The brains of patients suffering from Alzheimer's disease (AD) have three classical pathological hallmarks: amyloid-beta (Aβ) plaques, tau tangles, and neurodegeneration, including that of cholinergic neurons of the basal forebrain. However the relationship between Aβ burden and basal forebrain degeneration has not been extensively studied. To investigate this association, basal forebrain volumes were determined from magnetic resonance images of controls, subjects with amnestic mild cognitive impairment (aMCI) and AD patients enrolled in the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarkers and Lifestyle (AIBL) studies. In the AIBL cohort, these volumes were correlated within groups to neocortical gray matter retention of Pittsburgh compound B (PiB) from positron emission tomography images as a measure of Aβ load. The basal forebrain volumes of AD and aMCI subjects were significantly reduced compared to those of control subjects. Anterior basal forebrain volume was significantly correlated to neocortical PiB retention in AD subjects and aMCI subjects with high Aβ burden, whereas posterior basal forebrain volume was significantly correlated to neocortical PiB retention in control subjects with high Aβ burden. Therefore this study provides new evidence for a correlation between neocortical Aβ accumulation and basal forebrain degeneration. In addition, cluster analysis showed that subjects with a whole basal forebrain volume below a determined cut-off value had a 7 times higher risk of having a worse diagnosis within ~18 months.

The basal forebrain degenerates in Alzheimer’s disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants’ ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy.

AbbreviationsChAT: Choline acetyl transferase dMRI: diffusion MRI FA: fractional anisotropy MCI: mild cognitive impairment MRI: magnetic resonance imaging p75 NTR : p75 neurotrophin receptor PB: phosphate buffer PBS: phosphate buffered saline ROI: region of interest SAP: saporin KeywordsCholinergic basal forebrain, tractography, p75 neurotrophin receptor, MRI, diffusion weighted imaging, neurodegeneration 3

Alzheimer's disease is characterized by cognitive decline, neuronal degeneration, and the accumulation of amyloid-beta (Aβ). Although, the neurotoxic Aβ peptide is widely believed to trigger neuronal dysfunction and degeneration in Alzheimer's disease, the mechanism by which this occurs is poorly defined. Here we describe a novel, Aβ-triggered apoptotic pathway in which Aβ treatment leads to the upregulation of G-protein activated inwardly rectifying potassium (GIRK/Kir3) channels, causing potassium efflux from neurons and Aβ-mediated apoptosis. Although, GIRK channel activity is required for Aβ-induced neuronal degeneration, we show that it is not sufficient, with coincident signaling by the p75 neurotrophin receptor (p75NTR) also required for potassium efflux and cell death. Our results identify a novel role for GIRK channels in mediating apoptosis, and provide a previously missing mechanistic link between the excitotoxicity of Aβ and its ability to trigger cell death pathways, such as that mediated by p75NTR. We propose that this death-signaling pathway contributes to the dysfunction of neurons in Alzheimer's disease and is responsible for their eventual degeneration.

The basal forebrain, a grey matter region located in the medial and ventral aspects of the mammalian brain, consists of highly heterogeneous populations of cells including, but not limited to: cholinergic, GABAergic, glutamatergic and calbindin-positive neurons. The function of the basal forebrain has been linked to mediating reward-related behaviours,

Prior research indicates that positive search training (PST) may be a promising home-based computerised treatment for childhood anxiety disorders. It explicitly trains anxious individuals in adaptive, goal-directed attention-search strategies to search for positive and calm information and ignore goal-irrelevant negative cues. Although PST reduces anxiety symptoms, its neural effects are unknown. The main aim of this study was to examine changes in neural activation associated with changes in attention processing of positive and negative stimuli from pre- to post-treatment with PST in children with anxiety disorders. Children's neural activation was assessed with functional magnetic resonance imaging (fMRI) during a visual-probe task indexing attention allocation to threat-neutral and positive-neutral pairs. Results showed pre- to post-treatment reductions in anxiety symptoms and neural reactivity to emotional faces (angry and happy faces, relative to neutral faces) within a broad neural network linking frontal, temporal, parietal and occipital regions. Changes in neural reactivity were highly inter-correlated across regions. Neural reactivity to the threat-bias contrast reduced from pre- to post-treatment in the mid/posterior cingulate cortex. Results are considered in relation to prior research linking anxiety disorders and treatment effects with functioning of a broad limbic-cortical network involved in emotion reactivity and regulation, and integrative functions linking emotion, memory, sensory and motor processes and attention control.

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