Patients with uterine cervical cancer are generally treated with both intracavitary brachytherapy (ICBT) and external beam radiotherapy (EBRT) using a midline block in Japan. However the actual total dose delivered to the rectum is hard to calculate, because the location of the high dose region may not be identical for each fraction. To calculate the cumulative dose more accurately, we have adapted the deformable image registration (DIR) method and analyzed the difference between the cumulative rectal dose by adding rectal D2cc (simple rectal D2cc) and the cumulative rectal D2cc estimated on the basis of DIR (DIR-based rectal D2cc). Fourteen patients with primary uterine cervical cancer radically treated with high-dose-rate ICRT and EBRT using a midline block were analyzed. When we compared simple rectal D2cc and DIR-based rectal D2cc, the total rectal doses were calculated as the biologically equivalent dose in 2-Gy fractions (EQD2). Simple rectal D2cc was defined as the dose of simply summed D2cc in EBRT and every fractions of ICRT. The calculation method of DIR-based rectal D2cc was shown in Table. Dice similarity coefficient (DSC) was calculated to evaluate the concordance between CT images before and after deformable registration. Statistical analysis was conducted using the Student's t-test. The mean DSC of rectal contours between reference CT and CT of EBRT was significantly improved from 0.43 before DIR to 0.85 after DIR (p < 0.005). Similarly, the value between reference CT and CT of ICBT was significantly ameliorated from 0.60 to 0.87 (p < 0.005). Simple rectal D2cc ranged from 70.5Gy to 88.5, and DIR-based rectal D2cc from 65.5Gy to 87.4Gy. Ten of 14 patients (71%) had higher simple rectal D2cc than DIR-based rectal D2cc, and the mean dose using simple rectal D2cc was 1.3 Gy higher than that using DIR-based rectal D2cc. DIR method may allow us to track more accurate total dose from multiple treatment planning CT of radical radiotherapy for uterine cervical cancer. The clinical impact of difference between simple rectal D2cc and DIR-based rectal D2cc warrants further investigation.Scientific Abstract 2681; TableProcedures of DIR method1. Making treatment plans2. Replacement of CT values using in-house software to improve CT images noise3. DIR of CT images in Velocity AI4. DIR of dose distribution converted to EQD2 in Velocity AI5. Integration of dose distributions of each EBRT and ICBT in Velocity AI Open table in a new tab

To investigate the clinical outcomes of non-invasive stereotactic radiosurgery for brain metastases of lung cancer in our institution. Sixty-seven patients with 109 brain metastases of lung cancer treated with non-invasive stereotactic radiosurgery between 1998 and 2011 were retrospectively analyzed. The median age was 63 years (range, 29-82). Sixty-four patients and 3 patients were previously diagnosed with non-small cell lung cancer and small cell lung cancer, respectively. Performance status by ECOG were 0-1 in 47 patients and 2-3 in 20 patients. Median Brinkmann index (BI) was 450 (range, 0-2580). The median size of metastatic lesions was 11 mm (range, 3- 55 mm) and the numbers of brain metastases were 1 in 37 patients, 2 in 19 patients, 3 in 7 patients, and ≥4 in 4 patients. Twenty-eight patients had uncontrolled primary disease and 34 patients had extracranial metastases. Seventy-six lesions were treated with a single fraction with the median dose of 24 Gy and 30 lesions were treated with 3 fractions with median doses of 30 Gy. The median follow-up time was 9.4 months (range, 0.4- 125). The in-field recurrence (IFR), intracranial recurrence (ICR) and overall survival (OS) rates were calculated using Kaplan-Meier method. Univariate (log-rank test) and multivariate (Cox proportional hazard model) were used to assess predictive factors associated with OS. Thirteen patients and 32 patients had IFR and ICR, respectively. The 1-year IFR rate was 16.7% and 1-year ICR rate was 46.8%. The median survival time was 13.1 months and the 1- and 3-year OS rate were 54.8% and 25.9%, respectively. On multivariate analysis, three factors were found to be statistically significant predictors of OS: (1) presence of uncontrolled primary disease at the time of treatment with hazard ratio (HR) of 3.04 (p = 0.002); (2) BI >1000 with HR of 2.75 (p = 0.007); and (3) pulmonary metastases with HR of 3.54 (p = 0.009). Radionecrosis and neurocognitive disorder after radiosurgery were observed in 5 patients (7%) and 3 patients (4%), respectively. Our study indicated that non-invasive stereotactic radiosurgery for brain metastases of lung cancer was safe and effective for local control. Uncontrolled primary disease, high BI, and pulmonary metastases at the treatment were significant risk factor for OS.

Linear-quadratic (LQ) model has been widely utilized to characterize radiosensitivity as well as fractionation sensitivity. It is a common practice to convert different dose fractionation schemes based on the LQ model. However, molecular factors that determine parameters in the LQ model are not well defined. We analyzed 52 of 54 solid cancer cell lines from the NCI-60 cancer cell line panel. The standard colony-forming assay was conducted to estimate α and β values in the LQ model. Based on the derived α and β values, the cell lines were categorized into three groups with low (< 0.15), intermediate (0.15-0.4), or high (> 0.4) α value; or low (< 0.015), intermediate (0.015-0.05), or high (> 0.05) β value. Gene expression profiles at basal level in the NCI-60 cell lines were searched and obtained from the publicly accessible microarray database. We used three independent datasets consisting of 427 samples. The raw microarray data were integrated into one dataset following preprocessing and quantile-normalization. Then, gene expression profiles were compared for the cell lines with low vs high α values, or for the cell lines with low vs high β values, respectively. The 52 cell lines varied widely in α and β values. Mean α and β values were 0.26 (range, 0.0001-0.82) Gy-1 and 0.036 (range, 0.003-0.091) Gy-2, respectively. There was no significant association between the α and the β values. Using the parametric analysis of gene set enrichment, differential gene expressions for α and β values were evaluated for pre-defined 1452 gene sets in the Gene Ontology. Following a correction of multiple comparisons with false discovery rate = 0.05, either positive or negative correlations were found between 29 gene sets and α values. Similarly, 125 gene sets were significantly associated with β values. Of these gene sets, only three gene sets were overlapped both for α and β values. We found pre-defined gene sets that associate with α or β values independently. The results may suggest that there are potential molecular targets not only for intrinsic radiosensitivity but also for fractionation sensitivity, which raises the question whether a modulation of fractionation sensitivity is possible in cancer cells.

OBJECTIVES:A cross-sectional study to establish whether a subject's cognitive state can be predicted based on regional values obtained from brain cortical maps of FDDNP Distribution Volume Ratio (DVR), which shows the pattern of beta amyloid and neurofibrillary binding, along with those of early summed FDDNP PET images (reflecting the pattern of perfusion) was performed. METHODS:Dynamic FDDNP PET studies were performed in a group of 23 subjects (8 control (NL), 8 Mild Cognitive Impairment (MCI) and 7 Alzheimer's Disease (AD) subjects). FDDNP DVR images were mapped to the MR derived hemispheric cortical surface map warped into a common space. A set of Regions of Interest (ROI) values of FDDNP DVR and early summed FDDNP PET (0-6 min post tracer injection), were thus calculated for each subject which along with the MMSE score were used to construct a linear mathematical model relating ROI values to MMSE. After the MMSE prediction models were developed, the models' predictive ability was tested in a non-overlapping set of 8 additional individuals, whose cognitive status was unknown to the investigators who constructed the predictive models. RESULTS:Among all possible subsets of ROIs, we found that the standard deviation of the predicted MMSE was 1.8 by using only DVR values from medial and lateral temporal and prefrontal regions plus the early summed FDDNP value in the posterior cingulate gyrus. The root mean square prediction error for the eight new subjects was 1.6. CONCLUSION:FDDNP scans reflect progressive neuropathology accumulation and can potentially be used to predict the cognitive state of an individual.

1 LENITEM Laboratory of Epidemiology, Neuroimaging & Telemedicine IRCCS Centro S. Giovanni di Dio FBF, Brescia, Italy 2 Machine Vision Laboratory, Department of Mathemat ics and Computer Science, University of Udine, Udin e, Italy 3 Neuroradiology Unit, Hospital Città di Brescia, B rescia 4 Laboratory of Neuro Imaging, Department of Neurol ogy, UCLA School of Medicine, Los Angeles, CA, USA 5 Psychogeriatrics Ward – IRCCS Centro S. Giovanni di Dio FBF, Brescia, Italy 6 AFaR Associazione Fatebenefratelli per la Ricerca , Rome, Italy

Objectives: To assess quantitatively the cortical pattern profile of regional FDDNP binding to beta-amyloid and neurofibrillary tangles on MR derived cortical maps, FDDNP PET images were corrected for movement and partial volume (PV), and optimized for kernel size.Methods: FDDNP DVR PET images from 23 subjects (7 with Alzheimer's disease (AD), 6 with mild cognitive impairment and 10 controls) were obtained from Logan analysis using cerebellum as reference. A hemispheric cortical surface model for each subject was extracted from the MRI. The same transformations were applied to the FDDNP DVR PET images to map them into the same space. The cortical map with PV correction was calculated as the ratio of the DVR cortical surface and that of the simulated map, created from the mask derived from MRI and smoothed to the PET resolution. Discriminant analysis was used to order the FDDNP DVR cortical surfaces based on subjects' disease state. Linear regression was used to assess the rate of change of DVR vs. MMSE for each hemispheric cortical surface point.Results: The FDDNP DVR Cortical surface corrected for movement and PV had less hemispheric asymmetry. Optimal kernel size was determined to be 9 mm. The corrected cortical surface map of FDDNP DVR showed clear spatial pattern that was consistent with the known pathological progression of AD.Conclusion: Correcting for movement, PV as well as optimizing kernel size provide sensitive statistical analysis of FDDNP distribution which confirms in the living brain known pathology patterns earlier observed with cognitive decline with brain specimens. (C) 2009 Elsevier Inc. All rights reserved.

In this study, a computational mapping technique was used to examine the three-dimensional profile of the lateral ventricles in autism. T1-weighted three-dimensional magnetic resonance images of the brain were acquired from 20 males with autism (age: 10.1 +/- 3.5 years) and 22 male control subjects (age: 10.7 +/- 2.5 years). The lateral ventricles were delineated manually and ventricular volumes were compared between the two groups. Ventricular traces were also converted into statistical three-dimensional maps, based on anatomical surface meshes. These maps were used to visualize regional morphological differences in the thickness of the lateral ventricles between patients and controls. Although ventricular volumes measured using traditional methods did not differ significantly between groups, statistical surface maps revealed subtle, highly localized reductions in ventricular size in patients with autism in the left frontal and occipital horns. These localized reductions in the lateral ventricles may result from exaggerated brain growth early in life. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

This paper investigates the performance of a new multivariate method for tensor-based morphometry (TBM). Statistics on Riemannian manifolds are developed that exploit the full information in deformation tensor fields. In TBM, multiple brain images are warped to a common neuroanatomical template via 3-D nonlinear registration; the resulting deformation fields are analyzed statistically to identify group differences in anatomy. Rather than study the Jacobian determinant (volume expansion factor) of these deformations, as is common, we retain the full deformation tensors and apply a manifold version of Hotelling's T-2 test to them, in a Log-Euclidean domain. In 2-D and 3-D magnetic resonance imaging (MRI) data from 26 HIV/AIDS patients and 14 matched healthy subjects, we compared multivariate tensor analysis versus univariate tests of simpler tensor-derived indices: the Jacobian determinant, the trace, geodesic anisotropy, and eigenvalues of the deformation tensor, and the angle of rotation of its eigenvectors. We detected consistent, but more extensive patterns of structural abnormalities, with multivariate tests on the full tensor manifold. Their improved power was established by analyzing cumulative p-value plots using false discovery rate (FDR) methods, appropriately controlling for false positives. This increased detection sensitivity may empower drug trials and large-scale studies of disease that use tensor-based morphometry.

Alzheimer's disease (AD) is characterized by great clinical variability. The identification of measurable features, such as imaging markers, associated with genetic and non-genetic factors could thus be helpful for therapeutic development. Previous MRI studies suggest that the Apolipoprotein E (APOE) e4 allele has region-specific effects on brain atrophy in AD, and is associated with reduced temporal lobe volume [1], [2]. However less is known about its effect on the cortical mantle. Aim of this study was to compare APOE-related patterns of atrophy over the cortical mantle in AD patients. We studied AD patients carrying (e4+, n=15, age 72±10SD years) and not carrying (e4-, n=14, age 69±9) the e4 allele of APOE and compared them to 29 age-matched controls (age 70±9). Each subject underwent clinical evaluation, a neuropsychological battery, and high-resolution MRI. Regions of cortical gray matter (GM) loss were identified using the UCLA cortical pattern matching technique[3]. Patients who were e4+ and e4- had similar global cognitive deterioration (MMSE: 20±3 and 20±5, p=.862; t-test). Both patient groups showed diffuse cortical atrophy, sparing only the sensory and motor areas, the anterior cingulate and medial orbitofrontal cortex (p=.0001 for both e4+ vs controls and e4- vs controls, for the left and right hemisphere; permutation test [4]; Fig. 1, top panel). GM loss ranged between 15–20% in both e4+ and e4- groups (Fig. 1, bottom panel). Regions of greater atrophy in carriers than non-carriers mapped to the temporal lobes (Fig. 2, bottom panel), showing a trend for significance in the lateral lobe (p=.051 in the right hemisphere; permutation test with small volume correction; Fig. 2, top panel) and entorhinal cortex (p=.078 in the left hemisphere; Fig. 2, top panel). The opposite effect, mapping to the frontal and retrosplenial cortex (Fig. 2, bottom panel), was not significant (p>.138; Fig. 2, top panel). This study supports the hypothesis of greater vulnerability of the temporal regions in APOE e4 carriers. These results, if confirmed in larger samples, could aid in development of specific therapeutic treatments in preclinical Alzheimer disease.

OBJECTIVE:To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation-1 protein and to aberrant cognition and behavior. METHODS:This study included 84 children and adolescents with the fragile X full mutation and 72 typically developing control subjects matched for age and sex. Brain morphology was assessed with volumetric, voxel-based, and surface-based modeling approaches. Intelligence quotient was evaluated with standard cognitive testing, whereas abnormal behaviors were measured with the Autism Behavior Checklist and the Aberrant Behavior Checklist. RESULTS:Significantly increased size of the caudate nucleus and decreased size of the posterior cerebellar vermis, amygdala, and superior temporal gyrus were present in the fragile X group. Subjects with fragile X also demonstrated an abnormal profile of cortical lobe volumes. A receiver operating characteristic analysis identified the combination of a large caudate with small posterior cerebellar vermis, amygdala, and superior temporal gyrus as distinguishing children with fragile X from control subjects with a high level of sensitivity and specificity. Large caudate and small posterior cerebellar vermis were associated with lower fragile X mental retardation protein levels and more pronounced cognitive deficits and aberrant behaviors. INTERPRETATION:Abnormal development of specific brain regions characterizes a neuroanatomic phenotype associated with fragile X syndrome and may mediate the effects of FMR1 gene mutations on the cognitive and behavioral features of the disorder. Fragile X syndrome provides a model for elucidating critical linkages among gene, brain, and cognition in children with serious neurodevelopmental disorders.

Amyloid plaques and tau neurofibrillary tangles, the pathological hallmarks of Alzheimer's disease (AD), begin accumulating in the healthy human brain decades before clinical dementia symptoms can be detected. There is great interest in how this pathology spreads in the living brain and its association with cognitive deterioration. Using MRI-derived cortical surface models and four-dimensional animation techniques, we related cognitive ability to positron emission tomography (PET) signal from 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([(18)F]FDDNP), a molecular imaging probe for plaques and tangles. We examined this relationship at each cortical surface point in 23 older adults (10 cognitively intact, 6 with amnestic mild cognitive impairment, 7 with AD). [(18)F]FDDNP-PET signal was highly correlated with cognitive performance, even in cognitively intact subjects. Animations of [(18)F]FDDNP signal growth with decreased cognition across all subjects (http://www.loni.ucla.edu/ approximately thompson/FDDNP/video.html) mirrored the classic Braak and Braak trajectory in lateral temporal, parietal, and frontal cortices. Regions in which cognitive performance was significantly correlated with [(18)F]FDDNP signal include those that deteriorate earliest in AD, suggesting the potential utility of [(18)F]FDDNP for early diagnosis.

Declarative memory impairments are common in patients with bipolar illness, suggesting underlying hippocampal pathology. However, hippocampal volume deficits are rarely observed in bipolar disorder. Here we used surface-based anatomic mapping to examine hippocampal anatomy in bipolar patients treated with lithium relative to matched control subjects and unmedicated patients with bipolar disorder. High-resolution brain magnetic resonance images were acquired from 33 patients with bipolar disorder (21 treated with lithium and 12 unmedicated), and 62 demographically matched healthy control subjects. Three-dimensional parametric mesh models were created from manual tracings of the hippocampal formation. Total hippocampal volume was significantly larger in lithium-treated bipolar patients compared with healthy controls (by 10.3%; p=0.001) and unmedicated bipolar patients (by 13.9%; p=0.003). Statistical mapping results, confirmed by permutation testing, revealed localized deficits in the right hippocampus, in regions corresponding primarily to cornu ammonis 1 subfields, in unmedicated bipolar patients, as compared to both normal controls (p=0.01), and in lithium-treated bipolar patients (p=0.03). These findings demonstrate the sensitivity of these anatomic mapping methods for detecting subtle alterations in hippocampal structure in bipolar disorder. The observed reduction in subregions of the hippocampus in unmedicated bipolar patients suggests a possible neural correlate for memory deficits frequently reported in this illness. Moreover, increased hippocampal volume in lithium-treated bipolar patients may reflect postulated neurotrophic effects of this agent, a possibility warranting further study in longitudinal investigations.

OBJECTIVE To compare the volumes of the caudate nucleus, using traditional volumetry and a three-dimensional brain mapping technique, in a group of individuals with late-life depression and a group of age- and education-equated nondepressed comparison subjects. DESIGN Cross-sectional. SETTING University Medical Center. PARTICIPANTS Twenty-three nondemented subjects with late-life depression and 15 age- and education-equated elderly comparison subjects (depressed mean years of age: 70.5 +/- 5.7 SD, comparison subjects = 69.9 years +/- 6.4) with no history of psychiatric or neurologic disease. MEASUREMENTS Structural magnetic resonance imaging. Three-dimensional (3-D) surface models were created from manually traced outlines of the caudate nucleus from spoiled gradient echo images. Models were geometrically averaged across subjects and statistical maps created to localize any regional volume differences between groups. RESULTS Relative to comparison subjects, depressed subjects had significantly lower mean volumes for both the left (p = 0.029) and right (p = 0.052) caudate nucleus as well as total caudate volume (p = 0.032). Total volumes were 13.1% less in the depressed group (13.5% on the left and 12.6% on the right). 3-D maps further localized these reductions to the caudate head. Volume reductions were correlated with depression severity, as measured by the 17-item Hamilton Depression Rating Scale. CONCLUSION Late-life depression is associated with left and right caudate nucleus reduction especially in anterior portions. Among depressed subjects, greater caudate reduction was associated with more severe depression. These results are consistent with growing evidence that the anterior caudate nucleus, especially the head, may be structurally and functionally abnormal in affective disorders.

Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 +/- 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group x time interactions.

We investigated the associations between Boston naming and the animal fluency tests and cortical atrophy in 19 probable AD and 5 multiple domain amnestic mild cognitive impairment patients who later converted to AD. We applied a surface-based computational anatomy technique to MRI scans of the brain and then used linear regression models to detect associations between animal fluency and Boston Naming Test (BNT) performance and cortical atrophy. The global permutation-corrected significance for the maps associating BNT performance with cortical atrophy was p = .0124 for the left and p = .0196 for the right hemisphere and for the animal fluency maps p = .055 for the left and p = .073 for the right hemisphere. The degree of language impairment correlated with cortical atrophy in the left temporal and parietal lobes (BA 20, 21, 37, 39, 40, and 7), bilateral frontal lobes (BA 8, 9, and 44) and the right temporal pole (BA 38). Using a novel 3D mapping technique, we demonstrated that in AD language abilities are strongly influenced by the integrity of the perisylvian cortical regions.