We are currently working on a number of projects in the lab. Here are some examples of what we are doing now.
Both brain aging and dementia are characterized by the deposition of proteins that abnormally aggregate in the brain. The key proteins are amyloid, or more specifically β-amyloid (or Aβ), and tau. Both of these proteins are characteristically found in the brains of patients with Alzheimer’s disease (AD), Aβ is the major constituent of the amyloid plaque, and tau is the major constituent of the neurofibrillary tangle. Scientists have long debated the relative roles of these proteins in the pathogenesis of AD. In addition to AD, both of these proteins are deposited in the brains of healthy older people, even those without any symptoms of cognitive loss. The combination of amyloid and tau imaging have opened the door to understanding how normal aging might be different from early AD, to define the earliest stages of AD, and to understand basic mechanisms of aging and dementia.
Using PIB to image the amount and distribution of β-amyloid deposition in a variety of neurodegenerative disorders including Alzheimer’s disease, vascular dementia (dementia with stroke) and frontotemporal dementia. The PIB-PET images are related to cognitive function, diagnosis, and FDG-PET. The goal of this project is to determine whether amyloid imaging can be used diagnostically, and also to understand interactions between cerebrovascular disease and β-amyloid deposition. These studies will also ultimately relate imaging variables to measures of brain pathology obtained at autopsy.
PIB-PET imaging of normal cognitive aging. It is well known that a proportion of older people have β-amyloid plaques in the brain that are detected at autopsy. With PIB imaging we can detect this amyloid during life, and relate it to cognitive ability. We are also performing functional MRI scans to understand how and whether these amyloid plaques affect brain function, and whether the brain can compensate for the β-amyloid deposition. Individuals who are imaged are also followed longitudinally to see if the amyloid deposition is related to long-term change in cognition.
PET scans taken with the amyloid imaging agent C-11 PIB. Top row indicates lack of tracer binding in a normal older person. Bottom row indicates extensive cortical uptake, consistent with diffuse deposition of beta-amyloid in an AD patient
Tau imaging in normal aging and dementia. Tau is specifically interesting in aging because it is deposited in the medial temporal lobe, including the hippocampus and entorhinal cortex, structures intimately involved in memory. By combining measurements of tau with MRI measures of brain function and structure, we can investigate whether and how tau deposition may be related to memory loss often experienced by older people. In AD, tau deposition at postmortem has been linked to dementia severity, so tau imaging might be a useful way to stage AD and monitor experimental therapies.
PET scans using the tracer F-18 AV-1451 indicating Tau deposition. Top row indicates tracer uptake in an AD patient. Bottom row indicates tracer uptake in the hippocampus (arrows) of a normal older person.
fMRI and Episodic Memory in Aging
Memory impairment is one of the hallmark cognitive dysfunctions in healthy aging and a major symptom of Alzheimer’s disease. There is extensive evidence that episodic memory, or memory for ‘events’, declines with age. A challenge for episodic memory that must be overcome is the significant overlap across day-to-day experiences – events in our lives share many similar features which can induce interference (e.g. parking your car in the same parking lot every day), yet we are able to recall specific memories (e.g. today’s parking spot versus yesterday’s). Thus, a key requirement for episodic memory must be to distinguish among these similar experiences. Pattern separation is a potential mechanism that reduces this interference among similar experiences by using non-overlapping representations.
Current projects use different types of brain imaging to measure brain activity during a memory task (functional magnetic resonance imaging, fMRI) and beta-amyloid levels or tau in the brain (positron emission tomography, PET) to examine relationships between brain activation and pathology in cognitively normal older adults.
A recent study aimed to determine if higher brain activation at baseline drives beta-amyloid accumulation in humans. We found that cognitively normal older adults with greater brain activity at baseline showed greater beta-amyloid accumulation over time. Specifically, it appears that hippocampal activation, a brain region involved in memory processing, is linked to increasing levels of beta-amyloid in the brain. Furthermore, beta-amyloid accumulation was related to greater memory decline over time (Leal, Landau, Bell, & Jagust, in press).
Other current projects include performing high-resolution fMRI during a novel pattern separation task to examine hippocampal-neocortical dynamics and how activity patterns relate to forgetting over 24 hours. We plan to investigate the influence of tau pathology on medial temporal lobe functioning in normal aging will the goal of gaining a better understanding of the network changes in cognitively normal aging and to improve dissociation of normal and pathological aging.
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a multicenter study that is designed to explore and validate the use of biomarkers in aging and dementia. The primary biomarkers include structural MRI scans and PET scans of both glucose metabolism (FDG) and amyloid. In addition, subjects undergo lumbar puncture for measurement of CSF Abeta and tau, as well as extensive cognitive testing. Currently 800 participants – 400 with mild cognitive impairment, 200 with Alzheimer’s disease, and 200 healthy older controls – are enrolled at about 60 centers in North America. Our laboratory is the coordinating center for the PET core and one of the primary data analysis labs.
Subjects are studied approximately annually with repeated scans and cognitive tests. Goals of the project include assessing the use of these techniques as outcomes in clinical trials, with the hopes that these biomarkers might ultimately be validated as surrogate measures of drug efficacy. Already, it is clear that these scans will be able to lower the sample sizes of clinical trials since their variability is smaller than the variability seen with cognitive tests. In addition, these biomarkers are being examined for their ability to enrich cohorts of potential subjects who are most likely to show cognitive decline or dementia over time. For example, by scanning individuals with normal cognition or very mild cognitive impairment we may be able to select individuals at high risk of decline who would benefit from therapy and could participate meaningfully in a clinical trial. This project has generated large amounts of data including imaging, cognitive, biochemical, and genetic measures all of which are publicly available.
More information can be found at ADNI HOME
Dopamine Working Memory and Aging
Changes in prefrontal cortical structure and function, along with decline in working memory ability, are both well established features of aging. Mechanisms underlying these changes could include both β-amyloid deposition and cerebrovascular disease (see project 1). In addition, loss of nigro-striatal and ventral tegmental-prefrontal dopaminergic neurons are known to occur with advancing age, and dopamine is well established as an important neurotransmitter that mediates working memory function. Thus, the goal of this project is to relate changes in brain dopamine to age-related decline in working memory performance. We are using a variety of approaches to measuring brain dopamine, and relating changes in brain dopamine to brain activation during working memory tasks using fMRI.
Current projects use [18F]Flurometatyrosine (FMT) with PET as an indicator of presynaptic dopamine synthesis capacity, and these FMT measures are relate to both working memory ability and fMRI activation. In addition, we are using [11C]Racolpride to directly measure brain dopamine release during a working memory task. These measures of dopamine release will also be compared to fMRI activation and behavioral performance. The basic hypotheses driving these investigations are that changes in brain dopamine will result in reduced activation in brain regions known to receive afferent projections from striatum, and that these changes will be related to cognitive ability.
PET scan with the tracer [11C]Racolpride to directly measure brain dopamine release during a working memory task.