ADRC Project 1
Amyloid Imaging in Subjective Cognitive Decline
Project Leader: Beth Snitz, PhD
Epidemiologic evidence suggests that subjective memory complaints in aging confer some degree of risk for subsequent cognitive decline and/or progression to dementia. There is also accumulating evidence that Alzheimer Disease (AD)-biomarkers, including amyloid-beta (Aβ) pathology, are associated with subjective cognitive complaints in otherwise healthy older individuals – a clinical state describe as Subjective Cognitive Decline (SCD). In the AD research community, growing interest in SCD as potentially the earliest detectable symptoms of AD is further fueled by the goal of increasingly earlier identification of risk in intervention and secondary prevention trials. However, a boundary shift of preclinical AD closer toward normal cognitive aging poses many challenges. Subjective memory complaints and concerns are common, perhaps even normative, among older adults. To date, we lack informative data addressing how to best to distinguish among etiologies of subjective cognitive complaints, including normal cognitive aging. Individual differences in personality traits and mood symptoms are known to be important correlates of subjective cognitive complaints; how these psychological factors interact and whether they are independent of underlying AD pathophysiology is not yet understood.
The goal of the proposed Project is to further knowledge about how SCD and Aβ pathology may be associated. To achieve this, we will recruit and study a sample of 58 older volunteers who have presented in a medical setting with concerns about memory or other cognitive decline, but who also have normal objective test performance. We will test the hypothesis that SCD is associated with a higher proportion of Aβ-positive individuals, as assessed by Pittsburgh compound B (PiB)-PET imaging, compared to age- and education-matched cognitively normal controls without presenting concerns. Further, we hypothesize that Aβ-positive (compared to Aβ-negative) SCD will be associated with 1) questionnaire-measured variables, including the personality trait ‘emotional instability,’ episodic memory complaints and degree of dysfunction in daily life; and 2) other AD-biomarker variables reflective of brain changes, including structural and functional MRI, and subtle deficits on more challenging cognitive tests. To the degree possible, an exploratory aim is to compare rates of incident mild cognitive impairment (MCI) through Clinical Core follow-up, as a function of baseline Aβ status. This Project will provide the foundation for further longitudinal study, with the longer-term goal of determining which biomarker and psychological features of SCD are predictive of clinical progression to MCI and AD. Findings from this Project will further inform models of the AD-pathophysiological sequence in relation to very early behavioral and symptomatic change.
ADRC Project 2
PET Imaging of Tau in Elderly Controls, MCI, and AD
Project Leader: Chester Mathis, PhD
The neuropathologic definition of Alzheimer’s disease (AD) relies on the presence of two well-characterized protein aggregates in the brain, amyloid-beta (Aβ) plaques and hyperphosphorylated tau in the form of neurofibrillary tangles. The widespread use of Aβ positron emission tomography (PET) imaging technology has helped identify the prevalence of significant Aβ deposition in vivo in the elderly population, in which elevated levels of Aβ are found in about 30% of cognitively normal elderly (NC) subjects at a mean age of about 75 years old, 60% of mild cognitive impairment (MCI) subjects, and 90% of clinically diagnosed AD subjects. Efforts to develop tau-selective PET imaging agents have been successful recently with the application of several new tau PET radioligands, including the radioligand [18F]T807 (T807). We propose to characterize the behavior of T807, in concert with other biomarkers of neurodegeneration, in NC, MCI, and AD subjects.
In cross-sectional studies, we will investigate regional differences in brain tau load in the different subject groups and compare the in vivo topology of abnormal tau deposition with the pattern predicted by postmortem Braak staging. We will leverage existing data on [18F]2-fluoro-2-deoxy-D-glucose (FDG) hypometabolism, hippocampal volume (HV) loss, [11C]Pittsburgh Compound-B (PiB) measures of Aβ load, and cognitive performance measures in subjects recruited from NC, MCI and AD cohorts at the University of Pittsburgh in whom these biomarker measures have been obtained with separate funding to correlate with the T807 PET results. Following cross-sectional evaluation of tau load in the different groups, we will rescan all subjects using T807 at 30 months to evaluate longitudinal changes in T807 signal and compare tau changes with changes in the other biomarker measures in the same subjects. The combination of in vivo tau and Aβ imaging has the potential to provide a more complete view of the pathological progression of AD from prodromal to end-stage phases.
Three NC groups will be evaluated in the proposed studies and compared to amyloid-positive MCI and AD groups. These NC groups include: amyloid-negative NC with no abnormal FDG and HV markers (Stage-0 NC); amyloid-positive NC with or without abnormal FDG and/or HV markers (Stage-1 and Stage-2 NC); and amyloid-negative NC with abnormal FDG and/or HV markers, characterized as “suspected non-amyloid pathophysiology (SNAP)”. Early studies indicate that some SNAP subjects may be on an AD pathway of cognitive decline and some may be on non-AD pathways. It is not clear whether neocortical tauopathy precedes Aβ abnormalities in SNAP subjects or whether the order of tau vs. Aβ dysregulation will distinguish which pathway SNAP subjects take. In vivo topographic changes in tau deposition relative to changes in Aβ deposition will be determined using T807 PET imaging in concert with PiB PET imaging. It is anticipated that the use of both T807 and PiB in these studies will help clarify the temporal sequences of tau and Aβ changes in mesial temporal cortex and neocortical brain regions in normal aging and in AD pathways.
ADRC Project 3
Neuropathology of Psychosis in Alzheimer’s disease
Project Leader: Robert Sweet, M.D.
Co-Project Leader: Julia Kofler, M.D.
A more severe phenotype of Alzheimer disease (AD) is identified by the occurrence of psychosis. AD with psychosis (AD+P) is common, with a cumulative incidence of ~ 40%-60% in subjects with AD. AD+P subjects have more rapid cognitive decline, increased disability, and greater mortality than AD subjects without psychosis (AD-P). Current empiric treatments for psychosis in AD have limited efficacy and are associated with substantial toxicity, motivating efforts to identify the underlying neurobiology of AD+P.
We have assembled a large brain tissue collection of AD cases characterized antemortem for psychosis, placing us in a unique position to address this need. This project will test our overarching model that AD+P results from specific biologic processes that modify AD-related neurodegeneration, yielding more rapid cognitive decline and psychotic symptoms. This model initially derived from our observation that the occurrence of psychosis in AD is familial, a finding which has since been replicated in two independent cohorts. Brain imaging and neuropathologic studies provide further evidence of a characteristic neurobiology of AD+P, with exaggerated reductions of gray matter volume, blood flow, glucose metabolism, and increased phosphotau (pTau) burden in multiple neocortical regions. Additional AD+P risk may also result from comorbid neocortical stage Lewy body pathology. Nevertheless, in our preliminary data, after accounting for all of these pathologies, unexplained causation of psychosis in AD remains. The more rapid cognitive decline in AD+P, and observations that synapse loss is the strongest correlate of cognitive impairment, suggest that synaptic dysfunction and loss is one source of the “missing” neuropathology in AD+P. Additionally, recent genetic studies have highlighted inflammation as having a more central role in AD neurodegeneration than previously appreciated, and inflammation, especially when affecting synaptic proteins, is strongly associated with psychosis. We therefore propose a set of specific aims designed to determine the proportion of AD+P explained by these pathologies:
- To quantify the burden of AD and comorbid neuropathologies within neocortical regions in AD+P and AD-P subjects;
- To evaluate markers of synaptic dysfunction and loss in AD+P;
- To evaluate markers of inflammation in AD+P. Combining a Sr. Investigator (Sweet) with expertise in the synaptic pathology of psychosis and a Jr. Investigator (Kofler) with expertise in the neuropathology and immunology of AD provides strong scientific synergy, increased likelihood of success, and an opportunity for career development.
Completion of these aims will provide the necessary basis for future mechanistic studies assessing whether interventions to alter affected pathways (pTau, synaptic signaling & inflammatory) may slow synaptic impairment and cognitive decline downstream of Aβ in model systems. In addition, our findings will inform how much each pathologic process contributes to AD+P risk, and allow evaluation of whether that weighting differs across individuals, which could be important for future efforts at personalized therapeutics.