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The prevalence of Alzheimer’s disease is projected to reach 13 million in the U.S. by 2050. Although major efforts have been made to avoid this outcome, so far there are no treatments that can stop or reverse the progressive cognitive decline that defines Alzheimer’s disease. The utilization of preventative treatment before significant cognitive decline has occurred may ultimately be the solution, necessitating a reliable biomarker of preclinical/prodromal disease stages to determine which older adults are most at risk. Quantitative cerebral blood flow is a promising potential early biomarker for Alzheimer’s disease, but the spatiotemporal patterns of altered cerebral blood flow in Alzheimer’s disease are not fully understood. The current systematic review compiles the findings of 81 original studies that compared resting gray matter cerebral blood flow in older adults with mild cognitive impairment or Alzheimer’s disease and that of cognitively normal older adults and/or assessed the relationship between cerebral blood flow and objective cognitive function. Individuals with Alzheimer’s disease had relatively decreased cerebral blood flow in all brain regions investigated, especially the temporoparietal and posterior cingulate, while individuals with mild cognitive impairment had consistent results of decreased cerebral blood flow in the posterior cingulate but more mixed results in other regions, especially the frontal lobe. Most papers reported a positive correlation between regional cerebral blood flow and cognitive function. This review highlights the need for more studies assessing cerebral blood flow changes both spatially and temporally over the course of Alzheimer’s disease, as well as the importance of including potential confounding factors in these analyses.

AIM: Exposure to prenatal opioids may adversely impact the developing brain networks. The aim of this pilot study was to evaluate alterations in amygdalar functional connectivity in human infants with prenatal opioid exposure. METHODS: In this prospective IRB approved study, we performed resting state functional MRI (rs-fMRI) in 10 infants with prenatal opioid exposure and 12 infants without prenatal drug exposure at

ObjectiveTo study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC.MethodsCollegiate athletes (n = 219, 82 concussed athletes, 68 contact-sport controls, and 69 non–contact-sport controls) were included from the Concussion Assessment, Research and Education Consortium. The participants completed clinical assessments and DTI at 4 time points: 24 to 48 hours after injury, asymptomatic state, 7 days after return-to-play, and 6 months after injury. Tract-based spatial statistics was used to investigate group differences in DTI metrics and to identify white-matter areas with persistent abnormalities. Generalized linear mixed models were used to study longitudinal changes and associations between outcome measures and DTI metrics. Cox proportional hazards model was used to study effects of white-matter abnormalities on recovery time.ResultsIn the white matter of concussed athletes, DTI-derived mean diffusivity was significantly higher than in the controls at 24 to 48 hours after injury and beyond the point when the concussed athletes became asymptomatic. While the extent of affected white matter decreased over time, part of the corpus callosum had persistent group differences across all the time points. Furthermore, greater elevation of mean diffusivity at acute concussion was associated with worse clinical outcome measures (i.e., Brief Symptom Inventory scores and symptom severity scores) and prolonged recovery time. No significant differences in DTI metrics were observed between the contact-sport and non–contact-sport controls.ConclusionsChanges in white matter were evident after SRC at 6 months after injury but were not observed in contact-sport exposure. Furthermore, the persistent white-matter abnormalities were associated with clinical outcomes and delayed recovery time.

Background: Cluster headache is a severe headache, which causes severe impairment in the quality of life of the patients. Here, we report a successful experience of relieving cluster headache by puncturing the superficial engorged venules of the ipsilateral leg. Case presentation: This 72-year-old female with severe refractory cluster headache came from the United States to Taiwan to search for alternative therapy. Her headache was characterized by excruciating, stabbing pain on the left head, primarily around the orbital area with extension to temporal and occipital area, and accompanied with left nasal obstruction. Based upon the classic acupuncture method, her headache was dramatically and totally relieved by puncture upon superficial engorged venules of ipsilateral leg. Conclusion: This case reminded us that classic bloodletting acupuncture could be an alternative strategy for cases with refractory cluster headache. Besides, the connection between leg engorged venules and head suggesting the existence of some novel reflex, worthy of investigation in the future.

Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.

The goal of the current study was to introduce a new methodology that holds a promise to be used in hippocampus-aging studies using sub-millimeter super-resolution hybrid diffusion imaging (HYDI) MRI.HYDI diffusion data were acquired in two groups of older and younger healthy participants recruited from the Indiana Alzheimer's Disease Research Center and community. These data were then transformed into super-resolution diffusion images before the hippocampal subfield analyses. We studied the correlation between the subjects' age and the structural connectivity involving the hippocampal subfields and the connectivity between the whole hippocampus and the cerebral cortex.Structural integrity derived from the tractography streamlines between the hippocampal subfields was reduced in older than younger adults.The findings offered a new promising framework, and they opened avenues for future studies to explore the relationship between the structural connectivity in the hippocampal area and different types of dementia.

Introduction Diffusion magnetic resonance imaging may allow for microscopic characterization of white matter degeneration in early stages of Alzheimer's disease. Methods Multishell Diffusion magnetic resonance imaging data were acquired from 100 participants (40 cognitively normal, 38 with subjective cognitive decline, and 22 with mild cognitive impairment [MCI]). White matter microscopic degeneration in 27 major tracts of interest was assessed using diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging, and q-space imaging. Results Lower DTI fractional anisotropy and higher radial diffusivity were observed in the cingulum, thalamic radiation, and forceps major of participants with MCI. These tracts of interest also had the highest predictive power to discriminate groups. Diffusion metrics were associated with cognitive performance, particularly Rey Auditory Verbal Learning Test immediate recall, with the highest association observed in participants with MCI. Discussion While DTI was the most sensitive, neurite orientation dispersion and density imaging and q-space imaging complementarily characterized reduced axonal density accompanied with dispersed and less restricted white matter microstructures., Highlights • Mild cognitive decline poses microstructural alterations in white matter tracts. • The alterations include higher axonal dispersion and lower tissue restriction. • Diffusion metrics are associated with cognitive outcomes in AD continuum.

Background: Traumatic brain injury (TBI) is a leading cause of death and disability throughout the world, estimated to carry an annual global incidence of over 27 million cases. Mild TBI (mTBI), commonly known as concussion, is the mildest form of TBI and accounts for roughly 90% of all head injuries. Sports-related concussion (SRC) contributes significantly to this statistic with millions of athletes sustaining high-impact injuries in contact sports such as football, soccer, and lacrosse. By examining the white-matter microstructure, diffusion tensor imaging (DTI) has shown excellent capabilities for detecting pathophysiologic changes after SRC and monitoring symptom progression. Biomarkers including neurofilament light (NfL) and tau have been implicated in SRC and may provide insight into the duration of post-concussive symptoms. At this time, very few studies have been published evaluating the relationship between these serum biomarkers and alterations to DTI metrics. Methods: In the present study, we examined the association between serum biomarkers NfL and tau to further understand the relationship between these biomarkers and neuroimaging findings seen with diffusion tensor imaging (DTI) after exposure to a sports-related concussive event. Results: Serum tau levels decreased significantly at the 24-48h post-injury time point compared to 6h post-injury. Serum tau levels then elevated significantly at the asymptomatic time point in comparison to the 24-48h post-injury time point. The serum tau level was significantly associated with higher mean diffusivity (MD) in the white-matter tracts. Serum NfL had minimal associations with white matter diffusion metrics. Conclusion and Potential Impact: This research serves to better inform future investigations into the relationship between DTI metrics and serum biomarkers in the context of mTBI and SRC. This information may contribute to the development of a simple bedside serum analysis with potential to offer tremendous insight into the comprehensive brain health of patients who are being evaluated for SRC, thereby streamlining the therapeutic process and providing more accessible healthcare to patients in locations where advanced imaging techniques are not readily accessible.

Purpose:The purpose of this study was to investigate the effect of an intensive 8-day Samyama meditation program on the brain functional connectivity using resting-state functional MRI (rs-fMRI).Methods:Thirteen Samyama program participants (meditators) and 4 controls underwent fMRI brain scans before and after the 8-day residential meditation program. Subjects underwent fMRI with a blood oxygen level dependent (BOLD) contrast at rest and during focused breathing. Changes in network connectivity before and after Samyama program were evaluated. In addition, validated psychological metrics were correlated with changes in functional connectivity.Results:Meditators showed significantly increased network connectivity between the salience network (SN) and default mode network (DMN) after the Samyama program (p< 0.01). Increased connectivity within the SN correlated with an improvement in self-reported mindfulness scores (p< 0.01).Conclusion:Samyama, an intensive silent meditation program, favorably increased the resting-state functional connectivity between the salience and default mode networks. During focused breath watching, meditators had lower intra-network connectivity in specific networks. Furthermore, increased intra-network connectivity correlated with improved self-reported mindfulness after Samyama.Clinical Trials Registration:[https://clinicaltrials.gov], Identifier: [NCT04366544]. Registered on 4/17/2020.

Following more than a century of phenotypic measurement of natural selection processes, much recent work explores relationships between molecular genetic measurements and realized fitness in the next generation. We take a novel approach to the study of contemporary selective pressure by examining which genetic variants are “sustained” in populations as mortality exposure declines. Specifically, we deploy a so-called “regional GWAS” that links the infant mortality rate (IMR) by place and year in the UK with common genetic variants among cohorts in the UK Biobank. These cohorts (born 1936-1970) saw a decline in IMR from above 65 per 1,000 to under 20 per 1,000, with substantial subnational variation and spikes alongside wartime exposures. Our results show several genome-wide significant loci, including LCT and TLR10/1/6, related to area-level cohort IMR exposure during gestation and infancy. Genetic correlations are found across multiple domains, including fertility, cognition, health behaviors, and health outcomes, suggesting an important role for cohort selection in modern populations.

We wish to suggest the possibility there is a link between the brain and hematopoiesis in the bone marrow and that in the future it may be possible to use such information for better understanding of the regulation of hematopoiesis, and for efficacious treatment of hematopoietic disorders.

Multiple sclerosis is a neurodegenerative and inflammatory disease, a hallmark of which is demyelinating lesions in the white matter. We hypothesized that alterations in white matter microstructures can be non-invasively characterized by advanced diffusion magnetic resonance imaging. Seven diffusion metrics were extracted from hybrid diffusion imaging acquisitions via classic diffusion tensor imaging, neurite orientation dispersion and density imaging, and q-space imaging. We investigated the sensitivity of the diffusion metrics in 36 sets of regions of interest in the brain white matter of six female patients (age 52.8 ± 4.3 years) with multiple sclerosis. Each region of interest set included a conventional T2-defined lesion, a matched perilesion area, and normal-appearing white matter. Six patients with multiple sclerosis (n = 5) or clinically isolated syndrome (n = 1) at a mild to moderate disability level were recruited. The patients exhibited microstructural alterations from normal-appearing white matter transitioning to perilesion areas and lesions, consistent with decreased tissue restriction, decreased axonal density, and increased classic diffusion tensor imaging diffusivity. The findings suggest that diffusion compartment modeling and q-space analysis appeared to be sensitive for detecting subtle microstructural alterations between perilesion areas and normal-appearing white matter.

Flaws, such as porous structure and small grains easily occur during Cu(In,Ga)Se2 (CIGS) thin film absorber preparation from nanocrystallites have been the major obstacle to practical application of this technology. The selenization process parameter effects on the densification, microstructure, and electrical properties were investigated in this study using scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and Hall-effect analyzer. Grain size was observed nearly independent of the selenization time but increased with increasing selenium mass in the graphite box for selenized CIGS film at 500 °C. Pre-sintering at 2 bar N2 atmosphere overpressure can effectively suppress the in-plane tensile stress generated by the shrinkage mismatch between the CIGS and Mo-coated glass substrate during 500 °C sintering, leading to better densification. The pre-sintered and selenized CIGS film exhibited good electrical properties suitable for solar cell applications.

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. Methadone accumulated in the placenta and fetal brain, but methadone levels in offspring dropped rapidly at birth which was associated with symptoms and behaviors consistent with neonatal opioid withdrawal. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition. Furthermore, these behavioral alterations were associated with reduced neuronal density in the motor cortex and a disruption in motor neuron intrinsic properties and local circuit connectivity. The present study adds to the limited body of work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring physical and neurobehavioral development., eLife digest The far-reaching opioid crisis extends to babies born to mothers who take prescription or illicit opioids during pregnancy. Opioids such as oxycodone and methadone can freely cross the placenta from mother to baby. With the rising misuse of and addiction to opioids, the number of babies born physically dependent on opioids has risen sharply over the last decade. Although these infants are only passively exposed to opioids in the womb, they can still experience withdrawal symptoms at birth. This withdrawal is characterized by irritability, excessive crying, body shakes, problems with feeding, fevers and diarrhea. While considerable attention has been given to treating opioid withdrawal in newborn babies, little is known about how these children develop in their first years of life. This is, in part, because it is difficult for researchers to separate drug-related effects from other factors in a child’s home environment that can also disrupt their development. In addition, the biological mechanisms underpinning opioid-related impairments to infant development also remain unclear. Animal models have been used to study the effects of opioid exposure during pregnancy (termed prenatal exposure) on infants. These models, however, could be improved to better replicate the typical pattern of opioid use among pregnant women. Recognizing this gap, Grecco et al. have developed a mouse model of prenatal methadone exposure where female mice that were previously dependent on oxycodone were treated with methadone throughout their pregnancy. Methadone is an opioid drug commonly prescribed for treating opioid use disorder in pregnant women and was found to accumulate at high levels in the fetal brain of mice, which fell quickly after birth. The offspring also experienced withdrawal symptoms. Grecco et al. then examined the physical, behavioral and brain development of mice born to opioid-treated mothers. These included assessments of the animals’ motor skills, sensory reflexes and behavior in their first four weeks of life. Additional experiments tested the properties of nerve cells in the brain to examine cell-level changes. The assessments showed that methadone exposure in the womb impaired the physical growth of offspring and this persisted into ‘adolescence’. Prenatal methadone exposure also delayed progress towards key developmental milestones and led to hyperactivity in three-week-old mice. Moreover, Grecco et al. found that these mice had reduced neuron density and cell-to-cell connectivity in the part of the brain which controls movement. These findings shed light on the potential consequences of prenatal methadone exposure on physical, behavioral and brain development in infants. This model could also be used to study new potential treatments or intervention strategies for offspring exposed to opioids during pregnancy.

IntroductionHead injuries (HI) are a risk factor for dementia, but the underlying etiology is not fully known. Understanding whether tau might mediate this relationship is important.MethodsCognition and tau deposition were compared between 752 individuals with (impaired, n=302) or without cognitive impairment (CN, n=450) with amyloid and [18F]flortaucipir positron emission tomography, HI history information, and cognitive testing from the Alzheimer's Disease Neuroimaging Initiative and the Indiana Memory and Aging Study.ResultsSixty-three (38 CN, 25 impaired) reported a history of HI. Higher neuropsychiatric scores and poorer memory were observed in those with a history of HI. Tau was higher in individuals with a history of HI, especially those who experienced a loss of consciousness (LOC). Results were driven by impaired individuals, especially amyloid beta-positive individuals with history of HI with LOC.DiscussionThese findings suggest biological changes, such as greater tau, are associated with HI in individuals with cognitive impairment. Small effect sizes were observed; thus, further studies should replicate and extend these results.

Background/Objective: Brain tumors are the most common solid cancer in children and cause significant mortality and morbidity. We compare the effectiveness of different parameters in predicting tumor grade between dynamic contrast enhancement (DCE), intravoxel incoherent motion (IVIM), dynamic susceptibility contrast (DSC) perfusion and diffusion weighted imaging (DWI). Methods: A retrospective blinded review of pediatric brain tumors with DCE, IVIM, DWI, and DSC was performed. Parametric maps were registered to T2 weighted images. Volumetric regions of interest (ROI) were manually segmented from solid tumor components for each patient by a neuroradiologist (CH), neuroradiology fellow (BG), and medical student (EC). Resulting mean values for parameters from DCE (Ktrans, Kep, Ve, Vp,), IVIM (D, D*, f), DSC (rCBV) and DWI (ADC) were compared using Student’s t-test for high- and low-grade tumor groups based on WHO grading from pathology. For significant parameters, receiver operating characteristic (ROC) analysis with area under curve (AUC) was performed. Results: 20 subjects were included with 9 low grade and 11 high grade tumors. Significant differences between low versus high grade were demonstrated for D (10−3 mm2/s) (1.4±0.4 vs 0.9±0.2, p=0.01), f (0.04±0.02 vs 0.07±0.02, p=0.02), ADC (10−3 mm2/s) (1.4±0.4 vs 0.9±0.3, p=0.009) and rCBV (2.2±0.9 vs 4.7±2.1, p=0.003). No significant difference was found for D* or any DCE parameter. AUC from ROC was similar for all significant parameters [D (0.81, p=0.003); f (0.80, p=0.003); ADC (0.83, p=0.001); rCBV (0.83, p=0.0005)]. Conclusion: D and f parameters from IVIM can significantly differentiate high versus low grade pediatric brain tumors similar to ADC and rCBV. Conversely, no DCE parameter was significant. Scientific Implications: The results will assist the selection of MRI sequences that best predict tumor grade, as well as guide tumor biopsy for the most aggressive tumor portions. Further study of these techniques may correlate with molecular profiling and predict outcome.

Background: Traditionally, the accumulation of amyloid beta peptides (Aβ) and tau proteins are considered the main pathological hallmarks of AD due to their impact on cortical microstructural organization, which leads to dendritic deficit and neuronal loss. Additionally, it is hypothesized that these pathophysiological processes may induce axonal and oligodendrocyte dysfunction exacerbating myelin impairment. The objective of this cross-sectional study is to estimate the degree of alterations in white matter (WM) microstructural organization associated with pathological proteins at the pre-clinical stage of AD. Methods: To achieve this, diffusion magnetic resonance imaging (dMRI) data and cerebrospinal fluid (CSF) samples were obtained from 84 patients determined to be cognitively normal using neurophysiological tests. CSF samples were analyzed for levels of CSF total tau (T-tau), phosphorylated tau (p-tau181), and Aβ42. The participants were then divided into two groups based on their biomarker (BM) levels (BM+: T-tau/Aβ42 ³ 0.18, and BM-: T-tau/Aβ42 < 0.18). The level of WM integrity was determined through Free Water Eliminating Diffusion Tensor Imaging (FWEDTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) analysis of the dMRI data. Results: Comparisons of WM integrity between the two groups showed a significant reduction in diffusivity in BM+ participants, relative to the BM- group. Additionally, region of interest (ROI)/cluster-based analysis displayed significant associations between levels of CSF biomarkers (T-tau, T-tau/Aβ42, and p-tau/Aβ42) with sophisticated diffusion metrices in multiple regions. CSF Aβ42 alone lacked significant association with white matter alterations. Conclusion: These results suggest that the processes behind pathological protein accumulation influence WM integrity in pre-symptomatic AD, and are primarily driven by tau proteins. Therefore, CSF models which include both measures of tau and Aβ42 are better indicators of AD in its non-dormant stages.

Background: Diagnosis of AD is often started via cognitive tests such as the Mini Mental Status Exam (MMSE) or Montreal Cognitive Assessment (MOCA) with the diagnosis being finalized with autopsy. Currently, positron emission tomography (PET) tracers are used to visualize tau and beta amyloid accumulation in the brain. These imaging techniques demonstrate significant correlations with cognitive decline and have been used to aid in the diagnosis of AD. Particularly, tau accumulation has been shown to progress in a distinct pattern and has been linked to white matter degeneration. We hypothesized that tau accumulation and white matter degeneration in different brain regions have unique correlation patterns with domain-specific neuropsychiatric test scores. Methods: This study included 87 older adults (57 cognitively normal subjects and 27 mild cognitive impairment) from the Indiana Alzheimer’s Disease Center. All participants underwent tau-PET ([18F] Flortaucipir PET) and diffusion MRI (dMRI) exams. Tau accumulation was quantified with tau-PET SUVR. White-matter structural connectivity (SC), which probes the integrity of white-matter connections of the brain, was quantified by metrices extracted from dMRI using network analysis. Both tau accumulation and SC measurements were quantified in 84 cortical region of interests (ROIs) and were compared to their domain specific neuropsychiatric test scores with linear regression analysis. Results: The verbal memory, visual memory, and visuospatial ability all had unique region-specific correlations with white-matter degeneration and tau accumulation. Verbal memory was solely correlated with tau accumulation. Visual memory was related to both tau accumulation and white-matter SC. Finally, visuospatial ability was only correlated with white-matter SC. Potential Impact: This data reveals that although there is a tight interplay between tau accumulation and white-matter degeneration, they affect brain functions in different ways. Specifically, grey-matter tau accumulation is associated with overall memory loss and decrease in the white-matter connectivity affects the visual-related information processing.

Diffusion tensor imaging (DTI) has been employed for over 2 decades to noninvasively quantify central nervous system diseases/injuries. However, DTI is an inadequate simplification of diffusion modeling in the presence of coexisting inflammation, edema and crossing nerve fibers. We employed a tissue phantom using fixed mouse trigeminal nerves coated with various amounts of agarose gel to mimic crossing fibers in the presence of vasogenic edema. Diffusivity measures derived by DTI and diffusion basis spectrum imaging (DBSI) were compared at increasing levels of simulated edema and degrees of fiber crossing. Furthermore, we assessed the ability of DBSI, diffusion kurtosis imaging (DKI), generalized q-sampling imaging (GQI), q-ball imaging (QBI) and neurite orientation dispersion and density imaging to resolve fiber crossing, in reference to the gold standard angles measured from structural images. DTI-computed diffusivities and fractional anisotropy were significantly confounded by gel-mimicked edema and crossing fibers. Conversely, DBSI calculated accurate diffusivities of individual fibers regardless of the extent of simulated edema and degrees of fiber crossing angles. Additionally, DBSI accurately and consistently estimated crossing angles in various conditions of gel-mimicked edema when compared with the gold standard (r2 = 0.92, P = 1.9 × 10-9 , bias = 3.9°). Small crossing angles and edema significantly impact the diffusion orientation distribution function, making DKI, GQI and QBI less accurate in detecting and estimating fiber crossing angles. Lastly, we used diffusion tensor ellipsoids to demonstrate that DBSI resolves the confounds of edema and crossing fibers in the peritumoral edema region from a patient with lung cancer metastasis, while DTI failed. In summary, DBSI is able to separate two crossing fibers and accurately recover their diffusivities in a complex environment characterized by increasing crossing angles and amounts of gel-mimicked edema. DBSI also indicated better angular resolution compared with DKI, QBI and GQI.

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition which were associated with alterations in motor neuron functioning and connectivity. The present study adds to the limited work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring development.

Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model – neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-β PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.

There has been a recent call for longitudinal cohort studies to track the physiological recovery of sport-related concussion (SRC) and its relationship with clinical recovery. Resting-state functional magnetic resonance imaging (rs-fMRI) has shown potential for detecting subtle changes in brain function after SRC. We investigated the effects of SRC on rs-fMRI metrics assessing local connectivity (regional homogeneity; REHO), global connectivity (average nodal strength), and the relative amplitude of slow oscillations of rs-fMRI (fractional amplitude of low-frequency fluctuations; fALFF). Athletes diagnosed with SRC (n = 92) completed visits with neuroimaging at 24–48 h post-injury (24 h), after clearance to begin the return-to-play (RTP) progression (asymptomatic), and 7 days following unrestricted RTP (post-RTP). Non-injured athletes (n = 82) completed visits yoked to the schedule of matched injured athletes and served as controls. Concussed athletes had elevated symptoms, worse neurocognitive performance, greater balance deficits, and elevated psychological symptoms at the 24-h visit relative to controls. These deficits were largely recovered by the asymptomatic visit. Concussed athletes still reported elevated psychological symptoms at the asymptomatic visit relative to controls. Concussed athletes also had elevated REHO in the right middle and superior frontal gyri at the 24-h visit that returned to normal levels by the asymptomatic visit. Additionally, REHO in these regions at 24 h predicted psychological symptoms at the asymptomatic visit in concussed athletes. Current results suggest that SRC is associated with an acute alteration in local connectivity that follows a similar time course as clinical recovery. Our results do not indicate strong evidence that concussion-related alterations in rs-fMRI persist beyond clinical recovery.

Sport-related concussion (SRC) has become a major health problem, affecting millions of athletes each year. Despite the increasing occurrence and prevalence of SRC, its underlying mechanism and recovery course have yet to be fully elucidated. The National Collegiate Athletic Association–Department of Defense Grand Alliance: Concussion Assessment, Research and Education (CARE) Consortium is a large-scale, multisite study of the natural history of concussion across multiple sports. The Advanced Research Core (ARC) of CARE is focused on the advanced biomarker assessment of a reduced subject cohort. This paper reports findings from two ARC sites to evaluate cerebral blood flow (CBF) changes in acute SRC, as measured using advanced arterial spin labeling (ASL) magnetic resonance imaging (MRI). We compared relative CBF maps assessed in 24 concussed contact sport athletes obtained at 24–48 h after injury to those of a control group of 24 matched contact sport players. Significantly less CBF was detected in several brain regions in concussed athletes, while clinical assessments also indicated clinical symptom and performance impairments in SRC patients. Correlations were found between decreased CBF in acute SRC and clinical assessments, including Balance Error Scoring System total score and Immediate Post-Concussion Assessment and Cognitive Test memory composite and impulse control composite scores, as well as days from injury to asymptomatic. Although using different ASL MRI sequences, our preliminary results from two sites are consistent with previous reports and suggest that advanced ASL MRI methods might be useful for detecting acute neurobiological changes in acute SRC.

Purpose To accelerate high-resolution diffusion imaging, rotating single-shot acquisition (RoSA) with composite reconstruction is proposed. Acceleration was achieved by acquiring only one rotating single-shot blade per diffusion direction, and high-resolution diffusion-weighted (DW) images were reconstructed by using similarities of neighboring DW images. A parallel imaging technique was implemented in RoSA to further improve the image quality and acquisition speed. RoSA performance was evaluated by simulation and human experiments. Methods A brain tensor phantom was developed to determine an optimal blade size and rotation angle by considering similarity in DW images, off-resonance effects, and k-space coverage. With the optimal parameters, RoSA MR pulse sequence and reconstruction algorithm were developed to acquire human brain data. For comparison, multishot echo planar imaging (EPI) and conventional single-shot EPI sequences were performed with matched scan time, resolution, field of view, and diffusion directions. Results The simulation indicated an optimal blade size of 48 × 256 and a 30 ° rotation angle. For 1 × 1 mm2 in-plane resolution, RoSA was 12 times faster than the multishot acquisition with comparable image quality. With the same acquisition time as SS-EPI, RoSA provided superior image quality and minimum geometric distortion. Conclusion RoSA offers fast, high-quality, high-resolution diffusion images. The composite image reconstruction is model-free and compatible with various diffusion computation approaches including parametric and nonparametric analyses. Magn Reson Med 79:264–275, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

PurposeDiffusion tensor imaging (DTI) has been employed for over two decades to noninvasively quantify central nervous system (CNS) diseases/injuries. However, DTI is an inadequate simplification of diffusion modeling in the presence of co-existing inflammation, edema, and crossing nerve fibers.MethodsWe employed a tissue phantom using fixed mouse trigeminal nerves coated with various amounts of agarose gel to mimic crossing fibers in the presence of vasogenic edema. Diffusivity measures derived by DTI and diffusion basis spectrum imaging (DBSI) were compared at increasing levels of simulated edema and degrees of fiber crossing. Further, we assessed the ability of DBSI, diffusion kurtosis imaging (DKI), generalized q-sampling imaging (GQI), q-ball imaging (QBI), and neurite orientation dispersion and density imaging (NODDI) to resolve fiber crossing, in reference to the gold standard angles measured from structural images.ResultsDTI-computed diffusivities and fractional anisotropy (FA) were significantly confounded by gelmimicked edema and crossing fibers. Conversely, DBSI calculated accurate diffusivities of individual fibers regardless of the extent of simulated edema and degrees of fiber crossing angles. Additionaly, DBSI accurately and consistently estimated crossing angles in various conditions of gel-mimicked edema when comparing with gold standard (r2=0.92, p=1.9×10−9, bias=3.9°). Small crossing angles and edema sinficantly impact dODF, making DKI, GQI and QBI less accurate in detecting and estimating fibers corrsing angles. Lastly, we demonstrate DBSI’s superiority over DTI for recovering and delineating white matter tracts in peritumoral edema for preoperative planning of surgical resection.ConclusionsDBSI is able to separate two crossing fibers and accurately recover their diffusivities in a complex environment characterized by increasing crossing angles and amounts of gel-mimicked edema. DBSI also indicated better angular resolution capability compared with DKI, QBI and GQI.

Background and Hypothesis: Preterm delivery is a major source of infant morbidity and mortality and is difficult to predict. The process of cervical ripening prior to delivery has known histologic changes including breakdown of collagen and increasing water content. It is hypothesized that the diffusion of water, which can be measured on MRI, will increase as the cervical water content increases. Diffusion weighted imaging (DWI) is a form of MRI that measures the random Brownian motion of water molecules (represented as the apparent diffusion coefficient (ADC)). Intravoxel incoherent motion (IVIM) MRI further subdivides the ADC into microcapillary perfusion (D*) and diffusion (D). We hypothesize that as the pregnant cervix ripens near delivery, diffusion of water within the cervix (ADC and D) will increase without changes in the capillary perfusion (D*). We sought to determine the relationship between ADC, D*, D, gestational age, and time to delivery in a cohort of volunteer pregnant females. Experimental Design or Project Methods: DWI and IVIM MR studies from a cohort of 45 volunteer pregnant females with no known underlying fetal anomalies were examined. Subglandular and stromal cervix thickness and cervical length were measured along with the ADC, D*, and D of the subglandular and stromal cervix. Gestational history and delivery information was documented. Results: Subglandular ADC inversely correlated with time to delivery (r=-0.393, p=0.052). Although not significant, subglandular D revealed a trend of increasing with increased gestation age (r=0.261, p=0.149). Subglandular ADC also varied inversely with thickness of the subglandular cervix (r=-0.352, p=0.047). Subglandular D* varied inversely with maternal age (r=-0.380, p=0.028). Conclusion and Potential Impact: Our data support the hypothesized trend of increased diffusion of water within the cervix with unchanged capillary perfusion as a normal pregnancy progressed throughout the second and third trimesters. This study suggests that diffusion measures (ADC and D) follow a predictable progression during the course of a normal pregnancy and have the potential to provide a means of predicting preterm labor in the setting of preterm cervical ripening.

Objective: A recent systematic review determined that the physiological effects of concussion may persist beyond clinical recovery. Preclinical models suggest that ongoing physiological effects are accompanied by increased cerebral vulnerability that is associated with risk for subsequent, more severe injury. This study examined the association between signal alterations on diffusion tensor imaging following clinical recovery of sport-related concussion in athletes with and without a subsequent second concussion. Methods: Average mean diffusivity (MD) was calculated in a region of interest (ROI) in which concussed athletes (n = 82) showed significantly elevated MD acutely after injury (

Previous studies have shown that mild traumatic brain injury (mTBI) can cause abnormalities in clinically relevant magnetic resonance imaging (MRI) sequences. No large-scale study, however, has prospectively assessed this in athletes with sport-related concussion (SRC). The aim of the current study was to characterize and compare the prevalence of acute, trauma-related MRI findings and clinically significant, non-specific MRI findings in athletes with and without SRC. College and high-school athletes were prospectively enrolled and participated in scanning sessions between January 2015 through August 2017. Concussed contact sport athletes (n = 138; 14 female [F]; 19.5 ± 1.6 years) completed up to four scanning sessions after SRC. Non-concussed contact (n = 135; 15 F; 19.7 ± 1.6) and non-contact athletes (n = 96; 15 F; 20.0 ± 1.7) completed similar scanning sessions and served as controls. Board-certified neuroradiologists, blinded to SRC status, reviewed T(1)-weighted and T(2)-weighted fluid-attenuated inversion recovery and T(2)*-weighted and T(2)-weighted images for acute (i.e., injury-related) or non-acute findings that prompted recommendation for clinical follow-up. Concussed athletes were more likely to have MRI findings relative to contact (30.4% vs. 15.6%; odds ratio [OR] = 2.32; p = 0.01) and non-contact control athletes (19.8%; OR = 2.11; p = 0.04). Female athletes were more likely to have MRI findings than males (43.2% vs. 19.4%; OR = 2.62; p = 0.01). One athlete with SRC had an acute, injury-related finding; group differences were largely driven by increased rate of non-specific white matter hyperintensities in concussed athletes. This prospective, large-scale study demonstrates that

PURPOSE: Diffusion tensor imaging (DTI) may be helpful in assessing optic pathway integrity as a marker for treatment in neurofibromatosis type 1 (NF1) patients with optic gliomas (OG). However, susceptibility artifacts are common in typical single-shot echo planar imaging (ssDTI). A readout-segmented multi-shot EPI technique (rsDTI) was utilized to minimize susceptibility distortions of the skull base and improve quantitative metrics. METHODS: Healthy controls, children with NF1 without OG, and NF1 with OG± visual symptoms were included. All subjects were scanned with both rsDTI and ssDTI sequences sequentially. Diffusion metrics and deterministic fiber tracking were calculated. Tract count, volume, and length were also compared by a two-factor mixed ANOVA. RESULTS: Five healthy controls, 7 NF1 children without OG, and 12 NF1 children with OG were imaged. Six OG patients had visual symptoms. Four subjects had no detectable optic pathway fibers on ssDTI due to susceptibility, for which rsDTI was able to delineate. Tract count (p < 0.001), tract volume (p < 0.001), and FA (P

The hippocampus has been widely studied using neuroimaging, as it plays an important role in memory and learning. However, hippocampal subfield information is difficult to capture by standard magnetic resonance imaging (MRI) techniques. To facilitate morphometric study of hippocampal subfields, ADNI introduced a high resolution (0.4mm in plane) T2-weighted turbo spin-echo sequence that requires 8 minutes. With acceleration, the protocol can be acquired in 4 minutes. We performed a comparative study of hippocampal subfield volumes using standard and accelerated protocols on a Siemens Prisma 3T MRI in an independent sample of older adults that included 10 cognitively normal controls, 9 individuals with subjective cognitive decline, 10 with mild cognitive impairment, and 6 with a clinical diagnosis of Alzheimer’s disease (AD). The Automatic Segmentation of Hippocampal Subfields (ASHS) software was used to segment 9 primary labeled regions including hippocampal subfields and neighboring cortical regions. Intraclass correlation coefficients were computed for reliability tests between 4 and 8 minute scans within and across the four groups. Pairwise group analyses were performed, covaried for age, sex and total intracranial volume, to determine whether the patterns of group differences were similar using 4 versus 8 minute scans. The 4 and 8 minute protocols, analyzed by ASHS segmentation, yielded similar volumetric estimates for hippocampal subfields as well as comparable patterns of differences between study groups. The accelerated protocol can provide reliable imaging data for investigation of hippocampal subfields in AD-related MRI studies and the decreased scan time may result in less vulnerability to motion.