Citations

ABSTRACT Background and Purpose In idiopathic normal pressure hydrocephalus (iNPH) patients, cerebrospinal fluid (CSF) flow is typically evaluated with a cardiac‐gated two‐dimensional (2D) phase‐contrast (PC) MRI through the cerebral aqueduct. This approach is limited by the evaluation of a single location and does not account for respiration effects on flow. In this study, we quantified the cardiac and respiratory contributions to CSF movement at multiple intracranial locations using a real‐time 2D PC‐MRI and evaluated the diagnostic value of CSF dynamics biomarkers in classifying iNPH patients. Methods This study included 37 participants: 16 iNPH, 10 Alzheimer's disease (AD), and 11 cognitively unimpaired (CU) controls. Anatomical and real‐time (non‐gated) PC images were acquired in a 3T Philips scanner. CSF flow was assessed at the foramen magnum, fourth ventricle, Sylvian fissure, lateral ventricle, and cerebral aqueduct. We calculated three CSF dynamics biomarkers: mean velocity amplitude, cardiac signal power, and respiratory signal power. Biomarkers from each location were evaluated for classifying iNPH versus AD and CU using support vector machine (SVM). A p ‐value of 0.05 or less was considered statistically significant. Results The velocity amplitude and cardiac signal power were significantly reduced in iNPH compared to CU ( p < 0.005) and AD ( p < 0.05) at the lateral ventricle. The SVM model using biomarkers from the lateral ventricle performed significantly better at classifying iNPH than the other locations in terms of accuracy ( p < 0.005) and diagnostic odds ratio ( p < 0.05). Conclusion Evaluation of CSF movement beyond the cerebral aqueduct may aid in identifying patients with and understanding the pathophysiology of iNPH.

Abstract Functional MRI (fMRI) is widely used to spatially localize neural activity in the brain associated with functional stimuli. Functional MR Elastography (fMRE) has recently been introduced as a complementary approach that measures the mechanical response to functional stimulus. The hypothesis of the current study is that the stiffness change in fMRE is proportional to the underlying neural activity. This hypothesis is tested by measuring the median stiffness change in the visual cortex as a function of luminance-matched contrast intensity of a checkerboard visual stimulus in 16 healthy subjects. The fMRE signal in the visual cortex was observed to be proportional to the contrast intensity of the visual stimulus. In regions of activation, fMRE signal increased in the range of 2 ± 1% to 5.8 ± 1% and fMRI signal increased by the expected 0.4 ± 0.2% to 0.9 ± 0.2%, for contrast levels of 5% to 100%, respectively. In conclusion, this study shows that the fMRE signal in the visual cortex can be directly modulated by the contrast intensity of a visual stimulus. The presence of some overlap between fMRI and fMRE regions of activation may suggest two distinct mechanisms governing the fMRI and fMRE signals, which will be investigated in future studies.

Diseases of the carotid arteries can be classified into different categories based on their origin. Atherosclerotic carotid disease remains the most encountered arterial wall pathology. However, other less-common non-atherosclerotic diseases can have detrimental clinical consequences if not appropriately recognized. The underlying histological features of each disease process may result in imaging findings that possess features that are obvious of the disease. However, some carotid disease processes may have histological characteristics that manifest as non-specific radiologic findings. The purpose of this manuscript is to review various non-atherosclerotic causes of carotid artery disease as well as their histologic-radiologic characteristics to aid in the appropriate recognition of these less-commonly encountered pathologies.

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.

Abstract Vascular brain injury results in loss of structural and functional connectivity and leads to cognitive impairment. Its various manifestations, including microinfarcts, microhaemorrhages and white matter hyperintensities, result in microstructural tissue integrity loss and secondary neurodegeneration. Among these, tissue microstructural alteration is a relatively early event compared with atrophy along the aging and neurodegeneration continuum. Understanding its association with cognition may provide the opportunity to further elucidate the relationship between vascular health and clinical outcomes. Magnetic resonance elastography offers a non-invasive approach to evaluate tissue mechanical properties, providing a window into the microstructural integrity of the brain. This retrospective study evaluated brain stiffness as a potential biomarker for vascular brain injury and its role in mediating the impact of vascular dysfunction on cognitive impairment. Seventy-five participants from the Mayo Clinic Study of Aging underwent brain imaging using a 3T MR imager with a spin-echo echo-planar imaging sequence for magnetic resonance elastography and T1- and T2-weighted pulse sequences. This study evaluated the effects of vascular biomarkers (white matter hyperintensities and cardiometabolic condition score) on brain stiffness using voxelwise analysis. Partial correlation analysis explored associations between brain stiffness, white matter hyperintensities, cardiometabolic condition and global cognition. Mediation analysis determined the role of stiffness in mediating the relationship between vascular biomarkers and cognitive performance. Statistical significance was set at P-values &lt; 0.05. Diagnostic accuracy of magnetic resonance elastography stiffness for white matter hyperintensities and cardiometabolic condition was evaluated using receiver operator characteristic curves. Voxelwise linear regression analysis indicated white matter hyperintensities negatively correlate with brain stiffness, specifically in periventricular regions with high white matter hyperintensity levels. A negative association between cardiovascular risk factors and stiffness was also observed across the brain. No significant patterns of stiffness changes were associated with amyloid load. Global stiffness (µ) negatively correlated with both white matter hyperintensities and cardiometabolic condition when all other covariables including amyloid load were controlled. The positive correlation between white matter hyperintensities and cardiometabolic condition weakened and became statistically insignificant when controlling for other covariables. Brain stiffness and global cognition were positively correlated, maintaining statistical significance after adjusting for all covariables. These findings suggest mechanical alterations are associated with cognitive dysfunction and vascular brain injury. Brain stiffness significantly mediated the indirect effects of white matter hyperintensities and cardiometabolic condition on global cognition. Local cerebrovascular diseases (assessed by white matter hyperintensities) and systemic vascular risk factors (assessed by cardiometabolic condition) impact brain stiffness with spatially and statistically distinct effects. Global brain stiffness is a significant mediator between vascular disease measures and cognitive function, highlighting the value of magnetic resonance elastography-based mechanical assessments in understanding this relationship.

AbstractBackgroundThe cardiac and respiratory cycles have been suggested as major drivers of cerebrospinal fluid(CSF) flow. The glymphatic system, one of the mechanisms for the clearance of amyloid‐beta and tau proteins, relies heavily on the movement(flow) of the CSF, and thus, investigating the forces that modulate the CSF flow is essential for understanding the glymphatic flux. Because breathing is trainable through exercise and self‐directed methods, various breathing methods may enhance the CSF flow.MethodReal‐time phase‐contrast MRI(pc‐MRI) was used to measure the CSF flow at the foramen magnum on a 3T. Fast resting‐state fMRI(rsfMRI;TR400ms) was conducted on a compact 3T. Under an IRB‐approved protocol, participants were instructed to breathe slowly and deeply, and subsequently switch to their spontaneous breathing. For rsfMRI data preprocessing, we performed motion correction, skull stripping, spatial smoothing(4mm), temporal filtering(0.01 to 0.1Hz), and linear and quadratic temporal trends removal. fMRI time courses were then normalized to Z‐score at each voxel before being averaged. On the pcMRI, the phase was summed in a CSF region‐of‐interest and plotted vs time. Additionally, we confirmed for possible confounding effects such as head motion or motion‐induced susceptibility changes.ResultrsfMRI findings showed that deep breathing promoted large oscillations in the CSF flow in the ventricles, while spontaneous breathing did not(Figure 1). Additionally, deep breathing resulted in large oscillations in lobar cortical regions. Similar results were observed in the pcMRI, with larger CSF velocity through the foramen magnum during the deep breathing compared to the spontaneous breathing(Figure 2A‐B). The cumulative summation result showed that the volume of CSF flow was increased during deep breathing(Figure 2C).ConclusionThis study provides new evidence that slow and deep breathing promotes CSF flow and global brain BOLD signal, which may be useful in promoting circulation in the brain. The study’s findings also open new avenues for research in the field of neurovascular coupling and mechanisms associated with glymphatic clearance. As hampered CSF flow and/or worsen glymphatic clearance have been shown to associate with pathological aging and dementia, including Alzheimer’s disease and Parkinson’s disease, future research is needed explore the potential of breathing training methods as a non‐pharmacological intervention to support brain health.

AbstractBackgroundCognitive decline with aging and neurodegeneration is caused by various neurobiological processes at molecular, cellular, and organ levels. Advanced imaging techniques that detect tissue microstructural alterations may predict cognitive decline earlier than atrophy measures. Tissue‐level mechanical properties are thought to primarily reflect the rigidity and tension of extracellular matrix‐cytoskeleton matrix (https://doi.org/10.1038/s41586‐019‐1516‐5) and can be measured noninvasively by Magnetic Resonance Elastography (MRE) (https://doi.org/10.1126/science.7569924). These properties are sensitive to pathophysiological processes that characterize neurological disease including dementias. This study examines the role of medial temporal lobe stiffness in predicting global cognitive decline in participants along the Alzheimer’s disease spectrum.MethodSeventy‐five participants underwent MRE, MRI, amyloid PET imaging, and cognitive assessments with informed consent, and the study was approved by the Mayo Clinic IRB. MRE stiffness maps were calculated by neural network inversion, and medial temporal (MT) stiffness extracted (https://doi.org/10.1002/mrm.29226https://doi.org/10.1016/j.nicl.2023.103328). White matter hyperintensity (WMH) load, average cortical thickness of AD signature regions, PiB‐PET standardized uptake ratio (PiB‐SUVr), and global cognition z‐scores were each computed (https://doi.org/10.1016/j.neurobiolaging.2020.09.005). Linear mixed effect models were used to assess the effects of MT‐stiffness and its interaction with follow‐up time on global cognition. The additional effects of cortical thickness, WMH, and PiB‐SUVr, and their interactions with cognition follow‐up time were evaluated.ResultTable 1 summarizes results from three mixed effect models. MT‐stiffness and its interaction with time were significant predictors in models 1 (MT‐stiffness only) and 2 (MT‐stiffness+cortical thickness). In model 3 (MT‐stiffness+cortical thickness+PiB‐ratio+WMH), MT‐stiffness alone did not reach significance (P= 0.058), but its interaction with time was a significant predictor. Fig.1 shows global cognition z‐scores with age. Figs. 2A,2B, and 2C show global cognition prediction trajectories. These results suggest that softer MT‐stiffness predicts faster cognitive decline. MT‐stiffness was a significant predictor of cognitive score even when controlling for other biomarkers such as cortical thickness, PiB‐SUVr, and WMH. These results indicate that stiffness measurements can add predictive value regarding cognitive decline in addition to atrophy and amyloidosis.ConclusionBrain mechanical alterations capture microstructural changes that may aid in understanding disease progression and provide information about future cognitive decline in elderly participants along the Alzheimer’s disease continuum.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH ( P =0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03652181.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project ( https://www.clinicaltrials.gov ; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% ( P =0.03) and 100% ( P =0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years ( P =0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.