P430
Poster Presentations: P1
Figure 3. Transfer function metrics of dynamic cerebral pressure-flow relation measured during a sit-stand maneuver. Group-averaged plots were generated from sleep systolic blood pressure dippers and non-dippers. The highlights represent the frequency where a sit-stand maneuver was performed.
the Petersen criteria. Cortical Ab depositions were measured by 18 F-florbetapir positron emission tomography and expressed as standardized uptake value ratio (SUVR) relative to the cerebellar uptake. The posterior cingulate, precuneus, and mean cortex were selected a priori as regions of interest. Ambulatory BP was recorded to measure awake and sleep BP changes. The dipping status of sleep BP (i.e., percent change from awake BP) was calculated individually and dichotomized to the dipper (10%) and nondipper ( 5 affected vessels). Generalized additive models were used to assess the association between CAA density scores and CASI performance at last cognitive exam. Results: A total of 476 brains (56%) displayed moderate or higher CAA lesion density in one or more regions; 303 (36%) had no CAA pathology in all regions assessed. Consistent with previously reported autopsy series, CAA lesion counts were higher in leptomeningeal than parenchymal tissue, rarely occurring in parenchymal vessels without also being observed in adjacent leptomeningeal vessels. CAA was more common in subjects with an APOE ε4 allele and in subjects with Alzheimer plaque and tangle pathology, but was also present in subjects without either of these features. In univariate analyses, parenchymal CAA lesion density was weakly associated with CASI score at last cognitive assessment (e.g., .07 points lower CASI score per unit increase in mean neocortical CAA density score, p¼0.03). However this association disappeared after controlling for neuritic plaque or neurofibrillary tangle density levels. In 291 subjects lacking Alzheimer neuritic plaque in the frontal lobe, there was no evidence that CAA lesion density was associated with global cognitive performance regardless of brain region or CAA summary measure tested (all p > 0.38). Conclusions: In this population-based series of Japanese-American men, CAA
Poster Presentations: P1
lesions were common, but there was little evidence that these lesions had an appreciable effect on cognitive function or risk of dementia beyond that attributable to their correlation with amyloid accumulation in neuritic plaques.
P1-210
COMPARISON OF BUTYRYLCHOLINESTERASE AND b-AMYLOID AS DIAGNOSTIC MARKERS FOR THE DEFINITIVE DIAGNOSIS OF ALZHEIMER’S DISEASE
Ian R. Macdonald1, Sajedeh Uzbak1, G. Andrew Reid1, Meghan Cash1, Earl Martin2, Sultan Darvesh1,2, 1Dalhousie University, Halifax, NS, Canada; 2Mount Saint Vincent University, Halifax, NS, Canada. Contact e-mail:
[email protected] Background: b-amyloid (Ab) plaques are one of the neuropathological hallmarks of Alzheimer’s disease (AD). However, a significant number of older individuals possess Ab plaques but are cognitively intact. Early and definitive discrimination between AD and cognitively normal with Ab plaque (NwAb) individuals remains challenging. Butyrylcholinesterase (BuChE) is a serine hydrolase that accumulates in Ab plaques in the AD brain. It is hypothesized that BuChE accumulates in Ab plaques to a greater degree in AD compared to NwAb individuals. Thus, detecting BuChE associated with Ab plaques has the potential to provide definitive diagnosis of AD during life and distinguish individuals with AD from NwAb. We present the quantification of BuChE and Ab in post-mortem human brain tissues to determine suitability for discriminating NwAb from AD. Methods: AD, NwAb, and cognitively normal brain tissues were obtained from the Maritime Brain Tissue Bank, Halifax, Canada. These tissues were stained for BuChE activity using histochemical techniques and for fibrillar Ab plaques using thioflavin-S and Ab plaque burden using immunohistochemistry. Brain tissues were quantified for staining as a percentage of the total cortical area. The percentage of BuChE, Ab, and thioflavin-S stained plaque pathology was averaged for each brain and compared. Differences between AD, NwAb, and cognitively normal brains were determined. Results: AD brain tissues demonstrated higher levels of BuChE, Ab, and thioflavin-S plaques relative to NwAb brain tissues. NwAb brains demonstrated marker levels intermediate to AD and cognitively normal brains. With respect to distinguishing NwAb from AD brains, both thioflavin-S and Ab staining were higher in AD compared to NwAb brains. However, staining of BuChE-associated plaques was markedly greater than either Ab or thioflavin-S for distinguishing between AD and NwAb. Thus, compared to total Ab, BuChE represents a more sensitive marker for the diagnosis of AD. Conclusions: Early distinction between individuals with AD and those who are cognitively normal but possess Ab plaques remains a challenge. We present preliminary data suggesting that BuChE is a more sensitive marker, compared to Ab, to detect AD. Early and definitive diagnosis based on BuChE as a biomarker could facilitate timely intervention and management of individuals with AD.
P1-211
GENETIC INFLUENCES ON AMYLOID ANGIOPATHYAND WHITE MATTER PATHOLOGY IN FAMILIAL ALZHEIMER’S DISEASE: A COMPARISON OF APP AND PSEN1 MUTATIONS
Natalie S. Ryan1, Phoebe Walsh1, Priya Gami1, Claire Troakes2, Martin N. Rossor3, Nick C. Fox3, Tamas Revesz1, Tammaryn Lashley1, 1 University College London, London, United Kingdom; 2Institute of Psychiatry, London, United Kingdom; 3UCL Institute of Neurology, London, United Kingdom. Contact e-mail:
[email protected]
P431
Background: Cerebral amyloid angiopathy (CAA) is a common but heterogeneous feature of Alzheimer’s disease (AD), emerging as an important factor in amyloid-modifying therapy trials. Familial AD (FAD) treatment trials therefore raise interest in the variable occurrence of CAA associated with different mutations. Neuroimaging studies have indicated particularly extensive white matter involvement in PSEN1-associated FAD, which could have various pathological substrates. We investigated whether there was neuropathological evidence of more severe CAA, white matter pathology or inflammatory change in PSEN1 compared with APP mutation carriers. Methods: Clinical and pathological data from 20 cases with FAD secondary to mutations in PSEN1 (n¼10) and APP (n¼10) were studied. All APP mutations lay outside the amyloid-beta coding domain. Tissue sections (7-mm thick) from parietal and occipital cortex were immunostained with an anti-Ab antibody and the severity of CAA was semiquantitatively analysed. Further immunohistochemical studies assessed axonal density/ integrity (RT97), myelination (MBP), astrocytic (GFAP) and microglial (CD68 and Iba1) response in deep white matter compared to U-fibres, which were used as an internal control in each case. Ratios of deep white matter to U-fibre staining density were compared between the mutation groups. Results: The severity of occipital CAA was significantly greater in the PSEN1 than APP group (p¼0.0001), despite similar disease durations and younger ages at onset in the PSEN1 cases. The PSEN1 group demonstrated lower axonal density/integrity in occipital (p¼0.009) and parietal (p¼0.05) deep white matter compared with the APP group. There was some evidence that younger ages at onset were associated with a greater immune/inflammatory response in the deep white matter for both the PSEN1 and APP mutation groups. In the PSEN1 group, shorter disease durations were associated with greater loss of myelin and axonal density/integrity in the parietal deep white matter. Conclusions: The PSEN1 cases in this study demonstrated more severe occipital CAA and a greater loss of axonal density/integrity in the parieto-occipital deep white matter than APP cases with similar disease duration. This study supports observations from neuroimaging studies, of more extensive white matter pathology in association with PSEN1 mutations, highlighting the potential importance of considering APP and PSEN1 mutation carriers separately in FAD research.
P1-212
NEUROPATHOLOGIC CHARACTERIZATION OF CEREBRAL b-AMYLOID ANGIOPATHY IN FAMILIAL CEREBRAL HEMORRHAGE
Kathy Newell1, Jill R. Murrell2, Jayashree Sundararajan1, Phillip Hylton1, Bernardino Ghetti2, 1University of Kansas Medical Center, Kansas City, KS, USA; 2Indiana University School of Medicine, Indianapolis, IN, USA. Contact e-mail:
[email protected] Background: The most common form of cerebral amyloid angi-
opathy (CAA) is associated with deposits of b-amyloid protein in blood vessels of the cerebral cortex and leptomeninges, often resulting in multiple hemorrhages, ranging from lobar to microscopic. b-amyloid-CAA is frequently associated with Alzheimer disease (AD) pathology; however, it can also be sporadic without AD pathology. Less commonly, widespread b-amyloid-CAA is seen in Hereditary cerebral hemorrhage with amyloidosis-Dutch type. Methods: A 64 year-old man with multiple cerebral hemorrhages was studied clinically and radiologically with MRI and cerebral angiography. At death, his brain was studied neuropathologically with histological and
