Cortical Microinfarcts Research Articles

Associations between cortical microinfarcts, hippocampal atrophy, and cerebral small vessel disease

AbstractBackgroundBrain cortical microinfarcts (CMI) are negatively correlated with cognitive function in both normal aging and Alzheimer’s disease (AD). High‐field structural magnetic resonance imaging (MRI) has facilitated in vivo detection of CMIs but their significance and underlying pathological mechanism remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and relative periventricular white matter cerebral blood flow (PVWM CBF) in healthy individuals. PVWM CBF is thought to provide a measure of cerebral small vessel function.Method76 cognitively intact subjects age 65 ± 15 years were scanned using a hybrid 7T/3T protocol. CMIs were counted by visual inspection on T1‐weighted MP2RAGE (0.7mm3) and FLAIR (0.8mm3) scans obtained at 7T. T1‐weighted MPRAGE, FLAIR and 3D arterial spin labeling (ASL) data were also acquired at 3T and were used to calculate cortical thickness, WMH volume, and regional CBF. Spearman and Pearson bivariate tests were used for statistical analyses.Result185 CMIs were detected in 63 of 76 (83%) 7T scans (range:0‐8, 66% multiple CMIs). Age and sex were not significantly correlated with CMI number.A significant positive Pearson correlation was seen between the number of CMIs and log‐transformed WMH volume (r(74)= 0.23, p=0.04) and a more significant negative correlation between the number of CMIs and PVWM CBF normalized to global CBF was also observed (r(74)= ‐0.37, p=0.003).Significant negative correlations between CMI number and mean cortical thickness in Brodmann area 35 (BA35) (r(73)= ‐0.24, p=0.04) and parahippocampal cortex (r(73)= ‐0.26, p=0.03) was observed with nonsignificant trends in BA36 and entorhinal cortex.ConclusionSignificant correlations between the CMI number and both relative PVWM CBF and WMH volume suggests a contribution of small vessel ischemic disease in the development of CMIs. The negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for CMIs and Alzheimer’s disease that may be mediated by cerebral amyloid angiopathy.

Brain Deep Medullary Veins on 7T MRI in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer's disease. So far, DMVs have not been evaluated in CAA. To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n = 8), symptomatic D-CAA mutation carriers (n = 8), and controls (n = 25). Hemorrhagic MRI markers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. Quantitative DMV parameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA. This study indicates that vascular amyloid-β deposition does not affect DMV parameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA.

3D Cube FLAIR plus HyperSense compressed sensing is superior to 2D T2WI FLAIR scanning regarding image quality, spatial resolution, detection rate for cortical microinfarcts.

3-dimention (3D) Cube isotropic volumetric magnetic resonance imaging (MRI) facilitates comprehensive recognition of microinfarcts while it takes long scanning time. HyperSense compressed sensing is an emerging technique for accelerating MRI acquisition to reduce scanning time, while its application along with 3D Cube MRI for microinfarcts is seldom reported. Therefore, this study aimed to investigate the efficiency of 3D Cube FLAIR plus HyperSense compressed sensing technique versus conventional 2-dimention (2D) FLAIR scanning in the detection of cortical microinfarcts (CMIs).Totally 59 patients with cerebrovascular disease were enrolled then scanned by 3D Cube FLAIR plus HyperSense compressed sensing and 2D T2WI FLAIR sequences. The image quality scores, signal-to-noise ratio (SNR) for gray matter (GM), SNR for white matter (WM), their contrast-to-noise ratio (WM-to-GM CNR), detected number of CMIs were evaluated.3D Cube FLAIR plus HyperSense showed a dramatically increased scores of uniformity, artifact, degree of lesion displacement, and overall image quality compared to 2D T2WI FLAIR. Meanwhile, it exhibited similar SNRwm and SNRgm, but a higher WM-to-GM contrast-to-noise ratio compared with 2D T2WI FLAIR. Furthermore, the scanning time of 3D Cube FLAIR plus HyperSense and 2D T2WI FLAIR were both set as 2.5 minutes. Encouragingly, 244 CMIs were detected by 3D Cube FLAIR plus HyperSense, which was higher compared to 2D T2WI FLAIR (106 detected CMIs).3D Cube FLAIR plus HyperSense compressed sensing is superior to 2D T2WI FLAIR scanning regarding image quality, spatial resolution, detection rate for CMIs; meanwhile, it does not increase the scanning time. These findings may contribute to early detection and treatment of stroke.

Spectrum of concomitant brain vascular lesions in pediatric diffuse gliomas

Cerebrovascular disease represents a threatening factor for brain cancer survivors. However, a comprehensive evaluation of small vessel disease related to gliomas has not yet been performed. This study aims to characterize concomitant vascular lesions in pediatric diffuse gliomas and identify their association with the molecular subgroup of tumors. We performed a retrospective pathological study of biopsy samples of 77 pediatric patients with diffuse gliomas, treated in Belarusian Research Center for Pediatric Oncology, Hematology and Immunology. Eight molecular subgroups were identified by immunohistochemical and cytogenetic studies (H3K27mut, ALT, IDH1mut, BRAFmut-PXA, FGFR1, BRAFmut/FGFR2, RTK, MYB). In each group microvessel density/area (MVD/MVA), tumor vessels co-option and signs of small vessels disease (SVD) were determined. The levels of microvascularization significantly differed between the molecular subgroups of diffuse gliomas, indicating the presence of intrinsic pro-angiogenic activity there. The highest values of MVD/MVA, as well as rate of hemorrhagic necrosis, were found in the BRAFmut/FGFR2, RTK groups. SVD was common in the adjacent tissues of gliomas and occurred in 32.5 % of cases. High grade SVD was associated with the BRAFmut/FGFR2 and IDH1mut subgroups. BRAFmut/FGFR2 tumors were more aggressive and caused cortical microinfarctions in 84,6 % and leukoaraiosis in 87.5 % of cases. IDH1mut tumors were mainly linked with cortical microinfarctions (60 % of cases). The results of the study suggest that concomitant small vascular lesions are common in adjacent tumor tissue and can significantly influence the overall rate of cerebrovascular disease in convalescents with diffuse gliomas.

Microinfarcts in the Deep Gray Matter on 7T MRI: Risk Factors, MRI Correlates, and Relation to Cognitive Functioning-The SMART-MR Study.

The clinical relevance of cortical microinfarcts has recently been established; however, studies on microinfarcts in the deep gray matter are lacking. We examined the risk factors and MR imaging correlates of microinfarcts in the deep gray matter on 7T MR imaging and their relation to cognitive functioning. Within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, 213 patients (mean age, 68 [SD, 8] years) had a risk-factor assessment, 7T and 1.5T brain MR imaging, and a cognitive examination. Microinfarcts on 7T MR imaging were defined as lesions of <5 mm. Regression models were used to examine the age-adjusted associations among risk factors, MR imaging markers, and microinfarcts. Cognitive function was summarized as composite and domain-specific z scores. A total of 47 microinfarcts were found in 28 patients (13%), most commonly in the thalamus. Older age, history of stroke, hypertension, and intima-media thickness were associated with microinfarcts. On 1.5T MR imaging, cerebellar infarcts (relative risk = 2.75; 95% CI, 1.4-5.33) and lacunes in the white (relative risk = 3.28; 95% CI, 3.28-6.04) and deep gray matter (relative risk = 3.06; 95% CI, 1.75-5.35) were associated with microinfarcts, and on 7T MR imaging cortical microinfarcts (relative risk = 2.33; 95% CI, 1.32-4.13). Microinfarcts were also associated with poorer global cognitive functioning (mean difference in the global z score between patients with multiple microinfarcts versus none = -0.97; 95% CI, -1.66 to -0.28, P = .006) and across all cognitive domains. Microinfarcts in the deep gray matter on 7T MR imaging were associated with worse cognitive functioning and risk factors and MR imaging markers of small-vessel and large-vessel disease. Our findings suggest that microinfarcts in the deep gray matter may represent a novel imaging marker of vascular brain injury.

Retinal parameters, cortical cerebral microinfarcts, and their interaction with cognitive impairment.

Quantitative changes in retinal vessels and thinning of optic nerves have been associated with subclinical (atherosclerosis, inflammation) and clinical age-related brain pathologies (stroke and neurodegeneration). However, data on the association between both retinal vascular and neuronal parameters with cortical cerebral microinfarcts (CMIs) and how these factors jointly influence cognition are lacking. We investigated the association of retinal vascular and neuronal changes with CMIs on 3 T MRI and explored their interaction with cognitive impairment in a memory-clinic population. A total of 538 participants were included. Retinal vascular parameters (caliber, tortuosity, and fractal dimension) were measured from retinal fundus photographs using a semi-automated computer-assisted program. Retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thicknesses were obtained from optical coherence tomography. Cortical CMIs were defined as hypointense on T1-weighted MRI, <5 mm in diameter and restricted to the cortex. Cognition was assessed using Clinical Dementia Rating Sum-of-Boxes (CDR-SoB) score and detailed neuropsychological test. Multivariable regression analysis was conducted adjusting for age, sex, hypertension, hyperlipidemia, diabetes mellitus, smoking, diagnosis, white matter hyperintensities volume, lacunes, and cerebral microbleeds. Larger venular caliber (Rate ratios (RR): 1.15, 95% CI: 1.01-1.38, p = 0.014), increased venular fractal dimension (RR: 1.58, 95% CI: 1.31-1.91, p ⩽ 0.001), increased venular tortuosity (RR: 1.54, 95% CI: 1.35-1.75, p ⩽ 0.001), and thinner GC-IPL (RR: 1.24, 95% CI: 1.13-1.36, p ⩽ 0.001) were associated with CMI counts. Among individuals in highest tertile of retinal parameters, a significant interaction was observed between venular tortuosity (RR: 1.12, 95% CI: 1.02-1.22, p-interaction = 0.014) and GC-IPL (RR: 1.05, 95% CI: 1.01-1.11, p-interaction < 0.001) with CMIs on CDR-SoB. Retinal vascular and neuronal parameters are associated with cortical CMIs, and persons with both pathologies are likely to have cognitive impairment. Further studies may be warranted to evaluate the clinical utility of retinal parameters and CMI in risk prediction for cognitive dysfunction.

Association of Traumatic Brain Injury With and Without Loss of Consciousness With Neuropathologic Outcomes in Community-Dwelling Older Persons

A history of traumatic brain injury (TBI) has been considered a risk factor for Alzheimer dementia. However, the specific association of TBI, even without loss of consciousness (LOC), with pathologic findings that underlie Alzheimer dementia, including Alzheimer disease (AD), non-AD neurodegenerative, and vascular pathologic findings, remains unclear. To examine the association between TBI with and without LOC and neuropathologic findings in community-based cohorts. This cross-sectional analysis used neuropathologic data from 1689 participants from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. These studies began enrollment in 1994, 1997, and 2004, respectively. The current study's data set was frozen on April 3, 2021, when the mean (SD) length of follow-up for the participants was 8.7 (5.5) years. Traumatic brain injury exposure was assessed using a standardized, self-reported questionnaire at baseline and annual follow-up visits. Participants were categorized into those (1) without TBI exposure (n = 1024), (2) with TBI with LOC (n = 161), or (3) with TBI without LOC (n = 504). Neuropathologic measures of amyloid-β, paired helical filament tangles, neocortical Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, gross infarcts, and microinfarcts were assessed. Multiple linear regression and logistic regression models were used to determine whether TBI with or without LOC (compared with no TBI exposure as the reference group) was associated with neuropathologic outcomes after adjusting for age at death, sex, and educational level. Whether the apolipoprotein E (APOE) ε4 allele and sex differences modified associations was also examined. A total of 1689 participants (1138 [67%] women and 551 [33%] men; mean [SD] age at death, 89.2 [6.7] years; 80 [5%] Black, 46 [3%] Latino, 1639 [97%] non-Latino, and 1601 [95%] White) participated in the study. Compared with participants without TBI, participants with TBI with LOC had a greater amyloid-β load (estimate, 0.25; 95% CI, 0.06-0.43; P = .008) and higher odds of having 1 or more gross infarcts (odds ratio [OR], 1.45; 95% CI, 1.04-2.02; P = .02) and 1 or more microinfarcts (OR, 1.70; 95% CI, 1.21-2.38; P = .002), particularly subcortical microinfarcts (OR, 1.85; 95% CI, 1.23-2.79; P = .002). Those with TBI without LOC had higher odds of neocortical Lewy bodies (OR, 1.37; 95% CI, 1.01-1.87; P = .04) and 1 or more cortical microinfarcts (OR, 1.43; 95% CI, 1.09-1.87; P = .008). The association of TBI with and without LOC with vascular pathologic outcomes persisted after controlling for vascular risk factors and vascular disease burden. Traumatic brain injury with or without LOC was not associated with paired helical filament tangles, transactive response DNA-binding protein 43, or hippocampal sclerosis. No interactions occurred with APOE ε4 or sex. This cross-sectional analysis suggests that a history of TBI, even without LOC, is associated with age-related neuropathologic outcomes, both neurodegenerative and vascular. The variation in the neuropathologic outcomes in individuals with and without LOC may provide clues to potential mechanisms, diagnoses, and management in persons with TBI.

Post-Stroke Cognitive Impairment and Dementia.

Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID. Manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes. Although studies of PSCID historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age, lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular risk factors, and a history of prior stroke increase risk of PSCID. Stroke characteristics, in particular stroke severity, lesion volume, lesion location, multiplicity and recurrence, also influence PSCID risk. Understanding the complex interaction between an acute stroke event and preexisting brain pathology remains a priority and will be critical for developing strategies for personalized prediction, prevention, targeted interventions, and rehabilitation. Current challenges in the field relate to a lack of harmonization of definition and classification of PSCID, timing of diagnosis, approaches to neurocognitive assessment, and duration of follow-up after stroke. However, evolving knowledge on pathophysiology, neuroimaging, and biomarkers offers potential for clinical applications and may inform clinical trials. Preventing stroke and PSCID remains a cornerstone of any strategy to achieve optimal brain health. We summarize recent developments in the field and discuss future directions closing with a call for action to systematically include cognitive outcome assessment into any clinical studies of poststroke outcome.

The Association Between Standard Electrocardiography and Cerebral Small Vessel Disease in a Memory Clinic Study.

P-wave terminal force in lead V1 (PTFV1) on electrocardiography has been associated with atrial fibrillation and ischemic stroke. To investigate whether PTFV1 is associated with cerebral small vessel disease (CSVD) markers and etiological subtypes of cognitive impairment and dementia. Participants were recruited from ongoing memory clinic study between August 2010 to January 2019. All participants underwent physical and medical evaluation along with an electrocardiography and 3 T brain magnetic resonance imaging. Participants were classified as no cognitive impairment, cognitive impairment no dementia, vascular cognitive impairment no dementia, and dementia subtypes (Alzheimer's disease and vascular dementia). Elevated PTFV1 was defined as > 4,000μV×ms and measured manually on ECG. Of 408 participants, 78 (19.1%) had elevated PTFV1 (37 women [47%]; mean [SD] age, 73.8 [7.2] years). The participants with elevated PTFV1 had higher burden of lacunes, cerebral microbleeds (CMB), and cortical microinfarcts. As for the CMB location, persons with strictly deep CMB and mixed CMB had significantly higher PTFV1 than those with no CMB (p = 0.005, p = 0.007). Regardless of adjustment for cardiovascular risk factors and/or heart diseases, elevated PTFV1 was significantly associated with presence of CMB (odds ratio, 2.26; 95% CI,1.33-3.91). Elevated PTFV1 was associated with CSVD, especially deep CMB. PTFV1 in vascular dementia was also higher compared to Alzheimer's disease. Thus, PTFV1 might be a potential surrogate marker of brain-heart connection and vascular brain damage.

The Impact of Cortical Cerebral Microinfarcts on Functional Outcomes in Patients With Ischemic Stroke.

The present study examined cortical cerebral microinfarcts (CMIs) on a 3T magnetic resonance imaging and investigated the impact of CMIs on the comprehensive functional outcomes during the post-stroke rehabilitation period. Patients with acute phase of first-ever ischemic stroke were retrospectively recruited (n = 62) and divided into 2 groups with and without CMIs. Clinical parameters including age, sex, stroke lesion laterality, location, the National Institutes of Health Stroke Scale score, as well as history of hypertension, dyslipidemia, diabetes mellitus, and smoking were obtained. Functional outcomes were assessed twice at baseline and one month later with the Korean version of the Mini-Mental State Examination, the Berg balance scale (BBS), and the functional independence measure. Partial correlation and multiple linear regression analyses were used to examine the relationship between the presence of CMIs and the change in functional outcomes. At least one CMI was reported in 27 patients, who were older (p = 0.043). The presence of CMIs was significantly associated with functional impairment in all 3 functional outcomes, after controlling for confounding factors (p < 0.05). CMIs might contribute to poor functional outcomes during the post-stroke rehabilitation period. These results suggest that CMIs should be considered when establishing rehabilitation treatment strategies or making a prognosis.

Association Between Cerebral Cortical Microinfarcts and Perilesional Cortical Atrophy on 3T MRI.

Cerebral cortical microinfarcts (CMIs) are a novel MRI marker of cerebrovascular disease (CeVD) that predicts accelerated cognitive decline. Presence of CMIs is known to be associated with global cortical atrophy, although the mechanism linking the two is unclear. Our primary objective was to examine the relation between CMIs and cortical atrophy and to establish possible perilesional atrophy surrounding CMIs. Our secondary objective was to examine the role of cortical atrophy in CMI-associated cognitive impairment. Patients were recruited from 2 Singapore memory clinics between December 2010 and September 2013 and included if they received the diagnosis no objective cognitive impairment, cognitive impairment (with or without a history of stroke), or Alzheimer or vascular dementia. Cortical thickness, chronic CMIs, and MRI markers of CeVD were assessed on 3T MRI. Patients underwent cognitive testing. Cortical thickness was compared globally between patients with and without CMIs, regionally within individual patients with CMIs comparing brain regions with CMIs to the corresponding contralateral region without CMIs, and locally within individuals patients in a 50-mm radius of CMIs. Global cortical thickness was analyzed as mediator in the relation between CMI and cognitive performance. Of the 238 patients (mean age 72.5 years, SD 9.1 years) enrolled, 75 had ≥1 CMIs. Patient with CMIs had a 2.1% lower global cortical thickness (B = -0.049 mm, 95% confidence interval [CI] 0.091 to -0.007, p = 0.022) compared to patients without CMIs, after correction for age, sex, education, and intracranial volume. In patients with CMIs, cortical thickness in brain regions with CMIs was 2.2% lower than in contralateral regions without CMIs (B = -0.048 mm [95% CI -0.071 to -0.026], p < 0.001). In a 20-mm radius area surrounding the CMI core, cortical thickness was lower than in the area 20 to 50 mm from the CMI core (mean difference -0.06 mm [-0.10 to -0.02], p = 0.002). Global cortical thickness was a significant mediator in the relationship between CMI presence and cognitive performance as measure with the Mini-Mental State Examination (B = -0.12 [-0.22 to -0.01], p = 0.025). We found cortical atrophy surrounding CMIs, suggesting a perilesional effect in a cortical area many times larger than the CMI core. Our findings support the notion that CMIs affect brain structure beyond the actual lesion site.

Retinal parameters, cortical microinfarcts and functional cognitive impairment

AbstractBackgroundQuantitative changes in retinal vessels and thinning of optic nerves have been associated with subclinical and clinical age‐related brain pathologies. However, data on the association between both retinal vascular and neuronal parameters with cortical cerebral microinfarcts and how these factors jointly contribute to functional cognitive impairment is lacking. We investigate the association of retinal vascular and neuronal changes with cortical CMIs on 3T MRI and to explore their interaction in relation to functional cognitive impairment in a memory‐clinic population.MethodA total of 538 participants (mean age:72.6±7.8 years) were included. Retinal vascular parameters (caliber, tortuosity, fractal dimension) were measured from retinal fundus photographs using a semi‐automated computer‐assisted program. Retinal nerve fiber layer (RNFL) and ganglion cell‐inner plexiform layer (GC‐IPL) thicknesses were obtained from spectral domain‐optical coherence tomography. Cortical CMIs were defined as hypointense lesions on T1‐weighted images, &lt;5mm in diameter, restricted to the cortex, and perpendicular to the cortical surface. Functional cognitive impairment was assessed on Clinical Dementia Rating Sum‐of‐Boxes (CDR‐SoB) score.ResultLarger venular caliber (Rate ratios (RR):1.21, 95%CI:1.03‐1.42), increased venular fractal dimension (RR:1.25, 95%CI:1.07‐1.46), increased venular tortuosity (RR:1.08, 95%CI:1.02‐1.15) and thinner GC‐IPL (RR:1.22, 95%CI:1.12‐1.32) were associated with increasing CMI counts. A significant interaction term was found between venular fractals, venular tortuosity, thinner GC‐IPL and RNFL and cortical CMIs (p&lt;0.05) on CDR‐SoB scores. Among individuals in highest tertile of retinal parameters, a significant interaction was observed between venular tortuosity (RR:1.14, 95%CI:1.09‐1.19, p‐interaction&lt;0.001), GC‐IPL (RR:1.23, 95%CI:1.13‐1.34, p‐interaction&lt;0.001) and RNFL (RR:1.48, 95%CI:1.31‐1.68, p‐interaction=0.002) with CMIs on CDR‐SoB scores.ConclusionWe showed that retinal vascular and neuronal parameters are associated with cortical CMIs independent of risk factors. Moreover, there was an interaction between retinal parameters and cortical CMIs on CDR‐SoB. Further studies may be warranted to evaluate the potential clinical utility of retinal parameters in risk prediction for CMIs.

Associations between cortical microinfarcts and MRI markers of neurodegeneration and cerebrovascular disease in aging

AbstractBackgroundCortical microinfarcts (CMI) are associated with cognitive impairment in both healthy aging and dementia, though the mechanisms underlying CMIs remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and cerebral blood flow (CBF) in older subjects.MethodNeuroimaging data from 55 cognitively intact older subjects scanned using a hybrid 7T/3T protocol were analyzed. CMIs were manually identified on T1‐weighted MP2RAGE data (0.7mm isotropic resolution) obtained at 7T (Figure 1). Cortical thickness, WMH volume and whole brain CBF were obtained with T1‐weighted, FLAIR and 3D background suppressed arterial spin labeling (ASL) imaging, all acquired at 3T and were available from N=39, 49 and 48 subjects of the N=55 subjects respectively. Spearman’s bivariate nonparametric test was used for statistical analyses.ResultCohort demographics and imaging results are summarized in Table 1. 111 CMIs were detected in 43 of 55 (78%) of 7T T1‐weighted and FLAIR MRI scans (range:0‐6, 56% multiple CMIs). Age and sex were not significantly correlated with the number of CMIs. A negative correlation between the number of CMIs and mean BA36 cortical thickness was observed (r(37)= ‐0.348, p=0.03) (Figure 2). A similar trend was also observed in entorhinal and parahippocampal cortices. No significant correlation was seen between the number of CMIs and WMH volume. No significant correlation was observed between the number of CMIs and CBF in whole brain, gray matter, or white matter.ConclusionThe percentage of subjects showing CMIs is higher than previous 3T studies suggesting improved sensitivity of high‐resolution 7T MRI for detection of CMIs. Contrary to prior reports the lack of correlation between the number of CMIs and either WMH volume or CBF suggests that cerebrovascular insufficiency and small vessel ischemic disease may not be the underlying pathologic mechanisms causing CMIs, at least in cognitively intact older subjects. However, the negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for Alzheimer’s disease and CMIs that may be mediated by cerebral amyloid angiopathy.

Cortical microinfarcts along the Alzheimer's disease continuum in adults with Down syndrome

AbstractBackgroundCortical microinfarcts (CMI) are emerging biomarkers of vascular damage that are visually detectable with 3T‐MRI, associated with cognitive decline, and more frequent in AD patients. However, no study assessed CMI in Down syndrome (DS), a genetically determined form of AD. Therefore, we aimed to quantify CMI in a population‐based cohort of adults with DS and assess the relationship with age, sex, clinical status, and APOE genotype.MethodCross‐sectional, proof‐of‐principle study. We selected 31 adults with DS from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort with available 3T‐MR (8 asymptomatic, 11 prodromal AD, and 12 AD dementia individuals; target sample size: 200 DABNI subjects). An expert neuroradiologist blind to clinical diagnosis, age, and APOE status visually analyzed the 3T‐MRI images following previously validated protocol (Figure 1) to detect and manually segment CMI. First, we compared the presence and volume of CMI in the different clinical groups along the AD continuum, in APOEε4 carriers vs. non‐carriers, and in males vs. females using Chi‐square, Mann‐Whitney, or Kruskal‐Wallis tests when appropriate. Then, we assessed the association between the volume of CMI and age using Spearman's correlation test.ResultCMI were detected in 68% of adults with DS. The frequency of CMI was nominally higher in the prodromal and demented (73% and 75%, respectively) compared to the asymptomatic group (50%, p=0.46) and in males (70%) than females (64%, p=0.72), and significantly higher in APOEε4 carriers (100%) than non‐carriers (58%, p=0.05). The volume of CMI was nominally higher in prodromal and AD dementia patients (16.7 and 12.3mm3, respectively) than in asymptomatic subjects (2.6mm3, p=0.46), in males (12.3 mm3) than in females (7.9mm3, p=0.32), and in APOEε4 carriers (14.9mm3) compared to non‐carriers (7.9mm3, p=0.11) (Tables 1, 2 and 3). No correlations between age and CMI were observed (p=0.37, rSpearman= ‐0.17) (Figure 2).ConclusionCMI are detectable using 3T‐MRI in adults with DS and are more frequent than in the general population (6% in non‐demented elderly and 32% in AD dementia patients). They are more prevalent in APOEε4 carriers and might increase along the AD continuum and be more frequent in males.

Small Vessel Disease, a Marker of Brain Health: What the Radiologist Needs to Know.

Small vessel disease, a disorder of cerebral microvessels, is an expanding epidemic and a common cause of stroke and dementia. Despite being almost ubiquitous in brain imaging, the clinicoradiologic association of small vessel disease is weak, and the underlying pathogenesis is poorly understood. The STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria have standardized the nomenclature. These include white matter hyperintensities of presumed vascular origin, recent small subcortical infarcts, lacunes of presumed vascular origin, prominent perivascular spaces, cerebral microbleeds, superficial siderosis, cortical microinfarcts, and brain atrophy. Recently, the rigid categories among cognitive impairment, vascular dementia, stroke, and small vessel disease have become outdated, with a greater emphasis on brain health. Conventional and advanced small vessel disease imaging markers allow a comprehensive assessment of global brain heath. In this review, we discuss the pathophysiology of small vessel disease neuroimaging nomenclature by means of the STRIVE criteria, clinical implications, the role of advanced imaging, and future directions.

Assessing cortical cerebral microinfarcts on iron-sensitive MRI in cerebral small vessel disease

Recent studies suggest that a subset of cortical microinfarcts may be identifiable on T2* but invisible on T1 and T2 follow-up images. We aimed to investigate whether cortical microinfarcts are associated with iron accumulation after the acute stage. The RUN DMC – InTENse study is a serial MRI study including individuals with cerebral small vessel disease (SVD). 54 Participants underwent 10 monthly 3 T MRIs, including diffusion-weighted imaging, quantitative R1 (=1/T1), R2 (=1/T2), and R2* (=1/T2*) mapping, from which MRI parameters within areas corresponding to microinfarcts and control region of interests (ROIs) were retrieved within 16 participants. Finally, we compared pre- and post-lesional values with repeated measures ANOVA and post-hoc paired t-tests using the mean difference between lesion and control ROI values. We observed 21 acute cortical microinfarcts in 7 of the 54 participants (median age 69 years [IQR 66–74], 63% male). R2* maps demonstrated an increase in R2* values at the moment of the last available follow-up MRI (median [IQR], 5 [5–14] weeks after infarction) relative to prelesional values (p = .08), indicative of iron accumulation. Our data suggest that cortical microinfarcts are associated with increased R2* values, indicative of iron accumulation, possibly due to microhemorrhages, neuroinflammation or neurodegeneration, awaiting histopathological verification.

Cortical cerebral microinfarcts on 7T MRI: Risk factors, neuroimaging correlates and cognitive functioning – The Medea-7T study

We determined the occurrence and association of cortical cerebral microinfarcts (CMIs) at 7 T MRI with risk factors, neuroimaging markers of small and large vessel disease, and cognitive functioning. Within the Medea-7T study, a diverse cohort of older persons with normal cognition, patients with vascular disease, and memory clinic patients, we included 386 participants (68 ± 9 years) with available 7 T and 1.5 T/3T brain MRI, and risk factor and neuropsychological data. CMIs were found in 10% of participants and were associated with older age (RR = 1.79 per +10 years, 95%CI 1.28–2.50), history of stroke or TIA (RR = 4.03, 95%CI 2.18–7.43), cortical infarcts (RR = 5.28, 95%CI 2.91–9.55), lacunes (RR = 5.66, 95%CI 2.85–11.27), cerebellar infarcts (RR = 2.73, 95%CI 1.27–5.84) and decreased cerebral blood flow (RR = 1.35 per −100 ml/min, 95%CI 1.00–1.83), after adjustment for age and sex. Furthermore, participants with >2 CMIs had 0.5 SD (95%CI 0.05–0.91) lower global cognitive performance, compared to participants without CMIs. Our results indicate that CMIs on 7 T MRI are observed in vascular and memory clinic patients with similar frequency, and are associated with older age, history of stroke or TIA, other brain infarcts, and poorer global cognitive functioning.

The severity of microstrokes depends on local vascular topology and baseline perfusion.

Cortical microinfarcts are linked to pathologies like cerebral amyloid angiopathy and dementia. Despite their relevance for disease progression, microinfarcts often remain undetected and the smallest scale of blood flow disturbance has not yet been identified. We employed blood flow simulations in realistic microvascular networks from the mouse cortex to quantify the impact of single-capillary occlusions. Our simulations reveal that the severity of a microstroke is strongly affected by the local vascular topology and the baseline flow rate in the occluded capillary. The largest changes in perfusion are observed in capillaries with two inflows and two outflows. This specific topological configuration only occurs with a frequency of 8%. The majority of capillaries have one inflow and one outflow and is likely designed to efficiently supply oxygen and nutrients. Taken together, microstrokes bear potential to induce a cascade of local disturbances in the surrounding tissue, which might accumulate and impair energy supply locally.

Intracranial Atherosclerotic Burden and Cerebral Parenchymal Changes at 7T MRI in Patients With Transient Ischemic Attack or Ischemic Stroke.

The relevance of intracranial vessel wall lesions detected with MRI is not fully established. In this study (trial identification number: NTR2119; www.trialregister.nl), 7T MRI was used to investigate if a higher vessel wall lesion burden is associated with more cerebral parenchymal changes in patients with ischemic stroke or transient ischemic attack (TIA). MR images of 82 patients were assessed for the number of vessel wall lesions of the large intracranial arteries and for cerebral parenchymal changes, including the presence and number of cortical, small subcortical, and deep gray matter infarcts; lacunes of presumed vascular origin; cortical microinfarcts; and periventricular and deep white matter hyperintensities (WMHs). Regression analyses showed that a higher vessel wall lesion burden was associated with the presence of small subcortical infarcts, lacunes of presumed vascular origin, and deep gray matter infarcts (relative risk 1.18; 95% CI, 1.03–1.35) and presence of moderate-to-severe periventricular WMHs (1.21; 95% CI, 1.03–1.42), which are all manifestations of small vessel disease (SVD). The burden of enhancing vessel wall lesions was associated with the number of cortical microinfarcts only (1.48; 95% CI, 1.04–2.11). These results suggest an interrelationship between large vessel wall lesion burden and cerebral parenchymal manifestations often linked to SVD or, alternatively, that vascular changes occur in both large and small intracranial arteries simultaneously.

Identification of hippocampal cortical microinfarcts on postmortem 3-T magnetic resonance imaging

Cortical microinfarcts (CMI) are increasingly recognized in the neurological community as a biomarker related to cognitive impairment and dementia. If their radiological depiction has been largely described in experimental settings using ultra-high-field magnetic resonance imaging (MRI), less is known about their visibility on routinely used 3-T MRI. In this radiologic-pathologic correlation study, using 3-T post-mortem MRI, we searched for hippocampal CMI, in a double-blinded fashion, and found that only 4/36, or 11%, were clearly demonstrated on both radiological and histopathological exams.