Positron Emission Tomography Markers Research Articles

Can white matter hyperintensities based Fazekas visual assessment scales inform about Alzheimer’s disease pathology in the population?

BackgroundWhite matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer’s disease (AD) pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, AD imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging.MethodsWe identified 1144 participants from the Mayo Clinic Study of Aging consisting of a population-based sample from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET, and tau-PET standardized uptake value ratio, automated WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC).ResultsPeriventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p < 0.001). Both periventricular WMH and deep WMH showed weak associations with amyloidosis (R = 0.07, p = < 0.001), and none with tau burden. We found substantial agreement between data from the two scanners for Fazekas measurements (ICC = 0.82 and 0.74). The automated WMH volume had high discriminating power for identifying participants with Fazekas ≥ 2 (area under curve = 0.97) and showed poor correlation with amyloid and tau PET markers similar to the visual grading.ConclusionOur study investigated risk factors underlying WMH spatial patterns and their impact on global cognition, with no discernible differences between periventricular and deep WMH. We observed minimal impact of amyloidosis on WMH severity. These findings, coupled with enhanced inter-scanner reproducibility of WMH data, suggest the combinability of inter-scanner data assessed by harmonized protocols in the context of vascular contributions to cognitive impairment and dementia biomarker research.

Intrinsic and secondary epileptogenicity in focal cortical dysplasia type II.

Favorable seizure outcome is reported following resection of bottom-of-sulcus dysplasia (BOSD). We assessed the distribution of epileptogenicity and dysplasia in and around BOSD to better understand this clinical outcome and the optimal surgical approach. We studied 27 children and adolescents with magnetic resonance imaging (MRI)-positive BOSD who underwent epilepsy surgery; 85% became seizure-free postresection (median=5.0 years follow-up). All patients had resection of the dysplastic sulcus, and 11 had additional resection of the gyral crown (GC) or adjacent gyri (AG). Markers of epileptogenicity were relative cortical hypometabolism on preoperative 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and spiking, ripples, fast ripples, spike-high-frequency oscillation cross-rate, and phase amplitude coupling (PAC) on preresection and postresection electrocorticography (ECoG), all analyzed at the bottom-of-sulcus (BOS), top-of-sulcus (TOS), GC, and AG. Markers of dysplasia were increased cortical thickness on preoperative MRI, and dysmorphic neuron density and variant allele frequency of somatic MTOR mutations in resected tissue, analyzed at similar locations. Relative cortical metabolism was significantly reduced and ECoG markers were significantly increased at the BOS compared to other regions. Apart from spiking and PAC, which were greater at the TOS compared to the GC, there were no significant differences in PET and other ECoG markers between the TOS, GC, and AG, suggesting a cutoff of epileptogenicity at the TOS rather than a tapering gradient on the cortical surface. MRI and tissue markers of dysplasia were all maximal in the BOS, reduced in the TOS, and mostly absent in the GC. Spiking and PAC reduced significantly over the GC after resection of the dysplastic sulcus. These findings support the concept that dysplasia and intrinsic epileptogenicity are mostly limited to the dysplastic sulcus in BOSD and support resection or ablation confined to the MRI-visible lesion as a first-line surgical approach. 18 F-FDG PET and ECoG abnormalities in surrounding cortex seem to be secondary phenomena.

Association between tau uptake and verbal fluency converge in language centers

AbstractBackgroundRecent studies have shown that pathological tau accumulation, a hallmark of Alzheimer’s disease (AD), is closely related to cognitive deficits in older populations. Semantic deficits, measured using tests of category verbal fluency, are among the features of early clinical stages of AD presentations. While the association between semantic decline and AD biomarkers have been evaluated, the use of a novel tau positron emission tomography (PET) tracer [18F]MK6240, remains relatively unexplored. The present study aims to evaluate whether tau accumulation is associated with participants’ performance on both category and letter fluency neuropsychological tests and whether category fluency performance is disproportionately impaired in AD in comparison to letter fluency.MethodThe study was conducted in a population of 298 individuals (188 cognitively unimpaired, 110 cognitively impaired). The D‐KEFS Category Fluency test was used to assess semantic knowledge while Letter Fluency was used to measure lexical speed access. Participants also underwent the Mini‐Mental State Examination (MMSE) to assess overall global cognitive functioning. Accumulation of tau was assessed with [18F]MK6240 PET and standardized uptake value ratio (SUVRs) were calculated between 90 to 110 min post‐injection, using cerebellum grey matter as the reference region. A voxel‐based regression model evaluated the relationship between the cognitive scoring and the PET marker [18F]MK6240, correcting for age, sex, education, diagnosis and RFT was used to account for multiple comparisons.ResultThis study found negative associations between Category and Letter Fluency scores and tau accumulation. Notably, stronger associations were found in the Category Fluency grouping. The associated regions are mainly in the left hemisphere in language related regions and the temporal lobe. Letter Fluency scores demonstrated the strongest association in the frontal regions. Comparatively, the MMSE scores were strongly associated with tau accumulation in both right and left hemispheres.ConclusionTau accumulation is associated with language dysfunction and is a major driver of domain‐specific cognitive impairment across the AD spectrum. Associations were more pronounced in the left hemisphere for both semantic knowledge and lexical speed. These results also suggest that tau accumulation is more strongly associated with semantic knowledge as indicated by uptake in language related areas.

Association between tau uptake and verbal fluency converge in language centers

AbstractBackgroundRecent studies have shown that pathological tau accumulation, a hallmark of Alzheimer’s disease (AD), is closely related to cognitive deficits in older populations. Semantic deficits, measured using tests of category verbal fluency, are among the features of early clinical stages of AD presentations. While the association between semantic decline and AD biomarkers have been evaluated, the use of a novel tau positron emission tomography (PET) tracer [18F]MK6240, remains relatively unexplored. The present study aims to evaluate whether tau accumulation is associated with participants’ performance on both category and letter fluency neuropsychological tests and whether category fluency performance is disproportionately impaired in AD in comparison to letter fluency.MethodThe study was conducted in a population of 298 individuals (188 cognitively unimpaired, 110 cognitively impaired). The D‐KEFS Category Fluency test was used to assess semantic knowledge while Letter Fluency was used to measure lexical speed access. Participants also underwent the Mini‐Mental State Examination (MMSE) to assess overall global cognitive functioning. Accumulation of tau was assessed with [18F]MK6240 PET and standardized uptake value ratio (SUVRs) were calculated between 90 to 110 min post‐injection, using cerebellum grey matter as the reference region. A voxel‐based regression model evaluated the relationship between the cognitive scoring and the PET marker [18F]MK6240, correcting for age, sex, education, diagnosis and RFT was used to account for multiple comparisons.ResultThis study found negative associations between Category and Letter Fluency scores and tau accumulation. Notably, stronger associations were found in the Category Fluency grouping. The associated regions are mainly in the left hemisphere in language related regions and the temporal lobe. Letter Fluency scores demonstrated the strongest association in the frontal regions. Comparatively, the MMSE scores were strongly associated with tau accumulation in both right and left hemispheres.ConclusionTau accumulation is associated with language dysfunction and is a major driver of domain‐specific cognitive impairment across the AD spectrum. Associations were more pronounced in the left hemisphere for both semantic knowledge and lexical speed. These results also suggest that tau accumulation is more strongly associated with semantic knowledge as indicated by uptake in language related areas.

Blood pressure variability and plasma Alzheimer’s disease biomarkers in older adults

Blood pressure variability is an emerging risk factor for Alzheimer’s disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer’s disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer’s disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55–88, mean age 69.9 [8.2 SD]), elevated blood pressure variability over 5 min was associated with lower levels of plasma Aβ1–42 (standardized ß = − 0.36 [95% CI − 0.61, − 0.12]; p = 0.005; adjusted R2 = 0.28) and Aβ1–42: Aβ1–40 ratio (ß = − 0.49 [95% CI − 0.71, − 0.22]; p < 0.001; adjusted R2 = 0.28), and higher levels of total tau (ß = 0.27 [95% CI 0.01, 0.54]; p = 0.04; adjusted R2 = 0.19) and Ptau181:Aβ1–42 ratio (ß = 0.26 [95% CI 0.02, 0.51]; p = 0.04; adjusted R2 = 0.22). Findings suggest higher blood pressure variability is linked to plasma biomarkers of increased Alzheimer’s disease pathophysiology.

Pericoronary and periaortic adipose tissue density are associated with inflammatory disease activity in Takayasu arteritis and atherosclerosis.

AimsTo examine pericoronary adipose tissue (PCAT) and periaortic adipose tissue (PAAT) density on coronary computed tomography angiography for assessing arterial inflammation in Takayasu arteritis (TAK) and atherosclerosis.Methods and resultsPCAT and PAAT density was measured in coronary (n = 1016) and aortic (n = 108) segments from 108 subjects [TAK + coronary artery disease (CAD), n = 36; TAK, n = 18; atherosclerotic CAD, n = 32; matched controls, n = 22]. Median PCAT and PAAT densities varied between groups (mPCAT: P < 0.0001; PAAT: P = 0.0002). PCAT density was 7.01 ± standard error of the mean (SEM) 1.78 Hounsfield Unit (HU) higher in coronary segments from TAK + CAD patients than stable CAD patients (P = 0.0002), and 8.20 ± SEM 2.04 HU higher in TAK patients without CAD than controls (P = 0.0001). mPCAT density was correlated with Indian Takayasu Clinical Activity Score (r = 0.43, P = 0.001) and C-reactive protein (r = 0.41, P < 0.0001) and was higher in active vs. inactive TAK (P = 0.002). mPCAT density above −74 HU had 100% sensitivity and 95% specificity for differentiating active TAK from controls [area under the curve = 0.99 (95% confidence interval 0.97–1)]. The association of PCAT density and coronary arterial inflammation measured by 68Ga-DOTATATE positron emission tomography (PET) equated to an increase of 2.44 ± SEM 0.77 HU in PCAT density for each unit increase in 68Ga-DOTATATE maximum tissue-to-blood ratio (P = 0.002). These findings remained in multivariable sensitivity analyses adjusted for potential confounders.ConclusionsPCAT and PAAT density are higher in TAK than atherosclerotic CAD or controls and are associated with clinical, biochemical, and PET markers of inflammation. Owing to excellent diagnostic accuracy, PCAT density could be useful as a clinical adjunct for assessing disease activity in TAK.

Prognostic Value of Baseline and Interim Positron Emission Tomography Markers in Diffuse Large B-cell Lymphoma Patients: A Real-world Perspective.

Prognostic Value of Baseline and Interim Positron Emission Tomography Markers in Diffuse Large B-cell Lymphoma Patients: A Real-world Perspective.

Towards clinical application of tau PET tracers for diagnosing dementia due to Alzheimer's disease.

The recent development of several tau positron emission tomography (PET) tracers represents a major milestone for the Alzheimer's disease (AD) field. These tau PET tracers bind tau neurofibrillary tangles, a key neuropathological characteristic of AD that is tightly linked to synaptic loss, brain atrophy, and cognitive decline. It is notable that these tau PET tracers show low uptake in most non-AD tauopathies and other neurodegenerative disorders, resulting in a diagnostic specificity that is superior to that of amyloid beta (Aβ) PET and biofluid markers, especially at an older age when incidental Aβ pathology is common. Furthermore, tau PET tracers diagnostically outperform widely used MRI markers. Given its excellent diagnostic performance due to the combination of high sensitivity and specificity for detecting tau pathology in AD dementia, we hypothesize that tau PET can become an important diagnostic tool in specialized clinics for the differential diagnosis of dementia syndromes where AD is among the major possible underlying diseases.

Copper-mediated nucleophilic radiofluorination of [18 F]β-CFT for positron emission tomography imaging of dopamine transporter.

[18 F]β-CFT is a positron emission tomography (PET) ligand for imaging of dopamine transporter. It was proved to be a sensitive PET marker to detect presynaptic dopaminergic hypofunction in Parkinson's disease. In recent years, copper-mediated 18 F-fluorination of aryl boronic esters has been successful in some molecules containing aromatic groups. In this study, we describe the novel synthetic strategy of [18 F]β-CFT by copper-mediated nucleophilic radiofluorination with pinacol-derived aryl boronic esters upon reaction with [18 F]KF/K222 and Cu (OTf)2 (py)4 . The radiolabeling protocol was optimized with [18 F]fluoride elution method and amount of copper catalyst used. [18 F]β-CFT is obtained from boronic ester precursors in 2.2% to 10.6% non-isolated radiochemical yield (RCY). Purified [18 F]β-CFT with >99% radiochemical purity (RCP) and high molar activity was obtained in validation runs. The radiolabeling procedure is straightforward and can easily be adapted for clinical use.

A Modest Increase in 11C-PK11195-Positron Emission Tomography TSPO Binding in Depression Is Not Associated With Serum C-Reactive Protein or Body Mass Index

BackgroundImmune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)–targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to 1) test the hypothesis of significant case-control differences in TSPO binding in the anterior cingulate cortex, prefrontal cortex, and insula regions; and 2) explore the relationship between cerebral TSPO binding and peripheral blood C-reactive protein (CRP) concentration. MethodsA total of 51 depressed subjects with Hamilton Depression Rating Scale score >13 (median 17; interquartile range, 16–22) and 25 healthy control subjects underwent dynamic brain 11C-PK11195 PET and peripheral blood immune marker characterization. Depressed subjects were divided into high CRP (>3 mg/L; n = 20) and low CRP (<3 mg/L; n = 31). ResultsAcross the three regions, TSPO binding was significantly increased in depressed versus control subjects (η2p = .09; F1,71 = 6.97, p = .01), which was not influenced by body mass index. The case-control difference was greatest in the anterior cingulate cortex (d = 0.49; t74 = 2.00, p = .03) and not significant in the prefrontal cortex or insula (d = 0.27 and d = 0.36, respectively). Following CRP stratification, significantly higher TSPO binding was observed in low-CRP depression compared with controls (d = 0.53; t54 = 1.96, p = .03). These effect sizes are comparable to prior major depressive disorder case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures. ConclusionsConsistent with previous findings, there is a modest increase in TSPO binding in depressed patients compared with healthy control subjects. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or body mass index poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.

Neuropathological and Biomarker Findings in Parkinson's Disease and Alzheimer's Disease: From Protein Aggregates to Synaptic Dysfunction.

There is mounting evidence that Parkinson’s disease (PD) and Alzheimer’s disease (AD) share neuropathological hallmarks, while similar types of biomarkers are being applied to both. In this review we aimed to explore similarities and differences between PD and AD at both the neuropathology and the biomarker levels, specifically focusing on protein aggregates and synapse dysfunction. Thus, amyloid-β peptide (Aβ) and tau lesions of the Alzheimer-type are common in PD and α-synuclein Lewy-type aggregates are frequent findings in AD. Modern neuropathological techniques adding to routine immunohistochemistry might take further our knowledge of these diseases beyond protein aggregates and down to their presynaptic and postsynaptic terminals, with potential mechanistic and even future therapeutic implications. Translation of neuropathological discoveries to the clinic remains challenging. Cerebrospinal fluid (CSF) and positron emission tomography (PET) markers of Aβ and tau have been shown to be reliable for AD diagnosis. Conversely, CSF markers of α-synuclein have not been that consistent. In terms of PET markers, there is no PET probe available for α-synuclein yet, while the AD PET markers range from consistent evidence of their specificity (amyloid imaging) to greater uncertainty of their reliability due to off-target binding (tau imaging). CSF synaptic markers are attractive, still needing more evidence, which currently suggests those might be non-specific markers of disease progression. It can be summarized that there is neuropathological evidence that protein aggregates of AD and PD are present both at the soma and the synapse. Thus, a number of CSF and PET biomarkers beyond α-synuclein, tau and Aβ might capture these different faces of protein-related neurodegeneration. It remains to be seen what the longitudinal outcomes and the potential value as surrogate markers of these biomarkers are.

Multiple markers contribute to risk of progression from normal to mild cognitive impairment

ObjectiveTo identify a parsimonious set of markers that optimally predicts subsequent clinical progression from normal to mild cognitive impairment (MCI). Methods250 clinically normal adults (mean age = 73.6 years, SD = 6.0) from the Harvard Aging Brain Study were assessed at baseline on a wide set of markers, including magnetic resonance imaging markers of gray matter thickness and volume, white matter lesions, fractional anisotropy, resting state functional connectivity, positron emission tomography markers of glucose metabolism and β-amyloid (Aβ) burden, and a measure of vascular risk. Participants were also tested annually on a battery of clinical and cognitive tests (median follow-up = 5.0 years, SD = 1.66). We applied least absolute shrinkage and selection operator (LASSO) Cox models to determine the minimum set of non-redundant markers that predicts subsequent clinical progression from normal to MCI, adjusting for age, sex, and education. Results23 participants (9.2%) progressed to MCI over the study period (mean years of follow-up to diagnosis = 3.96, SD = 1.89). Progression was predicted by several brain markers, including reduced entorhinal thickness (hazard ratio, HR = 1.73), greater Aβ burden (HR = 1.58), lower default network connectivity (HR = 1.42), and smaller hippocampal volume (HR = 1.30). When cognitive test scores were added to the model, the aforementioned neuroimaging markers remained significant and lower striatum volume as well as lower scores on baseline memory and processing speed tests additionally contributed to progression. ConclusionAmong a large set of brain, vascular and cognitive markers, a subset of markers independently predicted progression from normal to MCI. These markers may enhance risk stratification by identifying clinically normal individuals who are most likely to develop clinical symptoms and would likely benefit most from therapeutic intervention.

Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain.

Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of vortioxetine by comparing its effect to the SSRI citalopram on the binding of [11C]AZ10419369 to the 5-HT1B receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of vortioxetine was determined by [11C]MADAM PET measurements before and after administration of vortioxetine (0.1-3.0 mg/kg) and data were used to confirm clinically relevant dosing in subsequent PET measurements with [11C]AZ10419369. The 5-HT1B receptor binding was significantly decreased after 0.3 mg/kg of citalopram in the dorsal raphe nucleus (5%), as well as after 0.3 mg/kg of vortioxetine in six brain regions (~25%) or 1.0 mg/kg of vortioxetine in all 12 examined regions (~48%). Moreover, there was no effect of 1.0 mg/kg of vortioxetine on the binding of [11C]Cimbi-36 to the 5-HT2A receptor, which has comparable sensitivity to 5-HT release as [11C]AZ10419369 binding. In conclusion, at clinically relevant doses, vortioxetine induced larger reductions in [11C]AZ10419369 binding than citalopram. These observations suggest that vortioxetine binds to the 5-HT1B receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT1B receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.

Stress Myocardial Blood Flow Heterogeneity Is a Positron Emission Tomography Biomarker of Ventricular Arrhythmias in Patients With Hypertrophic Cardiomyopathy

Patients with hypertrophic cardiomyopathy (HC) are at increased risk of sudden cardiac death. Abnormalities in myocardial blood flow (MBF) detected by positron emission tomography (PET) are common in HC, but a PET marker that identifies patients at risk of sudden cardiac death is lacking. We hypothesized that disparities in regional myocardial perfusion detected by PET would identify patients with HC at risk of ventricular arrhythmias. To test this hypothesis, we quantified global and regional MBFs by 13NH3-PET at rest and at stress, and developed a heterogeneity index to assess MBF heterogeneity in 133 symptomatic patients with HC. The MBF heterogeneity index was computed by dividing the highest by the lowest regional MBF value, at rest and after vasodilator stress, in each patient. High stress MBF heterogeneity was defined as an index of ≧1.85. Patients with HC were stratified by the presence or the absence of ventricular arrhythmias, defined as sustained ventricular tachycardia (VT) and/or nonsustained VT, during follow-up. We found that global and regional MBFs at rest and stress were similar in patients with HC with or without ventricular arrhythmias. Variability in regional stress MBF was observed in both groups, but the stress MBF heterogeneity index was significantly higher in patients with HC who developed ventricular arrhythmias (1.82 ± 0.77 vs 1.49 ± 0.25, p <0.001). A stress MBF heterogeneity index of ≧1.85 was an independent predictor of both sustained VT (hazard ratio 16.1, 95% confidence interval 3.2 to 80.3) and all-VT (sustained-VT + nonsustained VT: hazard ratio 3.7, 95% confidence interval 1.4 to 9.7). High heterogeneity of stress MBF, reflected by an MBF heterogeneity index of ≥1.85, is a PET biomarker for ventricular arrhythmias in symptomatic patients with HC.

A Hierarchical Bayesian Model for the Identification of PET Markers Associated to the Prediction of Surgical Outcome after Anterior Temporal Lobe Resection.

We develop an integrative Bayesian predictive modeling framework that identifies individual pathological brain states based on the selection of fluoro-deoxyglucose positron emission tomography (PET) imaging biomarkers and evaluates the association of those states with a clinical outcome. We consider data from a study on temporal lobe epilepsy (TLE) patients who subsequently underwent anterior temporal lobe resection. Our modeling framework looks at the observed profiles of regional glucose metabolism in PET as the phenotypic manifestation of a latent individual pathologic state, which is assumed to vary across the population. The modeling strategy we adopt allows the identification of patient subgroups characterized by latent pathologies differentially associated to the clinical outcome of interest. It also identifies imaging biomarkers characterizing the pathological states of the subjects. In the data application, we identify a subgroup of TLE patients at high risk for post-surgical seizure recurrence after anterior temporal lobe resection, together with a set of discriminatory brain regions that can be used to distinguish the latent subgroups. We show that the proposed method achieves high cross-validated accuracy in predicting post-surgical seizure recurrence.

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aβ1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

Interim [18f] fluorodeoxyglucose positron emission tomography (PET) for early metabolic assessment of response to PEB chemotherapy for metastatic seminoma: Preliminary findings.

381 Background: A risk-adapted strategy for metastatic seminoma may further refine the necessary burden of chemotherapy while sparing futile treatment. The objective of this study was to evaluate the association of the early metabolic response to cisplatin, etoposide, and bleomycin (PEB) and dimensional response. Methods: Patients (pts) with newly-diagnosed seminoma and who were candidate to PEB were staged at baseline by computed tomography (CT), PET and serum tumor markers (STM). Then, restaging with PET after 2 cycles of PEB (PET2), and with CT after treatment (3-4 cycles [CT3-4]) were provided. One (greatest) target lesion was chosen to evaluate metabolic/dimensional changes. Wilcoxon rank sum test was used to analyze the association between PET response and either the shrinkage of target lesion (primary endpoint) or baseline, or final dimensions. Results: In the time-frame 02/2009-11/2013, 37 pts have been enrolled. Two pts had CSIIA, 13 CSIIB, 13 CSIIC, and 9 CSIII. 3 had an intermediate prognosis because of liver (n=1) and bone (n=2) disease. The latter were recognized by PET while having a bone-negative CT scan. 4 had a retroperitoneal and 1 a mediastinal primary. All pts had a PET-positive target disease. After 2 cycles of PEB, 27 pts (72.9%) had a metabolic complete response (CR), 10 a partial response (PR). 12 pts had a CR at CT3-4. Median follow up was 18 months (IQR: 13-23). A significant association was found between PET2 response and baseline (p=0.003), final diameter (p&lt;0.001), and % of tumor shrinkage (p=0.014). Pts with PET2 CR had a median residual diameter of 1.2 cm (IQR: 1-1.9) while pts with PET2 PR 3.75 cm (IQR: 2.6-6.1, p=0.002). 6 Pts received RT after PEB. 2/10 pts with PET2 PR had a relapse (0/27 CR). Conclusions: A significant association was found between PET2 response and tumor shrinkage in pts with metastatic seminoma. PET2 CR pts could be predicted not to need additional re-imaging or treatment after PEB, and simplifying the follow up should be an endpoint. PET2 PR category includes pts yielding a difficult-to-treat disease. A detailed cost-efficacy analysis of the strategy will be required further.

Multiple Brain Markers are Linked to Age-Related Variation in Cognition.

Age-related alterations in brain structure and function have been challenging to link to cognition due to potential overlapping influences of multiple neurobiological cascades. We examined multiple brain markers associated with age-related variation in cognition. Clinically normal older humans aged 65-90 from the Harvard Aging Brain Study (N = 186) were characterized on a priori magnetic resonance imaging markers of gray matter thickness and volume, white matter hyperintensities, fractional anisotropy (FA), resting-state functional connectivity, positron emission tomography markers of glucose metabolism and amyloid burden, and cognitive factors of processing speed, executive function, and episodic memory. Partial correlation and mediation analyses estimated age-related variance in cognition shared with individual brain markers and unique to each marker. The largest relationships linked FA and striatum volume to processing speed and executive function, and hippocampal volume to episodic memory. Of the age-related variance in cognition, 70-80% was accounted for by combining all brain markers (but only ∼20% of total variance). Age had significant indirect effects on cognition via brain markers, with significant markers varying across cognitive domains. These results suggest that most age-related variation in cognition is shared among multiple brain markers, but potential specificity between some brain markers and cognitive domains motivates additional study of age-related markers of neural health.

SU-E-J-215: Onboard Split PET Including the Effects of Attenuation, Scatter, and Random Events

Purpose: Positron emission tomography (PET) using split PET geometry was investigated as an on-board system for functional imaging and PET marker tracking, specifically with tomotherapy. The open dual ring PET would allow measurement of both inter and intra-fractional variation, improving the delineation of tumor volume at any stage in the radiation treatment delivery process. We present results from data obtained using Monte Carlo simulations including the effects of attenuation, random events, and scatter. Methods: PET design was accomplished via Monte Carlo simulations with GATE, the Geant4 Application for Emission Tomography. Images were reconstructed using Software for Image Reconstruction (STIR) with a fully 3D ordered subset expectation maximization (OSEM) image reconstruction technique. Results: Monte Carlo simulations of the split PET geometry indicate that including physical factors that degrade image quality such as attenuation, random events, and scatter still prove the feasibility of near real-time PET for both inter and intra-fractional radiation delivery. The image quality of scan times under 1 minute reveals that it is possible to utilize PET scanning and reconstruction during the treatment session intrafractionally. GATE also simulates the depth information but does not correct obliqueness of the path of line of response so the data is much moremore » realistic than the data obtained with ray tracing. Conclusion: Onboard split PET with TomoTherapy can generate quality images under 1 minute scan times without the need to correct for attenuation, scatter, random events, or depth information of the interaction.« less

Hypoxia in Head and Neck Cancer in Theory and Practice: A PET-Based Imaging Approach

Hypoxia plays an important role in tumour recurrence among head and neck cancer patients. The identification and quantification of hypoxic regions are therefore an essential aspect of disease management. Several predictive assays for tumour oxygenation status have been developed in the past with varying degrees of success. To date, functional imaging techniques employing positron emission tomography (PET) have been shown to be an important tool for both pretreatment assessment and tumour response evaluation during therapy. Hypoxia-specific PET markers have been implemented in several clinics to quantify hypoxic tumour subvolumes for dose painting and personalized treatment planning and delivery. Several new radiotracers are under investigation. PET-derived functional parameters and tracer pharmacokinetics serve as valuable input data for computational models aiming at simulating or interpreting PET acquired data, for the purposes of input into treatment planning or radio/chemotherapy response prediction programs. The present paper aims to cover the current status of hypoxia imaging in head and neck cancer together with the justification for the need and the role of computer models based on PET parameters in understanding patient-specific tumour behaviour.