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Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer's disease.

ABSTRACT: We compared accuracy of hippocampus and basal forebrain cholinergic system (BFCS) atrophy to predict cortical amyloid burden in 179 cognitively normal subjects (CN), 269 subjects with early stages of mild cognitive impairment (MCI), 136 subjects with late stages of MCI, and 86 subjects with Alzheimer's disease (AD) dementia retrieved from the Alzheimer's Disease Neuroimaging Initiative database. Hippocampus and BFCS volumes were determined from structural magnetic resonance imaging scans at 3 Tesla, and cortical amyloid load from AV45 (florbetapir) positron emission tomography scans. In receiver operating characteristics analyses, BFCS volume provided significantly more accurate classification into amyloid-negative and -positive categories than hippocampus volume. In contrast, hippocampus volume more accurately identified the diagnostic categories of AD, late and early MCI, and CN compared with whole and anterior BFCS volume, whereas posterior BFCS and hippocampus volumes yielded similar diagnostic accuracy. In logistic regression analysis, hippocampus and posterior BFCS volumes contributed significantly to discriminate MCI and AD from CN, but only BFCS volume predicted amyloid status. Our findings suggest that BFCS atrophy is more closely associated with cortical amyloid burden than hippocampus atrophy in predementia AD.

SUBMITTER: Teipel S

PROVIDER: S-EPMC4120959 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer's disease.

Teipel Stefan S Heinsen Helmut H Amaro Edson E Grinberg Lea T LT Krause Bernd B Grothe Michel M

Neurobiology of aging 20131028 3

We compared accuracy of hippocampus and basal forebrain cholinergic system (BFCS) atrophy to predict cortical amyloid burden in 179 cognitively normal subjects (CN), 269 subjects with early stages of mild cognitive impairment (MCI), 136 subjects with late stages of MCI, and 86 subjects with Alzheimer's disease (AD) dementia retrieved from the Alzheimer's Disease Neuroimaging Initiative database. Hippocampus and BFCS volumes were determined from structural magnetic resonance imaging scans at 3 Te ...[more]

PMID: 24176625

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Project description:BackgroundThe degeneration of the cholinergic circuit from the basal forebrain to the hippocampus contributes to memory loss in patients suffering from Alzheimer's disease (AD). However, the internal relationships between the acetylcholine (Ach) cycle and memory decline during the early stages of AD currently remain unknown. Here, we investigate the mechanisms underlying the activation of the cholinergic circuit and its impact on learning and memory using APP/PS1 mice models.MethodsNovel object recognition and Morris water maze tests were used to measure learning and memory function. Magnetic resonance spectrum (MRS) imaging was applied to longitudinally track changes in neurochemical metabolism in APP/PS1 mice aged 2, 4, 6, and 8 months. The number of neurons and the deposition of Aβ plaques were measured using Nissl, immunohistochemistry, and Thioflavin S staining. We then employed a chemogenetic strategy to selectively activate the cholinergic circuit from the medial septal nucleus (MS) and the vertical limb of the diagonal band nucleus (VDB) on the basal forebrain to the hippocampus. MRS and immunoblotting techniques were used to measure the neurochemical metabolism levels and cholinergic-related proteins, respectively.ResultsWe found that the levels of choline (Cho) in the basal forebrain were markedly higher compared to other brain regions and that its decrease along with N-acetyl aspartate (NAA) levels in the hippocampus was accompanied by memory deficits in APP/PS1 mice aged 4, 6, and 8 months. In terms of pathology, we observed that the deposition of Aβ plaques gradually aggravated throughout the cerebral cortex and hippocampus in APP/PS1 mice aged 6 and 8 months, while no Aβ deposition was detected in the basal forebrain. In contrast, the activity of choline acetyltransferase (ChAT) enzyme in the basal forebrain was decreased at 6 months of age and the cholinergic neurons were lost in the basal forebrain at 8 months of age. In addition, the activation of the cholinergic circuit from the MS and VDB to the hippocampus using chemical genetics is able to improve learning and reduce memory impairment in APP/PS1 mice. Similarly, the levels of Cho in the basal forebrain; NAA in the hippocampus, as well as the expression of ChAT and vesicular acetylcholine transporter (vAchT) in the basal forebrain; and muscarinic acetylcholine receptor 2 (CHRM2) in the hippocampus all increased.ConclusionsThese findings demonstrate that the neurochemical Cho and NAA of the cholinergic circuit can be used as biomarkers to enable the early diagnosis of AD. In addition, memory impairment in APP/PS1 mice can be attenuated using chemical genetics-driven Ach cycle activity of the cholinergic circuit.

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Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer's disease.

Publications

Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer's disease.

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