Chet Mathis

IMAGING β-AMYLOID BURDEN IN AGING AND DEMENTIA

Objective: To compare brain β-amyloid (Aβ) burden measured with [11C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias. Methods: Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Aβ burden was quantified using PIB distribution volume ratio. Results: Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an “AD-like” (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-ε4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis. Conclusions: Pittsburgh Compound B PET findings match histopathologic reports of β-amyloid (Aβ) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Aβ deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Aβ may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Aβ may benefit this condition.

Relationships between biomarkers in aging and dementia.

Background: PET imaging using [18F]fluorodeoxyglucose (FDG) and [11C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid β-amyloid protein (Aβ1-42) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood. Methods: Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Aβ1-42, t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as “positive” or “negative” for AD based on cutoffs established in patients with AD and controls from other cohorts. Results: Dichotomous categorization showed substantial agreement between PIB-PET and CSF Aβ1-42 measures (91% agreement, κ = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, κ = 0.50), and minimal agreement for other comparisons (κ <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Aβ1-42. Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Aβ1-42, t-tau, and p-tau181p, whereas FDG-PET was correlated only with Aβ1-42. Conclusions: PET and CSF biomarkers of Aβ agree with one another but are not related to cognitive impairment. [18F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.

Imaging amyloid deposition in Lewy body diseases

Background: Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). Objectives: To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features. Methods: Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio. Results: Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function. Conclusions: Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism. GLOSSARY: AAL = Automated Anatomic Labeling; AD = Alzheimer disease; ADRC = Alzheimer’s Disease Research Center; AMNART = American version of the National Adult Reading Test; ANCOVA = analysis of covariance; BDS = Blessed Dementia Scale; CAA = cerebral amyloid angiopathy; CDR = Clinical Dementia Rating; CDR-SB = Clinical Dementia Rating Sum of Boxes; DLB = dementia with Lewy bodies; DVR = distribution volume ratio; FCSRT = Cued Selective Reminding Test; FRSRT = Free Selective Reminding Test; H&Y = Hoehn and Yahr; MGH = Massachusetts General Hospital; MMSE = Mini-Mental State Examination; NC = normal control; NFT = neurofibrillary tangle; NPIQ = Neuropsychiatric Inventory Questionnaire; NS = not significant; PD = Parkinson disease; PDD = Parkinson disease dementia; PiB = Pittsburgh Compound B; ROI = region of interest; SPM2 = Statistical Parametric Mapping; UKPDSBRC = UK Parkinson’s Disease Society Brain Bank Research Center; UPDRS = United Parkinson’s Disease Rating Scale; WAIS-R = Wechsler Adult Intelligence Scale–Revised.

11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration

Background: The PET tracer 11C-labeled Pittsburgh Compound-B (11C-PIB) specifically binds fibrillar amyloid-beta (Aβ) plaques and can be detected in Alzheimer disease (AD). We hypothesized that PET imaging with 11C-PIB would discriminate AD from frontotemporal lobar degeneration (FTLD), a non-Aβ dementia. Methods: Patients meeting research criteria for AD (n = 7) or FTLD (n = 12) and cognitively normal controls (n = 8) underwent PET imaging with 11C-PIB (patients and controls) and 18F-fluorodeoxyglucose (18F-FDG) (patients only). 11C-PIB whole brain and region of interest (ROI) distribution volume ratios (DVR) were calculated using Logan graphical analysis with cerebellum as a reference region. DVR images were visually rated by a blinded investigator as positive or negative for cortical 11C-PIB, and summed 18F-FDG images were rated as consistent with AD or FTLD. Results: All patients with AD (7/7) had positive 11C-PIB scans by visual inspection, while 8/12 patients with FTLD and 7/8 controls had negative scans. Of the four PIB-positive patients with FTLD, two had 18F-FDG scans that suggested AD, and two had 18F-FDG scans suggestive of FTLD. Mean DVRs were higher in AD than in FTLD in whole brain, lateral frontal, precuneus, and lateral temporal cortex (p < 0.05), while DVRs in FTLD did not significantly differ from controls. Conclusions: PET imaging with 11C-labeled Pittsburgh Compound-B (11C-PIB) helps discriminate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD). Pathologic correlation is needed to determine whether patients with PIB-positive FTLD represent false positives, comorbid FTLD/AD pathology, or AD pathology mimicking an FTLD clinical syndrome.

Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB

Objective: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Aβ) deposition in vivo in individuals without dementia. Method: [11C]PiB images were obtained to measure fibrillar Aβ burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [11C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. Results: [11C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. Conclusions: Higher Aβ deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Aβ deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.

Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease

Objective: This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-β concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD). Methods: Choline acetyltransferase (ChAT) activity, [3H]PiB binding, and soluble amyloid-β1–42 (Aβ42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging–Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimers Disease, and Braak stage. Results: Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [3H]PiB binding and soluble Aβ42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [3H]PiB binding, increased soluble Aβ42, lower MMSE score, presence of the APOE*4 allele, and more advanced AD pathology. Conclusions: Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aβ42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.

CHAPTER 16 – Scatter Correction for Brain Receptor Quantitation in 3D PET

This chapter investigates the performance of the two correction algorithms when applied to scatter from activity outside the field of view. Two studies with the Utah phantom have been presented in the chapter: In the first, the entire water-filled phantom contains uniform activity with the exception of the short cylinder, which contains only water, and a chamber, which is empty. The fraction of scattered events in the image can then be estimated from the mean value in a region of interest placed on the short (cold) cylinder expressed as a fraction of the activity in the inner cylinder. In the second study, the annulus contains approximately four times the activity in the inner cylinder to simulate increased cortical uptake. In addition, the long cylinder contains twice the background activity to simulate uptake in subcortical structures. This chapter also explores the quantitative potential of 3D positron emission tomography (PET), and in particular the efficacy of the two scatter correction procedures, when applied to neuroreceptor ligand studies. For this, a ligand for imaging central benzodiazepine receptors is used.

Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease

Objective: To evaluate alterations in cerebral blood flow (CBF) using arterial spin-labeled MRI in autosomal dominant Alzheimer disease (ADAD) mutation carriers (MCs) in relation to cerebral amyloid and compared with age-matched healthy controls. Background: Recent work has identified alterations in CBF in elderly subjects with mild cognitive impairment and Alzheimer dementia using MRI. However, similar studies are lacking in ADAD. Subjects with ADAD are generally free of significant vascular disease and offer the opportunity to measure CBF early in the pathologic process before significant symptom onset when unique markers might be identified. Methods: Fourteen MCs (presenilin-1 and amyloid beta precursor protein) (Clinical Dementia Rating [CDR] 0 = 9, CDR 0.5 = 4, CDR 1 = 1) and 50 controls underwent 3-tesla pulsed arterial spin-labeled MRI. SPM8 was used to test the effect of MC status at the voxel level on CBF before and after controlling for age and CDR. Results: MCs had decreased perfusion in the caudate and inferior striatum bilaterally even after controlling for age and CDR. In MCs, separate areas of decreased CBF were associated with increasing cerebral amyloid and to decreased performance of attention and executive function. Conclusions: Early CBF changes were identified in asymptomatic and mildly symptomatic subjects with ADAD, particularly in the anterior striatum. Furthermore, amyloid deposition was associated with decreased CBF in a number of regions including anterior and posterior cortical areas. Both amyloid and decreased CBF were associated with declines primarily in executive cognitive function.

PET Measurement of Endogenous Neurotransmitter Activity Using High and Low Affinity Radiotracers

Functional imaging of the in vivo competition of dopamine-D 2 radioligands with endogenous dopamine has provided indirect measures of dopamine activity. Binding parameter changes ( > 20%) have been observed for [ 11 C]raclopride positron emission tomography studies performed after d-amphetamine administration, and this sensitivity has been partially attributed to its low D 2 receptor affinity. In this work, a d-amphetamine pretreatment/bolus radiotracer injection paradigm was used to examine binding parameter changes for the high and low affinity benzamides, [ 18 F]fallypride and [ 11 C]raclopride; and a preliminary examination of [ 18 F]fallypride extrastriatal D 2 binding at baseline and after haloperidol pretreatment was performed. [ 11 C]aclopride studies were performed in baboons at baseline and after d-amphetamine pretreatment (0.6 mg/kg, n = 3 or 1.0 mg/kg, n = 2). Two baboons had additional [ 18 F]fallypride studies at baseline and after d-amphetamine, and a third baboon was studied at baseline and after haloperidol pretreatment (1 mg/kg). Kinetic analyses provided distribution volume (DV) and DV-de-rived binding potential (BP DV ) estimates. For [ 11 C]raclopride, the average striatal BP DV change was – 26 ± 2.6% for the 0.6-mg/kg amphetamine dose, with slightly greater changes of −31 and −39% after the 1.0-mg/kg dose. Lower striatal changes were observed for [ 18 F]fallypride: – 14% (0.6 mg/kg) and – 29% (1.0 mg/kg). Baseline regional BP DV values were highly correlated (r 2 > 0.9) with human D 2 receptor rank order but did not correlate after 1 mg/kg haloperidol pretreatment (r 2 0.1).Functional imaging of the in vivo competition of dopamine-D2radioligands with endogenous dopamine has provided indirect measures of dopamine activity. Binding parameter changes (> 20%) have been observed for [11C]raclopride positron emission tomography studies performed after d-amphetamine administration, and this sensitivity has been partially attributed to its low D2 receptor affinity. In this work, a d-amphetamine pretreatment/bolus radiotracer injection paradigm was used to examine binding parameter changes for the high and low affinity benzamides, [18F]fallypride and [11C]raclopride; and a preliminary examination of [18F]fallypride extrastriatal D2 binding at baseline and after haloperidol pretreatment was performed. [11C]aclopride studies were performed in baboons at baseline and after d-amphetamine pretreatment (0.6 mg/kg, n = 3 or 1.0 mg/kg, n = 2). Two baboons had additional [18F]fallypride studies at baseline and after d-amphetamine, and a third baboon was studied at baseline and after haloperidol pretreatment (1 mg/kg). Kinetic analyses provided distribution volume (DV) and DV-de-rived binding potential (BPDV) estimates. For [11C]raclopride, the average striatal BPDV change was –26 ± 2.6% for the 0.6-mg/kg amphetamine dose, with slightly greater changes of −31 and −39% after the 1.0-mg/kg dose. Lower striatal changes were observed for [18F]fallypride: –14% (0.6 mg/kg) and –29% (1.0 mg/kg). Baseline regional BPDVvalues were highly correlated (r2 > 0.9) with human D2 receptor rank order but did not correlate after 1 mg/kg haloperidol pretreatment (r2 < 0.1).

Quantitative and statistical analyses of PET imaging studies of amyloid deposition in humans

In vivo amyloid imaging could aid in earlier detection of Alzheimers disease (AD) and anti-amyloid therapy development. We compared quantitative region-of-interest (ROI) and voxel-based statistical analyses of positron emission tomography (PET) studies of the /sup 11/C-labeled amyloid-imaging agent, PIB. High specific activity PIB PET studies were performed in 5 AD and 5 control subjects (ECAT HR+, 10-15 mCi, arterial input, 90 min). Magnetic resonance (MR) imaging was performed (ROI delineation). Quantitative analyses yielded regional PIB retention values (i.e., DVratio (DVR): radiotracer distribution volume (DV) normalized to the cerebellar reference DV). Statistical parametric mapping (SPM) and partial least squares (PLS) analyses were applied to PIB DVR images (arterial based) that were spatially normalized to an elderly MR template (55-90 years, n=268). The regional tissue response functions (fast and slow kinetic components) were consistent with the DVR values. The ROI, SPM (p<.025, 50 voxel extent, false discovery correction), and PLS (saliences) analyses yielded marked PIB retention in areas of AD brain that were consistent with known areas of amyloid deposition in AD, as compared to reference retention in areas unaffected by amyloid in AD (white matter, cerebellum, control brain). Voxel-based analyses of PIB PET data will likely prove valid and robust for mapping amyloid deposition on a cross-sectional and longitudinal basis in AD.