Although neuropsychological impairment, reduced cerebral activity, brain atrophy, and cerebrospinal fluid abnormalities are known to occur in "healthy elderly controls" who subsequently progress to dementia, comparisons of neuropsychological tests with biomarkers remain relatively rare in follow-up studies of healthy subjects. In order to make these comparisons in larger samples, studies designed to predict the evolution from the pre-dementia to the dementia stage of AD must be reviewed. Such studies try to predict which subjects, among those classified as "mild cognitive impairment" (MCI) or "questionable AD" convert to the diagnosis of AD. Eric Salmon, MD, PhD, of the University of Liège (Belgium) reviewed such comparative studies in a plenary session presentation at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease, held in Vienna, Austria.
Dr. Salmon performed a literature review for support or refutation of three hypotheses. Hypothesis one posits that biomarkers are more useful than neuropsychological assessment in predicting conversion from MCI to AD. Hypothesis two argues that neuropsychological assessment is more useful than biomarkers for the same prediction. Hypothesis 3 suggests that there are significant advantages in the use of a combination of markers.
Studies supporting each of the hypotheses were identified. Three reported that hippocampal atrophy or temporoparietal hypometabolism are slightly better predictors of evolution from MCI to AD than neuropsychological tests. A recent study in a large population of MCI subjects found that a combination of neuropsychological tests was superior to neuroimaging, while another showed that neuropsychological variables were better predictors than ApoE status. Four studies showed that a combination of medial temporal atrophy and cognitive impairment or a combination of brain activity and neuropsychological tests provided the most accurate classification of converters and non-converters.
Most (but not all) studies showed that neuropsychological variables remain important predictors of evolution to dementia, even in populations where neuroimaging or other biomarkers are available. Neuropsychological tests are particularly sensitive to the early "changes of mind" that precede AD or even MCI. Decreased verbal fluency were observed 12 years before the diagnosis of AD was made in one study, and declines in episodic memory, executive function, and semantic knowledge were observed two years before the diagnosis of MCI in another study.
Long-term memory remains the best neuropsychological predictor, and it is frequently associated with a measure of global cognition. However, combinations of neuropsychological tests are needed because a single test cannot fully evaluate subtle changes in networks. The best test for the detection of MCI is not necessarily the best test for the detection of progression from MCI to AD. Moving forward, it is anticipated that refinements will be made in neuropsychological variables, as they will be in neuroimaging and other biomarkers.
[N.B.: The superiority of the combination of biomarkers and neuropsychological tests was apparent in an ICAD press conference presenting results from ADNI studies of early detection of AD. Two of the three studies included a neuropsychological test along with an imaging biomarker as part of the most accurate assessment protocol. The third study did not evaluate neuropsychological tests.]