P1‐349: Advancing Clinical And Biomarker Research In Ad: The Lead Study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152716/1/alzjjalz201906904.pd

Measuring the salience of the economy : the effects of economic conditions on voter perceptions and turnout in Mississippi

Past studies concerning the effects of economic conditions on voter perceptions have tended to generalize their findings to the entire national electorate. Such generalizations fail to account for the different ideologies, lifestyles, and economic conditions that exist from state to state. In the current study, I compare the effects of subjective financial evaluations with the effects of objective economic indicators on voter perceptions and turnout in the state of Mississippi. The purpose is to determine the extent to which past findings on the national level hold up on the state level, with Mississippi as the subject of analysis. Using data from the Mississippi Poll and employing a logistic regression method, the findings show that Mississippian‟s perceptions of political figures are more strongly influenced by subjective financial evaluations. Voter turnout, on the other hand, was more strongly influenced by objective economic indicators than personal financial satisfaction

Neurodegeneration in the Longitudinal Evaluation of Early Onset Alzheimer- s Disease Study (LEADS) sample: Results from the MRI core

BackgroundApproximately 5% of the 5.6 million (- ¼280,000) 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163855/1/alz046338.pd

Cognitive, neuropsychiatric and imaging comparisons between early- onset and late- onset Alzheimer- s disease participants from LEADS and ADNI3

BackgroundThe 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171134/1/alz056676.pd

Increased white matter MRI T1 hypointensity volume in young- onset Alzheimer- s disease patients is not accounted for by age or cardiovascular risk factors

BackgroundWhite 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163844/1/alz045577.pd

Amyloid and tau PET in sporadic early- onset Alzheimer- s disease: Preliminary results from LEADS

BackgroundPrevious 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163854/1/alz041613.pd