Anosognosia predicts default mode network hypometabolism and clinical progression to dementia

Abstract

Objective: To identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.

Methods: We stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [¹⁸F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [¹⁸F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia.

Results: We found that participants with impaired awareness had lower [¹⁸F]fluorodeoxyglucose uptake and increased [¹⁸F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [¹⁸F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame.

Conclusions: Our results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.

Figure 1. Determination of intact and impaired awareness groups

(A) Steps for determining intact and impaired awareness groups. The threshold for the discrepancy score that optimized sensitivity and specificity at differentiating between patients with Alzheimer disease (AD) and healthy controls is 0.5. (B) Receiver operating characteristic (ROC) curve displays sensitivity and specificity at distinguishing between patients with AD and healthy controls. (C) Distribution of participants with mild cognitive impairment (MCI) according to patient–caregiver discrepancy on everyday cognition (ECog). Patient–caregiver discrepancy scores lower than 0.5 indicate impaired awareness (red) and scores above 0.5 indicate intact awareness (blue). AUC = area under the curve.

Figure 2. Anosognosia in mild cognitive impairment is a clinical manifestation of Alzheimer disease (AD) pathophysiology

AD biomarker profiles of intact and impaired awareness groups, corrected for age, sex, years of education, and APOE ε4 status. Bars in the box and whisker plots display the 5th and 95th percentiles and the horizontal line shows the median. Bonferroni-corrected p values are displayed for each biomarker. For β-amyloid (Aβ) _1–42, lower scores indicate lower Aβ concentrations in CSF, thus indicating higher concentrations of brain Aβ. When employing Alzheimer’s Disease Assessment Scale–cognitive subscale scores as an additional covariate, only total tau remained significant (p = 0.03). p-tau = phosphorylated tau; SUVR = standardized uptake value ratio.

Figure 3. Regional differences in brain metabolism and amyloid deposition

T statistical parametric map corrected for multiple comparisons using random field theory at p < 0.001, overlaid on the Montreal Neurological Institute 152 reference template. (A) The impaired awareness group had greater [¹⁸F]florbetapir binding in the precuneus, posterior cingulate cortex, right lateral parietal, and lateral temporal cortical regions. (B) The impaired awareness group showed decreased [¹⁸F]FDG binding in the posterior cingulate cortex. Both these results remained significant when employing Alzheimer’s Disease Assessment Scale–cognitive subscale scores as a covariate.

Figure 4. Anosognosia predicts hypometabolism in neural structures vulnerable to Alzheimer disease

T statistical parametric map corrected for multiple comparisons using random field theory at p < 0.001, overlaid on the Montreal Neurological Institute 152 reference template. Patients with mild cognitive impairment in the impaired awareness group showed greater decline in [¹⁸F]FDG uptake in the posterior cingulate cortex/precuneus, basal forebrain, and medial temporal lobes at 24-month follow-up compared to patients in the intact awareness group. When employing Alzheimer’s Disease Assessment Scale–cognitive subscale scores as a covariate, decline in [¹⁸F]FDG uptake remained significant in the bilateral medial temporal lobes and the basal forebrain.