ABSTRACT
INTRODUCTION: Diagnosis of Alzheimer's disease (AD) in vivo, by molecular imaging of amyloid or tau, is constrained because similar changes can be found in brains of cognitively normal individuals. Butyrylcholinesterase (BChE), which becomes associated with these structures in AD, could elevate the accuracy of AD diagnosis by focusing on BChE pathology in the cerebral cortex, a region of scant BChE activity in healthy brain. METHODS: N-methylpiperidin-4-yl 4-[123I]iodobenzoate, a BChE radiotracer, was injected intravenously into B6SJL-Tg(APPSwFlLon, PSEN1∗M146 L∗L286 V) 6799Vas/Mmjax (5XFAD) mice and their wild-type (WT) counterparts for comparative single photon emission computed tomography (SPECT) studies. SPECT, computed tomography (CT), and magnetic resonance imaging (MRI) enabled comparison of whole brain and regional retention of the BChE radiotracer in both mouse strains. RESULTS: Retention of the BChE radiotracer was consistently higher in the 5XFAD mouse than in WT, and differences were particularly evident in the cerebral cortex. DISCUSSION: Cerebral cortical BChE imaging with SPECT can distinguish 5XFAD mouse model from the WT counterpart.
ABSTRACT
Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of ß-amyloid (Aß) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Aß pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Aß plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Aß than 5XFAD mice at the same age. Therefore, BChE may have a role in Aß pathogenesis. Furthermore, in AD, diminished glucose metabolism in the brain can be detected in vivo with positron emission tomography (PET) imaging following 2-deoxy-2-(18F)fluoro-D-glucose (18FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Aß burden, whole brain and regional uptake of 18FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT5XFAD and WTBChE-KO) strains at 5months. Diminished fibrillar Aß burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brain 18FDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction in 18FDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT5XFAD. Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WTBChE-KO, while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Aß, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid/metabolism , Butyrylcholinesterase/deficiency , Fluorodeoxyglucose F18/pharmacology , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Amyloid/genetics , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Basal Ganglia/metabolism , Brain/metabolism , Butyrylcholinesterase/genetics , Butyrylcholinesterase/metabolism , Disease Models, Animal , Female , Gene Knockout Techniques , Glucose/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Plaque, Amyloid/metabolism , Positron-Emission Tomography/methods , Radiopharmaceuticals/pharmacokineticsABSTRACT
Amyloid-ß (Aß) plaques are a neuropathological hallmark of Alzheimer's disease (AD); however, a significant number of cognitively normal older adults can also have Aß plaques. Thus, distinguishing AD from cognitively normal individuals with Aß plaques (NwAß) based on Aß 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 Aß, thioflavin-S, and BChE quantification of 26 postmortem brain tissues; AD (nâ=â8), NwAß (nâ=â6), cognitively normal without plaques (nâ=â8), 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 Aß 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, Aß 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 NwAß and AD, due to the virtual absence of BChE-associated plaques in NwAß brains. Furthermore, BChE did not associate with pathology of the other dementias. In this sample, BChE-associated pathology provided better diagnostic performance (AUCâ=â1.0, sensitivity/specificityâ=â100% /100%) when compared to Aß (AUCâ=â0.98, 100% /85.7%). These findings highlight the predictive value of BChE as a biomarker for AD that could facilitate timely disease diagnosis and management.
Subject(s)
Alzheimer Disease/pathology , Brain/metabolism , Butyrylcholinesterase/metabolism , Plaque, Amyloid/pathology , Aged , Aged, 80 and over , Amyloid beta-Peptides/metabolism , Brain/pathology , Diagnosis , Female , Humans , Male , Middle Aged , Plaque, Amyloid/metabolism , Psychiatric Status Rating Scales , ROC CurveABSTRACT
Butyrylcholinesterase (BuChE) is an enzyme capable of hydrolysing a wide variety of esters including acetylcholine, a molecule involved in neurotransmission and modulation of immune cell activity. In the brain, BuChE is expressed in white matter and certain populations of neurons and glia. Multiple sclerosis (MS) is an autoimmune disease affecting white matter characterized by neuroinflammation and neurodegeneration in the central nervous system. Here we demonstrate alterations in BuChE activity in MS white matter lesions, including diminished enzyme activity associated with myelin and an increased activity in cells with microglial morphology. Increased BuChE activity within MS lesions could contribute to the pro-inflammatory immune responses through hydrolysis of acetylcholine and to demyelination through hydrolytic deacylation of myelin proteins such as proteolipid protein. This suggests that BuChE could be a potential target for novel disease-modifying strategies for MS.
