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[Display omitted] Microinfarcts are widespread in the elderly, accompanied by varying degrees of cognitive decline. Continuous theta burst stimulation (cTBS) has been demonstrated to be neuroprotective on cognitive dysfunction, but the underlying cellular mechanism has been still not clear. In the present study, we evaluated the effects of cTBS on cognitive function and brain pathological changes in mice model of microinfarcts. The spatial learning and memory was assessed by Morris water maze (MWM), Glymphatic clearance efficiency was evaluated using in vivo two-photon imaging. The loss of neurons, activation of astrocytes and microglia, the expression and polarity distribution of the astrocytic aquaporin-4 (AQP4) were assessed by immunofluorescence staining. Our results showed that cTBS treatment significantly improved the spatial learning and memory, accelerated the efficiency of glymphatic clearance, up-regulated the AQP4 expression and improved the polarity distribution of AQP4 in microinfarcts mice. Besides, cTBS treatment increased the number of surviving neurons, whereas decreased the activated astrocytes and microglia. Our study suggested that cTBS accelerated glymphatic clearance and inhibited the excessive gliogenesis, which ultimately exerted neuroprotective effects on microinfarcts mice. [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]

Background: Limited data exist on the significance of acute cerebral microinfarcts (A-CMIs) in the context of acute ischemic stroke (AIS). We aimed to determine the profile and prognostic significance of A-CMIs on magnetic resonance imaging (MRI) in patients presenting with AIS. Methods: A prospective single-center series of patients with AIS who had 3T MRIs between March 2013 and December 2019. The presence, number, and location of A-CMIs on diffusion-weighted imaging, and markers of cerebral small vessel disease (CSVD), macroinfarcts features, and etiology were classified as cardioembolism (CE) or large artery atherosclerosis (LAA) or none. Results: Among 273 patients, A-CMIs were detected in 130 patients (47.6%), of whom cortical A-CMIs were found in 95 (73.0%) patients. Patients with A-CMIs were significantly older, less likely to have diabetes mellitus, and more likely to have atrial fibrillation and an embolic source (CE or LAA) compared to other patients. Patients with A-CMI had a higher frequency of macroinfarcts (diameter >20 mm), more often multiple and distributed in single or multiple vessel territories than other patients. An embolic source (LAA or CE) was independently associated with cortical A-CMIs (LAA adjusted odds ratio [aOR] 4.0 95% confidence interval [CI] 1.6–9.5; CE aOR 2.5, 95% CI 1.1–5.6), whereas lacunes were independently related to subcortical A-CMIs (aOR 2.6, 95% CI 1.2–5.8). Conclusions: We have shown A-CMIs occur in cortical and subcortical regions in nearly half of AIS patients, where microembolism and CSVD are, respectively, the key presumed etiological mechanism. [ABSTRACT FROM AUTHOR]

Background: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. Methods: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110–139 mm Hg versus 140–179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. Results: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00–5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71–1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. Conclusions: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565). [ABSTRACT FROM AUTHOR]

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]

Cerebral amyloid angiopathy is a common small vessel disease in the elderly involving vascular amyloid-β deposition. Cerebral amyloid angiopathy is one of the leading causes of intracerebral hemorrhage and a significant contributor to age-related cognitive decline. The awareness of a diagnosis of cerebral amyloid angiopathy is important in clinical practice as it impacts decisions to use lifelong anticoagulation or nonpharmacological alternatives to anticoagulation such as left atrial appendage closure in patients who have concurrent atrial fibrillation, another common condition in older adults. This review summarizes the latest literature regarding the management of patients with sporadic cerebral amyloid angiopathy, including diagnostic criteria, imaging biomarkers for cerebral amyloid angiopathy severity, and management strategies to decrease intracerebral hemorrhage risk. In a minority of patients, the presence of cerebral amyloid angiopathy triggers an autoimmune inflammatory reaction, referred to as cerebral amyloid angiopathy-related inflammation, which is often responsive to immunosuppressive treatment in the acute phase. Diagnosis and management of cerebral amyloid angiopathy-related inflammation will be presented separately. While there are currently no effective therapeutics available to cure or halt the progression of cerebral amyloid angiopathy, we discuss emerging avenues for potential future interventions. [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]

Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI—ex vivo MRI—histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI−/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls (p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of microinfarcts. [ABSTRACT FROM AUTHOR]

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]

Brain microinfarcts are common in aging and are associated with cognitive impairment. Anterior and posterior watershed border zones lie at the territories of the anterior, middle, and posterior cerebral arteries, and are more vulnerable to hypoperfusion than brain regions outside the watershed areas. However, little is known about microinfarcts in these regions and how they relate to cognition in aging. Participants from the Rush Memory and Aging Project, a community-based clinical-pathologic study of aging, underwent detailed annual cognitive evaluations. We examined 356 consecutive autopsy cases (mean age-at-death, 91 years [SD = 6.16]; 28% men) for microinfarcts from 3 watershed brain regions (2 anterior and 1 posterior) and 8 brain regions outside the watershed regions. Linear regression models were used to examine the association of cortical watershed microinfarcts with cognition, including global cognition and 5 cognitive domains. Microinfarcts in any region were present in 133 (37%) participants, of which 50 had microinfarcts in watershed regions. Persons with multiple microinfarcts in cortical watershed regions had lower global cognition (estimate = −0.56, standard error (SE) = 0.26, p = 0.03) and lower cognitive function in the specific domains of working memory (estimate = −0.58, SE = 0.27, p = 0.03) and visuospatial abilities (estimate = −0.57, SE = 0.27, p = 0.03), even after controlling for microinfarcts in other brain regions, demographics, and age-related pathologies. Neither the presence nor multiplicity of microinfarcts in brain regions outside the cortical watershed regions were related to global cognition or any of the 5 cognitive domains. These findings suggest that multiple microinfarcts in watershed regions contribute to age-related cognitive impairment. [ABSTRACT FROM AUTHOR]

The incidence and severity of cerebrovascular disease (CVD) increase with advancing age, as does the risk of developing Alzheimer's disease (AD). Not surprisingly, heterogeneous forms of CVD may coexist with AD changes in the ‘ageing brain’. These include angiopathies (affecting both large and small arteries) that result from ‘classical’ risk factors (hypertension, smoking and diabetes) and others (cerebral amyloid angiopathy) that are biochemically closely linked to AD. The morphologic consequences of these various vascular diseases are infarcts and/or haemorrhages of varying sizes within the brain, which lead to neurocognitive decline that may mimic AD – though the vascular abnormalities are usually detectable by neuroimaging. More subtle effects of CVD may include neuroinflammation and biochemical ‘lesions’ that have no reliable morphologic correlate and thus escape the attention of even an experienced Neuropathologist. The pathogenesis of hippocampal injury resembling ischaemic change – commonly seen in the brains of geriatric subjects – remains controversial. In recent years, genetically determined forms of microangiopathy (e.g. CADASIL, CARASIL, Trex1‐related microangiopathies, CARASAL, familial forms of cerebral amyloid angiopathy or CAA) have provided interesting cellular and molecular clues to the pathogenesis of sporadic microvascular disease such as arteriolosclerosis and AD‐related CAA. [ABSTRACT FROM AUTHOR]

Microinfarcts result in a transient loss of the blood-brain barrier (BBB) in the ischemic territory. This leads to the extravasation of blood proteins into the brain parenchyma. It is not clear how these proteins are removed. Here we studied the role of perivascular spaces in brain clearance from extravasated blood proteins. Male and female Wistar rats were infused with microspheres of either 15, 25, or 50 μm in diameter (n = 6 rats per group) via the left carotid artery. We infused either 25,000 microspheres of 15 μm, 5500 of 25 μm, or 1000 of 50 μm. One day later, rats were infused with lectin and hypoxyprobe to label perfused blood vessels and hypoxic areas, respectively. Rats were then euthanized and perfusion-fixed. Brains were excised, sectioned, and analyzed using immunostaining and confocal imaging. Microspheres induced a size-dependent increase in ischemic volume per territory, but the cumulative ischemic volume was similar in all groups. The total volumes of ischemia, hypoxia and infarction affected 1–2 % of the left hemisphere. Immunoglobulins (IgG) were present in ischemic brain tissue surrounding lodged microspheres in all groups. In addition, staining for IgG was found in perivascular spaces of blood vessels nearby areas of BBB disruption. About 2/3 of these vessels were arteries, while the remaining 1/3 of these vessels were veins. The subarachnoid space (SAS) of the affected hemisphere stained stronger for IgG than the contralateral hemisphere in all groups: +27 %, +44 % and +27 % respectively. Microspheres of various sizes induce a local loss of BBB integrity, evidenced by parenchymal IgG staining. The presence of IgG in perivascular spaces of both arteries and veins distinct from the ischemic territories suggests that both contribute to the removal of blood proteins. The strong staining for IgG in the SAS of the affected hemisphere suggests that this perivascular route egresses via the CSF. Perivascular spaces therefore play a previously unrecognized role in tissue clearance of fluid and extravasated proteins after BBB disruption induced by microinfarcts. • Microinfarcts induce leakage of blood proteins across the blood-brain barrier. • Immunoglobulins appear in perivascular spaces nearby sites of leakage. • Perivascular spaces of both arteries and veins may contribute to clearance of blood proteins into the cerebrospinal fluid. [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]

Microinfarcts are common in patients with cognitive decline and dementia. Allopurinol (ALLO), a xanthine oxidase (XO) enzyme inhibitor, has been found to reduce proinflammatory molecules and oxidative stress in the vasculature. We here examined the effect of pre-treatment with allopurinol on the cortical microinfarction. C57BL/6J mice were subjected to a permanent single penetrating arteriole occlusion induced by two-photon laser irradiation. Infarction volume, the activation of glial cells and nitrosative stress in the ischemic brain was assessed using immunohistochemistry. Pre-treatment with ALLO achieved 42% reduction of infarct volume and significantly reduced microglia infiltration, astrocyte proliferation and nitrosative stress in the ischemic brain. These data indicate that ALLO protects against microinfarcts possibly through inhibition of nitrosative stress and attenuation of microglia infiltration as well as astrocytes reactivation. [ABSTRACT FROM AUTHOR]

This article highlights select advances in the management of stroke, including stem cell therapy, endovascular therapy, and physical therapy. It discusses the gender and sex effect, the global importance of intracerebral hemorrhage, the role of the extracellular matrix in cerebral small vessel disease, and the clinical trials network, StrokeNet. [ABSTRACT FROM PUBLISHER]

Cerebral microinfarcts (CMIs) are a common finding in neuropathological studies of aging and dementia. Recently, it has become possible to detect CMIs in vivo. We studied CMI occurrence in 29 patients with mild cognitive impairment or early Alzheimer's disease (AD) and 22 non-demented individuals on 7Tesla MRI. CMI occurrence in patients (55%) and controls (45%) was not significantly different. In patients, CMI number tended to be related to microbleed number (p = 0.07). This first in vivo study of CMIs in early AD does not confirm findings from autopsy studies. Further studies are needed to clarify the role of CMIs in AD. [ABSTRACT FROM AUTHOR]

Neuroimaging with iron-sensitive MR sequences [gradient echo T2* and susceptibility-weighted imaging (SWI)] identifies small signal voids that are suspected brain microbleeds. Though the clinical significance of these lesions remains uncertain, their distribution and prevalence correlates with cerebral amyloid angiopathy (CAA), hypertension, smoking, and cognitive deficits. Investigation of the pathologies that produce signal voids is necessary to properly interpret these imaging findings. We conducted a systematic correlation of SWI-identified hypointensities to tissue pathology in postmortem brains with Alzheimer’s disease (AD) and varying degrees of CAA. Autopsied brains from eight AD patients, six of which showed advanced CAA, were imaged at 3T; foci corresponding to hypointensities were identified and studied histologically. A variety of lesions was detected; the most common lesions were acute microhemorrhage, hemosiderin residua of old hemorrhages, and small lacunes ringed by hemosiderin. In lesions where the bleeding vessel could be identified, β-amyloid immunohistochemistry confirmed the presence of β-amyloid in the vessel wall. Significant cellular apoptosis was noted in the perifocal region of recent bleeds along with heme oxygenase 1 activity and late complement activation. Acutely extravasated blood and hemosiderin were noted to migrate through enlarged Virchow– Robin spaces propagating an inflammatory reaction along the local microvasculature; a mechanism that may contribute to the formation of lacunar infarcts. Correlation of imaging findings to tissue pathology in our cases indicates that a variety of CAA-related pathologies produce MR-identified signal voids and further supports the use of SWI as a biomarker for this disease. [ABSTRACT FROM AUTHOR]

Current neuropathologic consensus criteria for diagnosis of dementia yield a classification of processes that likely contributed to dementia in that individual. While dementia diagnosis currently relies on clinical criteria, practicing neuropathologists and researchers might benefit from a simple, accurate risk scoring protocol for the neuropathologic diagnosis of dementia. Using 232 consecutive autopsies from the population-based Adult Changes in Thought study, we developed two logistic regression-based risk scoring systems; one solely using neuropathologic measures and a second additionally including demographic information. Inverse-probability weighting was used to adjust for inherent selection bias in autopsy-based studies of dementing illnesses. Both systems displayed high levels of predictive accuracy; bias-adjusted area-under-the-curve statistics were 0.78 (95% CI 0.71, 0.85) and 0.87 (95% CI 0.83, 0.92), indicating improved performance with the inclusion of demographic characteristics, specifically age and birth cohort information. Application of the combined neuropathlogy/demographic model yielded bias-adjusted sensitivity and specificity of 81% each. In contrast, application of NIA-Reagan criteria yielded sensitivity and specificity of 53% and 84%. Our proposed scoring systems provide neuropathologists with tools to make a diagnosis, and interpret their diagnosis in the light of known sensitivity and specificity estimates. Evaluation in independent samples will be important to verify our findings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Click here to view the accompanying paper in this volume. [ABSTRACT FROM AUTHOR]