Brain structure and connectivity mediate the association between lifestyle and cognition: The Maastricht Study.

Life-course exposure to risk and protective factors impacts brain macro- and micro-structure, which in turn affects cognition. The concept of brain-age gap assesses brain health by comparing an individual's neuroimaging-based predicted age with their calendar age. A higher BAG implies accelerated brain ageing and is expected to be associated with worse cognition. In this study, we comprehensively modelled mutual associations between brain health and lifestyle factors, brain age and cognition in a large, middle-aged population. For this study, cognitive test scores, lifestyle and 3T MRI data for n = 4881 participants [mean age (± SD) = 59.2 (±8.6), 50.1% male] were available from The Maastricht Study, a population-based cohort study with extensive phenotyping. Whole-brain volumes (grey matter, cerebrospinal fluid and white matter hyperintensity), cerebral microbleeds and structural white matter connectivity were calculated. Lifestyle factors were combined into an adapted LIfestyle for BRAin health weighted sum score, with higher score indicating greater dementia risk. Cognition was calculated by averaging z-scores across three cognitive domains (memory, information processing speed and executive function and attention). Brain-age gap was calculated by comparing calendar age to predictions from a neuroimaging-based multivariable regression model. Paths between LIfestyle for BRAin health tertiles, brain-age gap and cognitive function were tested using linear regression and structural equation modelling, adjusting for sociodemographic and clinical confounders. The results show that cerebrospinal fluid, grey matter, white matter hyperintensity and cerebral microbleeds best predicted brain-age gap (R 2 = 0.455, root mean squared error = 6.44). In regression analysis, higher LIfestyle for BRAin health scores (greater dementia risk) were associated with higher brain-age gap (standardized regression coefficient ß = 0.126, P < 0.001) and worse cognition (ß = -0.046, P = 0.013), while higher brain-age gap was associated with worse cognition (ß=-0.163, P < 0.001). In mediation analysis, 24.7% of the total difference in cognition between the highest and lowest LIfestyle for BRAin health tertile was mediated by brain-age gap (ß indirect = -0.049, P < 0.001; ß total = -0.198, P < 0.001) and an additional 3.8% was mediated via connectivity (ß indirect = -0.006, P < 0.001; ß total = -0.150, P < 0.001). Findings suggest that associations between health- and lifestyle-based risk/protective factors (LIfestyle for BRAin health) and cognition can be partially explained by structural brain health markers (brain-age gap) and white matter connectivity markers. Lifestyle interventions targeted at high-risk individuals in mid-to-late life may be effective in promoting and preserving cognitive function in the general public.

The neurovascular unit and its correlation with cognitive performance in patients with cerebral small vessel disease: a canonical correlation analysis approach.

Growing evidence indicates an important role of neurovascular unit (NVU) dysfunction in the pathophysiology of cerebral small vessel disease (cSVD). Individually measurable functions of the NVU have been correlated with cognitive function, but a combined analysis is lacking. We aimed to perform a unified analysis of NVU function and its relation with cognitive performance. The relationship between NVU function in the white matter and cognitive performance (both latent variables composed of multiple measurable variables) was investigated in 73 patients with cSVD (mean age 70 ± 10 years, 41% women) using canonical correlation analysis. MRI-based NVU function measures included (1) the intravoxel incoherent motion derived perfusion volume fraction (f) and microvascular diffusivity (D*), reflecting cerebral microvascular flow; (2) the IVIM derived intermediate volume fraction (fint), indicative of the perivascular clearance system; and (3) the dynamic contrast-enhanced MRI derived blood-brain barrier (BBB) leakage rate (Ki) and leakage volume fraction (VL), reflecting BBB integrity. Cognitive performance was composed of 13 cognitive test scores. Canonical correlation analysis revealed a strong correlation between the latent variables NVU function and cognitive performance (r 0.73; p = 0.02). For the NVU, the dominating variables were D*, fint, and Ki. Cognitive performance was driven by multiple cognitive tests comprising different cognitive domains. The functionality of the NVU is correlated with cognitive performance in cSVD. Instead of focusing on individual pathophysiological mechanisms, future studies should target NVU dysfunction as a whole to acquire a coherent understanding of the complex disease mechanisms that occur in the NVU in cSVD.Trial registration: NTR3786 (Dutch Trial Register).

DeepFLAIR: A neural network approach to mitigate signal and contrast loss in temporal lobes at 7 Tesla FLAIR images.

BACKGROUND AND PURPOSE: Higher magnetic field strength introduces stronger magnetic field inhomogeneities in the brain, especially within temporal lobes, leading to image artifacts. Particularly, T2-weighted fluid-attenuated inversion recovery (FLAIR) images can be affected by these artifacts. Here, we aimed to improve the FLAIR image quality in temporal lobe regions through image processing of multiple contrast images via machine learning using a neural network. METHODS: Thirteen drug-resistant MR-negative epilepsy patients (age 29.2 ± 9.4y, 5 females) were scanned on a 7 T MRI scanner. Magnetization-prepared (MP2RAGE) and saturation-prepared with 2 rapid gradient echoes, multi-echo gradient echo with four echo times, and the FLAIR sequence were acquired. A voxel-wise neural network was trained on extratemporal-lobe voxels from the acquired structural scans to generate a new FLAIR-like image (i.e., deepFLAIR) with reduced temporal lobe inhomogeneities. The deepFLAIR was evaluated in temporal lobes through signal-to-noise (SNR), contrast-to-noise (CNR) ratio, the sharpness of the gray-white matter boundary and joint-histogram analysis. Saliency mapping demonstrated the importance of each input image per voxel. RESULTS: SNR and CNR in both gray and white matter were significantly increased (p < 0.05) in the deepFLAIR's temporal ROIs, compared to the FLAIR. The gray-white matter boundary sharpness was either preserved or improved in 10/13 right-sided temporal regions and was found significantly increased in the ROIs. Multiple image contrasts were influential for the deepFLAIR reconstruction with the MP2RAGE second inversion image being the most important. CONCLUSIONS: The deepFLAIR network showed promise to restore the FLAIR signal and reduce contrast attenuation in temporal lobe areas. This may yield a valuable tool, especially when artifact-free FLAIR images are not available.

Intravoxel incoherent motion as a surrogate marker of perfused vascular density in rat brain.

Intravoxel incoherent motion (IVIM) MRI has emerged as a valuable technique for the assessment of tissue characteristics and perfusion. However, there is limited knowledge about the relationship between IVIM-derived measures and changes at the level of the vascular network. In this study, we investigated the potential use of IVIM MRI as a noninvasive tool for measuring changes in cerebral vascular density. Variations in quantitative immunohistochemical measurements of the vascular density across different regions in the rat brain (cortex, corpus callosum, hippocampus, thalamus, and hypothalamus) were related to the pseudo-diffusion coefficient D* and the flowing blood fraction f in healthy Wistar rats. We assessed whether region-wise differences in the vascular density are reflected by variations in the IVIM measurements and found a significant positive relationship with the pseudo-diffusion coefficient (p < 0.05, ß = 0.24). The effect of cerebrovascular alterations, such as blood-brain barrier (BBB) disruption on the perfusion-related IVIM parameters, is not well understood. Therefore, we investigated the effect of BBB disruption on the IVIM measures in a rat model of metabolic and vascular comorbidities (ZSF1 obese rat) and assessed whether this affects the relationship between the cerebral vascular density and the noninvasive IVIM measurements. We observed increased vascular permeability without detecting any differences in diffusivity, suggesting that BBB leakage is present before changes in the tissue integrity. We observed no significant difference in the relationship between cerebral vascular density and the IVIM measurements in our model of comorbidities compared with healthy normotensive rats.

Microvascular Dysfunction and Whole-Brain White Matter Connectivity: The Maastricht Study.

BACKGROUND: Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole-brain white matter connectivity. METHODS AND RESULTS: Cross-sectional data from The Maastricht Study, a Dutch population-based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light-induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (ß per SD, 0.066 [95% CI, 0.017-0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures. CONCLUSIONS: These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole-brain white matter connectivity.

How subjective CT image quality assessment becomes surprisingly reliable: pairwise comparisons instead of Likert scale.

OBJECTIVES: The aim of this study is to improve the reliability of subjective IQ assessment using a pairwise comparison (PC) method instead of a Likert scale method in abdominal CT scans. METHODS: Abdominal CT scans (single-center) were retrospectively selected between September 2019 and February 2020 in a prior study. Sample variance in IQ was obtained by adding artificial noise using dedicated reconstruction software, including reconstructions with filtered backprojection and varying iterative reconstruction strengths. Two datasets (each n = 50) were composed with either higher or lower IQ variation with the 25 original scans being part of both datasets. Using in-house developed software, six observers (five radiologists, one resident) rated both datasets via both the PC method (forcing observers to choose preferred scans out of pairs of scans resulting in a ranking) and a 5-point Likert scale. The PC method was optimized using a sorting algorithm to minimize necessary comparisons. The inter- and intraobserver agreements were assessed for both methods with the intraclass correlation coefficient (ICC). RESULTS: Twenty-five patients (mean age 61 years ± 15.5; 56% men) were evaluated. The ICC for interobserver agreement for the high-variation dataset increased from 0.665 (95%CI 0.396-0.814) to 0.785 (95%CI 0.676-0.867) when the PC method was used instead of a Likert scale. For the low-variation dataset, the ICC increased from 0.276 (95%CI 0.034-0.500) to 0.562 (95%CI 0.337-0.729). Intraobserver agreement increased for four out of six observers. CONCLUSION: The PC method is more reliable for subjective IQ assessment indicated by improved inter- and intraobserver agreement. CLINICAL RELEVANCE STATEMENT: This study shows that the pairwise comparison method is a more reliable method for subjective image quality assessment. Improved reliability is of key importance for optimization studies, validation of automatic image quality assessment algorithms, and training of AI algorithms. KEY POINTS: • Subjective assessment of diagnostic image quality via Likert scale has limited reliability. • A pairwise comparison method improves the inter- and intraobserver agreement. • The pairwise comparison method is more reliable for CT optimization studies.

Effect of Magnetic Resonance Image Quality on Structural and Functional Brain Connectivity: The Maastricht Study.

In population-based cohort studies, magnetic resonance imaging (MRI) is vital for examining brain structure and function. Advanced MRI techniques, such as diffusion-weighted MRI (dMRI) and resting-state functional MRI (rs-fMRI), provide insights into brain connectivity. However, biases in MRI data acquisition and processing can impact brain connectivity measures and their associations with demographic and clinical variables. This study, conducted with 5110 participants from The Maastricht Study, explored the relationship between brain connectivity and various image quality metrics (e.g., signal-to-noise ratio, head motion, and atlas-template mismatches) that were obtained from dMRI and rs-fMRI scans. Results revealed that in particular increased head motion (R2 up to 0.169, p < 0.001) and reduced signal-to-noise ratio (R2 up to 0.013, p < 0.001) negatively impacted structural and functional brain connectivity, respectively. These image quality metrics significantly affected associations of overall brain connectivity with age (up to -59%), sex (up to -25%), and body mass index (BMI) (up to +14%). Associations with diabetes status, educational level, history of cardiovascular disease, and white matter hyperintensities were generally less affected. This emphasizes the potential confounding effects of image quality in large population-based neuroimaging studies on brain connectivity and underscores the importance of accounting for it.

Cerebral Microvascular Perfusion Assessed in Elderly Adults by Spin-Echo Dynamic Susceptibility Contrast MRI at 7 Tesla.

Perfusion measures of the total vasculature are commonly derived with gradient-echo (GE) dynamic susceptibility contrast (DSC) MR images, which are acquired during the early passes of a contrast agent. Alternatively, spin-echo (SE) DSC can be used to achieve specific sensitivity to the capillary signal. For an improved contrast-to-noise ratio, ultra-high-field MRI makes this technique more appealing to study cerebral microvascular physiology. Therefore, this study assessed the applicability of SE-DSC MRI at 7 T. Forty-one elderly adults underwent 7 T MRI using a multi-slice SE-EPI DSC sequence. The cerebral blood volume (CBV) and cerebral blood flow (CBF) were determined in the cortical grey matter (CGM) and white matter (WM) and compared to values from the literature. The relation of CBV and CBF with age and sex was investigated. Higher CBV and CBF values were found in CGM compared to WM, whereby the CGM-to-WM ratios depended on the amount of largest vessels excluded from the analysis. CBF was negatively associated with age in the CGM, while no significant association was found with CBV. Both CBV and CBF were higher in women compared to men in both CGM and WM. The current study verifies the possibility of quantifying cerebral microvascular perfusion with SE-DSC MRI at 7 T.

Lower cerebral blood flow predicts cognitive decline in patients with vascular cognitive impairment.

INTRODUCTION: Chronic cerebral hypoperfusion is one of the assumed pathophysiological mechanisms underlying vascular cognitive impairment (VCI). We investigated the association between baseline cerebral blood flow (CBF) and cognitive decline after 2 years in patients with VCI and reference participants. METHODS: One hundred eighty-one participants (mean age 66.3 ± 7.4 years, 43.6% women) underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) and neuropsychological assessment at baseline and at 2-year follow-up. We determined the association between baseline global and lobar CBF and cognitive decline with multivariable regression analysis. RESULTS: Lower global CBF at baseline was associated with more global cognitive decline in VCI and reference participants. This association was most profound in the domain of attention/psychomotor speed. Lower temporal and frontal CBF at baseline were associated with more cognitive decline in memory. DISCUSSION: Our study supports the role of hypoperfusion in the pathophysiological and clinical progression of VCI. HIGHLIGHTS: Impaired cerebral blood flow (CBF) at baseline is associated with faster cognitive decline in VCI and normal aging. Our results suggest that low CBF precedes and contributes to the development of vascular cognitive impairment. CBF determined by ASL might be used as a biomarker to monitor disease progression or treatment responses in VCI.

Association of hippocampal subfield volumes with prevalence, course and incidence of depressive symptoms: The Maastricht Study.

BACKGROUND: Late-life depression has been associated with volume changes of the hippocampus. However, little is known about its association with specific hippocampal subfields over time. AIMS: We investigated whether hippocampal subfield volumes were associated with prevalence, course and incidence of depressive symptoms. METHOD: We extracted 12 hippocampal subfield volumes per hemisphere with FreeSurfer v6.0 using T1-weighted and fluid-attenuated inversion recovery 3T magnetic resonance images. Depressive symptoms were assessed at baseline and annually over 7 years of follow-up (9-item Patient Health Questionnaire). We used negative binominal, logistic, and Cox regression analyses, corrected for multiple comparisons, and adjusted for demographic, cardiovascular and lifestyle factors. RESULTS: A total of n = 4174 participants were included (mean age 60.0 years, s.d. = 8.6, 51.8% female). Larger right hippocampal fissure volume was associated with prevalent depressive symptoms (odds ratio (OR) = 1.26, 95% CI 1.08-1.48). Larger bilateral hippocampal fissure (OR = 1.37-1.40, 95% CI 1.14-1.71), larger right molecular layer (OR = 1.51, 95% CI 1.14-2.00) and smaller right cornu ammonis (CA)3 volumes (OR = 0.61, 95% CI 0.48-0.79) were associated with prevalent depressive symptoms with a chronic course. No associations of hippocampal subfield volumes with incident depressive symptoms were found. Yet, lower left hippocampal amygdala transition area (HATA) volume was associated with incident depressive symptoms with chronic course (hazard ratio = 0.70, 95% CI 0.55-0.89). CONCLUSIONS: Differences in hippocampal fissure, molecular layer and CA volumes might co-occur or follow the onset of depressive symptoms, in particular with a chronic course. Smaller HATA was associated with an increased risk of incident (chronic) depression. Our results could capture a biological foundation for the development of chronic depressive symptoms, and stresses the need to discriminate subtypes of depression to unravel its biological underpinnings.

Blood-Brain Barrier Disruption and Perivascular Spaces in Small Vessel Disease and Neurodegenerative Diseases: A Review on MRI Methods and Insights.

Perivascular spaces (PVS) and blood-brain barrier (BBB) disruption are two key features of cerebral small vessel disease (cSVD) and neurodegenerative diseases that have been linked to cognitive impairment and are involved in the cerebral waste clearance system. Magnetic resonance imaging (MRI) offers the possibility to study these pathophysiological processes noninvasively in vivo. This educational review provides an overview of the MRI techniques used to assess PVS functionality and BBB disruption. MRI-visible PVS can be scored on structural images by either (subjectively) counting or (automatically) delineating the PVS. We highlight emerging (diffusion) techniques to measure proxies of perivascular fluid and its movement, which may provide a more comprehensive understanding of the role of PVS in diseases. For the measurement of BBB disruption, we explain the most commonly used MRI technique, dynamic contrast-enhanced (DCE) MRI, as well as a more recently developed technique based on arterial spin labeling (ASL). DCE MRI and ASL are thought to measure complementary characteristics of the BBB. Furthermore, we describe clinical studies that have utilized these MRI techniques in cSVD and neurodegenerative diseases, particularly Alzheimer's disease (AD). These studies demonstrate the role of PVS and BBB dysfunction in these diseases and provide insight into the large overlap, but also into the differences between cSVD and AD. Overall, MRI techniques may provide valuable insights into the pathophysiological mechanisms underlying these diseases and have the potential to be used as markers for disease progression and treatment response. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Thinner inner retinal layers are associated with lower cognitive performance, lower brain volume, and altered white matter network structure-The Maastricht Study.

INTRODUCTION: The retina may provide non-invasive, scalable biomarkers for monitoring cerebral neurodegeneration. METHODS: We used cross-sectional data from The Maastricht study (n = 3436; mean age 59.3 years; 48% men; and 21% with type 2 diabetes [the latter oversampled by design]). We evaluated associations of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses with cognitive performance and magnetic resonance imaging indices (global grey and white matter volume, hippocampal volume, whole brain node degree, global efficiency, clustering coefficient, and local efficiency). RESULTS: After adjustment, lower thicknesses of most inner retinal layers were significantly associated with worse cognitive performance, lower grey and white matter volume, lower hippocampal volume, and worse brain white matter network structure assessed from lower whole brain node degree, lower global efficiency, higher clustering coefficient, and higher local efficiency. DISCUSSION: The retina may provide biomarkers that are informative of cerebral neurodegenerative changes in the pathobiology of dementia.

Peripheral Pain Captured Centrally: Altered Brain Morphology on MRI in Small Fiber Neuropathy Patients With and Without an SCN9A Gene Variant.

The current study aims to characterize brain morphology of pain as reported by small fiber neuropathy (SFN) patients with or without a gain-of-function variant involving the SCN9A gene and compare these with findings in healthy controls without pain. The Neuropathic Pain Scale was used in patients with idiopathic SFN (N = 20) and SCN9A-associated SFN (N = 12) to capture pain phenotype. T1-weighted, structural magnetic resonance imaging (MRI) data were collected in patients and healthy controls (N = 21) to 1) compare cortical thickness and subcortical volumes and 2) quantify the association between severity, quality, and duration of pain with morphological properties. SCN9A-associated SFN patients showed significant (P < .017, Bonferroni corrected) higher cortical thickness in sensorimotor regions, compared to idiopathic SFN patients, while lower cortical thickness was found in more functionally diverse regions (eg, posterior cingulate cortex). SFN patient groups combined demonstrated a significant (Spearman's ρ = .44-.55, P = .005-.049) correlation among itch sensations (Neuropathic Pain Scale-7) and thickness of the left precentral gyrus, and midcingulate cortices. Significant associations were found between thalamic volumes and duration of pain (left: ρ = -.37, P = .043; right: ρ = -.40, P = .025). No associations were found between morphological properties and other pain qualities. In conclusion, in SCN9A-associated SFN, profound morphological alterations anchored within the pain matrix are present. The association between itch sensations of pain and sensorimotor and midcingulate structures provides a novel basis for further examining neurobiological underpinnings of itch in SFN. PERSPECTIVE: Cortical thickness and subcortical volume alterations in SFN patients were found in pain hubs, more profound in SCN9A-associated neuropathy, and correlated with itch and durations of pain. These findings contribute to our understanding of the pathophysiological pathways underlying chronic neuropathic pain and symptoms of itch in SFN.

The added value of risk assessment and subsequent targeted treatment for epileptic seizures after stroke: An early-HTA analysis.

INTRODUCTION: The development of post-stroke epilepsy (PSE) is related to a worse clinical outcome in stroke patients. Adding a biomarker to the clinical diagnostic process for the prediction of PSE may help to establish targeted and personalized treatment for high-risk patients, which could lead to improved patient outcomes. We assessed the added value of a risk assessment and subsequent targeted treatment by conducting an early Health Technology Assessment. METHODS: Interviews were conducted with four relevant stakeholders in the field of PSE to obtain a realistic view of the current healthcare and their opinions on the potential value of a PSE risk assessment and subsequent targeted treatment. The consequences on quality of life and costs of current care of a hypothetical care pathway with perfect risk assessment were modeled based on information from a literature review and the input from the stakeholders. Subsequently, the maximum added value (the headroom) was calculated. Sensitivity analyses were performed to test the robustness of this result to variation in assumed input parameters, i.e. the accuracy of the risk assessment, the efficacy of anti-seizure medication (ASM), and the probability of patients expected to develop PSE. RESULTS: All stakeholders considered the addition of a predictive biomarker for the risk assessment of PSE to be of value. The headroom amounted to €12,983. The sensitivity analyses demonstrated that the headroom remained beneficial when varying the accuracy of the risk assessment, the ASM efficacy, and the number of patients expected to develop PSE. DISCUSSION: We showed that a risk assessment for PSE development is potentially valuable. This work demonstrates that it is worthwhile to undertake clinical studies to evaluate biomarkers for the prediction of patients at high risk for PSE and to assess the value of targeted prophylactic treatment.

Associations of an individual's need for cognition with structural brain damage and cognitive functioning/impairment: cross-sectional population-based study.

BACKGROUND: High cognitive activity possibly reduces the risk of cognitive decline and dementia. AIMS: To investigate associations between an individual's need to engage in cognitively stimulating activities (need for cognition, NFC) and structural brain damage and cognitive functioning in the Dutch general population with and without existing cognitive impairment. METHOD: Cross-sectional data were used from the population-based cohort of the Maastricht Study. NFC was measured using the Need For Cognition Scale. Cognitive functioning was tested in three domains: verbal memory, information processing speed, and executive functioning and attention. Values 1.5 s.d. below the mean were defined as cognitive impairment. Standardised volumes of white matter hyperintensities (WMH), cerebrospinal fluid (CSF) and presence of cerebral small vessel disease (CSVD) were derived from 3T magnetic resonance imaging. Multiple linear and binary logistic regression analyses were used adjusted for demographic, somatic and lifestyle factors. RESULTS: Participants (n = 4209; mean age 59.06 years, s.d. = 8.58; 50.1% women) with higher NFC scores had higher overall cognition scores (B = 0.21, 95% CI 0.17-0.26, P < 0.001) and lower odds for CSVD (OR = 0.74, 95% CI 0.60-0.91, P = 0.005) and cognitive impairment (OR = 0.60, 95% CI 0.48-0.76, P < 0.001) after adjustment for demographic, somatic and lifestyle factors. The association between NFC score and cognitive functioning was similar for individuals with and without prevalent cognitive impairment. We found no significant association between NFC and WMH or CSF volumes. CONCLUSIONS: A high need to engage in cognitively stimulating activities is associated with better cognitive functioning and less presence of CSVD and cognitive impairment. This suggests that, in middle-aged individuals, motivation to engage in cognitively stimulating activities may be an opportunity to improve brain health.

Exploring the core network of the structural covariance network in childhood absence epilepsy.

Childhood absence epilepsy (CAE) is a generalized pediatric epilepsy, which is generally considered to be a benign condition since most children become seizure-free before reaching adulthood. However, cognitive deficits and changes of brain morphological have been previously reported in CAE. These morphological changes, even if they might be very subtle, are not independent due to the underlying network structure and can be captured by the structural covariance network (SCN). In this study, SCNs were used to quantify the structural brain network for children with CAE as well as controls. Seventeen children with CAE (6-12y) and fifteen controls (6-12y) were included. To estimate the SCN, T1-weighted images were acquired and parcellated into 68 cortical regions. Graph measures characterizing the core network architecture, i.e. the assortativity and rich-club coefficient, were calculated for all individuals. Multivariable linear regression models, including age and sex as covariates, were used to assess differences between children with CAE and controls. Additionally, potential relations between the core network and cognitive performance was investigated. A lower assortativity (i.e. less efficiently organized core network organization) was found for children with CAE compared to controls. Moreover, better cognitive performance was found to relate to stronger assortative mixing pattern (i.e. more efficient core network structure). Rich-club coefficients did not differ between groups, nor relate to cognitions. The core network organization of the SCN in children with CAE tend to be less efficient organized compared to controls, and relates to cognitive performance, and therefore this study provides novel insights into the SCN organization in relation to CAE and cognition.

Imaging Interstitial Fluid With MRI: A Narrative Review on the Associations of Altered Interstitial Fluid With Vascular and Neurodegenerative Abnormalities.

Interstitial fluid (ISF) refers to the fluid between the parenchymal cells and along the perivascular spaces (PVS). ISF plays a crucial role in delivering nutrients and clearing waste products from the brain. This narrative review focuses on the use of MRI techniques to measure various ISF characteristics in humans. The complementary value of contrast-enhanced and noncontrast-enhanced techniques is highlighted. While contrast-enhanced MRI methods allow measurement of ISF transport and flow, they lack quantitative assessment of ISF properties. Noninvasive MRI techniques, including multi-b-value diffusion imaging, free-water-imaging, T2 -decay imaging, and DTI along the PVS, offer promising alternatives to derive ISF measures, such as ISF volume and diffusivity. The emerging role of these MRI techniques in investigating ISF alterations in neurodegenerative diseases (eg, Alzheimer's disease and Parkinson's disease) and cerebrovascular diseases (eg, cerebral small vessel disease and stroke) is discussed. This review also emphasizes current challenges of ISF imaging, such as the microscopic scale at which ISF has to be measured, and discusses potential focus points for future research to overcome these challenges, for example, the use of high-resolution imaging techniques. Noninvasive MRI methods for measuring ISF characteristics hold significant potential and may have a high clinical impact in understanding the pathophysiology of neurodegenerative and cerebrovascular disorders, as well as in evaluating the efficacy of ISF-targeted therapies in clinical trials. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

The dependence of cerebral interstitial fluid on diffusion-sensitizing directions: A multi-b-value diffusion MRI study in a memory clinic sample.

Three-component intravoxel incoherent motion (3C-IVIM) imaging with spectral analysis provides a proxy for interstitial fluid (ISF) (e.g., in perivascular spaces (PVS), granting a potential marker for altered cerebral clearance. When 3C-IVIM images are acquired with three orthogonal diffusion-sensitizing directions, these are often averaged into the Trace image. This may result in loss of valuable direction-specific information, particularly in PVS-rich regions (basal ganglia (BG) and centrum semiovale (CSO)). This study assessed the dependence of individual diffusion-sensitizing directions to the ISF fraction in PVS-rich regions. Additionally, we explored the value of diffusion direction-specific information on ISF characteristics in distinguishing thirty-one patients with cognitive impairment (CI) (Alzheimer's disease (n = 15) or Mild Cognitive Impairment (n = 16)) from thirty cognitively healthy elderly controls (CON). Multi-b-value diffusion-weighted images were acquired in three orthogonal directions (L-R (left-right), A-P (anterior-posterior) and S-I (superior-inferior)) at 3 T. Voxel-based spectral analysis using non-negative least squares was conducted to independently analyze the L-R, A-P, S-I, and Trace images. 3C-IVIM measures were first compared between diffusion-sensitizing directions and the Trace within the BG using repeated measures ANOVA. Subsequently, the 3C-IVIM measures were compared per direction between the CI and CSO group in the BG and CSO with multivariable linear regression. Our results show that the ISF fraction significantly differs between all diffusion-sensitizing directions and Trace in the BG, with the highest ISF fraction detected using S-I. Solely using S-I, a higher ISF fraction was identified in CI compared to CON in the BG (p = .020) and CSO (p = .046). Thereby, this study found that the measured ISF fraction depends on the acquired diffusion-sensitizing direction, where S-I is most sensitive to detect ISF and differences between CI and CON. The Trace approach is not always sensitive enough to ISF characteristics. Solely acquiring S-I may offer an alternative to reduce scanning time.

Comparing the efficacy of data-driven denoising methods for a multi-echo fMRI acquisition at 7T.

In functional magnetic resonance imaging (fMRI) of the brain the measured signal is corrupted by several (e.g. physiological, motion, and thermal) noise sources and depends on the image acquisition. Imaging at ultrahigh field strength is becoming increasingly popular as it offers increased spatial accuracy. The latter is of particular benefit in brainstem neuroimaging given the small cross-sectional area of most nuclei. However, physiological noise scales with field strength in fMRI acquisitions. Although this problem is in part solved by decreasing voxel size, it is clear that adequate physiological denoising is of utmost importance in brainstem-focused fMRI experiments. Multi-echo sequences have been reported to facilitate highly effective denoising through TE-dependence of Blood Oxygen Level Dependent (BOLD) signals, in a denoising method referred to as multi-echo independent component analysis (ME-ICA). It has not been explored previously how ME-ICA compares to other data-driven denoising approaches at ultrahigh field strength. In the current study, we compared the efficacy of several denoising methods, including anatomical component based correction (aCompCor), Automatic Removal of Motion Artifacts (ICA-AROMA) aggressive and non-aggressive options, ME-ICA, and a combination of ME-ICA and aCompCor. We assessed several data quality metrics, including temporal signal-to-noise ratio (tSNR), delta variation signal (DVARS), spectral density of the global signal, functional connectivity and Shannon spectral entropy. Moreover, we looked at the ability of each method to uncouple the global signal and respiration. In line with previous reports at lower field strengths, we demonstrate that after applying ME-ICA, the data is best post-processed in order to remove spatially diffuse noise with a method such as aCompCor. Our findings indicate that ME-ICA combined with aCompCor and the aggressive option of ICA-AROMA are highly effective denoising approaches for multi-echo data acquired at 7T. ME-ICA combined with aCompCor potentially preserves more signal-of-interest as compared to the aggressive option of ICA-AROMA.

Plasma ceramides relate to mild cognitive impairment in middle-aged men: The Maastricht Study.

Introduction: There is an urgent need for biomarkers identifying individuals at risk of early-stage cognitive impairment. Using cross-sectional data from The Maastricht Study, this study included 197 individuals with mild cognitive impairment (MCI) and 200 cognitively unimpaired individuals aged 40 to 75, matched by age, sex, and educational level. Methods: We assessed the association of plasma sphingolipid and ceramide transfer protein (CERT) levels with MCI and adjusted for potentially confounding risk factors. Furthermore, the relationship of plasma sphingolipids and CERTs with magnetic resonance imaging brain volumes was assessed and age- and sex-stratified analyses were performed. Results: Associations of plasma ceramide species C18:0 and C24:1 and combined plasma ceramide chain lengths (ceramide risk score) with MCI were moderated by sex, but not by age, and higher levels were associated with MCI in men. No associations were found among women. In addition, higher levels of ceramide C20:0, C22:0, and C24:1, but not the ceramide risk score, were associated with larger volume of the hippocampus after controlling for covariates, independent of MCI. Although higher plasma ceramide C18:0 was related to higher plasma CERT levels, no association of CERT levels was found with MCI or brain volumes. Discussion: Our results warrant further analysis of plasma ceramides as potential markers for MCI in middle-aged men. In contrast to previous studies, no associations of plasma sphingolipids with MCI or brain volumes were found in women, independent of age. These results highlight the importance of accounting for sex- and age-related factors when examining sphingolipid and CERT metabolism related to cognitive function.