Centrum Semiovale Research Articles

Intravoxel incoherent motion magnetic resonance imaging in the assessment of brain microstructure and perfusion in idiopathic normal-pressure hydrocephalus.

To determine the relationship between intravoxel incoherent motion (IVIM) MRI parameters and clinical changes post-tap test (TT) in idiopathic normal-pressure hydrocephalus (iNPH) patients. Forty-four probable iNPH patients underwent 3T MRI before and after TT. IVIM parameters were calculated from eight different bilateral regions of interest in basal ganglia, centrum semiovale, and corona radiata. Patients were categorized based on TT response into positive (group 1) and negative (group 2) groups. A Welch two-sample t-test was used to compare differences in D, D*, f, and ADC between the two groups, while a paired t-test was employed to assess the changes within each group before and after TT. These parameters were then correlated with clinical results. In the lenticular and thalamic nuclei, D value was significantly lower in the group 1 compared to group 2 both pre- and post-TT (p = 0.002 and p = 0.007 respectively). Post-TT, the positive response group exhibited a notably reduced D* value (p = 0.012) and significantly higher f values (p = 0.028). In the corona radiata and centrum semiovale, a significant post-TT reduction in D* was observed in the positive response group (p = 0.017). Within groups, the positive response cohort showed a significant post-TT increase in ADC (p < 0.001) and a decrease in D* (p = 0.007). IVIM permits the acquisition of important non-invasive information about tissue and vascularization in iNPH patients. Enhanced perfusion in the lenticular and thalamic nuclei may suggest the role of re-established microvascular and glymphatic pathways, potentially elucidating the functional improvement in motor function after TT in iNPH patients.

Patients with normal pressure hydrocephalus have fewer enlarged perivascular spaces in the centrum semiovale compared to cognitively unimpaired individuals

IntroductionEnlarged perivascular spaces (ePVS) may be an indicator of glymphatic dysfunction. Limited studies have evaluated the role of ePVS in idiopathic normal pressure hydrocephalus (iNPH). We aimed to characterize the distribution and number of ePVS in iNPH compared to controls. MethodsThirty-eight patients with iNPH and a pre-shunt MRI were identified through clinical practice. Age- and sex-matched controls who had negative MRIs screening for intracranial metastases were identified through a medical record linkage system. The number of ePVS were counted in the basal nuclei (BN) and centrum semiovale (CS) using the Wardlaw method blinded to clinical diagnosis. Imaging features of disproportionately enlarged subarachnoid space hydrocephalus (DESH), callosal angle, Fazekas white matter hyperintensity (WMH) grade, and the presence of microbleeds and lacunes were also evaluated. ResultsBoth iNPH patients and controls had a mean age of 74 ± 7 years and were 34% female with equal distributions of hypertension, dyslipidemia, diabetes, stroke, and history of smoking. There were fewer ePVS in the CS of patients with iNPH compared to controls (12.66 vs. 20.39, p < 0.001) but the same in the BN (8.95 vs. 11.11, p = 0.08). This remained significant in models accounting for vascular risk factors (p = 0.002) and MRI features of DESH and WMH grade (p = 0.03). ConclusionsFewer centrum semiovale ePVS may be a biomarker for iNPH. This pattern may be caused by mechanical obstruction due to upward displacement of the brain leading to reduced glymphatic clearance.

MRI-visible enlarged perivascular spaces in basal ganglia rather than centrum semiovale was associated with aneurysmal subarachnoid hemorrhage.

The subarachnoid space is continuous with the perivascular compartment in the central nervous system. However, whether the topography and severity of enlarged perivascular spaces (EPVS) correlates with spontaneous subarachnoid hemorrhage (SAH) remains unknown. Based on the underlying arteriopathy distributions, we hypothesized that EPVS in basal ganglia (BG-EPVS) are more closely associated with aneurysmal subarachnoid hemorrhage (aSAH) than other SAH without aneurysm. Magnetic resonance imaging (MRI) scans of 271 consecutive SAH survivors with and without aneurysm were analyzed for EPVS and other markers of imaging data. In the subgroup analysis, we compared the clinical characteristics and EPVS of SAH participants with and without pre-existing known risk factors (hypertension, diabetes, and smoking history) using multivariable logistic regression. Patients with aSAH (n = 195) had a higher severity of BG-EPVS and centrum semiovale EPVS (CSO-EPVS) than those without aneurysm (n = 76). Importantly, BG-EPVS predominance pattern (BG-EPVS>CSO-EPVS) only existed in aSAH survivors rather than other SAH without aneurysm. In the subgroup analysis, interestingly, we also found that a high degree of BG-EPVS showed an independent relationship with aSAH in patients without pre-existing risk factors (e.g., hypertension). In this cohort study, BG-EPVS predominance pattern was associated with aSAH patients compared with those without aneurysm. Moreover, BG-EPVS still showed a strong association with aSAH survivors without pre-existing vascular risk factors. Our present study suggested the BG-EPVS as a potential MRI-visible characteristic would shed light on the pathogenesis of glymphatic function at the skull base for aSAH.

Quantitative comparison of CSVD imaging markers between patients with possible amyloid small vessel disease and with non-amyloid small vessel disease

The spatial distribution patterns of cerebral microbleeds are associated with different types of cerebral small vessel disease (CSVD). This study aims to examine the disparities in brain imaging markers of CSVD among patients diagnosed with possible amyloid and non-amyloid small vessel disease. The head MR scans including susceptibility-weighted imaging (SWI) sequences from 351 patients at our institute were collected for analysis. CSVD imaging markers were quantified or graded across various CSVD dimensions in the patient images. Patients were categorized into the cerebral amyloid angiopathy group (CAA), hypertensive arteriopathy group (HA), or mixed small vessel disease group (Mixed), based on the spatial distribution of microbleeds. White matter lesions (WML) were segmented using an artificial neural network and assessed via a voxel-wise approach. Significant differences were observed among the three groups in several indices: microbleed count, lacune count at the centrum semiovale and basal ganglia levels, grade of enlarged perivascular space (EPVS) at the basal ganglia, and white matter lesion volume. These indices were substantially higher in the Mixed group compared to the other groups. Additionally, the incidences of cerebral hemorrhages (χ2 = 7.659, P = 0.006) and recent small subcortical infarcts (χ2 = 4.660, P = 0.031) were significantly more frequent in the HA group than in the CAA group. These results indicate that mixed spatial distribution patterns of microbleeds demonstrated the highest burden of cerebral small vessel disease. Microbleeds located in the deep brain regions were associated with a higher incidence of recent small subcortical infarcts and cerebral hemorrhages compared to those in the cortical areas.

Deep-learning-based segmentation of perivascular spaces on T2-Weighted 3T magnetic resonance images.

Studying perivascular spaces (PVSs) is important for understanding the pathogenesis and pathological changes of neurological disorders. Although some methods for automated segmentation of PVSs have been proposed, most of them were based on 7T MR images that were majorly acquired in healthy young people. Notably, 7T MR imaging is rarely used in clinical practice. Herein, we propose a deep-learning-based method that enables automatic segmentation of PVSs on T2-weighted 3T MR images. Twenty patients with Parkinson's disease (age range, 42-79 years) participated in this study. Specifically, we introduced a multi-scale supervised dense nested attention network designed to segment the PVSs. This model fosters progressive interactions between high-level and low-level features. Simultaneously, it utilizes multi-scale foreground content for deep supervision, aiding in refining segmentation results at various levels. Our method achieved the best segmentation results compared with the four other deep-learning-based methods, achieving a dice similarity coefficient (DSC) of 0.702. The results of the visual count of the PVSs in our model correlated extremely well with the expert scoring results on the T2-weighted images (basal ganglia: rs = 0.845, P < 0.001; rs = 0.868, P < 0.001; centrum semiovale: rs = 0.845, P < 0.001; rs = 0.823, P < 0.001 for raters 1 and 2, respectively). Experimental results show that the proposed method performs well in the segmentation of PVSs. The proposed method can accurately segment PVSs; it will facilitate practical clinical applications and is expected to replace the method of visual counting directly on T1-weighted images or T2-weighted images.

Inferior Frontal Sulcal Hyperintensity on Fluid-Attenuated Inversion Recovery Is Related to Cerebrospinal Fluid Clearance via Putative Meningeal Lymphatics.

Inferior frontal sulcal hyperintensity (IFSH) on FLAIR sequence may indicate elevated cerebrospinal fluid (CSF) wastes. The objective of this study was to investigate its association with the clearance function of putative meningeal lymphatic vessels (mLVs). We included patients who underwent FLAIR sequence and dynamic contrast MRI with intrathecal administration of contrast agent. The visibility of IFSH was quantitatively assessed by measuring the mean signal intensity of inferior frontal sulci on 2D FLAIR. The clearance function of putative mLVs was defined as the percentage change of signal unite ratio in the parasagittal dura from baseline to 4.5, 15 and 39 hours after intrathecal injection on dynamic contrast MRI. Additionally, imaging markers of cerebral small vessel disease, including white matter hyperintensities and enlarged perivascular spaces, were measured. Correlation analysis and linear regression were employed to verify the association of IFSH with the clearance function of mLVs. A total of 76 patients were included in the study. The visibility of IFSH was found to be associated with the percentage change of signal unite ratio in parasagittal dura from baseline to 15 and 39 hours in adjusted analyses. Furthermore, the visibility of IFSH was positively related to the age, scores of both periventricular and deep white matter hyperintensities, and the grade of enlarged perivascular spaces in centrum semiovale. These findings suggest that the visibility of IFSH on 2D FLAIR may serve as an indicator of clearance dysfunction of mLVs and may be implicated in the development of cerebral small vessel disease.

Improving Vessel Visibility and Applying Artificial Intelligence to Autodetect Brain Metastasis for a 3D MR Imaging Sequence Capable of Simultaneous Images with and without Blood Vessel Suppression.

The purposes of this study were 1) to improve vessel visibility of our MR sequence by modifying k-space filling and 2) to verify the usefulness of applying artificial intelligence (AI) for volume isotropic simultaneous interleaved bright- and black-blood examination (VISIBLE) with compressed sensitivity encoding (CS) in autodetecting brain metastases. We modified 3 sequences of VISIBLE (Centric, Reversed Centric, and Startup Echo 30). The Centric sequence is a prototype. The Reversed Centric filled the k-space in a reversed centric manner to improve vessel visibility. The Startup Echo 30 implemented dummy echoes to further improve vessel visibility. Vessel visibility was evaluated in one slice at the level of the centrum semiovale. The sensitivity, specificity, the area under the curve (AUC), and false positives of detecting brain metastases using AI were evaluated among 3 sequences. Statistical comparisons were performed using a one-way analysis of variance, followed by Friedman and Dunn's multiple comparison tests. The number of visualized vessels was significantly lower in the Centric (39.3 ± 9.7, P < 0.05) and Reversed Centric (44.2 ± 9.8, P < 0.05) methods than in the magnetization-prepared rapid gradient echo (49.3 ± 9.1) but comparable in the Startup Echo 30 method (44.9 ± 8.8, P > 0.05). No significant differences existed in sensitivity, specificity, and AUC among the 3 methods. False positives achieved using the Reversed Centric method were significantly fewer (54 false positives) than those achieved using the Centric (85 false positives) and Startup Echo 30 (68 false positives) methods (P = 0.0092). Vessel visibility was improved by modifying the k-space filling, which may reduce false positives. The AI model for VISIBLE with CS achieved good performance in autodetection of brain metastases. The AI model for VISIBLE with CS can help radiologists diagnose brain metastases in clinical practice.

Associations of Lipoprotein(a) Level with Cerebral Small Vessel Disease in Patients with Alzheimer's Disease.

This study aimed to examine the association of lipoprotein(a) [Lp(a)] level with the burden of cerebral small vessel disease (CSVD) in patients with Alzheimer's disease (AD). Data from 111 consecutive patients with AD admitted to Nanjing First Hospital from 2015 to 2022 were retrospectively analyzed in this study. Serum Lp(a) concentrations were grouped into tertiles (T1-T3). Brain magnetic resonance imaging (MRI) was rated for the presence of CSVD, including enlarged perivascular spaces (EPVS), lacunes, white-matter lesions, and cerebral microbleeds (CMBs). The CSVD burden was calculated by summing the scores of each MRI marker at baseline. A binary or ordinal logistic regression model was used to estimate the relationship of serum Lp(a) levels with CSVD burden and each MRI marker. Patients with higher tertiles of Lp(a) levels were less likely to have any CSVD (T1, 94.6%; T2, 78.4%; T3, 66.2%; p = 0.013). Multivariable analysis found that Lp(a) levels were inversely associated with the presence of CSVD (T2 vs. T1: adjusted odds ratio [aOR] 0.132, 95% confidence interval [CI] 0.018-0.946, p = 0.044; T3 vs. T1: aOR 0.109, 95% CI 0.016-0.737, p = 0.023) and CSVD burden (T3 vs. T1: aOR 0.576, 95% CI 0.362-0.915, p = 0.019). The independent relationship between Lp(a) levels and individual CSVD features was significant for moderate-to-severe EPVS in the centrum semiovale (T2 vs. T1: aOR 0.059, 95% CI 0.006-0.542, p = 0.012; T3 vs. T1: aOR 0.029, 95% CI 0.003-0.273, p = 0.002) and CMBs (T3 vs. T1: aOR 0.144, 95% CI 0.029-0.716, p = 0.018). In this study, serum Lp(a) level was inversely associated with CSVD in AD patients.

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.

Influence of threshold selection and image sequence in in-vivo segmentation of enlarged perivascular spaces

BackgroundGrowing interest surrounds perivascular spaces (PVS) as a clinical biomarker of brain dysfunction given their association with cerebrovascular risk factors and disease. Neuroimaging techniques allowing quick and reliable quantification are being developed, but, in practice, they require optimisation as their limits of validity are usually unspecified. New methodWe evaluate modifications and alternatives to a state-of-the-art (SOTA) PVS segmentation method that uses a vesselness filter to enhance PVS discrimination, followed by thresholding of its response, applied to brain magnetic resonance images (MRI) from patients with sporadic small vessel disease acquired at 3 T. ResultsThe method is robust against inter-observer differences in threshold selection, but separate thresholds for each region of interest (i.e., basal ganglia, centrum semiovale, and midbrain) are required. Noise needs to be assessed prior to selecting these thresholds, as effect of noise and imaging artefacts can be mitigated with a careful optimisation of these thresholds. PVS segmentation from T1-weighted images alone, misses small PVS, therefore, underestimates PVS count, may overestimate individual PVS volume especially in the basal ganglia, and is susceptible to the inclusion of calcified vessels and mineral deposits. Visual analyses indicated the incomplete and fragmented detection of long and thin PVS as the primary cause of errors, with the Frangi filter coping better than the Jerman filter. Comparison with existing methodsLimits of validity to a SOTA PVS segmentation method applied to 3 T MRI with confounding pathology are given. ConclusionsEvidence presented reinforces the STRIVE-2 recommendation of using T2-weighted images for PVS assessment wherever possible. The Frangi filter is recommended for PVS segmentation from MRI, offering robust output against variations in threshold selection and pathology presentation.

Reduced GABA concentration in patients with white matter hyperintensities.

To investigate potential alterations of white matter hyperintensities (WMHs) on J-edited MR spectroscopy (MRS) measures of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA). Twenty-four WMHs patients and 20 healthy controls (HCs) were recruited to undergo magnetic resonance spectroscopy (MRS) scan at 3T from voxels in left centrum semiovale white matter, using the MEGA point resolved spectroscopy (MEGA-PRESS) technique with the MATLAB-based Gannet tool to estimate GABA+ co-edited macromolecule (GABA+) levels and using Tarquin software to estimate levels of glutamate + glutamine (Glx), total N-acetylaspartate (tNAA), total choline (tCho), and total creatine (tCr). Independent t-tests or Mann-Whitney U-tests were used to test group differences between WMHs and HCs. Additionally, WMHs patients were divided into mild and moderate-severe WMHs subgroup according to the Fazekas scale. Analysis of variance (ANOVA) and post-hoc tests were used among WMHs subgroups and HCs. We found there was a significant reduction in GABA+ levels (p = 0.018) in WMHs patients compared with healthy controls. In subgroup analyses, there was also a significant reduction of GABA+ levels in moderate-severe WMHs subgroup (p = 0.037) and mild WMHs subgroup (p = 0.047) when compared to HCs. Besides, the moderate-severe WMHs subgroup had significantly higher levels of tCho compared with healthy controls (p = 0.019). In conclusion, reduced GABA+ levels in WMHs patients and elevated tCho levels in moderate-severe WMHs were observed when compared with HCs. These results demonstrate that abnormalities of the GABAergic system and choline metabolism may contribute to the pathogenesis of WMHs.

Inflammatory and synaptic PET imaging in behavioural variant frontotemporal dementia caused by a repeat expansion in C9orf72 (C9orf72‐FTD)

AbstractBackgroundPathophysiological mechanisms associated with neurodegeneration include chronic neuroinflammation and synaptic dysfunction/loss. Radiotracer [11C]PBR28 is a marker of inflammation which binds to a translocator protein expressed by activated microglia. [11C]UCB‐J is a marker of synaptic density which binds to synaptic vesicle protein 2A. We evaluated both tracers as biomarkers of C9orf72‐FTD.MethodThree individuals with C9orf72‐FTD (mean age 62.7 years) underwent two PET scans between 3 and 13 months apart using [11C]PBR28 and [11C]UCB‐J. Dynamic PET data were acquired for 90 minutes following injection of each tracer. Arterial plasma input functions were generated from arterial blood samples. Participants also had volumetric MRI scans for each PET scan. Age‐matched controls from different cohorts underwent the same procedures (n = 5 for [11C]PBR28; n = 17 for [11C]UCB‐J).Regions of interest (ROIs) were defined on co‐registered T1‐weighted MR images using the CIC anatomical atlas. [11C]PBR28 BPND values were generated using a simplified reference tissue model with a cerebellar reference region. [11C]UCB‐J DVR‐1 values were generated using regional VT normalised to the VT in the centrum semiovale. ROI volumes were expressed as a percentage of total intracranial volume. W‐scores computed from each control cohort, using age and gender as covariates, illustrated the magnitude of differences between cases and controls. W‐scores &gt;1.65 were considered abnormal for [11C]PBR28 and ←1.65 for [11C]UCB‐J and MRI.Result[11C]PBR28 w‐scores indicated significant neuroinflammation in FTD but varied between cases. Differences in BPND were greater than in volume in frontal/temporal/cingulate cortices in the individual with the longest disease duration (DD) (16‐17 years). Inversely, in the individual with the shortest DD (1‐2 years), there were greater differences in volume than BPND in most ROIs.[11C]UCB‐J w‐scores indicated significant synaptic dysfunction/loss and were lower than w‐scores of volume in all cortical ROIs. In the individual with the longest DD, differences in [11C]PBR28 were greater than in [11C]UCB‐J in most ROIs. An inverse pattern again observed in the individual with the shortest DD suggests synaptic dysfunction/loss may precede significant neuroinflammation.ConclusionInflammatory and synaptic PET may provide more sensitive biomarkers of C9orf72‐FTD than MRI. Variability in PET signal within this genotype may be explained by DD.

APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.MethodIndependently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.ResultAfter accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.ConclusionThese findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.

Contributions of enlarged perivascular spaces and white matter hyperintensities to cognitive performance in the Alzheimer’s disease continuum – shared and unique effects

AbstractBackgroundIndependent contributions of enlarged perivascular spaces (ePVS) to cognition remain elusive due to their intertwining with white matter hyperintensities (WMH). We studied the unique and shared effects of ePVS and WMH on cognitive performance in 397 subjects along the Alzheimer’s disease (AD) continuum.MethodsWe quantified baseline volumes of WMH, basal ganglia (BG) and centrum semiovale (CSO) ePVS in participants of the multicentre DELCODE study (Controls = 81/Subjective Cognitive Decline = 151/Mild Cognitive Impairment = 79/AD = 45/AD relatives = 41) and regressed age, sex, pTau181, and image quality out of them.We established cognitive domain scores (memory, working memory, language, executive, visuospatial) based on a comprehensive cognitive test battery and confirmatory factor analysis, and assessed preclinical Alzheimer’s cognitive composite (PACC5) scores.Using principle component (PC) analysis, we estimated unique and shared variances. We began by extracting the first PC (PC1)—a weighted average of ePVS and WMH volumes—which indicated overall cerebrovascular dysfunction (Figure 1). We then regressed PC1 out of ePVS and WMH volumes to estimate their unique variances, which should reflect glymphatic function and white matter (WM) damage, respectively.For each cognitive domain, we compared null linear regression models (years of education, age, sex, pTau181, and image quality) to those enriched with the shared (PC1) and unique variances of BG‐/CSO‐ePVS and WMH.ResultsOverall cerebrovascular dysfunction—PC1—substantially affected all cognitive domains negatively.BG‐ePVS’ unique variance—surrogate for glymphatic function—contributed to better memory (B = 0.19, 95%‐CI[0.02;0.36]), language (B = 0.25, 95%‐CI[0.09;0.42]) and PACC5 performance (B = 0.25, 95%‐CI[0.07;0.43]) beyond overall cerebrovascular dysfunction. However, WM damage—WMH unique variance—contributed more substantially and negatively to the same cognitive domains (memory: R²PC1 = 0.365&lt;R²PC1+BG‐ePVS = 0.372&lt;R²PC1+WMH = 0.382; language: R²PC1 = 0.353&lt;R²PC1+BG‐ePVS = 0.366&lt;R²PC1+WMH = 0.370; PACC5: R²PC1 = 0.300&lt;R²PC1+BG‐ePVS = 0.313&lt;R²PC1+WMH = 0.324; Table 1), and moreover to executive (B = ‐0.10, 95%‐CI[‐0.18;‐0.02]) and visuospatial performance (B = ‐0.07, 95%‐CI[‐0.14;‐0.00]).CSO‐ePVS’ unique variance did not correlate with any cognitive domain.ConclusionsOverall cerebrovascular dysfunctions and WM damage—reflected by the shared variance between ePVS and WMH as well as the unique WMH variance—contributed distinctively to poorer cognitive performance. The contrasting positive impact of unique BG‐ePVS variance could represent a “glymphatic or vascular reserve” in a region important for different cognitive processes—this hypothesis, however, requires further investigation.

Baseline cerebrovascular reactivity predicts longitudinal enlarged perivascular space burden in the basal ganglia among cognitively normal older adults

AbstractBackgroundIncreasing evidence suggests that enlarged perivascular spaces (ePVS) on magnetic resonance images (MRIs) are associated with cognitive dysfunction in aging. However, the etiology of ePVS remains unknown. Here we tested the possibility that cerebrovascular dysfunction, as assessed by an MRI measure of cerebrovascular reactivity (CVR), may contribute to ePVS development.Method79 cognitively normal, older adults (46 women, age range 60‐84) were recruited to undergo baseline MRI scanning and follow‐up scanning approximately 2.5 years later. Of the 79 participants scanned at baseline, 50 returned for follow‐up. Participants were scanned on a 3T Siemens Prisma scanner with a 64‐channel head coil. All scanning methods were identical across time points and included collection of T1‐weighted, T2‐weighted FLAIR, and quantitative susceptibility mapping (QSM) images. Cerebrovascular dysfunction was assessed using CVR, a measure of the ability of cerebrovasculature to dilate in response to vasoactive stimuli. Participants underwent blocked administration of breathing either room air or hypercapnic gas, while blood‐oxygen‐level‐dependent (BOLD) functional magnetic resonance imaging (fMRI) was performed. CVR values were computed for baseline scans in specific regions by dividing change in BOLD signal by change in end‐tidal CO2. Baseline and follow‐up ePVS counts were performed by a single rater who was blinded to participant demographics. ePVS were individually and manually counted using STRIVE criteria in a representative, axial slice of the basal ganglia (BGePVS) and centrum semiovale (CSePVS).ResultBGePVS and CSePVS significantly increased during the follow‐up period. Mixed effects models indicated that baseline basal ganglia CVR values significantly predicted increased BGePVS counts after controlling for age, sex, education, and time point (p = &lt;0.001). Furthermore, this effect was present bilaterally: Baseline CVR in the left hemisphere predicted increased BGePVS in the left hemisphere (p = &lt;0.001) and baseline CVR in the right hemisphere predicted increased BGePVS in the right hemisphere (p = &lt;0.001). Conversely, there was no longitudinal relationship between baseline CVR and increased CSePVS (p = 0.449).ConclusionThese results demonstrate that low baseline CVR is a risk factor for later development of ePVS. Localization of these findings to the basal ganglia suggests that it is particularly vulnerable to cerebrovascular dysfunction.

APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.MethodIndependently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.ResultAfter accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.ConclusionThese findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.

The Neuropathological Correlates of White Matter Hyperintensities in Cerebral Amyloid Angiopathy

AbstractBackgroundCerebral amyloid angiopathy (CAA) is a common cause of intracerebral hemorrhage and cognitive impairment in older individuals. Hallmark manifestations of CAA on MRI include cortical hemorrhages, as well as perivascular spaces (PVS) in the white matter centrum semiovale and white matter hyperintensities (WMH) in a subcortical multi‐spot pattern. We performed an ex vivo MRI‐neuropathological study to: 1) determine the relationship between WMH volume and CAA severity, and 2) assess the histopathological substrate of confluent WMH, WMH in a multi‐spot pattern (WM_MS), and normal‐appearing white matter (NAWM).MethodNineteen autopsy cases with pathologically confirmed CAA (age 75±8y; 7F) and five non‐CAA controls (age 88±5y; 3F) were included. Formalin‐fixed hemispheres underwent 3T MRI, including a T2‐weighted (500µm isotropic resolution, to obtain manual WMH segmentations) and a T2*‐weighted sequence (1mm isotropic resolution, to automatically segment hemisphere volume using SynthSeg). After scanning, five pre‐defined standard areas were sampled from each brain, then processed to obtain manually assessed arteriolosclerosis scores and AI‐derived cortical and leptomeningeal CAA area measurements. In the CAA cases, specific areas with ex vivo MRI‐observed WM_MS (n = 7), confluent WMH (n = 9), and NAWM (n = 9) were sampled. Sections were stained with LH&amp;E (to determine WM rarefaction, % PVS area, and degree of arteriolosclerosis), and CD68 (a marker of activated microglia, to assess density of CD68‐positive cells).ResultTotal normalized WMH volume did not differ between CAA cases (0.037±0.024) and non‐CAA controls (0.027±0.026) (Mann‐Whitney U test 36, p = 0.31). Within the CAA cases, a multivariable regression model corrected for age at death revealed that normalized WMH volume was associated with cortical CAA area (p = 0.010) and arteriolosclerosis (p = 0.066), but not leptomeningeal CAA area (p = 0.94). Targeted neuropathological assessment revealed that WM rarefaction, arteriolosclerosis score, and density of CD68‐positive cells were higher in areas with WMH compared to WM_MS and NAWM. In contrast, % PVS area was higher in WM_MS compared to WMH and NAWM.ConclusionThe observed differences in neuropathological correlates between WMH in a multi‐spot pattern and confluent WMH in CAA suggest different pathophysiological mechanisms. Future studies are needed to determine these mechanisms as well as the causal relationship between cortical CAA severity and WMH burden.

Effects of enlarged perivascular space in Parkinson’s disease and related cognitive decline

AbstractBackgroundThe glymphatic system plays a key role in brain toxics clearance. Many studies demonstrated that disrupted glymphatic system is responsible for insufficient clearance of Aβ and tau protein in Alzheimer’s disease. Its contribution in Parkinson’s disease (PD) and related cognitive function decline has not been fully studied. Enlarged perivascular space (PVS) may be a sign of glymphatic function decline, hence leading to PD pathology and PD‐related cognitive function decline. Our objective was to study the PVS in PD and related cognitive function decline.MethodHigh‐resolution T1‐weighted and T2‐weighted MRI data were acquired from 60 PD patients and 58 age‐ and sex‐matched controls. The PVS from the centrum semiovale of the white matter (CS), striatum (ST) and midbrain (MB) of the basal ganglia were segmented using the enhanced images from T1‐ and T2‐weighted images. Total intracranial volumes (TIV) were obtained to account for individual head sizes. Montreal Assessment of Cognition (MoCA) was used to quantify cognitive function. MDS‐UPDRS III scores were obtained for motor function deficits. ANCOVA was used to compare PVS metrics between PD patients and controls adjusted for age, sex, and TIV. Multiple regression was used to corelate PVS metrics and MoCA in PD patients with age, sex, MDS‐UPDRS III score and TIV as covariates.ResultCompared to controls, PD patients had enlarged PVS in MB (p = 0.0028), but not in CS and ST. PVS metrics were strongly associated with age (p &lt; 0.0001 for CS, p &lt; 0.0001 for ST, and p = 0.0092 for MB), but only PVS in MB was associated sex (p = 0.0001). In PD patients, the MoCA was associated with the PVS in CS (p = 0.0132), MB (p = 0.0275) and total PVS (p = 0.0088) but only trending with PVS in ST (p = 0.0737). There is no association between MoCA and PVS metrics in controls.ConclusionOur findings suggested that PD patients have enlarged PVS in the midbrain, and their cognitive function is associated with enlarged PVS in both CS and MB. The enlarged PVS might be an etiological factor for PD pathology and related cognitive decline.

Diffusion-weighted Imaging Detection of Acute Ischemia Brain Lesions in Spontaneous Intracerebral Hemorrhage Associated with White Matter Hyperintensities, Enlarged Perivascular Spaces and Diabetes Mellitus.

Diffusion-weighted imaging (DWI) is commonly detected after spontaneous intracerebral hemorrhage (sICH) and is associated with poor functional outcomes. However, the etiology and significance of DWI lesions remain unclear. Thus, our study aimed to explore the prevalence and risk factors of acute ischemic lesions in sICH and discussed the possible mechanisms. We conducted a retrospective review of a consecutive cohort of 408 patients from June 2013 to October 2019 with sICH, who had brain computed tomography (CT) and magnetic resonance imaging (MRI) within 14 days of symptoms onset. Acute ischemic lesions were assessed on MRI using DWI lesions. We compared the clinical and imaging characteristics of patients with and without DWI lesions. The data were analyzed by univariate and multivariate logistic regression. Among the enrolled 408 patients, the mean age was 56.8 ± 14.5 years, 68 (16.7%) of them had been diagnosed with diabetes mellitus (DM). DWI lesions were observed in 89 (21.8%) patients, and most of them had a history of lacunar infarctions, which were located in cortical or subcortical. In multivariate logistic regression analysis, DM (odds ratio (OR) 3.962, p <0.001), severe deep white matter hypertensities (DWMH) (OR 2.463, p =0.001) and severe centrum semiovale enlarged perivascular spaces (CSO-EPVS) (OR 2.679, p =0.001) were independently associated with the presence of DWI lesions. In our cohort, we found DM, severe DWMH and severe CSO-EPVS were the independent risk factors in sICH patients with DWI lesions.

A 63-Year-Old Man with Neurofibromatosis Type 1 and Intracerebral Astrocytoma: A Case Report

Background: Neurofibromatosis type 1 (NF-1) is one of the hereditary neurocutaneous disorders. Neurofibromatosis type 1 has broad clinical manifestations that can occur in the skin, bones, eyes, and nervous system. In progressive cases, NF-1 can malign and cause intracerebral tumor lesions. Astrocytoma, especially pilocytic astrocytoma, is one of the tumor classes that patients with NF-1 can develop with far-reaching disease progression. This case report presents a case of NF-1 with intracerebral astrocytoma.&#x0D; Case presentation: A 63-year-old man with whole body lumps since childhood presented with weakness in the right limbs 1 month ago. 3 months earlier, the patient also had a full-body seizure for 1 minute twice. The patient then underwent a magnetic resonance imaging (MRI) examination of the brain and found a mass in the left centrum semiovale, left corona radiata, left insular, left external capsule, and left frontotemporoparietal lobe with a size of 7.2 x 5.3 x 6.2 cm. The patient then underwent a VP shunt followed by tumor resection. The tumor was successfully evacuated, and histopathological examination with hematoxylin &amp; eosin (HE) staining revealed glioblastoma multiformis. The patient also underwent histopathologic examination with Ki-67 immunohistochemistry (IHC) staining and showed pilocytic astrocytoma.&#x0D; Conclusion: Craniotomy of tumor excision is the definitive therapy in neurofibromatosis patients accompanied by intracerebral astrocytoma.