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Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4hydroxyphenylethyleneglycol (MHPG), A beta 42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of A beta 42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes. (C) 2021 The Authors. Published by Elsevier Inc.

Introduction: Dorsal pathway dysfunctions are thought to underlie visuospatial processing problems in Alzheimer disease (AD). Prior studies reported compensatory mechanisms in the dorsal or ventral pathway in response to these functional changes. Since functional and structural connectivity are interrelated, these functional changes could be interpreted as a disconnection between both pathways. To better understand functional alterations in the dorsal pathway, we combined functional imaging with diffusion tensor imaging (DTI) in patients with mild cognitive impairment (MCI), a likely prodromal stage of AD. Methods: Eighteen older male individuals with amnestic MCI (aMCI) and 18 male cognitively healthy individuals, matched for age (range 59-75 years) and education, performed an object recognition task in the Magnetic Resonance Imaging (MRI) scanner. Neural activation was measured during recognition of non-canonically versus canonically oriented objects. Regions showing activation differences between groups were also investigated by DTI. Results: Recognition of non-canonical objects elicited increased frontal, temporal and parietal activation. Combining the functional MRI (fMRI) with the DTI results showed less deactivation in areas with decreased diffusion (mediolateral parietal and orbitofrontal) and increased activation in areas with increased diffusion (parietal and temporal) in aMCI patients. Finally, in aMCI patients decreased diffusion was found in the hippocampal cingulum, connecting both pathways. Conclusions: Our results showed increased activation in early AD patients in ventral and dorsal pathways. A decrease in deactivation and diffusion suggests functional reorganization, while increased activation and diffusion suggests compensatory processes. This is the first study showing structural evidence for functional reorganization, which may be related to connectivity loss in the cingulum. (C) 2012 Elsevier Ltd. All rights reserved.