Evidence of Pericyte Damage in a Cognitively Normal Cohort: Association With CSF and PET Biomarkers of Alzheimer Disease.

BACKGROUND: Blood-brain barrier (BBB) dysfunction is emerging as an important pathophysiologic factor in Alzheimer disease (AD). Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-ß (PDGFRß) is a biomarker of BBB pericyte injury and has been implicated in cognitive impairment and AD. METHODS: We aimed to study CSF PDGFRß protein levels, along with CSF biomarkers of brain amyloidosis and tau pathology in a well-characterized population of cognitively unimpaired individuals and correlated CSF findings with amyloid-PET positivity. We performed an institutional review board (IRB)-approved cross-sectional analysis of a prospectively enrolled cohort of 36 cognitively normal volunteers with available CSF, Pittsburgh compound B PET/CT, Mini-Mental State Exam score, Global Deterioration Scale, and known apolipoprotein E ( APOE ) ε4 status. RESULTS: Thirty-six subjects were included. Mean age was 63.3 years; 31 of 36 were female, 6 of 36 were amyloid-PET-positive and 12 of 36 were APOE ε4 carriers. We found a moderate positive correlation between CSF PDGFRß and both total Tau (r=0.45, P =0.006) and phosphorylated Tau 181 (r=0.51, P =0.002). CSF PDGFRß levels were not associated with either the CSF Aß42 or the amyloid-PET. CONCLUSIONS: We demonstrated a moderate positive correlation between PDGFRß and both total Tau and phosphorylated Tau 181 in cognitively normal individuals. Our data support the hypothesis that BBB dysfunction represents an important early pathophysiologic step in AD, warranting larger prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00094939.

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET.

INTRODUCTION: Mapping of microscopic changes in the perivascular space (PVS) of the cerebral cortex, beyond magnetic resonance-visible PVS in white matter, may enhance our ability to diagnose Alzheimer's disease (AD) early. METHODS: We used the cerebrospinal fluid (CSF) water fraction (CSFF), a magnetic resonance imaging-based biomarker, to characterize brain parenchymal CSF water, reflecting microscopic PVS in parenchyma. We measured CSFF and amyloid beta (Aß) using 11 C Pittsburgh compound B positron emission tomography to investigate their relationship at both the subject and voxel levels. RESULTS: Our research has demonstrated a positive correlation between the parenchymal CSFF, a non-invasive imaging biomarker indicative of parenchymal glymphatic clearance, and Aß deposition, observed at both individual and voxel-based assessments in the posterior cingulate cortex. DISCUSSION: This study shows that an increased parenchymal CSFF is associated with Aß deposition, suggesting that CSFF could serve as a biomarker for brain glymphatic clearance, which can be used to detect early fluid changes in PVS predisposing individuals to the development of AD. HIGHLIGHTS: Cerebrospinal fluid fraction (CSFF) could be a biomarker of parenchymal perivascular space. CSFF is positively associated with amyloid beta (Aß) deposition at subject level. CSFF in an Aß+ region is higher than in an Aß- region in the posterior cingulate cortex. Correspondence is found between Aß deposition and glymphatic clearance deficits measured by CSFF.

Acetazolamide-augmented BOLD MRI to Assess Whole-Brain Cerebrovascular Reactivity in Chronic Steno-occlusive Disease Using Principal Component Analysis.

Background Exhaustion of cerebrovascular reactivity (CVR) portends increased stroke risk. Acetazolamide-augmented blood oxygenation level-dependent (BOLD) MRI has been used to estimate CVR, but low signal-to-noise conditions relegate its use to terminal CVR (CVRend) measurements that neglect dynamic features of CVR. Purpose To demonstrate comprehensive characterization of acetazolamide-augmented BOLD MRI response in chronic steno-occlusive disease using a computational framework to precondition signal time courses for dynamic whole-brain CVR analysis. Materials and Methods This study focused on retrospective analysis of consecutive patients with unilateral chronic steno-occlusive disease who underwent acetazolamide-augmented BOLD imaging for recurrent minor stroke or transient ischemic attack at an academic medical center between May 2017 and October 2020. A custom principal component analysis-based denoising pipeline was used to correct spatially varying non-signal-bearing contributions obtained by a local principal component analysis of the MRI time series. Standard voxelwise CVRend maps representing terminal responses were produced and compared with maximal CVR (CVRmax) as isolated from binned (per-repetition time) denoised BOLD time course. A linear mixed-effects model was used to compare CVRmax and CVRend in healthy and diseased hemispheres. Results A total of 23 patients (median age, 51 years; IQR, 42-61, 13 men) who underwent 32 BOLD examinations were included. Processed MRI data showed twofold improvement in signal-to-noise ratio, allowing improved isolation of dynamic characteristics in signal time course for sliding window CVRmax analysis to the level of each BOLD repetition time (approximately 2 seconds). Mean CVRmax was significantly higher than mean CVRend in diseased (5.2% vs 3.8%, P < .01) and healthy (5.5% vs 4.0%, P < .01) hemispheres. Several distinct time-signal signatures were observed, including nonresponsive; delayed/blunted; brisk; and occasionally nonmonotonic time courses with paradoxical features in normal and abnormal tissues (ie, steal and reverse-steal patterns). Conclusion A principal component analysis-based computational framework for analysis of acetazolamide-augmented BOLD imaging can be used to measure unsustained CVRmax through twofold improvements in signal-to-noise ratio. © RSNA, 2023 Supplemental material is available for this article.

Diaschisis Profiles in the Cerebellar Response to Hemodynamic Stimuli: Insights From Dynamic Measurement of Cerebrovascular Reactivity to Identify Occult and Transient Maxima.

BACKGROUND: Crossed cerebellar diaschisis (CCD) refers to depressions in perfusion and metabolism within the cerebellar hemisphere contralateral to supratentorial disease. Prior investigation into CCD in cerebrovascular reactivity (CVR) has been limited to terminal CVR estimations (CVRend ). We recently have demonstrated the presence of unsustained CVR maxima (CVRmax ) using dynamic CVR analysis, offering a fully dynamic characterization of CVR to hemodynamic stimuli. PURPOSE: To investigate CCD in CVRmax from dynamic blood oxygen level-dependent (BOLD) MRI, by comparison with conventional CVRend estimation. STUDY TYPE: Retrospective. POPULATION: A total of 23 patients (median age: 51 years, 10 females) with unilateral chronic steno-occlusive cerebrovascular disease, without prior knowledge of CCD status. FIELD STRENGTH/SEQUENCE: A 3-T, T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) and acetazolamide-augmented BOLD imaging performed with a gradient-echo echo-planar imaging (EPI) sequence. ASSESSMENT: A custom denoising pipeline was used to generate BOLD-CVR time signals. CVRend was established using the last minute of the BOLD response relative to the first-minute baseline. Following classification of healthy versus diseased cerebral hemispheres, CVRmax and CVRend were calculated for bilateral cerebral and cerebellar hemispheres. Three independent observers evaluated all data for the presence of CCD. STATISTICAL TESTS: Pearson correlations for comparing CVR across hemispheres, two-proportion Z-tests for comparing CCD prevalence, and Wilcoxon signed-rank tests for comparing median CVR. The level of statistical significance was set at P ≤ 0.05. RESULTS: CCD-related changes were observed on both CVRend and CVRmax maps, with all CCD+ cases identifiable by inspection of either map. Diseased cerebral and contralateral cerebellar hemispheric CVR correlations in CCD+ patients were stronger when using CVRend (r = 0.728) as compared to CVRmax (r = 0.676). CVR correlations between healthy cerebral hemispheres and contralateral cerebellar hemispheres were stronger for CVRmax (r = 0.739) than for CVRend (r = 0.705). DATA CONCLUSION: CCD-related alterations could be observed in CVR examinations. Conventional CVRend may underestimate CVR and could exaggerate CCD. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 3.

Application of AtMYB75 as a reporter gene in the study of symbiosis between tomato and Funneliformis mosseae.

Composite plants containing transgenic hairy roots produced with Agrobacterium rhizogenes-mediated transformation have become an important method to study the interaction between plants and arbuscular mycorrhizal fungi (AMF). Not all hairy roots induced by A. rhizogenes are transgenic, however, which leads to requirement of a binary vector to carry a reporter gene to distinguish transgenic roots from non-transformed hairy roots. The beta-glucuronidase gene (GUS) and fluorescent protein gene often are used as reporter markers in the process of hairy root transformation, but they require expensive chemical reagents or imaging equipment. Alternatively, AtMYB75, an R2R3 MYB transcription factor from Arabidopsis thaliana, recently has been used as a reporter gene in hairy root transformation in some leguminous plants and can cause anthocyanin accumulation in transgenic hairy roots. Whether AtMYB75 can be used as a reporter gene in the hairy roots of tomato and if the anthocyanins accumulating in the roots will affect AMF colonization, however, are still unknown. In this study, the one-step cutting method was used for tomato hairy root transformation by A.rhizogenes. It is faster and has a higher transformation efficiency than the conventional method. AtMYB75 was used as a reporter gene in tomato hairy root transformation. The results showed that the overexpression of AtMYB75 caused anthocyanin accumulation in the transformed hairy roots. Anthocyanin accumulation in the transgenic hairy roots did not affect their colonization by the arbuscular mycorrhizal fungus, Funneliformis mosseae strain BGC NM04A, and there was no difference in the expression of the AMF colonization marker gene SlPT4 in AtMYB75 transgenic roots and wild-type roots. Hence, AtMYB75 can be used as a reporter gene in tomato hairy root transformation and in the study of symbiosis between tomato and AMF.

Multimodal assessment of brain fluid clearance is associated with amyloid-beta deposition in humans.

PURPOSE: The present study investigates a multimodal imaging assessment of glymphatic function and its association with brain amyloid-beta deposition. METHODS: Two brain CSF clearance measures (vCSF and DTI-ALPS) were derived from dynamic PET and MR diffusion tensor imaging (DTI) for 50 subjects, 24/50 were Aß positive (Aß+). T1W, T2W, DTI, T2FLAIR, and 11C-PiB and 18F-MK-6240 PET were acquired. Multivariate linear regression models were assessed with both vCSF and DTI-ALPS as independent variables and brain Aß as the dependent variable. Three types of models were evaluated, including the vCSF-only model, the ALPS-only model and the vCSF+ALPS combined model. Models were applied to the whole group, and Aß subgroups. All analyses were controlled for age, gender, and intracranial volume. RESULTS: Sample demographics (N=50) include 20 males and 30 females with a mean age of 69.30 (sd=8.55). Our results show that the combination of vCSF and ALPS associates with Aß deposition (p < 0.05, R2 = 0.575) better than either vCSF (p < 0.05, R2 = 0.431) or ALPS (p < 0.05, R2 = 0.372) alone in the Aß+ group. We observed similar results in whole-group analyses (combined model: p < 0.05, R2 = 0.287; vCSF model: p <0.05, R2 = 0.175; ALPS model: p < 0.05, R2 = 0.196) with less significance. Our data also showed that vCSF has higher correlation (r = -0.548) in subjects with mild Aß deposition and DTI-ALPS has higher correlation (r=-0.451) with severe Aß deposition subjects. CONCLUSION: The regression model with both vCSF and DTI-ALPS is better associated with brain Aß deposition. These two independent brain clearance measures may better explain the variation in Aß deposition than either term individually. Our results suggest that vCSF and DTI-ALPS reflect complementary aspects of brain clearance functions.

MicroRNA-590-3p inhibits T helper 17 cells and ameliorates inflammation in lupus mice.

T helper 17 (Th17) cells have a pathogenic effect in many autoimmune diseases. Inhibition of Th17 cells can alleviate the inflammatory damage in autoimmune diseases. Our previous study found that microRNA-590-3p (miR-590-3p) was involved in the differentiation of Th17 cells in systemic lupus erythematosus (SLE). Here, we demonstrated that an increase in Th17 cells was correlated with low expression of miR-590-3p in patients with SLE and in lupus mice. Upregulation of miR-590-3p reduced the differentiation and promoted apoptosis of Th17 cells. Subsequent experiments demonstrated that miR-590-3p promoted apoptosis in Th17 cells by inhibiting autophagy. Autophagy-related 7 (Atg7) was the direct target of miR-590-3p that blocked the autophagy pathway. Finally, treatment of MRL/lpr mice with miR-590-3p agomir ameliorated lupus nephritis and skin lesions. Our work revealed that miR-590-3p inhibited Th17 cells by suppressing autophagy and that increased miR-590-3p expression was able to ameliorate the clinical symptoms of lupus. Therefore, miR-590-3p may be a promising therapeutic target for SLE and other Th17 cell-dependent autoimmune diseases.

Discovery of the oncogenic MDM2, a direct binding target of berberine and a potential therapeutic, in multiple myeloma.

Recent studies have suggested the potency of berberine (BBR) for multiple cancer treatments, including multiple myeloma (MM). However, the direct target and underlying mechanism of BBR remain largely understood in MM. Here, we demonstrated that BBR inhibited cell proliferation and acted synergistically with bortezomib in MM.1S cells. BBR treatment induced MM cell cycle arrest by downregulating several cell cycle-related proteins. Murine double minute 2 (MDM2) as a BBR-binding protein was identified by surface plasmon resonance image (SPRi) analysis and molecular docking. Overexpression of MDM2 is associated with MM progression and a poor prognosis. Knockdown MDM2 by siRNA transfection can repress MM malignant progression and attenuate the BBR sensitivity to MM.1S cells. BBR treatment induced the degradation of MDM2 through the ubiquitin-proteasome system and reactivated P53/P21 in MM cells. Overall, our data has illustrated that MDM2, as a binding protein of BBR for the first time, may serve as a potential therapeutic option for MM.

Increased Posterior Tibial Slope and Meniscal Slope Could Be Risk Factors for Meniscal Injuries: A Systematic Review.

PURPOSE: The purpose of this systematic review was to summarize the available evidence and examine the relation between the posterior tibial slope (PTS) and meniscal slope (MS) and the incidence of meniscal injury. METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception to February 23, 2021. Cohort studies investigating the association between PTS or MS and the risk of meniscal injury were included. Two authors independently conducted the literature search, data extraction, and quality assessment. RESULTS: Sixteen studies with a total of 2,670 patients were included. For meniscal injury with an anterior cruciate ligament tear, the lateral PTS in the lateral meniscal root tear group (range, 8.0°-12.6°) was significantly higher than that in the control group (range, 4.0°-10.7°). Furthermore, there appeared to be a relation between a greater medial MS and the presence of a ramp lesion (range, 2.6°-6.7° for ramp lesion vs 2.0°-5.1° for control). For degenerative meniscal injury, the medial PTS in the medial meniscal posterior root tear group (range, 6.15°-10.4°) was significantly greater than that in the control group (range, 4.0°-9.8°). CONCLUSIONS: On the basis of the available evidence, for meniscal injury with an anterior cruciate ligament tear, an increased lateral PTS was associated with a higher risk of lateral meniscal tears and lateral meniscal posterior root tears. Furthermore, there appeared to be a relation between an increased medial MS and a higher risk of ramp lesions. For degenerative meniscal injury, most of the included studies showed that a larger medial PTS could increase the risk of medial meniscal tears and medial meniscal posterior root tears. LEVEL OF EVIDENCE: Level III, systematic review of Level III studies.

BaTiF6:Mn4+ Red Phosphor: Synthesis of Single Crystals at Room Temperature and the High Hydrolysis-Resistant Property.

Due to the low solubility of BaF2, the BaTiF6:Mn4+ phosphor for whitelight-emitting diodes application has been generally synthesized by the hydrothermal route, during which process the valence of the manganese dopant is difficult to be controlled as tetravalent. In this paper, a new synthesis method that proceeded at room temperature was reported. This method uses BaTiOF4 as the precursor and allows for the control of the phase transformation rate from BaTiOF4 to BaTiF6 in the K2MnF6/HF acid solution. Benefitting from that, we successfully prepared red-emitting BaTiF6:Mn4+ elongated crystals with a single-crystal nature up to a record-breaking length of 200-300 µm. The effects of the crystallinity of the BaTiOF4 precursor on its phase transformation rate into BaTiF6 and on the optimal Mn4+ doping concentration were studied. The BaTiF6:Mn4+ single-crystal phosphor exhibits relatively excellent hydrolysis-resistant behavior after being immersed in water for 3 h, at which condition the commercial K2SiF6:Mn4+ has become brown. This study may inspire the room-temperature preparation of other hydrolysis-resistant alkali earth fluorotitanate or fluorosilicate phosphors with stable tetravalent manganese doping.

Visualization of Vaccine Dynamics with Quantum Dots for Immunotherapy.

The direct visualization of vaccine fate is important to investigate its immunoactivation process to elucidate the detailed molecular reaction process at single-molecular level. Yet, visualization of the spatiotemporal trafficking of vaccines remains poorly explored. Here, we show that quantum dot (QD) nanomaterials allow for monitoring vaccine dynamics and for amplified immune response. Synthetic QDs enable efficient conjugation of antigen and adjuvants to target tissues and cells, and non-invasive imaging the trafficking dynamics to lymph nodes and cellular compartments. The nanoparticle vaccine elicits potent immune responses and anti-tumor efficacy alone or in combination with programmed cell death protein 1 blockade. The synthetic QDs showed high fluorescence quantum yield and superior photostability, and the reliable and long-term spatiotemporal tracking of vaccine dynamics was realized for the first time by using the synthetic QDs, providing a powerful strategy for studying immune response and evaluating vaccine efficacy.

One-step generation of composite soybean plants with transgenic roots by Agrobacterium rhizogenes-mediated transformation.

BACKGROUND: Agrobacterium rhizogenes-mediated (ARM) transformation is a highly efficient technique for generating composite plants composed of transgenic roots and wild-type shoot, providing a powerful tool for studying root biology. The ARM transformation has been established in many plant species, including soybean. However, traditional transformation of soybean, transformation efficiency is low. Additionally, the hairy roots were induced in a medium, and then the generated composite plants were transplanted into another medium for growth. This two-step operation is not only time-consuming, but aggravates contamination risk in the study of plant-microbe interactions. RESULTS: Here, we report a one-step ARM transformation method with higher transformation efficiency for generating composite soybean plants. Both the induction of hairy roots and continuous growth of the composite plants were conducted in a single growth medium. The primary root of a 7-day-old seedling was decapitated with a slanted cut, the residual hypocotyl (maintained 0.7-1 cm apical portion) was inoculated with A. rhizogenes harboring the gene construct of interest. Subsequently, the infected seedling was planted into a pot with wet sterile vermiculite. Almost 100% of the infected seedlings could produce transgenic positive roots 16 days post-inoculation in 7 tested genotypes. Importantly, the transgenic hairy roots in each composite plant are about three times more than those of the traditional ARM transformation, indicating that the one-step method is simpler in operation and higher efficiency in transformation. The reliability of the one-step method was verified by CRISPR/Cas9 system to knockout the soybean Rfg1, which restricts nodulation in Williams 82 (Nod-) by Sinorhizobium fredii USDA193. Furthermore, we applied this method to analyze the function of Arabidopsis YAO promoter in soybean. The activity of YAO promoter was detected in whole roots and stronger in the root tips. We also extended the protocol to tomato. CONCLUSIONS: We established a one-step ARM transformation method, which is more convenient in operation and higher efficiency (almost 100%) in transformation for generating composite soybean plants. This method has been validated in promoter functional analysis and rhizobia-legume interactions. We anticipate a broad application of this method to analyze root-related events in tomato and other plant species besides soybean.

Forced conceptual thought induced by electrical stimulation of the left prefrontal gyrus involves widespread neural networks.

BACKGROUND: Early accounts of forced thought were reported at the onset of a focal seizure, and characterized as vague, repetitive, and involuntary intellectual auras distinct from perceptual or psychic hallucinations or illusions. Here, we examine the neural underpinnings involved in conceptual thought by presenting a series of 3 patients with epilepsy reporting intrusive thoughts during electrical stimulation of the left lateral prefrontal cortex (PFC) during invasive surgical evaluation. We illustrate the widespread networks involved through two independent brain imaging modalities: resting state functional magnetic resonance imaging (fMRI) (rs-fMRI) and task-based meta-analytic connectivity modeling (MACM). METHODS: We report the clinical and stimulation characteristics of three patients with left hemispheric language dominance who demonstrate forced thought with functional mapping. To examine the brain networks underlying this phenomenon, we used the regions of interest (ROI) centered at the active electrode pairs. We modeled functional networks using two approaches: (1) rs-fMRI functional connectivity analysis, representing 81 healthy controls and (2) meta-analytic connectivity modeling (MACM), representing 8260 healthy subjects. We also determined the overlapping regions between these three subjects' rs-fMRI and MACM networks through a conjunction analysis. RESULTS: We identified that left PFC was associated with a large-scale functional network including frontal, temporal, and parietal regions, a network that has been associated with multiple cognitive functions including semantics, speech, attention, working memory, and explicit memory. CONCLUSIONS: We illustrate the neural networks involved in conceptual thought through a unique patient population and argue that PFC supports this function through activation of a widespread network.

Cortical gray-white matter blurring and declarative memory impairment in MRI-negative temporal lobe epilepsy.

Magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) may be a distinct syndrome from TLE with mesial temporal sclerosis (TLE-MTS). Imaging and neuropsychological features of TLE-MTS are well-known; yet, these features are only beginning to be described in MRI-negative TLE. This study examined whether a quantitative measure of cortical gray and white matter blurring (GWB) was elevated in the temporal lobes ipsilateral to the seizure onset zone of individuals with MRI-negative TLE relative to TLE-MTS and healthy controls (HCs) and whether GWB elevations were associated with neuropsychological comorbidity. Gray-white matter blurring from 34 cortical regions and hippocampal volumes were quantified and compared across 28 people with MRI-negative TLE, 15 people with TLE-MTS, and 51 HCs. Declarative memory was assessed with standard neuropsychological tests and the intracarotid amobarbital procedure (IAP). In the group with MRI-negative TLE (left and right onsets combined), hippocampal volumes were within normal range but GWB was elevated, relative to HCs, across several mesial and lateral temporal lobe regions ipsilateral to the seizure onset zone. Gray-white matter blurring did not differ between the groups with TLE-MTS and HC or between the groups with TLE-MTS and MRI-negative TLE. The group with MRI-negative TLE could not be distinguished from the group with TLE-MTS on any of the standard neuropsychological tests; however, ipsilateral hippocampal volumes and IAP memory scores were lower in the group with TLE-MTS than in the group with MRI-negative TLE. The group with left MRI-negative TLE had lower general cognitive abilities and verbal fluency relative to the HC group, which adds to the characterization of neuropsychological comorbidities in left MRI-negative TLE. In addition, ipsilateral IAP memory performance was reduced relative to contralateral memory performance in MRI-negative TLE, indicating some degree of ipsilateral memory dysfunction. There was no relationship between hippocampal volume and IAP memory scores in MRI-negative TLE; however, decreased ipsilateral IAP memory scores were correlated with elevated GWB in the ipsilateral superior temporal sulcus of people with left MRI-negative TLE. In sum, GWB elevations in the ipsilateral temporal lobe of people with MRI-negative TLE suggest that GWB may serve as a marker for reduced structural integrity in regions in or near the seizure onset zone. Although mesial temporal abnormalities might be the major driver of memory dysfunction in TLE-MTS, a loss of structural integrity in lateral temporal lobe regions may contribute to IAP memory dysfunction in MRI-negative TLE.

Focal Cortical Anomalies and Language Impairment in 16p11.2 Deletion and Duplication Syndrome.

Individuals with copy number variants (CNV) in the 16p11.2 chromosomal region are at high risk for language disorders. We investigate whether the extent and location of focal cortical anomalies are associated with language impairment in individuals with 16p11.2 CNVs. High-resolution T1-weighted MRI scans from 30 16p11.2 deletion (16p-del), 25 16p11.2 duplication (16p-dup), and 90 noncarrier controls (NCC) were analyzed to derive personalized cortical anomaly maps through single-case cortical thickness (CT) comparison to age-matched normative samples. Focal cortical anomalies were elevated in both 16p-del and 16p-dup and their total extent was inversely correlated with Full-Scale IQ. Clusters of abnormally thick cortex were more extensive in the 16p-del group and clusters of abnormally thin cortex were more extensive in the 16p-dup group. Abnormally thick clusters were more extensive in left lateral temporal and bilateral postcentral and mesial occipital regions in 16p-del. Focal cortical anomalies in the left middle temporal region and pars opercularis (Broca's region) of children with 16-del were associated with lower scores on a comprehensive language evaluation. Results extend neuroanatomical findings in 16p11.2 syndrome to include spatially heterogenous focal cortical anomalies that appear to disrupt language ability in accordance with the functional specialization of left frontotemporal regions.

Low Rank plus Sparse decomposition of ODFs for improved detection of group-level differences and variable correlations in white matter.

A novel approach is presented for group statistical analysis of diffusion weighted MRI datasets through voxelwise Orientation Distribution Functions (ODF). Recent advances in MRI acquisition make it possible to use high quality diffusion weighted protocols (multi-shell, large number of gradient directions) for routine in vivo study of white matter architecture. The dimensionality of these data sets is however often reduced to simplify statistical analysis. While these approaches may detect large group differences, they do not fully capitalize on all acquired image volumes. Incorporation of all available diffusion information in the analysis however risks biasing the outcome by outliers. Here we propose a statistical analysis method operating on the ODF, either the diffusion ODF or fiber ODF. To avoid outlier bias and reliably detect voxelwise group differences and correlations with demographic or behavioral variables, we apply the Low-Rank plus Sparse (L+S) matrix decomposition on the voxelwise ODFs which separates the sparse individual variability in the sparse matrix S whilst recovering the essential ODF features in the low-rank matrix L. We demonstrate the performance of this ODF L+S approach by replicating the established negative association between global white matter integrity and physical obesity in the Human Connectome dataset. The volume of positive findings p<0.01,227cm3, agrees with and expands on the volume found by TBSS (17 cm3), Connectivity based fixel enhancement (15 cm3) and Connectometry (212 cm3). In the same dataset we further localize the correlations of brain structure with neurocognitive measures such as fluid intelligence and episodic memory. The presented ODF L+S approach will aid in the full utilization of all acquired diffusion weightings leading to the detection of smaller group differences in clinically relevant settings as well as in neuroscience applications.

Parahippocampal and Entorhinal Resection Extent Predicts Verbal Memory Decline in an Epilepsy Surgery Cohort.

The differential contribution of medial-temporal lobe regions to verbal declarative memory is debated within the neuroscience, neuropsychology, and cognitive psychology communities. We evaluate whether the extent of surgical resection within medial-temporal regions predicts longitudinal verbal learning and memory outcomes. This single-center retrospective observational study involved patients with refractory temporal lobe epilepsy undergoing unilateral anterior temporal lobe resection from 2007 to 2015. Thirty-two participants with Engel Class 1 and 2 outcomes were included (14 left, 18 right) and followed for a mean of 2.3 years after surgery (±1.5 years). Participants had baseline and postsurgical neuropsychological testing and high-resolution T1-weighted MRI scans. Postsurgical lesions were manually traced and coregistered to presurgical scans to precisely quantify resection extent of medial-temporal regions. Verbal learning and memory change scores were regressed on hippocampal, entorhinal, and parahippocampal resection volume after accounting for baseline performance. Overall, there were no significant differences in learning and memory change between patients who received left and right anterior temporal lobe resection. After controlling for baseline performance, the extent of left parahippocampal resection accounted for 27% (p = .021) of the variance in verbal short delay free recall. The extent of left entorhinal resection accounted for 37% (p = .004) of the variance in verbal short delay free recall. Our findings highlight the critical role that the left parahippocampal and entorhinal regions play in recall for verbal material.

Resting-state functional MRI distinguishes temporal lobe epilepsy subtypes.

OBJECTIVE: We assessed whether presurgical resting state functional magnetic resonance imaging (fMRI) provides information for distinguishing temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) from TLE without MTS (TLE-noMTS). METHODS: Thirty-four patients with TLE and 34 sex-/age-matched controls consented to a research imaging protocol. MTS status was confirmed by histologic evaluation of surgical tissue (TLE-MTS = 16; TLE-noMTS = 18). The fractional amplitude of low-frequency fluctuations (fALFFs) in the blood oxygen level-dependent (BOLD) resting-state fMRI signal, a marker of local metabolic demand at rest, was averaged at five regions of interest (ROIs; hippocampus, amygdala, frontal, occipital, and temporal lobe), along with corresponding volume and cortical thickness estimates. ROIs were labeled ipsilateral or contralateral according to seizure lateralization and compared across TLE-MTS, TLE-noMTS, and healthy controls (HCs). MTS status was regressed on ipsilateral hippocampal volume and fALFF to test for independent contributions. RESULTS: The TLE-MTS group had reduced fALFF in the ipsilateral amygdala and hippocampus; whereas, the TLE-noMTS group had marginally reduced fALFF in the ipsilateral amygdala but not hippocampus. These results were consistently obtained with and without application of global signal regression (GSR). Ipsilateral hippocampal volume contributed to 37% of the variance in MTS status (p < 0.001) and fALFF contributed an additional 10% (p = 0.021). Two MTS cases were accurately classified with fALFF but not volume, and three were accurately classified with volume but not fALFF. At the lobar level, fALFF (with GSR) was reduced in the ipsilateral temporal and bilateral frontal lobes of patients with TLE-MTS and bilateral frontal lobes of patients with TLE-noMTS in the context of normal cortical thickness. SIGNIFICANCE: This study indicates that resting-state fMRI provides complementary functional information for MTS classification. Findings validate fALFF as a measure of regional brain integrity in TLE and highlight the value of using multi-modal imaging to provide independent diagnostic information in presurgical epilepsy evaluations.

Transient and chronic seizure-induced inflammation in human focal epilepsy.

In animal models, inflammation is both a cause and consequence of seizures. Less is known about the role of inflammation in human epilepsy. We performed positron emission tomography (PET) using a radiotracer sensitive to brain inflammation in a patient with frontal epilepsy ~36 h after a seizure as well as during a seizure-free period. When statistically compared to a group of 12 matched controls, both of the patient's scans identified a frontal (supplementary motor area) region of increased inflammation corresponding to his clinically defined seizure focus, but the postseizure scan showed significantly greater inflammation intensity and spatial extent. These results provide new information about transient and chronic neuroinflammation in human epilepsy and may be relevant to understanding the process of epileptogenesis and guiding therapy.