Predictors of white matter hyperintensities in the elderly Congolese population.

Background: White matter hyperintensities (WMHs) are strongly linked to cardiovascular risk factors and other health conditions such as Alzheimer's disease. However, there is a dearth of research on this topic in low-income countries and underserved populations, especially in the Democratic Republic of Congo (DRC) where the population is aging rapidly with increasing cardiovascular risk factors and dementia-related diseases. This study evaluates health factors associated with WMH in the elderly Sub-Saharan Africa (SSA), specifically Congolese adults. Methods: In a cross-sectional study of 77 people from the DRC, participants underwent neuroimaging to analyze WMH volume and completed clinical evaluation, laboratory-based blood exams, self-reported questionnaires, and interviews. A simple linear regression model was conducted to test the association between WMH and potential predictors (neurological status, age, sex, hypertension, diabetes, tobacco abuse, stroke, high cholesterol, cardiovascular medication, and alcohol abuse). Stepwise selection and backward elimination analyses were performed to obtain the final model. Finally, a multiple linear regression model was conducted to assess the association between WMH and variables retained in the final model (neurological status, sex, and age). Results: Of the 77 individuals, 47 (61%) had dementia, 40 (52.6%) were males, and the mean age was 73 years (± 8.0 years standard deviation). In simple linear regression models, WMH was significantly associated with dementia (expß1=1.75, 95% CI=1.14 - 2.71, p-value=0.01) though it had a weak association with age (expß1=1.03, 95% CI=1.00 - 1.05, p-value=0.05) and sex (male) (expß1=0.66, 95% CI=0.43 - 1.01, p-value=0.05). In multiple linear regression models, WMH was statistically significantly associated with dementia (expß1=1.97, 95% CI=1.31 - 2.95, p-value =0.001), male sex (expß2=0.54, 95% CI=0.36 - 0.80, p-value=0.003), and age (expß3=1.03, 95% CI=1.00 - 1.06, p-value=0.03). However, WMH was not significantly associated with common cardiovascular risk factors, such as high blood pressure, diabetes, tobacco use, obesity, and high cholesterol levels. Conclusion: WMH is significantly associated with neurological status, sex, and age in the Congolese population. Understanding these predictors may improve our ability to diagnose, assess, and develop preventative treatments for white matter disease in SSA/DRC populations, where neuroimaging is difficult to obtain.

Impact of white matter networks on risk for memory decline following resection versus ablation in temporal lobe epilepsy.

BACKGROUND: With expanding neurosurgical options in epilepsy, it is important to characterise each options' risk for postoperative cognitive decline. Here, we characterise how patients' preoperative white matter (WM) networks relates to postoperative memory changes following different epilepsy surgeries. METHODS: Eighty-nine patients with temporal lobe epilepsy with T1-weighted and diffusion-weighted imaging as well as preoperative and postoperative verbal memory scores (prose recall) underwent either anterior temporal lobectomy (ATL: n=38) or stereotactic laser amygdalohippocampotomy (SLAH; n=51). We computed laterality indices (ie, asymmetry) for volume of the hippocampus and fractional anisotropy (FA) of two deep WM tracts (uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF)). RESULTS: Preoperatively, left-lateralised FA of the ILF was associated with higher prose recall (p<0.01). This pattern was not observed for the UF or hippocampus (ps>0.05). Postoperatively, right-lateralised FA of the UF was associated with less decline following left ATL (p<0.05) but not left SLAH (p>0.05), while right-lateralised hippocampal asymmetry was associated with less decline following both left ATL and SLAH (ps<0.05). After accounting for preoperative memory score, age of onset and hippocampal asymmetry, the association between UF and memory decline in left ATL remained significant (p<0.01). CONCLUSIONS: Asymmetry of the hippocampus is an important predictor of risk for memory decline following both surgeries. However, asymmetry of UF integrity, which is only severed during ATL, is an important predictor of memory decline after ATL only. As surgical procedures and pre-surgical mapping evolve, understanding the role of frontal-temporal WM in memory networks could help to guide more targeted surgical approaches to mitigate cognitive decline.

Magnetic resonance evidence of increased iron content in subcortical brain regions in asymptomatic Alzheimer's disease.

While iron over-accumulation has been reported in late stage Alzheimer's disease (AD), whether this occurs early in the asymptomatic stage of AD remains unknown. We aimed to assess brain iron levels in asymptomatic AD using quantitative MR relaxometry of effective transverse relaxation rate (R2*) and longitudinal relaxation rate (R1), and recruited 118 participants comprised of three groups including healthy young participants, and cognitively normal older individuals without or with positive AD biomarkers based on cerebrospinal fluid (CSF) proteomics analysis. Compared with the healthy young group, increased R2* was found in widespread cortical and subcortical regions in the older groups. Further, significantly higher levels of R2* were found in the cognitively normal older subjects with positive CSF AD biomarker (i.e., asymptomatic AD) compared with those with negative AD biomarker in subcortical regions including the left and right caudate, left and right putamen, and left and right globus pallidus (p < .05 for all regions), suggesting increased iron content in these regions. Subcortical R2* of some regions was found to significantly correlate with CSF AD biomarkers and neuropsychological assessments of visuospatial functions. In conclusion, R2* could be a valuable biomarker for studying early pathophysiological changes in AD.

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-ß42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-ß42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.

Superior Verbal Memory Outcome After Stereotactic Laser Amygdalohippocampotomy.

Objective: To evaluate declarative memory outcomes in medically refractory epilepsy patients who underwent either a highly selective laser ablation of the amygdalohippocampal complex or a conventional open temporal lobe resection. Methods: Post-operative change scores were examined for verbal memory outcome in epilepsy patients who underwent stereotactic laser amygdalohippocampotomy (SLAH: n = 40) or open resection procedures (n = 40) using both reliable change index (RCI) scores and a 1-SD change metric. Results: Using RCI scores, patients undergoing open resection (12/40, 30.0%) were more likely to decline on verbal memory than those undergoing SLAH (2/40 [5.0%], p = 0.0064, Fisher's exact test). Patients with language dominant procedures were much more likely to experience a significant verbal memory decline following open resection (9/19 [47.4%]) compared to laser ablation (2/19 [10.5%], p = 0.0293, Fisher's exact test). 1 SD verbal memory decline frequently occurred in the open resection sample of language dominant temporal lobe patients with mesial temporal sclerosis (8/10 [80.0%]), although it rarely occurred in such patients after SLAH (2/14, 14.3%) (p = 0.0027, Fisher's exact test). Memory improvement occurred significantly more frequently following SLAH than after open resection. Interpretation: These findings suggest that while verbal memory function can decline after laser ablation of the amygdalohippocampal complex, it is better preserved when compared to open temporal lobe resection. Our findings also highlight that the dominant hippocampus is not uniquely responsible for verbal memory. While this is at odds with our simple and common heuristic of the hippocampus in memory, it supports the findings of non-human primate studies showing that memory depends on broader medial and lateral TL regions.

MRI-guided stereotactic laser corpus callosotomy for epilepsy: distinct methods and outcomes.

OBJECTIVE: Several small series have described stereotactic MRI-guided laser interstitial thermal therapy for partial callosotomy of astatic and generalized tonic-clonic (GTC) seizures, especially in association with Lennox-Gastaut syndrome. Larger case series and comparison of distinct stereotactic methods for stereotactic laser corpus callosotomy (SLCC), however, are currently lacking. The objective of this study was to report seizure outcomes in a series of adult patients with epilepsy following anterior, posterior, and complete SLCC procedures and to compare the results achieved with a frameless stereotactic surgical robot versus direct MRI guidance frames. METHODS: The authors retrospectively reviewed sequential adult epilepsy surgery patients who underwent SLCC procedures at a single institution. They describe workflows, stereotactic errors, percentage disconnection, hospitalization durations, adverse events, and seizure outcomes after performing anterior, posterior, and complete SLCC procedures using a frameless stereotactic surgical robot versus direct MRI guidance platforms. RESULTS: Thirteen patients underwent 15 SLCC procedures. The median age at surgery was 29 years (range 20-49 years), the median duration of epilepsy was 21 years (range 9-48 years), and median postablation follow-up was 20 months (range 4-44 months). Ten patients underwent anterior SLCC with a median 73% (range 33%-80%) midsagittal length of callosum acutely ablated. Following anterior SLCC, 6 of 10 patients achieved meaningful (> 50%) reduction of target seizures. Four patients underwent posterior (completion) SLCC following prior anterior callosotomy, and 1 patient underwent complete SLCC as a single procedure; 3 of these 5 patients experienced meaningful reduction of target seizures. Overall, 8 of 10 patients in whom astatic seizures were targeted and treated by anterior and/or posterior SLCC experienced meaningful improvement. SLCC procedures with direct MRI guidance (n = 7) versus a frameless surgical robot (n = 8) yielded median radial accuracies of 1.1 mm (range 0.2-2.0 mm) versus 2.4 mm (range 0.6-6.1 mm; p = 0.0011). The most serious adverse event was a clinically significant intraparenchymal hemorrhage in a patient who underwent the robotic technique. CONCLUSIONS: This is the largest reported series of SLCC for epilepsy to date. SLCC provides seizure outcomes comparable to open surgery outcomes reported in the literature. Direct MRI guidance is more accurate, which has the potential to reduce the risks of SLCC. Methodological advancements and larger studies are needed.

Radiofrequency Ablation Through Previously Effective Deep Brain Stimulation Leads for Parkinson Disease: A Retrospective Series.

BACKGROUND: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is the surgical method of choice to treat the canonical symptoms of Parkinson disease, occasionally surgical sites become infected or the hardware erodes, necessitating explantation. Usual practice is to remove and reimplant replacement leads after tissue healing, leaving patients without the clinical benefits of DBS for several months, and at risk for DBS withdrawal in some, and some patients are no longer good surgical candidates for reimplantation. Radiofrequency ablation through the DBS lead is an option for these patients. METHODS: We performed a retrospective chart review of all patients who underwent radiofrequency ablation of the STN or GPi through indwelling DBS leads performed before hardware removal at our institution. We generated patient-specific anatomic models to determine lesion locations and volumes. RESULTS: Six patients underwent radiofrequency ablation of the STN (n = 4) and GPi (n = 2) through indwelling DBS leads. All 6 of these patients initially showed comparable motor symptom relief to that experienced with DBS before lesioning, with 4 patients sustaining meaningful long-term (≥2 years) improvement. Better outcomes were achieved in those patients with a higher percentage of the planned target lesioned. CONCLUSIONS: Radiofrequency ablation through indwelling DBS leads before explantation could be considered a viable alternative to subsequent reimplantation or stereotactic lesion in patients with Parkinson disease in whom hardware explantation is necessary, if the patient achieved substantive symptom relief with DBS. This approach avoids symptom exacerbation while awaiting revision surgery.

Neuroimaging correlates of cognitive changes after bariatric surgery.

BACKGROUND: Obesity has been associated with cognitive deficits and increased risk for developing dementia. Bariatric surgery may result in improved cognitive function; however, the underlying structural and functional brain correlates are unclear. OBJECTIVES: This longitudinal study explores the hypothesis that specific brain regions and networks underlie cognitive changes after bariatric surgery. SETTING: University Hospital, United States. METHODS: Seventeen patients were recruited for this prospective cohort study, including 9 patients undergoing bariatric surgery, and 8 age-, sex-, and education level-matched healthy, nonobese control patients. Bariatric patients underwent longitudinal neuropsychologic tests and magnetic resonance imaging (MRI) scans both before and 6 months after surgery. One patient was lost to follow-up. The same neuropsychologic tests and MRI scans were performed for control patients. Differences in MRI and neuropsychologic testing between bariatric patients and control patients, and longitudinal changes within bariatric patients were assessed. RESULTS: At baseline, bariatric patients demonstrated deficits in cognitive function relative to control patients, including pattern comparison (P = .009) and picture sequence memory (P = .004), which improved after significant weight loss. Baseline cognitive deficits in bariatric patients were accompanied by significantly lower left executive control network connectivity on resting-state functional MRI relative to control patients (P = .028), but differences resolved or diminished after bariatric surgery. Longitudinal improvements in pattern comparison performance correlated significantly with increases in left executive control network connectivity (r = .819; P = .013). No significant group or longitudinal differences were found in brain perfusion or brain white matter lesions. CONCLUSIONS: Individuals with obesity undergoing bariatric surgery exhibit deficits in cognitive function and specific alterations of brain networks; however, cognitive performance can improve, and executive control network connectivity can increase after weight loss from bariatric surgery.

Mechanisms and Risk Factors Contributing to Visual Field Deficits following Stereotactic Laser Amygdalohippocampotomy.

Selective laser amygdalohippocampotomy (SLAH) is a minimally invasive surgical treatment for medial temporal lobe epilepsy. Visual field deficits (VFDs) are a significant potential complication. The objective of this study was to determine the relationship between VFDs and potential mechanisms of injury to the optic radiations and lateral geniculate nucleus. We performed a retrospective cross-sectional analysis of 3 patients (5.2%) who developed persistent VFDs after SLAH within our larger series (n = 58), 15 healthy individuals and 10 SLAH patients without visual complications. Diffusion tractography was used to evaluate laser catheter penetration of the optic radiations. Using a complementary approach, we evaluated evidence for focal microstructural tissue damage within the optic radiations and lateral geniculate nucleus. Overablation and potential heat radiation were assessed by quantifying ablation and choroidal fissure CSF volumes as well as energy deposited during SLAH.SLAH treatment parameters did not distinguish VFD patients. Atypically high overlap between the laser catheter and optic radiations was found in 1/3 VFD patients and was accompanied by focal reductions in fractional anisotropy where the catheter entered the lateral occipital white matter. Surprisingly, lateral geniculate tissue diffusivity was abnormal following, but also preceding, SLAH in patients who subsequently developed a VFD (all p = 0.005).In our series, vision-related complications following SLAH, which appear to occur less frequently than following open temporal lobe -surgery, were not directly explained by SLAH treatment parameters. Instead, our data suggest that variations in lateral geniculate structure may influence susceptibility to indirect heat injury from transoccipital SLAH.

Cerebrospinal Fluid Pressure Reduction Results in Dynamic Changes in Optic Nerve Angle on Magnetic Resonance Imaging.

BACKGROUND: Optic nerve sheath tortuosity is a previously reported, but incompletely characterized, finding in idiopathic intracranial hypertension (IIH). We hypothesized that optic nerve angle (ONA), as a quantitative measure of tortuosity, would change dynamically with cerebrospinal fluid (CSF) pressure status of patients with IIH immediately before and after lumbar puncture (LP). METHODS: Consecutive patients with suspected IIH referred for MRI and diagnostic LP were prospectively enrolled in this single institution, institutional review board-approved study. Each patient underwent a pre-LP MRI, diagnostic LP with opening pressure (OP) and closing pressure (CP), and then post-LP MRI all within 1 session. Sagittal and axial ONAs were measured on multiplanar T2 SPACE images by 2 neuroradiologists on pre- and post-LP MRI. Effects of measured pressure and CSF volume removal on changes in ONA were analyzed as was interrater reliability for ONA measurement. RESULTS: Ten patients with IIH were included {all female, median age 29 (interquartile range [IQR] 25-32)}. All patients had elevated OP (median 37, IQR 34-41 cm H2O), and significantly reduced CP (median 18, IQR 16-19 cm H2O, P < 0.001) after CSF removal (IQR 13-16 mL). Within patients, mean ONAs (sagittal and axial) were significantly lower before (162 ± 9°, 163 ± 10°) than after (168 ± 7°, 169 ± 5°) LP (P = 0.001, 0.008, respectively). Interrater reliability was higher with sagittal ONA measurements (0.89) than axial (0.72). CONCLUSIONS: ONA changes with short-term CSF pressure reduction in patients with IIH, establishing optic nerve tortuosity as a dynamic process related to CSF status.

Simultaneous perfusion and permeability assessments using multiband multi-echo EPI (M2-EPI) in brain tumors.

PURPOSE: To study a multiband multi-echo EPI (M2-EPI) sequence for dynamic susceptibility contrast (DSC) perfusion imaging with leakage correction and vascular permeability measurements, and to evaluate the benefits of increased temporal resolution provided by this acquisition strategy on the accuracy of perfusion and permeability estimations. METHODS: A novel M2-EPI sequence was developed, and a pharmacokinetic model accounting for contrast agent extravasation was used to produce perfusion maps and additional vascular permeability maps. The advantage of M2-EPI for DSC perfusion imaging was demonstrated in vivo in 5 patients with brain tumors, and numerical simulations were performed to evaluate the advantage of improved temporal resolution afforded by the technique. RESULTS: In contrast to underestimations of cerebral blood volume (CBV) in tumors using the single-echo acquisition strategy, M2-EPI provided more plausible estimates of CBV. A quantitative evaluation showed higher estimated values of CBV and mean transit time in tumor tissues using M2-EPI (CBV: 3.08 ± 0.78 mL/100 g versus 1.56 ± 1.38 mL/100 g [P = .006]; mean transit time: 4.94 ± 1.17 seconds versus 1.83 ± 2.06 seconds [P = 0.033]). Numerical simulations showed that higher temporal resolution provided by M2-EPI was associated with more accurate estimates of cerebral blood flow, CBV, and permeability parameters. CONCLUSION: The novel M2-EPI acquisition strategy for DSC imaging facilitates leakage-corrected perfusion measurements with additional permeability assessments and more accurate estimates of perfusion/permeability parameters, and may be used as a quantitative tool for the diagnosis, prognosis, and treatment monitoring of brain tumors.

Apparent diffusion coefficient quantification as an early imaging biomarker of response and predictor of survival following yttrium-90 radioembolization for unresectable infiltrative hepatocellular carcinoma with portal vein thrombosis.

PURPOSE: To investigate early diffusion-weighted imaging (DWI) at 30-days post-yttrium-90 (Y-90) radioembolization as a predictor of treatment response and survival in unresectable infiltrative hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT). MATERIALS AND METHODS: In a prospective study, 18 consecutive patients with unresectable infiltrative HCC and PVT underwent Y-90 therapy. MR imaging was obtained pre Y-90, and at 1 and 3 months post-therapy with DWI fat-suppressed tri-directional diffusion gradient (b = 50, 400, 800 s/mm(2)). Response was evaluated using target mRECIST and EASL. Relative change in apparent diffusion coefficient (ADC) value of tumors was evaluated. Statistical analysis using receiver operator characteristic curves was performed. Paired t test and Pearson correlation coefficient (r) were used to assess intra- and inter-observer variability. Survival analysis was performed using Kaplan-Meier estimation and log-rank test. RESULTS: Mean ADC values of all HCC's at baseline and at 30-days post-Y90 therapy was 0.86 × 10(-3) and 1.17×10(-3) mm(2)/s, respectively (p < 0.001). Tumors with objective response by mRECIST had significantly increased ADC value when compared to "non-responders" (1.27 vs. 1.05×10(-3) mm(2)/s, p = 0.002). A >30% increase in ADC value at 30-days was found to be at least 90% sensitive in predicting response at 90 days. A >30% increase in ADC value at 30-days predicted significantly prolonged survival. CONCLUSION: A 30% increase in ADC value at 30-days measured post Y90 is a reproducible early imaging response biomarker predicting tumor response and prolonged survival following Y-90 therapy in infiltrative HCC with PVT.

Ionising radiation-free whole-body MRI versus (18)F-fluorodeoxyglucose PET/CT scans for children and young adults with cancer: a prospective, non-randomised, single-centre study.

BACKGROUND: Imaging tests are essential for staging of children with cancer. However, CT and radiotracer-based imaging procedures are associated with substantial exposure to ionising radiation and risk of secondary cancer development later in life. Our aim was to create a highly effective, clinically feasible, ionising radiation-free staging method based on whole-body diffusion-weighted MRI and the iron supplement ferumoxytol, used off-label as a contrast agent. METHODS: We compared whole-body diffusion-weighted MRI with standard clinical (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT scans in children and young adults with malignant lymphomas and sarcomas. Whole-body diffusion-weighted magnetic resonance images were generated by coregistration of colour-encoded ferumoxytol-enhanced whole-body diffusion-weighted MRI scans for tumour detection with ferumoxytol-enhanced T1-weighted MRI scans for anatomical orientation, similar to the concept of integrated (18)F-FDG PET/CT scans. Tumour staging results were compared using Cohen's κ statistics. Histopathology and follow-up imaging served as the standard of reference. Data was assessed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01542879. FINDINGS: 22 of 23 recruited patients were analysed because one patient discontinued before completion of the whole-body scan. Mean exposure to ionising radiation was 12·5 mSv (SD 4·1) for (18)F-FDG PET/CT compared with zero for whole-body diffusion-weighted MRI. (18)F-FDG PET/CT detected 163 of 174 malignant lesions at 1325 anatomical regions and whole-body diffusion-weighted MRI detected 158. Comparing (18)F-FDG PET/CT to whole-body diffusion-weighted MRI, sensitivities were 93·7% (95% CI 89·0-96·8) versus 90·8% (85·5-94·7); specificities 97·7% (95% CI 96·7-98·5) versus 99·5% (98·9-99·8); and diagnostic accuracies 97·2% (93·6-99·4) versus 98·3% (97·4-99·2). Tumour staging results showed very good agreement between both imaging modalities with a κ of 0·93 (0·81-1·00). No adverse events after administration of ferumoxytol were recorded. INTERPRETATION: Ferumoxytol-enhanced whole-body diffusion-weighted MRI could be an alternative to (18)F-FDG PET/CT for staging of children and young adults with cancer that is free of ionising radiation. This new imaging test might help to prevent long-term side-effects from radiographic staging procedures. FUNDING: Thrasher Research Fund and Clinical Health Research Institute at Stanford University.

Radiation induced brain injury: assessment of white matter tracts in a pre-clinical animal model using diffusion tensor MR imaging.

We aim to study radiation induced white matter injury in a pre-clinical model using Diffusion tensor MR imaging (DTI). Nineteen 12-week old Sprague-Dawley rats were irradiated to the right hemisphere using a linear accelerator. The dose distribution map was coregistered to the DTI map to generate the actual radiation dose to each white matter tract. Rats underwent longitudinal DTI scans at five time points from 4 to 48 weeks post-radiation with histological evaluations. Fractional anisotropy (FA) of the external capsule, fornix, cerebral peduncle, anterior commissure, optic tract and optic nerve was evaluated. Radiation dose was highest at the ipsilateral external capsule and fornix (29.4 ± 1.3 and 29.8 ± 1.1 Gy, respectively). Optic nerve received 50 % dose to the external capsule and other white matter tracts received 80 % dose. Significantly lower FA was firstly found in the ipsilateral external capsule at 4 weeks post-radiation and in the ipsilateral fornix at 40 weeks post-radiation compared to the contralateral side. Significantly lower FA was found in contralateral optic nerve compared to ipsilateral optic nerve at 48 weeks post-radiation despite ipsilateral optic nerves receiving higher radiation dose than contralateral optic nerve (p = 0.021). No differences were found in other white matter regions until 48 weeks. Histology indicated demyelination, axonal degeneration and coagulative necrosis in all injured white matter. DTI can serve as a promising tool for assessment of radiation induced white matter injury and regional radiosensitivity of white matter tracts.

Contrast-enhanced functional blood volume imaging (CE-fBVI): enhanced sensitivity for brain activation in humans using the ultrasmall superparamagnetic iron oxide agent ferumoxytol.

Functional MRI (fMRI) brain studies performed in the presence of a steady-state or "blood pool" contrast agent yields activation maps that are weighted for cerebral blood volume (CBV). Previous animal experiments suggest significant contrast-to-noise ratio (CNR) improvements, but these studies have not yet been performed in humans due to the lack of availability of a suitable agent. Here we report the use of the USPIO ferumoxytol (AMAG Pharmaceuticals, Inc., Cambridge, MA) for functional brain activation in humans, termed contrast enhanced functional blood volume imaging (CE-fBVI). Four subjects were scanned during a unilateral finger tapping task with standard blood-oxygen level dependent (BOLD) imaging before contrast and CE-fBVI after contrast injection. The CE-fBVI response showed both a fast (5.8±1.3 s) and a slow (75.3±27.5 s) component of CBV response to stimuli. A significant CNR gain of approximately 2-3 was found for CE-fBVI compared to BOLD fMRI. Interestingly, less susceptibility-related signal dropouts were observed in the inferior frontal and temporal lobes with CE-fBVI. The combination of higher CNR and better spatial specificity, enabled by CE-fBVI using blood pool USPIO contrast agent opens the door to higher resolution brain mapping.

Longitudinal diffusion tensor magnetic resonance imaging study of radiation-induced white matter damage in a rat model.

Radiation-induced white matter (WM) damage is a major side effect of whole brain irradiation among childhood cancer survivors. We evaluate longitudinally the diffusion characteristics of the late radiation-induced WM damage in a rat model after 25 and 30 Gy irradiation to the hemibrain at 8 time points from 2 to 48 weeks postradiation. We hypothesize that diffusion tensor magnetic resonance imaging (DTI) indices including fractional anisotropy (FA), trace, axial diffusivity (lambda(//)), and radial diffusivity (lambda( perpendicular)) can accurately detect and monitor the histopathologic changes of radiation-induced WM damage, measured at the EC, and that these changes are dose and time dependent. Results showed a progressive reduction of FA, which was driven by reduction in lambda(//) from 4 to 40 weeks postradiation, and an increase in lambda( perpendicular) with return to baseline in lambda(//) at 48 weeks postradiation. Histologic evaluation of irradiated WM showed reactive astrogliosis from 4 weeks postradiation with reversal at 36 weeks, and demyelination, axonal degeneration, and necrosis at 48 weeks postradiation. Moreover, changes in lambda(//) correlated with reactive astrogliosis (P < 0.01) and lambda( perpendicular) correlated with demyelination (P < 0.01). Higher radiation dose (30 Gy) induced earlier and more severe histologic changes than lower radiation dose (25 Gy), and these differences were reflected by the magnitude of changes in lambda(//) and lambda( perpendicular). DTI indices reflected the histopathologic changes of WM damage and our results support the use of DTI as a biomarker to noninvasively monitor radiation-induced WM damage.

Diffusion tensor magnetic resonance imaging finding of discrepant fractional anisotropy between the frontal and parietal lobes after whole-brain irradiation in childhood medulloblastoma survivors: reflection of regional white matter radiosensitivity?

PURPOSE: To test the hypothesis that fractional anisotropy (FA) is more severely reduced in white matter of the frontal lobe compared with the parietal lobe after receiving the same whole-brain irradiation dose in a cohort of childhood medulloblastoma survivors. METHODS AND MATERIALS: Twenty-two medulloblastoma survivors (15 male, mean [+/- SD] age = 12.1 +/- 4.6 years) and the same number of control subjects (15 male, aged 12.0 +/- 4.2 years) were recruited for diffusion tensor magnetic resonance imaging scans. Using an automated tissue classification method and the Talairach Daemon atlas, FA values of frontal and parietal lobes receiving the same radiation dose, and the ratio between them were quantified and denoted as FFA, PFA, and FA(f/p), respectively. The Mann-Whitney U test was used to test for significant differences of FFA, PFA, and FA(f/p) between medulloblastoma survivors and control subjects. RESULTS: Frontal lobe and parietal lobe white matter FA were found to be significantly less in medulloblastoma survivors compared with control subjects (frontal p = 0.001, parietal p = 0.026). Moreover, these differences were found to be discrepant, with the frontal lobe having a significantly larger difference in FA compared with the parietal lobe. The FA(f/p) of control and medulloblastoma survivors was 1.110 and 1.082, respectively (p = 0.029). CONCLUSION: Discrepant FA changes after the same irradiation dose suggest radiosensitivity of the frontal lobe white matter compared with the parietal lobe. Special efforts to address the potentially vulnerable frontal lobe after treatment with whole-brain radiation may be needed so as to balance disease control and treatment-related morbidity.

White matter anisotropy in post-treatment childhood cancer survivors: preliminary evidence of association with neurocognitive function.

PURPOSE: We aim to determine if the loss of white matter fractional anisotropy (FA), measured by diffusion tensor magnetic resonance imaging (DTI), in post-treatment childhood medulloblastoma (MED) and acute lymphoblastic leukemia (ALL) survivors correlate with intelligence quotient (IQ) scores. MATERIALS AND METHODS: MED and ALL survivors (n = 30; 20 male, 10 female; age range, 6.0 to 22.1 years; mean, 13.1 years) were recruited for DTI and IQ tests. In this cross-sectional study, age-matched normal control (n = 55; 32 male, 23 female; age range, 6.0 to 23 years; mean, 12.1 years) DTI was obtained to compute percentage difference in white matter FA (DeltaFA%) for each patient compared with the age-matched control group. Multivariate regression analysis was performed to determine the relationships between DeltaFA%, age at treatment, irradiation dose, time interval from treatment, and full-scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ). Receiver operating characteristics curves were used to determine the best DeltaFA% cutoffs for predicting FSIQ, VIQ, and PIQ of less than 85. RESULTS: DeltaFA% had a significant effect on FSIQ (adjusted r2 = 0.439; P < .001), VIQ (adjusted r(2) = 0.237; P = .028), and PIQ (adjusted r(2) = 0.491; P < .001) after adjusting for the effects of age at treatment, irradiation dose, and time interval from treatment. The best DeltaFA% value to predict less than 85 scores in FSIQ, VIQ, and PIQ was -3.3% with specificities of 100% and sensitivities ranging from 77.8% to 87.5%. CONCLUSION: Our preliminary findings suggest that white matter FA may be a clinically useful biomarker for the assessment of treatment-related neurotoxicity in post-treatment childhood cancer survivors.

Mapping radiation dose distribution on the fractional anisotropy map: applications in the assessment of treatment-induced white matter injury.

We describe a method to map whole brain radiation dose distribution on to diffusion tensor MR (DT-MR) fractional anisotropy (FA) images and illustrate its applications for studying dose-effect relationships and regional susceptibility in two childhood medulloblastoma survivors. To determine the FA changes voxel-by-voxel in white matter, the post-treatment follow-up FA maps were coregistered to baseline pre-treatment FA maps and automatic segmentation for white matter was carried out. DeltaFA maps representing relative FA change in white matter were hence generated for visual inspection and quantitative analysis. The radiation dose distribution, calculated from radiotherapy plan and exported as images, was coregistered to baseline FA images. DT-MR imaging and processing noise was small with root mean square value of 1.49% for mean DeltaFA. We evaluated the mean DeltaFA changes of regions-of-interest according to radiation dose regions to provide an estimate of the dose-response and found increasing reduction in mean DeltaFA with increasing radiation dose up to 45 Gy after which there was a reversal in the mean FA trend and mean FA approached baseline value. We also found more severe mean FA reduction in the frontal lobes compared to the parietal lobes despite the same radiation dose, suggesting regional susceptibility in the frontal lobe, and mean FA increase in the brainstem after radiation in both patients. We conclude that the method described may be useful in estimating dose-effect relationships and studying regional susceptibility of the brain to radiation in medulloblastoma survivors.