Steven Ng

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.

Visual Assessment Versus Quantitative Assessment of 11C-PIB PET and 18F-FDG PET for Detection of Alzheimer's Disease

Amyloid-β (Aβ) imaging with N-methyl-11C-2-(4′-methylamino-phenyl)-6-hydroxy-benzothiazole (11C-6-OH-BTA-1; also known as 11C-PIB) shows a robust increase in cortical binding in Alzheimers disease (AD). The aim of this study was to explore the clinical potential of Aβ imaging for the diagnosis of AD by comparison of the accuracy of visual reading of 11C-PIB images with quantitative analysis and 18F-FDG. Methods: Fifteen AD patients (age, 71.1 ± 11.3 y [mean ± SD]; mini-mental state examination [MMSE], 18.9 ± 9.3 [mean ± SD]) and 25 healthy control (HC) subjects (age, 71.9 ± 6.82 y; MMSE ≥ 28) underwent 90-min dynamic 11C-PIB PET and 20-min static 18F-FDG PET. 11C-PIB images, generated from data acquired between 40 and 70 min after injection, and 18F-FDG images were rated separately by 2 readers as normal, possible AD, or probable AD. Quantitative analyses used the distribution volume ratio (DVR) of frontal cortex, parietotemporal cortex, posterior cingulate, and caudate nucleus for 11C-PIB and standardized uptake value ratio (SUVR) of parietotemporal cortex and posterior cingulate for 18F-FDG, using cerebellar cortex as the reference region. Receiver-operating-characteristic (ROC) analysis was performed to compare the accuracy of quantitative measures. To determine the effect of age on diagnostic accuracy, the median age of the AD subjects (74 y) was chosen to separate the cohort into younger (64.4 ± 5.8 y) and older (78.6 ± 4.1 y) groups. Results: Visual agreement between readers was excellent for 11C-PIB (κ = 0.90) and good for 18F-FDG (κ = 0.56). 11C-PIB was more accurate than 18F-FDG both on visual reading (accuracy, 90% vs. 70%, P = 0.05) and ROC analysis (95% vs. 83%, P = 0.02). Accuracy declined more with 18F-FDG than with 11C-PIB in the older group. Conclusion: Visual analysis of 11C-PIB images appears more accurate than visual reading of 18F-FDG for identification of AD and has accuracy similar to quantitative analysis of a 90-min dynamic scan. The accuracy of 11C-PIB PET is limited by cortical binding in some healthy elderly subjects, consistent with postmortem studies of cerebral Aβ. Longitudinal follow-up is required to determine if this represents detection of preclinical AD.

Radiation Dosimetry of β-Amyloid Tracers 11C-PiB and 18F-BAY94-9172

β-Amyloid (Aβ) imaging has great potential to aid in the diagnosis of Alzheimer disease and the development of therapeutics. The radiation dosimetry of Aβ radioligands may influence their application; therefore, we calculated and compared the effective doses (EDs) of 11C-PiB and a new 18F-labeled ligand, 18F-BAY94-9172. Methods: Attenuation-corrected whole-body scans were performed at 0, 15, 30, 45, and 60 min after injection of 350 ± 28 MBq (mean ± SD) of 11C-PiB in 6 subjects and at 0, 20, 60, 120, and 180 min after injection of 319 ± 27 MBq of 18F-BAY94-9172 in 3 subjects. Coregistered CT was used to define volumes of interest (VOIs) on the PET images. The source organs were the brain, lungs, liver, kidneys, spleen, and vertebrae. The VOIs for the contents of the gallbladder, urinary bladder, lower large intestine, upper large intestine, and small intestine were also defined. Total activity in each organ at each time point was calculated by use of reference organ volumes. The resultant time–activity curves were fitted with constrained exponential fits, and cumulated activities were determined. A dynamic bladder voiding model was used. The OLINDA/EXM program was used to calculate the whole-body EDs from the acquired data. Results: For 11C-PiB, the highest absorbed doses were in the gallbladder wall (44.80 ± 29.30 μGy/MBq), urinary bladder wall (26.30 ± 8.50 μGy/MBq), liver (19.88 ± 3.58 μGy/MBq), and kidneys (12.92 ± 3.37 μGy/MBq). The ED was 5.29 ± 0.66 μSv/MBq. For 18F-BAY94-9172, the highest doses were also in the gallbladder wall (132.40 ± 43.40 μGy/MBq), urinary bladder wall (24.77 ± 7.36 μGy/MBq), and liver (39.07 ± 8.31 μGy/MBq). The ED was 14.67 ± 1.39 μSv/MBq. Conclusion: The estimated organ doses for 11C-PiB were comparable to those reported in earlier research. With the doses used in published studies (300–700 MBq), the EDs would range from 1.6 to 3.7 mSv. The ED of 18F-BAY94-9172 was 30% lower than that of 18F-FDG and, at the published dose of 300 MBq, would yield an ED of 4.4 mSv. The dosimetry of both Aβ radioligands is suitable for clinical and research applications.

La lunga attesa: towards a molecular approach to neuroimaging and therapeutics in Alzheimer's disease.

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are Aβ amyloid plaques, neurofibrillary tangles (NFT), synaptic loss and reactive gliosis. Current diagnosis of AD is made by clinical, neuropsychologic, and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography (CT) and magnetic resonance imaging (MRI) is based on nonspecific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of AD. Functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single photon emission computed tomography (SPECT), possibly in conjuction with other related Aβ biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of AD, as well as in assessing prognosis. With the advent of new therapeutic strategies aimed at reducing the Aβ amyloid burden in the brain, there is increasing interest in the development of MRI contrast agents and PET and SPECT radioligands that will permit the assessment of Aβ amyloid burden in vivo.

O1-04-02: Initial results from human studies of a novel F-18 PET ligand for brain beta-amyloid imaging

with best practice methods to deliver care primarily via small group homes and that dementia care takes up a disproportionate amount of staff time in small care settings. Conclusions: To address early stage dementia related services in the most effective manner, a concerted effort needs to be in place to aid local service entities adapt services to dementia-related presentations among ID clientele, set up coordinated training for staff, secure funds for adapting group homes for community “dementia-capable” care, and construction of clinical support services and augmentation of family support services for parents and other kin carers.

O1-04-06: Correlation of memory dysfunction and amyloid burden in mild cognitive impairment

and MCI patients needed to evaluate a putative disease-slowing treatment in a six-month clinical trial, using PET images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu ADNI). Methods: Baseline and approximately sixmonth follow-up ADNI PET images were compared in separate analyses of 16 AD patients, 27 MCI patients and 27 NC using SPM5. Using the atlas coordinate with the maximally significant CMRgl decline in the respective AD and MCI comparison, power analyses were performed to estimate the number of patients needed to evaluate a putative primary prevention therapy in a six-month multi-center clinical trial. Results: There was a trend for approximately six-month MMSE declines in the AD patients (P 0.06) and MCI patients (P 0.06) but not in the NC (P 0.86). The AD patients had six-month CMRgl declines in left temporal, parietal and precuneus regions (maximal reduction 3.0%), the MCI patients had six-month CMRgl declines in bilateral temporal, right parietal and right frontal regions (maximal reduction 2.0%), and the NC had had six-month declines in the left temporal cortex (P 0.001, uncorrected for multiple comparisons). Using the maximal, left temporal CMRgl declines in each patient group, we estimate the need for at least 224 AD patients or 642 MCI patients per treatment arm to detect a putative disease-slowing treatment efficacy to reduce sixmonth CMRgl declines by 25% with 80% power (one-tailed P 0.005, uncorrected for multiple comparisons) in a multi-center clinical trial. Conclusions: This study provides preliminary information about sixmonth CMRgl declines in AD and MCI patients and a preliminary estimate of the number of patients needed to detect CMRgl effects in six-month clinical trials of putative disease-slowing treatments.