Objective: To examine whether the association between longitudinal cBF degeneration and cognitive decline in PD is mediated by parallel atrophy of cortical areas.

Background: Degeneration of the cortically-projecting cholinergic basal forebrain (cBF) is an early pathologic feature of both Alzheimer’s disease and Parkinson’s disease (PD) that associates with cognitive decline [1,2]. In AD, it has been shown that the effect of cBF degeneration on cognitive decline is mediated by parallel atrophy of the denervated cortical regions [1,3].Whether similar associations exist in PD and whether these depend on the presence of comorbid AD pathology is yet to be explored.

Method: We studied 162 de novo PD patients who underwent serial 3T MRI scanning within the Parkinson’s Progression Markers Initiative (average follow-up: 2.4±1.7 years). Gray matter volumes of the cBF and 34 bilateral cortical regions were automatically extracted using established procedures within SPM12. Individual slopes of MoCA score changes and regional volume changes were estimated from the serial measurements using linear-mixed models, controlled for age, sex, education, and intracranial volume (in case of volume changes). Associations between longitudinal cBF degeneration, cortical atrophy, and cognitive decline were assessed using Pearson correlations and mediation effects were assessed using Sobel’s test. Complementary analyses assessed associations between cBF degeneration and cortical atrophy separately for CSF amyloid-β-positive (N=57) and –negative (N=105) patient groups.

Results: Longitudinal cBF degeneration was highly correlated with parallel atrophy of specific cortical limbic and association areas, most notably the temporal and posterior medial cortices [figure1a]. Interestingly, significant associations were observed independent of amyloid-β status [figure1b,c]. The association between longitudinal cBF degeneration and decline in MoCA scores [figure2a] was significantly mediated by parallel atrophy of specific neocortical association areas [figure2b,c].

Conclusion: These findings establish a link between longitudinal atrophy of the cBF and cognition-relevant cortical areas in early-stage PD, which is largely independent of AD co-pathology.

References: [1] Grothe MJ, Heinsen H, Amaro E, Grinberg LT, Teipel SJ. Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment. Cereb Cortex. 2016;26:2411–26.
[2] Ray NJ, Bradburn S, Murgatroyd C, Toseeb U, Mir P, Kountouriotis GK, et al. In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson’s disease. Brain. 2018;141:165–76.
[3] Schmitz TW, Mur M, Aghourian M, Bedard MA, Spreng RN. Longitudinal Alzheimer’s Degeneration Reflects the Spatial Topography of Cholinergic Basal Forebrain Projections. Cell Rep [Internet]. ElsevierCompany.; 2018;24:38–46. Available from: https://doi.org/10.1016/j.celrep.2018.06.001

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-between-longitudinal-degeneration-of-the-cholinergic-basal-forebrain-and-cognition-relevant-cortical-areas-in-early-stage-pd/