Meghan K. Cash

Butyrylcholinesterase Is Associated With β-Amyloid Plaques in the Transgenic APPSWE/PSEN1dE9 Mouse Model of Alzheimer Disease

Abstract Histochemical analysis of Alzheimer disease (AD) brain tissues indicates that butyrylcholinesterase (BuChE) is present in &bgr;-amyloid (A&bgr;) plaques. The role of BuChE in AD pathology is unknown, but an animal model developing similar BuChE-associated A&bgr; plaques could provide insights. The APPSWE/PSEN1dE9 transgenic mouse (ADTg), which develops A&bgr; plaques, was examined to determine if BuChE associates with these plaques, as in AD. We found that in mature ADTg mice, BuChE activity associated with A&bgr; plaques. The A&bgr;-, thioflavin-S– and BuChE-positive plaques mainly accumulated in the olfactory structures, cerebral cortex, hippocampal formation, amygdala, and cerebellum. No plaques were stained for acetylcholinesterase activity. The distribution and abundance of plaque staining in ADTg closely resembled many aspects of plaque staining in AD. Butyrylcholinesterase staining consistently showed fewer plaques than were detected with A&bgr; immunostaining but a greater number of plaques than were visualized with thioflavin-S. Double-labeling experiments demonstrated that all BuChE-positive plaques were A&bgr; positive, whereas only some BuChE-positive plaques were thioflavin-S positive. These observations suggest that BuChE is associated with a subpopulation of A&bgr; plaques and may play a role in AD plaque maturation. A further study of this animal model could clarify the role of BuChE in AD pathology.

Cholinesterases in Normal and Alzheimer's Disease Primary Olfactory Gyrus

Alzheimers disease (AD) is characterized by cholinergic dysfunction and deposition of β‐amyloid (Aβ) plaques and tau neurofibrillary tangles (NFTs) in the brain. Olfactory abnormalities often precede cognitive symptoms in AD, indicating early involvement of pathology in olfactory structures. The cholinergic system is important not only in cognition but also in modulation of the olfactory system. The primary olfactory gyrus (POG) is comprised of the olfactory tract, anterior olfactory nucleus (AON) and olfactory area (OA). Because of the importance of the olfactory and cholinergic systems, we examined the anatomical and cholinergic organization of the POG in normal human brain and neuropathology in AD.

Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer’s Disease

Amyloid-β (Aβ) plaques are a neuropathological hallmark of Alzheimer’s disease (AD); however, a significant number of cognitively normal older adults can also have Aβ plaques. Thus, distinguishing AD from cognitively normal individuals with Aβ plaques (NwAβ) based on Aβ plaque detection is challenging. It has been observed that butyrylcholinesterase (BChE) accumulates in plaques preferentially in AD. Thus, detecting BChE-associated plaques has the potential as an improved AD biomarker. We present Aβ, thioflavin-S, and BChE quantification of 26 postmortem brain tissues; AD (n = 8), NwAβ (n = 6), cognitively normal without plaques (n = 8), and other common dementias including corticobasal degeneration, frontotemporal dementia with tau, dementia with Lewy bodies, and vascular dementia. Pathology burden in the orbitofrontal cortex, entorhinal cortex, amygdala, and hippocampal formation was determined and compared. The predictive value of Aβ and BChE quantification was determined, via receiver-operating characteristic plots, to evaluate their AD diagnostic performance using sensitivity, specificity, and area under curve (AUC) metrics. In general, Aβ and BChE-associated pathology were greater in AD, particularly in the orbitofrontal cortex. In this region, the largest increase (9.3-fold) was in BChE-associated pathology, observed between NwAβ and AD, due to the virtual absence of BChE-associated plaques in NwAβ brains. Furthermore, BChE did not associate with pathology of the other dementias. In this sample, BChE-associated pathology provided better diagnostic performance (AUC = 1.0, sensitivity/specificity = 100% /100%) when compared to Aβ (AUC = 0.98, 100% /85.7%). These findings highlight the predictive value of BChE as a biomarker for AD that could facilitate timely disease diagnosis and management.

Cerebral glucose metabolism, pathology and behaviour in the 5XFAD mouse model of Alzheimer's disease

IC-P-045 CEREBRAL GLUCOSE METABOLISM, PATHOLOGYAND BEHAVIOR IN THE 5XFAD MOUSE MODEL OFALZHEIMER’S DISEASE Ian Macdonald, Drew DeBay, Tim O’Leary, Andrew Reid, Meghan Cash, Courtney Jollymore, George Mawko, Steve Burrell, Chris Bowen, Earl Martin, Richard Brown, Sultan Darvesh, Dalhousie University, Halifax, Nova Scotia, Canada; National Research Council, Halifax, Nova Scotia, Canada; Mount Saint Vincent University, Halifax, Nova Scotia, Canada. Contact e-mail: Ian.Macdonald@dal.ca

Comparison of butyrylcholinesterase and β-amyloid as diagnostic markers for the definitive diagnosis of Alzheimer’s disease

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.

CLINICOPATHOLOGICAL CORRELATION OF NEURODEGENERATIVE CASES IN A DEMENTIA UNIT

NPI total normal 102(55.4) 19(61.3) 0.34 altered 82(44.6) 12(38.7) Desilusion normal 182 (97.8) 31(100) 0.71 altered 2(1.1) 0 Hallucination normal 178 (95.7) 31 (100) 0.70 altered 6(3.2) 0 Agitation/Aggression normal 165 (88.7) 29 2(93.5) 0.31 altered 19 (10.2) 2 (6.5) Depression/Dysphoria normal 157 (84.40) 26 (83.9) 0.34 altered 27 (14.5) 5(16.1) Anxiety normal 142 (76.3) 26 (83.9) 0.77 altered 41 (22) 5(16.1) Elation/Euphoria normal 180 (96.8) 30 (96.8) 0.56 altered 3 (1.6) 1 (3.2) Apathy/Indifference normal 161 (86.6) 26 (83.9) 0.58 altered 23 (12.4) 5(16.1) Disinhibition normal 181 (98.4) 30 (96.8) 0.46 altered 3 (1.6) 1 (3.2) Irritability/Lability normal 165 (88.7) 27 (87.1) 0.31 altered 19 (10.2) 4(12.9) Aberrant Motor Behavior normal 179 (96.2) 31 (100) 0.51 altered 5 (2.7) 0 Sleep Behavior Disorders normal 152 (81.7) 30 (96.8) 0.04 altered 32 (17.2) 1 (3.2) Apetite/Eating Changes normal 142 (76.3) 26 (83.9) 0.56 altered 43 (23.1) 5(16.1)

ALTERNATIVE CEREBRAL GLUCOSE UPTAKE METRICS DETECT EARLY METABOLIC CHANGES IN THE 5XFAD MOUSE MODEL OF ALZHEIMER'S DISEASE

Background: Changes in visual and auditory function have been reported in patients with clinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI), but the relationship of these measures to known biomarkers of AD neuropathology is unknown. Thus, the goal of this study was to test the hypothesis that sensory measures, including visual (contrast sensitivity) and auditory function (pure tone audiometry), are associated with neuroimaging biomarkers of AD, including amyloid deposition (measured with [11 C]PiB PET) and hippocampal volume. Methods: 31 participants, including 13 healthy age-matched controls (HC), 6 euthymic older adults with subjective cognitive decline (SCD) but no neuropsychological deficits, and 12 patients with MCI, were included in the present analysis. All participants underwent a test of contrast sensitivity, measured using frequency doubling technology (FDT-2) as previously described [1], pure tone audiometry to test tonal hearing, and structural MRI. A subset of participants also underwent [11 C]PiB PET imaging (n1⁄412 [3 HC, 3 SCD, 6 MCI]). Structural MRI scans were processed using FreeSurfer version 5.1. [11 C]PiB PET scans were processed using standard techniques in SPM8. Mean PiB standardized uptake value ratio (SUVR) was extracted from a global cortical grey matter region of interest. Contrast sensitivity (duration of FDT-2 exam) and tonal hearing at high frequency (mean tonal intensity at 8000Hz) were compared between diagnostic groups. The relationship of these sensory measures to global PiB uptake and hippocampal atrophy was evaluated using a linear regression model. Results: No significant difference between diagnostic groups was observed for either visual function or tonal hearing at 8000 Hz in this small sample (Fig. 1A & 1B). However, visual function (duration of FDT-2 exam) was significantly associated with amyloid deposition (p1⁄40.001, Fig. 1C). Tonal hearing and hippocampal volume were also significantly associated (p1⁄40.001, Fig. 1D). Conclusions: Visual and auditory changes in individuals at risk and during prodromal stages of AD are associated with neuroimaging biomarkers of AD pathology, including amyloid deposition and neurodegeneration. Non-invasive and inexpensive measures of visual and auditory sensory function warrant further investigation as potential biomarkers of early stage AD pathology. [1] Risacher et al. (2013) Neurobiol Aging. IC-P-098 ALTERNATIVE CEREBRAL GLUCOSE UPTAKE METRICS DETECT EARLY METABOLIC CHANGES IN THE 5XFAD MOUSE MODEL OFALZHEIMER’S DISEASE Drew R. DeBay, Ian R. Macdonald, G. Andrew Reid, Tim P. O’Leary, Courtney T. Jollymore, Meghan K. Cash, GeorgeMawko, Steve Burrell, Earl Martin, Chris V. Bowen, Richard E. Brown, Sultan Darvesh, Dalhousie University, Halifax, Nova Scotia, Canada; Mount Saint Vincent University, Halifax, Nova Scotia, Canada. Contact e-mail: drdebay@dal.ca

Butyrylcholinesterase-associated neuropathology in early-onset familial Alzheimer's disease

Positive Correlation isthmuscingulate parahippocampal lateralorbitofrontal supramarginal inferiortemporal fusiform inferiorparietal temporalpole middletemporal superiortemporal parsopercularis inferiortemporal bankssts fusiform entorhinal insula parstriangularis caudalmiddlefrontal transversetemporal inferiorparietal precentral superiorparietal supramarginal temporalpole entorhinal middletemporal superiortemporal inferiortemporal caudalmiddlefrontal fusiform supramarginal parahippocampal superiorfrontal paracentral rostralmiddlefrontal rostralmiddlefrontal inferiorparietal caudalmiddlefrontal supramarginal entorhinal bankssts inferiortemporal parahippocampal superiorparietal fusiform isthmuscingulate superiorfrontal lateralorbitofrontal parsopercularis middletemporal parstriangularis superiortemporal insula inferiortemporal caudalmiddlefrontal parahippocampal inferiorparietal rostralmiddlefrontal superiorfrontal fusiform supramarginal entorhinal

Butyrylcholinesterase, Aβ and thioflavin-S plaques in the transgenic APPSWE/PSEN1dE9 mouse model of Alzheimer's disease

ization of the rat model of Alzheimer’s disease compared to wild type controls reveals early dysregulation of molecular pathways that are expected to contribute to AD pathology, as well as additional pathways that may represent novel targets for therapeutic intervention. These early changes might well represent preclinical features of the Abeta-driven pathology. Further characterization of this transgenic rat model will include analysis of biomarker profiles.