Presented at the Brain99 Imaging Conference, June 1999. Journal of Cerebral Blood Flow and Metabolism, 19(Suppl 1):S4.

DOES THE ENTORHINAL PATHOLOGY EXPLAIN THE DISCORDANCE BETWEEN GLUCOSE METABOLIC AND PATHOLOGIC CHANGES IN VERY EARLY ALZHEIMER'S DISEASE?

S Minoshima, DK Kuhl, DJ Cross, HA Buchtel, PB Pennell, B Giordani, S Berent, NL Foster, DA Ross, TR Henry

Departments of Internal Medicine, Neurology, Psychiatry, Psychology, and Neurosurgery. The University of Michigan, Ann Arbor, Michigan, U.S.A.

INTRODUCTION: Recent pathologic examinations of early Alzheimer's disease revealed the occurrence of classic pathologic changes in the entorhinal cortex of the medial temporal lobe [1]. Energy metabolic studies of very early Alzheimer's disease and subjects at risk for Alzheimer's disease [2, 3], in contrast, consistently demonstrated initial metabolic changes in the posterior cingulate cortex and/or in the lateral neocortex. We hypothesized that this discordance may be explained by the disruption of the entorhinal output to the other limbic and association cortices caused by early Alzheimer's pathology and tested this hypothesis in humans using positron emission tomography.

METHODS: To characterize energy metabolic abnormalities in very early Alzheimer's disease, we recruited prospectively 23 patients with isolated memory impairment without general cognitive decline and followed up for 6.513.5 years (mean1SD). Initially, all subjects underwent positron emission tomography with [F-18]fluorodeoxyglucose. Ten patients progressed to probable or definite Alzheimer's disease (NINCDS-ADRDA criteria, age 7016 years, 3 females) during the follow up. The initial PET scans of these patients were compared to 10 normal controls of similar age (7014 years, 5 females). Then, we examined changes in the cerebral activity of 9 patients with left temporal lobe epilepsy (3017 years, 5 females) before and after (68117 days after surgery) left temporal lobectomy that removed the left hippocampus and a substantial portion of the entorhinal cortex. Cerebral activities were assessed using O-15 water PET techniques with non-cognitive non-emotional shape presentation to maintain the similar attentional level between sessions. All PET scans were transformed to the standard stereotactic coordinate systems and analyzed by statistical pixel-by-pixel and region-of-interest analyses with controlling multiple comparisons for pixels and regions. RESULTS: In very early Alzheimer's disease, significant metabolic reduction (p<0.05) was found in the posterior cingulate cortex (-19% as compared to normal controls) and in the parietal cortex (-15%) bilaterally. Statistical subtraction maps confirmed a severe reduction in the posterior cingulate and parietal cortices, but also moderate metabolic reduction (-9% to -11%) in the other lateral association cortices with relative sparing of the primary cortices and subcortical structures (-4% to -9%). In the epilepsy patients, the resection of the left mesiotemporal cortex significantly reduced cerebral activity in the left lateral temporal neocortex (-12%); the left thalamus (-4%); the left striatum (-6%); and posterior cingulate cortex bilaterally (-4%) in addition to severe metabolic deficit in the left hippocampus, amygdala, and anterior parahippocampal cortex consistent with resection. However, temporal lobectomy did not produce reductions in the lateral parietal association cortices (2% to 4% relative increase), right temporal association cortex (3%), frontal association cortex (2% to 4%). There was no pattern of preferential sparing of the primary cortices as was observed in very early Alzheimer's disease.

COMMENTS: The removal of the mesiotemporal cortex introduced reduction in cerebral activity in the posterior cingulate cortex that coincided with the area of metabolic reduction observed in very early Alzheimer's disease. These results may be supported by the evidence of neuronal connections between the entorhinal cortex and the posterior cingulate cortex [4] and by primary glucose consumption in the region of synapses instead of cell bodies [5]. However, the significant metabolic reduction in the lateral neocortex in very early Alzheimer's disease cannot be explained by pathologic deafferentation from the mesiotemporal lobe. These findings indicate the presence of global degenerative processes in very early Alzheimer's disease [6] that are not assessed by classic pathologic changes such as neurofibrillary tangles.

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