Large-Scale Functional Brain Network Abnormalities in Alzheimer’s Disease: Insights from Functional Neuroimaging

Bradford C Dickerson,Reisa A Sperling

doi:10.1155/2009/610392

Abstract

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) have begun to reveal abnormalities in large-scale memory and cognitive brain networks. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies have focused on this region of the brain. Yet it is clear that other regions of the large-scale episodic memory network are affected early in the disease as well, and fMRI has begun to illuminate functional abnormalities in frontal, temporal, and parietal cortices as well in MCI and AD. Besides predictable hypoactivation of brain regions as they accrue pathology and undergo atrophy, there are also areas of hyperactivation in brain memory and cognitive circuits, possibly representing attempted compensatory activity. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. Additional work with “resting state” fMRI data is illuminating functional-anatomic brain circuits and their disruption by disease. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, which will hopefully one day be useful for demonstrating beneficial effects of treatments being tested in clinical trials.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia [60]
To acknowledge that multiple non-neural factors may confound the interpretation of changes in the hemodynamic response measured by blood-oxygen level dependent (BOLD) Functional MRI (fMRI), such as age- and disease-related changes in neurovascular coupling [12,21], AD-specific alterations in vascular physiology [75], and resting hypoperfusion and metabolism in mild cognitive impairment (MCI) and AD [37], which may result in an amplified BOLD fMRI signal during activation [18,24,40]
We recently extended a preliminary analysis of fMRI as a predictor of dementia in MCI [33]

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia [60]. Typically, the symptoms of the disease begin with insidious episodic memory difficulties after the sixth decade of life and progress gradu-. It may be possible to reverse some aspects of this damage, it would be ideal to initiate treatment with neuroprotective medications at a time when – or even before – AD is mildly symptomatic, ideally prior to dementia [25] To approach this goal, our capability needs to be improved to identify individuals with very mild symptoms of the disease while they are still largely independent in daily function [28]. Given the growing body of evidence that alterations in synaptic function are present very early in the disease process, possibly long before the development of clinical symptoms and even significant neuropathology [20,91], fMRI may be useful for detecting alterations in brain function that may be present very early in the course of AD. We will review fMRI data regarding functional abnormalities in MCI and AD, with an emphasis on large-scale networks subserving memory

Functional MRI

Large-scale brain networks supporting normal memory function

FMRI in MCI and AD

MTL hyperactivation as a predictive biomarker in MCI

Conclusions