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BACKGROUND: Acute brain infarction detected by diffusion-weighted magnetic resonance imaging (DW-MRI) is common after transcatheter aortic valve replacement (TAVR), but its clinical relevance is uncertain. OBJECTIVES: The authors investigated the relationship between DW-MRI total lesion number (TLN), individual lesion volume (ILV), and total lesion volume (TLV) and clinical stroke outcomes after TAVR. METHODS: Patient-level data were pooled from 4 prospective TAVR embolic protection studies, with consistent predischarge DW-MRI acquisition and core laboratory analysis. C-statistic was used to determine the best DW-MRI measure associated with clinical stroke. RESULTS: A total of 495 of 603 patients undergoing TAVR completed the predischarge DW-MRI. At 30 days, the rate of clinical ischemic stroke was 6.9%. Acute ischemic brain injury was seen in 85% of patients with 5.5 ± 7.3 discrete lesions per patient, mean ILV of 78.2 ± 257.1 mm3, and mean TLV of 555 ± 1,039 mm3. The C-statistic was 0.84 for TLV, 0.81 for number of lesions, and 0.82 for maximum ILV in predicting ischemic stroke. On the basis of the TLV cutpoint as defined by receiver operating characteristic (ROC), patients with a TLV >500 mm3 (vs TLV ≤500 mm3) had more ischemic stroke (18.2% vs 2.3%; P < 0.0001), more disabling strokes (8.8% vs 0.9%; P < 0.0001), and less complete stroke recovery (44% vs 62.5%; P = 0.001) at 30 days. CONCLUSIONS: Our study confirms that the number, size, and total volume of acute brain infarction defined by DW-MRI are each associated with clinical ischemic strokes, disabling strokes, and worse stroke recovery in patients undergoing TAVR and may have value as surrogate outcomes in stroke prevention trials. (A Prospective, Randomized Evaluation of the TriGuard™ HDH Embolic Deflection Device During TAVI [DEFLECT III]; NCT02070731) (A Study to Evaluate the Neuro-embolic Consequences of TAVR [NeuroTAVR]; NCT02073864) (The REFLECT Trial: Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation [REFLECT I]; NCT02536196) (The REFLECT Trial: Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation [REFLECT II]; NCT02536196).
Subject(s)
Diffusion Magnetic Resonance Imaging , Transcatheter Aortic Valve Replacement , Humans , Diffusion Magnetic Resonance Imaging/methods , Transcatheter Aortic Valve Replacement/adverse effects , Male , Female , Aged, 80 and over , Aged , Aortic Valve Stenosis/surgery , Aortic Valve Stenosis/diagnostic imaging , Prospective Studies , Postoperative Complications/diagnostic imaging , Postoperative Complications/etiology , Ischemic Stroke/etiology , Ischemic Stroke/diagnostic imaging , Clinical RelevanceABSTRACT
BACKGROUND: People with multiple sclerosis (pwMS) have greater prevalence of comorbid cardiovascular diseases (CVD) when compared to the general population despite similar frequency of CV risk factors. OBJECTIVE: Determine the impact of comorbid-onset of CVD diagnosis on long-term confirmed disability progression (CDP). METHODS: 276 pwMS (29 clinically isolated syndrome, 130 relapsing-remitting and 117 progressive) were clinically followed an average of 14.9 years, with a mean of 14.4 clinical visits. Retrospective electronic medical records (EMR) review determined CVD diagnoses (hypertension, hyperlipidemia, diabetes, and heart disease) at baseline and over the follow-up. CDP was determined with ≥1.0 point Expanded Disability Status Scale (EDSS) increase from EDSS <5.5, or ≥ 0.5-point increase from ≥5.5, and was sustained on next clinical visit. RESULTS: A significantly shorter time to overall CDP was detected in 213 pwMS who had an existing (28 pwMS) or developed new onset (185 pwMS) of CVD, compared to 63 CVD-healthy pwMS over the follow-up (13.4 vs 15.9 years, Mantel-Cox p < 0.001), independent of baseline age and EDSS score. The CVD diagnosis preceded the CDP in 103 pwMS (55.7%), occurred after CDP in 71 pwMS (38.4%) and was concurrent in 11 pwMS (5.9%). Using mixed-effect models adjusted for significant age (F = 56.5, p < 0.001) and time effects (F = 67.8, p < 0.001), the CVD-onset diagnosis was associated with greater accrual of disability, as measured by longitudinal increase in EDSS score (F = 4.207, p = 0.04). Sex was not significant predictor of future disability in our cohort. CONCLUSION: PwMS with an existing or new onset of comorbid CVD diagnosis showed accelerated disability worsening over long-term. There was no temporal relationship between the onset of CVD and CDP within the group that had CVD-onset diagnosis.
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Increased choroid plexus (CP) volume has been recently implicated as a potential predictor of worse multiple sclerosis (MS) outcomes. The biomarker signature of CP changes in MS are currently unknown. To determine the blood-based biomarker characteristics of the cross-sectional and longitudinal MRI-based CP changes in a heterogeneous group of people with MS (pwMS), a total of 202 pwMS (148 pwRRMS and 54 pwPMS) underwent MRI examination at baseline and at a 5-year follow-up. The CP was automatically segmented and subsequently refined manually in order to obtain a normalized CP volume. Serum samples were collected at both timepoints, and the concentration of 21 protein measures relevant to MS pathophysiology were determined using the Olink™ platform. Age-, sex-, and BMI-adjusted linear regression models explored the cross-sectional and longitudinal relationships between MRI CP outcomes and blood-based biomarkers. At baseline, there were no significant proteomic predictors of CP volume, while at follow-up, greater CP volume was significantly associated with higher neurofilament light chain levels, NfL (standardized ß = 0.373, p = 0.001), and lower osteopontin levels (standardized ß = -0.23, p = 0.02). Higher baseline GFAP and lower FLRT2 levels were associated with future 5-year CP % volume expansion (standardized ß = 0.277, p = 0.004 and standardized ß = -0.226, p = 0.014, respectively). The CP volume in pwMS is associated with inflammatory blood-based biomarkers of neuronal injury (neurofilament light chain; NfL) and glial activation such as GFAP, osteopontin, and FLRT2. The expansion of the CP may play a central role in chronic and compartmentalized inflammation and may be driven by glial changes.
Subject(s)
Biomarkers , Choroid Plexus , Magnetic Resonance Imaging , Multiple Sclerosis , Humans , Female , Male , Biomarkers/blood , Multiple Sclerosis/blood , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Choroid Plexus/diagnostic imaging , Choroid Plexus/pathology , Adult , Middle Aged , Cross-Sectional Studies , Neurofilament Proteins/blood , Osteopontin/blood , Proteomics , Glial Fibrillary Acidic Protein/bloodABSTRACT
Cognitive impairment is common in multiple sclerosis and negatively impacts quality of life. Cognitive status has yet to be described in people with severe progressive multiple sclerosis, in whom conventional neuropsychological testing is exceptionally difficult. The objective for the study was to characterize cognitive performance in severe progressive multiple sclerosis and compare them with age-, sex- and disease duration-matched less disabled people with multiple sclerosis using a specifically developed auditory, non-motor test of attention/cognitive processing speed-Auditory Test of Processing Speed. Also, we aimed to determine the relationship between cognitive performance and MRI-based outcomes in these matched cohorts. The Comprehensive Assessment of Severely Affected Multiple Sclerosis study was carried out at the University at Buffalo and the Boston Home, a skilled nursing facility in Dorchester, MA. Inclusion criteria were age 30-80 years and expanded disability status scale 3.0-6.5 for community-dwelling and 7.0-9.5 for skilled nursing facility people with multiple sclerosis. The cognitive assessment was performed using the Brief International Cognitive Assessment for Multiple Sclerosis consisting of Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test-2nd edition along with Auditory Test of Processing Speed, Paced Auditory Serial Addition Test-3 second and Controlled Oral Word Association Test. MRI scans were retrospectively collected and analysed for lesion and volumetric brain measurements. The rate of completion and performance of the cognitive tests was compared between the groups, and the relationship with MRI measures was determined using sex, age and years of education-adjusted linear regression models. Significantly greater percentage of the severe multiple sclerosis group completed Auditory Test of Processing Speed when compared with the current gold standard of Symbol Digit Modalities Test (93.2% versus 65.9%). Severe progressive multiple sclerosis had worse cognitive performance in all cognitive domains with greatest differences for cognitive processing speed (Symbol Digit Modalities Test > Paced Auditory Serial Addition Test-3 second > Auditory Test of Processing Speed, Cohen's d < 2.13, P < 0.001), learning and memory (Cohen's d < 1.1, P < 0.001) and language (Controlled Oral Word Association Test with Cohen's d = 0.97, P < 0.001). Multiple cognitive domains were significantly associated with lower thalamic (standardized ß < 0.419, P < 0.006) and cortical (standardized ß < 0.26, P < 0.031) volumes. Specially designed (auditory) cognitive processing speed tests may provide more sensitive screening of cognitive function in severe progressive multiple sclerosis. The cognitive profile of severe multiple sclerosis is proportional to their physical outcomes and best explained by decreased grey matter volume.
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BACKGROUND: Because secondary progressive multiple sclerosis (SPMS) is associated with worse prognosis, early predictive tools are needed. We aimed to use systematic literature review and advanced methods to create and validate a clinical tool for estimating individual patient risk of transition to SPMS over five years. METHODS: Data from the Jacobs Multiple Sclerosis Center (JMSC) and the Multiple Sclerosis Center Amsterdam (MSCA) was collected between 1994 and 2022. Participants were relapsing-remitting adult patients at initial evaluation. We created the tool in four stages: (1) identification of candidate predictors from systematic literature review, (2) ordinal cutoff determination, (3) feature selection, (4) feature weighting. RESULTS: Patients in the development/internal-validation/external-validation datasets respectively (n = 787/n = 522/n = 877) had a median age of 44.1/42.4/36.6 and disease duration of 7.7/6.2/4.4 years. From these, 12.6 %/10.2 %/15.4 % converted to SPMS (median=4.9/5.2/5.0 years). The DAAE Score was named from included predictors: Disease duration, Age at disease onset, Age, EDSS. It ranges from 0 to 12 points, with risk groups of very-low=0-2, low=3-7, medium=8-9, and high≥10. Risk of transition to SPMS increased proportionally across these groups in development (2.7 %/7.4 %/18.8 %/40.2 %), internal-validation (2.9 %/6.8 %/26.8 %/36.5 %), and external-validation (7.5 %/9.6 %/22.4 %/37.5 %). CONCLUSION: The DAAE Score estimates individual patient risk of transition to SPMS consistently across datasets internationally using clinically-accessible data. With further validation, this tool could be used for clinical risk estimation.
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BACKGROUND: Several studies have shown the different relationships between cognitive functions and structural magnetic resonance imaging (MRI) measurements in people with multiple sclerosis (pwMS). However, there is an ongoing debate regarding the magnitude of correlation between MRI measurements and specific cognitive function tests. This systematic review and meta-analysis aimed to synthesize the most consistent correlations between MRI measurements and cognitive function in pwMS. METHODS: PubMed/MEDLINE, Embase, Scopus, and Web of Science databases were systematically searched up to February 2023, to find relevant data. The search utilized syntax and medical subject headings (MeSH) relevant to cognitive performance tests and MRI measurements in pwMS. The R software version 4.3.3 with random effect models was used to estimate the pooled effect sizes. RESULTS: 13,559 studies were reviewed, of which 136 were included. The meta-analyses showed that thalamic volume had the most significant correlations with Symbol Digit Modalities Test (SDMT) r = 0.47 (95 % CI: 0.39 to 0.56, p < 0.001, I2 = 88 %), Brief Visual Memory Test-Revised-Total Recall (BVMT-TR) r = 0.51 (95 % CI: 0.36 to 0.66, p < 0.001, I2 = 81 %), California Verbal Learning Test-II-Total Recall (CVLT-TR) r = 0.47 (95 % CI: 0.34 to 0.59, p < 0.001, I2 = 69 %,), and Delis-Kaplan Executive Function System (DKEFS) r = 0.48 (95 % CI: 0.34 to 0.63, p < 0.001, I2 = 22 %,). CONCLUSION: We conclude that thalamic volume exhibits highest relationships with information processing speed (IPS), visuospatial learning-memory, verbal learning-memory, and executive function in pwMS. A comprehensive understanding of the intricacies of the mechanisms underpinning this association requires additional research.
Subject(s)
Magnetic Resonance Imaging , Multiple Sclerosis , Humans , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/physiopathology , Multiple Sclerosis/pathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/physiopathology , Cognition/physiology , Neuropsychological Tests , Brain/diagnostic imaging , Brain/physiopathology , Brain/pathologyABSTRACT
Multiple sclerosis (MS) is increasingly understood not only as a white matter disease but also involving both the deep and cortical gray matter (GM). GM pathology in people with MS (pwMS) includes the presence of lesions, leptomeningeal inflammation, atrophy, altered iron concentration, and microstructural changes. Studies using 7T and 3T MR imaging with optimized protocols established that GM damage is a principal driver of disease progression in pwMS. Future work is needed to incorporate the assessment of these GM imaging biomarkers into the clinical workup of pwMS and the assessment of treatment efficacy.
Subject(s)
Gray Matter , Magnetic Resonance Imaging , Multiple Sclerosis , Neuroimaging , Humans , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Gray Matter/diagnostic imaging , Gray Matter/pathology , Magnetic Resonance Imaging/methods , Neuroimaging/methods , Brain/diagnostic imaging , Brain/pathologyABSTRACT
BACKGROUND: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. OBJECTIVE: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. METHODS: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. RESULTS: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized ß = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized ß = -0.14, p = 0.028) in a linear regression model. CONCLUSIONS: PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.
Subject(s)
Atrophy , Cognitive Dysfunction , Magnetic Resonance Imaging , Multiple Sclerosis, Relapsing-Remitting , Thalamus , Humans , Multiple Sclerosis, Relapsing-Remitting/pathology , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Multiple Sclerosis, Relapsing-Remitting/complications , Female , Male , Adult , Thalamus/pathology , Thalamus/diagnostic imaging , Cognitive Dysfunction/pathology , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/diagnostic imaging , Atrophy/pathology , Middle Aged , Magnetic Resonance Imaging/methods , Retrospective Studies , Longitudinal StudiesABSTRACT
BACKGROUND: A subgroup of people with multiple sclerosis (pwMS) will develop severe disability. The pathophysiology underlying severe MS is unknown. The comprehensive assessment of severely affected MS (CASA-MS) was a case-controlled study that compared severely disabled in skilled nursing (SD/SN) (EDSS ≥ 7.0) to less-disabled (EDSS 3.0-6.5) community dwelling (CD) progressive pwMS, matched on age-, sex- and disease-duration (DDM). OBJECTIVES: To identify neuroimaging and molecular biomarker characteristics that distinguish SD/SN from DDM-CD progressive pwMS. METHODS: This study was carried at SN facility and at a tertiary MS center. The study collected clinical, molecular (serum neurofilament light chain, sNfL and glial acidic fibrillary protein, sGFAP) and MRI quantitative lesion-, brain volume-, and tissue integrity-derived measures. Statistical analyses were controlled for multiple comparisons. RESULTS: 42 SD/SN and 42 DDM-CD were enrolled. SD/SN pwMS showed significantly lower cortical volume (CV) (p < 0.001, d = 1.375) and thalamic volume (p < 0.001, d = 0.972) compared to DDM-CD pwMS. In a logistic stepwise regression model, the SD/SN pwMS were best differentiated from the DDM-CD pwMS by lower CV (p < 0.001) as the only significant predictor, with the accuracy of 82.3%. No significant differences between the two groups were observed for medulla oblongata volume, a proxy for spinal cord atrophy and white matter lesion burden, while there was a statistical trend for numerically higher sGFAP in SD/SN pwMS. CONCLUSIONS: The CASA-MS study showed significantly more gray matter atrophy in severe compared to less-severe progressive MS.
Subject(s)
Cerebral Cortex , Gray Matter , Magnetic Resonance Imaging , Multiple Sclerosis , Neuroimaging , Humans , Male , Female , Middle Aged , Gray Matter/diagnostic imaging , Gray Matter/pathology , Case-Control Studies , Adult , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Neuroimaging/methods , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Severity of Illness Index , Neurofilament Proteins/blood , Aged , Biomarkers/bloodABSTRACT
Introduction: CHRFAM7A, a uniquely human fusion gene, has been associated with neuropsychiatric disorders including Alzheimer's disease, schizophrenia, anxiety, and attention deficit disorder. Understanding the physiological function of CHRFAM7A in the human brain is the first step to uncovering its role in disease. CHRFAM7A was identified as a potent modulator of intracellular calcium and an upstream regulator of Rac1 leading to actin cytoskeleton reorganization and a switch from filopodia to lamellipodia implicating a more efficient neuronal structure. We performed a neurocognitive-MRI correlation exploratory study on 46 normal human subjects to explore the effect of CHRFAM7A on human brain. Methods: Dual locus specific genotyping of CHRFAM7A was performed on genomic DNA to determine copy number (TaqMan assay) and orientation (capillary sequencing) of the CHRFAM7A alleles. As only the direct allele is expressed at the protein level and affects α7 nAChR function, direct allele carriers and non-carriers are compared for neuropsychological and MRI measures. Subjects underwent neuropsychological testing to measure motor (Timed 25-foot walk test, 9-hole peg test), cognitive processing speed (Symbol Digit Modalities Test), Learning and memory (California Verbal Learning Test immediate and delayed recall, Brief Visuospatial Memory Test-Revised immediate and delayed recall) and Beck Depression Inventory-Fast Screen, Fatigue Severity Scale. All subjects underwent MRI scanning on the same 3 T GE scanner using the same protocol. Global and tissue-specific volumes were determined using validated cross-sectional algorithms including FSL's Structural Image Evaluation, using Normalization, of Atrophy (SIENAX) and FSL's Integrated Registration and Segmentation Tool (FIRST) on lesion-inpainted images. The cognitive tests were age and years of education-adjusted using analysis of covariance (ANCOVA). Age-adjusted analysis of covariance (ANCOVA) was performed on the MRI data. Results: CHRFAM7A direct allele carrier and non-carrier groups included 33 and 13 individuals, respectively. Demographic variables (age and years of education) were comparable. CHRFAM7A direct allele carriers demonstrated an upward shift in cognitive performance including cognitive processing speed, learning and memory, reaching statistical significance in visual immediate recall (FDR corrected p = 0.018). The shift in cognitive performance was associated with smaller whole brain volume (uncorrected p = 0.046) and lower connectivity by resting state functional MRI in the visual network (FDR corrected p = 0.027) accentuating the cognitive findings. Conclusion: These data suggest that direct allele carriers harbor a more efficient brain consistent with the cellular biology of actin cytoskeleton and synaptic gain of function. Further larger human studies of cognitive measures correlated with MRI and functional imaging are needed to decipher the impact of CHRFAM7A on brain function.
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BACKGROUND: The choroid plexus (CP), located within the ventricles of the brain and the primary producer of cerebrospinal fluid, has been shown to be enlarged in patients with multiple sclerosis (MS) and linked to periventricular remyelination failure. Atrophied T2-lesion volume (aT2-LV), a promising neurodegenerative imaging marker in progressive MS (PMS), reflects the volume of periventricular lesions subsumed into cerebrospinal fluid over the follow-up. METHODS: In a cohort of 143 people with relapsing-remitting MS (RRMS) and 53 with PMS, we used 3T magnetic resonance imaging (MRI) to quantify CP volume (CPV) at baseline and aT2-LV over an average of 5.4 years of follow-up. Partial correlations, adjusting for age and sex, and linear regression analyses were used to assess the relationships between imaging measures. RESULTS: In both cohorts, CPV was associated with aT2-LV in both the RRMS group (r = 0.329, p < 0.001) as well as the PMS group (r = 0.522, p < 0.001). In regression analyses predicting aT2-LV, ventricular volume (final adjusted R2 = 0.407, p < 0.001) explained additional variance beyond age, sex, and T2-lesion volume in the RRMS group while CPV (final adjusted R2 = 0.446, p = 0.009) was retained in the PMS group. CONCLUSION: Findings from this study suggest that the CP enlargement is associated with future neurodegeneration, with a particularly relevant role in PMS.
Subject(s)
Cerebral Ventricles , Choroid Plexus , Magnetic Resonance Imaging , Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Humans , Female , Male , Adult , Middle Aged , Choroid Plexus/pathology , Choroid Plexus/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/pathology , Multiple Sclerosis, Chronic Progressive/diagnostic imaging , Multiple Sclerosis, Chronic Progressive/pathology , Cerebral Ventricles/diagnostic imaging , Cerebral Ventricles/pathology , Disease Progression , Follow-Up Studies , Atrophy/pathologyABSTRACT
BACKGROUND: Brain hypoperfusion is linked with worse physical, cognitive and MRI outcomes in multiple sclerosis (MS). Understanding the proteomic signatures related to hypoperfusion could provide insights into the pathophysiological mechanism. METHODS: 140 people with MS (pwMS; 86 clinically isolated syndrome (CIS)/relapsing-remitting (RRMS) and 54 progressive (PMS)) were included. Cerebral arterial blood flow (CABF) was determined using ultrasound Doppler measurement as the sum of blood flow in the bilateral common carotid arteries and vertebral arteries. Proteomic analysis was performed using the Multiple Sclerosis Disease Activity (MSDA) test assay panel performed on the Olink™ platform. The MSDA test measures the concentrations of 18 proteins that are age and sex-adjusted. It utilizes a stacked classifier logistic regression model to determine 4 disease pathway scores (immunomodulation, neuroinflammation, myelin biology, and neuroaxonal integrity) as well as an overall disease activity score (1 to 10). MRI measures of T2 lesion volume (LV) and whole brain volume (WBV) were derived. RESULTS: The pwMS were on average 54 years old and had an average CABF of 951 mL/min. There were no differences in CABF between CIS/RRMS vs. PMS groups. Lower CABF levels were correlated with the overall disease activity score (r = -0.26, p = 0.003) and with the neuroinflammation (r = -0.29, p = 0.001), immunomodulation (r = -0.26, p = 0.003) and neuroaxonal integrity (r = -0.23, p = 0.007) pathway scores. After age and body mass index (BMI)-adjustment, lower CABF remained associated with the neuroinflammatory (r = -0.23, p = 0.011) and immunomodulation (r = -0.20, p = 0.024) pathway scores. The relationship between CABF and the neuroinflammation pathway score remained significant after adjusting for T2-LV and WBV (p = 0.038). Individual analyses identified neurofilament light chain, CCL-20 and TNFSF13B as contributors. When compared to the highest quartile (>1133.5 mL/min), the pwMS in the lowest CABF quartile (<764 mL/min) had greater overall disease activity score (p = 0.003), neuroinflammation (p = 0.001), immunomodulation (p = 0.004) and neuroaxonal integrity pathway scores (p = 0.007). CONCLUSION: Lower cerebral arterial perfusion in MS is associated with changes in neuroinflammatory/immunomodulation pathways and their respective proteomic biomarkers. These findings may suggest a relationship between the hypoperfusion and pro-inflammatory MS changes rather than being merely an epiphenomenon subsequent to lower energy demands.
Subject(s)
Cerebrovascular Circulation , Neuroinflammatory Diseases , Proteomics , Humans , Female , Middle Aged , Male , Cerebrovascular Circulation/physiology , Neuroinflammatory Diseases/immunology , Neuroinflammatory Diseases/diagnostic imaging , Neuroinflammatory Diseases/physiopathology , Adult , Immunomodulation , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/physiopathology , Multiple Sclerosis/blood , Magnetic Resonance Imaging , Brain/diagnostic imaging , Demyelinating Diseases/diagnostic imaging , Demyelinating Diseases/physiopathology , Cerebral Arteries/diagnostic imaging , Cerebral Arteries/physiopathologyABSTRACT
BACKGROUND: Atrophied lesion volume (aLV), a proposed biomarker of disability progression in multiple sclerosis (MS) and transition into progressive MS (PMS), depicts chronic periventricular white matter (WM) pathology. Meningeal infiltrates, imaged as leptomeningeal contrast enhancement (LMCE), are linked with greater cortical pathology. OBJECTIVES: To determine the relationship between serum-derived proteomic data with the development of aLV and LMCE in a heterogeneous group of people with MS (pwMS). METHODS: Proteomic and MRI data for 202 pwMS (148 clinically isolated syndrome /relapsing-remitting MS and 54 progressive MS (PMS)) were acquired at baseline and at 5.4-year follow-up. The concentrations of 21 proteins related to multiple MS pathophysiology pathways were derived using a custom-developed Proximity Extension Assay on the Olink™ platform. The accrual of aLV was determined as the volume of baseline T2-weighted lesions that were replaced by cerebrospinal fluid over the follow-up. Regression models and age-adjusted analysis of covariance (ANCOVA) were used. RESULTS: Older age (standardized beta = 0.176, p = 0.022), higher glial fibrillary acidic protein (standardized beta = 0.312, p = 0.001), and lower myelin oligodendrocyte glycoprotein levels (standardized beta = -0.271, p = 0.002) were associated with accrual of aLV over follow-up. This relationship was driven by the pwPMS population. The presence of LMCE at the follow-up visit was not predicted by any baseline proteomic biomarker nor cross-sectionally associated with any protein concentration. CONCLUSION: Proteomic markers of glial activation are associated with chronic lesional WM pathology (measured as aLV) and may be specific to the progressive MS phenotype. LMCE presence in MS does not appear to relate to proteomic measures.
Subject(s)
Atrophy , Magnetic Resonance Imaging , Neuroglia , Proteomics , Humans , Female , Male , Middle Aged , Adult , Neuroglia/pathology , Neuroglia/metabolism , Atrophy/pathology , Multiple Sclerosis, Chronic Progressive/diagnostic imaging , Multiple Sclerosis, Chronic Progressive/pathology , Multiple Sclerosis, Chronic Progressive/cerebrospinal fluid , Multiple Sclerosis/pathology , Multiple Sclerosis/diagnostic imaging , Disease Progression , Inflammation/pathology , Inflammation/diagnostic imaging , Glial Fibrillary Acidic Protein/metabolism , Biomarkers , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/pathology , Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid , White Matter/diagnostic imaging , White Matter/pathologyABSTRACT
BACKGROUND: Expanded Disability Status Scale (EDSS) is limited when utilized in highly disabled people with multiple sclerosis (pwMS). OBJETIVE: To explore the relationship between disability measures and MRI outcomes in severely-affected pwMS. METHODS: PwMS recruited from The Boston Home (TBH), a specialized residential facility for severly-affected pwMS and University at Buffalo (UB) MS Center were assessed using EDSS, MS Severity Scale, age-related MSS, Scripps Neurological Rating Scale (SNRS) and Combinatorial Weight-Adjusted Disability Score (CombiWISE). In all scores except SNRS, higher score indicates greater disability. MRI measures of T1, T2-lesion volume (LV), whole brain, gray matter, medulla oblongata and thalamic volumes (WBV, GMV, MOV, TV) and thalamic dysconnectivity were obtained. RESULTS: Greatest disability differences between the TBH and UB pwMS were in SNRS (24.4 vs 71.9, p < 0.001, Cohen's d = 4.05) and CombiWISE (82.3 vs. 38.9, p < 0.001, Cohen's d = 4.02). In combined analysis of all pwMS, worse SNRS scores were correlated with worse MRI pathology in 8 out of 9 outcomes. EDSS only with 3 measures (GMV, MOV and TV). In severely-affected pwMS, SNRS was associated with T1-LV, T2-LV and WBV (not surviving false discovery rate (FDR) correction for multiple comparisons) whereas EDSS did not. CONCLUSION: Granular and dynamic disability measures may bridge the clinico-radiologcal gap present in severely affected pwMS.
Subject(s)
Disability Evaluation , Magnetic Resonance Imaging , Multiple Sclerosis , Severity of Illness Index , Humans , Female , Male , Adult , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/physiopathology , Multiple Sclerosis/pathology , Middle Aged , Brain/diagnostic imaging , Brain/pathology , Brain/physiopathologyABSTRACT
Quantitative analysis of the biologically-active metabolites of vitamin D (VitD), which are crucial in regulating various physiological and pathological processes, is important for clinical investigations. Liquid chromatography-tandem mass spectrometry (LC-MS) has been widely used for this purpose but existing LC-MS methods face challenges in achieving highly sensitive and accurate quantification of low-abundance VitD metabolites while maintaining high throughput and robustness. Here we developed a novel pipeline that combines a trapping-micro-LC-(T-µLC) with narrow-window-isolation selected-reaction monitoring MS(NWI-SRM) for ultra-sensitive, robust and high-throughput quantification of VitD metabolites in serum samples after derivatization. The selective-trapping and delivery approach efficiently removes matrix components, enabling high-capacity sample loading and enhancing sensitivity, throughput, and robustness. The NWI-SRM further improves the sensitivity by providing high selectivity. The lower limits of quantification (LOQs) achieved were markedly lower than any existing LC-MS methods: 1.0 pg/mL for 1,25(OH)2D3, 5.0 pg/mL for 24,25(OH)2D3, 30 pg/mL for both 25(OH)D2 and 25(OH)D3, all within a 9-min cycle. The method is applied to quantify VitD metabolites from 218 patients with multiple sclerosis. This study revealed negative correlations(r=- 0.44 to - 0.51) between the levels of 25(OH)D2 and all the three D3 metabolites in multiple sclerosis patients.
Subject(s)
Liquid Chromatography-Mass Spectrometry , Multiple Sclerosis , Humans , Chromatography, Liquid , Tandem Mass Spectrometry , Vitamin DABSTRACT
INTRODUCTION: The etiology of multiple sclerosis (MS) remains unknown. Pathogenesis likely relies on a complex interaction between multiple environmental, genetic, and behavioral risk factors. However, a growing body of literature supports the role of a preceding Epstein-Barr virus (EBV) infection in the majority of cases. AREAS COVERED: In this narrative review, we summarize the latest findings regarding the potential role of EBV as a predisposing event inducing new onset of MS. EBV interactions with the genetic background and other infectious agents such as human endogenous retrovirus are explored. Additional data regarding the role of EBV regarding the rate of mid- and long-term disease progression is also discussed. Lastly, the effect of currently approved disease-modifying therapies (DMT) for MS treatment on the EBV-based molecular mechanisms and the development of new EBV-specific therapies are further reviewed. EXPERT OPINION: Recent strong epidemiological findings support that EBV may be the primary inducing event in certain individuals that shortly thereafter develop MS. More studies are needed in order to better understand the significant variability in susceptibility based on environmental factors such as EBV exposure. Future investigations should focus on determining the specific EBV-related risk antigen(s) and phenotyping people with likely EBV-induced MS. Targeting EBV via several different avenues, including development of an EBV vaccine, may become the mainstay of MS treatment in the future.
Subject(s)
Epstein-Barr Virus Infections , Herpesvirus 4, Human , Multiple Sclerosis , Humans , Multiple Sclerosis/virology , Multiple Sclerosis/immunology , Epstein-Barr Virus Infections/immunology , Herpesvirus 4, Human/immunology , AnimalsABSTRACT
The increasing use of neuroimaging in clinical research has driven the creation of many large imaging datasets. However, these datasets often rely on inconsistent naming conventions in image file headers to describe acquisition, and time-consuming manual curation is necessary. Therefore, we sought to automate the process of classifying and organizing magnetic resonance imaging (MRI) data according to acquisition types common to the clinical routine, as well as automate the transformation of raw, unstructured images into Brain Imaging Data Structure (BIDS) datasets. To do this, we trained an XGBoost model to classify MRI acquisition types using relatively few acquisition parameters that are automatically stored by the MRI scanner in image file metadata, which are then mapped to the naming conventions prescribed by BIDS to transform the input images to the BIDS structure. The model recognizes MRI types with 99.475% accuracy, as well as a micro/macro-averaged precision of 0.9995/0.994, a micro/macro-averaged recall of 0.9995/0.989, and a micro/macro-averaged F1 of 0.9995/0.991. Our approach accurately and quickly classifies MRI types and transforms unstructured data into standardized structures with little-to-no user intervention, reducing the barrier of entry for clinical scientists and increasing the accessibility of existing neuroimaging data.
ABSTRACT
BACKGROUND: Paramagnetic rim lesions (PRLs) have been linked to higher clinical disease severity and relapse frequency. However, it remains unclear whether PRLs predict future, long-term disease progression. OBJECTIVES: The study aimed to assess whether baseline PRLs were associated with subsequent long-term (10 years) Expanded Disability Status Scale (EDSS) increase and relapse frequency and, if so, whether PRL-associated EDSS increase was mediated by relapse. METHODS: This retrospective analysis included 172 people with multiple sclerosis (pwMS) with 1868 yearly clinical visits over a mean follow-up time of 10.2 years. 3T magnetic resonance imaging (MRI) was acquired at baseline and PRLs were assessed on quantitative susceptibility mapping (QSM) images. The associations between PRLs, relapse, and rate of EDSS change were assessed using linear models. RESULTS: PRL+ pwMS had greater overall annual relapse rate (ß = 0.068; p = 0.010), three times greater overall odds of relapse (exp(ß) = 3.472; p = 0.009), and greater rate of yearly EDSS change (ß = 0.045; p = 0.010) than PRL- pwMS. Greater PRL number was associated with greater odds of at least one progression independent of relapse activity (PIRA) episode over follow-up (exp(ß) = 1.171, p = 0.009). Mediation analysis showed that the association between PRL presence (yes/no) and EDSS increase was 96.7% independent of relapse number. CONCLUSION: PRLs are a marker of aggressive ongoing disease inflammatory activity, including more frequent future clinical relapses and greater long-term, relapse-independent disability progression.
Subject(s)
Brain , Multiple Sclerosis , Humans , Retrospective Studies , Prognosis , Brain/pathology , Multiple Sclerosis/pathology , Magnetic Resonance Imaging , Chronic Disease , Disease Progression , RecurrenceABSTRACT
BACKGROUND: A quantitative measurement of serum proteome biomarkers that would associate with disease progression endpoints can provide risk stratification for persons with multiple sclerosis (PwMS) and supplement the clinical decision-making process. MATERIALS AND METHODS: In total, 202 PwMS were enrolled in a longitudinal study with measurements at two time points with an average follow-up time of 5.4 years. Clinical measures included the Expanded Disability Status Scale, Timed 25-foot Walk, 9-Hole Peg, and Symbol Digit Modalities Tests. Subjects underwent magnetic resonance imaging to determine the volumetric measures of the whole brain, gray matter, deep gray matter, and lateral ventricles. Serum samples were analyzed using a custom immunoassay panel on the Olink™ platform, and concentrations of 18 protein biomarkers were measured. Linear mixed-effects models and adjustment for multiple comparisons were performed. RESULTS: Subjects had a significant 55.6% increase in chemokine ligand 20 (9.7 pg/mL vs. 15.1 pg/mL, p < 0.001) and neurofilament light polypeptide (10.5 pg/mL vs. 11.5 pg/mL, p = 0.003) at the follow-up time point. Additional changes in CUB domain-containing protein 1, Contactin 2, Glial fibrillary acidic protein, Myelin oligodendrocyte glycoprotein, and Osteopontin were noted but did not survive multiple comparison correction. Worse clinical performance in the 9-HPT was associated with neurofilament light polypeptide (p = 0.001). Increases in several biomarker candidates were correlated with greater neurodegenerative changes as measured by different brain volumes. CONCLUSION: Multiple proteins, selected from a disease activity test that represent diverse biological pathways, are associated with physical, cognitive, and radiographic outcomes. Future studies should determine the utility of multiple protein assays in routine clinical care.