ASSOCIATIONS BETWEEN MEASURES OF MEDIAL TEMPORAL LOBE NEURODEGENERATION AND ANOSOGNOSIA FOR MEMORY DEFICITS

Abstract

Loss of insight of memory deficits, anosognosia, is a common feature of Alzheimer's disease (AD). The basis of this metacognitive disturbance remains elusive, although evidence points to compromised brain regions critical for self-referential processing (e.g., cortical midline regions) and recently also medial temporal lobe (MTL) structures such as the hippocampus (Perrotin et al., 2015, Vannini et al., submitted). Here we aimed to further our understanding of the relationship between memory awareness and neurodegeneration in the MTL region. Thus, using a multimodal approach we examined the associations among in vivo measures of MTL tau deposition, tissue volume in six hippocampal subfields (HCsf: CA1, CA2/3, CA4, DG, subiculum and presubiculum) and memory awareness in a cohort of cognitively normal to mildly memory-impaired individuals. 94 older individuals (76.3yrs, SD=6.9, CDR 0=76, CDR≥0.5=18) participated in the study. HCsf volumes (FreeSurfer6) were corrected for intracranial volume. Flortaucipir (FTP) binding in the entorhinal cortex (EC) was expressed in SUVR and cerebellar gray was used as reference (partial volume corrected). Memory-awareness was assessed by regressing each person's memory performance on their subjective memory ratings. Age, gender, education and depression scores were controlled for in each statistical model. Increased EC Tau was associated with significantly lower volumes in all HCsf except for CA2/3 where it was trending (p=.075). Increased EC Tau was also associated with decreased memory awareness r=-0.5, p<.001. Of the HCsf only the subiculum (r=0.4, p<.001) and CA1 (r=0.3, p=.004) demonstrated a significant association, such that lower volume was associated with decreased memory awareness. Last, subiculum volume was found to partially mediate the relationship between EC Tau and memory awareness (bias-bootstrapping 95% BCI, [-0.63,-0.02]), Sobel test t=-2.1, p=.036 (Fig.1). None of the other HCsf showed a significant mediation effect. A) Schematic representation of the direct effect. B) The subiculum partially mediates the relationship between entorhinal Tau binding and memory awareness. Standardized regression coefficients are presented: a=the association between EC Tau and subiculum volume, b=the association between subiculum volume and memory awareness adjusted for the effect of EC Tau on memory awareness, c'= the association between EC Tau and memory awareness adjusting for subiculum volume, and c=the direct association between EC Tau and memory awareness. Standardized regression coefficients are also presented for the mediation (a*b) effects. All analyses are corrected for age, education, gender and depression score. *p=0.05, ***p=0.001. Abbreviations: BCI=bias-corrected confidence interval (bootstrapped), EC = entorhinal cortex.