+ (14%) or A+T− (15%) (p <.001). When analyses were restricted to exclude dementia diagnoses, significantly faster decline on all outcomes (p’s <.001, d = 0.06 – 0.36) was similarly observed in A+T+ adults compared to A−T−, A+T− and A−T+ adults (Figure 2). Cognitive trajectories were equivalent between A−T− and A+T− for all outcomes (p’s >.55).Conclusionln older adults with CVD pathology, A+T+ at autopsy was associated with greater cognitive decline over 10 years preceding death compared to A+T−, A−T+, and A−T− older adults. Faster cognitive decline in this group in the context of low final visit dementia diagnoses may suggest that post‐mortem A+T+ is associated with a steep trajectory of cognitive decline ante‐mortem, but that dementia progression is not inevitable.

Proteomic‐based Biological Aging Clock and MRI Markers of Cerebrovascular Disease: Atherosclerosis Risk in Community Study

AbstractBackgroundBiological aging state can be quantified by composite metrics called aging clocks using proteomics. Proteomic aging clocks (PACs) are accurate, easily measured, and are associated with age‐related diseases including Alzheimer’s Disease and Related Dementias. We aim to investigate whether an accelerated biological aging (a discrepancy between chronological age and PAC) is associated with subclinical cerebrovascular structural changes.Method1494 participants from the Atherosclerosis Risk in Communities (ARIC) Study with proteomics and 3T brain MRI data at ARIC visit 5 in 2011‐13 (mean age 76, 59% female, 25% Black) were included. Nearly 5000 plasma proteins were measured using the SomaScan assay. PAC was developed using elastic net regression model and was internally validated. Age acceleration was calculated as residuals after regressing PAC on chronological age (positive value indicates biological age is higher than the person’s chronological age). Linear and logistic regression models were used to assess the associations of age acceleration with white matter hyperintensity volume (in cm3, log2 transformed, median [IQR]: 11[6‐20]) and the presence of: subcortical (n = 281), lacunar (n = 263), and cortical infarcts (n = 150), and microbleeds (n = 355).ResultAccelerated age (median [IQR]:‐0.04[‐1.4,1.3]; correlation with chronological age = 0) was associated with MRI markers of cerebrovascular disease after adjusting for demographic, cardiovascular risk factors, education, and kidney function. Every five years higher age acceleration was associated with larger white matter hyperintensity volume (Difference:0.34[95%CI 0.19,0.49]), higher odds of lacunar (OR:1.61[1.13,2.30]), subcortical (OR:1.63[1.15, 2.32]), and cortical infarcts (OR:1.72[1.11,2.67]). There was no association with presence of microbleeds (OR:1.25[0.91,1.73]) (Figure). Findings were consistent after excluding participants with clinical stroke and there was no difference between APOEe4+ and APOEe4‐ participants.ConclusionHigher accelerated age is cross‐sectionally associated with a greater prevalence of MRI markers of cerebrovascular disease. Understanding this relation has potential to help with risk stratification and personalized prevention and treatment strategies to promote brain health.

White matter hyperintensity volume changes are associated with progressive hippocampal atrophy in Insight 46: the neuroscience sub‐study of the MRC National Survey of Health and Development, the British 1946 birth cohort

AbstractBackgroundWhite matter hyperintensity volume (WMHV) is a presumed marker of cerebrovascular disease associated with ageing, Alzheimer’s disease (AD) and vascular dementia. Higher baseline WMHV is associated with increased brain atrophy rate, with disproportionate effects in the hippocampus – a region affected early in AD. Understanding the relationships between longitudinal change in WMHV and hippocampal atrophy, while accounting for AD and cardiovascular risk factors, will increase our understanding of the multifactorial disease processes occurring during the early stages of AD.MethodRate of change in WMHV was calculated using Bayesian Model Selection (BaMoS) and total hippocampal atrophy rate was calculated using the Boundary Shift Integral (BSI), measured concurrently between two time‐points. Participants with major neurological disorders were excluded. Linear regression was used to test whether rates of WMHV change predicted rates of hippocampal atrophy while adjusting for total intracranial volume (TIV), sex and age. Further models adjusted for baseline PET amyloid‐β (Aβ) standard uptake value ratio (SUVR), ApoE‐e4 carrier status, and Framingham heart study cardiovascular risk (FHS‐CVS) aged 69, and tested for interactions with rate of WMHV change.Result308 individuals with high‐resolution isotropic MRI data at two time‐points were analysed in this study (Table 1). For every 1ml/year increase in WMHV there was an associated 0.013ml/year decrease in total hippocampal volume (Table 2, Model 1). This association remained when adjusting for Aβ SUVR (Table 2, Model 2), ApoE‐e4 status (Table 2, Model 3), and FHS‐CVS (Table 2, Model 4). A separate semi‐partial correlation analysis showed 4.6% of variance in rate of hippocampal atrophy was uniquely explained by rate of WMHV change when accounting for TIV, sex and age. There were no significant interactions between rate of WMHV change and Aβ, ApoE‐e4 or FHS‐CVS in relation to hippocampal atrophy rate.ConclusionIncreases in WMHV were significantly associated with progressive hippocampal atrophy accounting for head size, age and sex. These associations were not materially changed when adjusting for amyloid deposition, ApoE‐e4 or cardiovascular risk factors. These results suggest systemic processes that contribute to WMH development also contribute to hippocampal atrophy. Further work is required to determine the processes that drive this relationship.