Stefano Peca

Neurovascular decoupling is associated with severity of cerebral amyloid angiopathy

Objectives: We used functional MRI (fMRI), transcranial Doppler ultrasound, and visual evoked potentials (VEPs) to determine the nature of blood flow responses to functional brain activity and carbon dioxide (CO2) inhalation in patients with cerebral amyloid angiopathy (CAA), and their association with markers of CAA severity. Methods: In a cross-sectional prospective cohort study, fMRI, transcranial Doppler ultrasound CO2 reactivity, and VEP data were compared between 18 patients with probable CAA (by Boston criteria) and 18 healthy controls, matched by sex and age. Functional MRI consisted of a visual task (viewing an alternating checkerboard pattern) and a motor task (tapping the fingers of the dominant hand). Results: Patients with CAA had lower amplitude of the fMRI response in visual cortex compared with controls (p = 0.01), but not in motor cortex (p = 0.22). In patients with CAA, lower visual cortex fMRI amplitude correlated with higher white matter lesion volume (r = −0.66, p = 0.003) and more microbleeds (r = −0.78, p < 0.001). VEP P100 amplitudes, however, did not differ between CAA and controls (p = 0.45). There were trends toward reduced CO2 reactivity in the middle cerebral artery (p = 0.10) and posterior cerebral artery (p = 0.08). Conclusions: Impaired blood flow responses in CAA are more evident using a task to activate the occipital lobe than the frontal lobe, consistent with the gradient of increasing vascular amyloid severity from frontal to occipital lobe seen in pathologic studies. Reduced fMRI responses in CAA are caused, at least partly, by impaired vascular reactivity, and are strongly correlated with other neuroimaging markers of CAA severity.

Effects of aging on the association between cerebrovascular responses to visual stimulation, hypercapnia and arterial stiffness

Aging is associated with decreased vascular compliance and diminished neurovascular- and hypercapnia-evoked cerebral blood flow (CBF) responses. However, the interplay between arterial stiffness and reduced CBF responses is poorly understood. It was hypothesized that increased cerebral arterial stiffness is associated with reduced evoked responses to both, a flashing checkerboard visual stimulation (i.e., neurovascular coupling), and hypercapnia. To test this hypothesis, 20 older (64 ± 8 year; mean ± SD) and 10 young (30 ± 5 year) subjects underwent a visual stimulation (VS) and a hypercapnic test. Blood velocity through the posterior (PCA) and middle cerebral (MCA) arteries was measured concurrently using transcranial Doppler ultrasound (TCD). Cerebral and systemic vascular stiffness were calculated from the cerebral blood velocity and systemic blood pressure waveforms, respectively. Cerebrovascular (MCA: young = 76 ± 15%, older = 98 ± 19%, p = 0.004; PCA: young = 80 ± 16%, older = 106 ± 17%, p < 0.001) and systemic (young = 59 ± 9% and older = 80 ± 9%, p < 0.001) augmentation indices (AI) were higher in the older group. CBF responses to VS (PCA: p < 0.026) and hypercapnia (PCA: p = 0.018; MCA: p = 0.042) were lower in the older group. A curvilinear model fitted to cerebral AI and age showed AI increases until ~60 years of age, after which the increase levels off (PCA: R2 = 0.45, p < 0.001; MCA: R2 = 0.31, p < 0.001). Finally, MCA, but not PCA, hypercapnic reactivity was inversely related to cerebral AI (MCA: R2 = 0.28, p = 0.002; PCA: R2 = 0.10, p = 0.104). A similar inverse relationship was not observed with the PCA blood flow response to VS (R2 = 0.06, p = 0.174). In conclusion, older subjects had reduced neurovascular- and hypercapnia-mediated CBF responses. Furthermore, lower hypercapnia-mediated blood flow responses through the MCA were associated with increased vascular stiffness. These findings suggest the reduced hypercapnia-evoked CBF responses through the MCA, in older individuals may be secondary to vascular stiffening.

Two-dimensional in vivo dose verification using portal imaging and correlation ratios

The electronic portal imaging device (EPID) has the potential to be used for in vivo dosimetry during radiation therapy as an additional dose delivery check. In this study we have extended a method developed by A. Piermattei and colleagues in 2006 that made use of EPID transit images (acquired during treatment) to calculate dose in the isocenter point. The extension allows calculation of two‐dimensional dose maps of the entire radiation field at the depth of isocenter. We quantified the variability of the ratio of EPID signal to dose in the isocenter plane in Solid Water phantoms of various thicknesses and with various field sizes, and designed a field edge dose calculation correction. To validate the method, we designed three realistic conventional radiation therapy treatment plans on a thorax and head anthropomorphic phantom (whole brain, brain primary, lung tumor). Using CT data, EPID transit images, EPID signal‐to‐dose correlation, and our edge correction, we calculated dose in the isocenter plane and compared it with the treatment planning systems prediction. Gamma evaluation (3%, 3 mm) showed good agreement (Pγ<1 ≥ 96.5%) for all fields of the whole brain and brain primary plans. In the presence of lung, however, our algorithm overestimated dose by 7%–9%. This 2D EPID‐based in vivo dosimetry method can be used for posttreatment dose verification, thereby improving the safety and quality of patient treatments. With future work, it may be extended to measure dose in real time and to prevent harmful delivery errors. PACS numbers: 87.55.km, 87.55.Qr, 87.55.T‐

Therapeutic Strategies and Drug Development for Vascular Cognitive Impairment

Dementia is a large and growing health problem in developed and developing countries, with total costs approaching 1% of global gross domestic product, threatening the sustainability of healthcare systems.1 There are currently no disease‐modifying treatments for the most common cause of dementia, Alzheimer disease (AD). The second most common contributor to dementia risk is cerebrovascular disease.2 In contrast to AD, there is greater hope that vascular contributions to cognitive impairment can be prevented and treated. Recent evidence that the incidence of dementia is declining has prompted speculation, not yet confirmed, that this decline may be partly attributable to improved vascular care.3, 4 In this article, we review trial design and drug development for vascular cognitive impairment (VCI), focusing on symptomatic patients with vascular mild cognitive impairment (MCI) or dementia. First, we review axes along which vascular components of cognitive impairment can be addressed, including choice of trial population, trial intervention, and type of outcome. Second, we briefly review the pathophysiology of VCI, introducing the concept that trials may focus on disease modification, improving resilience, or enhancing cognition. Third, we systematically review prior drug trials for VCI patients according to drug class and trial size. Finally, we offer suggestions for methodological improvements for future trials.

Identification of neurovascular changes associated with cerebral amyloid angiopathy from subject-specific hemodynamic response functions.

Cerebral amyloid angiopathy (CAA) is a small-vessel disease preferentially affecting posterior brain regions. Recent evidence has demonstrated the efficacy of functional MRI in detecting CAA-related neurovascular injury, however, it is unknown whether such perturbations are associated with changes in the hemodynamic response function (HRF). Here we estimated HRFs from two different brain regions from block design activation data, in light of recent findings demonstrating how block designs can accurately reflect HRF parameter estimates while maximizing signal detection. Patients with a diagnosis of probable CAA and healthy controls performed motor and visual stimulation tasks. Time-to-peak (TTP), full-width at half-maximum (FWHM), and area under the curve (AUC) of the estimated HRFs were compared between groups and to MRI features associated with CAA including cerebral microbleed (CMB) count. Motor HRFs in CAA patients showed significantly wider FWHM (P = 0.006) and delayed TTP (P = 0.03) compared to controls. In the patient group, visual HRF FWHM was positively associated with CMB count (P = 0.03). These findings indicate that hemodynamic abnormalities in patients with CAA may be reflected in HRFs estimated from block designs across different brain regions. Moreover, visual FWHM may be linked to structural MR indications associated with CAA.

A Simple Method for 2-D In Vivo Dosimetry by Portal Imaging

Purpose: To improve patient safety and treatment quality, verification of dose delivery in radiotherapy is desirable. We present a simple, easy-to-implement, open-source method for in vivo planar dosimetry of conformal radiotherapy by electronic portal imaging device (EPID). Methods: Correlation ratios, which relate dose in the mid-depth of slab phantoms to transit EPID signal, were determined for multiple phantom thicknesses and field sizes. Off-axis dose is corrected for by means of model-based convolution. We tested efficacy of dose reconstruction through measurements with off-reference values of attenuator thickness, field size, and monitor units. We quantified the dose calculation error in the presence of thickness changes to simulate anatomical or setup variations. An example of dose calculation on patient data is provided. Results: With varying phantom thickness, field size, and monitor units, dose reconstruction was almost always within 3% of planned dose. In the presence of thickness changes from planning CT, the dose discrepancy is exaggerated by up to approximately 1.5% for 1 cm changes upstream of the isocenter plane and 4% for 1 cm changes downstream. Conclusion: Our novel electronic portal imaging device in vivo dosimetry allows clinically accurate 2-dimensional reconstruction of dose inside a phantom/patient at isocenter depth. Due to its simplicity, commissioning can be performed in a few hours per energy and may be modified to the user’s needs. It may provide useful dose delivery information to detect harmful errors, guide adaptive radiotherapy, and assure quality of treatment.

In Vivo EPID Dosimetry Detects Interfraction Errors in 3D-CRT of Rectal Cancer

BACKGROUND In vivo dosimetry can record the delivered dose during radiotherapy, which may be used to trigger adaptive radiotherapy or other user intervention. We demonstrate the use of our in-house in vivo electronic portal imaging dosimetry in quantifying interfraction dose variability in rectal cancer. METHODS We recorded MV images from nine treatment beams for six patients prone on the belly board, during 4-7 fractions, for a total of 50 measurements. Images were processed with our dosimetry system to produce dose maps. The dose map from the reference fraction was compared to all subsequent ones to determine interfraction delivery variation, yielding 41 dose difference maps. RESULTS We identified a number of dose discrepancies. In several patients, persistent gas bubbles may result in cumulative dose deviations large enough to warrant adaptive radiotherapy. In three patients, discrepancies in dose resulted from variability of patient positioning on the belly board. These issues were not readily identified by standard imaging procedures. CONCLUSION We are developing an open-source in vivo portal dosimetry method to automatically track delivered dose at every fraction. Results can be used to flag unexpected discrepancies, guide adaptive radiotherapy, or warrant image guidance. Further data is needed to test applicability with other treatment sites and setups.

In vivo Portal Imaging Dosimetry Identifies Delivery Errors in Rectal Cancer Radiotherapy on the Belly Board Device

Purpose: We recently developed a novel, open-source in vivo dosimetry that uses the electronic portal imaging device to detect dose delivery discrepancies. We applied our method on patients with rectal cancer treated on a belly board device. Methods: In vivo dosimetry was performed on 10 patients with rectal cancer treated prone on the belly board with a 4-field box arrangement. Portal images were acquired approximately once per week from each treatment beam. Our dosimetry method used these images along with the planning CT to reconstruct patient planar dose at isocenter depth. Results: Our algorithm proved sensitive to dose discrepancies and detected discordances in 7 patients. The majority of these were due to soft tissue differences between planning and treatment, present despite matching to bony anatomy. As a result of this work, quality assurance procedures have been implemented for our immobilization devices. Conclusion: In vivo dosimetry is a powerful quality assurance tool that can detect delivery discrepancies, including changes in patient setup and position. The added information on actual dose delivery may be used to evaluate equipment and process quality and to guide for adaptive radiotherapy.

SYSTEMATIC REVIEW OF RCTS OF INTERVENTIONS FOR VASCULAR COGNITIVE IMPAIRMENT

were dose proportional across the tested doses. SUVN-G3031 has achieved the projected efficacy concentrations and attained steady state on day 7 upon multiple administrations in healthy male subjects. SUVN-G3031 is well tolerated in humans with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration. Phase II enabling long term safety studies for SUVN-G3031 is currently ongoing. The Phase II study is being planned.

Poster — Thur Eve — 25: Sensitivity to inhomogeneities for an in-vivo EPID dosimetry method

Introduction: The electronic portal imaging device (EPID) has the potential to be used for in vivo dosimetry during radiotherapy as an additional dose delivery check. We recently proposed a simple method of using the EPID for 2D-IVD based on correlation ratios. In this work we have investigated the sensitivity of our EPID-IVD to inhomogeneities. Methods: We used slab phantoms that simulate water, bone, and lung, arranged in various geometries. To simulate body contours non-orthogonal to the field, we used a water wedge. CT data of these phantoms was imported into MATLAB, in conjunction with EPID images acquired during irradiation, to calculate dose inside the phantom in isocenter plane. Each phantom was irradiated using a linear accelerator while images were acquired with the EPID (cine mode). Comparisons between EPID-calculated and TPS dose maps were: pixel-by-pixel dose difference, and 3%,3mm gamma evaluation. Results: In the homogeneous case, CAX dose difference was 15% from the TPS. This suggests that this EPID-IVD is capable of detecting gross dose delivery errors even in the presence of inhomogeneities, supporting its utility as an additional patient safety device.