Normal-appearing White Matter Research Articles

Accelerated Cellular Senescence in Progressive Multiple Sclerosis: A Histopathological Study.

The neurodegenerative processes driving the build-up of disability in progressive multiple sclerosis (P-MS) have not been fully elucidated. Recent data link cellular senescence (CS) to neurodegeneration. We investigated for evidence of CS in P-MS and sought to determine its pattern. We used 53BP1, p16, and lipofuscin as markers of CS in white matter lesions (WMLs), normal appearing white matter (NAWM), normal appearing cortical gray matter (NAGM), control white matter (CWM), and control gray matter (CGM) on autopsy material from patient with P-MS and healthy controls. Senescence-associated secretory phenotype (SASP) factors were quantified in cerebrospinal fluid (CSF). P16+ cell counts were significantly increased in WMLs and GMLs, compared with NAWM, CWM, NAGM, and CGM and lipofuscin+ cells were significantly increased in WMLs, compared with NAWM and CWM, indicating more abundant CS in demyelinated lesions. The 53BP1+ cells in WMLs were significantly increased compared with NAWM and CWM. The 53BP1+ and p16+ cells were found significantly more abundant in acute active WMLs and GMLs, compared with chronic inactive lesions. Co-localization studies showed evidence of CS in neurons, astrocytes, oligodendrocytes, microglia, and macrophages. Among the quantified CSF SASP factors, IL-6, MIF, and MIP1a levels correlated with 53BP1+ cell counts in NAGM, whereas IL-10 levels correlated with p16+ cell counts in NAWM. P16+ cell counts in WMLs exhibited an inverse correlation with time to requiring a wheelchair and with age at death. Our data indicates that CS primarily affects actively demyelinating gray and WMLs. A higher senescent cell load in P-MS is associated with faster disability progression and death. ANN NEUROL 2025.

Brain tissue integrity in neuromyelitis optica spectrum disorder through T1-w/T2-w ratio, MTR and DTI.

The presence of diffuse brain damage in normal-appearing white matter (NAWM) and gray matter (NAGM) in neuromyelitis optica spectrum disorder (NMOSD) remains controversial. We aimed to address this controversy by applying a multiparametric MRI approach. Additionally, the association between MRI metrics and clinical variables was explored. In this cross-sectional study, we prospectively evaluated aquaporin-4-IgG positive NMOSD patients and healthy controls (HC) matched for age and sex. The clinical variables of interest were collected for each participant. The mean values of T1-w/T2-w ratio, magnetization transfer ratio (MTR), fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) were obtained in NAWM, NAGM, as well as in global and hypointense lesion masks. Global lesions refer to those typically associated with aquaporin-4-IgG positive NMOSD. Hypointense lesions were defined as areas of hypointense signal in both T1-w and fluid-attenuated inversion recovery (FLAIR) images. In total, we included 105 participants (59 NMOSD patients and 46 HC). T1-w/T2-w ratio was lower in NAWM of NMOSD patients versus HC (1.83 ± 0.14 vs 1.89 ± 0.14; p = 0.029), while no significant differences were found in NAWM or NAGM across the other metrics: (p range: 0.079 to 0.973). Hypointense lesions showed lower T1-w/T2-w ratio, MTR, and FA, and higher diffusivity metrics as compared to global lesion masks (p < 0.001). T1-w/T2-w ratio in NAWM was inversely correlated with time to start immunosuppressive therapy (r = - 0.278; p = 0.036) and with MD (r = - 0.325; p = 0.014). Microstructural integrity loss seems to be confined to focal tissue damage in NMOSD. Decreased T1-w/T2-w ratio in NAWM may reflect subclinical water accumulation due to astrocyte and blood-brain barrier dysfunction. Hypointense lesions have shown a severe degree of microstructural damage.

Clinical Relevance of 'Cap' and 'Track' Development after Recent Small Subcortical Infarct.

After a recent small subcortical infarct (RSSI), some patients develop perilesional or remote hyperintensities ('caps/tracks') to the index infarct on T2/FLAIR MRI. However, their clinical relevance remains unclear. We investigated the clinicoradiological correlates of 'caps/tracks', and their impact on long-term outcomes following RSSI. We identified participants with lacunar stroke and MRI-confirmed RSSI from 3 prospective studies. At baseline, we collected risk factors, RSSI characteristics, small vessel disease (SVD) features, and microstructural integrity on diffusion imaging. Over 1-year, we repeated MRI and recorded 'caps/tracks' blinded to other data. We evaluated predictors of 'caps/tracks', and their association with 1-year functional (modified Rankin Scale score ≥2), mobility (Timed Up-and-Go), cognitive outcomes (Montreal Cognitive Assessment [MoCA] score <26), and recurrent cerebrovascular events (stroke/transient ischemic attack/incident infarct) using multivariable regression. Among 185 participants, 93 (50.3%) developed 'caps/tracks' first detected at median 198 days after stroke. 'Caps/tracks' were independently predicted by baseline factors: larger RSSI, RSSI located in white matter, higher SVD score, and higher mean diffusivity in normal-appearing white matter (odds ratio [OR] [95% confidence interval {CI}], 1.15 [1.07-1.25], 6.01 [2.80-13.57], 1.77 [1.31-2.44], 1.42 [1.01-2.03]). At 1 year, 'cap/track' formation was associated with worse functional outcome (OR: 3.17, 95% CI: 1.28-8.22), slower gait speed (β: 0.13, 95% CI: 0.01-0.25), and recurrent cerebrovascular events (hazard ratio [HR]: 2.05, 95% CI: 1.05-4.02), but not with cognitive impairment. 'Caps/tracks' after RSSI are associated with worse clinical outcomes, and may reflect vulnerability to progressive SVD-related injury. Reducing 'caps/tracks' may offer early efficacy markers in trials aiming to improve outcome after lacunar stroke. ANN NEUROL 2025.

Assessing the Validity of Diffusion Weighted Imaging Models: A Study in Patients with Post-Surgical Lower-Grade Glioma.

Background: Diffusion weighted imaging (DWI) is used for monitoring purposes for lower-grade glioma (LGG). While the apparent diffusion coefficient (ADC) is clinically used, various DWI models have been developed to better understand the micro-environment. However, the validity of these models and how they relate to each other is currently unknown. Therefore, this study assesses the validity and agreement of these models. Methods: Fourteen post-treatment LGG patients and six healthy controls (HC) underwent DWI MRI on a 3T MRI scanner. DWI processing included diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), white matter tract integrity (WMTI), neurite orientation dispersion and density imaging (NODDI), and fixel-based analysis (FBA). Validity was assessed by delineating surgical cavity, peri-surgical cavity, and normal-appearing white matter (NAWM) in LGG patients, and white matter (WM) in HC. Spearman correlation assessed the agreement between DWI parameters. Results: All obtained parameters differed significantly across tissue types. Remarkably, WMTI showed that intra-axonal diffusivity was high in the surgical cavity and low in NAWM and WM. Most DWI parameters correlated well with each other, except for WMTI-derived intra-axonal diffusivity. Conclusion: This study shows that all parameters relevant for tumour monitoring and DWI-derived parameters for axonal fibre-bundle integrity (except WMTI-IAS-Da) could be used interchangeably, enhancing inter-DWI model interpretability.

Soma and neurite density abnormalities of paramagnetic rim lesions and core-sign lesions in multiple sclerosis.

In multiple sclerosis (MS), susceptibility-weighted imaging (SWI) may reveal white matter lesions (WML) with a paramagnetic rim ("paramagnetic rim lesions" [PRLs]) or diffuse hypointensity ("core-sign lesions"), reflecting different stages of WML evolution. Using thesoma and neurite density imaging (SANDI) model on diffusion-weighted magnetic resonance imaging (MRI), we characterized microstructural abnormalities of MS PRLs and core-sign lesions and their clinical relevance. Forty MS patients and 20 healthy controls (HC) underwent a 3T brain MRI. Using SANDI, the fractions of neurite (fneurite) and soma (fsoma) and size of soma (rsoma) were quantified in PRLs (including their core and rim separately), and core-sign lesions identified on SWI-phase. Among 1811 WMLs, 122 (6.7%) core-sign lesions and 97 (5.4%) PRLs were identified. Compared to HC and MS normal-appearing white matter, all MS WML showed significantly lower fneurite and fsoma and higher rsoma (FDR-p < 0.001). Compared to SWI-isointense WML, core-sign lesions showed a significantly higher fneurite, and lower fsoma and rsoma (FDR-p ≤ 0.005). Compared to SWI-isointense WML and core-sign lesions, PRLs showed a significantly lower fneurite, higher fsoma, and higher rsoma (FDR-p ≤ 0.001). The PRL-core showed significantly lower fneurite, and higher rsoma than PRL-rim (FDR-p < 0.001). Lower PRL fneurite (β ≤ -0.006, FDR-p ≤ 0.015) and higher rsoma (β ≥ 0.032, FDR-p ≤ 0.024) were significantly associated with a longer disease duration and more severe disability. In PRLs, the significant and clinically relevant neurite loss and increased soma fraction and size possibly reflect increased astrogliosis and activated microglia. Core-sign lesions exhibit milder axonal loss, microglia density and astrogliosis, supporting their less destructive nature.

The Value of Using Quantitative MRI based on Synthetic Acquisition and Apparent Diffusion Coefficient to Monitor Multiple Sclerosis Lesion Activity.

Multiple sclerosis (MS) is one of the most common disabling central nervous system diseases affecting young adults. Magnetic resonance imaging (MRI) is an essential tool for diagnosing and following up multiple sclerosis. Over the years, many MRI techniques have been developed to improve the sensitivity of MS disease detection. In recent years synthetic MRI (sMRI) and quantitative MRI (qMRI) have gained traction in neuroimaging applications, providing more detailed information than traditional acquisition methods. These techniques enable the detection of microstructural changes in the brain with high sensitivity and robustness to inter-scanner and inter-observer variability. This study aims to evaluate the feasibility of using these techniques to avoid administering intravenous gadolinium-based contrast agents (GBCAs) for assessing MS disease activity and monitoring. Forty-two known MS patients, aged 20 to 45, were scanned as part of their routine follow-up. MAGnetic resonance image Compilation (MAGiC) sequence, an implementation of synthetic MRI, was added to our institute's routine MS protocol to automatically generate quantitative maps of T1, T2, and PD. T1, T2, PD, and apparent diffusion coefficient (ADC) data were collected from regions of interest (ROIs) representing normalappearing white matter (NAWM), enhancing, and non-enhancing MS lesions. The extracted information was compared, and statistically analyzed, and the sensitivity and specificity were calculated. The mean R1 (the reciprocal of T1) value of the non-enhancing MS lesions was 0.694 s-1 (T1=1440 ms), for enhancing lesions 1.015 s-1 (T1=985ms), and for NAWM 1.514 s-1 (T1=660ms). For R2 (the reciprocal of T2) values, the mean value was 6.816 s-1 (T2=146ms) for nonenhancing lesions, 8.944 s-1 (T2=112 ms) for enhancing lesions, and 1.916 s-1 (T2=522 ms) for NAWM. PD values averaged 93.069% for nonenhancing lesions, 82.260% for enhancing lesions, and 67.191% for NAWM. For ADC, the mean value for non-enhancing lesions was 1216.60×10-6 mm2/s, for enhancing lesions 1016.66×10-6 mm2/s, and for NAWM 770.51×10-6 mm2/s. Our results indicate that enhancing and non-enhancing MS lesions significantly decrease R1 and R2 values. Non-enhancing lesions have significantly lower R1 and R2 values compared to enhancing lesions. Conversely, PD values are significantly higher in non-enhancing lesions than in enhancing lesions. For ADC, while NAWM has lower values, there was minimal difference between the mean ADC values of enhancing and non-enhancing lesions.

Noninvasive blood-brain barrier integrity mapping in patients with high-grade glioma and metastasis by multi-echo time-encoded arterial spin labeling.

In brain tumors, disruption of the blood-brain barrier (BBB) indicates malignancy. Clinical assessment is qualitative; quantitative evaluation is feasible using the K2 leakage parameter from dynamic susceptibility contrast MRI. However, contrast agent-based techniques are limited in patients with renal dysfunction and insensitive to subtle impairments. Assessing water transport times across the BBB (Tex) by multi-echo arterial spin labeling promises to detect BBB impairments noninvasively and potentially more sensitively. We hypothesized that reduced Tex indicates impaired BBB. Furthermore, we assumed higher sensitivity for Tex than dynamic susceptibility contrast-based K2, because arterial spin labeling uses water as a freely diffusible tracer. We acquired 3T MRI data from 28 patients with intraparenchymal brain tumors (World Health Organization Grade 3 & 4 gliomas [n = 17] or metastases [n = 11]) and 17 age-matched healthy controls. The protocol included multi-echo and single-echo Hadamard-encoded arterial spin labeling, dynamic susceptibility contrast, and conventional clinical imaging. Tex was calculated using a T2-dependent multi-compartment model. Areas of contrast-enhancing tissue, edema, and normal-appearing tissue were automatically segmented, and parameter values were compared across volumes of interest and between patients and healthy controls. Tex was significantly reduced (-20.3%) in contrast-enhancing tissue compared with normal-appearing gray matter and correlated well with |K2| (r = -0.347). Compared with healthy controls, Tex was significantly lower in tumor patients' normal-appearing gray matter (Tex,tumor = 0.141 ± 0.032 s vs. Tex,HC = 0.172 ± 0.036 s) and normal-appearing white matter (Tex,tumor = 0.116 ± 0.015 vs. Tex,HC = 0.127 ± 0.017 s), whereas |K2| did not differ significantly. Receiver operating characteristic analysis showed a larger area under the curve for Tex (0.784) than K2 (0.604). Tex is sensitive to pathophysiologically impaired BBB. It agrees with contrast agent-based K2 in contrast-enhancing tissue and indicates sensitivity to subtle leakage.

Association Between Paramagnetic Rim Lesions and Pulvinar Iron Depletion in Persons with Multiple Sclerosis

Background: The deep gray matter (DGM), especially the pulvinar, and the white matter surrounding chronic active lesions have demonstrated depleted iron levels, indicating a possible mechanistic link. However, no studies have investigated the potential relationship between these phenomena. Objectives: The study aimed to determine whether PRLs were associated with pulvinar iron depletion and, if so, whether this relationship was spatially mediated. Methods: This retrospective analysis included 139 people with MS (pwMS) and 43 HCs scanned at 3T MRI at baseline and after 5.4 ± 0.6 years. Pulvinar iron concentrations (cFe) and masses (mFe) were estimated from quantitative susceptibility maps and tested for associations with PRLs. A separate cohort of 96 pwMS with PRLs and propensity-matched HCs was included to evaluate peri-plaque normal-appearing white matter (NAWM) abnormalities. Results: PRL number was associated with greater decline in pulvinar cFe (β = -0.265, p = 0.005) and mFe (β = -0.256, p = 0.006). Peri-plaque NAWM susceptibility was increased 11mm surrounding PRLs, outside which shorter PRL-to-pulvinar distance was associated with greater decline in pulvinar cFe (β = 0.380, p = 0.005) and mFe (β = 0.348, p = 0.022). Conclusions: Our findings support a spatially-related relationship between PRLs and chronic pulvinar iron depletion.

Prediction of isocitrate dehydrogenase mutation status in WHO grade II glioma by diffusion kurtosis imaging.

Isocitrate dehydrogenase (IDH) mutation status serves as a crucial prognostic indicator for glioma, typically assessed via immunohistochemical analysis post-surgery. Given the invasiveness of this approach, perhaps we can utilise convenient and noninvasive magnetic resonance imaging (MRI) methods to predict IDH mutation status. However, the current landscape lacks a standardised MRI technique for accurately predicting IDH mutations. In this study, we explore the potential of MRI diffusion kurtosis imaging (DKI) in forecasting the IDH mutation status of WHO grade II brain gliomas. Twenty-five patients with WHO grade II gliomas were retrospectively included. Patients underwent routine MRI and DKI scanning before surgery, measuring tumoural solid portion, peritumoral oedema, and normal-appearing white matter (NAWM) DKI parameters, including fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK), axial kurtosis (Ka), and axial radial kurtosis (Kr). The DKI parameter corrections were made (tumour or oedema parameters values divided by the NAWM value) to obtain the rFA (ratio of FA), rMD (ratio of MD), rMK (ratio of MK), rKA (ratio of KA), and rKr (ratio of Kr) values. Postoperative specimens were made of wax blocks and analysed by Sanger gene sequencing. DKI parameters between the 2 groups were compared by independent sample t-tests. The ROC curve was used to analyse the diagnostic value of each parameter. Twenty-five patients were diagnosed with IDH-mutant (16 cases) and IDH-wild type (9 cases). The rFA and rMK values in the parenchymal region of IDH wild-type tumour were higher than those of IDH mutant, while the rMD values were lower than those of IDH mutant, and the difference between them was statistically significant (p < 0.05). The values of DKI parameters of peritumoral oedema in the 2 groups were not statistically significant. DKI can provide microstructural changes of diseased tissues and provide more imaging information for preoperative non-invasive judgment of IDH mutation status of WHO grade II gliomas. The values of rMK, rFA, and rMD are helpful in the assessment IDH mutation status, benefiting accurate diagnoses and treatment decisions.

Amide proton transfer weighted MRI measurements yield consistent and repeatable results in patients with gliomas: a prospective test-retest study.

Chemical exchange saturation transfer (CEST) imaging has emerged as a promising imaging biomarker, but its reliability for clinical practice remains uncertain. This study aimed to investigate the robustness of CEST parameters in healthy volunteers and patients with brain tumours. A total of n = 52 healthy volunteers and n = 52 patients with histologically confirmed glioma underwent two consecutive 3-T MRI scans separated by a 1-min break. The CEST measurements were reconstructed using two models: with and without fluid suppression and included the evaluation of both amide (amidePTw) and amine (aminePTw) offsets. Mean intensity values in healthy volunteers were compared from volumetric segmentations (VOI) of grey matter, white matter, and the whole brain. Mean intensity values in brain tumour patients were assessed from VOI of the contrast-enhancing, non-enhancing and whole tumour, as well as from the normal-appearing white matter. Test-retest reliability was assessed using ICC and Bland-Altman plots. The amidePTw/aminePTw signal intensity distribution was significantly affected by fluid suppression (p < 0.001 for each VOI). Test-retest reliability in healthy volunteers showed fair to excellent agreement (ICC = 0.53-0.74), with the highest signal intensity values observed by amidePTw (ICC = 0.73-0.74). In patients, an excellent agreement of both amidePTw and aminePTw measurements was observed across different tumour regions (ICC = 0.76-0.89), with the highest ICC for contrast-enhancing tumour measurements. Bland-Altman analysis indicated negligible systematic bias and no proportional bias in measurement errors. Measurements from amide/aminePTw imaging obtained from an adequately powered test-retest study yield consistent and reproducible results in glioma patients, as a prerequisite for robust imaging biomarker discovery in neuro-oncology. Question The clinical reliability of chemical exchange saturation transfer imaging remains uncertain, necessitating further investigation to establish its robustness as a biomarker in neuro-oncology. Findings This study demonstrates that amide/amine proton transfer imaging provides repeatable, high-agreement measurements in glioma patients, particularly in contrast-enhancing tumour regions. Clinical relevance This test-retest study demonstrates that chemical exchange saturation transfer imaging using two models and assessing amide and amine offsets yield consistent and repeatable results in glioma patients, as a prerequisite for robust imaging biomarker discovery for neuro-oncology studies and clinical practice.

Association of Cerebrovascular Reactivity With 1-Year Imaging and Clinical Outcomes in Small Vessel Disease: An Observational Cohort Study.

In patients with cerebral small vessel disease (SVD), impaired cerebrovascular reactivity (CVR) is related to worse concurrent SVD burden, but less is known about cerebrovascular reactivity and long-term SVD lesion progression and clinical outcomes. We investigated associations between cerebrovascular reactivity and 1-year progression of SVD features and clinical outcomes. Between 2018 and 2021, we recruited patients from the Edinburgh/Lothian stroke services presenting with minor ischemic stroke and SVD features as part of the Mild Stroke Study 3, a prospective observational cohort study (ISRCTN 12113543). We acquired 3T brain MRI at baseline and 1 year. At baseline, we measured cerebrovascular reactivity to 6% inhaled CO2 in subcortical gray matter, normal-appearing white matter, and white matter hyperintensities (WMH). At baseline and 1 year, we quantified SVD MRI features, incident infarcts, assessed stroke severity (NIH Stroke Scale), recurrent stroke, functional outcome (modified Rankin Scale), and cognition (Montreal Cognitive Assessment). We performed linear and logistic regressions adjusted for age, sex, and vascular risk factors, reporting the regression coefficients and odds ratios with 95% CIs. We recruited 208 patients of whom 163 (mean age and SD: 65.8 ± 11.2 years, 32% female) had adequate baseline CVR and completed the follow-up structural MRI. The median increase in WMH volume was 0.32 mL with (Q1, Q3) = (-0.48, 1.78) mL; 29% had a recurrent stroke or incident infarct on MRI. At 1 year, patients with lower baseline cerebrovascular reactivity in normal-appearing tissues had increased WMH (regression coefficient: B = -1.14 [-2.13, -0.14] log10 (%ICV) per %/mm Hg) and perivascular space volumes (B = -1.90 [-3.21, -0.60] log10 (%ROIV) per %/mm Hg), with a similar trend in WMH. CVR was not associated with clinical outcomes at 1 year. Lower baseline cerebrovascular reactivity predicted an increase in WMH and perivascular space volumes after 1 year. CVR should be considered in SVD future research and intervention studies.

Improving the Detection of Myelin Integrity in Multiple Sclerosis Using Selective Inversion Recovery for MRI With Quantitative Magnetization Transfer.

Selective inversion recovery quantitative magnetization transfer (SIR-qMT)-derived macromolecular to free water pool size ratio (PSR) and diffusion tensor imaging (DTI)-derived radial diffusivity (RD) are potential metrics for assessing myelin integrity in multiple sclerosis (MS). However, establishing their accuracy in identifying tissue injury is essential for clinical translation. To compare the accuracy and Cohen's effect size (ES) of PSR and RD in detecting and quantifying tissue injury in early MS. Cross-sectional prospective study. Fourty-three subjects with newly diagnosed MS (mean age 38 ± 11 years, 70% females) and 18 age- and sex-matched healthy controls (HCs; age 38 ± 12 years, 62.5% females). 3-T MRI using T1-weighted (T1-w) turbo spin echo, T2-w fluid-attenuated inversion recovery (FLAIR), DTI, and SIR-qMT sequences. T2-lesions were identified as hyperintense on T2-w-FLAIR, and chronic black holes (cBHs) by simultaneous T2-w-FLAIR hyperintensity and T1-w hypointensity. Regions of interest (ROIs) in normal-appearing white matter (NAWM) were classified as proximal (p) or distant (d) to lesions, while normal white matter (NWM) was identified in HCs. PSR and RD values of T2-lesions and cBHs were compared to their matched p/dNAWM and NWM in HCs. Comparisons were also made between T2-lesions and cBHs. Receiver operating characteristic curves evaluated metric accuracy, and paired t tests compared ES values of PSR and RD, with significance set at P < 0.050. We identified 823 T2-lesions, 392 cBHs, 426 p-, and 213 d-NAWM ROIs in patients, and 162 NWM ROIs in HCs. PSR differed significantly in all comparisons, while RD was differed in all except cBHs vs. T2-lesions (P = 0.051). PSR had significantly higher accuracy in differentiating T2-lesions from p/dNAWM and NWM, with a larger ES when comparing T2-lesions to p/dNAWM and NWM and cBHs to pNAWM and NWM. PSR offers superior accuracy and ES over RD in detecting tissue injury in MS. 1 TECHNICAL EFFICACY: Stage 2.

Longitudinal changes in white matter free water in cerebral small vessel disease: Relationship to cerebral blood flow and white matter fiber alterations.

White matter (WM) free water (FW) is a potential imaging marker for cerebral small vessel disease (CSVD). This study aimed to characterize longitudinal changes in WM FW and investigate factors contributing to its elevation in CSVD. We included 80 CSVD patients and 40 normal controls (NCs) with multi-modality MRI data. Cerebral blood flow (CBF) was measured, and fiber alterations were assessed using total apparent fiber density (AFDt). FW were extracted from whole WM, white matter hyperintensities (WMH) and normal-appearing WM (NAWM). Baseline and longitudinal FW elevation were compared between patients and NCs, and between WMH and NAWM. We investigated whether baseline vascular risk factor score, CBF, and AFDt could predict longitudinal FW elevation. Association between cognition and WM FW in CSVD was also assessed. Results shown that FW was higher and increased faster in CSVD compared to NCs and in WMH compared to NAWM. Baseline AFDt predicted longitudinal FW elevation in CSVD patients, while CBF predicted FW changes only in controls. WM FW was associated with cognitive impairment. These findings suggest that CSVD is associated with a faster increase in WM FW. Hypoperfusion and WM fiber alterations might accelerate FW elevation, which is associated with cognitive decline.

Differentiating Glioma Recurrence and Pseudoprogression by APTw CEST MRI.

Recurrent glioma is highly treatment resistant due to its metabolic, cellular, and molecular heterogeneity and invasiveness. Tumor monitoring by conventional MRI has shortcomings to assess these key glioma characteristics. Recent studies introduced chemical exchange saturation transfer for metabolic imaging in oncology and assessed its diagnostic value for newly diagnosed glioma. This prospective study investigates amide proton transfer-weighted (APTw) MRI at 3 T as an imaging biomarker to elucidate the molecular heterogeneity and invasion patterns of recurrent glioma in comparison to pseudoprogression (PsPD). We performed a monocenter, prospective trial and screened 371 glioma patients who received tumor monitoring between August 2021 and March 2024 at our institution. The study included IDH wildtype astrocytoma and IDH mutant astrocytoma and oligodendroglioma, graded according to the WHO 2021 classification. Patients had received clinical standard of care treatment including surgical resection and radiochemotherapy prior to study inclusion. Patients were monitored by 3 monthly MRI follow-up imaging, and response assessment was performed according to the RANO criteria. Within this cohort, we identified 30 patients who presented with recurrent glioma and 12 patients with PsPD. In addition to standard anatomical sequences (FLAIR and T1-w Gd-enhanced sequences), MRI included APTw imaging. After sequence co-registration, semiautomated segmentation was performed of the FLAIR lesion, CE lesion, resection cavity, and the contralateral normal-appearing white matter, and APTw signals were quantified in these regions of interest. APTw values were highest in solid, Gd-enhancing tumor parts as compared with the nonenhancing FLAIR lesion (APTw: 1.99% vs 1.36%, P = 0.001), whereas there were no detectable APTw alterations in the normal-appearing white matter (APTw: 0.005%, P < 0.001 compared with FLAIR). Patients with progressive disease had higher APTw levels compared with patients with PsPD (APTw: 1.99% vs 1.26%, P = 0.008). Chemical exchange saturation transfer identified heterogeneity within the FLAIR lesion that was not detectable by conventional sequences. There were also focal APTw signal peaks within contrast enhancing lesions as putative metabolic hotspots within recurrent glioma. The resection cavity developed an APTw increase at recurrence that was not detectable prior to recurrence nor in patients with PsPD (APTw before recurrence: 0.6% vs 2.68% at recurrence, P = 0.03). Our study shows that APTw imaging can differentiate PD and PsPD. We identify previously undetectable imaging patterns during glioma recurrence, which include alterations within resection cavity associated with disease progression. Our work highlights the clinical potential of APTw imaging for glioma monitoring and further establishes it as an imaging biomarker in neuro-oncology.

Heterogeneity and Penumbra of White Matter Hyperintensities in Small Vessel Diseases Determined by Quantitative MRI.

White matter hyperintensities (WMHs) are established structural imaging markers of cerebral small vessel disease. The pathophysiologic condition of brain tissue varies over the core, the vicinity, and the subtypes of WMH and cannot be interpreted from conventional magnetic resonance imaging. We aim to improve our pathophysiologic understanding of WMHs and the adjacently injured normal-appearing white matter in terms of microstructural and microvascular alterations using quantitative magnetic resonance imaging in patients with sporadic and genetic cerebral small vessel disease. Structural T2-weighted imaging, multishell diffusion imaging, and dynamic contrast-enhanced magnetic resonance imaging were performed at 3T in 44 participants with sporadic cerebral small vessel disease and 32 participants with monogenic cerebral small vessel disease (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; 59±12 years, 41 males) between June 2017 and May 2020 as part of the prospective, multicenter (Edinburgh, the United Kingdom; Maastricht, the Netherlands; and Munich, Germany), observational INVESTIGATE-SVDs study (Imaging Neurovascular, Endothelial and Structural Integrity in Preparation to Treat Small Vessel Diseases). The mean diffusivity, free water content, and perfusion (all derived from multishell diffusion imaging), as well as the blood-brain barrier leakage and plasma volume fraction (derived from dynamic contrast-enhanced magnetic resonance imaging), were compared between deep and periventricular WMH types using paired t tests. Additional spatial analyses were performed inside and outside the WMH types to determine the internal heterogeneity and the extent of the penumbras, that is, adjacent white matter at risk for conversion to WMH. Periventricular WMH had higher mean diffusivity, higher free water content, and more plasma volume compared with deep WMH (P<0.001, P=0.01, and P<0.001, respectively). No differences were observed in perfusion (P=0.94) and blood-brain barrier leakage (P=0.65) between periventricular and deep WMHs. The spatial analyses inside WMH and the adjacent white matter revealed a gradual gradient in white matter microstructure, free water content, perfusion, and plasma volume but not in blood-brain barrier leakage. We showed different pathophysiological heterogeneity of the 2 WMH types. Periventricular WMHs display more severe damage and fluid accumulation compared with deep WMH, whereas deep WMHs reflect stronger hypoperfusion in the lesion's core. URL: https://www.isrctn.com; Unique identifier: ISRCTN10514229.

Regional cerebral blood flow reflects both neurodegeneration and microvascular integrity across the Alzheimer's continuum.

Alzheimer's disease (AD) typically involves both neurodegenerative and vascular pathologies, each associated with reductions in cerebral blood flow (CBF). However, it remains unclear whether vascular and neural contributions to regional CBF can be differentiated. Using 3D background-suppressed arterial spin labeled perfusion magnetic resonance imaging, we evaluated regional CBF in a cohort of 257 participants across the AD continuum and assessed the impact of risk factors for both AD and small vessel disease (SVD) on regional CBF. Vascular risk factors (VRFs) were associated with reduced CBF in normal-appearing periventricular white matter, while amyloid positivity was associated with reduced CBF in the posterior cingulate cortex and precuneus. Putative SVD-sensitive regions in white matter exhibited diagnosis-related CBF changes comparable to those in typical AD cortical regions. Spatial patterns of hypoperfusion may differentiate AD and VRF-related effects on regional CBF. Our findings also support the contribution of SVD in AD pathogenesis. We used 3D background-suppressed pCASL MRI to evaluate CBF across the AD continuum. Putative SVD-sensitive regions in white matter exhibited diagnosis-related CBF changes. AD and/or SVD risk correlated with reduced CBF in AD and/or SVD-related regions. VRFs were associated with more widespread CBF reductions than amyloid positivity. Spatial patterns of hypoperfusion may differentiate AD and VRF-related effects.

Assessment of hypoxia and its dynamic evolution in glioblastoma via qBOLD MRI: a comparative study with metformin treatment

BackgroundTo investigate the accuracy of quantitative blood oxygen level-dependent (qBOLD) magnetic resonance imaging (MRI) in identifying hypoxia within glioblastoma and explore dynamic changes in oxygenation status of glioblastoma with and without metformin administration.MethodsThree healthy and seven C6-bearing rats underwent 7-T qBOLD MRI. Oxygen extraction fraction (OEF) and cerebral metabolism rate of O2 (CMRO2) were calculated from qBOLD data. Tumor tissues were stained using hypoxia-inducible factor-1α (HIF-1α) and pimonidazole. The correlation between the hypoxia markers and corresponding qBOLD-based parameters was analyzed. Six C6-bearing rats were divided into metformin-treated and control groups for a longitudinal study of qBOLD imaging changes, with scans conducted on the 12th, 15th, and 18th day post-tumor implantation.ResultsIn healthy rats, gray matter showed higher values than white matter in T2, T2*, cerebral blood volume (CBV), and cerebral blood flow (CBF), whereas OEF was lower. Glioblastoma tissues exhibited elevated T2, T2*, CBV, and CBF but decreased OEF and CMRO2 relative to normal-appearing white matter. No significant correlation was found between staining scores from HIF-1α and pimonidazole. T2* and T2 values were negatively correlated with pimonidazole scores in tumor regions. As the tumor progressed, OEF values increased with intra-tissue variations, whereas CMRO2 decreased. Metformin delayed the reduction of T2 and T2* values, with significant differences in OEF and CMRO2 values compared to controls on day 18.ConclusionT2* and T2 values were significantly associated with the hypoxia status in glioma. Metformin could potentially mitigate the progression of hypoxia in glioblastoma, which can be tracked by qBOLD parameters.Relevance statementThis study demonstrates the potential of qBOLD parameters in assessing glioma dynamic oxygen metabolism and the efficacy of metformin as an anti-hypoxic agent, providing insights into improving glioblastoma treatment strategies.Key PointsThe study investigated qBOLD imaging’s accuracy in identifying hypoxia status within glioblastoma.qBOLD effectively assesses hypoxia and its dynamic evolution in glioblastoma.qBOLD parameters assist in identifying a suitable patient demographic for metformin treatment.Graphical

Free water is a sensitive predictor of future white matter lesions

AbstractBackgroundCerebrovascular disease features as the most common comorbidity in older individuals with dementia. White matter (WM) injury identified through white matter hyperintensities (WMH) on FLAIR represents evident late‐stage pathophysiological manifestations of CVD. This study aims to assess the role of baseline microstructural WM integrity, using free water (FW), a measure from diffusion tensor imaging (DTI), in predicting WMH growth dynamic.MethodsOur study includes 271 individuals (age: 76±7, 60% female) from the UCD ADRC longitudinal cohort who underwent an MRI exam at two different date (mean time±SD: 2.7±1.2 years). We tracked individual lesions between baseline and follow‐up. Briefly, for each participant, distinct WMH region were labeled on their baseline and follow‐up scans, coregistered into the FSL template space. All lesions were then placed into three categories: 1) baseline WMH that do not get larger over time were labeled stagnant WMH, 2) baseline WMH that grow larger over time were labeled growing WMH, and (3) WMH identified only on follow‐up scans were labeled noncontiguous incident WMH. DTI‐derived mean signal of Free Water (FW) was computed for each individual WMH region at baseline, as well as within the normal appearing WM (NAWM). Using a linear mixed‐effect model, we investigated differences in baseline FW according each WMH tissue category and NAWM. Analyses were adjusted for age and sex.ResultsAt baseline, FW signal was found to be lower within NAWM as compared with growing WMH (b=‐0.11, pvalue&lt; 0.001, see Figure 1) and stagnant WMH (b=‐0.13, pvalue&lt; 0.001), and also with incident WMH (b=‐0.096, pvalue&lt; 0.001) suggesting that WM tissue where incident WMH are to emerge over time is already injured as compared to normal WM. Baseline FW for stagnant WMH was significantly higher than for growing (b=0.027, pvalue&lt; 0.001) and incident WMH (b=0.038, pvalue&lt; 0.001). Baseline FW for incident WMH was not found to be significantly different from baseline FW in growing WMH (b=0.011, pvalue=0.078).ConclusionOur results suggest that local FW measures predict the future incidence as well as the growth dynamic of lesions over time and emphasize the sensitivity of FW as a biomarker of early CVD‐related WM injury.

Effects of Amyloid Pathology and Vascular Risk Factors on Regional Cerebral Blood Flow Patterns

AbstractBackgroundRegional cerebral blood flow (CBF) can be noninvasively quantified using arterial spin labeled (ASL) perfusion MRI. In Alzheimer’s disease (AD) and mild cognitive impairment (MCI), hypoperfusion typically occurs in precuneus, posterior cingulate cortex (PCC), and hippocampus. Small vessel disease (SVD), a systemic disorder that commonly underlies vascular cognitive impairment, also causes brain hypoperfusion. Many dementia patients demonstrate both neurodegenerative and vascular pathologies, which may interact to accelerate cognitive decline. Here we used advanced background‐suppressed 3D ASL to assess CBF variations across the AD spectrum and in relation to risk factors for AD and SVD.MethodData from 258 participants comprising 180 cognitively unimpaired (CU), 54 MCI, and 24 AD participants, diagnosed by clinical consensus, were obtained from the Penn Alzheimer Disease Research Center. ASL CBF was quantified in gray matter (GM), white matter (WM), AD‐associated cortical regions of PCC+precuneus and hippocampus. We also considered normal‐appearing WM (NA‐WM) and periventricular WM (NA‐PVWM) in which voxels containing T2 white matter hyperintensities were excluded. PVWM is supplied exclusively by microvessels and may be a sensitive region for CBF reductions in SVD despite its small size. Global and regional CBF was compared across diagnostic groups. Furthermore, the influence of PET‐derived amyloid status and vascular risk factors (VRF: presence of any of hypertension, diabetes, obesity, hypercholesteremia, and smoking) on CBF were also evaluated.ResultAcross the AD spectrum, CBF was lower in AD‐associated cortical regions. AD also exhibited reduced CBF in GM, WM, NA‐WM, and NA‐PVWM (Table 1). Voxel‐wise comparisons of CBF contrasting amyloid‐positive or VRF‐positive MCI with corresponding amyloid‐negative or VRF‐negative CU showed that VRF effects were more widely distributed in GM and WM than amyloid status effects (Figure 1). There was a trend of reduced regional CBF with VRF‐positivity in amyloid‐positive AD+MCI suggesting an additive effect of VRF with amyloid and diagnosis (Figure 2).ConclusionPutative SVD regions showed diagnosis‐related CBF changes comparable in magnitude to typical AD cortical regions that may reflect vascular effects. Vascular risk was associated with more spatially distributed CBF reductions than amyloid status and may reflect its additive effect with amyloid on cognitive decline.

Image quality assessment and white matter hyperintensity quantification in two accelerated high-resolution 3D FLAIR techniques: Wave-CAIPI and deep learning-based SPACE.

To compare the image quality obtained using two accelerated high-resolution 3D fluid-attenuated inversion recovery (FLAIR) techniques for the brain-deep learning-reconstruction SPACE (DL-SPACE) and Wave-CAIPI FLAIR. A total of 123 participants who underwent DL-SPACE and Wave-CAIPI FLAIR brain imaging were retrospectively reviewed. In a qualitative analysis, two radiologists rated the quality of each image, including the overall image quality, artifacts, sharpness, fine-structure conspicuity, and lesion conspicuity based on Likert scales. In a quantitative analysis, the signal-to-noise ratio (SNR) for the normal-appearing white matter (NAWM) and lesion and the contrast-to-noise ratio (CNR) for a lesion were calculated and compared. Moreover, the volumes of white matter hyperintensities (WMHs) obtained with the two techniques were automatically quantified and compared. The DL-SPACE FLAIR technique demonstrated a significantly higher fine-structure conspicuity (P < 0.001), lower degree of artifacts (P < 0.001)and higher overall image quality (P = 0.001). The mean SNR values were significantly higher with the DL-SPACE FLAIR technique (NAWM, 43.95 vs. 31.6; lesion, 31.35 vs. 21.28; all, P < 0.001). Additionally, the mean CNR of the WMH was significantly higher with the DL-SPACE FLAIR technique (11.34 vs. 8.22; P < 0.001). The periventricular and deep WMH volumes were significantly larger with the DL-SPACE FLAIR technique (1.91±4.69 vs. 1.54±4.18; P < 0.001 and 0.26±0.42 vs. 0.23±0.38; P = 0.002, respectively). The DL-SPACE FLAIR technique produced images with superior quality, SNRand CNR compared with the Wave-CAIPI FLAIR technique with the same acquisition time.