RESUMEN
Brain amyloid-ß (Aß) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aß40 peptide, whereas Aß42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aß isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aß isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of Aß1-34, Aß1-37, Aß1-38, Aß1-39, Aß1-40, and Aß1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aß peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aß1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aß1-42, none of the Aß peptides were decreased in AD-like subjects compared with controls. All Aß peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without Aß1-42 in the model (since decreased Aß1-42 served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF Aß profiles. Peptides shorter than Aß1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aß accumulation. This study supports the potential use of this panel of CSF Aß peptides to indicate presence of CAA pathology with high accuracy.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Angiopatía Amiloide Cerebral , Humanos , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Femenino , Masculino , Anciano , Biomarcadores/líquido cefalorraquídeo , Persona de Mediana Edad , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano de 80 o más AñosRESUMEN
AIMS: Cerebral amyloid angiopathy (CAA)-related inflammation (CAA-RI) is a potentially reversible manifestation of CAA, histopathologically characterised by transmural and/or perivascular inflammatory infiltrates. We aimed to identify clinical, radiological and laboratory variables capable of improving or supporting the diagnosis of or predicting/influencing the prognosis of CAA-RI and to retrospectively evaluate different therapeutic approaches. METHODS: We present clinical and neuroradiological observations in seven unpublished CAA-RI cases, including neuropathological findings in two definite cases. These cases were included in a systematic analysis of probable/definite CAA-RI cases published in the literature up to 31 December 2021. Descriptive and associative analyses were performed, including a set of clinical, radiological and laboratory variables to predict short-term, 6-month and 1-year outcomes and mortality, first on definite and second on an expanded probable/definite CAA-RI cohort. RESULTS: Data on 205 definite and 100 probable cases were analysed. CAA-RI had a younger symptomatic onset than non-inflammatory CAA, without sex preference. Transmural histology was more likely to be associated with the co-localisation of microbleeds with confluent white matter hyperintensities on magnetic resonance imaging (MRI). Incorporating leptomeningeal enhancement and/or sulcal non-nulling on fluid-attenuated inversion recovery (FLAIR) enhanced the sensitivity of the criteria. Cerebrospinal fluid pleocytosis was associated with a decreased probability of clinical improvement and longer term positive outcomes. Future lobar haemorrhage was associated with adverse outcomes, including mortality. Immunosuppression was associated with short-term improvement, with less clear effects on long-term outcomes. The superiority of high-dose over low-dose corticosteroids was not established. CONCLUSIONS: This is the largest retrospective associative analysis of published CAA-RI cases and the first to include an expanded probable/definite cohort to identify diagnostic/prognostic markers. We propose points for further crystallisation of the criteria and directions for future prospective studies.
Asunto(s)
Angiopatía Amiloide Cerebral , Humanos , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/patología , Hemorragia Cerebral , Inflamación/patología , Imagen por Resonancia Magnética , Pronóstico , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Plasma amyloid beta (Aß) and tau are emerging as accessible biomarkers for Alzheimer's disease (AD). However, many assays exist with variable test performances, highlighting the need for a comparative assessment to identify the most valid assays for future use in AD and to apply to other settings in which the same biomarkers may be useful, namely, cerebral amyloid angiopathy (CAA). CAA is a progressive cerebrovascular disease characterized by deposition of Aß40 and Aß42 in cortical and leptomeningeal vessels. Novel immunotherapies for AD can induce amyloid-related imaging abnormalities resembling CAA-related inflammation. Few studies have evaluated plasma biomarkers in CAA. Identifying a CAA signature could facilitate diagnosis, prognosis, and a safer selection of patients with AD for emerging immunotherapies. This review evaluates studies that compare the diagnostic test performance of plasma biomarker techniques in AD and cerebrovascular and plasma biomarker profiles of CAA; it also discusses novel hypotheses and future avenues for plasma biomarker research in CAA.
Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Humanos , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Angiopatía Amiloide Cerebral/diagnóstico , Inflamación , BiomarcadoresRESUMEN
Cerebral amyloid angiopathy (CAA) is the most frequent cause of lobar hemorrhages in the brains of elderly individuals. It is characterized by the deposition of amyloidogenic proteins in the vessel wall of leptomeningeal and/or intracerebral blood vessels. Different proteins can cause CAA. Most frequently, the amyloid ß protein (Aß) is found to be deposited in CAA and indicates a link to Alzheimer's disease, because Aß is known to be deposited in amyloid plaques characteristic of Alzheimer's disease. Among other proteins that can also cause CAA, transthyretin (TTR) is the most important one because TTR amyloidosis can be successfully treated. Therefore, it is essential to diagnose TTR-related CAA even in biopsies taken in the context of cerebral hematoma evacuations if possible. The current "Boston criteria version 2.0" for the diagnosis of CAA highlight the importance of autopsy for the definite diagnosis of CAA and biopsies for the diagnosis of probable CAA. Here, we discuss the implications of Aß-related and non-Aß-related forms of CAA for their current diagnostic relevance also in the context of neurodegenerative diseases as well as the implications of the Boston criteria version 2.0 for neuropathological diagnosis.
Asunto(s)
Enfermedad de Alzheimer , Amiloidosis , Angiopatía Amiloide Cerebral , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/etiología , Encéfalo/patología , Amiloidosis/patología , Hemorragia Cerebral/etiologíaRESUMEN
Cerebral amyloid angiopathy (CAA) is a disease with several clinical manifestations. It is characterised by amyloid-beta deposition in cerebral blood vessels, making them prone to bleeding. The incidence of CAA increases with age and may be associated or co-exist with intraparenchymal neurodegenerative proteinopathies, which makes it an increasingly relevant condition for adult physicians in all areas of medical practice. The vast majority of cases of CAA are sporadic with a small minority of familial cases. CAA is asymptomatic in many older adults but increases the risk of fatal intracerebral or subarachnoid haemorrhage. We review the existing literature on CAA and summarise the key findings. We specifically explore clinical challenges relevant to CAA, particularly in diagnosis, management of intracranial haemorrhage and management of concurrent medical conditions.
Asunto(s)
Angiopatía Amiloide Cerebral , Hemorragia Subaracnoidea , Humanos , Anciano , Australia/epidemiología , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/epidemiología , Angiopatía Amiloide Cerebral/terapia , Hemorragias Intracraneales/complicaciones , Incidencia , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/epidemiología , Imagen por Resonancia MagnéticaRESUMEN
The majority of small vessel diseases is related to vascular risk factors or sporadic amyloid angiopathy, but a minority is caused by genetic, immune, or infectious diseases. In this article, we propose a pragmatic approach for the diagnosis and treatment of rare causes of cerebral small vessel disease.
La majorité des maladies des petits vaisseaux est liée à des facteurs de risque vasculaire ou à l'angiopathie amyloïde sporadique, mais une minorité est causée par des maladies génétiques, immunologiques ou infectieuses. Dans cet article, nous proposons une approche diagnostique et une prise en charge pragmatiques des maladies rares des petits vaisseaux cérébraux.
Asunto(s)
Angiopatía Amiloide Cerebral , Enfermedades de los Pequeños Vasos Cerebrales , Enfermedades Vasculares , Humanos , Encéfalo/irrigación sanguínea , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico , Factores de Riesgo , Enfermedades Vasculares/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnósticoRESUMEN
Cerebral amyloid angiopathy (CAA) is a common and well-defined small vessel disease characterized by the deposition of amyloid ß in the vascular wall. CAA causes devastating outcomes related to intracerebral hemorrhage and cognitive decline in older adults. The shared pathogenic pathway between CAA and Alzheimer's disease, co-occuring frequently in the same subject, has important implications for cognitive outcomes and novel anti-amyloid-ß immunotherapies. In this review, we present the epidemiology, pathophysiology, current diagnostic criteria of CAA, and future developments in the field.
L'angiopathie amyloïde cérébrale (AAC) est une maladie fréquente des petits vaisseaux, caractérisée par un dépôt de ß-amyloïde dans la paroi vasculaire entraînant des hémorragies cérébrales et un déclin cognitif. L'AAC et la maladie d'Alzheimer présentent des caractéristiques physiopathologiques communes et peuvent se retrouver chez un même individu. Cela influence le tableau cognitif et sera à prendre en compte lors de l'utilisation prochaine des nouvelles immunothérapies anti-amyloïde. Dans cet article, nous passons en revue l'épidémiologie, la pathophysiologie, les présentations cliniques ainsi que les critères diagnostiques de l'AAC et discutons des futurs développements dans le domaine.
Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Disfunción Cognitiva , Humanos , Anciano , Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/epidemiología , Enfermedad de Alzheimer/complicaciones , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/etiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiologíaRESUMEN
OBJECTIVE: We sought to determine whether extracranial carotid atherosclerotic disease (ECAD) is associated with increased key neurodegenerative pathology such as neurofibrillary tangle (NFT), beta-amyloid plaque, or cerebral amyloid angiopathy (CAA) accumulation, findings associated with Alzheimer's disease (AD) and other dementias. METHODS: Our prospective, longitudinal, clinicopathologic study, the AZSAND (Arizona study of aging and neurodegenerative disorders) and Brain and Body Donation Program, recorded the presence or absence of clinically diagnosed ECAD and performed semiquantitative density estimates of NFT, beta-amyloid plaque, and CAA at death. After adjusting for potential confounding factors determined by logistic regression analysis, histopathology density scores were evaluated in individuals with ECAD (n = 66) and those without ECAD (n = 125). RESULTS: We found that the presence of ECAD was associated with a 21% greater NFT burden at death compared with no ECAD (P = .02). Anatomically, an increased NFT burden was seen throughout the brain regions evaluated but was significant in the temporal lobe (P < .05) and entorhinal cortex (P = .02). In addition, we found that subjects who had undergone carotid endarterectomy (CEA), the surgical treatment of ECAD (n = 32), had decreased NFT densities compared with those with ECAD who had not undergone CEA (n = 66; P = .04). In contrast to NFT, ECAD was not associated with beta-amyloid plaques or CAA density. CONCLUSIONS: These findings indicate that ECAD is associated with the NFT burden in the temporal lobe and entorhinal cortex, which has clinical significance for AD and non-AD dementias and cognitive dysfunction. Further understanding of whether ECAD increases the risk of neurodegenerative brain changes is highly relevant because ECAD is a treatable disease that has not, otherwise, been evaluated for nor specifically treated as a dementia risk factor.
Asunto(s)
Enfermedad de Alzheimer/epidemiología , Enfermedades de las Arterias Carótidas/epidemiología , Angiopatía Amiloide Cerebral/epidemiología , Disfunción Cognitiva/epidemiología , Ovillos Neurofibrilares/patología , Placa Amiloide/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Región CA1 Hipocampal/patología , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/patología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/patología , Corteza Entorrinal/patología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Placa Amiloide/diagnóstico , Placa Amiloide/patología , Estudios Prospectivos , Medición de Riesgo/estadística & datos numéricos , Factores de RiesgoRESUMEN
BACKGROUND: CAA is a heterogeneous group of diseases caused by Aß deposition in the vascular walls, often leading to lobar ICH and cognitive impairment. Although CAA is rare in younger patients, it has been associated with specific mutations as well as with other causes. CASE PRESENTATION: We present four cases of patients with CAA and recurrent ICH who have a history of severe TBI in childhood. CONCLUSION: Our cases as well as review of the literature suggest that a history of TBI in patients with genetic predispositions such as male sex may be associated with CAA in young persons.
Asunto(s)
Angiopatía Amiloide Cerebral , Traumatismos Craneocerebrales , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/genética , Traumatismos Craneocerebrales/epidemiología , Predisposición Genética a la Enfermedad , Humanos , MasculinoRESUMEN
Cerebral amyloid angiopathy (CAA) is closely related to Alzheimer's disease (AD) despite having distinct pathomechanisms. The CAA modulates cognitive impairment within AD by synergistic effects. The pathophysiologic relations are complex and incompletely understood, possibly due to the heterogeneous nature of CAA with its different subtypes. Both diseases are characterized by a pathologic amyloid metabolism but the pathologic processing of amyloid precursor proteins is distinct. The manifestation of vascular and parenchymal amyloid deposits can either overlap or occur independently and isolated. The investigation of the specific contribution of co-occurring CAA within AD to cognitive deficits requires diagnostic methods that sufficiently identify CAA severity and complexity as well as detailed neuropsychological testing to precisely characterize the cognitive deficits and to draw conclusions regarding their etiology.
Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Disfunción Cognitiva , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/terapia , Disfunción Cognitiva/etiología , Humanos , Pruebas Neuropsicológicas , Placa Amiloide/complicacionesRESUMEN
Oral anticoagulation in patients with cerebral amyloid angiopathy is a therapeutic challenge. The association of cerebral amyloid angiopathy with intracerebral hemorrhage, a high mortality of intracerebral hemorrhage especially under oral anticoagulation and the high risk of recurrent bleeding require a multidisciplinary approach and a thorough risk-benefit analysis. Vitamin K antagonists increase the risk of intracerebral bleeding and the accompanying mortality by 60% and should be avoided if possible or reserved for special clinical situations (e.g. mechanical aortic valve replacement). Treatment with novel oral anticoagulants and antiplatelet drugs also increases the risk of cerebral bleeding and therefore needs a thorough risk-benefit evaluation. An interventional left atrial appendage closure is a promising therapeutic option especially in patients with an absolute arrythmia with atrial fibrillation. Furthermore, other clinical implications in patients with cerebral amyloid angiopathy are the subject of this review of the literature, such as special characteristics after acute ischemic stroke and the necessary secondary prophylaxis, with previous intracerebral hemorrhage and in patients with cognitive deficits.
Asunto(s)
Fibrilación Atrial , Angiopatía Amiloide Cerebral , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Anticoagulantes/uso terapéutico , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico , Humanos , Accidente Cerebrovascular/complicacionesRESUMEN
Cerebral amyloid angiopathy is a devastating cause of intracerebral hemorrhage for which there is no specific secondary stroke prevention treatment. Here we review the current literature regarding cerebral amyloid angiopathy pathophysiology and treatment, as well as what is known of the fibrinolytic pathway and its interaction with amyloid. We postulate that tranexamic acid is a potential secondary stroke prevention treatment agent in sporadic cerebral amyloid angiopathy, although further research is required.
Asunto(s)
Antifibrinolíticos/administración & dosificación , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Fibrinolisina/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/sangre , Anticuerpos Monoclonales/administración & dosificación , Angiopatía Amiloide Cerebral/sangre , Angiopatía Amiloide Cerebral/diagnóstico , Hemorragia Cerebral/sangre , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/tratamiento farmacológico , Fibrinolisina/metabolismo , Humanos , Ácido Tranexámico/administración & dosificaciónRESUMEN
OBJECTIVES: To clarify pathomechanisms of cerebral amyloid angiopathy-related inflammation/vasculitis (CAA-ri). METHODS: We collected cerebrospinal fluid (CSF) samples of nine patients with CAA-ri of before (acute CAA-ri group) and after treatment (post-treatment CAA-ri group) and nine patients with CAA (CAA without inflammation group). We examined anti-amyloid ß protein (Aß) antibody titer by ELISA, and measured 27 Cytokines, nine matrix metalloproteinases (MMPs), and four tissue inhibitors of MMPs (TIMPs) by multiplexed fluorescent bead-based immunoassay. RESULTS: We demonstrated TIMP-2 (median) in CSF of the acute CAA-ri group (30,994.49 pg/ml, p = 0.007) and the post-treatment CAA-ri group (36,430.97 pg/ml, p = 0.001) was significantly elevated compared to that of the CAA without inflammation group (22,013.58 pg/ml). TIMP-1 was also higher in the post-treatment CAA-ri group than that in the CAA without inflammation group (58,167.75 pg/ml vs. 45,770.03 pg/ml, p = 0.005). There was a significant positive correlation between TIMP-1 and anti-Aß antibodies in CAA-ri (rs = 0.900, p = 0.037). Median MMP-2 tended to be higher in the acute and post-treatment CAA-ri groups (10,619.82 pg/ml and 8396.98 pg/ml, respectively) than in the CAA without inflammation group (4436.34 pg/ml). Platelet-derived growth factor (PDGF)-BB levels before treatment were higher than those after treatment (median, 12.66 pg/ml vs. 6.39 pg/ml; p = 0.011) and correlated with the titer of anti-Aß antibodies (rs =0.900, p = 0.037). CONCLUSIONS: Elevated levels of MMP-2, TIMP-1, and TIMP-2 might be related to the development of CAA-ri. Elevation of PDGF-BB could be a useful marker for clinical diagnosis of CAA-ri.
Asunto(s)
Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/diagnóstico , Citocinas/líquido cefalorraquídeo , Mediadores de Inflamación/líquido cefalorraquídeo , Metaloproteasas/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
Cerebral amyloid angiopathy (CAA) most commonly presents with lobar intracerebral haemorrhage, though also with transient focal neurological episodes, cognitive impairment, as an incidental finding and rarely acutely or subacutely in patients developing an immune response to amyloid. Convexity subarachnoid haemorrhage, cortical superficial siderosis and lobar cerebral microbleeds are the other signature imaging features. The main implications of a diagnosis are the risk of intracerebral haemorrhage and frequent co-existence of antithrombotic indications. The risk of intracerebral haemorrhage varies by phenotype, being highest in patients with transient focal neurological episodes and lowest in patients with isolated microbleeds. There is only one relevant randomised controlled trial to CAA patients with antithrombotic indications: RESTART showed that in patients presenting with intracerebral haemorrhage while taking antiplatelets, restarting treatment appeared to reduce recurrent intracerebral haemorrhage and improve outcomes. Observational and indirect data are reviewed relevant to other scenarios where there are antithrombotic indications. In patients with a microbleed-only phenotype, the risk of ischaemic stroke exceeds the risk of intracerebral haemorrhage at all cerebral microbleed burdens. In patients with atrial fibrillation (AF), left atrial appendage occlusion, where device closure excludes the left atrial appendage from the circulation, can be considered where the risk of anticoagulation seems prohibitive. Ongoing trials are testing the role of direct oral anticoagulant (DOACs) and left atrial appendage occlusion in patients with intracerebral haemorrhage/AF but in the interim, treatment decisions will need to be individualised and remain difficult.
Asunto(s)
Isquemia Encefálica , Angiopatía Amiloide Cerebral , Accidente Cerebrovascular , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/diagnóstico por imagen , Fibrinolíticos/efectos adversos , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid ß (Aß) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aß deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aß cytotoxicity, Aß fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aß deposits and molecules that accumulate with Aß may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.
Asunto(s)
Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/terapia , Animales , Biomarcadores , Angiopatía Amiloide Cerebral/etiología , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/patología , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Proteoma , Proteómica/métodosRESUMEN
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the deposition of amyloid beta-peptide (Aß) aggregates. Aß aggregates lead to vessel rupture and intracerebral hemorrhages, detected by magnetic resonance imaging (MRI). Presenile CAA is usually genetically determined by mutations in the amyloid precursor protein (APP) gene. However, mutations after codon 200 in the presenilin 1 (PSEN1) gene have been reported to facilitate CAA onset. Here, we analyzed the genetic bases in a patient of 55 years old affected by CAA and cognitive decline. DNA was isolated and genetic analysis was performed by Next-Generation Sequencing (NGS). RNA was extracted and retro-transcribed to perform segregation analysis by TOPO-TA cloning. WB analysis was carried out to check the impact of the mutations on protein. Two compound heterozygous mutations in PSEN1 exon 10, such as a novel stop-gain mutation (c.1070C > G) and a pathogenic splice variant (c.1129A > T), were found by NGS. Both mutations altered the presenilin 1 protein, truncating its C-terminal portion. This is the first case of CAA and cognitive decline caused by two compound mutations in PSEN1. With this report, we suggest extending the genetic analysis to PSEN1 when cerebral microbleeds are observed by MRI investigation in a patient affected by presenile cognitive decline.
Asunto(s)
Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/genética , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Mutación , Presenilina-1/genética , Alelos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Análisis Mutacional de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Moleculares , Fenotipo , Presenilina-1/química , Conformación ProteicaRESUMEN
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.
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Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Hemorragia Cerebral/patología , Imagen de Difusión por Resonancia Magnética , Anciano de 80 o más Años , Autopsia/métodos , Angiopatía Amiloide Cerebral/diagnóstico , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodosAsunto(s)
Angiopatía Amiloide Cerebral/diagnóstico , Disfunción Cognitiva/etiología , Lóbulo Frontal/patología , Biopsia , Encéfalo/diagnóstico por imagen , Angiopatía Amiloide Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico por imagen , Diagnóstico Diferencial , Femenino , Cefalea/etiología , Humanos , Imagen por Resonancia Magnética , Trastornos de la Memoria/etiología , Meningoencefalitis/diagnóstico , Persona de Mediana EdadRESUMEN
OBJECTIVE: To describe the clinical, laboratory, and imaging features and course of patients with primary central nervous system vasculitis (PCNSV) presenting with an intracranial tumor-like mass (TLM). METHODS: We retrospectively studied a cohort of 191 consecutive patients with PCNSV seen at the Mayo Clinic, Rochester, MN over a 35-year period (1982-2017). 13/191 patients presented with a TLM. We compared the findings in these 13 patients with those from the 178 without this presentation. RESULTS: In 13 of 191 (6.8%) patients with TLM the diagnosis of PCNSV was established by cerebral biopsy. Granulomatous vasculitis was found in 11/13 patients, accompanied by vascular deposits of ß-amyloid peptide in 7. Compared to the 178 patients without TLM, the patients with TLM were more likely to be male (pâ¯=â¯0.04), and less likely to have a transient ischemic attack (pâ¯=â¯0.023), bilateral cerebral infarcts (pâ¯=â¯0.018), or vasculitic lesions on angiography (pâ¯=â¯0.045). They were more likely to have seizures (pâ¯=â¯0.022), gadolinium-enhanced lesions (pâ¯=â¯0.007), and amyloid angiopathy (pâ¯=â¯0.046). All 13 patients responded to therapy and 8/13 (61.5%) had a Rankin disability score of 0â¯at last visit. Overall, high disability scores (Rankin scores 4-6) at last follow-up were associated with increasing age (odds ratio, OR, 1.49) and cerebral infarction (OR, 3.47), but were less likely in patients with gadolinium-enhanced lesions (OR, 0.36) and amyloid angiopathy (OR, 0.21). CONCLUSION: In PCNSV a TLM at presentation represents a definable subgroup of patients with a favourable treatment response.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Vasculitis del Sistema Nervioso Central/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Biopsia , Neoplasias Encefálicas/etiología , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/etiología , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Evaluación de Síntomas , Vasculitis del Sistema Nervioso Central/etiologíaRESUMEN
INTRODUCTION: Blood-based biomarkers of pathophysiological brain amyloid ß (Aß) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. METHODS: We investigated whether plasma concentrations of the Aß1-40/Aß1-42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aß positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. RESULTS: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aß1-40/Aß1-42 ratio. The accuracy is not affected by the apolipoprotein E (APOE) ε4 allele, sex, or age. DISCUSSION: Our results encourage an independent validation cohort study to confirm the indication that the plasma Aß1-40/Aß1-42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design.