Rogalskı, Emily

AbstractPatients with early‐onset Alzheimer's disease (EOAD) are commonly excluded from large‐scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial‐ready network. LEADS will follow 400 amyloid beta (Aβ)‐positive EOAD, 200 Aβ‐negative EOnonAD that meet National Institute on Aging–Alzheimer's Association (NIA‐AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age‐matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18F]Florbetaben and [18F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post‐mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

AbstractBackgroundPrevious research has suggested that, compared to males, females are at greater risk for and have greater pathology burden in late onset. However, sex differences in early onset AD (EOAD) have not yet been studied.MethodWe included 167 participants [28 cognitively normal (CN, 68% females), 98 early onset AD (EOAD, 55% females), and 41 cognitively impaired amyloid‐negative (EOnonAD, 31% females] subjects from the Longitudinal Early‐Onset AD Study (LEADS) with available Flortaucipir PET, Florbetaben PET, and MRI data. Multiple linear regression (MLR) models including age and MMSE as covariates were used in the pooled sample to examine the effects of sex on hippocampal and white matter hyperintensity volume, mean cortical thickness, mean tau distribution by Braak regions and mean cortical amyloid SUVR. We also ran voxelwise MLR with sex as the predictor and cortical thickness, amyloid SUVR normalized to whole cerebellum, tau SUVR normalized to cerebellar crus, respectively, as the outcome measures while controlling for age, MMSE, and total intracranial volume (MRI only). Results are displayed at a cluster‐level FWE correction of p<0.05.ResultThere were no significant demographic differences between males and females in any diagnostic group. Across the pooled sample females showed significantly greater atrophy of the hippocampus (p=0.0001), greater tau SUVR in Braak regions 3&4 (p=0.05) and 5&6 (p=0.04) and trend for greater global amyloid uptake (p=0.074) (Table 2). The analyses in imaging space confirmed these findings and showed that the effects are driven by the EOAD group. Females showed greater amyloid deposition globally and greater tau deposition in the frontal, inferior parietal and temporal lobes (Figure 3).ConclusionFemale sex is associated with greater pathology burden in EOAD. Longitudinal studies will be needed to establish whether such difference translates in faster rates of progression in women relative to men.

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.

AbstractIntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s‐bvFTD; mean age 63.3 years; 34% female) and 99 familial (f‐bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f‐bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule‐associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f‐bvFTD were younger and had earlier age at onset. s‐bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores due to more frequent endorsement of depression and irritability.Discussionf‐bvFTD and s‐bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

AbstractIntroductionWe created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD.MethodsThe CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants.ResultsThe CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non‐fluent/agrammatic variant primary progressive aphasia participants.DiscussionThe global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

AbstractIntroductionThe Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.MethodsWe screened the major dementia‐associated genes in 302 sporadic and 390 familial (symptomatic or at‐risk) participants enrolled in these studies.ResultsAmong the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule‐associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.DiscussionOur study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

AbstractIntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial‐frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non–mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self‐monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial‐frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.