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Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution.

ABSTRACT: Patients with posterior cortical atrophy (PCA) often have Alzheimer disease (AD) at autopsy, yet are cognitively and anatomically distinct from patients with clinical AD. We sought to compare the distribution of ?-amyloid and glucose metabolism in PCA and AD in vivo using Pittsburgh compound B (PiB) and FDG-PET.Patients with PCA (n = 12, age 57.5 ± 7.4, Mini-Mental State Examination [MMSE] 22.2 ± 5.1), AD (n = 14, age 58.8 ± 9.6, MMSE 23.8 ± 6.7), and cognitively normal controls (NC, n = 30, age 73.6 ± 6.4) underwent PiB and FDG-PET. Group differences in PiB distribution volume ratios (DVR, cerebellar reference) and FDG uptake (pons-averaged) were assessed on a voxel-wise basis and by comparing binding in regions of interest (ROIs).Compared to NC, both patients with AD and patients with PCA showed diffuse PiB uptake throughout frontal, temporoparietal, and occipital cortex (p < 0.0001). There were no regional differences in PiB binding between PCA and AD even after correcting for atrophy. FDG patterns in PCA and AD were distinct: while both groups showed hypometabolism compared to NC in temporoparietal cortex and precuneus/posterior cingulate, patients with PCA further showed hypometabolism in inferior occipitotemporal cortex compared to both NC and patients with AD (p < 0.05). Patients with AD did not show areas of relative hypometabolism compared to PCA.Fibrillar amyloid deposition in PCA is diffuse and similar to AD, while glucose hypometabolism extends more posteriorly into occipital cortex. Further studies are needed to determine the mechanisms of selective network degeneration in focal variants of AD.

SUBMITTER: Rosenbloom MH

PROVIDER: S-EPMC3100124 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution.

Rosenbloom M H MH Alkalay A A Agarwal N N Baker S L SL O'Neil J P JP Janabi M M Yen I V IV Growdon M M Jang J J Madison C C Mormino E C EC Rosen H J HJ Gorno-Tempini M L ML Weiner M W MW Miller B L BL Jagust W J WJ Rabinovici G D GD

Neurology 20110427 21

<h4>Background/objective</h4>Patients with posterior cortical atrophy (PCA) often have Alzheimer disease (AD) at autopsy, yet are cognitively and anatomically distinct from patients with clinical AD. We sought to compare the distribution of β-amyloid and glucose metabolism in PCA and AD in vivo using Pittsburgh compound B (PiB) and FDG-PET.<h4>Methods</h4>Patients with PCA (n = 12, age 57.5 ± 7.4, Mini-Mental State Examination [MMSE] 22.2 ± 5.1), AD (n = 14, age 58.8 ± 9.6, MMSE 23.8 ± 6.7), and ...[more]

PMID: 21525424

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Project description:AimStreptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/A? pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice.MethodsCell-based assays for screening anti-amyloid compounds were established by assessing A? accumulation in HEK293-APPsw and CHO-APP cells, and A? clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate A? and sAPP? levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains.ResultsLX2343 (5-20 ?mol/L) dose-dependently decreased A? accumulation in HEK293-APPsw and CHO-APP cells, and promoted A? clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 ?mol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing A? clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the A? pathology in their brains.ConclusionLX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both A? production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.

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Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution.

Publications

Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution.

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