Elsevier

NeuroImage

Volume 42, Issue 4, 1 October 2008, Pages 1267-1274
NeuroImage

Hippocampal hyperperfusion in Alzheimer's disease

https://doi.org/10.1016/j.neuroimage.2008.06.006Get rights and content

Abstract

Many of the regions with the earliest atrophy in Alzheimer's Disease (AD) do not show prominent deficits on functional imaging studies of flow or metabolism. This paradox may provide unique insights into the pathophysiology of AD. We sought to examine the relationship between function and atrophy in AD using MRI blood flow and anatomic imaging. 22 subjects diagnosed with AD, mean Mini Mental State Exam (MMSE) score 22.2, and 16 healthy elderly controls were imaged with a volumetric arterial spin labeling blood flow MRI technique and an anatomical imaging method using the identical spatial resolution, image orientation, and spatial encoding strategy. Cerebral blood flow (CBF) and gray matter (GM) maps derived from the imaging were transformed to a standard anatomical space. GM and CBF maps were tested for significant differences between groups. Additionally, images were tested for regions with significant mismatch of the CBF and GM differences between groups. CBF was significantly lower in the bilateral precuneus, parietal association cortex and the left inferior temporal lobe but was non-significantly increased in the hippocampus and other medial temporal structures. After correction for GM loss, CBF was significantly elevated in the hippocampus and other medial temporal structures. The hippocampus and other regions affected early in AD are characterized by elevated atrophy-corrected perfusion per cm3 of tissue. This suggests compensatory or pathological elevation of neural activity, inflammation, or elevated production of vasodilators.

Introduction

Noninvasive imaging offers several advantages as a tool for the characterization of AD pathology. Imaging can provide an unbiased sampling of pathology throughout the entire brain and highlight its anatomic distribution and evolution over time. Noninvasive imaging is particularly well suited for measurement of indicators of tissue function, including metabolism and blood flow, which are difficult or impossible to determine postmortem. Finally, noninvasive imaging can be performed repeatedly in subjects making it ideal for diagnosing the disease at its earliest stages, characterizing progression of disease, and testing potential disease-modifying therapies.

Imaging studies in AD to date have been very successful at demonstrating early loss of tissue and metabolism in the disease. High resolution imaging of the brain with Magnetic Resonance Imaging (MRI) has highlighted the early and severe loss of tissue in the hippocampus (Jack et al., 1999), entorhinal cortex (Juottonen et al., 1998, Killiany et al., 2000), and some cortical areas (Baron et al., 2001, Chetelat et al., 2002, Killiany et al., 2000). Metabolic imaging with Positron Emission Tomography (PET) (Friedland et al., 1983, Reiman et al., 1996, Small et al., 1995) and blood flow imaging with PET and Single Photon Emission Computed Tomography (SPECT)(Bonte et al., 2001, Johnson et al., 1998) have highlighted loss of activity in temporal, parietal, and frontal association cortex, along with posterior cingulate cortex and precuneus.

More detailed inspection of the imaging studies, however, suggests regional differences in pathology. While medial temporal regions suffer devastating volumetric and neuronal loss, the presence of decreased metabolism is so difficult to detect that it is controversial, even without correction for reduced tissue volume (De Santi et al., 2001, Ishii et al., 1998a, Ishii et al., 1998b, Jagust et al., 1993, Matsuda et al., 2002a, Matsuda et al., 2002b, Mevel et al., 2007, Rodriguez et al., 2000). To further explore abnormalities of anatomy and function in the medial temporal lobes and other regions, we employed a whole-brain MRI technique for measurement of blood flow (Alsop and Detre, 1998, Alsop et al., 2000, Johnson et al., 2005, Sandson et al., 1996, Williams et al., 1992) in combination with anatomic MRI measures for imaging of patients diagnosed with probable AD and age matched controls.

Section snippets

Methods

Studies were performed on 22 patients and 16 age matched control subjects. 21 of the patients were clinically diagnosed with probable Alzheimer's disease at the time of imaging and met NINCDS-ADRA criteria (McKhann et al., 1984) for the diagnosis. The remaining patient was diagnosed with Mild Cognitive Impairment (MCI) (Petersen et al., 1999) at the time of imaging but was subsequently clinically diagnosed with AD 18 months after imaging. All subjects were studied following a protocol approved

Results

All 22 subjects diagnosed with AD and 16 controls successfully completed the study. A summary of subject information and cognitive testing performance is shown in Table 1. To determine changes with disease progression, a spectrum of patients from mild to severe disease were included, but the group was predominately mild, as indicated by the median MMSE of 24.

ASL CBF images of acceptable quality were obtained in all subjects. In the patients, temporo-parietal hypoperfusion was apparent in most

Discussion

While our results largely confirm prior functional imaging and atrophy studies, these combined results emphasize the elevation of blood flow in the hippocampus even early in Alzheimer's disease. While most prior studies using PET or SPECT for the measurement of blood flow have not highlighted this phenomenon, our findings are not irreconcilable. Most PET or SPECT flow studies do not correct for the severe atrophy which occurs in the medial temporal lobes early in the disease (Bonte et al., 2001

Acknowledgments

This work was supported in part by a research grant from the Alzheimer's Association, and by the National Institutes of Health through grants AG19599, MH65434, and NS047431.

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