Longitudinal hippocampal atrophy in hippocampal sclerosis of aging.

Hippocampal sclerosis of aging (HS-A) is a common degenerative neuropathology in older individuals and is associated with dementia. HS-A is characterized by disproportionate hippocampal atrophy at autopsy but cannot be diagnosed during life. Therefore, little is known about the onset and progression of hippocampal atrophy in individuals with HS-A. To better understand the onset and progression of hippocampal atrophy in HS-A, we examined longitudinal hippocampal atrophy using serial MRI in participants with HS-A at autopsy (HS-A+, n = 8) compared to participants with limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) without HS-A (n = 13), Alzheimer's disease neuropathologic change (ADNC) without HS-A or LATE-NC (n = 16), and those without these pathologies (n = 7). We found that participants with HS-A had lower hippocampal volumes compared to the other groups, and this atrophy preceded the onset of dementia. There was also some evidence that rates of hippocampal volume loss were slightly slower in those with HS-A. Together, these results suggest that the disproportionate hippocampal atrophy seen in HS-A may begin early prior to dementia.

Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old.

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.

Dementia is associated with medial temporal atrophy even after accounting for neuropathologies.

Brain atrophy is associated with degenerative neuropathologies and the clinical status of dementia. Whether dementia is associated with atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. We used data from National Alzheimer's Coordinating Center (n = 129) and Alzheimer's Disease Neuroimaging Initiative (n = 47) participants with suitable in vivo 3D-T1w MRI and autopsy data. We determined dementia status at the visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy and atherosclerosis. Voxel-based morphometry identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analysed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. We also examined models with dementia and Clinical Dementia Rating sum of the boxes as the outcome and explored the potential mediating effect of medial temporal lobe structure volumes on the relationship between pathology and cognition. We found strong associations for dementia with volumes of the hippocampus, amygdala and parahippocampus (semi-partial correlations ≥ 0.28, P < 0.0001 for all regions in National Alzheimer's Coordinating Center; semi-partial correlations ≥ 0.35, P ≤ 0.01 for hippocampus and parahippocampus in Alzheimer's Disease Neuroimaging Initiative). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). We also found that the volumes of the medial temporal lobe structures contributed towards explaining the variance in Clinical Dementia Rating sum of the boxes (ranging from 5% to 9%) independent of neuropathologies and partially mediated the association between Alzheimer's disease neuropathology and cognition. Even after accounting for the most common neuropathologies, dementia still had among the strongest associations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to the clinical status of dementia rather than Alzheimer's disease or other neuropathologies, with the potential exception of hippocampal sclerosis.

Neuroimaging in the Oldest-Old: A Review of the Literature.

The oldest-old, those 85 years and older, are the fastest growing segment of the population and present with the highest prevalence of dementia. Given the importance of neuroimaging measures to understand aging and dementia, the objective of this study was to review neuroimaging studies performed in oldest-old participants. We used PubMed, Google Scholar, and Web of Science search engines to identify in vivo CT, MRI, and PET neuroimaging studies either performed in the oldest-old or that addressed the oldest-old as a distinct group in analyses. We identified 60 studies and summarized the main group characteristics and findings. Generally, oldest-old participants presented with greater atrophy compared to younger old participants, with most studies reporting a relatively stable constant decline in brain volumes over time. Oldest-old participants with greater global atrophy and atrophy in key brain structures such as the medial temporal lobe were more likely to have dementia or cognitive impairment. The oldest-old presented with a high burden of white matter lesions, which were associated with various lifestyle factors and some cognitive measures. Amyloid burden as assessed by PET, while high in the oldest-old compared to younger age groups, was still predictive of transition from normal to impaired cognition, especially when other adverse neuroimaging measures (atrophy and white matter lesions) were also present. While this review highlights past neuroimaging research in the oldest-old, it also highlights the dearth of studies in this important population. It is imperative to perform more neuroimaging studies in the oldest-old to better understand aging and dementia.

Utility of MRI in the identification of hippocampal sclerosis of aging.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is a common pathology often misdiagnosed as Alzheimer's disease. We tested the hypothesis that participants with HS would have a magnetic resonance imaging (MRI)-detectable hippocampal pattern of atrophy distinct from participants without HS, both with and without Alzheimer's disease neuropathology (ADNP). METHODS: Query of the National Alzheimer's Coordinating Center database identified 198 participants with MRI and autopsy. Hippocampal subfields were segmented with FreeSurfer v6. Analysis of covariance for subfield volumes compared HS+ participants to those without HS, both with ADNP (HS-/ADNP+) and without (HS-/ADNP-). RESULTS: HS+ participants (N = 27, 14%) showed atrophied cornu ammonis 1 (CA1; left P < .001, ηp2  = 0.14; right P = .001, ηp2  = 0.09) and subiculum (left P < .001, ηp2  = 0.139; right P = .001, ηp2  = 0.085) compared to HS-/ADNP+ (N = 100, 51%). Compared to HS-/ADNP- (N = 71, 36%), HS+ also had atrophy in subiculum (left P < .001, ηp2  = 0.235; right P = .002, ηp2  = 0.137) and CA1 (left P < .001, ηp2  = 0.137; right P = .006, ηp2  = 0.070). DISCUSSION: Subiculum and CA1 atrophy from clinical MRI may be a promising in vivo biomarker for HS.

Neck disability in patients with cervical spondylosis is associated with altered brain functional connectivity.

Cervical degenerative disease is a major cause of neck disability, but it has been understudied in patients with cervical spondylotic (CS), largely due to the fact that the neurological impairment associated with this condition tends to be the primary treatment focus. This observational study examined the cerebral functional alterations occurring in advanced cervical spondylosis and myelopathy using resting state functional MRI. Associations between functional connectivity (FC) and neck disability using the Neck Disability Index (NDI) were assessed. Results of the study demonstrated an increase in FC with increasing in neck disability in regions associated with sensorimotor system (both postcentral gyri and precentral gyri, bilaterally, with the SMA; bilateral precentral gyri and the left postcentral gyrus, with the left superior frontal gyrus; bilateral SMA and the left putamen, with the superior frontal gyri). Accounting for the difference in neurological function (mJOA score), strong connectivity between the precentral gyri and the SMA associated with the neck disability. Consistent with studies in chronic pain conditions, these findings suggest neck disability is associated with altered cerebral FC in cervical spondylosis patients.

White Matter Hyperintensities and Hippocampal Atrophy in Relation to Cognition: The 90+ Study.

OBJECTIVES: To study the interactive effect of white matter hyperintensities (WMH) and hippocampal atrophy on cognition in the oldest old. DESIGN: Ongoing longitudinal study. SETTING: In Southern California, brain magnetic resonance imaging (MRI) scans were conducted between May 2014 and December 2017. PARTICIPANTS: Individuals from The 90+ Study with a valid brain MRI scan (N = 141; 94 cognitively normal and 47 with cognitive impairment). MEASUREMENTS: Cognitive testing was performed every 6 months with a mean follow-up of 2 years and included these tests: Mini-Mental State Examination (MMSE), modified MMSE (3MS), California Verbal Learning Test (CVLT) immediate recall over four trials and delayed recall, Digit Span Backward, Animal Fluency, and Trail Making Test (TMT) A, B, and C. We used one linear mixed model for each cognitive test to study the baseline and longitudinal association of WMH and hippocampal volume (HV) with cognition. Models were adjusted for age, sex, and education. RESULTS: Mean age was 94.3 years (standard deviation [SD] = 3.2 y). At baseline, higher WMH volumes were associated with worse scores on the 3MS, CVLT immediate and delayed recall, and TMT B. Lower HVs were associated with worse baseline scores on all cognitive tests, except for the Digit Span Backward. Longitudinally, higher WMH and lower HVs were associated with faster decline in the 3MS and MMSE, and lower HV was also associated with faster decline in the CVLT immediate recall. No association was observed between WMH and HV and no interaction between WMH and HV in their association with baseline cognition or cognitive decline. CONCLUSION: We show that WMH and hippocampal atrophy have an independent, negative effect on cognition that make these biomarkers relevant to evaluate in the diagnostic work-up of the oldest-old individuals with cognitive complaints. However, the predictive value of WMH for cognitive decline seems to be less evident in the oldest-old compared with a younger group of older adults. J Am Geriatr Soc 67:1827-1834, 2019.

Spinal Cord Perfusion MR Imaging Implicates Both Ischemia and Hypoxia in the Pathogenesis of Cervical Spondylosis.

OBJECTIVES: Although a number of studies have implicated ischemia and hypoxia in the pathogenesis of cervical spondylosis, quantification remains difficult and the role of ischemia and hypoxia on disease progression and disease severity in human cervical spondylosis remains largely unknown. Therefore, the objective of this study was to assess spinal cord perfusion and oxygenation in human cervical spondylosis and examine the relationship between perfusion, degree of spinal cord compression, and neurological status. METHODS: Twenty-two patients with cervical spondylosis with or without myelopathy received a dynamic susceptibility contrast perfusion MRI exam consisting of a novel spin-and-gradient echo echoplanar acquisition before, during, and following gadolinium-based contrast injection. Estimation of relative spinal cord blood volume (rSCBV), the reversible relaxation rate (R2á), and relative oxygen extraction fraction (rOEF = R2á/rSCBV) was performed at the site of compression and compared with anterior-posterior spinal cord diameter and modified Japanese Orthopedic Association (mJOA) score, a measure of neurological impairment. RESULTS: rSCBV was linearly correlated with both anterior-posterior cord diameter (R2 = 0.4667, P = 0.0005) and mJOA (R2 = 0.2274, P = 0.0248). R2á was linearly correlated with mJOA (R2 = 0.3998, P = 0.0016) but not cord diameter (R2 = 0.055; P = 0.2950). Also, rOEF was correlated with both cord diameter (R2 = 0.3440, P = 0.0041) and mJOA (R2 = 0.4699, P = 0.0004). CONCLUSIONS: Results support the hypothesis that spinal cord compression results in ischemia and hypoxia, and the degree of ischemia and hypoxia is proportional to the degree of neurological impairment.

Alterations in Cortical Thickness and Subcortical Volume are Associated With Neurological Symptoms and Neck Pain in Patients With Cervical Spondylosis.

BACKGROUND: Advanced cervical spondylosis (CS) can cause structural damage to the spinal cord resulting in long-term neurological impairment including neck pain and motor weakness. We hypothesized long-term structural reorganization within the brain in patients with CS. OBJECTIVE: To explore the associations between cortical thickness, subcortical volumes, neurological symptoms, and pain severity in CS patients with or without myelopathy and healthy controls (HCs). METHODS: High-resolution T1-weighted structural magnetic resonance imaging (MRI) scans from 26 CS patients and 45 HCs were acquired. Cortical thickness and subcortical volumes were computed and compared to the modified Japanese Orthopedic Association (mJOA) and the Neck Disability Index (NDI) scores. RESULTS: Cortical thinning within the superior frontal gyrus, anterior cingulate, precuneus, and reduction in putamen volume were associated with worsening neurological and pain symptoms. Among the strongest associations were cortical thickness within the left precuneus (R2 = 0.34) and left and right putamen (R2 = 0.43, 0.47, respectively) vs mJOA, and the left precuneus (R2 = 0.55), insula (R2 = 0.57), and right putamen (R2 = 0.54) vs NDI (P ≤ .0001 for all). Cortical thickness along Brodmann areas 3a, 4a, and 4p were also moderately associated with mJOA. Preliminary evidence also suggests that patients with CS may undergo cortical atrophy at a faster rate than HCs. CONCLUSION: Patients with CS appear to exhibit cortical thinning and atrophy with worsening neurological and pain symptoms in specific brain regions associated with sensorimotor and pain processing.

Changes in brain white matter structure are associated with urine proteins in urologic chronic pelvic pain syndrome (UCPPS): A MAPP Network study.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has yielded neuroimaging and urinary biomarker findings that highlight unique alterations in brain structure and in urinary proteins related to tissue remodeling and vascular structure in patients with Urological Chronic Pelvic Pain Syndrome (UCPPS). We hypothesized that localized changes in diffusion tensor imaging (DTI) measurements might be associated with corresponding changes in urinary protein levels in UCPPS. To test this hypothesis, we created statistical parameter maps depicting the linear correlation between DTI measurements (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) and urinary protein quantification (MMP2, MMP9, NGAL, MMP9/NGAL complex, and VEGF) in 30 UCPPS patients from the MAPP Research Network, after accounting for clinical covariates. Results identified a brainstem region that showed a strong correlation between both ADC (R2 = 0.49, P<0.0001) and FA (R2 = 0.39, P = 0.0002) with urinary MMP9 levels as well as a correlation between both ADC (R2 = 0.42, P = 0.0001) and FA (R2 = 0.29, P = 0.0020) and urinary MMP9/NGAL complex. Results also identified significant correlations between FA and urinary MMP9 in white matter adjacent to sensorimotor regions (R2 = 0.30, P = 0.002; R2 = 0.36, P = 0.0005, respectively), as well as a correlation in similar sensorimotor regions when examining ADC and urinary MMP2 levels (R2 = 0.42, P<0.0001) as well as FA and urinary MMP9/NGAL complex (R2 = 0.33, P = 0.0008). A large, diffuse cluster of white matter was identified as having a strong correlation between both ADC (R2 = 0.35, P = 0.0006) and FA (R2 = 0.43, P<0.0001) with urinary NGAL levels. In contrast, no significant association between DTI measurements and VEGF was observed. Results suggest that elevated MMP9 or MMP9/NGAL in UCPPS may be related to degenerative neuronal changes in brainstem nuclei through excitotoxicity, while also facilitating synaptic plasticity in sensorimotor regions.

Resting-State Functional Magnetic Resonance Imaging Connectivity of the Brain Is Associated with Altered Sensorimotor Function in Patients with Cervical Spondylosis.

OBJECTIVE: To determine the relationship between functional connectivity (FC) using resting-state functional magnetic resonance imaging (MRI) and neurological impairment in patients with cervical spondylosis and healthy controls. METHODS: A total of 24 patients with cervical spondylosis with or without myelopathy and 17 neurologically intact, healthy volunteer subjects were prospectively enrolled in a cross-sectional study involving observational MRI and evaluation of neurological function using the modified Japanese Orthopedic Association (mJOA) score. Seed-to-seed connectivity and seed-to-voxel connectivity on functional MRI data were performed using a general linear model of connectivity with respect to age and mJOA score. RESULTS: Increased FC was observed with increasing neurological impairment in patients with cervical stenosis within sensorimotor areas, including precentral gyrus, postcentral gyrus, and supplemental motor regions, using both seed-to-seed and seed-to-voxel analyses. The anterior cingulate showed increasing connectivity with the supplemental motor area, thalamus, and cerebellum with increasing neurological function. Similarly, the thalamus, cerebellum, and putamen presented with increasing connectivity to both the bilateral precuneus and the posterior cingulate with an increasing mJOA score. CONCLUSIONS: Patients with cervical spondylosis exhibiting neurological impairment experience changes in brain connectivity similar to that of patients with chronic traumatic spinal cord injury. These results suggest an increase in FC within sensorimotor regions with increasing neurological impairment and decreased connectivity between the cerebellum, putamen, and thalamus to the anterior and posterior cingulate and frontal lobe regions.

Post-chemoradiation volumetric response predicts survival in newly diagnosed glioblastoma treated with radiation, temozolomide, and bevacizumab or placebo.

Background: In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV). Methods: Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had >4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses. Results: A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline. Conclusions: The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

Mono-exponential, diffusion kurtosis and stretched exponential diffusion MR imaging response to chemoradiation in newly diagnosed glioblastoma.

PURPOSE: To quantify changes and prognostic value of diffusion MRI measurements obtained using mono-exponential, diffusion kurtosis imaging (DKI) and stretched exponential (SE) models prior and after chemoradiation in newly diagnosed glioblastoma (GBM). METHODS: Diffusion-weighted images (DWIs) were acquired in twenty-three patients following surgery, prior chemoradiation and within 7 days following completion of treatment, using b-values ranging from 0 to 5000s/mm2. Mono-exponential diffusion (apparent diffusion coefficient: ADC), isotropic (non-directional) DKI model with apparent diffusivity (Dapp) and kurtosis (Kapp) estimates as well as SE model with distributed-diffusion coefficient (DDC) and mean intra-voxel heterogeneity (α) were computed for all patients prior and after chemoradiation. Median values were calculated for normal appearing white matter (NAWM) and contrast-enhancing tumor (CET). The magnitudes of diffusion change prior and after chemoradiation were used to predict overall survival (OS). RESULTS: Diffusivity in NAWM was consistent for all diffusion measures during chemoradiation, while diffusivity measurements (ADC, Dapp and DDC) within CET changed significantly. A strong positive correlation existed between ADC, Dapp, and DDC measurements prior to chemoradiation; however, this association was weak following chemoradiation, suggesting a more complex microstructural environment after cytotoxic therapy. When combined with baseline tumor volume and MGMT status, age and ADC changes added significant prognostic values, whereas more complex diffusion models did not show significant value in predicting OS. CONCLUSIONS: Despite increased tissue complexity following chemoradiation, advanced diffusion models have longer acquisition times, provide largely comparable measures of diffusivity, and do not appear to provide additional prognostic value compared to mono-exponential ADC maps.

Volumetric response quantified using T1 subtraction predicts long-term survival benefit from cabozantinib monotherapy in recurrent glioblastoma.

Background: To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods: A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results: Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS. Conclusions: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia.

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs. PERSPECTIVE: Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system.

Reproducibility, temporal stability, and functional correlation of diffusion MR measurements within the spinal cord in patients with asymptomatic cervical stenosis or cervical myelopathy.

OBJECTIVE The purpose of this study was to quantify the reproducibility, temporal stability, and functional correlation of diffusion MR characteristics in the spinal cord in patients with cervical stenosis with or without myelopathy. The association between longitudinal diffusion tensor imaging (DTI) measurements and serial neurological function assessment was explored at both the group and individual level. METHODS Sixty-six nonoperatively treated patients with cervical stenosis were prospectively followed (3 months to > 5 years) using synchronous serial MRI and functional outcome assessment. A total of 183 separate MRI examinations were performed, separated by at least 3 months, and each patient had a minimum of 2 MRI scans (range 2-5 scans). Anatomical and DTI measurements were performed within the spinal cord at the C1-2 region as well as at the area of highest compression. Coefficients of variance (COVs) were compared across measurements in both reference tissue and areas of compression for anatomical measurements, fractional anisotropy (FA), and mean diffusivity (MD). The correlation between diffusion MR measures at the site of compression and evaluations of neurological function assessed using the modified Japanese Orthopaedic Association (mJOA) scale at multiple time points was evaluated. RESULTS The COVs for anatomical measurements (Torg ratio and canal diameter) were between 7% and 10%. The median COV for FA measurements at the site of compression was 9%, and for reference tissue at C1-2 it was 6%. The median COV for MD at the site of compression was approximately 12%, and for reference tissue at C1-2 it was 10%. The FA and MD measurements of C1-2 averaged 0.61 and 0.91 µm2/msec, respectively, whereas the FA and MD measurements at the site of compression averaged 0.51 and 1.26 µm2/msec, respectively. Both FA (slope = 0.037; R2 = 0.3281, p < 0.0001) and MD (slope = -0.074; R2 = 0.1101, p = 0.0084) were significantly correlated with the mJOA score. The FA decreased by approximately 0.032 units per mJOA unit decrease (R2 = 0.2037, p < 0.0001), whereas the MD was increased by approximately 0.084 µm2/msec for every mJOA unit decrease (R2 = 0.1016, p < 0.0001). CONCLUSIONS Quantitative DTI measurements of the spinal cord in patients with cervical stenosis with or without myelopathy have a median COV of 5%-10%, similar to anatomical measurements. The reproducibility of these measurements and significant correlation with functional outcome status suggest a potential role in the evaluation and longitudinal surveillance of nonoperatively treated patients. With respect to the specific DTI measurements, FA within the spinal cord appears slightly more sensitive to neurological function and more stable than measures of MD. Therefore, DTI of the spinal cord may be a clinically feasible imaging technique for longitudinally monitoring patients with cervical spondylotic myelopathy.

Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials.

Purpose: Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine.Experimental Design: Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADCL," the mean of the lower ADC distribution. Pretreatment ADCL, enhancing volume, and clinical variables were tested as independent prognostic factors for OS.Results: The coefficient of variance (COV) in double baseline ADCL measurements was 2.5% and did not significantly differ (P = 0.4537). An ADCL threshold of 1.24 µm2/ms produced the largest OS differences between patients (HR ∼ 0.5), and patients with an ADCL > 1.24 µm2/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADCL was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume.Conclusions: Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. Clin Cancer Res; 23(19); 5745-56. ©2017 AACR.

Baseline pretreatment contrast enhancing tumor volume including central necrosis is a prognostic factor in recurrent glioblastoma: evidence from single and multicenter trials.

BACKGROUND: The prognostic significance of baseline contrast enhancing tumor prior to second- or third-line therapy in recurrent glioblastoma (GBM) for overall survival (OS) remains controversial, particularly in the context of repeated surgical resection and/or use of anti-angiogenic therapy. In the current study, we examined recurrent GBM patients from both single and multicenter clinical trials to test whether baseline enhancing tumor volume, including central necrosis, is a significant prognostic factor for OS in recurrent GBM. METHODS: Included were 497 patients with recurrent GBM from 4 data sources: 2 single-center sites (University of Toronto, University of California Los Angeles) and 2 phase II multicenter trials (AVF3708G, Bevacizumab ± Irinotecan, NCT00345163; XL184-201, Cabozantinib, NCT00704288). T1 subtraction maps were used to define volume of contrast enhancing tumor, including central necrosis. Cox multivariable and univariate analyses were used to evaluate the relationship between tumor volume prior to second- or third-line therapy and OS. RESULTS: Both continuous measures of baseline tumor volume and tumors dichotomized into large (≥15cc) and small (<15cc) tumors were significant predictors of OS (P<.0001), independently of age and treatment. Univariate analysis demonstrated significant OS differences (P<.05) between large (≥15cc) and small (<15cc) tumors in patients under all therapeutic scenarios. Only patients treated with cabozantinib who previously failed anti-angiogenic therapy did not show an OS dependence on baseline tumor volume. CONCLUSIONS: Baseline tumor volume is a significant prognostic factor in recurrent GBM. Clinical trial treatment arms must have a balanced distribution of tumor size, and tumor size should be considered when interpreting therapeutic efficacy.

Multisite, multimodal neuroimaging of chronic urological pelvic pain: Methodology of the MAPP Research Network.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.

Topographical Distribution of Epileptogenic Tubers in Patients With Tuberous Sclerosis Complex.

Tuberous sclerosis complex is a multisystem genetic syndrome often affecting the central nervous system. The purpose of the current study was to identify topographical patterns in the distribution specific to epileptogenic (n = 37) and nonepileptogenic (n = 544) tubers throughout the brain for a cohort of 23 tuberous sclerosis complex patients with a history of seizures. Tubers localized to the inferior parietal lobes, middle frontal lobes, middle temporal lobes, or central sulcus regions were associated with a high frequency of epileptogenic tubers. Epileptogenic tubers occurred statistically more frequently within the inferior parietal lobe and within the central sulcus region in children younger than 1 or between 1 and 3 years old, respectively. Results imply seizure activity in tuberous sclerosis complex patients can be associated with the location of cortical tubers.