Multi‐modal Neuroimaging Phenotyping of Mnemonic Anosognosia in the Aging Brain

Abstract

AbstractBackgroundMnemonic anosognosia (i.e., unawareness) is a behavioral condition characterized by a lack of self‐awareness of objective memory decline. In the context of Alzheimer’s Disease (AD), unawareness may be a sign of predementia stages. It contributes to disease severity, symptomatology worsening, and caregiver burden and is a good predictor of clinical progression. Here, we use in‐vivo multi‐modal neuroimaging to profile the brain phenotype of individuals presenting altered self‐awareness of memory during aging.MethodsWe used amyloid‐ and tau‐PET (N = 335) and resting‐state fMRI (N = 713) data of individuals from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies (Table1A). The neurocognitive profile of unawareness was characterized using between‐groups comparisons (omnibus and post‐hoc analyses) of the objective (LM delayed memory, and FCSRT free and cued scores) and subjective (MACQ) memory measurements of individuals classified as unaware of their memory impairment, compared to aware, subjective‐complainers and control individuals. To characterize the cortical burden of amyloid and tau and their modulatory effect on functional connectivity networks, we applied whole‐brain voxel‐wise GLM analyses, region‐of‐interest associations, and graph‐theory metrics (e.g., degree centrality).ResultsUnaware and aware individuals perform worse than the control group in objective memory tests, while unaware individuals differ from aware but not from controls in MACQ (Table1B). The unaware group presents elevated amyloid and tau burden in midline core regions of the default mode network (DMN) compared to aware, complainer or control individuals (p‐value<0.05) (Figure1AB). Tau spreading in controls showed significant connectivity toward DMN and lateral and medial occipito‐parietal regions (Figure1C). Unawareness is characterized by an altered network connectivity pattern modulated by tau accumulation in which hyperconnectivity is observed mainly in midline DMN and posterior occipito‐parietal regions (p‐value<0.05) (Figure2A). Degree centrality revealed the main connectivity hubs altered by tau deposits in unaware individuals (e.g., posterior regions) (Figure2B).ConclusionsMnemonic anosognosia is an early behavioral biomarker of AD pathology. Unawareness of memory decline leads to distinct brain phenotype, characterized by increased amyloid and tau burden, along with functional network connectivity disruptions, in several areas of the self‐referential brain network, including the posterior cerebral cortex of the human brain.