Neuropathologic features associated with basal forebrain atrophy in Alzheimer disease

Abstract

<jats:sec><jats:title>Objective:</jats:title><jats:p>To study the neuropathological correlates of cholinergic basal forebrain atrophy as determined using ante-mortem MRI in the Alzheimer’s disease (AD) spectrum.</jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p>We determined associations between basal forebrain (BF) volume from antemortem MRI brain scans and post-mortem assessment of neuropathological features, including neuritic plaques, neurofibrillary tangles (NFT), Lewy body (LB) pathology, and TDP-43, in 64 cases of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. For comparison, we assessed neuropathological features associated with hippocampal and parahippocampal gyrus atrophy. In addition to region of interest-based analysis, we determined the association of neuropathological features with whole brain grey matter volume using regionally unbiased voxel-based volumetry.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>BF atrophy was associated with Thal amyloid phases (95% confidence interval -0.49 - -0.01, p=0.049) and presence of LB pathology (95% CI -0.54 - -0.06, p=0.015), as well as with the degree of LB pathology within the Nucleus basalis Meynert (NbM) (95% CI -0.54 - -0.07, p=0.025). These effects were no more significant after false discovery rate (FDR) correction. Hippocampal atrophy was significantly associated with the presence of TDP-43 pathology (95% CI -0.61 - -0.17, p=0.003; surviving FDR correction), in addition to dentate gyrus NFT load (95% CI -0.49 - -0.01, p = 0.044; uncorrected). Voxel-based analysis confirmed spatially restricted effects of Thal phases and presence of LB pathology on BF volume.</jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p>These findings indicate that neuropathological correlates of regional atrophy differ substantially between different brain regions that are typically involved in AD-related neurodegeneration, including different susceptibilities to common co-morbid pathologies.</jats:p></jats:sec>

Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer’s disease spectrum

“…In the analysis of amyloid stratified subgroups, our results are in accordance with previous studies reporting significant volume loss in MCI + and ADD + ( Grothe et al, 2014 , Kerbler et al, 2015 , Teipel et al, 2014a ). Previous combined volumetric and amyloid-PET studies in MCI ( Grothe et al, 2014 , Kerbler et al, 2015 , Teipel et al, 2014a ) had suggested that cBF volumetry was strongly associated to amyloid burden and this was recently supported by evidence from an imaging-neuropathological association study ( Teipel et al, 2020 ). Therefore, we had expected a stronger connection of cBF volume to amyloid status even in preclinical cases.…”

“…Further studies suggested that in preclinical and prodromal stages of AD, cBF volume may be even more sensitive to early degenerative changes than hippocampal or entorhinal cortex atrophy ( Kilimann et al, 2014 , Schmitz et al, 2016 ). In vivo MRI-PET studies and a recent imaging-neuropathological association study suggest that cBF atrophy may be associated with cortical amyloid pathology in prodromal and dementia stages of AD ( Grothe et al, 2014 , Kerbler et al, 2015 , Teipel et al, 2020 ).…”

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

“…Associations between neuroimaging measures and clinical outcomes can rarely be expected to be strictly linear and will generally depend on the functional consequences of the neurodegenerative process that is indexed by the macro-and microstructural neuroimaging alterations. A recent imaging-neuropathology association study found that CBF volume on structural MRI correlated with the extent of Lewy body pathology in the nucleus basalis of Meynert, but not with semi-quantitative assessments of cell loss in this region [29]. This indicates that the neuroimaging measures may also pick up relatively subtle tissue changes in response to neurodegenerative pathology [30].…”

Basal forebrain parvalbumin neurons modulate vigilant attention

“…Thus, understanding the underlying neural substrates is important for developing treatments. The basal forebrain (BF) is a brain region which degenerates in dementia [5][6][7] and is implicated in the negative effects of sleep disruption on vigilance and cognition 8,9 . Previous studies demonstrated that the BF controls cortical fast oscillations that underlie attention [10][11][12] and revealed the important role of cholinergic neurons [13][14][15] .…”

“…Neurotoxic lesions of the BF impair attention in rodents 26,27 and in primates 28,29 . Furthermore, BF degeneration is associated with cognitive deficits, including attention, in Alzheimer's and Parkinson's dementias [5][6][7] . Deficits in attention caused by BF lesions in animals and cognitive deficits associated with dementias have generally been associated with loss of BF cholinergic neurons and their effects in the cortex 13,[30][31][32][33][34] .…”