Sylvia Gong

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.

18F-THK523: a novel in vivo tau imaging ligand for Alzheimer’s disease

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimers disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimers disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.

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.

11C-PIB binding is increased in patients with cerebral amyloid angiopathy–related hemorrhage

Background: The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is inferred from clinical and structural imaging features. 11C-Pittsburgh compound B (PIB) is a PET ligand that binds to β-amyloid in extracellular plaques and vessel walls. We hypothesized that patients with a clinical diagnosis of CAA-related hemorrhage (CAAH) have increased 11C-PIB uptake and that the pattern differs from Alzheimer disease (AD). Methodology: Patients with CAAH based on established clinical criteria were studied using 11C-PIB PET and were compared with age-matched controls and patients with AD. Distribution volume ratio (DVR) parametric maps were created using the cerebellar cortex as a reference region. Results: Twelve patients with CAAH of mean age 73.9 (range 58-93) years were compared with 22 normal controls and 13 patients with AD of mean age 71.8 (59-83) and 73.8 (56-90) years, respectively. CAAH PIB median DVR binding was higher in cortical regions (1.69, interquartile range 1.44-1.97) compared with controls (1.32, 1.21-1.44, p = 0.002) but lower than AD (2.04, 1.93-2.26, p = 0.004). The occipital-global uptake ratio was lower among patients with AD than among patients with CAAH (p = 0.008), and the frontal-global uptake ratio was higher (p = 0.012). Conclusion: 11C-Pittsburgh compound B (PIB) binding is moderately increased in most patients with probable cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage. The distribution may differ from that seen in Alzheimer disease. 11C-PIB PET may assist in the in vivo diagnosis of CAA and serve as a surrogate marker for future therapeutic studies.

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.

Relationship between nicotinic receptors and cognitive function in early Alzheimer’s disease: A 2-[18F]fluoro-A-85380 PET study

Neuronal nicotinic acetylcholine receptors (nAChRs) are critical for higher order cognitive processes. Post-mortem studies suggest reductions in nAChRs (particularly the alpha(4)beta(2) subtype) with ageing and in Alzheimers disease (AD). This study aimed to; (1) quantify nAChR distribution in vivo with 2-[18F]fluoro-A-85380 (2-FA) in 15 early AD patients compared to 14 age-matched, healthy controls (HC) and (2) correlate nAChR distribution with cognitive performance in both groups. All participants were non-smokers and underwent cognitive testing along with a dynamic PET scan after injection of 200 MBq of 2-FA. Brain regional 2-FA binding was assessed through a simplified estimation of Distribution Volume (DV(S)). The AD group differed significantly from HC on all cognitive measures employed, with impairments on measures of attention, working memory, language, executive function, visuospatial ability, verbal learning and verbal memory (p<.05). Contrary to post-mortem data this study found no evidence of in vivo nAChR loss in early AD despite significant cognitive impairment. Furthermore, no correlation between nAChR and cognitive performance was found for either group. The findings of the current study suggest preservation of nAChRs early in AD supporting previous studies. It is possible that while the clinical 2-FA PET method described here may be insensitive in detecting changes in early AD, such changes may be detected in more advanced stages of the illness.

Hypoxia-targeted radiotherapy dose painting for head and neck cancer using (18)F-FMISO PET: a biological modeling study.

Abstract Background. This study investigates the use of 18F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC). Material and methods. The study cohort consisted of eight patients with HNSCC who were planned for definitive radiotherapy. Hypoxic subvolumes were automatically generated on pre-radiotherapy FMISO PET scans. Three radiotherapy plans were generated for each patient: a standard (STD) radiotherapy plan to a dose of 70 Gy, a uniform dose escalation (UDE) plan to the standard target volumes to a dose of 84 Gy, and a hypoxia dose-painted (HDP) plan with dose escalation only to the hypoxic subvolume to 84 Gy. Plans were compared based on tumor control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumor control probability (UTCP). Results. The mean TCP increased from 73% with STD plans to 95% with the use of UDE plans (p < 0.001) and to 93% with HDP plans (p < 0.001). The mean parotid NTCP increased from 26% to 44% with the use of UDE plans (p = 0.003), and the mean mandible NTCP increased from 2% to 27% with the use of UDE plans (p = 0.001). There were no statistically significant differences between any of the NTCPs between the STD plans and HDP plans. The mean UTCP increased from 48% with STD plans to 66% with HDP plans (p = 0.016) and dropped to 37% with UDE plans (p = 0.138). Conclusion. Hypoxia-targeted radiotherapy dose painting for head and neck cancer using FMISO PET is technically feasible, increases the TCP without increasing the NTCP, and increases the UTCP. This approach is superior to uniform dose escalation.

Reduced striatal D1 receptor binding in autosomal dominant nocturnal frontal lobe epilepsy

Background: Mutations of the neuronal nicotinic acetylcholine (nACh) receptor identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) lead to increased sensitivity to ACh. As activation of presynaptic nicotinic receptors augments the release of dopamine in the striatum and the prefrontal regions, we tested the hypothesis that that the α4-Ser248Phe mutation affects dopaminergic transmission. Methods: We measured D1 receptor binding using [11C]-SCH23390 and PET in 12 subjects with the α4-Ser248Phe mutation (3 men, mean age 41 ± 16 years) and 19 controls (8 men, mean age 36 ± 13 years) matched for gender, smoking status, and age. Parametric images were produced using the simplified reference region method. Both MRI-based regions of interest and voxel based analyses were used. Results: Reduced striatal [11C]-SCH23390 binding occurred with the mutation (controls 1.1 ± 0.1; ADNFLE 0.97 ± 0.2; p < 0.01). Statistical parametric mapping confirmed a region of reduced [11C]-SCH23390 binding in the right putamen in α4-Ser248Phe subjects compared to controls (309 voxels, local maxima 20 16 −2 mm; Zscore 3.57, p < 0.05). Conclusions: Reduced D1 receptor binding may represent increased extracellular dopamine levels or, more likely, receptor downregulation. Alterations in mesostriatal dopaminergic circuits may contribute to nocturnal paroxysmal motor activity in autosomal dominant nocturnal frontal lobe epilepsy.

Intensity Modulated Radiation Therapy Dose Painting for Localized Prostate Cancer Using 11C-choline Positron Emission Tomography Scans

PURPOSE To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using (11)C-choline positron emission tomography PET scans in patients with localized prostate cancer. METHODS AND MATERIALS This was an RT planning study of 8 patients with prostate cancer who had (11)C-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV(60%) and SUV(70%)). Three IMRT plans were generated for each patient: PLAN(78), which consisted of whole-prostate radiation therapy to 78 Gy; PLAN(78-90), which consisted of whole-prostate RT to 78 Gy, a boost to the SUV(60%) to 84 Gy, and a further boost to the SUV(70%) to 90 Gy; and PLAN(72-90), which consisted of whole-prostate RT to 72 Gy, a boost to the SUV(60%) to 84 Gy, and a further boost to the SUV(70%) to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCP(PET)) and on prostatectomy-defined volumes (TCP(path)), and rectal normal tissue complication probabilities (NTCP) were compared between the plans. RESULTS All plans for all patients reached prescription doses while adhering to dose constraints. TCP(PET) values for PLAN(78), PLAN(78-90), and PLAN(72-90) were 65%, 97%, and 96%, respectively. TCP(path) values were 71%, 97%, and 89%, respectively. Both PLAN(78-90) and PLAN(72-90) had significantly higher TCP(PET) (P=.002 and .001) and TCP(path) (P<.001 and .014) values than PLAN(78). PLAN(78-90) and PLAN(72-90) were not significantly different in terms of TCP(PET) or TCP(path). There were no significant differences in rectal NTCPs between the 3 plans. CONCLUSIONS IMRT dose painting for localized prostate cancer using (11)C-choline PET scans is technically feasible. Dose painting results in higher TCPs without higher NTCPs.

Histopathological correlation of 11C-choline PET scans for target volume definition in radical prostate radiotherapy

BACKGROUND AND PURPOSE To evaluate the accuracy of (11)C-choline PET scans in defining dominant intraprostatic lesions (DILs) for radiotherapy target volume definition. MATERIAL AND METHODS Eight men with prostate cancer who had (11)C-choline PET scans prior to radical prostatectomy were studied. Several methods were used to contour the DIL on the PET scans: visual, PET Edge, Region Grow, absolute standardised uptake value (SUV) thresholds and percentage of maximum SUV thresholds. Prostatectomy specimens were sliced in the transverse plane and DILs were delineated on these by a pathologist. These were then compared with the PET scans. The accuracy of correlation was assessed by the Dice similarity coefficient (DSC) and the Youden index. RESULTS The contouring method resulting in both the highest DSC and the highest Youden index was 60% of the maximum SUV (SUV(60%)), with values of 0.64 and 0.51, respectively. However SUV(60%) was not statistically significantly better than all of the other methods by either measure. CONCLUSIONS Although not statistically significant, SUV(60%) resulted in the best correlation between (11)C-choline PET and pathology amongst all the methods studied. The degree of correlation shown here is consistent with previous studies that have justified using imaging for DIL radiotherapy target volume definition.