Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Perivascular Spaces, Diffusivity Along Perivascular Spaces, and Free Water in Cerebral Small Vessel Disease.

BACKGROUND AND OBJECTIVES: Previous studies have linked the MRI measures of perivascular spaces (PVSs), diffusivity along the perivascular spaces (DTI-ALPS), and free water (FW) to cerebral small vessel disease (SVD) and SVD-related cognitive impairments. However, studies on the longitudinal associations between the three MRI measures, SVD progression, and cognitive decline are lacking. This study aimed to explore how PVS, DTI-ALPS, and FW contribute to SVD progression and cognitive decline. METHODS: This is a cohort study that included participants with SVD who underwent neuroimaging and cognitive assessment, specifically measuring Mini-Mental State Examination (MMSE), cognitive index, and processing speed, at 2 time points. Three MRI measures were quantified: PVS in basal ganglia (BG-PVS) volumes, FW fraction, and DTI-ALPS. We performed a latent change score model to test inter-relations between the 3 MRI measures and linear regression mixed models to test their longitudinal associations with the changes of other SVD MRI markers and cognitive performances. RESULTS: In baseline assessment, we included 289 participants with SVD, characterized by a median age of 67.0 years and 42.9% women. Of which, 220 participants underwent the follow-up assessment, with a median follow-up time of 3.4 years. Baseline DTI-ALPS was associated with changes in BG-PVS volumes (ß = -0.09, p = 0.030), but not vice versa (ß = -0.08, p = 0.110). Baseline BG-PVS volumes were associated with changes in white matter hyperintensity (WMH) volumes (ß = 0.33, p-corrected < 0.001) and lacune numbers (ß = 0.28, p-corrected < 0.001); FW fraction was associated with changes in WMH volumes (ß = 0.30, p-corrected < 0.001), lacune numbers (ß = 0.28, p-corrected < 0.001), and brain volumes (ß = -0.45, p-corrected < 0.001); DTI-ALPS was associated with changes in WMH volumes (ß = -0.20, p-corrected = 0.002) and brain volumes (ß = 0.23, p-corrected < 0.001). Furthermore, baseline FW fraction was associated with decline in MMSE score (ß = -0.17, p-corrected = 0.006); baseline FW fraction and DTI-ALPS were associated with changes in cognitive index (FW fraction: ß = -0.25, p-corrected < 0.001; DTI-ALPS: ß = 0.20, p-corrected = 0.001) and processing speed over time (FW fraction: ß = -0.29, p-corrected < 0.001; DTI-ALPS: ß = 0.21, p-corrected < 0.001). DISCUSSION: Our results showed that increased BG-PVS volumes, increased FW fraction, and decreased DTI-ALPS are related to progression of MRI markers of SVD, along with SVD-related cognitive decline over time. These findings may suggest that the glymphatic dysfunction is related to SVD progression, but further studies are needed.

Single-shot frequency offset measurement with HASTE using the selective parity approach.

Measurements of frequency offset are commonly required in MRI. The standard method measures the signal phase as a function of evolution time. Here we use a single shot turbo-spin-echo acquisition method to measure frequency offset at a single evolution time. After excitation the transverse magnetisation evolves during the evolution time, and is then repeatedly refocused. The phase is conjugated between alternate echoes. Using partial parallel acquisition techniques we obtain separate odd- and even- echo images. An iterative procedure ensures self-consistency between them. The difference in phase between the two images yields frequency offset maps. The technique was implemented at 3 Tesla and tested on a healthy human volunteer for a range of evolution times between 6 and 42 ms. A standard method using a similar readout train and multiple evolution times was used as a gold-standard measure. In a statistical comparison with the gold standard no evidence for bias or offset was found. There was no systematic variation in precision or accuracy as a function of evolution time. We conclude that the presented approach represents a viable method for the rapid generation of frequency offset maps with a high image quality and minimal distortion.

Changes in postictal cerebral perfusion are related to the duration of electroconvulsive therapy-induced seizures.

OBJECTIVE: Postictal symptoms may result from cerebral hypoperfusion, which is possibly a consequence of seizure-induced vasoconstriction. Longer seizures have previously been shown to cause more severe postictal hypoperfusion in rats and epilepsy patients. We studied cerebral perfusion after generalized seizures elicited by electroconvulsive therapy (ECT) and its relation to seizure duration. METHODS: Patients with a major depressive episode who underwent ECT were included. During treatment, 21-channel continuous electroencephalogram (EEG) was recorded. Arterial spin labeling magnetic resonance imaging scans were acquired before the ECT course (baseline) and approximately 1 h after an ECT-induced seizure (postictal) to quantify global and regional gray matter cerebral blood flow (CBF). Seizure duration was assessed from the period of epileptiform discharges on the EEG. Healthy controls were scanned twice to assess test-retest variability. We performed hypothesis-driven Bayesian analyses to study the relation between global and regional perfusion changes and seizure duration. RESULTS: Twenty-four patients and 27 healthy controls were included. Changes in postictal global and regional CBF were correlated with seizure duration. In patients with longer seizure durations, global decrease in CBF reached values up to 28 mL/100 g/min. Regional reductions in CBF were most prominent in the inferior frontal gyrus, cingulate gyrus, and insula (up to 35 mL/100 g/min). In patients with shorter seizures, global and regional perfusion increased (up to 20 mL/100 g/min). These perfusion changes were larger than changes observed in healthy controls, with a maximum median global CBF increase of 12 mL/100 g/min and a maximum median global CBF decrease of 20 mL/100 g/min. SIGNIFICANCE: Seizure duration is a key factor determining postictal perfusion changes. In future studies, seizure duration needs to be considered as a confounding factor due to its opposite effect on postictal perfusion.

Structural Network Efficiency Predicts Conversion to Incident Parkinsonism in Patients With Cerebral Small Vessel Disease.

BACKGROUND: To investigate whether structural network disconnectivity is associated with parkinsonian signs and their progression, as well as with an increased risk of incident parkinsonism. METHODS: In a prospective cohort (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study) consisting of 293 participants with small vessel disease (SVD), we assessed parkinsonian signs and incident parkinsonism over an 8-year follow-up. In addition, we reconstructed the white matter network followed by graph-theoretical analyses to compute the network metrics. Conventional magnetic resonance imaging markers for SVD were assessed. RESULTS: We included 293 patients free of parkinsonism at baseline (2011), with a mean age 68.8 (standard deviation [SD] 8.4) years, and 130 (44.4%) were men. Nineteen participants (6.5%) developed parkinsonism during a median (SD) follow-up time of 8.3 years. Compared with participants without parkinsonism, those with all-cause parkinsonism had higher Unified Parkinson's Disease Rating scale (UPDRS) scores and lower global efficiency at baseline. Baseline global efficiency was associated with UPDRS motor scores in 2011 (ß = -0.047, p < .001) and 2015 (ß = -0.84, p < .001), as well as with the changes in UPDRS scores during the 4-year follow-up (ß = -0.63, p = .004). In addition, at the regional level, we identified an inter-hemispheric disconnected network associated with an increased UPDRS motor score. Besides, lower global efficiency was associated with an increased risk of all-cause and vascular parkinsonism independent of SVD markers. CONCLUSIONS: Our findings suggest that global network efficiency is associated with a gradual decline in motor performance, ultimately leading to incident parkinsonism in the elderly with SVD. Global network efficiency may have the added value to serve as a useful marker to capture changes in motor signs.

Regional cortical thinning, demyelination and iron loss in cerebral small vessel disease.

The link between white matter hyperintensities (WMH) and cortical thinning is thought to be an important pathway by which WMH contributes to cognitive deficits in cerebral small vessel disease (SVD). However, the mechanism behind this association and the underlying tissue composition abnormalities are unclear. The objective of this study is to determine the association between WMH and cortical thickness, and the in vivo tissue composition abnormalities in the WMH-connected cortical regions. In this cross-sectional study, we included 213 participants with SVD who underwent standardized protocol including multimodal neuroimaging scans and cognitive assessment (i.e. processing speed, executive function and memory). We identified the cortex connected to WMH using probabilistic tractography starting from the WMH and defined the WMH-connected regions at three connectivity levels (low, medium and high connectivity level). We calculated the cortical thickness, myelin and iron of the cortex based on T1-weighted, quantitative R1, R2* and susceptibility maps. We used diffusion-weighted imaging to estimate the mean diffusivity of the connecting white matter tracts. We found that cortical thickness, R1, R2* and susceptibility values in the WMH-connected regions were significantly lower than in the WMH-unconnected regions (all Pcorrected < 0.001). Linear regression analyses showed that higher mean diffusivity of the connecting white matter tracts were related to lower thickness (ß = -0.30, Pcorrected < 0.001), lower R1 (ß = -0.26, Pcorrected = 0.001), lower R2* (ß = -0.32, Pcorrected < 0.001) and lower susceptibility values (ß = -0.39, Pcorrected < 0.001) of WMH-connected cortical regions at high connectivity level. In addition, lower scores on processing speed were significantly related to lower cortical thickness (ß = 0.20, Pcorrected = 0.030), lower R1 values (ß = 0.20, Pcorrected = 0.006), lower R2* values (ß = 0.29, Pcorrected = 0.006) and lower susceptibility values (ß = 0.19, Pcorrected = 0.024) of the WMH-connected regions at high connectivity level, independent of WMH volumes and the cortical measures of WMH-unconnected regions. Together, our study demonstrated that the microstructural integrity of white matter tracts passing through WMH is related to the regional cortical abnormalities as measured by thickness, R1, R2* and susceptibility values in the connected cortical regions. These findings are indicative of cortical thinning, demyelination and iron loss in the cortex, which is most likely through the disruption of the connecting white matter tracts and may contribute to processing speed impairment in SVD, a key clinical feature of SVD. These findings may have implications for finding intervention targets for the treatment of cognitive impairment in SVD by preventing secondary degeneration.

Network structure-function coupling and neurocognition in cerebral small vessel disease.

BACKGROUND: Cerebral small vessel disease is a leading cause of cognitive decline and vascular dementia. Small vessel disease pathology changes structural brain networks, but its impact on functional networks remains poorly understood. Structural and functional networks are closely coupled in healthy individuals, and decoupling is associated with clinical symptoms in other neurological conditions. We tested the hypothesis that structural-functional network coupling is related to neurocognitive outcomes in 262 small vessel disease patients. METHODS: Participants underwent multimodal magnetic resonance imaging and cognitive assessment in 2011 and 2015. Structural connectivity networks were reconstructed using probabilistic diffusion tractography, while functional connectivity networks were estimated from resting-state functional magnetic resonance imaging. Structural and functional networks were then correlated to calculate a measure of structural-functional network coupling for each participant. RESULTS: Lower whole-brain coupling was associated with reduced processing speed and greater apathy both cross-sectionally and longitudinally. In addition, coupling within the cognitive control network was associated with all cognitive outcomes, suggesting that neurocognitive outcomes in small vessel disease may be related to the functioning of this intrinsic connectivity network. CONCLUSIONS: Our work demonstrates the influence of structural-functional connectivity network decoupling in small vessel disease symptomatology. Cognitive control network function may be investigated in future studies.

A vision of 14 T MR for fundamental and clinical science.

OBJECTIVE: We outline our vision for a 14 Tesla MR system. This comprises a novel whole-body magnet design utilizing high temperature superconductor; a console and associated electronic equipment; an optimized radiofrequency coil setup for proton measurement in the brain, which also has a local shim capability; and a high-performance gradient set. RESEARCH FIELDS: The 14 Tesla system can be considered a 'mesocope': a device capable of measuring on biologically relevant scales. In neuroscience the increased spatial resolution will anatomically resolve all layers of the cortex, cerebellum, subcortical structures, and inner nuclei. Spectroscopic imaging will simultaneously measure excitatory and inhibitory activity, characterizing the excitation/inhibition balance of neural circuits. In medical research (including brain disorders) we will visualize fine-grained patterns of structural abnormalities and relate these changes to functional and molecular changes. The significantly increased spectral resolution will make it possible to detect (dynamic changes in) individual metabolites associated with pathological pathways including molecular interactions and dynamic disease processes. CONCLUSIONS: The 14 Tesla system will offer new perspectives in neuroscience and fundamental research. We anticipate that this initiative will usher in a new era of ultra-high-field MR.

Cerebral Small Vessel Disease Progression and the Risk of Dementia: A 14-Year Follow-Up Study.

OBJECTIVE: Cerebral small vessel disease (SVD) is considered the most important vascular contributor to cognitive decline and dementia, although a causal relation between its MRI markers and dementia still needs to be established. The authors investigated the relation between baseline SVD severity as well as SVD progression on MRI markers and incident dementia, by subtype, in individuals with sporadic SVD over a follow-up period of 14 years. METHODS: The study included 503 participants with sporadic SVD, and without dementia, from the prospective Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, with screening for baseline inclusion conducted in 2006. Follow-ups in 2011, 2015, and 2020 included cognitive assessments and MRI scans. Dementia was diagnosed according to DSM-5 criteria and stratified into Alzheimer's dementia and vascular dementia. RESULTS: Dementia as an endpoint was available for 498 participants (99.0%) and occurred in 108 participants (21.5%) (Alzheimer's dementia, N=38; vascular dementia, N=34; mixed-etiology Alzheimer's dementia/vascular dementia, N=26), with a median follow-up time of 13.2 years (interquartile range, 8.8-13.8). Higher baseline white matter hyperintensity (WMH) volume (hazard ratio=1.31 per 1-SD increase, 95% CI=1.02-1.67), presence of diffusion-weighted-imaging-positive lesions (hazard ratio=2.03, 95% CI=1.01-4.04), and higher peak width of skeletonized mean diffusivity (hazard ratio=1.24 per 1-SD increase, 95% CI=1.02-1.51) were independently associated with all-cause dementia and vascular dementia. WMH progression predicted incident all-cause dementia (hazard ratio=1.76 per 1-SD increase, 95% CI=1.18-2.63). CONCLUSIONS: Both baseline SVD severity and SVD progression were independently associated with an increase in risk of all-cause dementia over a follow-up of 14 years. The results suggest that SVD progression precedes dementia and may causally contribute to its development. Slowing SVD progression may delay dementia onset.

Dissociable Contributions of Thalamic-Subregions to Cognitive Impairment in Small Vessel Disease.

BACKGROUND: Structural network damage is a potentially important mechanism by which cerebral small vessel disease (SVD) can cause cognitive impairment. As a central hub of the structural network, the role of thalamus in SVD-related cognitive impairments remains unclear. We aimed to determine the associations between the structural alterations of thalamic subregions and cognitive impairments in SVD. METHODS: In this cross-sectional study, 205 SVD participants without thalamic lacunes from the third follow-up (2020) of the prospective RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort), which was initiated in 2006, Nijmegen, were included. Cognitive functions included processing speed, executive function, and memory. Probabilistic tractography was performed from thalamus to 6 cortical regions, followed by connectivity-based thalamic segmentation to assess each thalamic subregion volume and connectivity (measured by mean diffusivity [MD] of the connecting white matter tracts) with the cortex. Least absolute shrinkage and selection operator regression analysis was conducted to identify the volumes or connectivity of the total thalamus and 6 thalamic subregions that have the strongest association with cognitive performance. Linear regression and mediation analyses were performed to test the association of least absolute shrinkage and selection operator-selected thalamic subregion volume or MD with cognitive performance, while adjusting for age and education. RESULTS: We found that higher MD of the thalamic-motor tract was associated with worse processing speed (ß=-0.27; P<0.001), higher MD of the thalamic-frontal tract was associated with worse executive function (ß=-0.24; P=0.001), and memory (ß=-0.28; P<0.001), respectively. The mediation analysis showed that MD of thalamocortical tracts mediated the association between corresponding thalamic subregion volumes and the cognitive performances in 3 domains. CONCLUSIONS: Our results suggest that the structural alterations of thalamus are linked to cognitive impairment in SVD, largely depending on the damage pattern of the white matter tracts connecting specific thalamic subregions and cortical regions.

Cerebral Small Vessel Disease Progression Increases Risk of Incident Parkinsonism.

OBJECTIVE: Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross-sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow-up of 14 years. METHODS: This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow-up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed-effect models were constructed to estimate individual rate changes of MRI-characteristics. RESULTS: Follow-up for incident parkinsonism was near-complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR] = 1.46 per 1-SD increase, 95% confidence interval [CI] = 1.21-1.78), peak width of skeletonized mean diffusivity (HR = 1.66 per 1-SD increase, 95% CI = 1.34-2.05), and presence of lacunes (HR = 1.84, 95% CI = 0.99-3.42) were associated with increased risk of all-cause parkinsonism. Incident lacunes were associated with incident VaP (HR = 4.64, 95% CI = 1.32-16.32). INTERPRETATION: Both baseline SVD severity and SVD progression are independently associated with long-term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130-1141.

Combining arterial blood contrast with BOLD increases fMRI intracortical contrast.

BOLD fMRI is widely applied in human neuroscience but is limited in its spatial specificity due to a cortical-depth-dependent venous bias. This reduces its localization specificity with respect to neuronal responses, a disadvantage for neuroscientific research. Here, we modified a submillimeter BOLD protocol to selectively reduce venous and tissue signal and increase cerebral blood volume weighting through a pulsed saturation scheme (dubbed Arterial Blood Contrast) at 7 T. Adding Arterial Blood Contrast on top of the existing BOLD contrast modulated the intracortical contrast. Isolating the Arterial Blood Contrast showed a response free of pial-surface bias. The results suggest that Arterial Blood Contrast can modulate the typical fMRI spatial specificity, with important applications in in-vivo neuroscience.

Role of small acute hyperintense lesions in long-term progression of cerebral small vessel disease and clinical outcome: a 14-year follow-up study.

BACKGROUND: Small hyperintense lesions are found on diffusion-weighted imaging (DWI) in patients with sporadic small vessel disease (SVD). Their exact role in SVD progression remains unclear due to their asymptomatic and transient nature. The main objective is to investigate the role of DWI+lesions in the radiological progression of SVD and their relationship with clinical outcomes. METHODS: Participants with SVD were included from the Radboud University Nijmegen Diffusion tensor MRI Cohort. DWI+lesions were assessed on four time points over 14 years. Outcome measures included neuroimaging markers of SVD, cognitive performance and clinical outcomes, including stroke, all-cause dementia and all-cause mortality. Linear mixed-effect models and Cox regression models were used to examine the outcome measures in participants with a DWI+lesion (DWI+) and those without a DWI+lesion (DWI-). RESULTS: DWI+lesions were present in 45 out of 503 (8.9%) participants (mean age: 66.7 years (SD=8.3)). Participants with DWI+lesions and at least one follow-up (n=33) had higher white matter hyperintensity progression rates (ß=0.36, 95% CI=0.05 to 0.68, p=0.023), more incident lacunes (incidence rate ratio=2.88, 95% CI=1.80 to 4.67, p<0.001) and greater cognitive decline (ß=-0.03, 95% CI=-0.05 to -0.01, p=0.006) during a median follow-up of 13.2 (IQR: 8.8-13.8) years compared with DWI- participants. No differences were found in risk of all-cause mortality, stroke or dementia. CONCLUSION: Presence of a DWI+lesion in patients with SVD is associated with greater radiological progression of SVD and cognitive decline compared with patients without DWI+lesions.

Relating neural oscillations to laminar fMRI connectivity in visual cortex.

Laminar functional magnetic resonance imaging (fMRI) holds the potential to study connectivity at the laminar level in humans. Here we analyze simultaneously recorded electroencephalography (EEG) and high-resolution fMRI data to investigate how EEG power modulations, induced by a task with an attentional component, relate to changes in fMRI laminar connectivity between and within brain regions in visual cortex. Our results indicate that our task-induced decrease in beta power relates to an increase in deep-to-deep layer coupling between regions and to an increase in deep/middle-to-superficial layer connectivity within brain regions. The attention-related alpha power decrease predominantly relates to reduced connectivity between deep and superficial layers within brain regions, since, unlike beta power, alpha power was found to be positively correlated to connectivity. We observed no strong relation between laminar connectivity and gamma band oscillations. These results indicate that especially beta band, and to a lesser extent, alpha band oscillations relate to laminar-specific fMRI connectivity. The differential effects for alpha and beta bands indicate that they relate to different feedback-related neural processes that are differentially expressed in intra-region laminar fMRI-based connectivity.

A comparison of multiband and multiband multiecho gradient-echo EPI for task fMRI at 3 T.

A multiband (MB) echo-planar imaging (EPI) sequence is compared to a multiband multiecho (MBME) EPI protocol to investigate differences in sensitivity for task functional magnetic resonance imaging (fMRI) at 3 T. Multiecho sampling improves sensitivity in areas where single-echo-EPI suffers from dropouts. However, It requires in-plane acceleration to reduce the echo train length, limiting the slice acceleration factor and the temporal and spatial resolution Data were acquired for both protocols in two sessions 24 h apart using an adapted color-word interference Stroop task. Besides protocol comparison statistically, we performed test-retest reliability across sessions for different protocols and denoising methods. We evaluated the sensitivity of two different echo-combination strategies for MBME-EPI. We examined the performance of three different data denoising approaches: "Standard," "AROMA," and "FIX" for MB and MBME, and assessed whether a specific method is preferable. We consider using an appropriate autoregressive model order within the general linear model framework to correct TR differences between the protocols. The comparison between protocols and denoising methods showed at group level significantly higher mean z-scores and the number of active voxels for MBME in the motor, subcortical and medial frontal cortices. When comparing different echo combinations, our results suggest that a contrast-to-noise ratio weighted echo combination improves sensitivity in MBME compared to simple echo-summation. This study indicates that MBME can be a preferred protocol in task fMRI at spatial resolution (≥2 mm), primarily in medial prefrontal and subcortical areas.

Spatial Relation Between White Matter Hyperintensities and Incident Lacunes of Presumed Vascular Origin: A 14-Year Follow-Up Study.

BACKGROUND: The underlying mechanisms of incident lacunes regarding their spatial distribution remain largely unknown. We investigated the spatial distribution pattern and MRI predictors of incident lacunes in relation to white matter hyperintensity (WMH) over 14 years follow-up in sporadic small vessel disease. METHODS: Five hundred three participants from the ongoing prospective single-center Radboud University Nijmegen Diffusion Tensor and Magnetic resonance Cohort (RUN DMC) were recruited with baseline assessment in 2006 and follow ups in 2011, 2015, and 2020. Three hundred eighty-two participants who underwent at least 2 available brain MRI scans were included. Incident lacunes were systematically identified, and the spatial relationship between incident lacunes located in subcortical white matter and WMH were determined using a visual rating scale. Adjusted multiple logistic regression and linear mixed-effect regression models were used to assess the association between baseline small vessel disease markers, WMH progression, and incident lacunes. Participants with atrial fibrillation were excluded in multivariable analysis. RESULTS: Eighty incident lacunes were identified in 43 patients (mean age 66.5±8.2 years, 37.2% women) during a mean follow-up time of 11.2±3.3 years (incidence rate 10.0/1000 person-year). Sixty percent of incident lacunes were in the white matter, of which 48.9% showed no contact with preexisting WMH. Baseline WMH volume (odds ratio=2.5 [95% CI, 1.6-4.2]) predicted incident lacunes after adjustment for age, sex, and vascular risk factors. WMH progression was associated with incident lacunes independent of age, sex, baseline WMH volume, and vascular risk factors (odds ratio, 3.2 [95% CI, 1.5-6.9]). Baseline WMH volume and progression rate were higher in participants with incident lacunes in contact with preexisting WMH. No difference in vascular risk factors was observed regarding location or relation with preexisting WMH. CONCLUSIONS: The 2 different distribution patterns of lacunes regarding their relation to WMH may suggest distinct underlying mechanisms, one of which may be more closely linked to a similar pathophysiology as that of WMH. The longitudinal relation between WMH and lacunes further supports plausible shared mechanisms between the 2 key markers.

Determinants and Temporal Dynamics of Cerebral Small Vessel Disease: 14-Year Follow-Up.

BACKGROUND: The aim of this study is to investigate the temporal dynamics of small vessel disease (SVD) and the effect of vascular risk factors and baseline SVD burden on progression of SVD with 4 neuroimaging assessments over 14 years in patients with SVD. METHODS: Five hundred three patients with sporadic SVD (50-85 years) from the ongoing prospective cohort study (RUN DMC [Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort]) underwent baseline assessment in 2006 and follow-up in 2011, 2015, and 2020. Vascular risk factors and magnetic resonance imaging markers of SVD were evaluated. Linear mixed-effects model and negative binomial regression model were used to examine the determinants of temporal dynamics of SVD markers. RESULTS: A total of 382 SVD patients (mean [SD] 64.1 [8.4]; 219 men and 163 women) who underwent at least 2 serial brain magnetic resonance imaging scans were included, with mean (SD) follow-up of 11.15 (3.32) years. We found a highly variable temporal course of SVD. Mean (SD) WMH progression rate was 0.6 (0.74) mL/y (range, 0.02-4.73 mL/y) and 13.6% of patients had incident lacunes (1.03%/y) over the 14-year follow-up. About 4% showed net WMH regression over 14 years, whereas 38 out of 361 (10.5%), 5 out of 296 (2%), and 61 out of 231 (26%) patients showed WMH regression for the intervals 2006 to 2011, 2011 to 2015, and 2015 to 2020, respectively. Of these, 29 (76%), 5 (100%), and 57 (93%) showed overall progression across the 14-year follow-up, and the net overall WMH change between first and last scan considering all participants was a net average WMH progression over the 14-year period. Older age was a strong predictor for faster WMH progression and incident lacunes. Patients with mild baseline WMH rarely progressed to severe WMH. In addition, both baseline burden of SVD lesions and vascular risk factors independently and synergistically predicted WMH progression, whereas only baseline SVD burden predicted incident lacunes over the 14-year follow-up. CONCLUSIONS: SVD shows pronounced progression over time, but mild WMH rarely progresses to clinically severe WMH. WMH regression is noteworthy during some magnetic resonance imaging intervals, although it could be overall compensated by progression over the long follow-up.

Systematic validation of structural brain networks in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is considered a disconnection syndrome, which can be quantified using structural brain network analysis obtained from diffusion MRI. Network analysis is a demanding analysis approach and the added benefit over simpler diffusion MRI analysis is largely unexplored in SVD. In this pre-registered study, we assessed the clinical and technical validity of network analysis in two non-overlapping samples of SVD patients from the RUN DMC study (n = 52 for exploration and longitudinal analysis and n = 105 for validation). We compared two connectome pipelines utilizing single-shell or multi-shell diffusion MRI, while also systematically comparing different node and edge definitions. For clinical validation, we assessed the added benefit of network analysis in explaining processing speed and in detecting short-term disease progression. For technical validation, we determined test-retest repeatability.Our findings in clinical validation show that structural brain networks provide only a small added benefit over simpler global white matter diffusion metrics and do not capture short-term disease progression. Test-retest reliability was excellent for most brain networks. Our findings question the added value of brain network analysis in clinical applications in SVD and highlight the utility of simpler diffusion MRI based markers.