Anna Blanken

Relationship between hippocampal atrophy and neuropathology markers: a 7T MRI validation study of the EADC-ADNI Harmonized Hippocampal Segmentation Protocol

The pathologic validation of European Alzheimers Disease Consortium Alzheimer’s Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).

Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding

Objective: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. Methods: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimers Disease Neuroimaging Initiative 1 (ADNI1) participants with available [11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. Results: Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. Conclusions: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.

PROGENITOR RESERVE HYPOTHESIS: A MODEL FOR DISCOVERING PROTECTIVE FACTORS IN OLDER ADULTS AT RISK FOR DEMENTIA

of primary human astrocytes, human iPSCs are currently used as a source of astrocytes. However, existing methods for astrocyte generation are slow (up to 6 months) or require additional selection to reduce heterogeneity. Methods: To rapidly generate mature astrocytes for disease modeling, we have developed a novel protocol that uses inducible expression of astrocyte differentiation master transcription factors NFIA and SOX9 and an optimized astrocyte differentiation medium. Results: Human cortical or spinal astrocytes can be generated from normal or disease iPSCs in only one month. They express the key astrocyte markers GFAP and S100b at >90% and exhibit mature process-bearing morphologies. These astrocytes can promote neuron synapse formation and functional activity in MEA and calcium imaging applications, and elicit a strong and rapid pro-inflammatory response. Conclusions:This protocol represents an important tool for modeling neurological diseases using a human iPSC-based astrocyte-neuron coculture platform, allowing the role of diseased astrocytes in neuronal degeneration to be probed.

PATHOLOGIC VALIDATION OF THE EADC-ADNI HARMONIZED HIPPOCAMPAL PROTOCOL

monoclonal antibody, in patients with prodromal or mild Alzheimer’s disease (AD). Retrospective analyses of both bapineuzumab and solanezumab data have shown substantially higher percentages of negative amyloid PET findings in APOE ε4 non-carriers than in APOE ε4 carriers in the mild and moderate AD sub-study populations. We report our amyloid PET screening results by APOE ε4 status in the prodromal and mild AD study populations. Methods: During screening, patients fulfilling clinical criteria for either prodromal or mild AD underwent florbetapir PET scanning and APOE genotyping. Florbetapir PET scans were visually evaluated for amyloid plaque burden. Results: Data from the first 250 patients were included in this analysis. Similar to the bapineuzumab and solanezumab results, we have observed a substantially higher percentage of negative amyloid PET findings in APOE ε4 non-carriers than in APOE ε4 carriers (highlighted in bold in Table 1). However, the overall incidence of negative amyloid scans observed in 221AD103 is substantially higher than that reported in the two Phase III studies, likely attributable to the earlier stage of AD patients being recruited in this study (prodromal/mild, mean MMSE w 25 vs. mild/moderate AD, mean MMSE w21 in the Phase III studies). This finding is also consistent with the solanezumab results in that the percentage of negative amyloid PET findings was higher in mild (27%) than in moderate (13%) AD groups. Conclusions: These results suggest that: (1) selecting subjects having AD pathology based on clinical criteria remains a challenge; (2) enrichment by using amyloid PET imaging is effective and feasible; (3) enrichment by assessing amyloid plaque burden is critically important to clinical studies in early stages of AD because of a higher incidence of negative amyloid findings; and (4) APOE genotyping may potentially improve the economy of enrichment by amyloid PET, via lowering the likelihood of negative amyloid findings.

PATHOLOGIC VALIDATION OF THE HIPPOCAMPAL RADIAL DISTANCE SURFACE MAPPING TECHNIQUE

calculated using multiple algorithms. Algorithms included FreeSurfer/ReconAll/longitudinal v5.3.0, FSL/FIRST v5.0.4, AdaBoost, manual, multiple-atlas propagation and segmentation (MAPS) and MAPS with the hippocampal boundary shift integral option (MAPS-HBSI) (Leung et al. NeuroImage 2010;51:1345-1359). The difference between the PVC’s (non annualized) was calculated (BTBD). To compare the performance of any two algorithms, the absolute values of the BTBD for each subject were compared and the algorithm with the smallest absolute BTBDs was considered superior. Results: MAPS-HBSI had substantially better reproducibilities than all other algorithms. MAPS-HBSI had smaller absolute BTBD for the left hippocampus in 0.69 (FreeSurfer), 0.71 (FIRST), 0.72 (AdaBoost), 0.68 (manual), 0.81 (MAPS) fraction of subjects, all which had a p-value smaller than 0.002. The median absolute value of the BTBD (MAVBTBD) were 2.36 (FreeSurfer), 2.19 (FIRST), 2.61 (AdaBoost), 2.75 (manual), 3.41 (MAPS) and 1.29 (MAPS-HBSI). Previous comparisons of algorithm performances have often been based on a particular disease, such as AD, that can introduce confounding factors including natural disease variation and measurement error in disease classification. For example, previous assessments of the BSI option, based on AD group size (Leung et al. 2010), is 47% much less than the 164% found in this study. Conclusions: MAPS-HBSI has 70% better reproducibility than the nearest other hippocampal PVC algorithms due to the BSI option. The performance for BSI is 79% better than previously reported perhaps because of the disease independent assessment of the current study. The high reproducibility of MAPS-HBSI makes it much easier to compare the PVC of the left and right hippocampus for individual subjects and study the PVC variation in AD.

EFFECTS ON VENTRICULAR ENLARGEMENT WHEN COMPARING COGNITIVELY NORMAL ELDERLY AND PEOPLE WITH AMNESTIC AND NONAMNESTIC MILD COGNITIVE IMPAIRMENT

Background: Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) is widely used for the assessment of severity and/or therapy evaluation of Alzheimer’s disease (AD). But little is known concerning the spatial correlation of the brain regions to the performance in ADAScog. By using a newly developed 3-D statistical imaging software, Correlation Imaging Plots (CIPs), which can visualize the spatial correlation of regional cerebral blood flow (rCBF) with any continuous parameters, we tried to elucidate the relationship between rCBF and the score of Japanese version of ADAS-cog in AD patients. Methods: The present study was based on 55 patients with early stage of AD patients, 51 mild cognitive impairment (MCI) patients and 32 age-matched normal controls. All of them were right handed and those with cerebral organic lesions were excluded. They underwent 99mTc-ECD SPECT and ADAS-cog. We analyzed those data by using and CIPs program and statistical parametrical mapping (SPM) version 8 for comparison. In the SPM analysis, patients were classified into two groups according to the score of ADAS-cog: those with high performance (&x 10) and those with low performance (<10). Results: The ADAS-cog total score correlated with the hypoperfusion in bilateral posterior cingulate cortices, precuneus and superior and inferior parietal lobules in CIPs analysis. Among the ADAS-cog subscales, the orientation, recall and recognition scores correlated with rCBF in the similar regions. Construction score correlated with rCBF in left temporoparietal cortex. Only a small difference was observed in the same areas between the high and low perforamce groups in SPM analysis. Conclusions: Our results indicate that ADAS-cog reflects the bilateral parietal function which is predominantly associated with recall and orientation ability. These brain regions were supposed to be crucial for short-term memory.

BIN1 AND CR1 VARIANTS AFFECT COGNITIVE PERFORMANCE, NEURODEGENERATION, AND BRAIN AMYLOIDOSIS IN ADNI SUBJECTS

Anna Blanken, Daniel H. Silverman, Nare Torosyan, Manogna Manne, Beata Durcanova, Andrew J. Saykin, Clifford R. Jack, Liana G. Apostolova, UCLA, Los Angeles, California, United States; University of California, Los Angeles, Los Angeles, California, United States; Indiana University School of Medicine, Indianapolis, Indiana, United States; Mayo Clinic, Rochester, Minnesota, United States. Contact e-mail: ablanken@mednet.ucla.edu