Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Nov 27:7:105-13.
doi: 10.1016/j.nicl.2014.11.015. eCollection 2015.

Basal forebrain atrophy correlates with amyloid β burden in Alzheimer's disease

Georg M Kerbler  1 , Jürgen Fripp  2 , Christopher C Rowe  3 , Victor L Villemagne  4 , Olivier Salvado  2 , Stephen Rose  2 , Elizabeth J Coulson  1 ; Alzheimer's Disease Neuroimaging Initiative
Affiliations

Basal forebrain atrophy correlates with amyloid β burden in Alzheimer's disease

Georg M Kerbler et al. Neuroimage Clin. .

Abstract

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.

Keywords: 3D, 3-dimensional; AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; AIBL, Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging; Alzheimer's disease; Amyloid; Aβ, amyloid-beta; Basal forebrain; CSF, cerebrospinal fluid; GM, gray matter; HC, healthy control; MCI, mild cognitive impairment; MNI, Montreal Neurological Institute; MPM, maximum probability maps; MPRAGE, magnetization prepared rapid gradient echo; MRI, magnetic resonance imaging; Magnetic resonance imaging; OR, odds ratio; PET; PET, positron emission tomography; PiB, Pittsburgh compound B; SPSS, statistics software package for the social sciences; SUVR, standard uptake value ratio; SyN, symmetric normalization; T1W, T1-weighted; TG-ROC, two-graph receiver operating characteristic; WM, white matter; aMCI, amnestic mild cognitive impairment.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Basal forebrain masks of AD-specific changes in template space. Coronal slices illustrating the z-score map on a whole template brain (blue; top row A and B) calculated by comparing the HC and AD groups in the AIBL study. In the lower rows (A, B), a magnified view of the basal forebrain area is shown to better illustrate the z-score map (blue) as well as individual basal forebrain volumes. The BF raw mask (red; A, B) was used as a combination of the anterior and posterior parts for analysis of the whole basal forebrain area. The BF MPM mask (green; A, B) was used both as a combination of the anterior and posterior regions, and the anterior and posterior regions individually, to analyze the basal forebrain area. The same slices at different levels from rostral to caudal are shown in A and B, on a T1-weighted image. BF = basal forebrain, MPM = maximum probability map.
Fig. 2
Fig. 2
Group comparisons of basal forebrain volume in the AIBL and ADNI study cohorts. In the AIBL (A) study, the basal forebrain volume was significantly decreased in the AD and aMCI groups compared to controls. In the ADNI study (B), the basal forebrain volume of the AD subject group was significantly smaller than that of the HC and aMCI subject groups. Basal forebrain Volumes of the aMCI groups display high variability in both study cohorts. *** p < 0.001. Whiskers represent min/max values except data points (circles) more than 1.5 interquartile ranges away from the 75th percentile.
Fig. 3
Fig. 3
Correlation of BF raw volume (x-axis) to neocortical PiB retention (y-axis) in the AIBL study. The interaction between the two measures is shown for all subjects pooled together (A) as well for individual subject groups (B–E). The cut-off value used to determine high and low PiB status (0.71) at the baseline time point is indicated in (A) by the horizontal dashed line. Significant interactions were observed in the HC PiB+ (C) and AD (D) subject groups. Even though the correlation coefficient was high in the aMCI PiB+ group, the interaction was not significant. A linear fit line with 95% confidence interval is shown.
Fig. 4
Fig. 4
Significant correlations of anterior and posterior BF MPM posterior Volumes (x-axis) to neocortical PiB retention (y-axis) in the AIBL study. Whereas BF MPM anterior volume showed significant correlations in aMCI PiB+ (A) and AD (B) subjects, BF MPM posterior volume was significantly correlated to neocortical PiB retention in HC PiB+ (C) subjects. A linear fit line with 95% confidence interval is shown.
Fig. 5
Fig. 5
Delineations based on basal forebrain cluster analysis using the BF raw volume, highlighting the subjects in the AIBL study whose diagnosis worsened (‘converters’). In the AIBL study. Basal forebrain cut-off values of 0.00145 and 0.00163 were determined by hierarchical cluster analysis to distinguish three clusters (delineated by vertical dashed lines); the PiB cut-off value of 0.71 is indicated by the horizontal dashed line. Subjects are colored according to their group status at baseline. The mean basal forebrain volume for each group is as follows (given in mean ± SD): AD: 0.001414 ± 0.000138; aMCI: 0.001525 ± 0.000184; HC PiB+: 0.001612 ± 0.000089; HC PiB−: 0.001629 ± 0.000123. The converters are indicated by the diamond-shaped (conversion to AD), triangular (conversion to aMCI) and circular (reversion to HC) data points, with the fill showing the group status at baseline. All but one HC PiB+ to aMCI converting subject fall into the high or medium risk clusters. The subject reverting from aMCI to HC PiB+ group status is shown as a circular data point with a black border. aMCI to AD = aMCI diagnosis at baseline, AD diagnosis at follow up; aMCI to HC PiB+ = aMCI diagnosis at baseline, HC PiB+ diagnosis at follow up; HC PiB+ to AD = HC PiB+ diagnosis at baseline, AD diagnosis at follow up; HC (PiB+ or PiB−) to aMCI = HC diagnosis at baseline, aMCI diagnosis at follow up.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Avants B.B., Yushkevich P., Pluta J., Minkoff D., Korczykowski M., Detre J., Gee J.C. The optimal template effect in hippocampus studies of diseased populations. Neuroimage. 2010;49(3):2457–2466. 19818860 - PMC - PubMed
    1. Bourgeat P., Chételat G., Villemagne V.L., Fripp J., Raniga P., Pike K., Acosta O., Szoeke C., Ourselin S., Ames D., Ellis K.A., Martins R.N., Masters C.L., Rowe C.C., Salvado O. Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia. Neurology. 2010;74(2):121–127. 20065247 - PubMed
    1. Braak H., Alafuzoff I., Arzberger T., Kretzschmar H., Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006;112(4):389–404. 16906426 - PMC - PubMed
    1. Braak H., Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–259. 1759558 - PubMed
    1. Braak H., Del Tredici K. Alzheimer's disease: intraneuronal alterations precede insoluble amyloid-beta formation. Neurobiol. Aging. 2004;25(6):713–718. 15165692 [Discussion 743–716] - PubMed

Publication types

Substances