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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.

Background Recent advances in the neuroimaging field have rekindled the interest for the human cholinergic system. As the widespread projections from the basal forebrain to the cortex play an important role in learning, memory and other cognitive processes that are significantly impaired in disorders such as Alzheimer’s disease, Dementia with Lewy Bodies, and Vascular Dementia, it is favourable to assess the affected pathways and cortical regions in vivo. However, research is still limited and different imaging modalities need to be combined to advance our current understanding of the complex interplay between anatomical, functional and physiological features of the human brain cholinergic system. We developed an advanced framework using deterministic fibre‐tracking methods using diffusion‐tensor imaging (DTI), and partitioning of the human basal forebrain on T1‐weighted structural MRI data supported by resting‐state functional MRI (rs‐fMRI) data. Method A total of 197 cognitively healthy individuals were recruited. The rs‐fMRI, DTI, and T1 data were processed with MRtrix3, DPARSFA, and SPM12 in order to track pathways rising from basal forebrain subdivisions towards rs‐fMRI identified cortical areas. Result We identified two functionally relevant subdivisions of the basal forebrain by clustering based on functional connectivity characteristics. The resulting subdivisions resemble cytoarchitectonically defined subdivisions as revealed by stereotactic mappings. Distinct white matter tracts originated from individual basal forebrain subdivisions towards cortical cholinergic areas, each of which showed differential associations with relevant cognitive functions. Conclusion Here we present a novel method of combination of MRI‐based techniques to assess and visualize the human cholinergic system in vivo. The ability to functionally subdivide the basal forebrain and model cognitive‐specific cholinergic pathways and cortical cholinergic areas opens new opportunities to investigate Alzheimer's disease and other neurodegenerative diseases with cholinergic involvement, with possible diagnostic and prognostic use.

Background To determine the contribution of amyloid pathology and tau pathology in combination with cerebrovascular pathology, towards the neurodegeneration of the cholinergic white matter projections. Method We included a sample of 203 cognitively unimpaired individuals derived from the H70 Gothenburg Birth Cohort Studies (all of them 70‐years‐old, 51% female). Amyloid (A) and tau (T) pathology were determined by cerebrospinal fluid levels of Amyloid‐β42/40 ratio, Amyloid‐β38 and phosphorylated tau. Cerebrovascular pathology (V) was determined by automatically segmented white matter lesions detected in magnetic resonance imaging (MRI). Cholinergic white matter projections (i.e. cingulum pathway and external capsule pathway) were modelled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis. To assess association of the markers with the integrity of cholinergic projections we used random forest regression Result white matter lesion burden was the most important contributor towards the neurodegeneration of both cholinergic pathways (figure 1). Levels of Amyloid‐β38 and phosphorylated tau also contributed to the cholinergic pathways, especially to the external capsule pathway. Amyloid‐β42/40 ratio levels and APOE ε4 carriership did not show substantial contribution. Females showed poorer integrity in the external capsule pathway. Conclusion Underlying cerebrovascular disease (V) in cognitively unimpaired elderly plays a central role in the neurodegeneration (N) of the cholinergic pathways to the cerebral cortex. Future research should elucidate the impact of cerebrovascular pathology to the cholinergic disruption and cognitive impairment in pathological populations.

Background: Neurodegeneration of cholinergic pathways may be present in individuals with subjective cognitive decline (SCD). However, variability between SCD individuals in the integrity of cholinergic pathways needs to be elucidated. Our objective was to determine characteristics of neurodegeneration of cholinergic pathways in different SCD subtypes (i.e. amnestic vs. non-amnestic). Method: Individuals with amnestic SCD (n = 47), non-amnestic SCD (n = 38), and healthy controls without cognitive complaints (HC; n = 20) from the GENIC database were included (all: >60 years old; 58% females). White matter integrity was estimated by mean diffusivity (MD) on diffusion tensor imaging (DTI) for cingulum and external cholinergic pathways. Both pathways were previously modelled using tractography on DTI. Memory performance was measured based on Visual reproduction WMS-III and TAVEC (the Spanish version of the California Verbal Learning Test, CVLT). ANOVA and bivariate Pearson correlation were used for the statistical analysis. Result: Amnestic and non-amnestic SCD groups were comparable to HC in the integrity of cholinergic WM pathways. Bivariate Pearson correlation analyses showed different patterns of association between the cholinergic pathways and cognition within each group. In amnestic-SCD, worse WM integrity in both cholinergic pathways was associated with poorer immediate recall of visual information (external capsule: r xy = -0.42; p<0.05; cingulum: r xy = -0.34; p<0.05). In non-amnestic-SCD, worse WM integrity in both cholinergic pathways was associated with poorer delayed recall of verbal information (external capsule: r xy = -0.54; p<0.05; cingulum: r xy = -0.42; p<0.05); and worse WM integrity in the external capsule pathway was associated with poorer performance in immediate and delayed recall of visual information (r xy = -0.37; p<0.05 and r xy = -0.46; p<0.05). In HC, none of the cognitive outcomes was associated with the integrity of the cholinergic pathways. Conclusion:The cholinergic pathways were mainly associated with immediate recall in the amnestic SCD (i.e. acquisition of new information); whereas in non-amnestic SCD the integrity of cholinergic pathways was associated with several subcomponents of memory performance (i.e. acquisition and recall of new information). Thus, SCD sub-