Elsevier

Biological Psychiatry

Volume 74, Issue 5, 1 September 2013, Pages 340-347
Biological Psychiatry

Review
Resting State Functional Connectivity in Preclinical Alzheimer’s Disease

https://doi.org/10.1016/j.biopsych.2012.11.028Get rights and content

There has been a dramatic increase in the number of studies using resting state functional magnetic resonance imaging (rs-fMRI), a recent addition to imaging analysis techniques. The technique analyzes ongoing low-frequency fluctuations in the blood oxygen level-dependent signal. Through patterns of spatial coherence, these fluctuations can be used to identify the networks within the brain. Multiple brain networks are present simultaneously, and the relationships within and between networks are in constant dynamic flux. Resting state fMRI functional connectivity analysis is increasingly used to detect subtle brain network differences and, in the case of pathophysiology, subtle abnormalities in illnesses such as Alzheimer’s disease (AD). The sequence of events leading up to dementia has been hypothesized to begin many years or decades before any clinical symptoms occur. Here we review the findings across rs-fMRI studies in the spectrum of preclinical AD to clinical AD. In addition, we discuss evidence for underlying preclinical AD mechanisms, including an important relationship between resting state functional connectivity and brain metabolism and how this results in a distinctive pattern of amyloid plaque deposition in default mode network regions.

Section snippets

rs-fMRI in Mild Cognitive Impairment and AD

One of the most frequently used applications of rs-fMRI is in the characterization of brain networks in AD. Alzheimer’s disease usually begins insidiously, with episodic memory disturbance, and progresses toward a more general impairment in memory, executive function, language, visuospatial function, and other cognitive and behavioral domains. An important advantage of rs-fMRI imaging in AD is the ability to scan patients who are too impaired to actively participate in a task-based scanning

Preclinical AD

There is evidence for a prolonged phase of “pre-clinical AD” 47, 48 in which amyloid-β (Aβ) plaques are accumulating for a number of years before first disease symptoms. Pathological evidence first indicated that 20%–30% of nondemented elderly individuals who came to autopsy had evidence of amyloid deposition (49). Fibrillar amyloid deposition was then shown to be measurable in vivo with Pittsburgh compound B (PIB) PET scanning (50), and consistent with autopsy findings, PET studies (25)

rs-fMRI in Preclinical AD

Resting state fMRI functional connectivity analysis is increasingly used to detect subtle brain network abnormalities in illnesses such as AD. An important question has been whether the effects of fibrillar Aβ could be detected in brain functional studies as well as in molecular imaging studies before the development of cognitive change. Several studies using rs-fMRI 68, 69, 70 have supplied supporting evidence demonstrating that, as in AD and MCI, there is significantly decreased DMN

Relationship Between Resting State Functional Connectivity and Brain Metabolism

Part of the emerging puzzle might require a greater understanding of the relationship between resting state functional connectivity and brain metabolism. Measurements of brain energy metabolism with magnetic resonance spectroscopy 75, 76 in a variety of experimental settings have indicated that up to 80% of the entire energy consumption of the brain at rest is spent on glutamate cycling, with most of that energy produced by oxidative phosphorylation coupled to aerobic glycolysis. An observation

Timeline, Differential Diagnosis, and Future Directions

Resting state intrinsic activity might be as significant as if not more significant than evoked activity in terms of overall brain function. The intimate association between resting state activity and Aβ deposition reflects the characteristic pattern of amyloid deposition. As shown in Figure 3B, Aβ deposition seems to be the earliest event in preclinical AD measureable with imaging techniques, followed by alterations in resting state functional connectivity (see preceding text for exceptions),

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