Final Report Summary - MCI_AD PIB-PET_FMRI (Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer’s disease: Relating the Impact of Amyloid Burden with PIB-PET on Neuronal Activation as Assessed with fMRI)
Alzheimer’s disease (AD) is the most common and most feared form of dementia. It is characterized by progressive brain dysfunction, thought to be due to continuous degeneration of the central nervous system. Episodic memory impairment is typically one of the earliest and most prominent domains of cognitive impairment, with eventual deterioration of other cognitive skills leading to restricted ability to perform daily activities. Amyloid is one hallmark pathology of Alzheimer’s disease (AD), but is present in many clinically normal individuals. In addition, although the past decade has seen remarkable advances in our understanding of the basic pathobiology of AD, we still lack a complete mechanistic account of exactly how the early accumulation of amyloid pathology relates to the emergent clinical syndrome of memory impairment in humans. Thus, this knowledge could not only give insights into the disease pathology during the early stages of the disease but also help in finding reliable biomarkers for individuals at high risk of impending clinical decline (e.g. individuals with Mild Cognitive Impairment (MCI)).
This multimodal neuroimaging project, involving functional neuroimaging, investigated memory function in older adults with and without significant amyloid burden. We used data from a novel neuroimaging technique using the tracer Pittsburgh Compound B with positron emission tomography (PIB-PET) to measure the level of amyloid present in the brains of healthy, clinically normal older adults (see example in figure 1 demonstrating increased amyloid burden particularly in the posteromedial cortex of one representative subject from the study), MCI and patients with AD. PIB-PET was introduced for use in humans in 2004 and has rapidly become an important and cutting-edge research tool for distinguishing individuals without any clinical symptoms of dementia who might nonetheless be at risk for developing AD because of the high level of amyloid burden in their brains. To probe memory function we used a novel encoding/retrieval functional magnetic resonance imaging (fMRI) task paradigm involving a face-name association task. With this paradigm we recently demonstrated that successful encoding and subsequent retrieval of face-name associations in a group of young subjects are dependent on activity of the posteromedial cortices (see figure 2A; Vannini et al., 2011, Cerebral Cortex and Vannini et al., 2012, Human Brain Mapping).
Using a multimodal approach, by combining this fMRI paradigm and PET amyloid imaging (using PiB), we could further demonstrate that cognitively normal older individuals with high levels of amyloid burden had aberrant functional neuronal response in the posteromedial cortex (see figure 2B; Vannini et al., 2011, Neurobiology of Aging and Vannini et al., 2012, Cerebral Cortex). These results are potentially very important because it marks the memory processes in the posteromedial cortex as a very early indicator of dysfunction related to amyloid pathology, indicating that testing memory function with fMRI could provide a useful diagnostic marker of dysfunction that could be used in conjunction with amyloid imaging and other tests to identify individuals in a preclinical (that is, asymptomatic) stage of AD.
The incoming phase of the Marie Curie fellowship built on these previous findings from the outgoing phase and aimed to validate our main hypothesis that altered functional memory processes in the posteromedial cortex in cognitively normal older adults is an early indicator of progressive decline towards AD dementia due to increased amyloid pathology. Thus, during the incoming phase we combined amyloid imaging (using PiB-PET) with fMRI studies of memory processes (encoding and retrieval) in a sample of cognitively healthy older individuals, MCI and AD patients to improve our understanding of the pathophysiological mechanisms behind the memory decline seen in AD patients. Our results indicate that the individuals with neurodegenerative changes (MCI and AD patients) demonstrate similar aberrant functional neuronal response in the posteromedial cortex that we had observed in our cognitively healthy older individuals with increased amyloid pathology (see Fig 3). These results are exciting as they suggests that the functional alterations that we have previously observed over the course of normal aging can indeed be used to better discriminate age-related changes from pathological neurodegenerative processes.
(See figures in attachment).
This multimodal neuroimaging project, involving functional neuroimaging, investigated memory function in older adults with and without significant amyloid burden. We used data from a novel neuroimaging technique using the tracer Pittsburgh Compound B with positron emission tomography (PIB-PET) to measure the level of amyloid present in the brains of healthy, clinically normal older adults (see example in figure 1 demonstrating increased amyloid burden particularly in the posteromedial cortex of one representative subject from the study), MCI and patients with AD. PIB-PET was introduced for use in humans in 2004 and has rapidly become an important and cutting-edge research tool for distinguishing individuals without any clinical symptoms of dementia who might nonetheless be at risk for developing AD because of the high level of amyloid burden in their brains. To probe memory function we used a novel encoding/retrieval functional magnetic resonance imaging (fMRI) task paradigm involving a face-name association task. With this paradigm we recently demonstrated that successful encoding and subsequent retrieval of face-name associations in a group of young subjects are dependent on activity of the posteromedial cortices (see figure 2A; Vannini et al., 2011, Cerebral Cortex and Vannini et al., 2012, Human Brain Mapping).
Using a multimodal approach, by combining this fMRI paradigm and PET amyloid imaging (using PiB), we could further demonstrate that cognitively normal older individuals with high levels of amyloid burden had aberrant functional neuronal response in the posteromedial cortex (see figure 2B; Vannini et al., 2011, Neurobiology of Aging and Vannini et al., 2012, Cerebral Cortex). These results are potentially very important because it marks the memory processes in the posteromedial cortex as a very early indicator of dysfunction related to amyloid pathology, indicating that testing memory function with fMRI could provide a useful diagnostic marker of dysfunction that could be used in conjunction with amyloid imaging and other tests to identify individuals in a preclinical (that is, asymptomatic) stage of AD.
The incoming phase of the Marie Curie fellowship built on these previous findings from the outgoing phase and aimed to validate our main hypothesis that altered functional memory processes in the posteromedial cortex in cognitively normal older adults is an early indicator of progressive decline towards AD dementia due to increased amyloid pathology. Thus, during the incoming phase we combined amyloid imaging (using PiB-PET) with fMRI studies of memory processes (encoding and retrieval) in a sample of cognitively healthy older individuals, MCI and AD patients to improve our understanding of the pathophysiological mechanisms behind the memory decline seen in AD patients. Our results indicate that the individuals with neurodegenerative changes (MCI and AD patients) demonstrate similar aberrant functional neuronal response in the posteromedial cortex that we had observed in our cognitively healthy older individuals with increased amyloid pathology (see Fig 3). These results are exciting as they suggests that the functional alterations that we have previously observed over the course of normal aging can indeed be used to better discriminate age-related changes from pathological neurodegenerative processes.
(See figures in attachment).
