Research

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Projects currently ongoing in the Lab

Amyloid Imaging

amyloid Brain Amyloid Imaging in Aging and Dementia

Deposition of amyloid, or more specifically β-amyloid (or Aβ) is a characteristic feature of Alzheimer’s disease (AD). This Aβ is the main constituent of the amyloid plaque that is seen microscopically in the brain at post-mortem. While the cause of AD is still debated, many current theories implicate β-amyloid deposition as the key pathogenic event in AD. Until recently, the only way to see this protein was to examine a brain at postmortem. Within the past several years, a new technique has become available that makes use of positron-emitting radionuclides tagged to specific molecules that can be safely injected into people to create images of brain β-amyloid deposition. Our lab is currently using one of these PET tracers, [11C]PIB (or Pittsburgh Compound B) to image brain β-amyloid deposition in several related research projects. In all of these projects, research subjects undergo PIB-PET scanning, cognitive testing, and in many cases scanning with FDG (to measure brain glucose metabolism), structural magnetic resonance imaging (MRI) and functional MRI.

Specific projects in the lab include:

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.

References

[Oh2013] Association of gray matter atrophy with age, b-amyloid, and cognition in aging

[Marchant2013] The aging brain and cognition: Contribution of vascular injury and Ab to mild cognitive dysfunction

[Mormino2012] Not quite PIB-positive, not quite PIB-negative: slight PIB elevations in elderlynormal control subjects are biologically relevant

[Oh2012_2] Covarying alterations in Aβ deposition, glucose metabolism, and gray matter volume in cognitively normal elderly

[Mormino2011] Relationships between Beta-Amyloid and Functional Connectivity in Different Components of the Default Mode Network in Aging

[Furst2010] Cognition, glucose metabolism and amyloid burden in Alzheimer’s disease

[Rabinovici2010] Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden

[Jack2010] Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade.

[Jagust2009b] Mapping brain beta-amyloid.

[Rabinovici2008] AB amyloid and glucose metabolism in three variants of primary progressive aphasia.

[Rabinovici2007] 11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration.

[Boxer2007] Amyloid imaging in distinguishing atypical prion disease from Alzheimer’s disease.

[Jagust2008] Neuropathological basis of MR images in aging and dementia

[Mormino2008] Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects

[Kuczynski2009] An inverse association of cardiovascular risk and frontal lobe glucose metabolism

ADNI

adni_fdg Alzheimer’s Disease Neuroimaging Initiative

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.

meta_adni More information can be found at ADNI HOME

References

[Jagust2012] Apolipoprotein E, not fibrillar b-amyloid, reduces cerebral glucose metabolism in normal aging.

[Haight2012] Relative contributions of biomarkers in Alzheimer’s disease

[Landau2012] Lifetime cognitive engagement is associated with low beta-amyloid deposition

[Landau2012_3] Amyloid-β Imaging with Pittsburgh Compound B and Florbetapir:
Comparing Radiotracers and Quantification Methods.

[Lo2011] Longitudinal Change of Biomarkers in Cognitive Decline

[Landau2010] Comparing predictors of conversion and decline in mild cognitive impairment.

[Jagust2010] The Alzheimer’s Disease Neuroimaging Initiative positron emission tomography core.

[Jagust2009a] Relationships between biomarkers in aging and dementia.

[Haense2009] Performance of FDG PET for detection of Alzheimer’s disease in two independent multicentre samples (NEST-DD and ADNI)

[Petersen2010] Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization.

[Landau2009_2] Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI

Dopamine Working Memory and Aging

raclopride

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.

References

[Dang2012] Dopamine supports coupling of attention-related networks

[Dang2012_2] Striatal dopamine influences the default mode network to affect shifting between object features

[Klostermann2011] Dopamine and frontostriatal networks in cognitive aging

[Braskie2010] Correlations of striatal dopamine synthesis with default network deactivations during working memory in younger adults.

[Braskie2008] Relationship of striatal dopamine synthesis capacity to age and cognition

[Cools2008] Working memory capacity predicts dopamine synthesis capacity in the human striatum

[Cools2009] Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration

[Landau2009] Striatal dopamine and working memory

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