Screening for brain aneurysm in the Familial Intracranial Aneurysm study: frequency and predictors of lesion detection

Object Approximately 20% of patients with an intracranial saccular aneurysm report a family history of intracranial aneurysm (IA) or subarachnoid hemorrhage. A better understanding of predictors of aneurysm detection in familial IA may allow more targeted aneurysm screening strategies. Methods The Familial Intracranial Aneurysm (FIA) study is a multicenter study, in which the primary objective is to define the susceptibility genes related to the formation of IA. First-degree relatives (FDRs) of those affected with IA are offered screening with magnetic resonance (MR) angiography if they were previously unaffected, are ≥ 30 years of age, and have a history of smoking and/or hypertension. Independent predictors of aneurysm detection on MR angiography were determined using the generalized estimating equation version of logistic regression. Results Among the first 303 patients screened with MR angiography, 58 (19.1%) had at least 1 IA, including 24% of women and 11.7% of men. Ten (17.2%) of 58 affected patients had multiple aneurysms. Independent predictors of aneurysm detection included female sex (odds ratio [OR] 2.46, p = 0.001), pack-years of cigarette smoking (OR 3.24 for 20 pack-years of cigarette smoking compared with never having smoked, p < 0.001), and duration of hypertension (OR 1.26 comparing those with 10 years of hypertension to those with no hypertension, p = 0.006). Conclusions In the FIA study, among the affected patients’ FDRs who are > 30 years of age, those who are women or who have a history of smoking or hypertension are at increased risk of suffering an IA and should be strongly considered for screening

The Familial Intracranial Aneurysm (FIA) study protocol

BACKGROUND: Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms (IAs) occurs in about 20,000 people per year in the U.S. annually and nearly half of the affected persons are dead within the first 30 days. Survivors of ruptured IAs are often left with substantial disability. Thus, primary prevention of aneurysm formation and rupture is of paramount importance. Prior studies indicate that genetic factors are important in the formation and rupture of IAs. The long-term goal of the Familial Intracranial Aneurysm (FIA) Study is to identify genes that underlie the development and rupture of intracranial aneurysms (IA). METHODS/DESIGN: The FIA Study includes 26 clinical centers which have extensive experience in the clinical management and imaging of intracerebral aneurysms. 475 families with affected sib pairs or with multiple affected relatives will be enrolled through retrospective and prospective screening of potential subjects with an IA. After giving informed consent, the proband or their spokesperson invites other family members to participate. Each participant is interviewed using a standardized questionnaire which covers medical history, social history and demographic information. In addition blood is drawn from each participant for DNA isolation and immortalization of lymphocytes. High- risk family members without a previously diagnosed IA undergo magnetic resonance angiography (MRA) to identify asymptomatic unruptured aneurysms. A 10 cM genome screen will be performed to identify FIA susceptibility loci. Due to the significant mortality of affected individuals, novel approaches are employed to reconstruct the genotype of critical deceased individuals. These include the intensive recruitment of the spouse and children of deceased, affected individuals. DISCUSSION: A successful, adequately-powered genetic linkage study of IA is challenging given the very high, early mortality of ruptured IA. Design features in the FIA Study that address this challenge include recruitment at a large number of highly active clinical centers, comprehensive screening and recruitment techniques, non-invasive vascular imaging of high-risk subjects, genome reconstruction of dead affected individuals using marker data from closely related family members, and inclusion of environmental covariates in the statistical analysis

Association Between Anatomic and Clinical Indicators of Injury Severity After Moderate-Severe Traumatic Brain Injury: A Pilot Study Using Multiparametric Magnetic Resonance Imaging

This study sought to identify whether an anatomical indicator of injury severity as measured by multiparametric magnetic resonance imaging (MRI) including magnetic resonance elastography (MRE), is predictive of a clinical measure of injury severity after moderate-severe traumatic brain injury (TBI). Nine individuals who were admitted to acute inpatient rehabilitation after moderate-to-severe TBI completed a comprehensive MRI protocol prior to discharge from rehabilitation, which included conventional MRI with diffusion tensor imaging (DTI). Of those, five of nine also underwent brain MRE to measure the brain parenchyma stiffness. Clinical severity of injury was measured by the length of post-traumatic amnesia (PTA). MRI-assessed non-hemorrhage contusion score and hemorrhage score, DTI-measured white matter fractional anisotropy, and MRE-measured lesion stiffness were all assessed. A higher hemorrhagic score was significantly associated with a longer length of PTA (p?=?0.026). Participants with a longer PTA tended to have a higher non-hemorrhage contusion score and softer contusion lesions than the contralateral control side, although the small sample size did not allow for assessment of a significant association. To our knowledge, this is the first report applying MRI/MRE imaging protocol to quantitate altered brain anatomy after moderate-severe TBI and its association with PTA, a known clinical predictor of post-acute outcome. Future larger studies could lead to the development of prediction models that integrate clinical data with anatomical (MRI), structural (DTI), and mechanical (MRE) changes caused by TBI, to inform prognosis and care planning

Mirror aneurysms:a reflection on natural history

OBJECT: Investigators conducting the International Study of Unruptured Intracranial Aneurysms, sponsored by the National Institutes of Health, sought to evaluate predictors of future hemorrhage in patients who had unruptured mirror aneurysms. These paired aneurysms in bilateral arterial positions mirror each other; their natural history is unknown. METHODS: Centers in the US, Canada, and Europe enrolled patients for prospective assessment of unruptured intracranial aneurysms. Central radiological review confirmed the presence or absence of mirror aneurysms in patients without a history of prior subarachnoid hemorrhage (SAH) (Group 1). Outcome at 1 and 5 years and aneurysm characteristics are compared. RESULTS: Of 3120 patients with aneurysms treated in 61 centers, 376 (12%) had mirror aneurysms, which are more common in women than men (82% [n = 308] vs 73% [n = 1992], respectively; p <0.001) and in patients with a family history of aneurysm or SAH (p <0.001). Compared with patients with nonmirror saccular aneurysms, a greater percentage of patients with mirror aneurysms had larger (>10 mm) aneurysms (mean maximum diameter 11.7 vs 10.4 mm, respectively; p <0.001). The most common distribution for mirror aneurysms was the middle cerebral artery (34% [126 patients]) followed by noncavernous internal carotid artery (32% [121]), posterior communicating artery (16% [60]), cavernous internal carotid artery (13% [48]), anterior cerebral artery/anterior communicating artery (3% [13]), and vertebrobasilar circulation (2% [8]). When these patients were compared with patients without mirror aneurysms, no statistically significant differences were found in age (mean age 54 years in both groups), blood pressure, smoking history, or cardiac disease. Aneurysm rupture rates were similar (3.0% for patients with mirror aneurysms vs 2.8% for those without). CONCLUSIONS: Overall, patients with mirror aneurysms were more likely to be women, to report a family history of aneurysmal SAH, and to have larger aneurysms. The presence of a mirror aneurysm was not an independent predictor of future SAHs

Gradient Pre-Emphasis to Counteract First-Order Concomitant Fields on Asymmetric MRI Gradient Systems

Purpose: To develop a gradient pre-emphasis scheme that prospectively counteracts the effects of the first-order concomitant fields for any arbitrary gradient waveform played on asymmetric gradient systems, and to demonstrate the effectiveness of this approach using a real-time implementation on a compact gradient system. Methods: After reviewing the first-order concomitant fields that are present on asymmetric gradients, we developed a generalized gradient pre-emphasis model assuming arbitrary gradient waveforms to counteract their effects. A numerically straightforward, easily implemented approximate solution to this pre-emphasis problem was derived that was compatible with the current hardware infrastructure of conventional MRI scanners for eddy current compensation. The proposed method was implemented on the gradient driver subsystem, and its real-time use was tested using a series of phantom and in vivo data acquired from two-dimensional Cartesian phase-difference, echo-planar imaging, and spiral acquisitions. Results: The phantom and in vivo results demonstrated that unless accounted for, first-order concomitant fields introduce considerable phase estimation error into the measured data and result in images with spatially dependent blurring/distortion. The resulting artifacts were effectively prevented using the proposed gradient pre-emphasis. Conclusion: We have developed an efficient and effective gradient pre-emphasis framework to counteract the effects of first-order concomitant fields of asymmetric gradient systems. (C) 2016 International Society for Magnetic Resonance in Medici

Rituximab therapy for primary central nervous system vasculitis: A 6 patient experience and review of the literature

Objectives: To assess the efficacy and safety of Rituximab (RTX) in adult primary central nervous system vasculitis (PCNSV). Methods: We retrospectively assessed the effect of RTX in 6 patients with PCNSV. Five of the 6 were refractory to high dose glucocorticoids (GCs) and/or conventional immunosuppressants (IS). The sixth was newly diagnosed and received RTX in combination with GCs. Clinical evaluation, laboratory tests, and imaging modalities were performed at initial RTX administration and during the follow-up. Treatment response was assessed using the treating physician's global opinion regarding response and the degree of disability using the modified Rankin scale (mRS). We also performed a literature review for previous use of RTX in PCNSV using PubMed, Ovid Medline, and the Cochrane library. Results: The six patients (3 females) had a median age at diagnosis of 50.5 years (range 17–68 years). All had active disease when RTX was started. In 4 patients, RTX administration was associated with a marked reduction in the number of flares (from 18 before starting RTX to 3 after). One patient, after an initial improvement, had 2 flares when B cells were depleted and he was not able to reduce prednisone below 20 mg/day. A 6th patient had a flare when B cells recovered and retreatment with RTX re-induced and maintained remission. The median mRS score at last visit (median: 2; range 0–4) was lower than that prior to treatment (median 3; range 1–5). The median prednisone daily dose before RTX administration was significantly higher than that at last follow-up (p =.006). In the literature review, we identified 5 papers describing 7 patients treated with RTX. Six patients responded to RTX with clinical and MRI improvement with no reported flares after RTX treatment. Conclusions: Our data support a potential role for RTX treatment in selected patients with PCNSV

Regional brain stiffness changes across the Alzheimer's disease spectrum

Magnetic resonance elastography (MRE) is an MRI-based technique to noninvasively measure tissue stiffness. Currently well established for clinical use in the liver, MRE is increasingly being investigated to measure brain stiffness as a novel biomarker of a variety of neurological diseases. The purpose of this work was to apply a recently developed MRE pipeline to measure regional brain stiffness changes in human subjects across the Alzheimer's disease (AD) spectrum, and to gain insights into the biological processes underlying those stiffness changes by correlating stiffness with existing biomarkers of AD. The results indicate that stiffness changes occur mostly in the frontal, parietal and temporal lobes, in accordance with the known topography of AD pathology. Furthermore, stiffness in those areas correlates with existing imaging biomarkers of AD including hippocampal volumes and amyloid PET. Additional analysis revealed preliminary but significant evidence that the relationship between brain stiffness and AD severity is nonlinear and non-monotonic. Given that similar relationships have been observed in functional MRI experiments, we used task-free fMRI data to test the hypothesis that brain stiffness was sensitive to structural changes associated with altered functional connectivity. The analysis revealed that brain stiffness is significantly and positively correlated with default mode network connectivity. Therefore, brain stiffness as measured by MRE has potential to provide new and essential insights into the temporal dynamics of AD, as well as the relationship between functional and structural plasticity as it relates to AD pathophysiology

Identification of a Locus for Autosomal Dominant Polycystic Liver Disease, on Chromosome 19p13.2-13.1

Polycystic liver disease (PCLD) is characterized by the growth of fluid-filled cysts of biliary epithelial origin in the liver. Although the disease is often asymptomatic, it can, when severe, lead to complications requiring surgical therapy. PCLD is most often associated with autosomal dominant polycystic kidney disease (ADPKD); however, families with an isolated polycystic liver phenotype without kidney involvement have been described. The clinical presentation and histological features of polycystic liver disease in the presence or absence of ADPKD are indistinguishable, raising the possibility that the pathogenetic mechanisms in the diseases are interrelated. We ascertained two large families with polycystic liver disease without kidney cysts and performed a genomewide scan for genetic linkage. A causative gene, PCLD, was mapped to chromosome 19p13.2-13.1, with a maximum LOD score of 10.3. Haplotype analysis refined the PCLD interval to 12.5 cM flanked by D19S586/D19S583 and D19S593/D19S579. The discovery of genetic linkage will facilitate diagnosis and study of this underdiagnosed disease entity. Identification of PCLD will be instrumental to an understanding of the pathogenesis of cyst formation in the liver in isolated PCLD and in ADPKD