Associations of MRI-Derived Glymphatic System Impairment With Global White Matter Damage and Cognitive Impairment in Mild Traumatic Brain Injury: A DTI-ALPS Study.

BACKGROUND: Assessing the glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS) may be helpful for mild traumatic brain injury (mTBI) management. PURPOSE: To assess glymphatic function using DTI-ALPS and its associations with global white matter damage and cognitive impairment in mTBI. STUDY TYPE: Prospective. POPULATION: Thirty-four controls (44.1% female, mean age 49.2 years) and 58 mTBI subjects (43.1% female, mean age 48.7 years), including uncomplicated mTBI (N = 32) and complicated mTBI (N = 26). FIELD STRENGTH/SEQUENCE: 3-T, single-shot echo-planar imaging sequence. ASSESSMENT: Magnetic resonance imaging (MRI) was done within 1 month since injury. DTI-ALPS was performed to assess glymphatic function, and peak width of skeletonized mean diffusivity (PSMD) was used to assess global white matter damage. Cognitive tests included Auditory Verbal Learning Test and Digit Span Test (forward and backward). STATISTICAL TESTS: Neuroimaging findings comparisons were done between mTBI and control groups. Partial correlation and multivariable linear regression assessed the associations between DTI-ALPS, PSMD, and cognitive impairment. Mediation effects of PSMD on the relationship between DTI-ALPS and cognitive impairment were explored. P-value <0.05 was considered statistically significant, except for cognitive correlational analyses with a Bonferroni-corrected P-value set at 0.05/3 ≈ 0.017. RESULTS: mTBI showed lower DTI-ALPS and higher PSMD, especially in complicated mTBI. DTI-ALPS was significantly correlated with verbal memory (r = 0.566), attention abilities (r = 0.792), executive function (r = 0.618), and PSMD (r = -0.533). DTI-ALPS was associated with verbal memory (ß = 8.77, 95% confidence interval [CI] 5.00, 12.54), attention abilities (ß = 5.67, 95% CI 4.56, 6.97), executive function (ß = 2.34, 95% CI 1.49, 3.20), and PSMD (ß = -0.79, 95% CI -1.15, -0.43). PSMD mediated 46.29%, 20.46%, and 24.36% of the effects for the relationship between DTI-ALPS and verbal memory, attention abilities, and executive function. DATA CONCLUSION: Glymphatic function may be impaired in mTBI reflected by DTI-ALPS. Glymphatic dysfunction may cause cognitive impairment related to global white matter damage after mTBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

MRI-Visible Perivascular Spaces Associated With Cognitive Impairment in Military Veterans With Traumatic Brain Injury Mediated by CSF P-Tau.

Objective: To investigate the association of MRI-visible perivascular spaces (PVS) with cognitive impairment in military veterans with traumatic brain injury (TBI), and whether cerebrospinal fluid (CSF) p-tau and Aß mediate this effect. Materials and Methods: We included 55 Vietnam War veterans with a history of TBI and 52 non-TBI Vietnam War veterans from the Department of Defense Alzheimer's Disease Neuroimaging Initiative (ADNI) database. All the subjects had brain MRI, CSF p-tau, Aß, and neuropsychological examinations. MRI-visible PVS number and grade were rated on MRI in the centrum semiovale (CSO-PVS) and basal ganglia (BG-PVS). Multiple linear regression was performed to assess the association between MRI-visible PVS and cognitive impairment and the interaction effect of TBI. Additionally, mediation effect of CSF biomarkers on the relationship between MRI-visible PVS and cognitive impairment was explored in TBI group. Results: Compared with military control, TBI group had higher CSO-PVS number (p = 0.001), CSF p-tau (p = 0.022) and poorer performance in verbal memory (p = 0.022). High CSO-PVS number was associated with poor verbal memory in TBI group (ß = -0.039, 95% CI -0.062, -0.016), but not in military control group (ß = 0.019, 95% CI -0.004, 0.043) (p-interaction = 0.003). Further mediation analysis revealed that CSF p-tau had a significant indirect effect (ß = -0.009, 95% CI: -0.022 -0.001, p = 0.001) and mediated 18.75% effect for the relationship between CSO-PVS and verbal memory in TBI group. Conclusion: MRI-visible CSO-PVS was more common in Vietnam War veterans with a history of TBI and was associated with poor verbal memory, mediated partially by CSF p-tau.

Associations of MRI-visible perivascular spaces with longitudinal cognitive decline across the Alzheimer's disease spectrum.

OBJECTIVE: To investigate the characteristics and associations of MRI-visible perivascular spaces (PVS) with clinical progression and longitudinal cognitive decline across the Alzheimer's disease spectrum. METHODS: We included 1429 participants (641 [44.86%] female) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. PVS number and grade in the centrum semiovale (CSO-PVS), basal ganglia (BG-PVS), and hippocampus (HP-PVS) were compared among the control (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) groups. PVS were tested as predictors of diagnostic progression (i.e., CN to MCI/AD or MCI to AD) and longitudinal changes in the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog 13), Mini-Mental State Examination (MMSE), memory (ADNI-MEM), and executive function (ADNI-EF) using multiple linear regression, linear mixed-effects, and Cox proportional hazards modeling. RESULTS: Compared with CN subjects, MCI and AD subjects had more CSO-PVS, both in number (p < 0.001) and grade (p < 0.001). However, there was no significant difference in BG-PVS and HP-PVS across the AD spectrum (p > 0.05). Individuals with moderate and frequent/severe CSO-PVS had a higher diagnostic conversion risk than individuals with no/mild CSO-PVS (log-rank p < 0.001 for all) in the combined CN and MCI group. Further Cox regression analyses revealed that moderate and frequent/severe CSO-PVS were associated with a higher risk of diagnostic conversion (HR = 2.007, 95% CI = 1.382-2.914, p < 0.001; HR = 2.676, 95% CI = 1.830-3.911, p < 0.001, respectively). A higher CSO-PVS number was associated with baseline cognitive performance and longitudinal cognitive decline in all cognitive tests (p < 0.05 for all). CONCLUSIONS: CSO-PVS were more common in MCI and AD and were associated with cognitive decline across the AD spectrum.

Enlarged perivascular spaces and white matter hyperintensities in patients with frontotemporal lobar degeneration syndromes.

Objective: The aim of this study was to investigate the distribution characteristics of enlarged perivascular spaces (EPVS) and white matter hyperintensities (WMH) and their associations with disease severity across the frontotemporal lobar degeneration (FTLD) syndromes spectrum. Methods: This study included 73 controls, 39 progressive supranuclear palsy Richardson's syndrome (PSP-RS), 31 corticobasal syndrome (CBS), 47 behavioral variant frontotemporal dementia (bvFTD), 36 non-fluent variant primary progressive aphasia (nfvPPA), and 50 semantic variant primary progressive aphasia (svPPA). All subjects had brain magnetic resonance imaging (MRI) and neuropsychological tests, including progressive supranuclear palsy rating scale (PSPRS) and FTLD modified clinical dementia rating sum of boxes (FTLD-CDR). EPVS number and grade were rated on MRI in the centrum semiovale (CSO-EPVS), basal ganglia (BG-EPVS), and brain stem (BS-EPVS). Periventricular (PWMH) and deep (DWMH) were also graded on MRI. The distribution characteristics of EPVS and WMH were compared between control and disease groups. Multivariable linear regression analysis was performed to evaluate the association of EPVS and WMH with disease severity. Results: Compared with control subjects, PSP-RS and CBS had more BS-EPVS; CBS, bvFTD, and nfvPPA had less CSO-EPVS; all disease groups except CBS had higher PWMH (p < 0.05). BS-EPVS was associated with PSPRS in PSP-RS (ß = 2.395, 95% CI 0.888-3.901) and CBS (ß = 3.115, 95% CI 1.584-4.647). PWMH was associated with FTLD-CDR in bvFTD (ß = 1.823, 95% CI 0.752-2.895), nfvPPA (ß = 0.971, 95% CI 0.030-1.912), and svPPA (OR: 1.330, 95% CI 0.457-2.204). Conclusion: BS-EPVS could be a promising indicator of disease severity in PSP-RS and CBS, while PWMH could reflect the severity of bvFTD, nfvPPA, and svPPA.