Whole Brain Research Articles

A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER).

Background:Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer’s disease (AD).Objective:We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression.Methods:The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available.Results:The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment.Conclusion:WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

The breast graded prognostic assessment is associated with the survival outcomes in breast cancer patients receiving whole brain re-irradiation

Whole brain (WB) re-irradiation for breast cancer patients with progressive brain metastasis after first-course WB radiotherapy (WBRT) is controversial. In this study, we sought to investigate the association between the molecular sub-classifications and breast-specific Graded Prognostic Assessment (GPA, which includes the Karnofsky performance status, molecular subtypes, and age as its indices) and the outcomes of breast cancer patients who received WB re-irradiation. Twenty-three breast cancer patients who received WB re-irradiation for relapsed and progressive intracranial lesions after first-course WBRT between 2004 and 2016 were retrospectively reviewed. Patients were divided according to the 4 molecular subtypes of luminal A/B (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), luminal HER2 (HR+/HER2+), HER2 (HR-/HER2+), and triple negative (HR-/HER2-). The clinical and radiological responses and survival rates after WB re-irradiation were analyzed. At 1 month after WB re-irradiation, 13 of 23 patients (56.5%) exhibited disappearance or alleviation of neurological symptoms. The median survival time after WB re-irradiation was 2.93 months (95% confidence interval [CI], 1.79-4.08). After WB re-irradiation, patients with HER2-negative tumors had poorer median survival times than those with HER2-positive tumors (2.23 vs. 3.0 months, respectively; p = 0.022). Furthermore, patients with high breast GPA scores (2.5-4.0, n = 11) had longer median survivals than those with low-scores (0-2.0, n = 12) after WB re-irradiation (4.37 vs. 1.57 months, respectively; p < 0.005). WB re-irradiation may be a feasible treatment option for certain breast cancer patients who develop brain metastatic lesions after first-course WBRT when these lesions are ineligible for radiosurgery or surgery.

Autoimmune comorbidities in multiple sclerosis: what is the influence on brain volumes? A case-control MRI study.

Several studies indicated that multiple sclerosis (MS) is frequently associated with other autoimmune diseases. However, it is little known if the coexistence of these conditions may influence the radiologic features of MS, and in particular the brain volumes. To evaluate the effect of autoimmune comorbidities on brain atrophy in a large case-control MS population. A group of MS patients affected by a second autoimmune disorder, and a control MS group without any comorbidity, were recruited. Patients underwent a brain MRI and volumes of whole brain (WB), white matter (WM), and gray matter (GM) with cortical GM were estimated by SIENAX. The sample included 286 MS patients, of which 30 (10.5%) subjects with type 1 diabetes (T1D), 53 (18.5%) with autoimmune thyroiditis (AT) and 4 (0.1%) with celiac disease. Multiple regression analysis found an association between T1D and lower GM (p = 0.038) and cortical GM (p = 0.036) volumes, independent from MS clinical features and related to T1D duration (p < 0.01), while no association was observed with AT and celiac disease. Our data support the importance of considering T1D as possible factors influencing the brain atrophy in MS. Further studies are needed to confirm our data and to clarify the underlying mechanisms.

Abstract WP400: Magnetic Resonance-Derived Oxygen Extraction Fraction in White Matter Hyperintensities Compared to Normal Appearing White Matter

Introduction: White matter hyperintensities (WMH), a common neuroradiological feature seen with aging, increases the risk of stroke, dementia, disability and mortality. The underlying pathophysiology leading to WMH is incompletely understood. Here, we examined the role of regional cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in WMH. Methods: Subjects with WMH (n=9) and age-matched controls (n=9) were imaged in a 3T MRI Scanner. OEF was obtained using an asymmetric spin echo sequence while CBF was obtained with pseudo-continuous arterial spin labeling. WMH were graded according to Fazekas et al. For tissue-type quantification, CBF and OEF images were segmented to classify whole brain (WB), gray matter (GM), white matter (WM), white matter hyperintensities (WMH), and normal appearing white matter (NAWM). Results: CBF and OEF in WB, GM and WM did not differ between cohorts. However, differences emerged when comparing the WMH and NAWM segmented tissues. Specifically, CBF in WMH was less than half that seen in NAWM in the WMH group, and similarly lower than normal WM in controls. Moreover, OEF in WMH was higher compared to NAWM and WM in controls, but this did not reach statistical significance (Table). Conclusions: CBF and OEF did not differ between subjects with or without WMH. However, within the WMH group, regions of WMH had significantly lower but not absent CBF and trends towards higher OEF compared to NAWM and normal WM in controls. These data suggest that regions of WMH do not represent irreversibly infarcted tissue, but rather, may be viable tissue under chronic metabolic stress. Increased OEF in WMH may be a marker of salvageable brain tissue; However, additional work is needed to confirm these results.

Whole brain neuronal abnormalities in focal quantified with proton MR spectroscopy

ObjectiveTo test the hypothesis that localization-related epilepsy is associated with widespread neuronal dysfunction beyond the ictal focus, reflected by a decrease in patients’ global concentration of their proton MR spectroscopy (1H-MRS) observed marker, N-acetyl-aspartate (NAA). MethodsThirteen patients with localization-related epilepsy (7 men, 6 women) 40 ± 13 (mean ± standard-deviation) years old, 8.3 ± 13.4 years of disease duration; and 14 matched controls, were scanned at 3 T with MRI and whole-brain (WB) 1H MRS. Intracranial fractions of brain volume, gray and white matter (fBV, fGM, fWM) were segmented from the MRI, and global absolute NAA creatine (Cr) and choline (Cho) concentrations were estimated from their WB 1H MRS. These metrics were compared between patients and controls using an unequal variance t test. ResultsPatients’ fBV, fGM and fWM: 0.81 ± 0.07, 0.47 ± 0.04, 0.31 ± 0.04 were not different from controls’ 0.79 ± 0.05, 0.48 ± 0.04, 0.32 ± 0.02; nor were their Cr and Cho concentrations: 7.1 ± 1.1 and 1.3 ± 0.2 millimolar (mM) versus 7.7 ± 0.7 and 1.4 ± 0.1 mM (p > 0.05 all). Patients’ global NAA concentration: 11.5 ± 1.5 mM, however, was 12% lower than controls’ 13.0 ± 0.8 mM (p = 0.004). ConclusionsThese findings indicate that neuronal dysfunction in localization-related epilepsy extends globally, beyond the ictal zone, but without atrophy or spectroscopic evidence of other pathology. This suggests a diffuse decline in the neurons’ health, rather than their number, early in the disease course. WB 1H-MRS assessment, therefore, may be a useful tool for quantification of global neuronal dysfunction load in epilepsy.

Multiple sclerosis and HLA genotypes: A possible influence on brain atrophy

Background: The strongest genetic determinant for multiple sclerosis (MS) is located at the human leukocyte antigen (HLA) class II DRB1 and DQB1 loci. Objectives: To investigate the possible role of predisposing HLA genotypes in determining brain atrophy. Methods: HLA genotypes were categorized as high risk (two predisposing haplotypes) or medium/low risk (one or no predisposing haplotypes). Patients underwent a brain magnetic resonance imaging (MRI) study and volumes of white matter (WM), gray matter (GM), and whole brain (WB) were estimated with SIENAX. Longitudinal atrophy was also assessed with SIENA. Results: The study included 240 MS patients. In 51/240 (21%) subjects, a high-risk HLA genotype was observed, while medium- and low-risk HLA genotypes were 109/240 (45%) and 80/240 (34%), respectively. Multiple regression analysis found that the high-risk HLA genotype was associated with significant reduction in WB (p = 0.02) and GM (p = 0.03) volumes compared with the medium-/low-risk HLA genotypes, independently from MS clinical features. The longitudinal study included 60 patients and showed a brain volume loss of −0.79% in high-risk HLA genotype group versus −0.56% in low-risk HLA genotype. Conclusion: Our results suggest an influence of HLA genotype on WB and GM atrophy. Further investigations are necessary to confirm these findings.

Role of Intensity Modulated Radiotherapy with Concurrent and Adjuvant Chemotherapy With Temozolamide in Glioblastoma Multiforme

Background: Glioblastoma multiforme (GBM) is one of the most aggressive and common primary malignant brain tumors, comprising 16% of all primary brain and central nervous system neoplasms, with a grim prognosis despite maximal treatment. Median age of presentation is 65 years. Patients often present with symptoms of increased intracranial pressure, including headache and focal or progressive neurologic deficits. The recurrence of GBM is inevitable, its management often unclear and case dependent. The purpose of our study was to analyse the role of Intensity Modulated Radiotherapy (IMRF) with concurrent and adjuvant chemotherapy in Glioblastoma. Methods: In our study we retrospectively analysed the treatment outcome of 84 patients of Glioblastoma, treated in our institute Gandhi Medical College, Hamidia Hospital and Jawaharlal Nehru Cancer Hospital, Bhopal between July 2010-December 2014. Patients were divided into 2 groups and proper consents were taken to participate in clinical trial. A group of 42 patients were treated by traditional method of surgery and WB (Whole-brain) RT alone and other group patients were treated with maximal safe surgical resection, followed by concurrent intensity modulated radiotherapy, IMRF (started after 1 month) in 1.8–2 Gy fractions administered 5 days per week with temozolomide (TMZ) at a dose of 75 mg/m2 daily for 6 weeks and then adjuvant chemotherapy was started with TMZ 150 mg/m2 daily for 5 days for the first month. If tolerated, the dose is escalated up to 200 mg/m2 for 5 consecutive days per month for 1 year. Results: With an average follow-up of three years in 84 patients of GBM, group of patients treated with surgical resection and concurrent IMRF with TMZ, after surgery followed by adjuvant TMZ for one year demonstrated superior Progression Free Survival (PFS) of 15 months versus months with surgery and RT alone, as well as superior Overall Survival (OS) of 28 months versus 14 months with other group. The 5 year OS rate was <1% in 1st group and 5-10% in other group. Patients with WB (Whole-brain) RT developed endocrinopathy, neurocognitive toxicity and leukoencephalopathy. IFRT delivers external beam RT to the tumor with a 2–3 cm margin and hence minimises toxicity. Conclusions: This study shows the effectiveness of treating GBM patients with maximal safe surgical resection, followed by concurrent IMRF and TMZ and adjuvant chemotherapy with TMZ for long time. It not only improves PFS but also improves OS. Further understanding of underlying tumor biology is essential in developing more effective strategies. Research in gene therapy, antiangiogenic antagonists, combination chemotherapy and immunotherapies could be a ray of hope in treating GBM. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy. Clinical trial identification: GMC2508IND17 Legal entity responsible for the study: Gandhi Medical College, Bhopal, India Funding: Gandhi Medical College, Bhopal, India Disclosure: All authors have declared no conflicts of interest.

Global and regional brain atrophy is associated with low or retrograde facial vein flow in multiple sclerosis

Increased collateral facial vein (FV) flow may be associated with structural damage in patients with multiple sclerosis (MS). The objective was to assess differences in FV flow and magnetic resonance imaging (MRI)-derived outcomes in MS. The study included 136 MS patients who underwent neck and head vascular system examination by echo-color Doppler. Inflammatory MRI markers were assessed on a 3T MRI using a semi-automated edge detection and contouring/ thresholding technique. MRI volumetric outcomes of whole brain (WB), gray matter (GM), white matter (WM), cortex, ventricular cerebrospinal fluid (vCSF), deep gray matter (DGM), thalamus, caudate nucleus (CN), putamen, globus pallidus (GP), and hippocampus were calculated. Independent &lt;em&gt;t&lt;/em&gt;-test and ANCOVA, adjusted for age, were used to compare groups based on FV flow quartiles. Thirty-four MS patients with FV flow ≤327.8 mL/min (lowest quartile) had significantly lower WB (P&amp;lt;0.001), WM (P&amp;lt;0.001), thalamus (P=0.004), cortex (P=0.004), GM (P=0.004), DGM (P=0.008), hippocampus (P=0.005), and GP volumes (P=0.044) compared to 102 patients with FV flow of &amp;gt;327.8 mL/min (higher quartiles). There were no differences in T1-, T2- and gadolinium- enhancing lesion volumes between the quartile groups. The lack of an association between FV blood flow and inflammatory MRI measures in MS patients, but an association with brain atrophy, suggests that the severity of neurodegenerative process may be related to hemodynamic alterations. MS patients with more advanced global and regional brain atrophy showed low or retrograde FV volume flow.

Meta-analysis of transcriptomic datasets identifies genes enriched in the mammalian circadian pacemaker.

The master circadian pacemaker in mammals is located in the suprachiasmatic nuclei (SCN) which regulate physiology and behaviour, as well as coordinating peripheral clocks throughout the body. Investigating the function of the SCN has often focused on the identification of rhythmically expressed genes. However, not all genes critical for SCN function are rhythmically expressed. An alternative strategy is to characterize those genes that are selectively enriched in the SCN. Here, we examined the transcriptome of the SCN and whole brain (WB) of mice using meta-analysis of publicly deposited data across a range of microarray platforms and RNA-Seq data. A total of 79 microarrays were used (24 SCN and 55 WB samples, 4 different microarray platforms), alongside 17 RNA-Seq data files (7 SCN and 10 WB). 31 684 MGI gene symbols had data for at least one platform. Meta-analysis using a random effects model for weighting individual effect sizes (derived from differential expression between relevant SCN and WB samples) reliably detected known SCN markers. SCN-enriched transcripts identified in this study provide novel insights into SCN function, including identifying genes which may play key roles in SCN physiology or provide SCN-specific drivers.

Combining task‐related activation and connectivity analysis of fMRI data reveals complex modulation of brain networks

Task-related effects in functional magnetic resonance imaging (fMRI) data are usually analyzed with local activation approaches or integrative connectivity approaches, for example, by psychophysiological interaction (PPI) analysis. While both approaches are often applied to the same data set, a systematic combination of the results with a whole-brain (WB) perspective is rarely conducted and the relationship between task-dependent activation and connectivity effects is relatively unexplored. Here, we combined brain activation and graph theoretical analysis of WB-PPI results in an exemplary episodic memory data set of N = 136 healthy human participants and found regions with congruent as well as incongruent activation and connectivity changes between task and control conditions. A comparison with large-scale resting state networks showed that in congruent as well as incongruent regions task-positively modulated connections were mainly between-network connections, especially with the default mode network, while task-negatively modulated connections were mainly found within resting state networks. Over all regions, the strength of absolute activation effects was associated with the tendency to exhibit task-positive connectivity changes, mainly driven by a strong relationship in negatively activated regions. These results demonstrate that task demands lead to a complex modulation of brain networks and provide evidence that task-evoked activation and connectivity effects reflect separable and complementary information on the macroscale brain level assessed by fMRI. Hum Brain Mapp 38:5726-5739, 2017. © 2017 Wiley Periodicals, Inc.

Detection and Growth Pattern of Arcuate Fasciculus from Newborn to Adult.

Fractional anisotropy (FA) threshold is commonly used to perform diffusion MRI tractography. However, FA threshold may be one aspect of tractography that needs additional scrutiny in accurately assessing pathways in immature, developing brains, as well as in adult brains. Using high-angular resolution diffusion MRI (HARDI) tractography without an FA threshold, we identified the arcuate fasciculus (AF) of 83 healthy subjects ranging in age from 40 gestational weeks (GW) (newborns) to 28-year-old adults. The AF was identified in both hemispheres in all subjects with high inter-rater reliability. The detected AF included regions with very low FA values. The entire AF was segmented into anterior, posterior, and long tracts. Growth and laterality patterns were investigated using tract count (number of detected streamlines), total volume of imaging voxels (touched by the detected streamlines), mean length, mean FA, and mean apparent diffusion coefficient (ADC). Comparison of subjects under 3 years old, to those that were older, revealed the three AF tracts that took different developmental courses. As expected, the anterior and long tracts showed lower ADC values in subjects over 3 years old, while the posterior tract showed higher ADC in that same age range. The posterior tract did not show age-related effect in terms of FA, tract count, length, and volume. These results suggest that the posterior AF tract shows a matured state, indexed by most of the used measurements in early postnatal developmental ages, and ADC is a measurement that can detect further maturation of the posterior tract. Interestingly, in all tracts, hemispheric asymmetries were found in raw (left<right), and in whole brain (WB)-normalized (left>right) tract count, as well as in raw volume (left<right). In raw, and in WB-normalized length, as well as in WB-normalized volume, rightward asymmetry (left<right) was found only in the anterior tract; other tracts were not significantly affected by hemisphere. Although many previous studies have observed a leftward asymmetry in the AF, rightward asymmetry has also been reported in other studies, and together with the present report, the results in the literature are likely to reflect differences in the methods used.

Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis

Background: Immunoablation and autologous hematopoietic stem cell transplantation (IA/aHSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration. Objective: To model GM and WM volume changes after IA/aHSCT to further understand the effects seen on WB atrophy. Methods: GM and WM volume changes were calculated from serial baseline and follow-up magnetic resonance imaging (MRI) ranging from 1.5 to 10.5 years in 19 MS patients treated with IA/aHSCT. A mixed-effects model with two predictors (total busulfan dose and baseline T1-weighted WM lesion volume “T1LV”) characterized the time-courses after IA/aHSCT. Results: Accelerated short-term atrophy of 2.1% and 3.2% occurred in GM and WM, respectively, on average. Both busulfan dose and T1LV were significant predictors of WM atrophy, whereas only busulfan was a significant predictor of GM atrophy. Compared to baseline, a significant reduction in GM atrophy, not WM atrophy, was found. The average rates of long-term GM and WM atrophy were −0.18%/year (standard error (SE): 0.083) and −0.07%/year (SE: 0.14), respectively. Conclusion: Chemotherapy-related toxicity affected both GM and WM. WM was further affected by focal T1-weighted lesion-related pathologies. Long-term rates of GM and WM atrophy were comparable to those of normal-aging.

A serial 10-year follow-up study of brain atrophy and disability progression in RRMS patients

Background: We explored the evolution of brain atrophy in relation to development of confirmed disability progression (CDP) on serial 1.5T magnetic resonance imaging (MRI) scans over a 10-year period in 181 patients with early relapsing–remitting multiple sclerosis (RRMS). Methods: At 10-year follow-up, they were divided into those with (100) or without (76) CDP (confirmed after 48 weeks). Changes in whole brain (WB), cortical, gray matter (GM), white matter, and ventricular cerebrospinal fluid (vCSF) volumes were calculated on three-dimensional T1-weighted (3D-T1) scans between all available time points. Results: In multiple sclerosis (MS) patients with CDP compared to those without, the greatest effect size percentage volume change from baseline to follow-up was detected for WB (d = 0.55, −7.5% vs −5.2%, p < 0.001), followed by vCSF (d = 0.51, +41.1% vs +25.7%, p < 0.001), cortical (d = 0.49, −7.7% vs −6.2%, p = 0.001), and GM (d = 0.40, −7.1% vs −5.8%, p = 0.006) volumes. Mixed-effects model analysis, adjusted for age, sex, and treatment change, showed significant interactions between CDP status and percentage changes for WB and vCSF (p < 0.001), cortical (p = 0.02), and GM (p = 0.04) volumes. Conclusions: WB and cortical atrophy, and enlargement of vCSF spaces are associated with development of CDP on serial yearly MRI assessments over a period of 10 years.

Temporal Profile of Cerebrovascular Reactivity Impairment, Gray Matter Volumes, and Persistent Symptoms after Mild Traumatic Head Injury.

Increased awareness around neurocognitive deficits after mild traumatic brain injury (mTBI) has progressed the search for objective, diagnostic, and monitoring tools, yet imaging biomarkers for mTBI and recovery are not established in clinical use. It has been suggested that mTBI impairs cerebrovascular reactivity (CVR) to CO2, which could be related to post-concussive syndrome (PCS). We investigate CVR evolution after mTBI using blood-oxygen-level dependent (BOLD) magnetic resonance imaging (MRI) and possible correlation with PCS. A prospective cohort of 25 mTBI patients and 18 matched controls underwent BOLD MRI CVR measurements. A subset of 19 mTBI patients underwent follow-up testing. Visits took place at a mean of 63 and 180 days after injury. Symptoms were assessed with the Sport Concussion Assessment Tool 2 (SCAT2). Symptoms, CVR and brain volume [gray matter (GM), white matter (WM), and whole brain (WB)], age, and sex, were examined between groups and longitudinally within traumatic brain injury (TBI) patients. Traumatic brain injury participants were 72% males, mean age being 42.7 years. Control participants were 61% with mean age of 38.7 years. SCAT2 scores tended to improve among those mTBI patients with follow-up visits (p = 0.07); however, they did not tend to recover to scores of the healthy controls. Brain volumes were not statistically different between groups at the first visit (WM p = 0.71; GM p = 0.36). In mTBI patients, there was a reduction in GM volume between visits 1 and 2 (p = 0.0046). Although mean CVR indexes were similar (WM p = 0.27; GM p = 0.36; and WB p = 0.35), the correlation between SCAT2 and CVR was negative in controls (WM-r = -0.59; p = 0.010; GM-r = -0.56; p = 0.016; brain-r = -0.58; p = 0.012) and weaker and positive in mTBI (brain-r = 0.4; p = 0.046; GM-r = 0.4; p = 0.048). SCAT2 correlated with GM volume (r = 0.5215, p = 0.0075) in mTBI but not in controls (r = 0.2945, p = 0.2355). There is a correlation between lower GM CVR indexes and lower performance on SCAT2 in patients with mTBI, which seems to be associated with more symptoms. This correlation seems to persist well beyond 120 days. mTBI may lead to a decrease in GM volume in these patients.

SU-E-I-65: Estimation of Tagging Efficiency in Pseudo-Continuous Arterial Spin Labeling (pCASL) MRI

Purpose: pCASL was recommended as a potent approach for absolute cerebral blood flow (CBF) quantification in clinical practice. However, uncertainties of tagging efficiency in pCASL remain an issue. This study aimed to estimate tagging efficiency by using short quantitative pulsed ASL scan (FAIR-QUIPSSII) and compare resultant CBF values with those calibrated by using 2D Phase Contrast (PC) MRI. Methods: Fourteen normal volunteers participated in this study. All images, including whole brain (WB) pCASL, WB FAIR-QUIPSSII and single-slice 2D PC, were collected on a 3T clinical MRI scanner with a 8-channel head coil. DeltaM map was calculated by averaging the subtraction of tag/control pairs in pCASL and FAIR-QUIPSSII images and used for CBF calculation. Tagging efficiency was then calculated by the ratio of mean gray matter CBF obtained from pCASL and FAIR-QUIPSSII. For comparison, tagging efficiency was also estimated with 2D PC, a previously established method, by contrast WB CBF in pCASL and 2D PC. Feasibility of estimation from a short FAIR-QUIPSSII scan was evaluated by number of averages required for obtaining a stable deltaM value. Setting deltaM calculated by maximum number of averaging (50 pairs) as reference, stable results were defined within ±10% variation. Results: Tagging efficiencies obtained by 2D PC MRI (0.732±0.092) were significantly lower than which obtained by FAIRQUIPPSSII (0.846±0.097) (P<0.05). Feasibility results revealed that four pairs of images in FAIR-QUIPPSSII scan were sufficient to obtain a robust calibration of less than 10% differences from using 50 pairs. Conclusion: This study found that reliable estimation of tagging efficiency could be obtained by a few pairs of FAIR-QUIPSSII images, which suggested that calibration scan in a short duration (within 30s) was feasible. Considering recent reports concerning variability of PC MRI-based calibration, this study proposed an effective alternative for CBF quantification with pCASL.

TH-CD-207-02: Quantification of Dynamic Susceptibility Contrast MRI: Comparison of Calibration Methods Using Venous Output Function and Arterial Spin Labeling

Purpose: To evaluate the validity of the calibration of arterial input function (AIF) by using a venous output function (VOF) for the quantification of cerebral blood flow (CBF) in dynamic susceptibility contrast MRI (DSC-MRI), by comparing to the arterial spin labeling (ASL) measurement. Method: Fourteen patients with unilateral ICA stenosis enrolled in the study on a 3T clinical MRI scanner. The ASL-CBF map was calculated by averaging 45 dynamic points acquired by using a Q2TIPS sequence. For DSC perfusion analysis, AIF was selected to derive the relative CBF (rCBF) map and the delay (Tmax) map; VOF with signal saturation was corrected by a small vein which was amplified and time-shifted to match the base and flanks of the original VOF. The DSC-CBF map was corrected by two different patient-specific correction factors (CF): (1) CF1: the ratio of the mean ASL-and DSC-CBF obtained from the mask based on Tmax < 3s, the gray matter mask and the exclusion of large vessels; (2) CF2: the ratio of the area under the first-pass phase in AIF and VOF concentration time curves. Result: Average whole-brain (WB) DSC-CBF calculated by CF1 and CF2 showed the same precision (coefficient of variation [COV] = 22%), while CBFCF2 (100.26 ± 23.36 ml/100g/min [mean ± SD]) was higher than CBFCF1 (37.4 ± 8.1 ml/100g/min). Significant correlation (R= 0.632; P<0.05) was found between the results obtained from these two calibration approaches. Conclusion: The degree of linear correlation between the WB DSC-CBF estimates obtained by AIF PV correction and ASL-based correction was significant. Comparing with CBF values obtained using ASL, the DSC-CBF estimates were high even after applying AIF PV correction. The over-estimation may come from the partial volume effect in VOF and other sources of errors in the DSC-MRI quantification.

Comprehensive Craniospinal Radiation for Controlling Central Nervous System Leukemia

To determine the benefit of radiation therapy (RT) in resolution of neurologic symptoms and deficits and whether the type of RT fields influences central nervous system (CNS) control in adults with CNS leukemia. A total of 163 adults from 1996 to 2012 were retrospectively analyzed. Potential associations between use of radiation and outcome were investigated by univariate and multivariate analysis. The median survival time was 3.8 months after RT. Common presenting symptoms were headache in 79 patients (49%), cranial nerve VII deficit in 46 (28%), and cranial nerve II deficit in 44 (27%). RT was delivered to the base of skull in 48 patients (29%), to the whole brain (WB) in 67 (41%), and to the craniospinal axis (CS) in 48 (29%). Among 149 patients with a total of 233 deficits, resolution was observed in 34 deficits (15%), improvement in 126 deficits (54%), stability in 34 deficits (15%), and progression in 39 deficits (17%). The 12-month CNS progression-free survival was 77% among those receiving CS/WB and 51% among those receiving base of skull RT (P=.02). On multivariate analysis, patients who did not undergo stem cell transplantation after RT and base of skull RT were associated with worse CNS progression-free survival. Improvement or resolution of symptoms occurred in two thirds of deficits after RT. Comprehensive radiation to the WB or CS seems to offer a better outcome, especially in isolated CNS involvement.

Sex-related and tissue-specific effects of tobacco smoking on brain atrophy: assessment in a large longitudinal cohort of healthy elderly.

We investigated the cross-sectional and longitudinal effects of tobacco smoking on brain atrophy in a large cohort of healthy elderly participants (65–80 years). MRI was used for measuring whole brain (WB), gray matter (GM), white matter (WM), and hippocampus (HIP) volumes at study entry time (baseline, N = 1451), and the annualized rates of variation of these volumes using a 4-year follow-up MRI in a subpart of the cohort (N = 1111). Effects of smoking status (never, former, or current smoker) at study entry and of lifetime tobacco consumption on these brain phenotypes were studied using sex-stratified AN(C)OVAs, including other health parameters as covariates. At baseline, male current smokers had lower GM, while female current smokers had lower WM. In addition, female former smokers exhibited reduced baseline HIP, the reduction being correlated with lifetime tobacco consumption. Longitudinal analyses demonstrated that current smokers, whether men or women, had larger annualized rates of HIP atrophy, as compared to either non or former smokers, independent of their lifetime consumption of tobacco. There was no effect of smoking on the annualized rate of WM loss. In all cases, measured sizes of these tobacco-smoking effects were of the same order of magnitude than those of age, and larger than effect sizes of any other covariate. These results demonstrate that tobacco smoking is a major factor of brain aging, with sex- and tissue specific effects, notably on the HIP annualized rate of atrophy after the age of 65.

PET imaging of fatty acid amide hydrolase with [(18)F]DOPP in nonhuman primates.

Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (5–6 Ci·μmol–1) was administered intravenously (iv) to three baboons (2M/1F, 3–4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 μg/kg URB597: 0.058 mL/cm3/min), suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data.

Noncontrast mapping of arterial delay and functional connectivity using resting‐state functional MRI: A study in Moyamoya patients

To investigate if delays in resting-state spontaneous fluctuations of the BOLD (sfBOLD) signal can be used to create maps similar to time-to-maximum of the residue function (Tmax) in Moyamoya patients and to determine whether sfBOLD delays affect the results of brain connectivity mapping. Ten patients were scanned at 3 Tesla using a gradient-echo echo planar imaging sequence for sfBOLD imaging. Cross correlation analysis was performed between each brain voxel signal and a reference signal comprised of either the superior sagittal sinus (SSS) or whole brain (WB) average time course. sfBOLD delay maps were created based on the time shift necessary to maximize the correlation coefficient, and compared with dynamic susceptibility contrast Tmax maps. Standard and time-shifted resting-state BOLD connectivity analyses of the default mode network were compared. Good linear correlations were found between sfBOLD delays and Tmax using the SSS as reference (r(2) = 0.8, slope = 1.4, intercept = -4.6) or WB (r(2) = 0.7, slope = 0.8, intercept = -3.2). New nodes of connectivity were found in delayed regions when accounting for delays in the analysis. Resting-state sfBOLD imaging can create delay maps similar to Tmax maps without the use of contrast agents in Moyamoya patients. Accounting for these delays may affect the results of functional connectivity maps.