Hemostasis components in cerebral amyloid angiopathy and Alzheimer’s disease

Ziliotto, Nicole; Bernardi, Francesco; Piazza, Fabrizio

doi:10.1007/s10072-021-05327-7

Cited by 17 publications

(13 citation statements)

References 122 publications

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“…The review of lessons learned from the last decade of research confirmed the ARIA Paradox as the most accredited pathophysiologic model to explain the biological complexity of ARIA-E. 1 , 4 , 5 , 10 , 12 , 42 According to this model, ARIA-E is a complex and multifactorial phenomenon resulting from the imbalance between the removal of Aβ deposited in plaques, which is attributed to the dose, time, and type of anti-Aβ (auto)antibodies, and the downstream effects that an excessive mobilization of Aβ can cause on intramural periarterial drainage pathways, 43 which may account for increased transient CAA, cerebrovascular impairment, greater vascular permeability, and an easier extravasation of proteinaceous fluid and VE, particularly in ApoE ε4 carriers. 1 , 2 , 10 , 12 , 44 – 46 …”

Section: Discussionmentioning

confidence: 99%

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies

et al. 2022

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Background and Objectives:Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer’s disease (AD) immunotherapy with anti-amyloid-beta (Aβ) monoclonal antibodies (mAbs). ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased cerebrospinal fluid (CSF) levels of anti-Aβ autoantibodies. Although the pathophysiological mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex-vivo studies suggest that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated.Methods:Spatial distribution and temporal variations of microglial activation associated with ARIA-E and CSF anti-Aβ autoantibody levels at (sub)acute presentation and after corticosteroid therapy, in a longitudinal case series of patients with CAA-ri, an increasingly recognized spontaneous model of the iatrogenic ARIA-E in AD immunotherapy. Multimodal and multiparametric magnetic resonance imaging (MRI) for CAA and ARIA-E quantification, as measured with validated MRI scoring systems; CSF testing for anti-Aβ autoantibodies and AD biomarkers; 11C-PK11195 positron emission tomography (PET) for activated microglia.Results:At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial co-localization with ARIA-E compared to chronic age-related white matter change (ARWMC) imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation was greater in patients having AD and severe CAA concomitant disease, compared to patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at post-treatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation.Discussion:Our findings extend the current notion of ARIA-E by providing the first in vivo11C-PK11195-PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease..Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.

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Section: Discussionmentioning

confidence: 99%

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies

et al. 2022

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“…One possibility is the enrichment in fibrinolysis regulators we observed in T66M upregulated genes, none of which were differentially expressed among shared, or R47H/+-specific altered genes. In addition to their roles in blood clotting, fibrinolysis regulators can modulate extracellular matrix remodeling and blood-brain barrier permeability that can impact brain health (Patel et al, 2008; Ziliotto et al, 2021). Blood brain barrier damage and the presence of auto-antibodies have been reported in PLOSL patients, potentially due to dysregulated fibrinolysis (Errichiello et al, 2019; Kalimo et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Distinct effects of disease-associated TREM2 R47H/+ and T66M mutations on iPSC-derived microglia

Penney

Ralvenius

Loon

et al. 2022

Preprint

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Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). Distinct mutations in the microglial protein TREM2 (triggering receptor expressed on myeloid cells 2) are associated with different forms of neurodegeneration in humans; R47H/+ mutations increase AD risk, while loss-of-function mutations such as TREM2 T66M result in more severe forms of neurodegeneration. We employed gene editing and stem cell models to gain insight into the effects of these mutations on human iPSC-derived microglia. We found divergent effects of TREM2 R47H/+ and T66M mutations on gene expression, with R47H/+ cells exhibiting a pro-inflammatory gene expression signature. Both the TREM2 R47H/+ and T66M mutations caused similar impairments in microglial movement and the uptake of multiple substrates, while R47H/+ microglia were hyper-responsive to inflammatory stimuli, consistent with their gene expression signature. We developed an in vitro laser-induced injury model in neuron-microglia co-cultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, in xenotransplantation experiments, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density. Consistently, we observed upregulation of multiple complement cascade components in TREM2 R47H/+ microglia, suggesting that inappropriate synaptic pruning may underlie the effect. Thus, these findings identify shared and distinct effects of these two TREM2 mutations on microglial gene expression and function. While the TREM2 T66M mutation impairs microglial movement and uptake processes, the TREM2 R47H/+ mutation additionally confers multiple potentially detrimental effects on human microglia, likely to underlie its association with AD.

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“…A paper from Roussel et al ( 2009 ) reported that whereas aging does not have an effect on the expression and proteolytic activity of tPA in the intravascular space, it had a significant impact on its expression and activity in the brain parenchyma. As for the effects of pathological aging on tPA plasma levels, previous studies reported discordant findings, with studies showing either decrease (see Whelan et al, 2019 ; Ziliotto et al, 2021 for review), increase (Hagnelius et al, 2010 ), or no differences (Marksteiner et al, 2014 ) in AD patients compared to controls .…”

Section: Introductionmentioning

confidence: 99%

Plasma Levels of Tissue-Type Plasminogen Activator (tPA) in Normal Aging and Alzheimer's Disease: Links With Cognition, Brain Structure, Brain Function and Amyloid Burden

Tomadesso

Lizarrondo

Ali

et al. 2022

Front. Aging Neurosci.

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Tissue-type plasminogen activator (tPA) is a protease known for its fibrinolytic action but is also involved in physiological and pathophysiological aging processes; including amyloid elimination and synaptic plasticity. The aim of the study was to investigate the role of tPA in cognitive and brain aging. Therefore, we assessed the links between tPA plasma concentration and cognition, structural MRI, FDG-PET and Flobetapir-PET neuroimaging in 155 cognitively unimpaired adults (CUA, aged 20-85 years old) and 32 patients with Alzheimer's disease (ALZ). A positive correlation was found between tPA and age in CUA (p < 0.001), with males showing higher tPA than females (p = 0.05). No significant difference was found between ALZ patients and cognitively unimpaired elders (CUE). Plasma tPA in CUA negatively correlated with global brain volume. No correlation was found with brain FDG metabolism or amyloid deposition. Age-related tPA changes were associated to changes in blood pressure, glycemia and body mass index. Within the ALZ patients, tPA didn't correlate with any cognitive or neuroimaging measures, but only with physiological measures. Altogether our study suggests that increased tPA plasma concentration with age is related to neuronal alterations and cardiovascular risk factors.

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Hemostasis components in cerebral amyloid angiopathy and Alzheimer’s disease

Cited by 17 publications

References 122 publications

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies

Distinct effects of disease-associated TREM2 R47H/+ and T66M mutations on iPSC-derived microglia

Plasma Levels of Tissue-Type Plasminogen Activator (tPA) in Normal Aging and Alzheimer's Disease: Links With Cognition, Brain Structure, Brain Function and Amyloid Burden

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