ObjectiveTo identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.

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We studied the efficacy and safety of oral tetrahydroaminoacridine (THA) combined with lecithin in 52 patients with Alzheimer's disease. The maximal tolerated dose of THA (up to 100 mg per day) was determined during an eight-week titration period, after which the tolerated dose of THA or placebo was given during two sequential randomized periods of treatment lasting eight weeks each. Highly purified lecithin (4.7 g per day) was administered during all phases of the study. Efficacy was expressed in terms of scores on the Mini-Mental State (MMS) test, the modified MMS test, the Hierarchic Dementia Scale, the Rapid Disability Rating Scale-II, and the behavioral scale of Reisberg et al. Safety was assessed by careful clinical monitoring as well as serial measurements of liver aminotransferases. Forty-six patients completed the titration period, and 39 completed the double-blind period, during which only the MMS score showed a small but significant increase (P less than 0.05) after four weeks of treatment with THA. Autonomic side effects of THA were common but mild. Reversible elevations of serum aspartate and alanine aminotransferase levels to three or more times the upper limit of normal occurred in 17 percent of patients; most of the patients affected were women. A liver biopsy performed in one patient showed resolving focal liver-cell necrosis. These studies fail to demonstrate a significant clinical benefit of THA given orally in a maximal dose of 100 mg per day over a period of eight weeks in combination with lecithin.

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