Joseph L. Webb

Peripheral versus Central Index of Metabolic Dysfunction and Associations with Clinical and Pathological Outcomes in Alzheimer’s Disease

BACKGROUND/OBJECTIVE Insulin-like growth factor binding protein 2 (IGFBP-2) regulates blood glucose levels, facilitates hippocampal synaptic plasticity and may have a predictive value for Alzheimers disease (AD) diagnosis. METHODS IGFBP-2 levels were studied in plasma in 566 subjects and in cerebrospinal fluid (CSF) in 245 subjects across the AD spectrum from the Alzheimers Disease Neuroimaging Initiative (ADNI). Variants in the IGFBP-2 gene were examined. Linear mixed modeling in SPSS tested main effects of IGFBP-2 and interactions with APOE4 on neurocognitive indices and biomarkers. Voxel-wise regression was used to gauge IGFBP-2 and regional grey matter and glucose metabolism associations. RESULTS Each point increase in IGFBP-2 corresponded to a three times greater likelihood of having mild cognitive impairment (MCI) or AD. IGFBP-2 showed beneficial associations with respect to cognitive scores in individuals with two APOE4 alleles. Higher IGFBP-2 predicted higher insulin resistance, but not CSF amyloid or tau. Voxel-wise analyses showed that plasma IGFBP-2 predicted lower grey matter volume and FDG metabolism in a large area spanning the frontal, temporal, and occipital lobes. CSF IGFBP-2 levels showed similar voxel-wise analysis results, but were uniquely associated with CSF amyloid and tau. Analysis of single nucleotide polymorphisms (SNPs) in IGFBP-2 showed that subjects carrying risk alleles versus common alleles had increased risk of AD and lower memory scores. Voxel-wise analyses of these SNPs also implicated the hippocampus and prefrontal cortex. CONCLUSIONS IGFBP-2 is associated with AD risk and outcomes; plasma IGFBP-2 provides stronger predictive power for brain outcomes, while CSF IGFBP-2 provides improved predictive accuracy for AD CSF biomarkers.

AD FAMILY HISTORY MODULATES EFFECTS OF TOMM40 ‘523’ POLY-T ON MTL ATROPHY AND HYPOMETABOLISM IN PRECLINICAL AND AD COHORTS

associated with vascular risk factors (VRF), which are also under considerable genetic influence. Using a monozygotic twin design, this study examines the contribution of genetic factors and VRF on regional WMH burden. Methods: Cognitively healthy elderly monozygotic twins were included from the PreclinAD study. VRF were assessed using the Framingham risk score. WMH load was estimated using an automated algorithm and regionally classified according to anatomical lobes and distance from ventricular system (4 equidistant layers ranging from periventricular to subcortical). We first assessed

NEUROPEPTIDE YY PLASMA CONCENTRATIONS IN ALZHEIMER’S DISEASE

Background: Blood-based biomarkers have been extensively studied for many diseases due to accessibility and convenience. Plasma b-Amyloid (Ab) has been a potential candidate for an Alzheimer’s disease (AD) biomarker although it is controversial, and many researchers are still investigating the relationship between plasma Ab and brain amyloid deposition. Brain acetylcholinesterase (AchE) is another key factor closely related to AD because cholinergic neurons are the main victim during AD pathogenesis. Methods:Cross-sectional study of 374 participants (212 cognitively normal, 104 mild cognitive impairment, and 58 AD dementia) with Pittsburgh-compound B PET (PiBPET) imaging data was performed. We discovered a special treatment of protease inhibitors and phosphatase inhibitors (MPP) novel method for stabilized detection of plasma Ab42 and Ab40 (MPP-Ab42 and MPP-Ab40) using X-map technology. Also, we compared plasma AchE protein levels from same 374 participants above in MPP-Abs measurement, and AchE levels were measured by ELISA. Results: MPP-Ab42/40 (MPP-Abs) levels in plasma showed significant reduction in positive amyloid deposition (PiB+) patients compared with subjects with PiB negative amyloid deposition (PiB-) (***P < 0.0001), and we discovered the significant increase of plasma AchE level in PiB+ compared to PiB-. Also, both MPP-Ab42/40 and AchE represented significant correlation with PiB retention values (SUVR). Furthermore, combined detection of MPP-Ab42/40 level with AchE level in plasma indicate brain Ab accumulation positivity better than one factor either MPP-Ab42/40 level or AchE level (***P < 0.001). ROC curve represented increased AUC values in combined detection of MPP-Ab42/40 level with AchE level. Conclusions:We propose that plasma MPP-Ab and AchE can be used as potential blood biomarkers for prediction of PiB-PET positivity in the brain.

AD FAMILY HISTORY IN NON-APOE4S MODULATES THE EFFECTS OF '523 TOMM40 ON NEUROPATHOLOGY AND MEMORY DECLINE

mild cognitive impairment (MCI) patients from the ADNI, (2) 194 clinically normal (CN) older participants from the ADNI (age 60 to 90), and (3) 1322 CN younger participants from the Brain Genomics Superstruct Project (age 18 to 35). Results:Within MCI and older CN, elevated PGRS was associated with smaller hippocampus volume and greater cognitive decline. PGRS was also associated with hippocampus volume within young CN. This pattern was evident when examining the liberal PGRS, but not the conservative PGRS. All effects were independent of age and APOE4 status. Conclusions:An impact of common genetic risk loci distributed throughout the genome is detectable in younger and older nondemented individuals. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia.

INSULIN RESISTANCE AND LONGITUDINAL ASSOCIATIONS WITH TEMPORAL ATROPHY ACROSS THE ALZHEIMER'S DISEASE SPECTRUM

aration between GM and CBFmarkers. Within modalities some positional variance existed, especially within the GM markers where the Gaussian fit was not robust over cross-validation samples. Conclusions:This EBM analysis suggests that ASL-MRI-based perfusion changes occur later in the AD disease course than GM volume changes. We should be careful in generalizing these findings which might arise from ASL-MRI being less sensitive than T1-weighted MRI. Our findings therefore only hold for the current regional measures, cohort, and ASL-MRI technique. Our future work concerns evaluation of other potentially more sensitive ASL-MRI-based markers.

FAMILY HISTORY MODULATES TOMM40'S EFFECT ON ALZHEIMER'S DISEASE VASCULAR RISK FACTORS AND NEURODEGENERATION

EFFECT ON ALZHEIMER’S DISEASE VASCULAR RISK FACTORS AND NEURODEGENERATION Joseph L. Webb, Michael W. Lutz, Alexandra M. V. Wennberg, Allen D. Roses, Sterling C. Johnson, Barbara B. Bendlin, Auriel A. Willette, Iowa State University, Ames, IA, USA; Duke University Bryan ADRC, Durham, NC, USA; 3 Mayo Clinic, Rochester, MN, USA; Duke University, Durham, NC, USA; Zinfandel Pharmaceuticals, Inc., Chapel Hill, NC, USA; Cabernet Pharmaceuticals, Chapel Hill, NC, USA; 7 Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI, USA; 8 Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 10 Wisconsin Alzheimer’s Institute, Madison, WI, USA; 11 Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, USA; National Institute on Aging/National Institutes of Health (NIA/NIH), Baltimore, MD, USA. Contact e-mail: jlwebb@iastate.edu