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INTRODUCTION: Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited. METHODS: Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts (N = 680; 89 ± 9 years old; 25% dementia) to the US‐representative Health and Retirement Study (N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross‐sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression. RESULTS: In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory. DISCUSSION: Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve. Highlights: Loneliness was associated with worse cognition in five domains.Loneliness was associated with the presence of microinfarcts.Loneliness moderated cognition–neuropathology associations.Transportability methods can provide insight into selection bias. [ABSTRACT FROM AUTHOR]

Mid-life high blood pressure (BP) is a risk factor for cerebral microinfarcts. Less is known about the relationship between late-life BP and cerebral microinfarcts, the examination of which is the objective of the current study. This case–control study analyzed data from 551 participants (94.6% aged ≥80 years; 58.6% women) in the Adult Changes in Thought (ACT) study who had autopsy data on microinfarcts and four values of systolic and diastolic blood pressure (SBP and DBP) before death. Using the average of four values, SBP was categorized using 10 mmHg intervals; a trend was defined as a ≥10 mmHg rise or fall from the first to fourth values (average gap of 6.5 years). Multivariable-adjusted regression models were used to examine the associations of BP and microinfarcts, adjusting for age, sex, last BP-to-death time, APOE genotype, and antihypertensive medication use. Microinfarcts were present in 274 (49.7%) participants; there were multiple in 51.8% of the participants, and they were located in cortical areas in 40.5%, subcortical areas in 29.6%, and both areas in 29.9% of the participants. All SBP categories (reference of 100–119 mmHg) and both SBP trends were associated with higher odds of both the presence and number of microinfarcts. The magnitude of these associations was numerically greater for subcortical than cortical microinfarcts. Similar associations were observed with DBP. These hypothesis-generating findings provide new information about the overall relationship between BP and cerebral microinfarcts in octogenarians. [ABSTRACT FROM AUTHOR]

Cerebral microinfarcts are associated with cognitive impairment and dementia. Small vessel diseases such as cerebral arteriolosclerosis and cerebral amyloid angiography (CAA) have been found to be associated with microinfarcts. Less is known about the associations of these vasculopathies with the presence, numbers, and location of microinfarcts. These associations were examined in the clinical and autopsy data of 842 participants in the Adult Changes in Thought (ACT) study. Both vasculopathies were categorized by severity (none, mild, moderate, and severe) and region (cortical and subcortical). Odds ratios (OR) and 95% CIs for microinfarcts associated with arteriolosclerosis and CAA adjusted for possible modifying covariates such as age at death, sex, blood pressure, APOE genotype, Braak, and CERAD were estimated. 417 (49.5%) had microinfarcts (cortical, 301; subcortical, 249), 708 (84.1%) had cerebral arteriolosclerosis, 320 (38%) had CAA, and 284 (34%) had both. Ors (95% CI) for any microinfarct were 2.16 (1.46–3.18) and 4.63 (2.90–7.40) for those with moderate (n = 183) and severe (n = 124) arteriolosclerosis, respectively. Respective Ors (95% CI) for the number of microinfarcts were 2.25 (1.54–3.30) and 4.91 (3.18–7.60). Similar associations were observed for cortical and subcortical microinfarcts. Ors (95% Cis) for the number of microinfarcts associated with mild (n = 75), moderate (n = 73), and severe (n = 15) amyloid angiopathy were 0.95 (0.66–1.35), 1.04 (0.71–1.52), and 2.05 (0.94–4.45), respectively. Respective Ors (95% Cis) for cortical microinfarcts were 1.05 (0.71–1.56), 1.50 (0.99–2.27), and 1.69 (0.73–3.91). Respective Ors (95% Cis) for subcortical microinfarcts were 0.84 (0.55–1.28), 0.72 (0.46–1.14), and 0.92 (0.37–2.28). These findings suggest a significant association of cerebral arteriolosclerosis with the presence, number, and location (cortical and subcortical) of microinfarcts, and a weak and non-significant association of CAA with each microinfarct, highlighting the need for future research to better understand the role of small vessel diseases in the pathogenesis of cerebral microinfarcts. [ABSTRACT FROM AUTHOR]

Abstract Background As currently defined, recent small subcortical infarcts (RSSI) do not have a lower size boundary, and the smallest diffusion-weighted imaging (DWI) infarcts, which we term acute subcortical cerebral microinfarcts (As-CMI) with lesion diameter less than 5 mm, might have clinical implications distinct from RSSI. We aimed to investigate the distinct characteristics of As-CMI as compared to the larger size of RSSI regarding vascular risk factors, clinical manifestation, radiological markers of SVD distribution, and outcomes. Methods In a consecutive cohort, patients were selected with a magnetic resonance DWI-confirmed RSSI between January 2010 and November 2020. We measured axial infarct diameter and classified patients into two groups: The As-CMI group (diameter

The mouse model of multiple cerebral infarctions, established by injecting fluorescent microspheres into the common carotid artery, is a recent development in animal models of cerebral ischemia. To investigate its effectiveness, mouse models of cerebral infarction were created by injecting fluorescent microspheres, 45–53 µm in diameter, into the common carotid artery. Six hours after modeling, fluorescent microspheres were observed directly through a fluorescence stereomicroscope, both on the brain surface and in brain sections. Changes in blood vessels, neurons and glial cells associated with microinfarcts were examined using fluorescence histochemistry and immunohistochemistry. The microspheres were distributed mainly in the cerebral cortex, striatum and hippocampus ipsilateral to the side of injection. Microinfarcts were found in the brain regions where the fluorescent microspheres were present. Here the lodged microspheres induced vascular and neuronal injury and the activation of astroglia and microglia. These histopathological changes indicate that this animal model of multiple cerebral infarctions effectively simulates the changes of various cell types observed in multifocal microinfarcts. This model is an effective, additional tool to study the pathogenesis of ischemic stroke and could be used to evaluate therapeutic interventions. This study was approved by the Animal Ethics Committee of the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences (approval No. D2021-03-16-1) on March 16, 2021.

Introduction: Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited., Methods: Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts (N = 680; 89 ± 9 years old; 25% dementia) to the US-representative Health and Retirement Study (N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross-sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression., Results: In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory., Discussion: Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve., Highlights: Loneliness was associated with worse cognition in five domains. Loneliness was associated with the presence of microinfarcts. Loneliness moderated cognition-neuropathology associations. Transportability methods can provide insight into selection bias., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Microglia, the resident immune cells in the central nervous system, canmonitor the microenvironment and actively respond to ischemic stroke and other brain injuries. In this procedure, microglia and neurons can cross-talk via transmembrane chemokine, Fractalkine (CX3CL1), to impact one another. We used a rat model of multifocal microinfarcts induced by the injection of fluorescent microspheres into the right common carotid artery and examined the morphological alteration of blood vessels, microglia, astrocytes, and neurons at 6 h, 1, 7, and 14 days after modeling, along with neurobehavioral tests and the staining of CX3CL1 in this study. Our results demonstrated that in the infarcted regions, astrocytes and microglia activated in response to neuronal degeneration and upregulation of cleaved caspase-3, which occurred concurrently with vascular alteration and higher expression of CX3CL1. We provided sequential histological data to shed light on the morphological changes after modeling, which would help in the identification of new targets and the choice of the ideal time window for therapeutic intervention in ischemic stroke. [ABSTRACT FROM AUTHOR]

Abstract Background Cerebral microinfarcts (MIs) lead to progressive cognitive impairments in the elderly, and there is currently no effective preventative strategy due to uncertainty about the underlying pathogenic mechanisms. One possibility is the dysfunction of GABAergic transmission and ensuing excitotoxicity. Dysfunction of GABAergic transmission induces excitotoxicity, which contributes to stroke pathology, but the mechanism has kept unknown. The secreted leucine-rich repeat (LRR) family protein slit homologue 2 (Slit2) upregulates GABAergic activity and protects against global cerebral ischemia, but the neuroprotective efficacy of Slit2 against MIs has not been examined. Methods Middle-aged Wild type (WT) and Slit2-Tg mice were divided into sham and MI treatment groups. MIs were induced in parietal cortex by laser-evoked arteriole occlusion. Spatial memory was then compared between sham and MI groups using the Morris water maze (MWM) task. In addition, neuronal activity, blood brain barrier (BBB) permeability, and glymphatic clearance in peri-infarct areas were compared using two-photon imaging, while GABAergic transmission, microglial activation, neuronal loss, and altered cortical connectivity were compared by immunofluorescent staining or western blotting. Results Microinfarcts increased the amplitude and frequency of spontaneous intracellular Ca2+ signals, reduced neuronal survival and connectivity within parietal cortex, decreased the number of GABAergic interneurons and expression of vesicular GABA transporter (VGAT), induced neuroinflammation, and impaired both glymphatic clearance and spatial memory. Alternatively, Slit2 overexpression attenuated dysfunctional neuronal Ca2+ signaling, protected against neuronal death in the peri-infarct area as well as loss of parietal cortex connectivity, increased GABAergic interneuron number and VGAT expression, attenuated neuroinflammation, and improved both glymphatic clearance and spatial memory. Conclusion Our results strongly suggest that overexpression of Slit2 protected against the dysfunction in MIs, which is a potential therapeutic target for cognition impairment in the elderly.

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. [ABSTRACT FROM AUTHOR]

Cortical superficial siderosis is an established haemorrhagic neuroimaging marker of cerebral amyloid angiopathy. In fact, cortical superficial siderosis is emerging as a strong independent risk factor for future lobar intracerebral haemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cortical superficial siderosis remain elusive. Here we use an in vivo MRI, ex vivo MRI, histopathology approach to assess the neuropathological correlates and vascular pathology underlying cortical superficial siderosis. Fourteen autopsy cases with cerebral amyloid angiopathy (mean age at death 73 years, nine males) and three controls (mean age at death 91 years, one male) were included in the study. Intact formalin-fixed cerebral hemispheres were scanned on a 3 T MRI scanner. Cortical superficial siderosis was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, 11 representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI-defined cortical superficial siderosis. In addition, samples were taken from predefined standard areas of the brain, blinded to MRI findings. Serial sections were stained for haematoxylin and eosin and Perls' Prussian blue, and immunohistochemistry was performed against amyloid-β and GFAP. Cortical superficial siderosis was present on ex vivo MRI in 8/14 cases (57%) and 0/3 controls (P = 0.072). Histopathologically, cortical superficial siderosis corresponded to iron-positive haemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels. Increased severity of cortical superficial siderosis was associated with upregulation of reactive astrocytes. Next, cortical superficial siderosis was assessed on a total of 65 Perls'-stained sections from MRI-targeted and untargeted sampling combined in cerebral amyloid angiopathy cases. Moderate-to-severe cortical superficial siderosis was associated with concentric splitting of the vessel wall (an advanced form of cerebral amyloid angiopathy-related vascular damage) in leptomeningeal vessels (P < 0.0001), but reduced cerebral amyloid angiopathy severity in cortical vessels (P = 0.048). In terms of secondary tissue injury, moderate-to-severe cortical superficial siderosis was associated with the presence of microinfarcts (P = 0.025), though not microbleeds (P = 0.973). Collectively, these data suggest that cortical superficial siderosis on MRI corresponds to iron-positive deposits in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. Cortical superficial siderosis appears to be the result of predominantly advanced cerebral amyloid angiopathy of the leptomeningeal vessels and may trigger secondary ischaemic injury in affected areas. [ABSTRACT FROM AUTHOR]

Background and purpose: Cerebral microinfarcts (CMIs) are associated with cognitive impairment and dementia. CMIs might affect cognitive performance through disruption of cerebral networks. We investigated in memory clinic patients whether cortical CMIs are clustered in specific brain regions and if presence of cortical CMIs is associated with reduced white matter (WM) connectivity in tracts projecting to these regions.Methods:164 memory clinic patients with vascular brain injury with a mean age of 72 ± 11 years (54% male) were included. All underwent 3 tesla MRI, including a diffusion MRI and cognitive testing. Cortical CMIs were rated according to established criteria and their spatial location was marked. Diffusion imaging-based tractography was used to reconstruct WM connections and voxel based analysis (VBA) to assess integrity of WM directly below the cortex. WM connectivity and integrity were compared between patients with and without cortical CMIs for the whole brain and regions with a high CMI burden.Results:30 patients (18%) had at least 1 cortical CMI [range 1–46]. More than 70% of the cortical CMIs were located in the superior frontal, middle frontal, and pre- and postcentral brain regions (covering 16% of the cortical surface). In these high CMI burden regions, presence of cortical CMIs was not associated with WM connectivity after correction for conventional neuroimaging markers of vascular injury. WM connectivity in the whole brain and WM voxels directly underneath the cortical surface did not differ between patients with and without cortical CMIs.Conclusion:Cortical CMIs displayed a strong local clustering in highly interconnected frontal, pre- and postcentral brain regions. Nevertheless, WM connections projecting to these regions were not disproportionally impaired in patients with compared to patients without cortical CMIs. Alternative mechanisms, such as focal disturbances in cortical structure and functioning, may better explain CMI associated cognitive impairment.

Small vessel disease is characterized by sporadic obstruction of small vessels leading to neuronal cell death. These microinfarcts often escape detection by conventional magnetic resonance imaging and are identified only upon postmortem examination. Our work explores a brain-wide microinfarct model in awake head-fixed mice, where occlusions of small penetrating arterioles are reproduced by endovascular injection of fluorescent microspheres. Mesoscopic functional connectivity was mapped longitudinally in awake GCaMP6 mice using genetically encoded calcium indicators for transcranial wide-field calcium imaging. Microsphere occlusions were quantified and changes in cerebral blood flow were measured with laser speckle imaging. The neurodeficit score in microinfarct mice was significantly higher than in sham, indicating impairment in motor function. The novel object recognition test showed a reduction in the discrimination index in microinfarct mice compared to sham. Graph-theoretic analysis of functional connectivity did not reveal significant differences in functional connectivity between sham and microinfarct mice. While behavioral tasks revealed impairments following microinfarct induction, the absence of measurable functional alterations in cortical activity has a less straightforward interpretation. The behavioral alterations produced by this model are consistent with alterations observed in human patients suffering from microinfarcts and support the validity of microsphere injection as a microinfarct model. [ABSTRACT FROM AUTHOR]

Background and purpose: Cerebral microinfarcts (CMIs) are associated with cognitive impairment and dementia. CMIs might affect cognitive performance through disruption of cerebral networks. We investigated in memory clinic patients whether cortical CMIs are clustered in specific brain regions and if presence of cortical CMIs is associated with reduced white matter (WM) connectivity in tracts projecting to these regions. Methods: 164 memory clinic patients with vascular brain injury with a mean age of 72 ± 11 years (54% male) were included. All underwent 3 tesla MRI, including a diffusion MRI and cognitive testing. Cortical CMIs were rated according to established criteria and their spatial location was marked. Diffusion imaging-based tractography was used to reconstruct WM connections and voxel based analysis (VBA) to assess integrity of WM directly below the cortex. WM connectivity and integrity were compared between patients with and without cortical CMIs for the whole brain and regions with a high CMI burden. Results: 30 patients (18%) had at least 1 cortical CMI [range 1–46]. More than 70% of the cortical CMIs were located in the superior frontal, middle frontal, and pre- and postcentral brain regions (covering 16% of the cortical surface). In these high CMI burden regions, presence of cortical CMIs was not associated with WM connectivity after correction for conventional neuroimaging markers of vascular injury. WM connectivity in the whole brain and WM voxels directly underneath the cortical surface did not differ between patients with and without cortical CMIs. Conclusion: Cortical CMIs displayed a strong local clustering in highly interconnected frontal, pre- and postcentral brain regions. Nevertheless, WM connections projecting to these regions were not disproportionally impaired in patients with compared to patients without cortical CMIs. Alternative mechanisms, such as focal disturbances in cortical structure and functioning, may better explain CMI associated cognitive impairment. [ABSTRACT FROM AUTHOR]

Clinical studies have revealed a strong link between increased burden of cerebral microinfarcts and risk for cognitive impairment. Since the sum of tissue damage incurred by microinfarcts is a miniscule percentage of total brain volume, we hypothesized that microinfarcts disrupt brain function beyond the injury site visible to histological or radiological examination. We tested this idea using a mouse model of microinfarcts, where single penetrating vessels that supply mouse cortex were occluded by targeted photothrombosis. We found that in vivo structural and diffusion MRI reliably reported the acute microinfarct core, based on spatial co-registrations with post-mortem stains of neuronal viability. Consistent with our hypothesis, c-Fos assays for neuronal activity and in vivo imaging of single vessel hemodynamics both reported functional deficits in viable peri-lesional tissues beyond the microinfarct core. We estimated that the volume of tissue with functional deficit in cortex was at least 12-fold greater than the volume of the microinfarct core. Impaired hemodynamic responses in peri-lesional tissues persisted at least 14 days, and were attributed to lasting deficits in neuronal circuitry or neurovascular coupling. These data show how individually miniscule microinfarcts could contribute to broader brain dysfunction during vascular cognitive impairment and dementia. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy is a common neuropathological finding in the ageing human brain, associated with cognitive impairment. Neuroimaging markers of severe cerebral amyloid angiopathy are cortical microbleeds and microinfarcts. These parenchymal brain lesions are considered key contributors to cognitive impairment. Therefore, they are important targets for therapeutic strategies and may serve as surrogate neuroimaging markers in clinical trials. We aimed to gain more insight into the pathological basis of magnetic resonance imaging-defined microbleeds and microinfarcts in cerebral amyloid angiopathy, and to explore the pathological burden that remains undetected, by using high and ultra-high resolution ex vivo magnetic resonance imaging, as well as detailed histological sampling. Brain samples from five cases (mean age 85 ± 6 years) with pathology-proven cerebral amyloid angiopathy and multiple microbleeds on in vivo clinical magnetic resonance imaging were subjected to high-resolution ex vivo 7 T magnetic resonance imaging. On the obtained high-resolution (200 μm isotropic voxels) ex vivo magnetic resonance images, 171 microbleeds were detected compared to 66 microbleeds on the corresponding in vivo magnetic resonance images. Of 13 sampled microbleeds that were matched on histology, five proved to be acute and eight old microhaemorrhages. The iron-positive old microhaemorrhages appeared approximately four times larger on magnetic resonance imaging compared to their size on histology. In addition, 48 microinfarcts were observed on ex vivo magnetic resonance imaging in three out of five cases (two cases exhibited no microinfarcts). None of them were visible on in vivo 1.5 T magnetic resonance imaging after a retrospective analysis. Of nine sampled microinfarcts that were matched on histology, five were confirmed as acute and four as old microinfarcts. Finally, we explored the proportion of microhaemorrhage and microinfarct burden that is beyond the detection limits of ex vivo magnetic resonance imaging, by scanning a smaller sample at ultra-high resolution, followed by serial sectioning. At ultra-high resolution (75 μm isotropic voxels) magnetic resonance imaging we observed an additional 48 microbleeds (compared to high resolution), which proved to correspond to vasculopathic changes (i.e. morphological changes to the small vessels) instead of frank haemorrhages on histology. After assessing the serial sections of this particular sample, no additional haemorrhages were observed that were missed on magnetic resonance imaging. In contrast, nine microinfarcts were found in these sections, of which six were only retrospectively visible at ultra-high resolution. In conclusion, these findings suggest that microbleeds on in vivo magnetic resonance imaging are specific for microhaemorrhages in cerebral amyloid angiopathy, and that increasing the resolution of magnetic resonance images results in the detection of more 'non-haemorrhagic' pathology. In contrast, the vast majority of microinfarcts currently remain under the detection limits of clinical in vivo magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25–30% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood–brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. [ABSTRACT FROM AUTHOR]

Background: To further our understanding of the pathophysiology of spontaneous intracerebral hemorrhage (ICH) and related injury, we provided a postmortem neuropathological examination of acute microvascular lesions (microbleeds and microinfarcts) within the perihematomal area., Methods: We included all consecutive cases (2005-2019) from the Lille University Hospital brain bank of ICH patients who died within the first month. Paraffin-embedded tissue sections from the perihematomal area were processed for several stainings and immunolabelings to investigate the presence of acute microbleeds and microinfarcts in the perihematomal area and to characterize surrounding neuronal and systemic inflammatory reaction (macrophages and neutrophils)., Results: We included 14 ICH cases (median age, 78 years; 10 females). Acute microbleeds were observed in the perihematomal area in 12/14 patients (86%, ranging from 1 through >10) and microinfarcts in 5/14 (36%, ranging from 1 through 4). Microbleeds were observed whatever the delay from ICH onset to death was, while most cases with acute microinfarcts were observed between day 3 and day 7 (n=3/5). Both lesions were characterized by an abundant accumulation of systemic inflammatory cells and necrotic areas., Conclusions: Acute microbleeds and microinfarcts might contribute to the propagation of secondary brain tissue damages after ICH. Our examinations also question the potential role of massive systemic inflammatory cells recruitment in the genesis of these microvascular injuries.

Microglia, the resident immune cells in the central nervous system, can monitor the microenvironment and actively respond to ischemic stroke and other brain injuries. In this procedure, microglia and neurons can cross-talk via transmembrane chemokine, Fractalkine (CX3CL1), to impact one another. We used a rat model of multifocal microinfarcts induced by the injection of fluorescent microspheres into the right common carotid artery and examined the morphological alteration of blood vessels, microglia, astrocytes, and neurons at 6 h, 1, 7, and 14 days after modeling, along with neurobehavioral tests and the staining of CX3CL1 in this study. Our results demonstrated that in the infarcted regions, astrocytes and microglia activated in response to neuronal degeneration and upregulation of cleaved caspase-3, which occurred concurrently with vascular alteration and higher expression of CX3CL1. We provided sequential histological data to shed light on the morphological changes after modeling, which would help in the identification of new targets and the choice of the ideal time window for therapeutic intervention in ischemic stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen, Cui, Zhang, Wang, Wang, Su, Xu, Liu, Guo and Bai.)

The mouse model of multiple cerebral infarctions, established by injecting fluorescent microspheres into the common carotid artery, is a recent development in animal models of cerebral ischemia. To investigate its effectiveness, mouse models of cerebral infarction were created by injecting fluorescent microspheres, 45-53 µm in diameter, into the common carotid artery. Six hours after modeling, fluorescent microspheres were observed directly through a fluorescence stereomicroscope, both on the brain surface and in brain sections. Changes in blood vessels, neurons and glial cells associated with microinfarcts were examined using fluorescence histochemistry and immunohistochemistry. The microspheres were distributed mainly in the cerebral cortex, striatum and hippocampus ipsilateral to the side of injection. Microinfarcts were found in the brain regions where the fluorescent microspheres were present. Here the lodged microspheres induced vascular and neuronal injury and the activation of astroglia and microglia. These histopathological changes indicate that this animal model of multiple cerebral infarctions effectively simulates the changes of various cell types observed in multifocal microinfarcts. This model is an effective, additional tool to study the pathogenesis of ischemic stroke and could be used to evaluate therapeutic interventions. This study was approved by the Animal Ethics Committee of the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences (approval No. D2021-03-16-1) on March 16, 2021., Competing Interests: None

Brain microinfarcts are prevalent in humans, however because of the inherent difficulty of identifying and localizing individual microinfarcts, brain-wide quantification is impractical. In mice, microinfarcts have been created by surgically introducing microemboli into the brain, but a major limitation of this model is the absence of automated methods to identify and localize individual occlusions. We present a novel and semi-automated workflow to identify the anatomic location of fluorescent emboli (microspheres) within the mouse brain through histologic processing and atlas registration. By incorporating vibratome block-face imaging with the QuickNII brain registration tool, we show that the anatomic location of microspheres can be accurately registered to brain structures within the Allen mouse brain (AMB) atlas (e. g , somatomotor areas, hippocampal region, visual areas, etc.). Compared with registering images of slide mounted sections to the AMB atlas, microsphere location was more accurately determined when block-face images were used. As a proof of principle, using this workflow we compared the distribution of microspheres within the brains of mice that were either perfused or immersion fixed. No significant effect of perfusion on total microsphere number or location was detected. In general, microspheres were distributed brain-wide, with the largest density found in the thalamus. In sum, our block-face imaging workflow enables efficient characterization of the widespread distribution of fluorescent microemboli, facilitating future investigation into the impact of microinfarct load and location on brain health., (Copyright © 2021 McDonald et al.)

ABSTRACT Cerebrovascular disease and AD pathology co-exist in most dementia cases, and microinfarcts (MIs), particularly if cortical and multiple, play an additive and independent role in AD cognitive impairment. The main cause of cortical MIs is chronic cerebral hypoperfusion but occlusive vascular diseases, embolism and blood-brain barrier disruptions, isolated or combined, may also play a role. The precise mechanisms by which MIs cause cognitive impairment are not well known, but one plausible explanation is that they are widespread and accompanied by diffuse hypoperfusion, hypoxia, oxidative stress and inflammation, particularly in the watershed areas of the tertiary association cortex, and hence could damage cognition networks and explain many of AD's cognitive and behavioral disturbances. Therefore, it is crucial to control vascular risk factors and avoid uncontrolled use of the antihypertensives, neuroleptics and other sedative drugs frequently prescribed to AD patients.

Background and Purpose: Carotid endarterectomy (CEA) is performed to prevent cerebral infarction, but a common side effect is cerebral microinfarcts. This study aimed to identify the variables related to the production of microinfarcts during CEA as well as determine their association with delayed postoperative infarction., Methods: This was a retrospective review of data collected prospectively from 548 patients who underwent CEA. The clinical characteristics of the patients and the incidence rates and causes of microinfarcts were analyzed. Microinfarcts were diagnosed by diffusion-weighted magnetic resonance imaging. The presence of delayed postoperative infarction was compared between microinfarct-positive and microinfarct-negative groups., Results: In total, 76 (13.86%) patients were diagnosed with microinfarcts. Preoperative neurological symptoms were significantly related to the incidence of microinfarcts [odds ratio (OR)=2.93, 95% confidence interval (CI)=1.72-5.00, p<0.001]. Shunt insertion during CEA was the only significant procedure-related risk factor (OR=1.42, 95% CI=1.00-2.19, p=0.05). The presence of microinfarcts did not significantly increase the incidence of delayed postoperative infarction (p=0.204)., Conclusions: In the present study, risk factors for microinfarcts after CEA included preoperative symptoms and intraoperative shunt insertion. Microinfarcts were not associated with delayed postoperative infarction., Competing Interests: The authors have no financial conflicts of interest.

Hippocampal focal T2 hyperintensities (HT2Hs), also referred to as hippocampal sulcal cavities, are a common finding on Magnetic Resonance (MR) images. There is uncertainty about their etiology and clinical significance. In this study we aimed to describe these HT2Hs in more detail using high resolution 7 Tesla MR imaging, addressing 1) the MR signal characteristics of HT2Hs, 2) their occurrence frequency, 3) their location within the hippocampus, and 4) their relation with age. We also performed an explorative post-mortem study to examine the histology of HT2Hs. Fifty-eight persons without a history of invalidating neurological or psychiatric disease (mean age 64 ± 8 years; range 43-78 years), recruited through their general practitioners, were included in this study. They all underwent 7 Tesla MRI, including a T1, T2, and FLAIR image. MR signal characteristics of the HT2Hs were assessed on these images by two raters. Also, the location and number of the HT2Hs were assessed. In addition, four formalin-fixed brain slices from two subjects were scanned overnight. HT2Hs identified in these slices were subjected to histopathological analysis. HT2Hs were present in 97% of the subjects (median number per person 10; range 0-20). All HT2Hs detected on the T2 sequence were hypointense on T1 weighted images. Of all HT2Hs, 94% was hypointense and 6% hyperintense on FLAIR. FLAIR hypointense HT2Hs were all located in the vestigial sulcus of the hippocampus, FLAIR hyperintense HT2Hs in the hippocampal sulcus or the gray matter. Post-mortem MRI and histopathological analysis suggested that the hypointense HT2Hs on FLAIR were cavities filled with cerebrospinal fluid. A hyperintense HT2H on FLAIR proved to be a microinfarct upon microscopy. In conclusion, hippocampal T2Hs are extremely common and unrelated to age. They can be divided into two types (hypo- and hyperintense on FLAIR), probably with different etiology.

Cerebrovascular disease and AD pathology co-exist in most dementia cases, and microinfarcts (MIs), particularly if cortical and multiple, play an additive and independent role in AD cognitive impairment. The main cause of cortical MIs is chronic cerebral hypoperfusion but occlusive vascular diseases, embolism and blood-brain barrier disruptions, isolated or combined, may also play a role. The precise mechanisms by which MIs cause cognitive impairment are not well known, but one plausible explanation is that they are widespread and accompanied by diffuse hypoperfusion, hypoxia, oxidative stress and inflammation, particularly in the watershed areas of the tertiary association cortex, and hence could damage cognition networks and explain many of AD's cognitive and behavioral disturbances. Therefore, it is crucial to control vascular risk factors and avoid uncontrolled use of the antihypertensives, neuroleptics and other sedative drugs frequently prescribed to AD patients., Competing Interests: Disclosure: The authors report no conflicts of interest.