Minocycline in Severe Cerebral Amyloid Angiopathy: A Single-Center Cohort Study

BACKGROUND: Evidence from animal studies suggests that minocycline may reduce lobar intracerebral hemorrhage (ICH) recurrence in cerebral amyloid angiopathy, possibly by inhibiting perivascular extracellular matrix degradation in cerebral small vessels. There is currently no evidence of its safety or efficacy in humans with cerebral amyloid angiopathy. METHODS AND RESULTS: To provide preliminary data to support future studies of minocycline’s efficacy, the authors performed a retrospective single-center cohort study to assess the incidence of recurrent ICH in patients with an aggressive clinical course of probable cerebral amyloid angiopathy who had been prescribed minocycline off-label via shared decision-making. Crude incidence rate ratios were calculated to compare incidence rates before versus after treatment. Sixteen patients (mean age at minocycline initiation, 66.3±3.5 years; women 62.5%; median of 3 lobar ICHs [range, 1–6]) were initiated on minocycline and followed for a median of 12.4 months (range, 1.8–61.4 months). Adverse events were reported in 4 of 16 patients (gastroenteric, n=3; dizziness, n=1) and were considered mild. ICH incidence sharply increased the year before minocycline initiation compared with the preceding years (2.18 [95% CI, 1.50–3.07] versus 0.40 [95% CI, 0.25–0.60] events per patient-year) and fell to 0.46 (95% CI, 0.23–0.83) events per patient-year afterwards. Incidence rate ratios of recurrent ICH after minocycline was lower (0.21 [95% CI, 0.11–0.42], P<0.0001) compared with the year before initiation. CONCLUSIONS: Minocycline appeared safe and generally tolerated in a small group of patients with clinically aggressive cerebral amyloid angiopathy and was associated with reduced ICH recurrence. Determining whether this reduction represents a biological response to minocycline rather than a regression to the mean, however, will require a future controlled treatment trial

The development of neurovascular coupling in the postnatal brain

In the adult brain, localized increases in neural activity almost always result in increases in local blood flow, a relationship essential for normal brain function. This coupling between neural activity and blood flow provides the basis for many neuroimaging techniques including functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS). However, functional brain imaging studies in newborns and children have detected a range of responses, including some entirely inverted with respect to those of the adult. Confusion over the properties of functional hemodynamics in the developing brain has made it challenging to interpret functional imaging data in infants and children. Additionally, developmental differences in functional hemodynamics would suggest postnatal neurovascular maturation and a unique metabolic environment in the developing brain. This thesis begins with a series of studies in which I tracked and characterized postnatal changes in functional hemodynamics in rodent models utilizing high-speed, high-resolution multi-spectral optical intrinsic and fluorescent signal imaging. I demonstrated that in early postnatal development increases in cortical blood flow do not occur in response to somatosensory stimulation. In fact, I observed stimulus-linked global vasoconstrictions in the brain. In slightly older age groups, I observed biphasic hemodynamic responses, with initial local hyperemia followed by global vasoconstriction, eventually progressing with age to recognizable adult-like hemodynamic responses. In these studies, I also found that the postnatal development of autoregulation is a potential confound in the study of early functional activation, and may account for some of the variability seen in prior human studies. Charting this progression led to the hypothesis that anomalous functional responses observed in human subjects are due to the postnatal development of neurovascular coupling itself. To directly assess neurovascular development, I performed a further set of studies in Thy1-GCaMP3 mice, permitting simultaneous observation of the development of neural function and connectivity along with functional hemodynamics. My results demonstrate that the spatiotemporal properties of neural development do not predict observed changes in the hemodynamic response, consistent with the parallel development of neural networks and neurovascular coupling. Confirming the presence of vascularly-uncoupled neural activity in the newborn brain led me to question how the brain supports its energy needs in the absence of evoked hyperemia, prompting the exploration of the potential metabolic bases and consequences of developmental changes in neurovascular coupling. Finally, I explore the cellular and vascular morphological and functional correlates of functional neurovascular development. My results confirm that neurovascular development occurs postnatally, which has critical implications for the interpretation of functional imaging studies in infants and children. My work also provides new insights into postnatal neural, metabolic, and vascular maturation and could have important implications for the care of infants and children, and for understanding the role of neurovascular development in the pathophysiology of developmental disorders

The Impact of Anti-Amyloid Immunotherapies on Stroke Care

Anti-amyloid immunotherapies have recently emerged as treatments for Alzheimer’s disease. While these therapies have demonstrated efficacy in clearing amyloid-β and slowing cognitive decline, they have also been associated with amyloid-related imaging abnormalities (ARIA) which include both edema (ARIA-E) and hemorrhage (ARIA-H). Given that ARIA have been associated with significant morbidity in cases of antithrombotic or thrombolytic therapy, an understanding of mechanisms of and risk factors for ARIA is of critical importance for stroke care. We discuss the latest data regarding mechanisms of ARIA, including the role of underlying cerebral amyloid angiopathy, and implications for ischemic stroke prevention and management

Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy

Abstract Background Cortical superficial siderosis (cSS) has recently emerged as one of the most important predictors of symptomatic intracerebral hemorrhage and is a risk factor for post-stroke dementia in cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is just a marker of severe CAA pathology or may itself contribute to intracerebral hemorrhage risk and cognitive decline. cSS is a chronic manifestation of convexal subarachnoid hemorrhage and is neuropathologically characterized by iron deposits in the superficial cortical layers. We hypothesized that these iron deposits lead to local neuroinflammation, a potentially contributory pathway towards secondary tissue injury. Methods Accordingly, we assessed the distribution of inflammatory markers in relation to cortical iron deposits in post-mortem tissue from CAA cases. Serial sections from the frontal, parietal, temporal, and occipital lobes of nineteen autopsy cases with CAA were stained with Perls’ Prussian blue (iron) and underwent immunohistochemistry against glial fibrillary acidic protein (GFAP, reactive astrocytes) and cluster of differentiation 68 (CD68, activated microglia/macrophages). Digitized sections were uploaded to the cloud-based Aiforia® platform, where deep-learning algorithms were utilized to detect tissue, iron deposits, and GFAP-positive and CD68-positive cells. Results We observed a strong local relationship between cortical iron deposits and reactive astrocytes. Like cSS-related iron, reactive astrocytes were mainly found in the most superficial layers of the cortex. Although we observed iron within both astrocytes and activated microglia/macrophages on co-stains, there was no clear local relationship between the density of microglia/macrophages and the density of iron deposits. Conclusion Iron deposition resulting from cSS is associated with local reactive astrogliosis

Neurovascular dynamics of repeated cortical spreading depolarizations after acute brain injury.

Cortical spreading depolarizations (CSDs) are increasingly suspected to play an exacerbating role in a range of acute brain injuries, including stroke, possibly through their interactions with cortical blood flow. We use simultaneous wide-field imaging of neural activity and hemodynamics in Thy1-GCaMP6f mice to explore the neurovascular dynamics of CSDs during and following Rose Bengal-mediated photothrombosis. CSDs are observed in all mice as slow-moving waves of GCaMP fluorescence extending far beyond the photothrombotic area. Initial CSDs are accompanied by profound vasoconstriction and leave residual oligemia and ischemia in their wake. Later, CSDs evoke variable responses, from constriction to biphasic to vasodilation. However, CSD-evoked vasoconstriction is found to be more likely during rapid, high-amplitude CSDs in regions with stronger oligemia and ischemia, which, in turn, worsens after each repeated CSD. This feedback loop may explain the variable but potentially devastating effects of CSDs in the context of acute brain injury

Blood-brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy

Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-β deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy-related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-β at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood-brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy-related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-β, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood-brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood-brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-β deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-β (Grade 0), and blood-brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2-4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood-brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood-brain barrier leakage as a potential trigger for subsequent perivascular inflammation

Histopathological correlates of hemorrhagic lesions on ex vivo MRI in immunized Alzheimer’s disease cases.

Hemorrhagic Amyloid-Related Imaging Abnormalities (ARIA-H) on MRI are frequently observed adverse events in the context of amyloid β (Aβ) immunotherapy trials in patients with Alzheimer’s disease (AD). The underlying histopathology and pathophysiological mechanisms of ARIA-H remain largely unknown, although coexisting cerebral amyloid angiopathy (CAA) may play a key role. Here, we used ex vivo MRI in cases that underwent Aβ immunotherapy during life to screen for hemorrhagic lesions and assess underlying tissue and vascular alterations. We hypothesized that these lesions would be associated with severe CAA.Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active Aβ immunization with AN1792 for AD (iAD cases). Eleven matched non-immunized AD cases from an independent brain brank were used as ‘controls’ (cAD cases). Formalin-fixed occipital brain slices were imaged at 7T MRI to screen for hemorrhagic lesions (i.e. microbleeds and cortical superficial siderosis). Samples with and without hemorrhagic lesions were cut and stained. AI-assisted quantification of Aβ plaque area, cortical and leptomeningeal CAA area, density of iron and calcium positive cells, and reactive astrocytes and activated microglia was performed.On ex vivo MRI, cortical superficial siderosis was observed in 5/10 iAD cases compared to 1/11 cAD cases (κ = 0.5). On histopathology, these areas revealed iron and calcium positive deposits in the cortex. Within the iAD group, areas with siderosis on MRI revealed greater leptomeningeal CAA and concentric splitting of the vessel walls compared to areas without siderosis. Moreover, greater density of iron positive cells in the cortex was associated with lower Aβ plaque area and a trend towards increased post-vaccination antibody titers. This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of hemorrhagic lesions observed in the context of Aβ immunotherapy. These findings suggest a possible role for CAA in the formation of ARIA-H, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against Aβ with available in vivo MRI during life