Diffusion magnetic resonance imaging of cerebrospinal fluid dynamics: Current techniques and future advancements.

Cerebrospinal fluid (CSF) plays a critical role in metabolic waste clearance from the brain, requiring its circulation throughout various brain pathways, including the ventricular system, subarachnoid spaces, para-arterial spaces, interstitial spaces, and para-venous spaces. The complexity of CSF circulation has posed a challenge in obtaining noninvasive measurements of CSF dynamics. The assessment of CSF dynamics throughout its various circulatory pathways is possible using diffusion magnetic resonance imaging (MRI) with optimized sensitivity to incoherent water movement across the brain. This review presents an overview of both established and emerging diffusion MRI techniques designed to measure CSF dynamics and their potential clinical applications. The discussion offers insights into the optimization of diffusion MRI acquisition parameters to enhance the sensitivity and specificity of diffusion metrics on underlying CSF dynamics. Lastly, we emphasize the importance of cautious interpretations of diffusion-based imaging, especially when differentiating between tissue- and fluid-related changes or elucidating structural versus functional alterations.

Paravascular fluid dynamics reveal arterial stiffness assessed using dynamic diffusion-weighted imaging.

Paravascular cerebrospinal fluid (pCSF) surrounding the cerebral arteries within the glymphatic system is pulsatile and moves in synchrony with the pressure waves of the vessel wall. Whether such pulsatile pCSF can infer pulse wave propagation-a property tightly related to arterial stiffness-is unknown and has never been explored. Our recently developed imaging technique, dynamic diffusion-weighted imaging (dynDWI), captures the pulsatile pCSF dynamics in vivo and can explore this question. In this work, we evaluated the time shifts between pCSF waves and finger pulse waves, where pCSF waves were measured by dynDWI and finger pulse waves were measured by the scanner's built-in finger pulse oximeter. We hypothesized that the time shifts reflect brain-finger pulse wave travel time and are sensitive to arterial stiffness. We applied the framework to 36 participants aged 18-82 years to study the age effect of travel time, as well as its associations with cognitive function within the older participants (N = 15, age > 60 years). Our results revealed a strong and consistent correlation between pCSF pulse and finger pulse (mean CorrCoeff = 0.66), supporting arterial pulsation as a major driver for pCSF dynamics. The time delay between pCSF and finger pulses (TimeDelay) was significantly lower (i.e., faster pulse propagation) with advanced age (Pearson's r = -0.44, p = 0.007). Shorter TimeDelay was further associated with worse cognitive function in the older participants. Overall, our study demonstrated pCSF as a viable pathway for measuring intracranial pulses and encouraged future studies to investigate its relevance with cerebrovascular functions.

Exploring Radial Asymmetry in MR Diffusion Tensor Imaging and Its Impact on the Interpretation of Glymphatic Mechanisms.

BACKGROUND: Diffusion imaging holds great potential for the non-invasive assessment of the glymphatic system in humans. One technique, diffusion tensor imaging along the perivascular space (DTI-ALPS), has introduced the ALPS-index, a novel metric for evaluating diffusivity within the perivascular space. However, it still needs to be established whether the observed reduction in the ALPS-index reflects axonal changes, a common occurrence in neurodegenerative diseases. PURPOSE: To determine whether axonal alterations can influence change in the ALPS-index. STUDY TYPE: Retrospective. POPULATION: 100 participants (78 cognitively normal and 22 with mild cognitive impairments) aged 50-90 years old. FIELD STRENGTH/SEQUENCE: 3T; diffusion-weighted single-shot spin-echo echo-planar imaging sequence, T1-weighted images (MP-RAGE). ASSESSMENT: The ratio of two radial diffusivities of the diffusion tensor (i.e., λ2/λ3) across major white matter tracts with distinct venous/perivenous anatomy that fulfill (ALPS-tracts) and do not fulfill (control tracts) ALPS-index anatomical assumptions were analyzed. STATISTICAL TESTS: To investigate the correlation between λ2/λ3 and age/cognitive function (RAVLT) while accounting for the effect of age, linear regression was implemented to remove the age effect from each variable. Pearson correlation analysis was conducted on the residuals obtained from the linear regression. Statistical significance was set at p < 0.05. RESULTS: λ2 was ~50% higher than λ3 and demonstrated a consistent pattern across both ALPS and control tracts. Additionally, in both ALPS and control tracts a reduction in the λ2/λ3 ratio was observed with advancing age (r = -0.39, r = -0.29, association and forceps tract, respectively) and decreased memory function (r = 0.24, r = 0.27, association and forceps tract, respectively). DATA CONCLUSIONS: The results unveil a widespread radial asymmetry of white matter tracts that changes with aging and neurodegeration. These findings highlight that the ALPS-index may not solely reflect changes in the diffusivity of the perivascular space but may also incorporate axonal contributions. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Hippocampal-subfield microstructures and their relation to plasma biomarkers in Alzheimer's disease.

Hippocampal subfields exhibit differential vulnerabilities to Alzheimer's disease-associated pathology including abnormal accumulation of amyloid-ß deposition and neurofibrillary tangles. These pathological processes extensively impact on the structural and functional interconnectivities of the subfields and may explain the association between hippocampal dysfunction and cognitive deficits. In this study, we investigated the degree of alterations in the microstructure of hippocampal subfields across the clinical continuum of Alzheimer's disease. We applied a grey matter-specific multi-compartment diffusion model (Cortical-Neurite orientation dispersion and density imaging) to understand the differential effects of Alzheimer's disease pathology on the hippocampal subfield microstructure. A total of 119 participants were included in this cross-sectional study. Participants were stratified into three categories, cognitively normal (n = 47), mild cognitive impairment (n = 52), and Alzheimer's disease (n = 19). Diffusion MRI, plasma biomarkers and neuropsychological test scores were used to determine the association between the microstructural integrity and Alzheimer's disease-associated molecular indicators and cognition. For Alzheimer's disease-related plasma biomarkers, we studied amyloid-ß, total tau and neurofilament light; for Alzheimer's disease-related neuropsychological tests, we included the Trail Making Test, Rey Auditory Verbal Learning Test, Digit Span and Montreal Cognitive Assessment. Comparisons between cognitively normal subjects and those with mild cognitive impairment showed significant microstructural alterations in the hippocampal cornu ammonis (CA) 4 and dentate gyrus region, whereas CA 1-3 was the most sensitive region for the later stages in the Alzheimer's disease clinical continuum. Among imaging metrics for microstructures, the volume fraction of isotropic diffusion for interstitial free water demonstrated the largest effect size in between-group comparisons. Regarding the plasma biomarkers, neurofilament light appeared to be the most sensitive biomarker for associations with microstructural imaging findings in CA4-dentate gyrus. CA 1-3 was the subfield which had stronger correlations between cognitive performance and microstructural metrics. Particularly, poor performance on the Rey Auditory Verbal Learning Test and Montreal Cognitive Assessment was associated with decreased intracellular volume fraction. Overall, our findings support the value of tissue-specific microstructural imaging for providing pathologically relevant information manifesting in the plasma biomarkers and neuropsychological outcomes across various stages of Alzheimer's disease.

Assessing pulsatile waveforms of paravascular cerebrospinal fluid dynamics within the glymphatic pathways using dynamic diffusion-weighted imaging (dDWI)

Cerebrospinal fluid (CSF) in the paravascular spaces of the surface arteries (sPVS) is a vital pathway in brain waste clearance. Arterial pulsations may be the driving force of the paravascular flow, but its pulsatile pattern remains poorly characterized, and no clinically practical method for measuring its dynamics in the human brain is available. In this work, we introduce an imaging and quantification framework for in-vivo non-invasive assessment of pulsatile fluid dynamics in the sPVS. It used dynamic Diffusion-Weighted Imaging (dDWI) at a lower b-values of 150s/mm2 and retrospective gating to detect the slow flow of CSF while suppressing the fast flow of adjacent arterial blood. The waveform of CSF flow over a cardiac cycle was revealed by synchronizing the measurements with the heartbeat. A data-driven approach was developed to identify sPVS and allow automatic quantification of the whole-brain fluid waveforms. We applied dDWI to twenty-five participants aged 18-82 y/o. Results demonstrated that the fluid waveforms across the brain showed an explicit cardiac-cycle dependency, in good agreement with the vascular pumping hypothesis. Furthermore, the shape of the CSF waveforms closely resembled the pressure waveforms of the artery wall, suggesting that CSF dynamics is tightly related to artery wall mechanics. Finally, the CSF waveforms in aging participants revealed a strong age effect, with a significantly wider systolic peak observed in the older relative to younger participants. The peak widening may be associated with compromised vascular compliance and vessel wall stiffening in the older brain. Overall, the results demonstrate the feasibility, reproducibility, and sensitivity of dDWI for detecting sPVS fluid dynamics of the human brain. Our preliminary data suggest age-related alterations of the paravascular pumping. With an acquisition time of under six minutes, dDWI can be readily applied to study fluid dynamics in normal physiological conditions and cerebrovascular/neurodegenerative diseases.

Structural connectivity mapping in human hippocampal-subfields using super-resolution hybrid diffusion imaging: a feasibility study.

PURPOSE: 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. METHODS: 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. RESULTS: Structural integrity derived from the tractography streamlines between the hippocampal subfields was reduced in older than younger adults. CONCLUSION: 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.

Tau-related white-matter alterations along spatially selective pathways.

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-ß 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.

The impact of edema and fiber crossing on diffusion MRI metrics assessed in an ex vivo nerve phantom: Multi-tensor model vs. diffusion orientation distribution function.

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.

Resting state functional MRI in infants with prenatal opioid exposure-a pilot study.

PURPOSE: 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 < 48 weeks corrected gestational age. Following standard preprocessing, we performed seed-based functional connectivity analysis with the right and left amygdala as the regions of interest after correcting for maternal depression and infant sex. We compared functional connectivity of the amygdala network between infants with and without prenatal opioid exposure. RESULTS: There were significant differences in connectivity of the amygdala seed regions to the several cortical regions including the medial prefrontal cortex in infants who had prenatal opioid exposure when compared with opioid naïve infants. CONCLUSION: This finding of increased amygdala functional connectivity in infants with in utero opioid exposure suggests a potential role of maternal opioid exposure on infants' altered amygdala function. This association with prenatal exposure needs to be replicated in future larger studies.

Rapid golden-angle diffusion-weighted propeller MRI for simultaneous assessment of ADC and IVIM.

PURPOSE: Golden-angle single-shot PROPLLER (GA-SS-PROP) is proposed to accelerate the PROPELLER acquisition for distortion-free diffusion-weighted (DW) imaging. Acceleration is achieved by acquiring one-shot per b-value and several b-values can be acquired along a diffusion direction, where the DW signal follows a bi-exponential decay (i.e. IVIM). Sparse reconstruction is used to reconstruct full resolution DW images. Consequently, apparent diffusion coefficient (ADC) map and IVIM maps (i.e., perfusion fraction (f) and the perfusion-free diffusion coefficient (D)) are obtained simultaneously. The performance of GA-SS-PROP was demonstrated with simulation and human experiments. METHODS: A realistic numerical phantom of high-quality diffusion images of the brain was developed. The error of the reconstructed DW images and quantitative maps were compared to the ground truth. The pulse sequence was developed to acquire human brain data. For comparison, fully sampled PROPELLER and conventional single-shot echo planar imaging (SS-EPI) acquisitions were performed. RESULTS: GA-SS-PROP was 5 times faster than conventional PROPELLER acquisition with comparable image quality. The simulation demonstrated that sparse reconstruction is effective in restoring contrast and resolution. The human experiments demonstrated that GA-SS-PROP achieved superior image fidelity compared to SS-EPI for the same acquisition time and same in-plane resolution (1 × 1 mm2). CONCLUSION: GA-SS-PROP offers fast, high-resolution and distortion-free DW images. The generated quantitative maps (f, D and ADC) can provide valuable information on tissue perfusion and diffusion properties simultaneously, which are desirable in many applications, especially in oncology. As a turbo spin-echo based technique, it can be applied in most challenging regions where SS-EPI is problematic.

Comparison of multi-shot and single shot echo-planar diffusion tensor techniques for the optic pathway in patients with neurofibromatosis type 1.

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 < 0.001) were significantly higher for rsDTI versus ssDTI for all subjects. MD (p < 0.001) and RD (p < 0.001) were significantly lower for rsDTI vs ssDTI. Finally, MD, AD, and RD had a significantly lower difference in NF1 children with visual symptoms compared to NF1 children without visual symptoms only on ssDTI scans. CONCLUSION: DTI with readout-segmented multi-shot EPI technique can better visualize the optic pathway and allow more confident measurements of anisotropy in NF1 patients. This is shown by a significant increase in FA, tract count, and volume with rsDTI versus ssDTI.

Rotating single-shot acquisition (RoSA) with composite reconstruction for fast high-resolution diffusion imaging.

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.

Age effects and sex differences in human brain white matter of young to middle-aged adults: A DTI, NODDI, and q-space study.

Microstructural changes in human brain white matter of young to middle-aged adults were studied using advanced diffusion Magnetic Resonance Imaging (dMRI). Multiple shell diffusion-weighted data were acquired using the Hybrid Diffusion Imaging (HYDI). The HYDI method is extremely versatile and data were analyzed using Diffusion Tensor Imaging (DTI), Neurite Orientation Dispersion and Density Imaging (NODDI), and q-space imaging approaches. Twenty-four females and 23 males between 18 and 55years of age were included in this study. The impact of age and sex on diffusion metrics were tested using least squares linear regressions in 48 white matter regions of interest (ROIs) across the whole brain and adjusted for multiple comparisons across ROIs. In this study, white matter projections to either the hippocampus or the cerebral cortices were the brain regions most sensitive to aging. Specifically, in this young to middle-aged cohort, aging effects were associated with more dispersion of white matter fibers while the tissue restriction and intra-axonal volume fraction remained relatively stable. The fiber dispersion index of NODDI exhibited the most pronounced sensitivity to aging. In addition, changes of the DTI indices in this aging cohort were correlated mostly with the fiber dispersion index rather than the intracellular volume fraction of NODDI or the q-space measurements. While men and women did not differ in the aging rate, men tend to have higher intra-axonal volume fraction than women. This study demonstrates that advanced dMRI using a HYDI acquisition and compartmental modeling of NODDI can elucidate microstructural alterations that are sensitive to age and sex. Finally, this study provides insight into the relationships between DTI diffusion metrics and advanced diffusion metrics of NODDI model and q-space imaging.

Improved mapping of interictal epileptiform discharges with EEG-fMRI and voxel-wise functional connectivity analysis.

OBJECTIVE: We describe a novel method to spatially map interictal epileptiform discharges (IEDs) through voxel-wise functional connectivity analysis of the functional magnetic resonance imaging (fMRI) portion of simultaneous electroencephalography (EEG)-fMRI data. This method measures the local synchronicity of fMRI signals associated with IED and, in contrast to conventional methods, does not require modeling of neural activities or hemodynamic response. METHODS: Simultaneous EEG-fMRI was performed on six patients with focal epilepsy. IED events were detected from the EEG data. The fMRI data was subdivided into time segments of 20 s in length, and then reorganized into one set of concatenated time series containing the IED events and many sets without IEDs. Local degree centrality (LDC), a metric of functional connectivity, was computed for each brain voxel to summarize its signal correlations to brain voxels within 14 mm of physical distance. This computation was repeated for each set of concatenated time series, yielding one whole-brain LDC map for time with the IED events and many maps for time without IED. A statistical score was computed for each voxel to detect the voxels with significant LDC value differences associated with IEDs. The fMRI data were also processed separately by conventional methods for comparison. RESULTS: In all six patients, regions with significant LDC increase during IEDs were concordant in location to both simultaneous EEG and the epileptogenic focus determined from separate clinical studies. In contrast, results from the conventional methods were concordant in only three patients. SIGNIFICANCE: We show that for focal epilepsy, voxel-wise functional connectivity analysis of EEG-fMRI data may improve IED localization and EEG concordance compared to the conventional analysis. This new analytic method may improve the robustness of interictal EEG-fMRI as a technique for mapping the epileptogenic focus, and helps study the local synchronization aspect of the epileptic network.

White matter microstructural changes in post-traumatic headache: A diffusion tensor imaging (DTI) study.

Introduction: Post-traumatic headache (PTH) is a common consequence of mild traumatic brain injury (mTBI) that can severely impact an individual's quality of life and rehabilitation. However, the underlying neuropathogenesis mechanisms contributing to PTH are still poorly understood. This study utilized diffusion tensor imaging (DTI) to detect microstructural alterations in the brains of mTBI participants with or at risk of developing PTH. Method: This study investigated associations between DTI metrics 1-month postinjury and pain sensitivity, as well as psychological assessments 6-months postinjury to identify differences between mTBI (n = 12) and healthy controls (HC; n = 10). MRI scans, including T1-weighted anatomical imaging and DTI were acquired at 1-month postinjury. Pain sensitivity assays included quantitative sensory testing and psychological assessment questionnaires at 1-month and 6-months postinjury. Results: Significant aberrations of mean axial diffusivity in the forceps major were observed in mTBI relative to HCs at 1-month postinjury (p =0.02). Within the mTBI group, DTI metrics at 1-month postinjury were significantly associated (p's < 0.05) with pain-related measures and psychological outcomes at 6-month postinjury in several white matter tracts (right sagittal stratum, left anterior thalamic radiation, left corticospinal tract, left insula, left superior longitudinal fasciculus). Notably, the associations between DTI metrics at 1-month postinjury and pain-related measures at 6-month postinjury showed significant group differences in the right sagittal stratum (p's < 0.01), white matter tract in left insula (p < 0.04), and left superior longitudinal fasciculus (p's < 0.05). Conclusion: This study suggests that "Post-Traumatic Stress Disorder for DSM-5" and "Center for Epidemiological Studies-Depression Scale" are the most sensitive psychological measures to early microstructural changes after mTBI, and that the DTI metrics are predictive of pain and psychological measures in mTBI. Together, these results suggest that white matter microstructure plays an important role in the PTH following mTBI.

Estimating the synaptic density deficit in Alzheimer's disease using multi-contrast CEST imaging.

In vivo noninvasive imaging of neurometabolites is crucial to improve our understanding of the underlying pathophysiological mechanism in neurodegenerative diseases. Abnormal changes in synaptic organization leading to synaptic degradation and neuronal loss is considered as one of the primary factors driving Alzheimer's disease pathology. Magnetic resonance based molecular imaging techniques such as chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) can provide neurometabolite specific information which may relate to underlying pathological and compensatory mechanisms. In this study, CEST and short echo time single voxel MRS was performed to evaluate the sensitivity of cerebral metabolites to beta-amyloid (Aß) induced synaptic deficit in the hippocampus of a mouse model of Alzheimer's disease. The CEST based spectra (Z-spectra) were acquired on a 9.4 Tesla small animal MR imaging system with two radiofrequency (RF) saturation amplitudes (1.47 µT and 5.9 µT) to obtain creatine-weighted and glutamate-weighted CEST contrasts, respectively. Multi-pool Lorentzian fitting and quantitative T1 longitudinal relaxation maps were used to obtain metabolic specific apparent exchange-dependent relaxation (AREX) maps. Short echo time (TE = 12 ms) single voxel MRS was acquired to quantify multiple neurometabolites from the right hippocampus region. AREX contrasts and MRS based metabolite concentration levels were examined in the ARTE10 animal model for Alzheimer's disease and their wild type (WT) littermate counterparts (age = 10 months). Using MRS voxel as a region of interest, group-wise analysis showed significant reduction in Glu-AREX and Cr-AREX in ARTE10, compared to WT animals. The MRS based results in the ARTE10 mice showed significant decrease in glutamate (Glu) and glutamate-total creatine (Glu/tCr) ratio, compared to WT animals. The MRS results also showed significant increase in total creatine (tCr), phosphocreatine (PCr) and glutathione (GSH) concentration levels in ARTE10, compared to WT animals. In the same ROI, Glu-AREX and Cr-AREX demonstrated positive associations with Glu/tCr ratio. These results indicate the involvement of neurotransmitter metabolites and energy metabolism in Aß-mediated synaptic degradation in the hippocampus region. The study also highlights the feasibility of CEST and MRS to identify and track multiple competing and compensatory mechanisms involved in heterogeneous pathophysiology of Alzheimer's disease in vivo.

Edge time series components of functional connectivity and cognitive function in Alzheimer's disease.

Understanding the interrelationships of brain function as measured by resting-state magnetic resonance imaging and neuropsychological/behavioral measures in Alzheimer's disease is key for advancement of neuroimaging analysis methods in clinical research. The edge time-series framework recently developed in the field of network neuroscience, in combination with other network science methods, allows for investigations of brain-behavior relationships that are not possible with conventional functional connectivity methods. Data from the Indiana Alzheimer's Disease Research Center sample (53 cognitively normal control, 47 subjective cognitive decline, 32 mild cognitive impairment, and 20 Alzheimer's disease participants) were used to investigate relationships between functional connectivity components, each derived from a subset of time points based on co-fluctuation of regional signals, and measures of domain-specific neuropsychological functions. Multiple relationships were identified with the component approach that were not found with conventional functional connectivity. These involved attentional, limbic, frontoparietal, and default mode systems and their interactions, which were shown to couple with cognitive, executive, language, and attention neuropsychological domains. Additionally, overlapping results were obtained with two different statistical strategies (network contingency correlation analysis and network-based statistics correlation). Results demonstrate that connectivity components derived from edge time-series based on co-fluctuation reveal disease-relevant relationships not observed with conventional static functional connectivity.

Association of Alzheimer's disease polygenic risk score with concussion severity and recovery metrics.

Identification of genetic alleles associated with both Alzheimer's disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset. We assessed six outcomes in 931 total participants. The outcomes were two concussion recovery measures (number of days to asymptomatic status, number of days to return to play (RTP)) and four concussion severity measures (scores on SAC and BESS, SCAT symptom severity, and total number of symptoms). We calculated PRS using a published score [1] and performed multiple linear regression (MLR) to assess the relationship of PRS with the outcomes. We also used t-tests and chi-square tests to examine outcomes by APOE genotype, and MLR to analyze outcomes in European and African genetic ancestry subgroups. Higher PRS was associated with longer injury to RTP in the normal RTP (<24 days) subgroup ( p = 0.024), and one standard deviation increase in PRS resulted in a 9.89 hour increase to the RTP interval. There were no other consistently significant effects, suggesting that high AD genetic risk is not strongly associated with more severe concussions or poor recovery in young adults. Future studies should attempt to replicate these findings in larger samples with longer follow-up using PRS calculated from diverse populations.

Spatial transcriptomic patterns underlying amyloid-ß and tau pathology are associated with cognitive dysfunction in Alzheimer's disease.

Amyloid-ß (Aß) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aß and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aß (gene-to-Aß associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aß and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aß and the gene-to-tau associations. These findings may explain the discordance between regional Aß and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.

The representation of biological classes in the human brain.

Evidence of category specificity from neuroimaging in the human visual system is generally limited to a few relatively coarse categorical distinctions-e.g., faces versus bodies, or animals versus artifacts-leaving unknown the neural underpinnings of fine-grained category structure within these large domains. Here we use fMRI to explore brain activity for a set of categories within the animate domain, including six animal species-two each from three very different biological classes: primates, birds, and insects. Patterns of activity throughout ventral object vision cortex reflected the biological classes of the stimuli. Specifically, the abstract representational space-measured as dissimilarity matrices defined between species-specific multivariate patterns of brain activity-correlated strongly with behavioral judgments of biological similarity of the same stimuli. This biological class structure was uncorrelated with structure measured in retinotopic visual cortex, which correlated instead with a dissimilarity matrix defined by a model of V1 cortex for the same stimuli. Additionally, analysis of the shape of the similarity space in ventral regions provides evidence for a continuum in the abstract representational space-with primates at one end and insects at the other. Further investigation into the cortical topography of activity that contributes to this category structure reveals the partial engagement of brain systems active normally for inanimate objects in addition to animate regions.