Elsevier

Biological Psychiatry

Volume 71, Issue 9, 1 May 2012, Pages 805-813
Biological Psychiatry

Archival Report
Atrophy of the Cholinergic Basal Forebrain Over the Adult Age Range and in Early Stages of Alzheimer's Disease

https://doi.org/10.1016/j.biopsych.2011.06.019Get rights and content

Background

The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer's disease (AD). However, there is a controversy regarding how the cholinergic lesion in AD relates to early and incipient stages of the disease. In vivo imaging studies on the structural integrity of the BFCS in normal and pathologic aging are rare.

Methods

We applied automated morphometry techniques in combination with high-dimensional image warping and a cytoarchitectonic map of basal forebrain cholinergic nuclei to a large cross-sectional data set of high-resolution magnetic resonance imaging scans, covering the whole adult age range (20–94 years; n = 211) as well as patients with very mild AD (Clinical Dementia Rating = .5; n = 69) and clinically manifest AD (AD; Clinical Dementia Rating = 1; n = 28). For comparison, we investigated hippocampus volume using automated volumetry.

Results

Volume of the BFCS declined from early adulthood on, and atrophy aggravated in advanced age. Volume reductions in very mild AD were most pronounced in posterior parts of the nucleus basalis of Meynert, whereas in AD, atrophy was more extensive and included the whole BFCS. In clinically manifest AD, the diagnostic accuracy of BFCS volume reached the diagnostic accuracy of hippocampus volume.

Conclusions

Our findings indicate that cholinergic degeneration in AD occurs against a background of age-related atrophy and that exacerbated atrophy in AD can be detected at earliest stages of cognitive impairment. Automated in vivo morphometry of the BFCS may become a useful tool to assess BF cholinergic degeneration in normal and pathologic aging.

Section snippets

Subjects

Magnetic resonance imaging (MRI) scans were retrieved from the Open Access Series of Imaging Studies (OASIS) database (26; http://www.oasis-brains.org) and included 211 healthy individuals (20–94 years) as well as 28 subjects with clinically manifest AD (CDR = 1, Mini Mental State Examination [MMSE] = 21.7 ± 3.8, age = 77.8 ± 7.0) and 69 subjects with very mild/questionable AD (vmAD; CDR = .5, MMSE = 25.6 ± 3.5, age = 76.2 ± 7.2). Demographics and global neuropsychological profiles of the

Age-related GM Loss Within the BFCS

Results of the voxel-wise linear regression analysis between age and GM volume of the BFCS are shown in Figure 1. Significant age-related reductions of bilateral GM volume within the BFCS were detected throughout the ROI, including the vertical (Ch2) and horizontal (Ch3) limb of the DB as well as anterior, intermediate, and posterior parts of the NBM (Ch4). Peak effects of age-related volume decline are listed in Table S2 in Supplement 1. They corresponded to anterior lateral (Ch4al), medial

Discussion

Here we demonstrate age-related decline of BFCS GM volume that begins in early adulthood and is aggravated in advanced age. The effects of age on BFCS GM volume were preserved, even when effects of age on overall cerebral GM volume were taken into account. Although there is only slight evidence from structural in vivo neuroimaging studies so far (18), age-related decreases of BF cholinergic neuron number and size starting early in adult life have been reported by a range of postmortem studies

References (58)

  • R. Schliebs et al.

    The cholinergic system in aging and neuronal degeneration

    Behav Brain Res

    (2011)
  • M. Sarter et al.

    Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities [review]

    Neurobiol Aging

    (2004)
  • J. Mazère et al.

    In vivo SPECT imaging of vesicular acetylcholine transporter using [(123)I]-IBVM in early Alzheimer's disease

    Neuroimage

    (2008)
  • J. Barnes et al.

    A meta-analysis of hippocampal atrophy rates in Alzheimer's disease

    Neurobiol Aging

    (2009)
  • A.H. Nagahara et al.

    Long-term reversal of cholinergic neuronal decline in aged non-human primates by lentiviral NGF gene delivery

    Exp Neurol

    (2009)
  • S. Lehericy et al.

    Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease

    J Comp Neurol

    (1993)
  • P.L. McGeer et al.

    Aging, Alzheimer's disease, and the cholinergic system of the basal forebrain

    Neurology

    (1984)
  • E.K. Perry

    The cholinergic system in old age and Alzheimer's disease

    Age Ageing

    (1980)
  • P.J. Whitehouse et al.

    Alzheimer disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis

    Ann Neurol

    (1981)
  • M. Mesulam

    The cholinergic lesion of Alzheimer's disease: Pivotal factor or side show?

    Learn Mem

    (2004)
  • M.L. Gilmor et al.

    Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer's disease

    J Comp Neurol

    (1999)
  • P. Tiraboschi et al.

    The decline in synapses and cholinergic activity is asynchronous in Alzheimer's disease

    Neurology

    (2000)
  • S.T. DeKosky et al.

    Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment

    Ann Neurol

    (2002)
  • C. Geula et al.

    Cholinergic neuronal and axonal abnormalities are present early in aging and in Alzheimer disease

    J Neuropathol Exp Neurol

    (2008)
  • M. Mesulam et al.

    Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum

    Ann Neurol

    (2004)
  • I. Sassin et al.

    Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert

    Acta Neuropathologica

    (2000)
  • H. Hanyu et al.

    MR analysis of the substantia innominata in normal aging, Alzheimer disease, and other types of dementia

    AJNR Am J Neuroradiol

    (2002)
  • S. George et al.

    MRI-based volumetric measurement of the substantia innominata in amnestic MCI and mild AD

    Neurobiol Aging

    (2009)
  • G.M. Halliday et al.

    Quantitation and three-dimensional reconstruction of Ch4 nucleus in the human basal forebrain

    Synapse

    (1993)
  • Cited by (220)

    • The basal forebrain serves social information processing

      2024, Current Opinion in Behavioral Sciences
    View all citing articles on Scopus
    View full text