Magnetic Resonance Imaging Markers Research Articles

Higher MRI lesion load in multiple sclerosis is related to the N-glycosylation changes of cerebrospinal fluid immunoglobulin G

BackgroundIntrathecal clonal expansion of antibody-producing plasma cells in multiple sclerosis (MS) perpetuates central nervous system injury and is associated with active demyelination. Immunoglobulin G (IgG) effector functions are modulated by linked N-glycan structures. The aim of the study was to detect potential differences in N-glycosylation of IgG in serum and cerebrospinal fluid (CSF) and total sera proteins between people with MS and those in whom the diagnosis of MS was excluded. Furthermore, we investigated the association with standard laboratory biomarkers of intrathecal inflammation as well as clinical and neuroradiological disease activity. MethodsThis cross-sectional study included patients with suspected demyelinating disease. MS diagnosis was based on the 2017 McDonald criteria and controls were patients with excluded MS diagnosis. N-glycans were compared with Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI) markers of disease activity and biomarkers of intrathecal inflammation (cell count, CSF-IgG concentration, percentage of intrathecal IgG, oligoclonal bands (OCB), virus-specific antibody index (MRZH reaction)). ResultsDifferences between groups were observed only in the CSF-IgG N-glycome. In MS, the presence of bisecting N-acetylglucosamine (Padj=2.63E-05) and monogalactosylation (Padj=1.49E-06) were more abundant and associated with positive OCBs. N-glycans monogalactosylated at the α6 arm FA2[6]G1 (r = 0.56) and FA2[6]BG1 (r = 0.45) correlated with percentage of intrathecal IgG, but not total CSF-IgG. This trait was also more abundant in MRZH positive people with MS who had higher MRI lesion load (P = 0.018) but unrelated to active lesions or EDSS. ConclusionsMore abundant monogalactosylation of intrathecally synthesized IgG is the most prominent trait in MS and is associated with higher MRI lesion load.

Correlation of blood pressure levels at different time periods throughout the day with total CSVD burden and MRI imaging markers.

Hypertension is an important risk factor for atherosclerotic cerebral small vessel disease (CSVD). Higher blood pressure is associated with a higher CSVD burden and the presence of relevant magnetic resonance imaging (MRI) markers. However, the effect of blood pressure level on CSVD burden and imaging markers including white matter hyperintensity (WHM), lacune, enlarged perivascular spaces (EPVS), and cerebral microbleed (CMB) remains unknown. The purpose of this study was to investigate the correlation between blood pressure level and CSVD burden at different time periods throughout the day. In total, 144 in-patients with CSVD (66.4 ± 9.8 years, 50% male) were enrolled and underwent brain MRI, and 24-h ambulatory blood pressure was assessed. Patients were categorized into five groups according to their MRI-evaluated total CSVD burden scores (0-4). Spearman's correlation analysis was performed to examine the correlation between blood pressure levels at different time periods and the total CSVD score or the markers of periventricular WMH, deep WMH, lacune, EPVS, and CMB. Of the 144 patients, 83.3% (120/144) harbored one or more CSVD markers of interest. The systolic blood pressure (SBP) of 24-h, daytime, nighttime, and morning differed significantly among the five groups. The SBP levels increased significantly with the total CSVD scores during 24 h (P = 0.018), daytime (P = 0.018), and nighttime (P = 0.035). Spearman's correlation analysis demonstrated that the SBP of 24 h, daytime, nighttime, and morning and the diastolic blood pressure (DBP) of 24 h and morning positively and significantly correlated with the total CSVD score (P < 0.05). A logistic regression analysis indicated that both morning SBP and DBP were independent risk factors for total CSVD burden (OR = 1.13, 95% CI: 1.02-1.23, P = 0.015; OR = 1.19, 95% CI: 1.06-1.33, P = 0.005). Spearman's correlation analysis indicated a significant positive correlation between morning SBP and higher deep WMH Fazekas score (r = 0.296, P < 0.001), EPVS grade in the basal ganglia (r = 0.247, P = 0.003), and the presence of lacune (r = 0.173, P = 0.038) and CMB (r = 0.326, P < 0.001). Morning DBP only correlated positively with the presence of CMB (r = 0.292, P < 0.001). Higher SBP signficantly correlated with total CSVD burden in patients with atherosclerotic CSVD. Early morning blood pressure level is an important indicator to reflect the severity of CSVD patients.

Paper 09: Serum Biochemical Biomarker Profiles Linked to Poor Knee Joint Health Are Not Associated with OA-Related Symptoms at 12 Months Post-ACLR

Objectives: Biochemical joint tissue changes are associated with the development of posttraumatic osteoarthritis (PTOA). Serial assessments of serum biomarkers related to cartilage degradation are predictive of symptomatic progression of idiopathic knee OA but have not been explored in patients with symptomatic PTOA following anterior cruciate ligament (ACL) injury. Both serum and synovial biomarker profiles of inflammation and cartilage degradation post-ACL injury and ACL reconstruction (ACLR) have been associated with deleterious changes of magnetic resonance imaging markers of tibiofemoral cartilage composition (i.e., lower proteoglycan density and poor collagen organization) which precede radiographic PTOA development. However, it is unclear if biochemical changes post-ACL injury and ACLR are also associated with clinically relevant knee OA symptoms. The purpose of this study was to determine if changes in biochemical biomarker profiles preoperatively to 6-months post-ACLR were associated with clinically relevant knee symptoms related to PTOA at 12-months post-ACLR. Methods: Participants with a primary history of ACL injury who were planning on undergoing ACLR with a bone-patellar tendon-bone autograft were included in the prospective, longitudinal cohort study. Serum was collected from participants at three separate study visits: i) preoperatively within 15 days of ACL injury; ii) 6 months post-ACLR; and iii) 12 months post-ACLR. Blood samples from the antecubital fossa were collected in 5 mL serum separation tube vacutainers, centrifuged at 3000 rpms and -4°C, and stored in aliquots at -80°C both preoperatively and 6 months post-ACLR. At 12 months post-ACLR, participants completed the Knee Injury and Osteoarthritis Outcome survey. Upon completion of the study, serum samples were batch processed using commercial enzyme-linked immunosorbent assays (ELISA) to determine biomarker concentrations of monocyte chemoattractant protein 1 (sMCP-1), cartilage oligomeric matrix protein (sCOMP), matrix metalloproteinase 3 (sMMP-3), and type-II collagen degradation to synthesis ratio (sC2C:sCPII) which assess inflammation, cartilage breakdown, cartilage degradation, and cartilage turnover, respectively. KOOS subscale scores were calculated on a scale of 0-100. Participants were classified as Symptomatic or Asymptomatic based on Englund et al. cut off scores for each KOOS subscale which were previously validated in patients with radiographic and symptomatic knee OA after a traumatic knee injury. A K-means cluster analysis was used to determine serum biochemical biomarker profiles based on z-score changes in sMCP-1, sCOMP, sMMP-3, sC2C:sCPII preoperatively to 6 months post-ACLR. One-way ANOVAs were used to determine statistically significant differences between biochemical biomarker changes and characterize the profiles of each group. Independent t-tests were used to assess differences in KOOS subscale scores between each group profile and P-values were Bonferroni corrected for multiple comparisons ( p&lt;0.0125). Cohen’s d effect sizes were calculated to determine the magnitude of differences between groups. Odds ratios (OR) and 95% confidence intervals (CIs) were also calculated to determine the odds of being classified as Symptomatic and reporting clinically relevant, OA-related symptoms. Results: Thirty-six participants completed all study visits and were dichotomized into groups based on changes in biochemical biomarker profiles over 6 months post-ACLR (Table 1). Group 1 (n=15) was characterized by increases in sMCP-1 and sCOMP preoperatively to 6-months post-ACLR (sMCP-1: p&lt;0.001, d=1.75, 95% CI=[0.96-2.52] and sCOMP: p&lt;0.001, d=1.45, 95% CI=[0.70-2.20]) and Group 2 (n=21) was characterized by decreases in sMCP-1 and sCOMP preoperatively to 6-months post-ACLR (Figure 1). No statistically significant differences were found for changes in sMMP-3 ( p=0.18, d=0.46, 95% CI=[-0.22-1.13]) or sC2C:sCPII ( p=0.10, d=-0.57, 95% CI=[-1.25-0.11]) preoperatively to 6-months post-ACLR between groups. Group 1 characterized by serum biochemical biomarker profiles with increasing sMCP-1 and sCOMP preoperatively to 6-months post-ACLR did not demonstrate statistically significant differences in self-reported knee pain ( p=0.72, d=-0.12, 95% CI=[-0.79-0.54]), symptoms ( p=0.96, d=0.02, 95% CI=[-0.64-0.68]), activities of daily living ( p=0.89, d=-0.05, 95% CI=[-0.71-0.62]), sport ( p=0.99, d=0.01, 95% CI=[-0.66-0.67]), or quality of life ( p=0.99, d=0.00, 95% CI=[-0.66-0.67) at 12 months post-ACLR (Figure 2) compared to Group 2 characterized by serum biochemical biomarker profiles with decreasing sMCP-1 and sCOMP preoperatively to 6-months post-ACLR. There were no statistically significant associations between serum biochemical biomarker groups and symptomatic OA status (OR=2.13, 95% CI=0.51-9.01). Conclusions: Pre-operative and post-ACLR changes in biochemical biomarker sampling revealed a group of ACLR patients with increased biomarker concentrations associated with inflammation (sMCP-1) and cartilage breakdown (sCOMP). Serum biomarker changes from the pre-operative to the 6-month post-ACLR time points had no predictive value with respect to patient reporting of clinically relevant knee OA symptoms 12 months post-ACLR. Therefore, serum biochemical changes post-ACLR may play a role in worsening knee joint health as reported in prior studies, but not poor symptom development related to PTOA. Future research is needed to assess the mechanistic role of biochemical changes in symptomatic PTOA development. [Table: see text]

Cardiovascular health, infection burden and their interactive association with brain volumetric and white matter integrity outcomes in the UK Biobank

BackgroundCardiovascular health is associated with brain magnetic resonance imaging (MRI) markers of pathology and infections may modulate this association. MethodsUsing data from 38,803 adults (aged 40–70 years) and followed-up for 5–15 years, we tested associations of prevalent total (47.5%) and hospital-treated infection burden (9.7%) with brain structural and diffusion-weighted MRI (i.e., sMRI and dMRI, respectively) common in dementia phenome. Poor white matter tissue integrity was operationalized with lower global and tract-specific fractional anisotropy (FA) and higher mean diffusivity (MD). Volumetric sMRI outcomes included total, gray matter (GM), white matter (WM), frontal bilateral GM, white matter hyperintensity (WMH), and selected based on previous associations with dementia. Cardiovascular health was measured with Life’s Essential 8 score (LE8) converted to tertiles. Multiple linear regression models were used, adjusting for intracranial volumes (ICV) for subcortical structures, and for demographic, socio-economic, and the Alzheimer’s Disease polygenic risk score for all outcomes, among potential confounders. ResultsIn fully adjusted models, hospital-treated infections were inversely related to GM (β ± SE: −1042 ± 379, p = 0.006) and directly related to WMH as percent of ICV (Loge transformed) (β ± SE:+0.026 ± 0.007, p < 0.001). Both total and hospital-treated infections were associated with poor WMI, while the latter was inversely related to FA within the lowest LE8 tertile (β ± SE:-0.0011 ± 0.0003, p < 0.001, PLE8×IB < 0.05), a pattern detected for GM, Right Frontal GM, left accumbens and left hippocampus volumes. Within the uppermost LE8 tertile, total infection burden was linked to smaller right amygdala while being associated with larger left frontal GM and right putamen volumes, in the overall sample. Within that uppermost tertile of LE8, caudate volumes were also positively associated with hospital-treated infections. ConclusionsHospital-treated infections had more consistent deleterious effects on volumetric and white matter integrity brain neuroimaging outcomes compared with total infectious burden, particularly in poorer cardiovascular health groups. Further studies are needed in comparable populations, including longitudinal studies with multiple repeats on neuroimaging markers.

Comparison of the clinical value of MRI and plasma markers for cognitive impairment in patients aged ≥75 years: a retrospective study.

Dementia has become the main cause of disability in older adults aged ≥75 years. Cerebral small vessel disease (CSVD) is involved in cognitive impairment (CI) and dementia and is a cause of vascular CI (VCI), which is manageable and its onset and progression can be delayed. Simple and effective markers will be beneficial to the early detection and intervention of CI. The aim of this study is to investigate the clinical application value of plasma amyloid β1-42 (Aβ42), phosphorylated tau 181 (p-tau181) and conventional structural magnetic resonance imaging (MRI) parameters for cognitive impairment (CI) in patients aged ≥75 years. We retrospectively selected patients who visited the Affiliated Hospital of Xuzhou Medical University and were clinically diagnosed with or without cognitive dysfunction between May 2018 and November 2021. Plasma indicators (Aβ42 and p-tau181) and conventional structural MRI parameters were collected and analyzed. Multivariate logistic regression and receiver operator characteristic (ROC) curve were used to evaluate the diagnostic value. One hundred and eighty-four subjects were included, including 54 cases in CI group and 130 cases in noncognitive impairment (NCI) groups, respectively. Univariate logistic regression analysis revealed that the percentages of Aβ42+, P-tau 181+, and Aβ42+/P-tau181+ showed no significant difference between the groups of CI and NCI (all P > 0.05). Multivariate logistic regression analysis showed that moderate/severe periventricular WMH (PVWMH) (OR 2.857, (1.365-5.983), P = 0.005), lateral ventricle body index (LVBI) (OR 0.413, (0.243-0.700), P = 0.001), and cortical atrophy (OR 1.304, (1.079-1.575), P = 0.006) were factors associated with CI. The combined model including PVWMH, LVBI, and cortical atrophy to detect CI and NCI showed an area under the ROC curve (AUROC) is 0.782, with the sensitivity and specificity 68.5% and 78.5%, respectively. For individuals ≥75 years, plasma Aβ42 and P-tau181 might not be associated with cognitive impairment, and MRI parameters, including PVWMH, LVBI and cortical atrophy, are related to CI. The cognitive statuses of people over 75 years old were used as the endpoint event in this study. Therefore, it can be considered that these MRI markers might have more important clinical significance for early assessment and dynamic observation, but more studies are still needed to verify this hypothesis.

Brain white matter and resting state eeg markers are abnormal in HIV subjects with relatively good cognitive status

AbstractBackgroundThis retrospective and exploratory study tested the concept that at the group level, human immunodeficiency virus (HIV) can significantly affect brain structure and function before the manifestation of significant cognitive deficits.MethodFrom a multicenter database, we selected structural 3T magnetic resonance imaging (MRI) and resting state eyes‐closed electroencephalographic (rsEEG) datasets in 30 HIV‐positive (HIV) subjects with relatively good cognitive status and serological markers (i.e., HIV‐RNA copies and CD4 count). Control datasets of matched non‐infected subjects included rsEEG (N = 50) and MRI (N = 30) recordings. MRI markers of interest in HIV were derived from gray matter (GM) volume decrements and white matter (WM) lesion load, while rsEEG markers were cortical source current density estimated by LORETA freeware at relevant delta (&lt; 4 Hz) and alpha (6‐12 Hz) individual frequency bands.ResultIn the HIV group, the subjects exhibited no abnormal score in neuropsychological tests. However, those subjects showed brain GM volume and WM abnormalities correlated with serum CD4 count (Figure 1). They also showed diffuse abnormalities in rsEEG alpha source activities.ConclusionAt the group level, HIV subjects with relatively good cognitive status can show abnormalities in both structural MRI and rsEEG markers. If cross‐validated in longitudinal studies, combined MRI and rsEEG markers may be a useful surrogate endpoint to test antiretroviral therapies with putative neuroprotective function.

Associations between dietary patterns and structural neuroimaging markers of relevance for dementia

AbstractBackgroundDiet is a lifestyle factors that could influence the risk of developing dementia. However, the impact of diet on the brain is not fully understood. Investigating associations between dietary patterns and neuroimaging markers of relevance for dementia could potentially increase this understanding.MethodThis study includes cross‐sectional data from the population‐based Gothenburg H70 Birth Cohort Studies, Sweden, including 610 dementia‐free 70‐year‐olds (born 1944, examined 2014‐16) with dietary and magnetic resonance imaging (MRI) data (54% women). Three dietary patterns were derived with principal component analysis, a western‐like pattern (e.g., refined cereal products, sweets, savory bakery/fast food), a Mediterranean‐like pattern (e.g., vegetables, fruits, whole grain cereal products) and a low‐fiber and high‐alcohol pattern (e.g., red meat/processed red meat, eggs, alcoholic beverages). Brain MRI markers were of overall neurodegeneration (i.e., mean cortical thickness), Alzheimer’s disease (AD) neurodegeneration (based on cortical thickness of AD‐signature areas), and vascular brain pathology including early abnormalities in the white matter microstructure (derived from diffusion tensor imaging) and small vessel disease (presence of white matter hyperintensities, lacunes, cerebral microbleeds, and/or perivascular spaces). In data analysis, linear and ordinal regression models were adjusted for sex, energy intake, educational level, physical activity level, smoking and body mass index.ResultResults from this study showed a positive association between higher adherence to the Mediterranean‐like dietary pattern and higher white matter microstructural integrity (B 0.077; 95% CI 0.002 – 0.153). Moreover, a higher adherence to the low‐fibre and high‐alcohol dietary pattern was negatively associated with total mean cortical thickness (B ‐0.011; 95% CI ‐0.019 – ‐0.003) and an AD signature of cortical thickness (mean entorhinal, inferior temporal, middle temporal, and fusiform thickness) (B ‐0.013; 95% CI ‐0.024 – ‐0.001) in the fully adjusted models. No associations were found between the dietary patterns and the small vessel disease markers. Nor were there any associations between the western‐like dietary pattern and the MRI markers.ConclusionThis study suggests that there may be an association between certain dietary patterns and dementia‐related alterations. These findings could be of importance for dementia prevention strategies and for future intervention studies investigating the effect of dietary patterns in relation to dementia.

Association of inflammatory proteins with cognitive aging, brain MRI markers, and incident dementia

AbstractBackgroundInflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer’s Disease (AD) dementia. We hypothesized that individual blood‐based inflammatory biomarkers would associate with cognitive function, brain magnetic resonance imaging (MRI) volumes, and risk for dementia in Framingham Heart Study (FHS) participants.MethodProtein biomarkers related to immune cells or associated with inflammatory responses including CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO were measured at FHS Offspring exam 7. We identified FHS Offspring participants who underwent neuropsychological (NP) testing (n = 2394) or brain MRI (n = 2135) within five years of the examination; and who were followed up 10 years after age 60 for incident all‐cause dementia (n = 1650). We used linear mixed effect models accounting for family relationships to investigate the associations between the protein biomarkers and NP test performance and brain MRI volumes and Cox proportional hazards models to examine the association with incident dementia. A false discovery rate (FDR) within each outcome set was computed to adjust for multiple testing and FDR ≤ 0.1 indicated significance.ResultParticipants from the NP and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (mean age 68 years) included 126 incident dementia cases within 10 years. In addition to CD14 which has an established association, we observed significant associations between higher CD40L and MPO with poorer NP performance from the executive function domain. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher sRAGE was associated with larger TCBV. Associations persisted after further adjusting for APOE ϵ4 carrier status and cardiovascular risk factors. None of the protein biomarkers included were significantly associated with risk of incident dementia, with trend towards an association for CD5L.ConclusionSince the proinflammatory factors CD5L, CD40L, sRAGE and MPO are associated with immune cells and are involved in vascular pathology, our study suggests the immune‐vascular axis is associated with cognitive and brain aging. If confirmed in other samples, our findings may provide informative biomarkers of abnormal brain aging.

Association between knee magnetic resonance imaging markers and knee symptoms over 6-9 years in young adults.

To describe associations between MRI markers with knee symptoms in young adults. Knee symptoms were assessed using the WOMAC scale during the Childhood Determinants of Adult Health Knee Cartilage study (CDAH-knee; 2008-2010) and at the 6- to 9-year follow-up (CDAH-3; 2014-2019). Knee MRI scans obtained at baseline were assessed for morphological markers (cartilage volume, cartilage thickness, subchondral bone area) and structural abnormalities [cartilage defects and bone marrow lesions (BMLs)]. Univariable and multivariable (age, sex, BMI adjusted) zero-inflated Poisson (ZIP) regression models were used for analysis. The participants' mean age in CDAH-knee and CDAH-3 were 34.95 (s.d. 2.72) and 43.27 (s.d. 3.28) years, with 49% and 48% females, respectively. Cross-sectionally, there was a weak but significant negative association between medial femorotibial compartment (MFTC) [ratio of the mean (RoM) 0.99971084 (95% CI 0.9995525, 0.99986921), P < 0.001], lateral femorotibial compartment (LFTC) [RoM 0.99982602 (95% CI 0.99969915, 0.9999529), P = 0.007] and patellar cartilage volume [RoM 0.99981722 (95% CI 0.99965326, 0.9999811), P = 0.029] with knee symptoms. Similarly, there was a negative association between patellar cartilage volume [RoM 0.99975523 (95% CI 0.99961427, 0.99989621), P = 0.014], MFTC cartilage thickness [RoM 0.72090775 (95% CI 0.59481806, 0.87372596), P = 0.001] and knee symptoms assessed after 6-9 years. The total bone area was negatively associated with knee symptoms at baseline [RoM 0.9210485 (95% CI 0.8939677, 0.9489496), P < 0.001] and 6-9 years [RoM 0.9588811 (95% CI 0.9313379, 0.9872388), P = 0.005]. The cartilage defects and BMLs were associated with greater knee symptoms at baseline and 6-9 years. BMLs and cartilage defects were positively associated with knee symptoms, whereas cartilage volume and thickness at MFTC and total bone area were weakly and negatively associated with knee symptoms. These results suggest that the quantitative and semiquantitative MRI markers can be explored as a marker of clinical progression of OA in young adults.

A structural magnetic resonance imaging review of clinical motor outcomes from deep brain stimulation in movement disorders.

Patients with movement disorders treated by deep brain stimulation do not always achieve successful therapeutic alleviation of motor symptoms, even in cases where surgery is without complications. Magnetic resonance imaging (MRI) offers methods to investigate structural brain-related factors that may be predictive of clinical motor outcomes. This review aimed to identify features which have been associated with variability in clinical post-operative motor outcomes in patients with Parkinson's disease, dystonia, and essential tremor from structural MRI modalities. We performed a literature search for articles published between 1 January 2000 and 1 April 2022 and identified 5197 articles. Following screening through our inclusion criteria, we identified 60 total studies (39 = Parkinson's disease, 11 = dystonia syndromes and 10 = essential tremor). The review captured a range of structural MRI methods and analysis techniques used to identify factors related to clinical post-operative motor outcomes from deep brain stimulation. Morphometric markers, including volume and cortical thickness were commonly identified in studies focused on patients with Parkinson's disease and dystonia syndromes. Reduced metrics in basal ganglia, sensorimotor and frontal regions showed frequent associations with reduced motor outcomes. Increased structural connectivity to subcortical nuclei, sensorimotor and frontal regions was also associated with greater motor outcomes. In patients with tremor, increased structural connectivity to the cerebellum and cortical motor regions showed high prevalence across studies for greater clinical motor outcomes. In addition, we highlight conceptual issues for studies assessing clinical response with structural MRI and discuss future approaches towards optimizing individualized therapeutic benefits. Although quantitative MRI markers are in their infancy for clinical purposes in movement disorder treatments, structural features obtained from MRI offer the powerful potential to identify candidates who are more likely to benefit from deep brain stimulation and provide insight into the complexity of disorder pathophysiology.

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (P6-3.011)

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (P6-3.011)

Assessment of Shared Neurologic Radiomic Markers Among Patients Diagnosed with Functional Seizure Disorder Utilizing a Novel Machine Learning Model (P6-12.007)

<h3>Objective:</h3> The objective of this study is to determine if a machine learning model can utilize magnetic resonance imaging (MRI) to differentiate patients with functional seizure disorder (FSD) from those with temporal lobe epilepsy (TLE). <h3>Background:</h3> FSD is a diagnosis associated with significant disability, but that is ultimately poorly understood. Although some studies have suggested anatomic commonalities among FSD patients, consistent MRI markers and underlying anatomic abnormalities have yet to be elucidated. Clear demonstration of these factors would result in easier diagnosis and may even aid in developing novel treatments for the condition. As the literature has yet to conclusively identify MRI markers, a machine learning model trained through MRI segmentation offers a novel method to classify radiographic markers that would not be detectable through traditional analysis methods. <h3>Design/Methods:</h3> After institutional review board approval, we retrospectively identified 64 patients with FSD and 23 with TLE who underwent workup in the epilepsy monitoring unit between 2015 and 2022. Patients were included in the study only if their typical episode was observed during EEG monitoring, thus confirming their diagnosis and study group. MRI for each patient was then pre-processed and systematically fed through a convolution neural network, generating a novel machine-learning model. <h3>Results:</h3> Although analysis and patient selection are still ongoing, our model has already identified several regions of interest. Currently, we have obtained a positive model certainty of 55% and a negative model certainty of 65% when training from the left thalamus, anterior corpus callosum, and left cerebral cortex. <h3>Conclusions:</h3> Our findings demonstrate promise in using machine learning when assessing complex disorders such as functional seizure disorder. Furthermore, continued work with our machine-learning model may aid in identifying anatomic MRI markers shared by patients with FSD. This work may ultimately expand the understanding of the underlying mechanisms and diagnostic methods available for the disorder. <b>Disclosure:</b> Mr. Moss has nothing to disclose. Ms. Schmid has nothing to disclose. An immediate family member of Dr. Bermeo Ovalle has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bioserenity. An immediate family member of Dr. Bermeo Ovalle has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. An immediate family member of Dr. Bermeo Ovalle has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunovion. An immediate family member of Dr. Bermeo Ovalle has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Greenwich Biosciences. An immediate family member of Dr. Bermeo Ovalle has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for SK Life Science. An immediate family member of Dr. Bermeo Ovalle has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Neurelis. An immediate family member of Dr. Bermeo Ovalle has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal on Clinical Neuropysiology. An immediate family member of Dr. Bermeo Ovalle has received publishing royalties from a publication relating to health care. Travis Stoub has nothing to disclose. Dr. O’Dwyer has nothing to disclose.

Twenty-four-hour ambulatory blood pressure variability and association with ischemic stroke subtypes in the subacute stage.

Blood pressure (BP) variability (BPV) increases the risk of cerebral disease in both hemorrhagic and ischemic strokes. However, whether BPV is associated with different types of ischemic stroke remains unclear. In this study, we explored the relationship between BPV and ischemic stroke subtypes. We enrolled consecutive patients aged 47-95 years with ischemic stroke in the subacute stage. We categorized them into four groups based on their artery atherosclerosis severity, brain magnetic resonance imaging markers, and disease history: large-artery atherosclerosis, branch atheromatous disease, small-vessel disease, and cardioembolic stroke. Twenty-four-hour ambulatory blood pressure monitoring was performed, and the mean systolic blood pressure/diastolic blood pressure, standard deviation, and coefficient of variation were calculated. A multiple logistic regression model and random forest were used to test the relationship between BP and BPV in the different types of ischemic stroke. A total of 286 patients, including 150 men (73.0 ± 12.3 years) and 136 women (77.8 ± 9.6 years) were included in the study. Of these, 86 (30.1%) patients had large-artery atherosclerosis, 76 (26.6%) had branch atheromatous disease, 82 (28.7%) had small-vessel disease, and 42 (14.7%) had cardioembolic stroke. There were statistically significant differences in BPV between subtypes of ischemic stroke in 24-h ambulatory blood pressure monitoring. The random forest model showed that BP and BPV were important features associated with ischemic stroke. Multinomial logistic regression analysis demonstrated that systolic blood pressure levels; systolic blood pressure variability at 24 h, daytime and nighttime; and nighttime diastolic blood pressure were independent risk factors for large-artery atherosclerosis after adjustment for confounders. When compared to branch atheromatous disease and small-vessel disease, nighttime diastolic blood pressure and standard deviation of diastolic blood pressure were significantly associated with patients in the cardioembolic stroke group. However, a similar statistical difference was not seen in patients with large-artery atherosclerosis. The results of this study indicate a discrepancy in blood pressure variability among different ischemic stroke subtypes during the subacute stage. Higher systolic blood pressure and systolic blood pressure variability during the 24 h, daytime, and nighttime, and nighttime diastolic blood pressure were independent predictors for large-artery atherosclerosis stroke. Increased nighttime diastolic BPV was an independent risk factor for cardioembolic stroke.

Image or scope: Magnetic resonance imaging and endoscopic testing for exocrine and endocrine pancreatic insufficiency in children

ObjectivesWe sought to evaluate associations between Magnetic Resonance Imaging (MRI) findings, exocrine pancreatic insufficiency (EPI) and endocrine insufficiency (prediabetes or diabetes) in children. MethodsThis was a retrospective study that included patients<21 years of age who underwent MRI and endoscopic pancreatic function testing (ePFT; reference standard for pancreatic exocrine function) within 3 months. MRI variables included pancreas parenchymal volume, secreted fluid volume in response to secretin, and T1 relaxation time. Data were analyzed for the full sample as well as the subset without acute pancreatitis (AP) at the time of imaging. ResultsOf 72 patients, 56% (40/72) were female with median age 11.4 years. A 5 mL decrease in pancreas parenchymal volume was associated with increased odds of exocrine pancreatic dysfunction by both ePFT (OR = 1.16, p = 0.02 full sample; OR = 1.29, p = 0.01 no-AP subset), and fecal elastase (OR = 1.16, p = 0.04 full sample; OR = 1.23, p = 0.02 no-AP subset). Pancreas parenchymal volume had an AUC 0.71 (95% CI: 0.59, 0.83) for predicting exocrine pancreatic dysfunction by ePFT and when combined with sex and presence of AP had an AUC of 0.82 (95% CI: 0.72, 0.92).Regarding endocrine function, decreased pancreas parenchymal volume was associated with increased odds of diabetes (OR = 1.16, p = 0.03), and T1 relaxation time predicted glycemic outcomes with an AUC 0.78 (95% CI: 0.55–1), 91% specificity and 73% sensitivity. ConclusionsPancreas parenchymal volume is an MRI marker of exocrine and endocrine pancreatic dysfunction in children. A model including sex, AP, and pancreas volume best predicted exocrine status. T1 relaxation time is also an MRI marker of endocrine insufficiency.

Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-β (Aβ) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aβ is also accumulated in Alzheimer's disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins. The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA. We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS. This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral β-amyloidosis.

Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome.

Prion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA). Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers. We included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined. iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype.

Cognitive versus Hemorrhagic Onset in Cerebral Amyloid Angiopathy: Neuroimaging Features.

Intracerebral hemorrhage and cognitive decline are typical clinical presentations of cerebral amyloid angiopathy (CAA). To determine whether magnetic resonance imaging (MRI) features differ between CAA with hemorrhagic versus cognitive onset. In this retrospective study, sixty-one patients with CAA were classified by onset presentation of the disease: hemorrhage (n=31) or cognitive decline (n=30). The two groups were compared for MRI markers of small vessel disease, namely cerebral microbleeds (CMBs), cortical superficial siderosis, white matter hyperintensities (WMHs), enlarged perivascular spaces, cortical microinfarcts, and visual rating scales for cortical atrophy. In the patients with cognitive onset, further exploratory analyses investigated MRI markers according to cerebrospinal fluid (CSF) and neuropsychological profiles. Patients with cognitive onset showed a higher prevalence of CMBs (p<0.001), particularly in temporal (p=0.015) and insular (p=0.002) lobes, and a higher prevalence of WMHs (p=0.012). Within the cognitive onset group, 12 out of 16 (75%) patients had an Alzheimer's disease (AD) CSF profile but did not differ in MRI markers from those without AD pathology. Patients with cognitive onset displayed a multidomain profile in 16 out of 23 (70%) cases; patients with this profile showed increased WMHs and CMBs in parietal lobes compared with the amnestic group (p=0.002) and dysexecutive group (p=0.032), respectively. Higher burdens of WMHs and CMBs, especially in temporal and insular lobes, are associated with the cognitive onset of CAA. MRI markers could help to shed light on the clinical heterogeneity of the CAA spectrum and its underlying mechanisms.

Classification of Alzheimer's disease based on hippocampal multivariate morphometry statistics.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and mild cognitive impairment (MCI) is associated with a high risk of developing AD. Hippocampal morphometry analysis is believed to be the most robust magnetic resonance imaging (MRI) markers for AD and MCI. Multivariate morphometry statistics (MMS), a quantitative method of surface deformations analysis, is confirmed to have strong statistical power for evaluating hippocampus. We aimed to test whether surface deformation features in hippocampus can be employed for early classification of AD, MCI, and healthy controls (HC). We first explored the differences in hippocampus surface deformation among these three groups by using MMS analysis. Additionally, the hippocampal MMS features of selective patches and support vector machine (SVM) were used for the binary classification and triple classification. By the results, we identified significant hippocampal deformation among the three groups, especially in hippocampal CA1. In addition, the binary classification of AD/HC, MCI/HC, AD/MCI showed good performances, and area under curve (AUC) of triple-classification model achieved 0.85. Finally, positive correlations were found between the hippocampus MMS features and cognitive performances. The study revealed significant hippocampal deformation among AD, MCI, and HC. Additionally, we confirmed that hippocampal MMS can be used as a sensitive imaging biomarker for the early diagnosis of AD at the individual level.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, &amp; Neuroimaging Advancing the Field of Neurology

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, &amp; Neuroimaging Advancing the Field of Neurology

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.