Baker, Laura D.

AbstractBackgroundThere is limited information on biomarker‐defined Alzheimer’s disease (AD) pathology in community‐recruited individuals of diverse racial and ethnic groups. Here, we assessed the association of race/ethnicity with baseline biomarkers and cognitive measures and hypothesized a lower impact of AD pathology in non‐Hispanic White (nHW) participants in the U.S. POINTER study clinical trial, which evaluates the benefits of a multidomain lifestyle intervention on cognition of community‐recruited at‐risk elderly individuals.MethodWe included 879 participants from the U.S. POINTER study enrolled in the imaging substudy (∼50% of participants) who self‐identified as nHW (n=644), African American/Black (AA/B, n=132), Asian (n=29), and Hispanic (n=74). Outcomes measures included global Aβ pathology (18F‐florbetaben), temporal meta‐ROI tau (18F‐MK‐6240), MRI‐measured white matter hyperintensity volume (WMH) volumes, global clinical dementia rating (gCDR), and global, executive, and memory standardized cognitive scores. The nHW participants were selected as reference. Power transformations normalized skewed distributions. Multivariable linear regressions include age, sex, education, Framingham risk score, and area deprivation index (ADI) as covariates.ResultAA/B harbored lower WMHs, and meta‐temporal tau ROI values. In the full model, 0.5 gCDR participants had higher centiloid values, were more likely to be AA/B and Hispanic, and had a greater burden of WMHs. In addition, higher centiloid values were associated with a 0.5 gCDR in all groups except for the AA/B participants. Hispanic, AA/B, and Asian participants had lower cognitive scores than the nHW group. A higher ADI score was associated with lower global and executive cognitive scores but not with WMH volume or Aβ centiloid score.ConclusionThe analyses of the community‐based U.S. POINTER indicate that AA/B individuals present differences in AD and related dementia biomarker values. nHW had higher fully adjusted cognitive scores. These results indicate a significant heterogeneity in the cognitive testing performance and biomarker values of individuals at risk for dementia in the community.

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aß) peptides and tau‐protein neurofibrillary tangles, hallmark features of Alzheimer’s disease (AD) pathology, have been concomitantly associated with white matter (WM) integrity loss, while a unique effect of each pathology on WM integrity in a more demographically diverse population remains unknown.MethodTo examine the degree to which each pathology affects WM integrity in a more diverse non‐demented cohort, Aß and tau PET, diffusion‐weighted imaging (DWI), and cognition (memory and executive function composites) were examined from the U.S. POINTER neuroimaging participants (N = 608; age = 68.34±5.2; 61.8% females; 29% Aß+) and a subset of Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (N = 291; age = 72.85±7.3; 50% females; 39% Aß+) (Table). Aß‐positivity was determined using tracer‐specific standardized cut‐offs. Tau SUVR was estimated for each Braak stage. For WM integrity, voxel‐based GLMs were applied to FSL‐processed fractional anisotropy (FA) maps using Braak stage tau SUVR and Aß‐positivity status, along with covariates of age, sex, and b‐value profiles.ResultIn U.S. POINTER, independent from Aß‐positivity status, greater tau burden in Braak stages I and II was related to lower FA across the tracts including the superior longitudinal fasciculus, fornix (cres), corpus callosum, and anterior thalamic radiation (Figure). Average FA from supra‐threshold clusters for Braak I and II significantly predicted executive function but not episodic memory. No association between FA and tau burden in Braak stages III/IV or V/VI was found. In the ADNI sample, greater tau burden in Braak I was related to lower FA mostly in left inferior longitudinal fasciculus and left uncinate fasciculus, while negative associations with FA became more diffuse with tau load in Braak III/IV and V/VI. Average FA from supra‐threshold clusters significantly predicted both episodic memory and executive function scores. Across both samples, after accounting for tau burden in each Braak stage, there were no association between Aß‐positivity status and WM integrity.ConclusionDistinct associations between tau burden, WM integrity, and cognition were found across the studies, indicating greater impact of early tau burden on WM integrity in U.S. POINTER, accounting for Aß‐positivity status. Factors contributing to the distinct associations across studies need further investigation.

Abstract INTRODUCTION The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. METHODS Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta‐amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. RESULTS A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ−, Aβ+ (29%) participants were older, had higher apolipoprotein E ( APOE ) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. DISCUSSION In this heterogenous, at‐risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non‐AD (Alzheimer's disease) pathway to brain injury and cognitive decline. Highlights The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle POINTER Imaging collected multimodal neuroimaging data in this unique, at‐risk cohort Amyloid burden was related to age, apolipoprotein E ( APOE ) ε4 carriage, and measures of disease progression Associations between amyloid and tau, and tau and cognition, were relatively weak CVD risk and tau pathology were independently related to memory

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a two‐year randomized controlled trial designed to evaluate the effects of lifestyle interventions on older adults aged 60‐79 years. The POINTER Imaging ancillary study employs arterial spin labeling (ASL) magnetic resonance imaging (MRI) with two inversion times, enabling the mapping of arterial transit time (ATT) and the investigation of its relationship with dementia risk factors. This study examines the effect of the Framingham Risk Score (FRS) on ATT, which provides hemodynamic information on the cerebral vasculature.MethodA subset of POINTER Imaging participants (n = 134; F/M = 81/53; age = 68.1±5.1; FRS = 11.3±10.4) from two imaging sites underwent two ASL MRI scans during the baseline session. Two 3D Pulsed ASL scans were obtained with TI1 of 790ms and TI2 values of 2000ms or 2750ms, providing delay times (between labeling and imaging) of 1210ms or 1960ms. ATT, the time required for blood to travel from the neck to the tissue, was estimated in the range of 1210ms and 1960ms using a kinetic model (Figure 1). ATT maps were normalized to a standard space, and a voxel‐wise linear regression (ATT∼age+sex+log(FRS)) was performed on ATT maps in gray matter to assess the effect of FRS on ATT. To control false positives, clusters smaller than 1.4ml were removed based on a simulation with α = 0.05.ResultFigure 2 depicts three clusters found in the occipital, precuneus and frontal gray matter regions, all of which demonstrate a positive relationship between ATT and log(FRS). Participants with higher FRS exhibit prolonged mean ATT values in the clusters as shown in Figure 3. After stratifying into sex groups, both groups show the same direction.ConclusionAlthough the detectable range of ATT with two ASL scans was limited, the analysis suggests that an increased risk of cardiovascular disease, as quantified by the Framingham Risk Score, can serve as an indicator of potential cerebrovascular disease leading to prolonged ATT, which is associated with arterial stiffness, and vascular resistance. The clusters demonstrating the association between FRS and ATT are the brain regions that may have heightened vulnerability to vascular risk factors, according to previous studies.

AbstractBackgroundMulticentric initiatives to study brain cognition in the elderly offers us a unique collection of brain imaging data accompanied by detailed neuroclinical and neuropsychological evaluations. U.S. POINTER and LatAm‐FINGERS, part of the World Wide FINGERS, are both large‐scale investigations of lifestyle interventions and its impact on cognitive function. These large‐scale detailed data may offer an unprecedented opportunity to compare diverse populations.MethodBaseline MRI of subjects from multiple US centers (POINTER‐US), distributed in 5 geographical regions, and from 9 latin‐american countries (LatAm‐FINGERS). The protocols vary from basic (3D T1, 3D FLAIR,T2* GRE, Cor T2 hippocampus, DWI) to advanced which also included ASL, rs‐FMRI and DTI. Demographic information and clinical, cognitive and neuropsychological assessment were also included.ResultMRI data was collected from 662 participants in the United States (about 65% of the total anticipated U.S. POINTER neuroimaging sample) and from 542 subjects from 9 countries in latin‐america (about 80% of the total anticipated LatAm‐FINGERS neuroimaging sample), with around 1200 participants scanned (table1).All participants have 3D T1, 3D FLAIR, T2* GRE images and either DWI or DTI images.Comparative demographics from the 2 datasets shows similar mean age, a predominance of females, and slight differences in education (table 2). This will allow us to compare multiethnic and multicultural volumetric and functional brain MRI information, as well as disease markers, associated with thorough neurological and clinical assessment. Reasons for not acquiring MRI were mainly due to claustrophobia or scanner unavailability.ConclusionThis is an exceptional opportunity to have comparative large‐scale databases, with anatomical and functional brain imaging from different populations, allowing us to study real world diverse brain data and better understand its relationships with demographics, health and risk characteristics, and cognition.

AbstractBackgroundA key focus of the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is recruitment of unimpaired older individuals at risk for cognitive decline with heterogeneous characteristics (under‐represented racial and ethnicity groups (URG), family history of cognitive decline, hypertension, geographic diversity), and a subset of individuals undergo PET and MRI.MethodTo examine effects of heterogeneity on relationships between risk factors, AD biomarkers (Aβ and entorhinal tau PET, hippocampal volume (HV)) and cognition (global, executive function, and memory) were examined from U.S. POINTER neuroimaging participants (N = 602, about 65% of the anticipated total sample) and a subset of Alzheimer’s Disease Neuroimaging Initiative participants (N = 503). Neuroimaging data were processed and analyzed using harmonized methods across studies. Some cohort‐specific measurements were standardized using a within‐cohort reference group (Aβ‐negative individuals <70yrs and with global CDR = 0).ResultU.S. POINTER imaging participants are younger than those in ADNI (68.6+/‐5.0yrs vs 70.7+/‐4.4yrs), more likely to be female (65% vs 58%) and from URG (27% vs 15%), and had lower education (14.7+/‐3.3yrs vs 16.7+/‐2.3yrs) and higher Framingham Cardiovascular Risk scores (9.9+/‐8.3 vs 7.7+/‐5.3). The groups differed on several AD biomarkers and cognitive measures (Table). In regression models, AD biomarkers were stronger predictors of cognitive performance in ADNI compared to POINTER. Specifically, Aβ+ individuals with elevated tau had disproportionately poorer cognitive performance in ADNI, and this relationship remained consistent across cognitive measures (Figure). Conversely, demographic/risk variables were stronger predictors in POINTER. Demographic/risk predictors (age, sex, education, race, and FRS) together explained twice as much variance in global cognition in POINTER compared to ADNI (Adjusted R2 = 29% vs 14%). The addition of AD biomarkers to the model further increased the amount of variance in global cognition explained from 14% to 34% in ADNI, but addition of AD biomarkers did not increase variance explained in the POINTER model.ConclusionHeterogeneity among study participants appears to influence baseline biomarker‐cognition relationships such that AD biomarkers explain more variability in cognitive performance in ADNI than POINTER. These findings further suggest that cohort characteristics may affect the potential influence of amyloid‐ and tau‐modifying treatments on cognition.

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate the effect of lifestyle interventions in cognitively unimpaired older adults (60‐79 years) at risk for decline/dementia. Here, using data from the POINTER Imaging ancillary substudy, we explore how Alzheimer’s disease pathology and cardiovascular risk influence brain structure, cognition and their relationship.MethodPOINTER Imaging participants underwent cross‐sectional MRI, [18F]Florbetaben (FBB) Aβ‐PET and [18F]MK6240 tau‐PET. FBB and MK6240 data were processed using previously validated methods. MRIs were processed with voxel‐based morphometry. To quantify cardiovascular risk, the Framingham risk score (FRS) was calculated for each participant. We used linear regression models in the whole sample as well as in Aβ status subgroups to evaluate voxel‐wise associations of brain structure, measured using voxel‐based morphometry, with age, FRS, AD pathology (cortical summary Aβ and entorhinal cortex (ERC) tau burden), and a global cognition composite score.ResultAcross all 624 participants (Table 1), cognition (age‐adjusted) was positively related to brain structure across temporal, frontal and medial parietal cortices (Fig. 1A). ERC tau‐PET was negatively associated with brain structure in bilateral medial temporal lobes (MTL) and, notably, in bilateral basal forebrain (Fig. 1B). FRS showed significant negative associations in superior temporal gyrus and occipital cortex (Fig. 1C), but tau‐PET associations remained similar when adjusting for FRS. In Aβ+ participants, cognition‐ and FRS‐structure relationships were weaker but tau‐PET‐structure associations were stronger and extended outside the MTL. In Aβ‐ participants, cognition‐ and FRS‐structure relationships were similar to those observed in the whole cohort and tau‐PET associations were no longer significant.ConclusionIn this heterogeneous cohort of older adults, tau was associated with brain structure in strikingly specific patterns that were related to Aβ but not to cardiovascular risk as measured by the FRS. Tau‐structure associations were restricted to temporal lobes and basal forebrain and were independent of more widespread cognition‐structure associations, indicating that factors other than tau may play a critical role. Our next steps include comparing the current cohort to others with different at‐risk characteristics (e.g., ADNI, Berkeley Aging Cohort Study).

AbstractBackgroundA key focus of the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is recruitment of unimpaired older individuals at risk for cognitive decline with heterogeneous characteristics (under‐represented racial and ethnicity groups (URG), family history of cognitive decline, hypertension, geographic diversity), and a subset of individuals undergo PET and MRI.MethodTo examine effects of heterogeneity on relationships between risk factors, AD biomarkers (Aß and entorhinal tau PET, hippocampal volume (HV)) and cognition (global, executive function, and memory) were examined from U.S. POINTER neuroimaging participants (N = 602, about 65% of the anticipated total sample) and a subset of Alzheimer’s Disease Neuroimaging Initiative participants (N = 503). Neuroimaging data were processed and analyzed using harmonized methods across studies. Some cohort‐specific measurements were standardized using a within‐cohort reference group (Aß‐negative individuals <70yrs and with global CDR = 0).ResultU.S. POINTER imaging participants are younger than those in ADNI (68.6+/‐5.0yrs vs 70.7+/‐4.4yrs), more likely to be female (65% vs 58%) and from URG (27% vs 15%), and had lower education (14.7+/‐3.3yrs vs 16.7+/‐2.3yrs) and higher Framingham Cardiovascular Risk scores (9.9+/‐8.3 vs 7.7+/‐5.3). The groups differed on several AD biomarkers and cognitive measures (Table). In regression models, AD biomarkers were stronger predictors of cognitive performance in ADNI compared to POINTER. Specifically, Aß+ individuals with elevated tau had disproportionately poorer cognitive performance in ADNI, and this relationship remained consistent across cognitive measures (Figure). Conversely, demographic/risk variables were stronger predictors in POINTER. Demographic/risk predictors (age, sex, education, race, and FRS) together explained twice as much variance in global cognition in POINTER compared to ADNI (Adjusted R2 = 29% vs 14%). The addition of AD biomarkers to the model further increased the amount of variance in global cognition explained from 14% to 34% in ADNI, but addition of AD biomarkers did not increase variance explained in the POINTER model.ConclusionHeterogeneity among study participants appears to influence baseline biomarker‐cognition relationships such that AD biomarkers explain more variability in cognitive performance in ADNI than POINTER. These findings further suggest that cohort characteristics may affect the potential influence of amyloid‐ and tau‐modifying treatments on cognition.

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate the effect of lifestyle interventions in older adults (60‐79 years). The POINTER Imaging ancillary study is collecting Arterial Spin Labeling (ASL) MRI data to map cerebral blood flow (CBF) and evaluate the effect of interventions in the perfusion imaging biomarker. The optimization of timing parameters is essential for robust and efficient acquisition of ASL MRI.MethodA subset (n=83; F/M=51/32; age=69.0±5.5) of POINTER Imaging participants at two imaging sites underwent two ASL MRI scans during the same baseline session. Two 3D Pulsed ASL were obtained with TI1 of 790ms and TI2 values of 2000ms or 2750ms, which provide the delay times (between labeling and imaging) of 1210ms or 1960ms. ASL images were quantified into a physiological unit of CBF, ml/100g/min, using a single compartment kinetic model. CBF maps from two scans were normalized into a standard space and a voxel‐wise paired t‐test was performed after site variations were harmonized and covariates (age and sex) were adjusted. The age and sex effects in the difference of CBF values between two scans were also examined using linear regression. To control false positives, clusters smaller than 41ml were removed based on a simulation with α=0.05.ResultThe CBF values in ASL MRI rely on the timing of image acquisition: only a fraction of label bolus arrives in the tissue with a short delay while images suffer from low signal due to the magnetization decay with a long delay. Figure 1 shows the regions that require a long delay time (red) or a short delay (blue). The difference in CBF is proportional to arterial transit time (ATT) and the analysis shows females have shorter ATT mainly in the peri‐Sylvian region (Figure 2). No cluster survived correction in the analysis of the aging effect.ConclusionThe acquisition of two CBF maps not only offers optimization of acquisition timing but provides an additional perfusion parameter, arterial transit time, which may be a potential biomarker of cerebrovascular pathophysiology.

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate the effect of lifestyle interventions in older adults (60‐79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting PET and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at‐risk sample.MethodPOINTER Imaging is actively enrolling 1250 participants, 23% from under‐represented racial/ethnic groups (URG), recruited from five U.S. POINTER clinical sites. Participants have undergone PET imaging with [18F]Florbetaben (FBB) to measure Aβ and [18F]MK‐6240 to measure tau burden, as well as MRI to measure brain morphometry, white matter hyperintensities and cerebral blood flow. FBB and MK‐6240 data were quality checked, pre‐processed, and quantified using previously validated methods. PET images were coregistered to a structural MRI, which was also used to create FreeSurfer‐defined reference regions and regions of interest. We examined PET imaging measures (global Aβ, regional tau) and basic demographic (age, sex, race/ethnicity) characteristics of the sample.Result96 participants (mean age 69.3±5.0) have been enrolled in POINTER Imaging. Of these, 59 (61%) are women and 22 (23%) are URG, which is similar to rates of women (75%) and URG (22%) in the main trial. This dataset is <10% of targeted enrollment, was predominantly recruited from 2/5 clinical sites and may not represent the final imaging cohort. FBB quantification (N=20) revealed a mean cortical summary SUVR of 1.09±0.12 (19.6±18.4 centiloids) (whole cerebellum normalization; previously validated positivity threshold=1.08), and 8/20 (40%) of these participants were Aβ+ (Fig. 1A). MK‐6240 quantification (N=23) showed predominantly no/minimal binding with a few exceptions in medial and lateral temporal lobes (Fig. 1B&C).ConclusionThe POINTER imaging study is meeting the target URG enrollment and representative of the main U.S. POINTER trial. Higher frequency of Aβ positivity than published in population cohorts coupled with greater cardiovascular risk factors among POINTER participants highlights our success in recruiting individuals at increased risk of cognitive decline.