Hippocampal hypometabolism predicts cognitive decline from normal aging
Introduction
The development of biomarkers for the preclinical detection of neurodegenerative disease is a vital step in developing prevention therapies. Testing a candidate marker for Alzheimer's disease (AD) or other dementias requires monitoring normal healthy elderly longitudinally until they express the clinical symptoms and receive the ultimate diagnostic confirmation. A suitably sensitive biomarker must accurately predict the clinical endpoint and demonstrate correlated progression with the clinical course of the disease (Frank et al., 2003). The low incidence and slow progression of normal elderly to dementia (Petersen et al., 1999) has been a major obstacle in the design of studies to identify brain predictors of future cognitive impairment.
Positron emission tomography (PET) imaging with 2-[18F]fluoro-2-deoxy-d-glucose (FDG) is a candidate modality for detecting the preclinical stages of dementia by measuring reductions in the cerebral metabolic rate for glucose (MRglc). FDG-PET studies show that brain MRglc is consistently reduced in AD and other major neurodegenerative disorders, as well as in mild cognitive impairment (MCI), a condition at high-risk for developing dementia (Gauthier et al., 2006, Petersen et al., 1999), the extent of the metabolic reduction being related to disease severity (see Mosconi, 2005, Nestor et al., 2004 for review). However, very little work has been done with FDG-PET to study the transition from normal aging to AD and other dementing disorders. FDG-PET studies show reduced brain MRglc in normal individuals at genetic risk for late-onset AD (Reiman et al., 2004, Small et al., 1995), but there are no longitudinal follow up studies documenting decline to MCI or AD in these subjects. In a previous FDG-PET study we examined the decline from normal aging to MCI, and reported that baseline hypometabolism in the hippocampal formation, a known early target site for pathology (Ball et al., 1985), predicts an MCI diagnosis (de Leon et al., 2001). However, this initial study with a small sample size was limited by a single 3-year follow-up examination and to a clinical endpoint of MCI. Therefore, uncertainty remains as to whether the brain abnormalities detected were due to AD.
The present longitudinal FDG-PET study in normal elderly subjects examines regional brain MRglc as a predictor and correlate of cognitive decline from normal aging over 6–14 years (for a total of 561 person-years, mean per person 7.2 years). This study expands on our prior work by expanding the sample size from 23 to 77 longitudinally followed subjects, increasing the number of follow-ups, and observing 11 subjects developing dementia, 6 of whom diagnosed with AD with 2 post-mortem confirmed diagnoses. Using a newly developed automated hippocampal sampling procedure (Mosconi et al., 2005), we demonstrate that hippocampal MRglc is a sensitive preclinical predictor of future cognitive impairment, as well as a longitudinal correlate of the decline from normal aging.
Section snippets
Subjects screening and diagnostic examinations
In response to public announcements at the Center for Brain Health at the New York University (NYU) School of Medicine, after extensive baseline evaluations which were repeated at each successive follow-up, a longitudinal study in 77 normal (NL) elderly subjects was completed, which included medical (history, physical, and laboratory), neurological, psychiatric, neuropsychological, clinical MRI, and FDG-PET examinations. This study was embedded in an ongoing NYU longitudinal clinical project
Clinical and neuropsychological study
All 77 NL subjects received a baseline FDG-PET scan and at least two follow-up clinical evaluations during a total of 561 person-years of follow-up (mean per person 7.2 years). During this interval, 11/77 (14%) of the baseline NL subjects developed dementia, of whom 6 fulfilled criteria for probable AD (NL–AD). Of the other 5 decliners (NL–non-AD), 3 subjects developed vascular dementia, 1 subject Parkinson's disease and 1 subject Fronto-temporal dementia. Decline to MCI was observed in 19/77
Differences between outcome groups at baseline
The baseline hippocampal MRglc was reduced for all declining groups as compared to NL–NL [F(3,75) = 5.23, p = .002], with 20% reductions in the NL subjects that developed dementia (i.e., 26% reduced in NL–AD, p = .002, and 13% reduced in NL–non-AD, p = .04), and 15% reductions in NL–MCI (p = .01) (Table 1 and Fig. 1). Moreover, hippocampal MRglc was 15% lower in NL–AD as compared to NL–non-AD (p = .01) (Table 1 and Fig. 1). No significant differences were found between NL–AD and NL–MCI and between
Discussion
This FDG-PET study shows that reductions in hippocampal MRglc during normal aging predict future cognitive decline and that greater rates of hippocampal MRglc reductions correlate with the progression to late-onset AD and MCI. Our findings also show that reduced hippocampal MRglc is associated with a shorter duration of survival time as normal. These results suggest that reduced hippocampal MRglc in normal aging is a risk factor for cognitive decline, and suggest that this measure may serve as
Conflicts of interest
None.
Acknowledgments
This work was supported by the NIH-NIA grants AG12101, AG13616, AG08051 and AG022374, and NIH NCRR MO1RR0096. We thank Joanna Fowler, David Schlyer and Gene-Jack Wang at Brookhaven National Laboratory, Upton, NY, for their support of the PET studies, Schantel Williams and Ronit Notkin at NYU for study coordination and psychometric testing.
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