Hippocampal hypometabolism predicts cognitive decline from normal aging

Abstract

Objective: This longitudinal study used FDG-PET imaging to predict and monitor cognitive decline from normal aging.

Methods: Seventy-seven 50-80-year-old normal (NL) elderly received longitudinal clinical examinations over 6-14 years (561 person-years, mean per person 7.2 years). All subjects had a baseline FDG-PET scan and 55 subjects received follow-up PET exams. Glucose metabolic rates (MRglc) in the hippocampus and cortical regions were examined as predictors and correlates of clinical decline.

Results: Eleven NL subjects developed dementia, including six with Alzheimer's disease (AD), and 19 declined to mild cognitive impairment (MCI), on average 8 years after the baseline exam. The baseline hippocampal MRglc predicted decline from NL to AD (81% accuracy), including two post-mortem confirmed cases, from NL to other dementias (77% accuracy), and from NL to MCI (71% accuracy). Greater rates of hippocampal and cortical MRglc reductions were found in the declining as compared to the non-declining NL.

Conclusions: Hippocampal MRglc reductions using FDG-PET during normal aging predict cognitive decline years in advance of the clinical diagnosis. Future studies are needed to increase preclinical specificity in differentiating dementing disorders.

Figure 1

Pons-adjusted baseline hippocampal (Hip) and posterior cingulate cortex (PCC) glucose metabolism (μmol/g/min) by outcome group. Symbols: NL-NL (black squares), NL-MCI (white circles), NL-AD (black circles), and NL-non AD (white diamonds).

Figure 1

Pons-adjusted baseline hippocampal (Hip) and posterior cingulate cortex (PCC) glucose metabolism (μmol/g/min) by outcome group. Symbols: NL-NL (black squares), NL-MCI (white circles), NL-AD (black circles), and NL-non AD (white diamonds).

Figure 2

Hippocampal glucose metabolism and the risk for Alzheimer’s disease (AD). Weibull survival regression curves of normal subjects whose hippocampal (Hip) metabolism (MRglc, μmol/g/min) at baseline was ≤24 (bold line), 25–29 (plain line), and ≥30 (dashed line). The prediction model shows that for baseline Hip MRglc ≤24 μmol/g/min the median predicted time to decline to AD is 7 years, for baseline Hip MRglc 25–29 μmol/g/min the median predicted time to decline to AD is 9.5 years, and for baseline Hip MRglc ≥30 μmol/g/min the median predicted time to decline to AD is greater than 14 years. The median estimated time to decline to AD for each tertile of Hip MRglc is indicated with dashed arrows.

Figure 3

Individual trajectories of Hip glucose metabolism (μmol/g/min, pons-adjusted, atrophy corrected values) derived from the mixed effects model are plotted relative to the time of the first PET examination for NL-NL (black squares), NL-MCI (white circles), and NL-AD (black circles).

Figure 4

Cortical MRglc reductions in NL-AD (Upper half) and NL-MCI (Lower half) at the time of decline relative to NL-NL. Areas of hypometabolism relative to NL-NL (represented on a red to yellow color coded scale) are displayed onto the left medial and left lateral views of a volume-rendered spatially normalized MRI image.

Figure 5

Longitudinal FDG-PET scans of one subject (female, baseline age: 73 years, education: 12 years, baseline MMSE: 30/30) that declined from NL (in 1991) to MCI (1994), and then to AD (1997), and had the AD diagnosis confirmed at post-mortem (2000). Axial mages are displayed in a negative-angulation running parallel to the hippocampal plane. The scans show progressive hippocampal (red arrows) and temporal cortex (white arrows) metabolic reductions.

Figure 6

Predicted origin of divergence and differentiation in hippocampal (Hip) glucose metabolism between clinical outcome groups. Bold arrows indicate the estimated time of the first significant reductions in Hip metabolism in the decliners as compared to NL-NL, which was 6 years before the baseline PET for NL-AD and 5 years before the baseline PET for NL-MCI.