No abstract

Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI). However, it is still unknown if these alterations can be found in individuals with subjective cognitive decline (SCD), and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the AD continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 405 participants (53 AD, 66 MCI, 174 SCD, and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Longitudinal Cognitive Impairment and Dementia Study (DELCODE). We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fiber-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the AD continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was employed to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the AD continuum, including individuals with SCD. The differences involved posterior cholinergic white matter in the SCD stage and extended to anterior frontal white matter in MCI and AD dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e., MCI and AD dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing SCD from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the SCD and MCI stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in SCD individuals, preceding the more widespread alterations found in MCI and AD. The integrity of the cholinergic pathways identified the early stages of AD better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.

Objectives:Several pathological processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers towards the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals.Methods:The contribution of amyloid and tau pathology was assessed through cerebrospinal fluid (CSF) levels of the Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions on magnetic resonance imaging (MRI). Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE 𝜀4 carriership were also included in the analysis as variables of interest.Results:We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals 70 years old, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (Increase in mean square error (IncMSE)=98.8% in external capsule pathway and IncMSE=93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic white matter degeneration, especially in the external capsule pathway (IncMSE=28.4% and IncMSE=23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE 𝜀4 carriers showed poorer integrity in the cingulum pathway (IncMSE=21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE=21.55%), which was independent of amyloid status as reflected by the non-significant differences in integrity when comparing amyloid positive versus amyloid negative women participants (T201=-1.55; p=0.123).Conclusions:In cognitively unimpaired older individuals, WM lesions play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.