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Baseline biomarkers of connectome disruption and atrophy predict future processing speed in early multiple sclerosis.

ABSTRACT: The development of accurate prognoses in multiple sclerosis is difficult, as the disease is characterized by heterogeneous patterns of brain abnormalities that relate in an unclear way to future impairments. Here, we use a statistical modeling approach to determine if the baseline pattern of connectome disruption due to T2-FLAIR lesions could predict a patient's future processing speed, as measured using the Symbol Digits Modality Test scores. Imaging data, demographics and Symbol Digits Modality Test scores were collected from 61 early relapsing remitting multiple sclerosis patients. The Network Modification Tool was used to estimate damage to the connectome by quantifying white matter abnormalities' effects on 1) global network properties, 2) regional connectivity and 3) connectivity between pairs of regions. MS subjects showed significant improvement of processing speed between baseline and follow-up (t?=?-2.6, p?=?0.0096); however, both baseline (t?=?-4.01, p?=?0.00012) and follow-up (t?=?-2.10, p?=?0.038) processing speed were significantly lower than age-matched healthy controls. Partial Least Squares Regression was used to create models that predict future processing speed from between baseline imaging metrics and demographics. The model based on region-pair disconnection and gray matter atrophy had the lowest AIC and highest prediction accuracy (R2?=?0.79) compared to models based on global (R2?=?0.41) or regional (R2?=?0.66) disconnection and gray matter atrophy, overlap with an ROI-based atlas and gray matter atrophy (R2?=?0.73) or gray matter atrophy alone (R2?=?0.71). We found that baseline measures of connectivity disruption in various parietal, temporal, occipital and subcortical regions and atrophy in the putamen were important predictors of future processing speed. We conclude that information about disruptions to pairwise brain connections is more informative of future processing speed than regional or global metrics or gray matter atrophy alone. The combination of quantitative disconnectome metrics, gray matter atrophy and statistical modeling approaches could enable clinicians in developing more accurate, individualized prognoses of future cognitive status in multiple sclerosis patients.

SUBMITTER: Kuceyeski A

PROVIDER: S-EPMC6019863 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Baseline biomarkers of connectome disruption and atrophy predict future processing speed in early multiple sclerosis.

Kuceyeski A A Monohan E E Morris E E Fujimoto K K Vargas W W Gauthier S A SA

NeuroImage. Clinical 20180508

The development of accurate prognoses in multiple sclerosis is difficult, as the disease is characterized by heterogeneous patterns of brain abnormalities that relate in an unclear way to future impairments. Here, we use a statistical modeling approach to determine if the baseline pattern of connectome disruption due to T2-FLAIR lesions could predict a patient's future processing speed, as measured using the Symbol Digits Modality Test scores. Imaging data, demographics and Symbol Digits Modalit ...[more]

PMID: 30013921

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Project description:Background and objectivesThalamic atrophy (TA) represents a biomarker of neurodegeneration and associated dysfunction/decline in physical and cognitive functioning among persons with multiple sclerosis (MS). Aerobic fitness, as an end point of exercise training, represents a promising target for restoring function in MS, but it is unknown if such effects differ by TA. This cross-sectional study examined whether aerobic fitness was differentially associated with cognitive processing speed and walking endurance in persons with MS who present with and without TA.Methods44 fully ambulatory persons with MS completed a graded exercise test for measuring aerobic fitness (VO2peak) and underwent 3T MRI for measuring TA, the Symbol Digit Modalities Test (SDMT), and the 6-min walk (6MW). We performed Spearman correlations (rs) among VO2peak, SDMT, and 6MW scores overall, and in persons with and without TA. We applied Fisher's z-test for comparing correlations based on TA status.ResultsWhen controlling for age, EDSS score, and global MRI measures of atrophy, VO2peak was strongly associated with SDMT scores (prs = 0.74, p < 0.01) and 6MW performance (prs = 0.77, p < 0.01) in persons with TA, whereas VO2peak was not associated with SDMT scores (prs = - 0.01, p = 0.99) or 6MW performance (prs = 0.25, p = 0.38) in those without TA. The correlations between VO2peak and SDMT (z = 2.86, p < 0.01) and VO2peak and 6MW (z = 2.33, p = 0.02) were significantly stronger in the TA group.DiscussionThis study provides initial evidence of strong, selective associations among aerobic fitness, cognitive processing speed, and walking endurance in persons with TA as a biomarker for MS-related neurodegeneration. Such data support TA as a moderator of the association among aerobic fitness, cognitive processing speed, and walking endurance in persons with MS. Future research should carefully consider the role of TA when designing trials of aerobic exercise, cognition, and mobility in MS.

Project description:Cognitive impairment affects about 50% of multiple sclerosis (MS) patients, but the mechanisms underlying this remain unclear. The default mode network (DMN) has been linked with cognition, but in MS its role is still poorly understood. Moreover, within an extended DMN network including the cerebellum (CBL-DMN), the contribution of cortico-cerebellar connectivity to MS cognitive performance remains unexplored. The present study investigated associations of DMN and CBL-DMN structural connectivity with cognitive processing speed in MS, in both cognitively impaired (CIMS) and cognitively preserved (CPMS) MS patients. 68 MS patients and 22 healthy controls (HCs) completed a symbol digit modalities test (SDMT) and had 3T brain magnetic resonance imaging (MRI) scans that included a diffusion weighted imaging protocol. DMN and CBL-DMN tracts were reconstructed with probabilistic tractography. These networks (DMN and CBL-DMN) and the cortico-cerebellar tracts alone were modeled using a graph theoretical approach with fractional anisotropy (FA) as the weighting factor. Brain parenchymal fraction (BPF) was also calculated. In CIMS SDMT scores strongly correlated with the FA-weighted global efficiency (GE) of the network [GE(CBL-DMN): ? = 0.87, R 2 = 0.76, p < 0.001; GE(DMN): ? = 0.82, R 2 = 0.67, p < 0.001; GE(CBL): ? = 0.80, R 2 = 0.64, p < 0.001]. In CPMS the correlation between these measures was significantly lower [GE(CBL-DMN): ? = 0.51, R 2 = 0.26, p < 0.001; GE(DMN): ? = 0.48, R 2 = 0.23, p = 0.001; GE(CBL): ? = 0.52, R 2 = 0.27, p < 0.001] and SDMT scores correlated most with BPF (? = 0.57, R 2 = 0.33, p < 0.001). In a multivariable regression model where SDMT was the independent variable, FA-weighted GE was the only significant explanatory variable in CIMS, while in CPMS BPF and expanded disability status scale were significant. No significant correlation was found in HC between SDMT scores, MRI or network measures. DMN structural GE is related to cognitive performance in MS, and results of CBL-DMN suggest that the cerebellum structural connectivity to the DMN plays an important role in information processing speed decline.

Project description:BackgroundCrucial to the success of clinical trials targeting early Alzheimer's disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers.MethodsLongitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into β-amyloid positive/negative (Aβ+/Aβ-)] subgroups. Baseline plasma (p-tau181 and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aβ+/Aβ- subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement.ResultsA total of 245 CN (35.0% Aβ+) and 361 MCI (53.2% Aβ+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aβ+ and Aβ- subgroups, including Aβ- CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI [area under the curve (AUC): 0.78-0.93] and more modestly in CN (0.65-0.73).ConclusionsThe present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aβ- CN indicates the potential use of these biomarkers in predicting a normal age-related decline.

Project description:Moyamoya disease is a rare cerebrovascular disorder associated with cognitive dysfunction. It is usually treated by surgical revascularization, but research on the neurocognitive outcomes of revascularization surgery is controversial. Given that neurocognitive impairment could affect the daily activities of patients with moyamoya disease, early detection of postoperative neurocognitive outcomes has the potential to improve patient management. In this study, we applied a well-established connectome-based predictive modelling approach to develop machine learning models that used preoperative resting-state functional connectivity to predict postoperative changes in processing speed in patients with moyamoya disease. Twelve adult patients with moyamoya disease (age range: 23-49 years; female/male: 9/3) were recruited prior to surgery and underwent follow-up at 1 and 6 months after surgery. Twenty healthy controls (age range: 24-54 years; female/male: 14/6) were recruited and completed the behavioural test at baseline, 1-month follow-up and 6-month follow-up. Behavioural results indicated that the behavioural changes in processing speed at 1 and 6 months after surgery compared with baseline were not significant. Importantly, we showed that preoperative resting-state functional connectivity significantly predicted postoperative changes in processing speed at 1 month after surgery (negative network: ρ = 0.63, P corr = 0.017) and 6 months after surgery (positive network: ρ = 0.62, P corr = 0.010; negative network: ρ = 0.55, P corr = 0.010). We also identified cerebro-cerebellar and cortico-subcortical connectivities that were consistently associated with processing speed. The brain regions identified from our predictive models are not only consistent with previous studies but also extend previous findings by revealing their potential roles in postoperative neurocognitive functions in patients with moyamoya disease. Taken together, our findings provide preliminary evidence that preoperative resting-state functional connectivity might predict the post-surgical longitudinal neurocognitive changes in patients with moyamoya disease. Given that processing speed is a crucial cognitive ability supporting higher neurocognitive functions, this study's findings offer important insight into the clinical management of patients with moyamoya disease.

Project description:Introduction: Individuals with multiple sclerosis (MS) are vulnerable to deficits in working memory (WM), but the search for neural correlates of WM within circumscribed areas has been inconclusive. Given the widespread neural alterations observed in MS, predictive modeling approaches that capitalize on whole-brain connectivity may better capture individual differences in WM. Materials and Methods: We applied connectome-based predictive modeling to functional magnetic resonance imaging data from WM tasks in two independent samples with relapsing-remitting MS. In the internal sample (ninternal = 36), cross-validation was used to train a model to predict accuracy on the Paced Visual Serial Addition Test from functional connectivity. We hypothesized that this MS-specific model would successfully predict performance on the N-back task in the validation cohort (nvalidation = 36). In addition, we assessed the generalizability of existing WM networks derived in healthy young adults to these samples, and we explored anatomical differences between the healthy and MS networks. Results: We successfully derived an MS-specific predictive model of WM in the internal sample (full: rs = 0.47, permuted p = 0.011), but the predictions were not significant in the validation cohort (rs = -0.047; p = 0.78, mean squared error [MSE] = 0.006, R2 = -2.21%). In contrast, the healthy networks successfully predicted WM in both MS samples (internal: rs = 0.33 p = 0.049, MSE = 0.009, R2 = 13.4%; validation cohort: rs = 0.46, p = 0.005, MSE = 0.005, R2 = 16.9%), demonstrating their translational potential. Discussion: Functional networks identified in a large sample of healthy individuals predicted significant variance in WM in MS. Networks derived in small samples of people with MS may have limited generalizability, potentially due to disease-related heterogeneity. The robustness of models derived in large clinical samples warrants further investigation. ClinicalTrials.gov ID: NCT03244696.

Dataset Information

Baseline biomarkers of connectome disruption and atrophy predict future processing speed in early multiple sclerosis.

Publications

Baseline biomarkers of connectome disruption and atrophy predict future processing speed in early multiple sclerosis.

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