Annie D. Cohen

The effects of normal aging on amyloid-β deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B.

In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer‐like neuropathology.

Longitudinal changes in amyloid positron emission tomography and volumetric magnetic resonance imaging in the nondemented Down syndrome population

Down syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimers disease (AD).

Reduced binding of Pittsburgh Compound-B in areas of white matter hyperintensities.

The amyloid imaging agent, Pittsburgh Compound-B, binds with high affinity to β-amyloid (Aβ) in the brain, and it is well established that PiB also shows non-specific retention in white matter (WM). However, little is known about retention of PiB in areas of white matter hyperintensities (WMH), abnormalities commonly seen in older adults. Further, it is hypothesized that WMH are related to both cognitive dysfunction and Aβ deposition. The goal of the present study was to explore PiB retention in both normal-appearing WM (NAWM) and WMH in a group of elderly, cognitively normal individuals. In a group of cognitively normal elderly (n = 64; 86.5 ± 2.6 years) two analyses were applied: (1) ROIs were placed over periventricular areas in which WMH caps are commonly seen on all subjects, regardless of WMH burden or size. (2) Subject-specific maps of NAWM and WMH were co-registered with the PiB-PET images and mean SUVR values were calculated in these NAWM and WMH maps. PiB retention was significantly reduced in the ROIs of subjects with high WMH compared to subjects with low WMH. Additionally, in subjects with high WMH, there was significantly lower PiB retention in subject-specific maps of WMH compared to NAWM, which was not observed in subjects with low WMH, likely because of the small size of WMH maps in this group. These data suggest that WM in areas of WMH binds PiB less effectively than does normal WM. Further exploration of this phenomenon may lead to insights about the molecular basis of the non-specific retention of amyloid tracers in white matter.

Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome

BACKGROUND The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimers disease (AD). OBJECTIVE The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. METHODS Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. RESULTS Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. CONCLUSIONS In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Imaging neurodegeneration in Down syndrome: brain templates for amyloid burden and tissue segmentation

The focus of Alzheimer’s disease (AD) neuroimaging research has shifted towards an investigation of the earliest stages of AD pathogenesis, which manifests in every young adult with Down syndrome (DS; trisomy 21) resulting from a deterministic genetic predisposition to amyloid precursor protein overproduction. Due to morphological differences in brain structure in the DS population, special consideration must be given to processing pipelines and the use of normative atlases developed for the non-DS population. Further, the use of typical MRI to MRI template spatial normalization is less desirable in this cohort due to a greater presence of motion artefacts in MRI images. The diffuse nature of PiB uptake and comparatively lower spatial resolution of the PET image permits the purposing of this modality as a template for spatial normalization, which can substantially improve the robustness of this procedure in the cases of MRI images with motion. The aim of this work was to establish standardized methods for spatial normalization and tissue type segmentation using DS specific templates in order to perform voxel-wise analyses. A total of 72 adults with DS underwent [11C]PiB PET to assess brain amyloid burden and volumetric MRI imaging. A DS specific PiB template for spatial normalization and a set of DS specific prior probability templates were created with two-pass methods. With implementation of this DS specific PiB template, no participants were excluded due to poor spatial normalization, thus maximizing the sample size for PiB analyses in standardized space. In addition, difference images between prior probability templates created from the general population and the DS population reflected known morphological differences, particularly in the frontal cortex. In conclusion, DS specific templates that account for unique challenges improve spatial normalization and tissue type segmentation, and provide a framework for reliable voxel-wise analysis of AD biomarkers in this atypical population.

AMYLOID BURDEN AND CORTICAL ATROPHY IN NON-DEMENTED DOWN SYNDROME

posterior cingulate, precuneus, and temporal, parietal, frontal, and occipital regions, consistent with prior findings in persons with AD dementia and MCI. In the cognitive unimpaired APOE4 carrier analysis, mean cortical florbetapir SUVRs were associated with less gray matter bilaterally in medial frontal regions. Conclusions: Fibrillar Ab burden is associated with reduced gray matter in brain regions known to be preferentially affected by AD—and it is preferentially associated with reduced gray matter in frontal regions in cognitively unimpaired persons at risk for AD.

COMPARISON OF IN VIVO [F-18]AV-1451 OFF-TARGET RETENTION IN AFRICAN-AMERICANS AND CAUCASIANS

differences between Ab-positive and Ab-negative subjects using t-tests. In the identified regions, we then assessed whether tau SUVR was related to CSF p-tau and cognition using linear regression models. Results: Only three individuals were classified as tau-positive (EC SUVR 1.3), while 15 were Ab-positive (SUVR 1.4; Fig.1a-b). Despite low tau signal, Ab-positive individuals had higher AV1451 SUVRs than Ab-negative ones in the EC, amygdala, inferior temporal, lateral occipital, fusiform and parahippocampal gyri (all p 0.03; Fig.2a-c). AV1451 SUVRs in all aforementioned regions (except inferior temporal and fusiform gyri) were positively associated with CSF p-tau (p<0.05; Fig.3a). Finally, higher EC, amygdala, inferior temporal and lateral occipital AV1451 SUVRs were associated with lower delayed memory, language, and total RBANS index scores (p<0.05; Fig.3b). There was no Ab status * AV1451-SUVR interaction on CSF p-tau or cognition. When the three tau-positive subjects were removed from the analyses, results remained similar. Conclusions: These findings indicate that, even in latemiddle-aged adults with relatively low AV1451 SUVRs, AV1451 binding in AD signature regions is significantly increased among Ab-positive individuals. Higher tau binding is also associated with higher CSF p-tau and lower cognition. Overall, this suggests that early tau-PET changes in AD-typical regions are clinically meaningful.

COMPARISON OF STRIATAL LONGITUDINAL CHANGES IN AMYLOID DEPOSITION IN NON-DEMENTED ELDERLY AND DOWN SYNDROME

P1-421 COMPARISON OF STRIATAL LONGITUDINAL CHANGES IN AMYLOID DEPOSITION IN NON-DEMENTED ELDERLYAND DOWN SYNDROME Dana L. Tudorascu, Charles M. Laymon, Davneet S. Minhas, Brian J. Lopresti, Julie C. Price, Chester Mathis, Howard J. Aizenstein, William E. Klunk, Benjamin L. Handen, Brad T. Christian, Annie Cohen, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; University of Pittsburgh, Pittsburgh, PA, USA; University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA. Contact e-mail: cohenad@upmc.edu