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Diagnosing mild traumatic brain injury using saliva RNA compared to cognitive and balance testing.

ABSTRACT: BACKGROUND:Early, accurate diagnosis of mild traumatic brain injury (mTBI) can improve clinical outcomes for patients, but mTBI remains difficult to diagnose because of reliance on subjective symptom reports. An objective biomarker could increase diagnostic accuracy and improve clinical outcomes. The aim of this study was to assess the ability of salivary noncoding RNA (ncRNA) to serve as a diagnostic adjunct to current clinical tools. We hypothesized that saliva ncRNA levels would demonstrate comparable accuracy for identifying mTBI as measures of symptom burden, neurocognition, and balance. METHODS:This case-control study involved 538 individuals. Participants included 251 individuals with mTBI, enrolled ?14 days postinjury, from 11 clinical sites. Saliva samples (n = 679) were collected at five time points (?3, 4-7, 8-14, 15-30, and 31-60 days post-mTBI). Levels of ncRNAs (microRNAs, small nucleolar RNAs, and piwi-interacting RNAs) were quantified within each sample using RNA sequencing. The first sample from each mTBI participant was compared to saliva samples from 287 controls. Samples were divided into testing (n = 430; mTBI = 201 and control = 239) and training sets (n = 108; mTBI = 50 and control = 58). The test set was used to identify ncRNA diagnostic candidates and create a diagnostic model. Model accuracy was assessed in the naïve test set. RESULTS:A model utilizing seven ncRNA ratios, along with participant age and chronic headache status, differentiated mTBI and control participants with a cross-validated area under the curve (AUC) of .857 in the training set (95% CI, .816-.903) and .823 in the naïve test set. In a subset of participants (n = 321; mTBI = 176 and control = 145) assessed for symptom burden (Post-Concussion Symptom Scale), as well as neurocognition and balance (ClearEdge System), these clinical measures yielded cross-validated AUC of .835 (95% CI, .782-.880) and .853 (95% CI, .803-.899), respectively. A model employing symptom burden and four neurocognitive measures identified mTBI participants with similar AUC (.888; CI, .845-.925) as symptom burden and four ncRNAs (.932; 95% CI, .890-.965). CONCLUSION:Salivary ncRNA levels represent a noninvasive, biologic measure that can aid objective, accurate diagnosis of mTBI.

SUBMITTER: Hicks SD

PROVIDER: S-EPMC7533415 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Diagnosing mild traumatic brain injury using saliva RNA compared to cognitive and balance testing.

Hicks Steven D SD Onks Cayce C Kim Raymond Y RY Zhen Kevin J KJ Loeffert Jayson J Loeffert Andrea C AC Olympia Robert P RP Fedorchak Gregory G DeVita Samantha S Rangnekar Aakanksha A Leddy John J Haider Mohammad N MN Gagnon Zofia Z McLoughlin Callan D CD Badia Matthew M Randall Jason J Madeira Miguel M Yengo-Kahn Aaron M AM Wenzel Justin J Heller Matthew M Zwibel Hallie H Roberts Aaron A Johnson Samantha S Monteith Chuck C Dretsch Michael N MN Campbell Thomas R TR Mannix Rebekah R Neville Christopher C Middleton Frank F

Clinical and translational medicine 20201001 6

<h4>Background</h4>Early, accurate diagnosis of mild traumatic brain injury (mTBI) can improve clinical outcomes for patients, but mTBI remains difficult to diagnose because of reliance on subjective symptom reports. An objective biomarker could increase diagnostic accuracy and improve clinical outcomes. The aim of this study was to assess the ability of salivary noncoding RNA (ncRNA) to serve as a diagnostic adjunct to current clinical tools. We hypothesized that saliva ncRNA levels would demon ...[more]

PMID: 33135344

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Project description:BackgroundA proportion of patients with mild traumatic brain injury (mTBI) suffer long-term consequences, and the reasons behind this are still poorly understood. One factor that may affect outcomes is cognitive reserve, which is the brain's ability to maintain cognitive function despite injury. It is often assessed through educational level or premorbid IQ tests. This study aimed to explore whether there were differences in post-concussion symptoms and symptom resolution between patients with mTBI and minor orthopedic injuries one week and three months after injury. Additional aims were to explore the relationship between cognitive reserve and outcome, as well as functional connectivity according to resting state functional magnetic resonance imaging (rs-fMRI).MethodFifteen patients with mTBI and 15 controls with minor orthopedic injuries were recruited from the emergency department. Assessments, including Rivermead Post-Concussion Questionnaire (RPQ), neuropsychological testing, and rs-fMRI scans, were conducted on average 7 days (SD = 2) and 122 days (SD = 51) after injury.ResultsAt the first time point, significantly higher rates of post-concussion symptoms (U = 40.0, p = 0.003), state fatigue (U = 56.5, p = 0.014), and fatigability (U = 58.5, p = 0.025) were observed among the mTBI group than among the controls. However, after three months, only the difference in post-concussion symptoms remained significant (U = 27.0, p = 0.003). Improvement in post-concussion symptoms was found to be significantly correlated with cognitive reserve, but only in the mTBI group (Spearman's rho = -0.579, p = .038). Differences in the trajectory of recovery were also observed for fatigability between the two groups (U = 36.5, p = 0.015). Moreover, functional connectivity differences in the frontoparietal network were observed between the groups, and for mTBI patients, functional connectivity differences in an executive control network were observed over time.ConclusionThe findings of this pilot study suggest that mTBI, compared to minor orthopedic trauma, is associated to both functional connectivity changes in the brain and concussion-related symptoms. While there is improvement in these symptoms over time, a small subgroup with lower cognitive reserve appears to experience more persistent and possibly worsening symptoms over time. This, however, needs to be validated in larger studies.Trial registrationNCT05593172. Retrospectively registered.

Project description:Traumatic brain injury (TBI) can be serious partly due to the challenges of assessing and treating its neurocognitive and affective sequelae. The effects of a single TBI may persist for years and can limit patients' activities due to somatic complaints (headaches, vertigo, sleep disturbances, nausea, light or sound sensitivity), affective sequelae (post-traumatic depressive symptoms, anxiety, irritability, emotional instability) and mild cognitive impairment (MCI, including social cognition disturbances, attention deficits, information processing speed decreases, memory degradation and executive dysfunction). Despite a growing amount of research, study comparison and knowledge synthesis in this field are problematic due to TBI heterogeneity and factors like injury mechanism, age at or time since injury. The relative lack of standardization in neuropsychological assessment strategies for quantifying sequelae adds to these challenges, and the proper administration of neuropsychological testing relative to the relationship between TBI, MCI and neuroimaging has not been reviewed satisfactorily. Social cognition impairments after TBI (e.g., disturbed emotion recognition, theory of mind impairment, altered self-awareness) and their neuroimaging correlates have not been explored thoroughly. This review consolidates recent findings on the cognitive and affective consequences of TBI in relation to neuropsychological testing strategies, to neurobiological and neuroimaging correlates, and to patient age at and assessment time after injury. All cognitive domains recognized by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) are reviewed, including social cognition, complex attention, learning and memory, executive function, language and perceptual-motor function. Affect and effort are additionally discussed owing to their relationships to cognition and to their potentially confounding effects. Our findings highlight non-negligible cognitive and affective impairments following TBI, their gravity often increasing with injury severity. Future research should study (A) language, executive and perceptual-motor function (whose evolution post-TBI remains under-explored), (B) the effects of age at and time since injury, and (C) cognitive impairment severity as a function of injury severity. Such efforts should aim to develop and standardize batteries for cognitive subdomains-rather than only domains-with high ecological validity. Additionally, they should utilize multivariate techniques like factor analysis and related methods to clarify which cognitive subdomains or components are indeed measured by standardized tests.

Project description:To investigate longitudinal changes in global and regional brain volume in patients 1 year after mild traumatic brain injury (MTBI) and to correlate such changes with clinical and neurocognitive metrics.This institutional review board-approved study was HIPAA compliant. Twenty-eight patients with MTBI (with 19 followed up at 1 year) with posttraumatic symptoms after injury and 22 matched control subjects (with 12 followed up at 1 year) were enrolled. Automated segmentation of brain regions to compute regional gray matter (GM) and white matter (WM) volumes was performed by using three-dimensional T1-weighted 3.0-T magnetic resonance imaging, and results were correlated with clinical metrics. Pearson and Spearman rank correlation coefficients were computed between longitudinal brain volume and neurocognitive scores, as well as clinical metrics, over the course of the follow-up period.One year after MTBI, there was measurable global brain atrophy, larger than that in control subjects. The anterior cingulate WM bilaterally and the left cingulate gyrus isthmus WM, as well as the right precuneal GM, showed significant decreases in regional volume in patients with MTBI over the 1st year after injury (corrected P < .05); this was confirmed by means of cross-sectional comparison with data in control subjects (corrected P < .05). Left and right rostral anterior cingulum WM volume loss correlated with changes in neurocognitive measures of memory (r = 0.65, P = .005) and attention (r = 0.60, P = .01). At 1-year follow-up, WM volume in the left cingulate gyrus isthmus correlated with clinical scores of anxiety (Spearman rank correlation r = -0.68, P = .007) and postconcussive symptoms (Spearman rank correlation r = -0.65, P = .01).These observations demonstrate structural changes to the brain 1 year after injury after a single concussive episode. Regional brain atrophy is not exclusive to moderate and severe traumatic brain injury but may be seen after mild injury. In particular, the anterior part of the cingulum and the cingulate gyrus isthmus, as well as the precuneal GM, may be distinctively vulnerable 1 year after MTBI.

Dataset Information

Diagnosing mild traumatic brain injury using saliva RNA compared to cognitive and balance testing.

Publications

Diagnosing mild traumatic brain injury using saliva RNA compared to cognitive and balance testing.

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