Two Different Hippocampal Measures Predict Verbal Memory Ability in Nondemented Older Adults
Possible Biomarkers for Mild Cognitive Impairment and Alzheimer Disease
ARTICLE IN BRIEF
Hippocampal aspartate/creatine ratio and hippocampal accounted for 30 percent of the variance in performance on standardized measures of verbal memory recall.
Hippocampal aspartate/creatine ratio and hippocampal volume both appear to independently predict verbal memory ability in nondemented older adults.
The two variables accounted for 30 percent of the variance in performance on standardized measures of verbal memory, particularly on a test involving immediate recall, according to an April 29 report in Neurology.
The finding of a relationship between verbal memory ability and hippocampal metabolism is important because it suggests a biological marker for memory impairment that may be more sensitive — and occur earlier — than decreases in hippocampal volume.
“Many studies have examined the volume of the hippocampus and shown that as volume decreases, memory performance declines,” said study author Molly E. Zimmerman, PhD, of Albert Einstein College of Medicine. “But decreases in volume may not be the most sensitive measure of hippocampal function.”
Hippocampal volume may decrease when neurons or glial cells die or when blood volume is reduced. And during the early onset of Alzheimer disease (AD), neurons may survive but function poorly.
“We hypothesized that poor neuronal function might predict memory performance and future dementia more sensitively than changes in volume that arise later,” Dr. Zimmerman said.
STUDY METHODS, FINDINGS
Between February 2004 and August 2006, a subset of 48 older adults was drawn from the Einstein Aging Study, a community-based volunteer sample of Bronx, NY, residents over the age of 70 years.
Volumetric measurements of the hippocampus and the intracranial midsagittal area were performed using MRI to account for individual differences in head size. MR spectroscopy (MRS) was used to ascertain n-acetyl-aspartate/creatine (NAA/Cr) levels, a measure of the number of functioning neurons.
“Reductions of NAA occur if neurons die or if they become less efficient in terms of metabolism,” Dr. Zimmerman explained. “This may be indicative of neurodegeneration during the preclinical onset of Alzheimer disease. Creatine is a marker of biochemical energy reserves of glia and neurons and is presumed to be stable, even in areas of pathology. We therefore use creatine content as a control for the metabolic ration of NAA/Cr.”
Neuropsychological evaluations were conducted to test verbal memory (including the Buschke and Grober Free and Cued Selective Reminding Test-Immediate Recall and Wechsler Memory Scale-Revised Logical Memory subtest) and attention and executive function (Trail Making Tests Parts A and B).
The investigators found that hippocampal NAA/Cr and volume independently and significantly predicted performance on the test of immediate recall (the Free and Cued Selective Reminding Test-Immediate Recall.) [See Figures 1 and 2.]
“The fact that our measure of metabolism (NAA/Cr ratio) is an independent predictor of memory performance, even after taking volume into account, supports our hypothesis that metabolic decline precedes cell death as a more sensitive indicator of dysfunction in the hippocampus,” Dr. Zimmerman told Neurology Today.
Moreover, the measures seem to be specific for verbal memory recall, because hippocampal volume and NAA/Cr were not significantly related to other cognitive measures of attention or executive function.
“These results have important clinical implications for an enhanced understanding of the biological substrates of age-related memory changes,” Dr. Zimmerman said. “In the long-term, they may improve patient care through identification of potential biomarkers of preclinical changes in cognitive abilities.”
She said longitudinal studies are needed to examine age-associated change in neuronal metabolism and to see if MRS measures are predictive of future cognitive decline in nondemented elderly.
ADVANCE IN EARLY PREDICTION OF ALZHEIMER DISEASE
Ronald C. Petersen, MD, PhD, director of the Mayo Clinic's Alzheimer's Disease Clinic, said the study findings advance the effort toward early prediction of mild cognitive impairment and Alzheimer disease.
“What this paper demonstrates is the complementary nature of structural imaging and neurochemical measurements in the hippocampus and their relationship to performance on the test of immediate recall,” Dr. Petersen said. “This is important work that moves the field in the direction of early prediction. Hopefully, we will be able to marry predictors with disease-modifying strategies in an attempt to prevent the damage being done to the hippocampus.”
Dr. Petersen noted that he and colleagues at Mayo published a report in the July 2000 Neurology that another metabolic marker—specifically, a rise in the myoinsotol/creatine ratio — also predicts cognitive impairment and shows up earlier than the decline in NAA/CR ratio.
Dr. Petersen said what is likely to emerge over time is not a single definitive biomarker for prediction of cognitive impairment, but a panel of markers independently associated with cognitive decline that will add incrementally to the risk for memory loss.
“They may include genetic characteristics, neuroimaging markers, biochemical markers, or a combination plus subtle performance measures,” he told Neurology Today. “Each is going to add a little independent predictor to refine the final probability for cognitive impairment or Alzheimer disease.”