Borowski, Bret

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.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract INTRODUCTION We compared white matter hyperintensities (WMHs) in early‐onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups in the Longitudinal Early‐Onset Alzheimer's Disease Study. METHODS We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t ‐tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. Highlights This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early‐onset amyloid‐negative cognitively impaired (EOnonAD) groups across all brain regions.

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.

ObjectiveTo determine the characteristics of participants with amyloid‐related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD).Methods142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β‐amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross‐sectional and longitudinal analyses evaluated potential ARIA‐related risk factors.ResultsEleven participants developed ARIA‐E, including 3 with mild symptoms. No ARIA‐E was reported under solanezumab while gantenerumab was associated with ARIA‐E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE‐ɛ4 carriers were more likely to develop ARIA‐E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA‐E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA‐E occurrence, all ARIA‐E participants were amyloid‐PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA‐H. Most ARIA‐E radiologically resolved after dose adjustment and developing ARIA‐E did not significantly increase odds of trial discontinuation. ARIA‐E was more frequently observed in the occipital lobe (90%). ARIA‐E severity was associated with age at time of ARIA‐E.InterpretationIn DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA‐E risk, with additional risk for individuals APOE‐ɛ4(+) or with microhemorrhage. ARIA‐E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729–744

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.

AbstractBackgroundThe overarching goal of the Longitudinal Early‐onset Alzheimer Disease study (LEADS) is to optimally characterize early‐onset AD (EOAD) and establish an EOAD clinical trials network. Here we report the baseline demographic and imaging biomarker comparisons of the LEADS cohort to late‐onset AD (LOAD) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3).Method123 amyloid‐positive EOAD, 47 amyloid‐negative EOnonAD, 60 cognitively normal young controls were compared to 130 amyloid‐positive LOAD, 110 amyloid‐negative LOnonAD and 286 amyloid‐negative cognitively normal older controls. To account for the effect of cognitive aging between EO and LO populations, each cognitive measure was Z‐transformed. Cortical and hippocampal atrophy were quantified using W‐scores adjusted for age, sex and total intracranial volume. Z‐scores and W‐scores were compared using t‐test or Wilcoxson rank test as appropriate. All p‐values were corrected for multiple comparisons using the false discovery rate correction.ResultEOAD showed greater pathology burden and greater cortical atrophy (AD signature) relative to LOAD. EOAD also showed greater cognitive impairment across all cognitive tests. EOAD showed greater functional impairment, more depression but less neuropsychiatric behaviors overall compared to LOAD (Table 1 and Figure 1, all ps<0.05). Repeating the analyses stratified by cognitive stage (MCI/dementia) or CDR global rating (0.5/1) did not result in any major differences.EOnonAD differed from LOnonAD by also showing greater impairment on all cognitive and functional measures There were no significant differences in amyloid and tau burden, or atrophy W‐scores between these groups. EOnonAD were more depressed and showed more functional impairment compared to LOnonAD (Table 2 and Figure 2, all ps<0.05). Repeating the analyses split by cognitive stage (MCI/dementia) or CDR global rating (0.5/1) did not result in any major differences.ConclusionConsistent with our preexisting hypotheses, EOAD and EOnonAD perform much worse relative to their LO counterparts. EOAD also show greater pathological burden as expected. The reported analyses were done in chronological rather than disease time (time since disease onset). Benchmarking individuals along the disease spectrum might prove to be a better strategy especially when conducting analyses on rate of disease progression.

AbstractBackgroundApproximately 5% of the 5.6 million (∼280,000) Americans with Alzheimer’s disease (AD) develop symptoms at age 65 or younger and are classified as having early‐onset AD (EOAD). Although EOAD and late‐onset AD (LOAD) share the same pathologic substrate, there are notable differences in their clinical and biological phenotypes. The Longitudinal Early‐onset AD study (LEADS) is a multi‐site, observational clinical and biomarker study of EOAD. In the present study we utilized the currently available LEADS imaging data to explore the spatial extent and magnitude of neurodegeneration EOADMethod95 amyloid positive patients with EOAD, 37 amyloid negative cognitively impaired patients (EOnonAD) , and 55 cognitively unimpaired controls (CNs) were included in the analysis. The magnitude of cortical thinning in the EOAD and EOnonAD groups was estimated using whole‐brain GLMs compared to the CN group. In addition, w‐scores were derived for each EOAD patient for these ROIs: average cortical thickness, hippocampal volume, AD‐signature cortical thickness (typically used in LOAD), and precuneus cortical thickness controlling for age, sex, and acquisition site. The utility of each ROI to differentiate EOAD patients from CNs was assessed by calculating the percentage of patients falling below a W‐threshold of ‐1.5.ResultIn EOAD, a distributed pattern of cortical thinning was observed in lateral temporal, parietal, and frontal cortex (p<.01), and was most prominent in the precuneus (Cohen’s d’ = 1.5). In the EOnonAD group, cortical thinning was observed but was highly variable across individuals. The w‐score analysis in the EOAD group yielded the following results: Mean Cortical thickness: Mean = ‐3.34, SD = 2.97, Classification = 72%.; Hippocampal volume: Mean = ‐2.96, SD = 2.39, Classification = 74%; AD Signature: Mean = ‐4.63, SD = 3.07, Classification = 80%; Precuneus: Mean = ‐5.98, SD = 4.1, Classification = 90%.ConclusionOur results are consistent with previous findings demonstrating cortical thinning in lateral parietal, precuneus, and lateral temporal lobes in EOAD with relatively less involvement of the medial temporal lobes. Our results also suggest that the precuneus may be especially vulnerable to neurodegeneration in patients with EOAD and may serve as a useful biomarker for patient classification.

AbstractBackgroundWhite matter (WM) hypointensity volume in T1 MRI correlates strongly with T2 hyperintensities and both are typically associated with advancing age and vascular brain injury (VBI). Recent research has suggested that Alzheimer’s Disease (AD) neuropathologic changes (ADNC) also increases WM hypointensity volume. Sporadic early onset AD (EOAD) patients provide a unique model to examine the relationship between ADNC biomarkers and WM hypointensity volume in the absence of advanced age, cardiovascular injury, or autosomal dominant genetic mutations.MethodIncluded in the analysis were sporadic EOAD patients (n = 75) and cognitively normal controls (n = 39) from the Longitudinal Alzheimer’s Disease Study (LEADS) for whom full demographic and health information were available. WM hypointensity volume in T1 MRI was segmented by Freesurfer and corrected for total white matter volume. Multiple‐factor ANOVA models with logarithmic transformations were used to determine the effects of age, cohort, and presence of cardiovascular conditions on WM hypointensity volume. Further multiple‐factor ANOVA models assessed whether the addition of covariates improved the model fit.ResultIn a reproduction of prior research, WM hypointensity volume was correlated with age for controls (p < 0.05), but not for EOAD patients. We additionally found an effect of cohort, such that EOAD patients had a higher mean WM hypointensity volume than controls when accounting for age (p < 0.05). No difference in the presence or number of cardiovascular conditions was found between groups. Additionally, no correlation was found between WM hypointensity volume and the presence or number of cardiovascular conditions. Including cardiovascular condition as a covariate failed to improve the model fit, even when accounting for interaction effects.ConclusionThese results support the hypothesis that patients with ADNC have higher WM hypointensity volume beyond what would be expected based on aging or cardiovascular risk factors. Further research is needed to assess the co‐localization of WM hypointensities with cortical degradation, amyloid pathology, and tau pathology.

AbstractBackgroundPrevious studies have reported that age modifies the distribution and burden of tau (and, to a lesser extent, amyloid) pathology in sporadic Alzheimer’s disease (AD). Here we present preliminary baseline amyloid and tau PET results from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS), a multi‐site longitudinal study of sporadic early‐onset AD.Method135 patients meeting clinical criteria for MCI or probable AD and 50 cognitively normal controls (all age<65 at enrollment) were enrolled at 12 US centers between August 2018 and December 2019 (Table 1). 18F‐Florbetaben amyloid‐PET (FBB) was used to assign patients to EOAD (amyloid‐positive) or EOnonAD (amyloid‐negative) subgroups based on visual rating and semi‐quantification. 130 patients and all controls had 18F‐Flortaucipir tau‐PET (FTP). Regional Standardized Uptake Value Ratios (SUVR) for FBB (whole cerebellum reference) and FTP (inferior cerebellar gray reference) were extracted using co‐registered 3T‐MRI.Result98 patients (72.6%) were amyloid PET‐positive (EOAD) and 37 (27.4%) were amyloid PET‐negative (EOnonAD). Compared to EOAD, EOnonAD patients had higher MMSE, MOCA and CDR sum‐of‐boxes (CDR‐SB) and were more frequently male (Table 1). Patients with EOAD showed elevated FBB and FTP SUVR in temporoparietal and frontal cortex compared to CN and EOnonAD (Figures 1‐2). In EOAD, MMSE, MOCA and CDR‐SB were significantly correlated with FTP SUVR (Figure 3), while no significant correlations were found with FBB SUVR. EOnonAD patients showed variable FTP binding ranging from negative to mildly elevated binding in anterior temporal and frontal cortex and underlying white matter. Two EOnonAD cases showed intense FTP binding comparable to typical EOAD cases, despite visually and quantitatively negative FBB scans.ConclusionPatients with clinically mild, sporadic EOAD typically show an extensive distribution and burden of tau pathology in the setting of positive amyloid PET. Global clinical measures correlate with tau but not amyloid PET. Over 25% of patients meeting clinical criteria for early‐onset MCI/probable AD have negative amyloid PET, suggesting alternative etiologies for cognitive decline. These findings will inform future design of drug trials in this important and under‐studied population.