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INTRODUCTION: Degeneration of cortical cholinergic projections from the nucleus basalis of Meynert (NBM) is characteristic of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), whereas involvement of cholinergic projections from the pedunculopontine nucleus (PPN) to the thalamus is less clear. METHODS: We studied both cholinergic projection systems using a free water‐corrected diffusion tensor imaging (DTI) model in the following cases: 46 AD, 48 DLB, 35 mild cognitive impairment (MCI) with AD, 38 MCI with Lewy bodies, and 71 controls. RESULTS: Free water in the NBM‐cortical pathway was increased in both dementia and MCI groups compared to controls and associated with cognition. Free water along the PPN‐thalamus tract was increased only in DLB and related to visual hallucinations. Results were largely replicated in an independent cohort. DISCUSSION: While NBM‐cortical projections degenerate early in AD and DLB, the thalamic cholinergic input from the PPN appears to be more selectively affected in DLB and might associate with visual hallucinations. Highlights: Free water in the NBM‐cortical cholinergic pathways is increased in AD and DLB.NBM‐cortical pathway integrity is related to overall cognitive performance.Free water in the PPN‐thalamus cholinergic pathway is only increased in DLB, not AD.PPN‐thalamus pathway integrity might be related to visual hallucinations in DLB. [ABSTRACT FROM AUTHOR]

Background: The early degeneration of the cholinergic nucleus basalis of Meynert (NBM) and its cortical projections is a hallmark of both dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). In addition to the NBM, the other major cholinergic projection system originates in the pedunculopontine nucleus (PPN) and provides innervation to the thalamus. Given that visual hallucinations are a hallmark of DLB, but not AD, and have recently been attributed to thalamic degeneration, we tested whether the PPN projection system is differentially altered in DLB compared to AD. Methods: NBM‐cortical and PPN‐thalamus white matter pathways were tracked using diffusion‐weighted imaging data from 46 patients with AD, 48 with DLB, 35 with mild cognitive impairment (MCI) with AD, 38 with MCI with Lewy bodies, and 71 control participants. A free‐water corrected DTI model was estimated. Free water fraction along the cholinergic pathways was compared between groups controlling for age, sex, and free water fraction from a white matter control mask. Multiple linear regression was applied to test associations with cognitive function, core Lewy body symptoms with a focus on visual hallucinations, and changes in cognition using longitudinal follow‐up data. Results: Free water fraction in the NBM lateral pathway was increased in both dementia and MCI groups compared to controls and this was associated with performance on overall cognition and phonemic fluency tests as well as with longitudinal changes in cognition (Figure 1). Free water fraction along the PPN‐thalamus tract was increased only in DLB patients while it appeared relatively spared in AD and this increase in the Lewy body patients was related to the presence of visual hallucinations (Figure 2). These results were largely replicated in an independent validation cohort (34 AD, 34 DLB, 35 controls). Conclusion: Our cross‐validated findings show that the cholinergic input to the thalamus from the PPN is selectively affected in DLB and contributes to visual hallucinations. [ABSTRACT FROM AUTHOR]

Background: Predictive models of tau‐PET accumulation have largely relied on the functional connectome to estimate its spatial patterns in Alzheimer's disease (AD). Patterns of global functional organization represent a promising avenue as they encapsulate many biological properties relevant to neurodevelopment, cognition and degeneration. We compared approaches based on local connectivity (from task‐free fMRI) and global organization (from FDG‐PET) to predict regional tau‐PET across AD phenotypes. Method: We included 430 cognitively unimpaired (CU) individuals (214 A+T‐, 216 A+T+) and 62 amnestic mild cognitive impairment (aMCI), 64 amnestic AD, 21 dysexecutive AD (dAD), 41 logopenic progressive aphasia (LPA) and 49 posterior cortical atrophy (PCA) patients (all A+T+) from the Alzheimer's Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Groups (referred to as "Mayo cohort"). The connectivity approach consisted of assessing the relationship between a region's tau level and its functional connectivity to the region of highest tau (epicenter). The global organization approach consisted of 1) performing a principal component analysis on 3000 FDG‐PET images that did not overlap with the Mayo cohort, 2) projecting FDG‐PET images of the Mayo cohort onto the low‐dimensional space generated in Step 1 and extracting corresponding weighted values across the first 100 components, 3) using these weighted values as predictors of regional tau‐PET in a linear model and determining optimal parameters based on predicted R2 values, and 4) using the parameters from the model built in Step 3 to predict tau‐PET in the ADNI cohort (n = 86) (Fig.2). Result: The connectivity‐based approach yielded adjusted R2 values ranging from 0.19‐0.45 across diagnostic groups (Fig.1). The global organization approach yielded averaged adjusted R2 and predicted R2 values of 0.71 and 0.63, respectively, in the Mayo cohort. Out‐of‐sample median R2 in the ADNI cohort was 0.41 (range 0.10‐0.60) (Fig.3). Conclusion: An unbiased approach based on the global functional organization of the brain and using an imaging modality widely used in clinical settings outperformed a connectome‐based one to predict regional tau‐PET across the AD phenotypic spectrum. Patterns of tau accumulation may better relate to the large‐scale physiology of the brain underlying specific mental functions rather than local connectivity factors. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α‐synuclein aggregations, but many DLB cases show significant Alzheimer's disease (AD) pathology in the form of β‐amyloid and tau. Our first objective was to investigate the effect of AD co‐pathology on functional network failure in DLB. Secondly, we studied how the distribution of tau relates to functional connectivity in DLB. Method: Twenty‐three DLB, 23 age‐ and sex‐matched AD, and 90 cognitively unimpaired (CU) participants underwent AV1451 tau‐PET, Pittsburgh compound‐B (PiB) PET, and resting state (rs)‐fMRI scans. The rs‐fMRI data were used to calculate the Network Failure Quotient (NFQ), a marker of functional network failure within the default mode network. The NFQ was then correlated with overall cortical tau standardized uptake value ratio (SUVr). The strength of inter‐regional functional connectivity was assessed using the Schaefer100 atlas. Tau‐PET covariance was measured as the correlation in AV1451 SUVr between any two regions across participants. The association between region‐to‐region functional connectivity and tau‐PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot‐ and coldspot) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot‐ and coldspots. Result: Overall higher cortical tau‐PET uptake correlated with higher NFQ (i.e. greater functional network failure) in DLB who were PiB+ (N=14, ρ=0.60, p=0.02), but not in DLB who were PiB‐ (N=9, ρ=‐0.06, p=0.87). Higher functional connectivity between regions was associated with higher tau covariance in CU, AD, and DLB, independent of PiB status. Higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher AV1451 SUVRs in the target region whereas higher functional connectivity to the tau coldspot (i.e. sensory‐motor cortex) was related to lower AV1451 SUVr in the target region. Conclusion: Greater tau burden in DLB patients with β‐amyloid co‐pathology is associated with an AD‐like functional network failure. As previously demonstrated within the AD spectrum, functional connectivity may contribute to the spreading of tau across the brain also in DLB. [ABSTRACT FROM AUTHOR]