Centrum Semiovale Perivascular Spaces Research Articles

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.

Meta-analysis of the relationship between the number and location of perivascular spaces in the brain and cognitive function.

Cerebral perivascular spaces are part of the cerebral microvascular structure and play a role in lymphatic drainage and the removal of waste products from the brain. Relationships of the number and location of such spaces with cognition are unclear. To meta-analyze available data on potential associations of severity and location of perivascular spaces with cognitive performance. We searched PubMed, EMBASE, Web of Science and the Cochrane Central Registry of Controlled Trials for relevant studies published between January 2000 and July 2023. Performance on different cognitive domains was compared to the severity of perivascular spaces in different brain regions using comprehensive meta-analysis. When studies report unadjusted and adjusted means, we use adjusted means for meta-analysis.The study protocol is registered in the PROSPERO database (CRD42023443460). We meta-analyzed data from 26 cross-sectional studies and two longitudinal studies involving 7908 participants. In most studies perivascular spaces was using a visual rating scale. A higher number of basal ganglia perivascular spaces was linked to lower general intelligence and attention. Moreover, increased centrum semiovale perivascular spaces were associated with worse general intelligence, executive function, language, and memory. Conversely, higher hippocampus perivascular spaces were associated with enhanced memory and executive function. Subgroup analyses revealed variations in associations among different disease conditions. A higher quantity of perivascular spaces in the brain is correlated with impaired cognitive function. The location of these perivascular spaces and the underlying disease conditions may influence the specific cognitive domains that are affected. The study protocol has been registered in the PROSPERO database (CRD42023443460).

Abstract WMP14: Cerebrospinal Fluid Beta-Amyloid Concentration and MRI Manifestations of Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with reduced cerebrospinal fluid (CSF) levels of the beta-amyloid (Aβ) 40- and 42-amino acid species, thought to reflect the burden of vascular Aβ deposition in the brain. Little is known regarding the association of CSF Aβ reduction with specific MRI manifestations of CAA. Methods: We identified 31 patients with CAA per Boston criteria v2.0 (1 definite, 27 probable, and 3 possible), who underwent CSF sampling for measurement of Aβ42, total tau (t-tau), and phospho-tau (p-tau) as part of their evaluation with ADmark (Athena Diagnostics). We assessed the following MRI manifestations of CAA while blinded to CSF biomarkers: the presence of cortical superficial siderosis (cSS), number of lobar cerebral microbleeds (CMBs), pattern and severity of white matter hyperintensities (WMH), and number of enlarged perivascular spaces in centrum semiovale (CSO-EPVS). Results: Median age of presentation was 69 years (range 56-89). Out of 31 patients, 19 were female (61.3%), 20 (64.5%) presented with cognitive impairment, 9 (29%) with intracerebral hemorrhage, and 2 (6.5%) with transient focal neurologic events. Mean (±SD) CSF Aβ42 concentration in our cohort was 359.3±126.7 pg/ml, substantially reduced relative to that reported in healthy controls. MRI manifestations associated with reduced Aβ42 without altered tau were presence of cSS (310±136 vs. 406±101, p=0.03) and higher burden of CSO-EPVS (307±101 vs. 431±127, p=0.005). Patients presented with cognitive impairment had higher tau levels (t-tau: 551±320 vs. 317±141, p=0.03; p-tau: 75.7±39.8 vs. 49.2±22.4, p=0.05) without altered Aβ42. Similar results were obtained when patients with possible CAA were excluded. Discussion: Our results suggest that presence of cSS and higher burden of CSO-EPVS are associated with lower Aβ42 concentration in CSF, potentially reflecting higher overall burden of vascular Aβ deposition in the brain. We found that higher tau concentrations in CSF are associated with cognitive impairment, presumably reflecting concomitant Alzheimer’s disease pathology. These results help inform interpretation of this clinically accessible test in practice and suggest potential mechanisms for specific CAA-related pathologies.

Association of MRI Visible Perivascular Spaces and Neurofilament Light Chain: The Framingham Heart Study.

Neurofilament light chain (NfL) is a marker of neuronal injury. Perivascular spaces (PVS) visible on magnetic resonance imaging (MRI) represent cerebral small vessel disease (CSVD) but their role as markers of neuronal injury needs further clarification. To relate PVS burden according to brain topography and plasma NfL. Framingham Heart Study (FHS) participants with brain MRI and NfL measurements were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) using validated methods and categorized based on counts. A mixed region variable representing high burden PVS in either BG or CSO was assessed. Multivariable linear regression analyses were used to relate PVS burden to log-transformed NfL levels in models adjusted for age, sex, FHS cohort, time between MRI and clinic exam, and image view (model 1), vascular risk factors (model 2), and white matter hyperintensity volume, covert brain infarcts, and cerebral microbleeds (model 3). Among 1,457 participants (68.1±8.5 years, 45% males), NfL levels increased with higher PVS burden. Multivariable analysis showed an association of high PVS burden strictly in BG with NfL (β= 0.117, 95% CI 0.014-0.221; p = 0.027), but attenuated in model 3. The associations were mainly in participants≥65 years (β= 0.122, 95% CI 0.015-0.229, p = 0.026), women (β= 0.156, 95% CI 0.024-0.288, p = 0.021), and APOE ɛ4 non-carriers (β= 0.140, 95% CI 0.017-0.263, p = 0.026). The association of strictly BG high PVS burden with NfL suggests a role for PVS as markers of neuroaxonal injury, but our results are hypothesis generating and require further replication.

Relation of MRI-Visible Perivascular Spaces and Other MRI Markers of Cerebral Small Vessel Disease.

Perivascular spaces (PVS) visible on brain MRI signal cerebral small vessel disease (CSVD). The coexistence of PVS with other CSVD manifestations likely increases the risk of adverse neurological outcomes. We related PVS to other CSVD manifestations and brain volumes that are markers of vascular brain injury and neurodegeneration. Framingham Heart Study (FHS) participants with CSVD ratings on brain MRI were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) into grades I-IV and a category reflecting high burden in single or mixed CSO-BG regions. We related PVS to covert brain infarcts (CBI), white matter hyperintensities (WMH), cerebral microbleeds (CMB), total brain, hippocampal, and cortical gray matter volumes using adjusted multivariable regression analyses. In 2454 participants (mean age 54 ± 12 years), we observed that higher PVS burden in both BG and CSO was related to CMB in lobar and deep brain regions and increased WMH. Greater CSO PVS burden was associated with decreased total cortical gray volumes. PVS are associated with ischemic markers of CSVD and neurodegeneration markers. Further studies should elucidate the causality between PVS and other CSVD manifestations.

Brain reserve is associated with cognition in AD and MCI patients with different vascualr risk factors status

AbstractBackgroundDementia due to Alzheimer’s disease (AD) is the major type of dementias in the world. In addition to amyloid plaques and neurofibrillary tangles, cerebrovascular disease is another important pathophysiological cause of AD. Cerebrovascular disease is highly associated with vascular risk factors (VRFs). Well‐treated VRFs might decrease the risk and progression of AD. However, findings on the impact of VRFs treatment status on cognitive decline after the diagnosis of AD established are unclear, and there is no direct evidence supporting well‐treated VRFs can slow down the AD progression.MethodThis study recruited mild cognitive impairment (MCI) and mild AD patients (CDR = 0.5 or 1) with at least one VRF from at Taichung Veteran General Hospital. The treatment status of the VRFs was identified and all participants were evaluated by a standard neuropsychological test battery. We collected the participants’ brain MRI done within one year and performed Apolipoprotein E genotyping. FreeSurfer was used for structural MRI reconstruction and calculated total gray matter volume, hippocampus volume, and AD signature cortical thickness. Cerebrovascular lesions, including perivascular spaces in centrum semiovale, basal ganglia and presence of lobar cerebral microbleeds (LCMBs), and the volume of white matter hyperintensities were estimated by visual rating scales and Lesion Segmentation Tool for Statistical Parametric Mapping. We analyzed the relationships among the treatment status of VRFs, neuropsychological tests, and brain MRI.ResultWe recruited 61 patients in this study. Four patients refused to keep involving the study, 6 patients were not compatible with the criteria of MCI and AD after neuropsychiatric testing, and 4 patients’ brain MRI images cannot be analyzed after quality checked. The remaining 47 patients (15 MCI patients and 32 AD patients) constituted the final sample for analysis. The patients with well‐controlled VRFs present with similar cognitive function compared to the patients with partially‐controlled VRFs even though the more severe hippocampal atrophy was noted in the patients with well controlled VRFs. The severity of white matter hyperintensities and other cerebrovascular lesions are not correlated with the cognitive function in MCI and AD patients.ConclusionBrain reserve in the AD and MCI patients with well‐controlled VRFs might contribute cognitive function

Associations of deep medullary veins with vascular risk factors, laboratory indicators, and cerebral small vessel disease: A population-based study.

Deep medullary veins (DMVs) were not considered a typical marker of cerebral small vessel disease (CSVD) due to limited understanding of their involvement in pathology of CSVD. This study aimsto investigate potential vascular risk factors for DMVs and their associations with CSVD. In total, 1909 community-dwelling participants were included in this analysis. Demographic, clinical, laboratory, and imaging data were collected. DMV scores (0-18) werecalculated as the sum of bilateral frontal, parietal, and occipital regional scores using a semiquantitative visual scale (0-3). The presence, total burden, and imaging markers of CSVD were assessed. Linear regression analyses were conducted to explore potential vascular factors for DMV scores. Binary and ordinal logistic regression analyses were performed to investigate the associations of DMV scores with CSVD and its markers. Mean age was 61.8(SD 6.5)years, and 1027 (53.8%) of participants were men. The median DMV scores were14 (IQR 12-16). DMV scores wererelated to age, male sex, body mass index, diastolic blood pressure, hypercholesterolaemia, atrial fibrillation, current drinking, total cholesterol, triglycerides, low-density lipoprotein, hemoglobin A1c, leukocytes, lymphocytes, hemoglobin, and platelets (p<.05). DMV scores wereassociated with the presence and total burden of CSVD (Rothwell's scale), modified white matter hyperintensity burden, and enlarged perivascular spaces in centrum semiovale (p<.05). However, these associations between DMV scoresand CSVD disappeared after adjusting for potential confounders. Several conventional vascular factors were associated with DMVs. The relationship between DMVs and CSVD was vulnerable, suggesting decreased visible and discontinuous DMVs may differ mechanistically from traditional markers of CSVD.

Sleep quality, perivascular spaces and brain health markers in ageing - A longitudinal study in the Lothian Birth Cohort 1936

BackgroundSleep is thought to play a major role in brain health and general wellbeing. However, few longitudinal studies have explored the relationship between sleep habits and imaging markers of brain health, particularly markers of brain waste clearance such as perivascular spaces (PVS), of neurodegeneration such as brain atrophy, and of vascular disease, such as white matter hyperintensities (WMH). We explore these associations using data collected over 6 years from a birth cohort of older community-dwelling adults in their 70s. MethodWe analysed brain MRI data from ages 73, 76 and 79 years, and self-reported sleep duration, sleep quality and vascular risk factors from community-dwelling participants in the Lothian Birth Cohort 1936 (LBC1936) study. We calculated sleep efficiency (at age 76), quantified PVS burden (at age 73), and WMH and brain volumes (age 73 to 79), calculated the white matter damage metric, and used structural equation modelling (SEM) to explore associations and potential causative pathways between indicators related to brain waste cleaning (i.e., sleep and PVS burden), brain and WMH volume changes during the 8th decade of life. ResultsLower sleep efficiency was associated with a reduction in normal-appearing white matter (NAWM) volume (β = 0.204, P = 0.009) from ages 73 to 79, but not concurrent volume (i.e. age 76). Increased daytime sleep correlated with less night-time sleep (r = −0.20, P < 0.001), and with increasing white matter damage metric (β = −0.122, P = 0.018) and faster WMH growth (β = 0.116, P = 0.026). Shorter night-time sleep duration was associated with steeper 6-year reduction of NAWM volumes (β = 0.160, P = 0.011). High burden of PVS at age 73 (volume, count, and visual scores), was associated with faster deterioration in white matter: reduction of NAWM volume (β = −0.16, P = 0.012) and increasing white matter damage metric (β = 0.37, P < 0.001) between ages 73 and 79. On SEM, centrum semiovale PVS burden mediated 5% of the associations between sleep parameters and brain changes. ConclusionSleep impairments, and higher PVS burden, a marker of impaired waste clearance, were associated with faster loss of healthy white matter and increasing WMH in the 8th decade of life. A small percentage of the effect of sleep in white matter health was mediated by the burden of PVS consistent with the proposed role for sleep in brain waste clearance.

Inflammatory biomarkers and MRI visible perivascular spaces: The Framingham Heart Study

We studied the association between inflammatory biomarkers and magnetic resonance imaging (MRI) visible perivascular spaces (PVS) in Framingham Heart Study participants free of stroke and dementia. PVS in the basal ganglia (BG) and centrum semiovale (CSO) were rated with validated methods and categorized based on counts. A mixed score of high PVS burden in neither, one or both regions was also evaluated. We related biomarkers representing various inflammatory mechanisms to PVS burden using multivariable ordinal logistic regression analysis accounting for vascular risk factors and other MRI markers of cerebral small vessel disease. Among 3604 participants (mean age 58±13 years, 47% males), significant associations were observed for intercellular adhesion molecule1, fibrinogen, osteoprotegerin, and P-selectin in relation to BG PVS, P-selectin for CSO PVS, and tumor necrosis factor receptor 2, osteoprotegerin and cluster of differentiation 40 ligand for mixed topography PVS. Therefore, inflammation may have a role in the pathogenesis of cerebral small vessel disease and perivascular drainage dysfunction represented by PVS, with different and shared inflammatory biomarkers depending on PVS topography.

MRI-Visible Perivascular Spaces and Risk of Incident Dementia: The Framingham Heart Study.

Perivascular spaces (PVS) visible on MRI scans may represent key aspects in the pathophysiology of stroke and dementia, including cerebral small vessel disease and glymphatic dysfunction. This study aimed to determine the association between MRI-visible PVS burden and the risk of incident dementia. This study included community-dwelling Framingham Heart Study Original and Offspring cohort participants with available brain MRI-PVS ratings, free of stroke and dementia. Multivariable Cox proportional hazard regression was used to obtain hazard ratios (HRs) and 95% CIs of the association between MRI-visible PVS and incident dementia. PVS were rated using validated methods in the basal ganglia (BG) and centrum semiovale (CSO). The outcomes included all-cause dementia, Alzheimer dementia (AD), and vascular dementia (VaD). One thousand four hundred forty-nine participants 50 years or older (46% male) were included. Over a median follow-up period of 8.3 years, the incidence of all-cause dementia, AD, and VaD was 15.8%, 12.5%, and 2.5%, respectively. In models that adjusted for vascular risk factors and cardiovascular disease, the hazard for dementia increased steadily as PVS burden increased, rising 2-fold for those with grade II PVS (HR 2.44, 95% CI 1.51-3.93) to 5-fold in participants with grade IV (HR 5.05, 95% CI 2.75-9.26) compared with grade I PVS in CSO. In the BG, hazards increased 1.6-fold (HR 1.62, 95% CI 1.15-2.27) for grade II to 2.6-fold (HR 2.67, 95% CI 1.04-6.88) for grade IV compared with grade I PVS. The association remained significant for CSO but not for BG, after adjustment for white matter hyperintensity volume (WMHV), covert infarcts, and total brain volume. Similar findings were observed for AD, but VaD, limited by a small number of events, was not statistically significant. Higher burden of PVS in CSO was associated with increased risk of developing dementia, independent of vascular risk factors, total brain volume, WMHVs, and covert infarcts. This finding supports a role for PVS as a subclinical MRI marker to identify individuals in subclinical stages at high risk of developing dementia who may benefit from early intervention.

Associations Between Vascular Risk Factors and Perivascular Spaces in Adults with Intact Cognition, Mild Cognitive Impairment, and Dementia.

Perivascular spaces (PVS) are fluid-filled compartments surrounding small intracerebral vessels that transport fluid and clear waste. We examined associations between PVS count, vascular and neurodegenerative risk factors, and cognitive status among the predominantly Hispanic participants of the FL-VIP Study of Alzheimer's Disease Risk. Using brain MRI (n = 228), we counted PVS in single axial image through the basal ganglia (BG) and centrum semiovale (CSO). PVS per region were scored as 0 (none), 1 (&lt;10), 2 (11-20), 3 (21-40), and 4 (&gt;40). Generalized linear models examined PVS associations with vascular risk factors and a composite vascular comorbidity risk (VASCom) score. Our sample (mean age 72±8 years, 61% women, 60% Hispanic, mean education 15±4 years, 33% APOE4 carriers) was 59% hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. PVS scores ranged from 0-4 in the BG (mean 1.3±0.7) and CSO (mean 1.2±0.9), and 0-7 combined (mean 2.5±1.4). In multivariable regression models, BG PVS was associated with age (β= 0.03/year, p &lt; 0.0001), Hispanic ethnicity (β= 0.29, p = 0.01), education (β= 0.04/year, p = 0.04), and coronary bypass surgery (β= 0.93, p = 0.02). CSO PVS only associated with age (β= 0.03/year, p &lt; 0.01). APOE4 and amyloid-β were not associated with PVS. BG PVS may be a marker of subclinical cerebrovascular disease. Further research is needed to validate associations and identify mechanisms linking BG PVS and cerebrovascular disease markers. PVS may be a marker of neurodegeneration despite our negative preliminary findings and more research is warranted. The association between BG PVS and Hispanic ethnicity also requires further investigation.

The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI–neuropathology diagnostic accuracy study

Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. US National Institutes of Health (R01 AG26484).

Combined Score of Perivascular Space Dilatation and White Matter Hyperintensities in Patients with Normal Cognition, Mild Cognitive Impairment, and Dementia.

Background and Objectives: Cerebral perivascular spaces (PVS) are part of the cerebral microvascular structure and play a role in lymphatic drainage and the removal of waste products from the brain. White matter hyperintensities (WMH) are hyperintense lesions on magnetic resonance imaging that are associated with cognitive impairment, dementia, and cerebral vascular disease. WMH and PVS are direct and indirect imaging biomarkers of cerebral microvascular integrity and health. In our research, we evaluated WMH and PVS enlargement in patients with normal cognition (NC), mild cognitive impairment (MCI), and dementia (D). Materials and Methods: In total, 57 participants were included in the study and divided into groups based on neurological evaluation and Montreal Cognitive Assessment results (NC group 16 participants, MCI group 29 participants, D group 12 participants). All participants underwent 3T magnetic resonance imaging. PVS were evaluated in the basal ganglia, centrum semiovale, and midbrain. WMHs were evaluated based on the Fazekas scale and the division between deep white matter (DWM) and periventricular white matter (PVWM). The combined score based on PVS and WMH was evaluated and correlated with the results of the MoCA. Results: We found statistically significant differences between groups on several measures. Centrum semiovale PVS dilatation was more severe in MCI and dementia group and statistically significant differences were found between D-MCI and D-NC pairs. PVWM was more severe in patients with MCI and dementia group, and statistically significant differences were found between D-MCI and D-NC pairs. Furthermore, we found statistically significant differences between the groups by analyzing the combined score of PVS dilatation and WMH. We did not find statistically significant differences between the groups in PVS dilation of the basal ganglia and midbrain and DWM hyperintensities. Conclusions: PVS assessment could become one of neuroimaging biomarkers for patients with cognitive decline. Furthermore, the combined score of WMH and PVS dilatation could facilitate diagnostics of cognitive impairment, but more research is needed with a larger cohort to determine the use of PVS dilatation and the combined score.

Asymmetric distribution of enlarged perivascular spaces in centrum semiovale may be associated with epilepsy after acute ischemic stroke.

ObjectiveTo investigate the factors influencing enlarged perivascular space (EPVS) characteristics at the onset of acute ischemic stroke (AIS), and whether the PVS characteristics can predict later post‐stroke epilepsy (PSE).MethodsA total of 312 patients with AIS were identified, of whom 58/312 (18.6%) developed PSE. Twenty healthy participants were included as the control group. The number of PVS in the basal ganglia (BG), centrum semiovale (CS), and midbrain (MB) was manually calculated on T2‐weighted MRI. The scores and asymmetry index (AI) of EPVS in each region were compared among the enrolled participants. Other potential risk factors for PSE were also analyzed, including NIHSS at admission and stroke etiologies.ResultsThe EPVS scores were significantly higher in the bilateral BG and CS of AIS patients compared to those of the control group (both p < 0.01). No statistical differences in EPVS scores in BG, CS, and MB were obtained between the PSE group and the nonepilepsy AIS group (all p > 0.01). However, markedly different AI scores in CS were found between the PSE group and the nonepilepsy AIS group (p = 0.004). Multivariable analysis showed that high asymmetry index of EPVS (AI≥0.2) in CS was an independent predictor for PSE (OR = 3.7, 95% confidence interval 1.5–9.1, p = 0.004).ConclusionsAsymmetric distribution of EPVS in CS may be an independent risk factor and a novel imaging biomarker for the development of PSE. Further studies to understand the mechanisms of this association and confirmation with larger patient populations are warranted.

Centrum Semiovale Perivascular Space and Amyloid Deposition in Spontaneous Intracerebral Hemorrhage.

We explored whether high-degree magnetic resonance imaging–visible perivascular spaces in centrum semiovale (CSO) are more prevalent in cerebral amyloid angiopathy (CAA) than hypertensive small vessel disease and their relationship to brain amyloid retention in patients with primary intracerebral hemorrhage (ICH). One hundred and eight spontaneous ICH patients who underwent magnetic resonance imaging and Pittsburgh compound B were enrolled. Topography and severity of enlarged perivascular spaces were compared between CAA-related ICH (CAA-ICH) and hypertensive small vessel disease–related ICH (non-CAA ICH). Clinical and image characteristics associated with high-degree perivascular spaces were evaluated in univariate and multivariable analyses. Univariate and multivariable models were performed to evaluate associations between the severity of perivascular spaces in CSO and amyloid retention in CAA-ICH and non–CAA-ICH cases. Patients with CAA-ICH (n=29) and non–CAA-ICH (n=79) had similar prevalence of high-degree perivascular spaces in CSO (44.8% versus 36.7%; P=0.507) and in basal ganglia (34.5% versus 51.9%; P=0.131). High-degree perivascular spaces in CSO were independently associated with the presence of lobar microbleed (odds ratio, 3.0 [95% CI, 1.1–8.0]; P=0.032). The amyloid retention was higher in those with high-degree than those with low-degree CSO-perivascular spaces in CAA-ICH (global Pittsburgh compound B standardized uptake value ratio, 1.55 [1.33–1.61] versus 1.13 [1.01–1.48]; P=0.003) but not in non–CAA-ICH. In CAA-ICH, the association between cerebral amyloid retention and the degree of perivascular spaces in CSO remained significant after adjustment for age and lobar microbleed number (P=0.004). Although high-degree magnetic resonance imaging–visible perivascular spaces are equally prevalent between CAA-ICH and non–CAA-ICH in the Asian cohort, the severity of magnetic resonance imaging–visible CSO-perivascular spaces may be an indicator of higher brain amyloid deposition in patients with CAA-ICH.

Abstract P59: Peak Width of Skeletonized Mean Diffusivity Outperforms Other Diffusion Tensor Imaging Metrics as Biomarker for Cognition in Memory-Clinic Subjects With Cerebral Amyloid Angiopathy

Introduction: Peak width of skeletonized mean diffusivity (PSMD) is a novel fully automated diffusion tensor imaging (DTI) marker that has been consistently associated with cognition in cerebral small vessel disease (SVD) cohorts, including cerebral amyloid angiopathy (CAA). We hypothesized that PSMD would be more strongly associated with cognitive performance compared to other conventional DTI metrics in our CAA sample. Methods: We recruited non-demented subjects with probable-CAA from a single-center memory-clinic cohort. We analyzed structural MRIs to compute a validated CAA burden score (0-6 points scale, based on the following MRI features: lobar microbleeds, superficial siderosis, perivascular spaces in centrum semiovale, and white matter hyperintensities). PSMD was obtained using a freely available script ( www.psmd-marker.com ). We used the same skeleton-mask to compute: mean of skeletonized mean diffusivity (mean MD) and mean of skeletonized fractional anisotropy (mean FA). We used linear regression analyses to explore relationships with CAA burden score and cognitive composite scores (processing speed, executive function, memory, and language - z-scores adjusted for age, sex and education level). Results: We included 43 subjects (mean age 74.4 ± 5.9 years; 48.8% female; PSMD median [IQR]: 4.05 [3.58 - 4.80] x 10 -4 mm 2 /s). In linear regression models adjusting for age, DTI metrics were significantly associated with CAA burden score (mean FA: β = -0.563, Adj. R 2 : 0.27; p &lt; 0.001; mean MD: β = 0.581; Adj. R 2 : 0.32; p &lt; 0.001; PSMD: β = 0.364, Adj. R 2 : 0.12; p = 0.018). PSMD was significantly associated with cognitive performance, specifically in the domains of executive function ( β = -0.568; Adj. R 2 : 0.25; p &lt; 0.001) and processing speed ( β = -0.447; Adj. R 2 : 0.19; p = 0.004). Other DTI metrics were not significantly associated with cognitive scores. Conclusion: In this CAA sample, all DTI metrics were associated with CAA burden scores, however, only PSMD was significantly associated with cognition, in domains that are commonly affected in vascular cognitive impairment. Our results warrant confirmation in larger samples, but support PSMD as biomarker for cognition in CAA, outperforming other conventional DTI metrics.

Abstract P442: The Association of Amyloid and Tau Burden With Centrum Semiovale Perivascular Spaces in Cerebral Amyloid Angiopathy

Background: The mechanisms linking cerebral amyloid angiopathy (CAA) to enlarged perivascular spaces in centrum semiovale (CSO-EPVS) and whether other Alzheimer’s Disease (AD) pathologies might affect CSO-EPVS are unclear. We hypothesized that amyloid but not tau load would independently correlate with CSO-EPVS in CAA. Methods: Fifty prospectively enrolled nondemented probable CAA patients underwent high-resolution structural MRI, Pittsburgh compound B (PiB, for amyloid), and 18 F-flortaucipir (FTP, for tau) PET imaging. Microbleeds (all lobar, LMB) were counted and white matter hyperintensity volume (WMH) was quantified. CSO-EPVS were counted on T 2 -MRI sequence and graded using a previously validated scale (range 0-4). A multivariate ordinal regression model was used to assess the independent associations between CSO-EPVS and mean cortical amyloid as well as tau deposition, after adjusting for relevant covariates. Results: Patients had a mean age of 69.3±7.2. Age, sex, presence of hypertension, intracerebral hemorrhage (ICH), LMB counts, and WMH were not associated with CSO-EPVS grades (p&gt;0.2 for all comparisons). Higher PiB uptake significantly correlated with increased CSO-EPVS (rho=0.45, p=0.001). Higher FTP showed a trend for correlation with CSO-EPVS (rho=0.26, p=0.069). In an ordinal regression model with CSO-EPVS grade as the dependent variable and both amyloid and tau levels included as predictors along with covariates presented above, the association of CSO-EPVS remained significant with higher PiB uptake (β=3.97, 95%CI 1.1-6.8, p=0.007) but not with FTP uptake (p=0.167). Conclusion: Results of this study suggest that CSO-EPVS is independently associated with amyloid but not with tau deposition in CAA. CSO-EPVS was not associated with age or classical vascular risk factors or presence of ICH. Our results support the view that vascular amyloid but not other AD pathologies such as tau might contribute to EPVS in patients with CAA.

Abstract 36: The Boston Criteria V2.0 for Cerebral Amyloid Angiopathy: Updated Criteria and Multicenter MRI-Neuropathology Validation

Introduction: The Boston criteria are used worldwide for in vivo diagnosis of cerebral amyloid angiopathy (CAA). Given substantial advances in CAA research, we aimed to update the Boston criteria and externally validate their diagnostic accuracy across the spectrum of CAA-related presentations and across international sites. Methods: As part of an International CAA Association multicenter study, we identified patients age 50 or older with potential CAA-related clinical presentations (spontaneous intracerebral hemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathologic assessment for the diagnosis of CAA. We derived Boston criteria v2.0 by selecting MRI features to optimize diagnostic specificity and sensitivity in a pre-specified derivation sample (Boston cases 1994 to 2012, n=159), then externally validated in pre-specified temporal (Boston cases 2012-2018, n=59) and geographical (non-Boston cases 2004-2018; n=123) validation samples and compared their diagnostic accuracy to the currently used modified Boston criteria. Results: Based on exploratory analyses in the derivation sample, we derived provisional criteria for probable CAA requiring presence of at least 2 strictly lobar hemorrhagic lesions (intracerebral hemorrhage, cerebral microbleed, or cortical superficial siderosis focus) or at least 1 strictly lobar hemorrhagic lesion and 1 white matter characteristic (severe degree of visible perivascular spaces in centrum semiovale or white matter hyperintensities multispot pattern). Sensitivity/specificity of the criteria were 74.8/84.6% in the derivation sample, 92.5/89.5% in the temporal validation sample, 80.2/81.5% in the geographic validation sample, and 74.5/95.0% in cases across all samples with autopsy as the diagnostic gold standard. The v2.0 criteria for probable CAA had superior accuracy to the currently modified Boston criteria (p&lt;0.005) in the autopsied cases. Conclusion: The Boston criteria v.2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their high specificity. Validation of the criteria across independent patient settings firmly supports their adoption into clinical practice and research.

Association of enlarged perivascular spaces and anticoagulant-related intracranial hemorrhage.

ObjectiveTo investigate whether enlarged perivascular spaces (PVS) within the basal ganglia or deep cerebral white matter are risk factors for intracranial hemorrhage in patients taking oral anticoagulants (OACs), independent of established clinical and radiologic risk factors, we conducted a post hoc analysis of Clinical Relevance of Microbleeds in Stroke (CROMIS-2) (atrial fibrillation [AF]), a prospective inception cohort study.MethodsPatients with atrial fibrillation and recent TIA or ischemic stroke underwent standardized MRI prior to starting OAC. We rated basal ganglia PVS (BGPVS) and centrum semiovale PVS (CSOPVS), cerebral microbleeds (CMBs), white matter hyperintensities, and lacunes. We dichotomized the PVS rating using a threshold of >10 PVS in the relevant region of either cerebral hemisphere. The primary outcome was symptomatic intracranial hemorrhage (sICH). We identified risk factors for sICH using Cox regression.ResultsA total of 1,386 participants with available clinical and imaging variables were followed up for a mean of 2.34 years; 14 sICH occurred (11 intracerebral). In univariable analysis, diabetes, CMB presence, lacune presence, and >10 BGPVS, but not CSOPVS, were associated with sICH. In a multivariable model incorporating all variables with significant associations in univariable analysis, >10 BGPVS (hazard ratio [HR] 8.96, 95% [CI] 2.41–33.4, p = 0.001) and diabetes (HR 3.91, 95% CI 1.34–11.4) remained significant risk factors for sICH.ConclusionEnlarged BGPVS might be a novel risk factor for OAC-related ICH. The strength of this association and potential use in predicting ICH in clinical practice should be investigated in larger cohorts.

Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases.

Background and Purpose- Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging. Methods- We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results- Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%-18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (β=0.468 [95% CI, 0.187-0.750]) and transverse sinus pulsatility (β=0.547 [95% CI, 0.309-0.786]) and adjusting for age, sex, and systolic blood pressure. Conclusions- Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular.