Search

Neuroimaging with [2,2-dimethyl-3-[(2R,3E)-3-oxidoiminobutan-2-yl]azanidylpropyl]-[(2R,3E)-3-hydroxyiminobutan-2-yl]azanide;oxo(99Tc)technetium-99(3+) ([99mTc]HMPAO) single photon emission computed tomography (SPECT) is used in Alzheimer's disease (AD) to evaluate regional cerebral blood flow (rCBF). Hypoperfusion in select temporoparietal regions has been observed in human AD. However, it is unknown whether AD hypoperfusion signatures are also present in the 5XFAD mouse model. The current study was undertaken to compare baseline brain perfusion between 5XFAD and wild-type (WT) mice using [99mTc]HMPAO SPECT and determine whether hypoperfusion is recapitulated in 5XFAD mice. 5XFAD and WT mice underwent a 45 min SPECT scan, 20 min after [99mTc]HMPAO administration. Whole brain and regional standardized uptake values (SUV) and regional relative standardized uptake values (SUVR) with whole brain reference were compared between groups. Brain perfusion was similar between WT and 5XFAD brains. Whole brain [99mTc]HMPAO retention revealed no significant difference in SUV (5XFAD, 0.372 ± 0.762; WT, 0.640 ± 0.955; p = 0.536). Similarly, regional analysis revealed no significant differences in [99mTc]HMPAO metrics between groups (SUV: 0.357 ≤ p ≤ 0.640; SUVR: 0.595 ≤ p ≤ 0.936). These results suggest apparent discrepancies in rCBF between human AD and the 5XFAD model. Establishing baseline perfusion patterns in 5XFAD mice is essential to inform pre-clinical diagnostic and therapeutic drug discovery programs. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of β-amyloid (Aβ) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Aβ pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Aβ plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Aβ than 5XFAD mice at the same age. Therefore, BChE may have a role in Aβ 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-( 18 F)fluoro-D-glucose ( 18 FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Aβ burden, whole brain and regional uptake of 18 FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT 5XFAD and WT BChE-KO ) strains at 5 months. Diminished fibrillar Aβ burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brain 18 FDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction in 18 FDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT 5XFAD . Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WT BChE-KO , while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Aβ, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The influence of butyrylcholinesterase (BChE) genetic polymorphism in Alzheimer's (AD) remains controversial. BCHE-K and BCHE-A genetic variants cause reduction of BChE, an enzyme implicated in AD. Some studies have reported a protective effect of BCHE-K, others suggest increased AD risk, particularly when associated with APOE4. We utilized a candidate gene-driven analyses to determine the effects of BCHE-K and BCHE-A on AD biomarkers using ADNI data (http://adni.loni.ucla.edu/). Methods: Participants were genotyped for BCHE-K (615) and BCHE-A (785), each stratified into control (C), MCI or AD groups. MRI, 18F-FDG and amyloid-PET were assessed. ANCOVA compared main effects of i)diagnosis, ii)BCHE-K, iii)BCHE-A and iv)APOE4 status on each biomarker with age, education and sex as covariates. Results: The allelic frequency was 20.8%, 4.6% and 26.5% for BCHE-K, BCHE-A and APOE4. For MRI, main effects for diagnosis were significant (p<0.0001), with reduction in whole-brain and selected regional volumes (7-27%, p=6x10-6) in AD vs. C. For 18FDG-PET, the main effect for diagnosis was significant (p=5x10-9), with 14% decrease in metabolism in AD vs. C (p=7x10-10). For amyloid-PET, the main effects for diagnosis and APOE4 status were significant (p=0.034; p=3x10-6), with 12% increase in retention in AD vs. C (p=0.023) and 16% increase among carriers of at least one APOE4 allele vs. non-carriers (p=8x10-6). No significant effects of these biomarkers were observed due to BCHE-K or BCHE-A status (p=0.209). Conclusions: These data suggest BCHE-K or BCHE-A may not significantly effect structural, metabolic or molecular AD biomarkers. Further ROI/voxel-wise analyses are warranted to uncover potential regional changes among AD BCHE variants. [ABSTRACT FROM AUTHOR]