Cholinergic Basal Forebrain Integrity and Cognition in Parkinson's Disease: A Reappraisal of Magnetic Resonance Imaging Evidence

Abstract

Cognitive impairment is a well-recognized and debilitating symptom of Parkinson's disease (PD). Degradation in the cortical cholinergic system is thought to be a key contributor. Both postmortem and in vivo cholinergic positron emission tomography (PET) studies have provided valuable evidence of cholinergic system changes in PD, which are pronounced in PD dementia (PDD). A growing body of literature has employed magnetic resonance imaging (MRI), a noninvasive, more cost-effective alternative to PET, to examine cholinergic system structural changes in PD. This review provides a comprehensive discussion of the methodologies and findings of studies that have focused on the relationship between cholinergic basal forebrain (cBF) integrity, based on T1- and diffusion-weighted MRI, and cognitive function in PD. Nucleus basalis of Meynert (Ch4) volume has been consistently reduced in cognitively impaired PD samples and has shown potential utility as a prognostic indicator for future cognitive decline. However, the extent of structural changes in Ch4, especially in early stages of cognitive decline in PD, remains unclear. In addition, evidence for structural change in anterior cBF regions in PD has not been well established. This review underscores the importance of continued cross-sectional and longitudinal research to elucidate the role of cholinergic dysfunction in the cognitive manifestations of PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; Parkinson's disease dementia; cholinergic basal forebrain; cholinergic system; cognition.

FIG. 1

Cholinergic basal forebrain (cBF) position and structure. (a, b) In vivo cholinergic basal forebrain atlas, as defined by Kilimann et al., displayed here on Montreal Neurological Institute (MNI) 152 template brain. cBF regions: cyan, Ch1‐2; yellow, Ch3; blue, lateral extension of anterior Ch4; red, anterior and intermediate Ch4; green, posterior Ch4. (c) A computer‐assisted three‐dimensional reconstruction of Ch clusters of the basal forebrain after gallocyanin staining postmortem is shown: green, Ch2; yellow, Ch3; gray, anteromedial‐anterolateral Ch4; red, intermediate Ch4; black, posterior Ch4; pink, juxta‐commissural cells. Ch1 is not shown. (Reproduced from Grinberg and Heinsen CC BY 4.0 DEED.) (d–f) Postmortem formalin‐fixed, paraffin‐embedded nucleus basalis of Meynert (NBM) sections stained with choline acetyltransferase (ChAT) immunohistochemistry and arranged rostrally to caudally starting from the most caudal aspect of the anterior commissure. Cholinergic neurons are shown in the anterior (d), intermediate (e), and posterior (f) divisions of the NBM. (Reproduced from Liu et al. CC BY.) [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Pathways connecting the nucleus basalis of Meynert (NBM) and the cortex. (a) The main cholinergic pathways in the left hemisphere based on observations by Selden et al and Hong and Jang. Green, medial cholinergic pathway; red, capsular division of the lateral cholinergic pathway; yellow, perisylvian division of the lateral cholinergic pathway; A, amygdala; AC, anterior commissure (lateral aspect); C, caudate; Cg, cingulate gyrus; F, frontal lobe (medial surface); GPi, globus pallidus (internus); IN, insular cortex; NBM, nucleus basalis of Meynert; Oc, occipital lobe (medial surface); OF, orbitofrontal cortex; P, putamen; Pr, parietal lobe (medial surface). The coronal section is presented approximately 6 mm posterior to the midpoint of the anterior commissure. (Reprinted from Neuroscience and Biobehavioral Reviews, 37(10), Gratwicke, J., Kahan, J., Zrinzo, L., Hariz, M., Limousin, P., Foltynie, T., Jahanshahi, M., The nucleus basalis of Meynert: A new target for deep brain stimulation in dementia? pp. 2676–2688, Copyright (2013), with permission from Elsevier.) (b) Tracks from the right NBM, to all right hemisphere cortical regions, modeled using probabilistic diffusion tractography (via constrained spherical deconvolution [MRtrix3 ³⁵ ]). Colors indicate fiber orientation: red, left–right; blue, superior (sup.)–inferior (inf.); green, anterior (ant.)–posterior (post.). Med., medial. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 3

Summary of postmortem histological evidence and anticipated changes in PD with mild cognitive impairment (PD‐MCI) of Ch4 neuron and projection integrity in PD. Adapted from Pepeu et al. Created with BioRender. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 4

Representations of cholinergic basal forebrain atlases in a multiplanar view of the Montreal Neurological Institute (MNI) 2009c asymmetric template (y = 5 mm; z = −25 mm). (a) As defined in the SPM Anatomy Toolbox, , , : green, Ch1‐2‐3; blue, Ch4. (b) As defined by Kilimann et al: green, Ch1‐2; blue, Ch3; red, Ch4. (c) Purple, Ch1‐2; cyan, Ch3‐4. (Reproduced from Gargouri et al. CC BY 4.0 DEED.) (d) As defined by Fritz et al: cholinergic basal forebrain as one region (orange). [Color figure can be viewed at wileyonlinelibrary.com]