Imaging Alzheimer Pathology in Late-Life Depression With PET and Pittsburgh Compound-B

Abstract

There is increasing evidence for an empiric link between late-life depression and Alzheimer disease (AD). The neuropathology of AD, previously only confirmed at autopsy, may now be detectable in vivo using selective imaging ligands for β-amyloid. Positron emission tomography (PET) with [ 11 C] 6-OH-BTA-1 [Pittsburgh Compound-B (PiB)] has shown high tracer retention in cortical areas in patients with clinical diagnoses of probable AD and low retention in age-matched controls. We also previously reported variable PiB retention in patients with mild cognitive impairment (MCI). In this study, we used PiB-PET to evaluate whether amyloid is present in elders with treated major depression, many of whom have persistent cognitive impairment. We evaluated 9 subjects with remitted major depression [3M: 6F, mean (SD) age=71.8(5.7) y]. Seven of the 9 depressed subjects also met criteria for the diagnosis of MCI. PiB-PET data from healthy elders [n=8; mean (SD) age=71.5(3.0) y] were used for comparison. PET was acquired with arterial sampling and PiB retention was quantified using magnetic resonance imaging-guided cortical regions and graphical analysis of time-activity data; arterial line failure led to exclusion of 1 depressed subject. The data demonstrated variably elevated PiB retention. PiB retention in the 2 depressed subjects with normal cognitive ability was in the range of nondepressed cognitively normal subjects. PiB retention in 3 of the 6 depressed subjects with MCI fell in the range of subjects with AD. PiB retention in the remaining Reprints: Meryl A. Butters, PhD, Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O'Hara St., Pittsburgh, PA 15213 (e-mail: buttersma@upmc.edu). Dr Reynolds receives research support (pharmaceutical supplies) from Glaxo Smith-Kline, Forest, Pfizer, Lilly, and Bristol Myers Squibb.GE Healthcare holds a license agreement with the University of Pittsburgh based on the technology described in this manuscript. Drs Klunk and Mathis are co-inventors of PiB and, as such, have a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of this manuscript. All other authors have no conflicts of interest with this work. Drs Butters, Meltzer, Klunk, Mathis, Price, and DeKosky as well as Mr Ziolko had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The current study will extend these findings to perform the first in vivo human investigation of whether amyloid neuropathology is present in elders with major depression. NIH Public Access METHODS AND MATERIALS Subject SelectionWe studied a total of 9 subjects over age 65 with treated late-life major depression [3 men, 6 women; mean (SD) age=71.8 (5.7) y] ( Table 1). All of these subjects presented to a late-life depression clinic and remitted with escitalopram as part of a...

Topologically Convergent and Divergent Structural Connectivity Patterns between Patients with Remitted Geriatric Depression and Amnestic Mild Cognitive Impairment

“…In addition, our high-resolution structural brain networks showed sporadic prefrontal regions that were associated with a discrepant nodal efficiency in the WM networks in the RGD compared with aMCI patients. The prefrontal lobe system usually plays a vital role in mood regulation and cognitive function (Milak et al, 2005;Bae et al, 2006), which is involved in the pathogenesis of RGD and aMCI (Butters et al, 2008). The finding further suggests that regional characteristics of the prefrontal regions may also be a valuable marker for distinguishing RGD from aMCI.…”

“…Specifically, approximately one-half of demonstrated brain ␤-amyloid accumulation in the aforementioned cortical areas among RGD is in a pattern characteristic of early AD (Butters et al, 2008). Such a changing pattern was also observed in amnestic mild cognitive impairment (aMCI) pathologic (Jagust et al, 2010) and neuroimaging (Pihlajamäki et al, 2009) studies.…”

“…Such a changing pattern was also observed in amnestic mild cognitive impairment (aMCI) pathologic (Jagust et al, 2010) and neuroimaging (Pihlajamäki et al, 2009) studies. aMCI has a probability of developing into AD with a prevalence of 10 -15% per year (Petersen et al, 1999), and a combination of aMCI and depression has been thought to represent the superimposed AD neuropathology (Butters et al, 2008). In particular, the predominance of cognitive impairments in aMCI involves memory dysfunction (Petersen et al, 1999), while RGD is particularly associated with dysfunction in executive control (Morimoto et al, 2011).…”

Cognitive trajectories associated with β-amyloid deposition in the oldest-old without dementia

“…While clinical depression was not assessed this study, the finding of Ab-status differences on the level of mean depressive symptom count is notable in light of growing evidence for an association between history of depression and risk for AD, 30 and between latelife depression and presence of AD-like Ab deposition. 31 We have shown that Ab deposition among oldest-old dementia-free survivors is associated with greater longitudinal cognitive decline. AD-like Ab deposition, measurable in about half of the population without dementia in the 9th and 10th decades of life, has demonstrable, if subtle, cognitive and behavioral correlates.…”

Temporal course of depressive symptoms during the development of Alzheimer disease

“…In a small study of persons without dementia, depression was associated with elevated cortical uptake of Pittsburgh Compound B, suggesting elevated ␤-amyloid. 32 In persons with AD, a history of depression has been associated with relatively higher levels of AD pathologic lesions. 33,34 However, in 2 large clinical-pathologic studies of persons with and without dementia, level of depressive symptoms in the last years of life was not related to the pathologic hallmarks of AD or other common dementias.…”