Jennifer M. Watchmaker

Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study.

Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes.

Lower cardiac index levels relate to lower cerebral blood flow in older adults

Objective: To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults. Methods: Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), APOE ε4 status, cognitive diagnosis, and regional tissue volume. Results: Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, p = 0.001) and right (β = 2.5, p = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, p = 0.003; right temporal lobe β = 2.5, p = 0.003). Cardiac index was unrelated to CBF in other regions assessed (p > 0.25) and CVR in all regions (p > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left (p < 0.0001) and right (p < 0.0001) temporal lobes. Conclusions: Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.

Noise concerns and post-processing procedures in cerebral blood flow (CBF) and cerebral blood volume (CBV) functional magnetic resonance imaging.

Functional neuroimaging with blood oxygenation level-dependent (BOLD) contrast has emerged as the most popular method for evaluating qualitative changes in brain function in humans. At typical human field strengths (1.5-3.0T), BOLD contrast provides a measure of changes in transverse water relaxation rates in and around capillary and venous blood, and as such provides only a surrogate marker of brain function that depends on dynamic changes in hemodynamics (e.g., cerebral blood flow and volume) and metabolism (e.g., oxygen extraction fraction and the cerebral metabolic rate of oxygen consumption). Alternative functional neuroimaging methods that are specifically sensitive to these constituents of the BOLD signal are being developed and applied in a growing number of clinical and neuroscience applications of quantitative cerebral physiology. These methods require additional considerations for interpreting and quantifying their contrast responsibly. Here, an overview of two popular methods, arterial spin labeling and vascular space occupancy, is presented specifically in the context of functional neuroimaging. Appropriate post-processing and experimental acquisition strategies are summarized with the motivation of reducing sensitivity to noise and unintended signal sources and improving quantitative accuracy of cerebral hemodynamics.

Cerebral hemodynamics and pseudo-continuous arterial spin labeling considerations in adults with sickle cell anemia

Sickle cell anemia (SCA) is a genetic disorder resulting in reduced oxygen carrying capacity and elevated stroke risk. Pseudo‐continuous arterial spin labeling (pCASL) measures of cerebral blood flow (CBF) may have relevance for stroke risk assessment; however, the effects of elevated flow velocity and reduced bolus arrival time (BAT) on CBF quantification in SCA patients have not been thoroughly characterized, and pCASL model parameters used in healthy adults are often applied to patients with SCA. Here, cervical arterial flow velocities and pCASL labeling efficiencies were computed in adults with SCA (n = 19) and age‐ and race‐matched controls without sickle trait (n = 7) using pCASL in sequence with phase contrast MR angiography (MRA). Controls (n = 7) and a subgroup of patients (n = 8) also underwent multi‐post‐labeling‐delay pCASL for BAT assessment. Mean flow velocities were elevated in SCA adults (velocity = 28.3 ± 4.1 cm/s) compared with controls (velocity = 24.5 ± 3.8 cm/s), and mean pCASL labeling efficiency (α) was reduced in SCA adults (α = 0.72) relative to controls (α = 0.91). In patients, mean whole‐brain CBF from phase contrast MRA was 91.8 ± 18.1 ml/100 g/min, while mean pCASL CBF when assuming a constant labeling efficiency of 0.86 was 75.2 ± 17.3 ml/100 g/min (p < 0.01), resulting in a mean absolute quantification error of 23% when a labeling efficiency appropriate for controls was assumed. This difference cannot be accounted for by BAT (whole‐brain BAT: control, 1.13 ± 0.06 s; SCA, 1.02 ± 0.09 s) or tissue T1 variation. In conclusion, BAT variation influences pCASL quantification less than elevated cervical arterial velocity and labeling efficiency variation in SCA adults; thus, a lower labeling efficiency (α = 0.72) or subject‐specific labeling efficiency should be incorporated for SCA patients.

Consensus statement on current and emerging methods for the diagnosis and evaluation of cerebrovascular disease.

Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state-of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue-level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD.

[18F]-FLT PET to predict early response to neoadjuvant therapy in KRAS wild-type rectal cancer: a pilot study

ObjectThis pilot study evaluated the utility of 3′-deoxy-3′[18F]-fluorothymidine ([18F]-FLT) positron emission tomography (PET) to predict response to neoadjuvant therapy that included cetuximab in patients with wild-type KRAS rectal cancers.MethodsBaseline [18F]-FLT PET was collected prior to treatment initiation. Follow-up [18F]-FLT was collected after three weekly infusions of cetuximab, and following a combined regimen of cetuximab, 5-FU, and radiation. Imaging-matched biopsies were collected with each PET study.ResultsDiminished [18F]-FLT PET was observed in 3/4 of patients following cetuximab treatment alone and in all patients following combination therapy. Reduced [18F]-FLT PET following combination therapy predicted disease-free status at surgery. Overall, [18F]-FLT PET agreed with Ki67 immunoreactivity from biopsy samples and surgically resected tissue, and was predictive of treatment-induced rise in p27 levels.ConclusionThese results suggest that [18F]-FLT PET is a promising imaging biomarker to predict response to neoadjuvant therapy that included EGFR blockade with cetuximab in patients with rectal cancer.

Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients

Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38–0.45) compared to controls (interquartile range = 0.29–0.38), similar to participants with SCA (interquartile range = 0.37–0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF.

Treatment of Progressive Herpes Zoster–Induced Vasculopathy with Surgical Revascularization: Effects on Cerebral Hemodynamics

BACKGROUND Herpes zoster ophthalmicus (HZO) is caused by reactivation of the herpes simplex virus in the trigeminal nerve. HZO-initiated cerebral vasculopathy is well characterized; however, there are no documented cases that report the efficacy of surgical revascularization for improving cerebral hemodynamics following progressive HZO-induced vasculopathy. We present a case in which quantitative anatomic and hemodynamic imaging were performed longitudinally before and after surgical revascularization in a patient with HZO and vasculopathic changes. CASE DESCRIPTION A 57-year-old female with history of right-sided HZO presented with left-sided hemiparesis and dysarthria and multiple acute infarcts. Angiography performed serially over a 2-month duration revealed progressive middle cerebral artery stenosis, development of new moyamoya-like lenticulostriate collaterals, and evidence of fibromuscular dysplasia in cervical portions of the internal carotid artery. Hemodynamic imaging revealed right hemisphere decreased blood flow and cerebrovascular reserve capacity. In addition to medical therapy, right-sided surgical revascularization was performed with the intent to reestablish blood flow. Follow-up imaging 13 months post revascularization demonstrated improved blood flow and vascular reserve capacity in the operative hemisphere, which paralleled symptom resolution. CONCLUSIONS HZO can lead to progressive, symptomatic intracranial stenoses. This report suggests that surgical revascularization techniques can improve cerebral hemodynamics and symptomatology in patients with aggressive disease when medical management is unsuccessful; similar procedures could be considered in managing HZO patients with advanced or progressive vasculopathy.

Are prophylactic antibiotics necessary prior to transarterial chemoembolization for hepatocellular carcinoma in patients with native biliary anatomy

Prophylactic antibiotics are frequently administered for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). In patients without previous biliary instrumentation, infection risk from TACE is low. We hypothesized that there is a negligible rate of infection in these patients without prophylactic antibiotics.

APOE GENOTYPE INFLUENCES HOW CEREBRAL BLOOD FLOW AND VASOREACTIVITY PREDICT NEUROPSYCHOLOGICAL DECLINE OVER AN 18-MONTH FOLLOW-UP: THE VANDERBILT MEMORY AND AGING STUDY

other groups, including sAD.Conclusions:Our results suggest a high frequency of microhemorrhages in DSAD cases in the occtx, more so than sAD. This along with the increased amount of CAA suggests that cerebrovascular pathology may be an under-recognized, yet significant contributor to aging and the development of dementia in peoplewith DS.We are currently in the process of quantifying microbleeds using MRI in the occtx in our aging DS cohort to link this pathology with cognitive decline. Funding from NIH/NICHD R01HD064993.