RESUMEN
Importance: Recent reports have suggested that cerebral amyloid angiopathy, a common cause of multiple spontaneous intracerebral hemorrhages (ICHs), may be transmissible through parenteral injection of contaminated cadaveric pituitary hormone in humans. Objective: To determine whether spontaneous ICH in blood donors after blood donation is associated with development of spontaneous ICH in transfusion recipients. Design, Setting, and Participants: Exploratory retrospective cohort study using nationwide blood bank and health register data from Sweden (main cohort) and Denmark (validation cohort) and including all 1â¯089â¯370 patients aged 5 to 80 years recorded to have received a red blood cell transfusion from January 1, 1970 (Sweden), or January 1, 1980 (Denmark), until December 31, 2017. Exposures: Receipt of red blood cell transfusions from blood donors who subsequently developed (1) a single spontaneous ICH, (2) multiple spontaneous ICHs, or (3) no spontaneous ICH. Main Outcomes and Measures: Spontaneous ICH in transfusion recipients; ischemic stroke was a negative control outcome. Results: A total of 759â¯858 patients from Sweden (median age, 65 [IQR, 48-73] years; 59% female) and 329â¯512 from Denmark (median age, 64 [IQR, 50-73] years; 58% female) were included, with a median follow-up of 5.8 (IQR, 1.4-12.5) years and 6.1 (IQR, 1.5-11.6) years, respectively. Patients who underwent transfusion with red blood cell units from donors who developed multiple spontaneous ICHs had a significantly higher risk of a single spontaneous ICH themselves, compared with patients receiving transfusions from donors who did not develop spontaneous ICH, in both the Swedish cohort (unadjusted incidence rate [IR], 3.16 vs 1.12 per 1000 person-years; adjusted hazard ratio [HR], 2.73; 95% CI, 1.72-4.35; P < .001) and the Danish cohort (unadjusted IR, 2.82 vs 1.09 per 1000 person-years; adjusted HR, 2.32; 95% CI, 1.04-5.19; P = .04). No significant difference was found for patients receiving transfusions from donors who developed a single spontaneous ICH in the Swedish cohort (unadjusted IR, 1.35 vs 1.12 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.84-1.36; P = .62) nor the Danish cohort (unadjusted IR, 1.36 vs 1.09 per 1000 person-years; adjusted HR, 1.06; 95% CI, 0.70-1.60; P = .73), nor for ischemic stroke as a negative control outcome. Conclusions and Relevance: In an exploratory analysis of patients who received red blood cell transfusions, patients who underwent transfusion with red blood cells from donors who later developed multiple spontaneous ICHs were at significantly increased risk of spontaneous ICH themselves. This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of cerebral amyloid angiopathy might explain this association.
Asunto(s)
Angiopatía Amiloide Cerebral , Hemorragia Cerebral , Enfermedades Transmisibles , Transfusión de Eritrocitos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Donantes de Sangre , Angiopatía Amiloide Cerebral/epidemiología , Angiopatía Amiloide Cerebral/etiología , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/etiología , Accidente Cerebrovascular Isquémico/etiología , Estudios Retrospectivos , Transfusión de Eritrocitos/efectos adversos , Sistema de Registros , Suecia/epidemiología , Dinamarca/epidemiología , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Anciano de 80 o más Años , Receptores de Trasplantes , Enfermedades Transmisibles/epidemiología , Enfermedades Transmisibles/etiología , Enfermedades Transmisibles/transmisiónRESUMEN
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
Host responses to anti-amyloid-ß (Aß) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aß clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aß drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aß were present throughout the cerebral cortex. Phagocytosis of parenchymal Aß plaques was noted. Changes suggestive of Aß and phosphorylated tau "clearing" were also noted. The findings overall suggest that anti-Aß treatment stimulated a host response to Aß, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aß phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases.
Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Femenino , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/terapia , Activador de Tejido Plasminógeno , Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/terapia , Angiopatía Amiloide Cerebral/etiología , Encéfalo/patología , Inmunoterapia/efectos adversosRESUMEN
Cerebral small vessel diseases (CSVDs) are prominent contributors to vascular cognitive impairment and dementia and can arise from a range of etiologies. Cerebral amyloid angiopathy (CAA) and hypertension (HTN), both prevalent in the elderly population, lead to cerebral microhemorrhages, macrohemorrhages, and white matter damage. However, their respective underlying mechanisms and molecular events are poorly understood. Here, we show that the transgenic rat model of CAA type 1 (rTg-DI) exhibits perivascular inflammation that is lacking in the spontaneously hypertensive stroke-prone (SHR-SP) rat model of HTN. Alternatively, SHR-SP rats display notable dilation of arteriolar perivascular spaces. Comparative proteomics analysis revealed few shared altered proteins, with key proteins such as ANXA3, H2A, and HTRA1 unique to rTg-DI rats, and Nt5e, Flot-1 and Flot-2 unique to SHR-SP rats. Immunolabeling confirmed that upregulation of ANXA3, HTRA1, and neutrophil extracellular trap proteins were distinctly associated with rTg-DI rats. Pathway analysis predicted activation of TGF-ß1 and TNFα in rTg-DI rat brain, while insulin signaling was reduced in the SHR-SP rat brain. Thus, we report divergent protein signatures associated with distinct cerebral vessel pathologies in the SHR-SP and rTg-DI rat models and provide new mechanistic insight into these different forms of CSVD.
Asunto(s)
Angiopatía Amiloide Cerebral , Enfermedades de los Pequeños Vasos Cerebrales , Hipertensión , Anciano , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/patología , Angiopatía Amiloide Cerebral/etiología , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/patología , Enfermedades de los Pequeños Vasos Cerebrales/patología , Modelos Animales de Enfermedad , Serina Peptidasa A1 que Requiere Temperaturas Altas/metabolismo , Humanos , Hipertensión/complicaciones , Hipertensión/metabolismo , Hipertensión/patología , Proteómica , Ratas , Ratas Endogámicas SHRRESUMEN
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 degenerative neurovascular disease in which the protein amyloid-beta accumulates in the vessel wall of cortical and leptomeningeal arteries. This may lead to acute lobar cerebral haemorrhage, which in case of CAA is fatal in 10-30% of cases. CAA may also present with transient focal neurological episodes (TFNE), the symptoms of which may mimic a transient ischaemic attack (TIA). Distinction between the two has important implications for therapy, as antithrombotics are relatively contra-indicated in CAA, but indicated after a TIA. We describe a patient with transient focal neurological deficits who was initially treated with antithrombotic therapy for a suspected TIA. Eventually, the diagnosis CAA was made and antithrombotic treatment was ceased. This case stresses the importance of considering the diagnosis CAA with TFNE in patients presenting with transient neurological deficits, in order to avoid an unnecessarily increased risk of symptomatic and possibly fatal cerebral haemorrhage.
Asunto(s)
Angiopatía Amiloide Cerebral/diagnóstico , Ataque Isquémico Transitorio/diagnóstico , Anciano , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/etiología , Hemorragia Cerebral , Diagnóstico Diferencial , Humanos , Imagen por Resonancia Magnética , Masculino , Diagnóstico Erróneo , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
We retrospectively studied the T2 star (T2*)-weighted magnetic resonance imaging (MRI) of a 40-year-old patient diagnosed with symptomatic early-onset cerebral amyloid angiopathy (CAA), occurring 34 years following childhood neurosurgery using a cadaveric dural patch. Our findings revealed that CAA associated with cadaveric dural transplantation could progress rapidly, sometimes with bilateral bleeding. This microbleed evolution is suggestive of water-soluble amyloid-ß transmission via cerebrospinal fluid alongside perivascular drainage pathways with deposition in the cerebral artery walls due to clearance disturbances. Multiple intracerebral hemorrhages associated with CAA with a childhood cadaveric dural graft should be considered a life-threatening medical complication.
Asunto(s)
Trasplante de Tejido Encefálico/efectos adversos , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Duramadre/cirugía , Imagen por Resonancia Magnética , Complicaciones Posoperatorias/diagnóstico por imagen , Adulto , Péptidos beta-Amiloides/líquido cefalorraquídeo , Cadáver , Angiopatía Amiloide Cerebral/etiología , Humanos , Masculino , Complicaciones Posoperatorias/etiologíaRESUMEN
Hypertension, including transient events, is a major risk factor for developing late-onset dementia and Alzheimer's disease (AD). Anti-hypertensive drugs facilitate restoration of normotension without amelioration of increased dementia risk suggesting that transient hypertensive insults cause irreversible damage. This study characterized the contribution of transient hypertension to sustained brain damage as a function of normal aging and AD. To model transient hypertension, we treated F344TgAD and non-transgenic littermate rats with L-NG-Nitroarginine methyl ester (L-NAME) for one month, ceased treatment and allowed for a month of normotensive recovery. We then examined the changes in the structure and function of the cerebrovasculature, integrity of white matter, and progression of AD pathology. As independent factors, both transient hypertension and AD compromised structural and functional integrity across the vascular bed, while combined effects of hypertension and AD yielded the largest deficits. Combined effects of transient hypertension and AD genotype resulted in loss of cortical myelin particularly in the cingulate cortex which is crucial for cognitive function. Increased cerebral amyloid angiopathy, a prominent pathology of AD, was detected after transient hypertension as were up- and down-regulation of proteins associated with cerebrovascular remodeling - osteopontin, ROCK1 and ROCK2, in F344TgAD rats even 30 days after restoration of normotension. In conclusion, transient hypertension caused permanent cerebrovasculature and brain parenchymal damage in both normal aging and AD. Our results corroborate human studies that have found close correlation between transient hypertension in midlife and white matter lesions later in life outlining vascular pathologies as pathological links to increased risk of dementia.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Encéfalo/patología , Angiopatía Amiloide Cerebral/etiología , Hipertensión/complicaciones , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/fisiopatología , Angiopatía Amiloide Cerebral/patología , Modelos Animales de Enfermedad , Femenino , Genotipo , Humanos , Masculino , Ratas , Ratas Endogámicas F344 , Ratas Transgénicas , Sustancia Blanca/patología , Sustancia Blanca/fisiopatologíaRESUMEN
A 76-year-old woman with a 7-year history of dementia presented to our hospital with generalized convulsive seizure for the first time. Contrast-enhanced brain magnetic resonance imaging revealed leptomeningeal enhancement mainly in the right occipital lobe and multiple lobar microbleeds in the bilateral cerebral and cerebellar subcortex. No white matter lesions were observed. A brain biopsy of the right parieto-occipital lobe revealed cerebral amyloid angiopathy (CAA). White matter lesions appeared in the right parieto-occipital lobe three days after the biopsy, and we considered inflammatory CAA. Three courses of methylprednisolone pulse followed by oral prednisolone therapy gradually reduced leptomeningeal and white matter lesions. An apolipoprotein E genotype investigation identified the ε2/ε3 genotype. In patients with inflammatory CAA, a risk of exacerbation should be considered after brain biopsy, in which the ε2 allele might play a role.
Asunto(s)
Biopsia/efectos adversos , Angiopatía Amiloide Cerebral/etiología , Leucoencefalopatías/etiología , Sustancia Blanca/patología , Administración Oral , Anciano , Alelos , Apolipoproteínas E/genética , Bencimidazoles/administración & dosificación , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/patología , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Inflamación , Leucoencefalopatías/tratamiento farmacológico , Leucoencefalopatías/genética , Leucoencefalopatías/patología , Lóbulo Occipital/patología , Lóbulo Parietal/patología , Prednisolona/administración & dosificación , Quimioterapia por PulsoRESUMEN
Dogs have been used as animal models for human diseases in which there is beta-amyloid (Aß) deposition in the central nervous system (CNS), such as Alzheimer's and cerebral amyloid angiopathy (CAA). However, many aspects of Aß deposition in the CNS of dogs still remain unknown. This study aimed to evaluate the deposition of Aß in different areas of the CNS of aged dogs from different breeds. Aß was detected in the brains of aged dogs, forming either senile plaques in the neuropil of cortical gray matter or within the walls of parenchymal or leptomeningeal blood vessels. There was a positive correlation between aging and senile plaques or CAA. In dogs older than 8 years, there was no correlation between the area of Aß plaques and age, with frontal, temporal, and occipital cortices being affected with approximately equal frequency. There was a positive correlation between Aß deposition in vessel walls and age. Importantly, CAA was associated with the occurrence of microperivascular hemorrhages in the brains of aged dogs. In conclusion, this study demonstrated that Aß deposition as plaques or within vessel walls are extremely heterogenous in dogs from different breeds and sizes. Although many features of this disease in dogs are similar to those observed in humans, the choice of dog breed and size as a model for human disease will substantially affect the pattern of Aß deposition.
Asunto(s)
Envejecimiento/metabolismo , Péptidos beta-Amiloides/metabolismo , Tamaño Corporal , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Perros , Enfermedad de Alzheimer/etiología , Animales , Vasos Sanguíneos/metabolismo , Encéfalo/irrigación sanguínea , Angiopatía Amiloide Cerebral/etiología , Placa Amiloide/metabolismoRESUMEN
Alzheimer's disease patients typically present with multiple co-morbid neuropathologies at autopsy, but the impact of these pathologies on cognitive impairment during life is poorly understood. In this study, we developed cognitive trajectories for patients with common co-pathologies in the presence and absence of Alzheimer's disease neuropathology. Cognitive trajectories were modelled in a Bayesian hierarchical regression framework to estimate the effects of each neuropathology on cognitive decline as assessed by the mini-mental state examination and the clinical dementia rating scale sum of boxes scores. We show that both TDP-43 proteinopathy and cerebral amyloid angiopathy associate with cognitive impairment of similar magnitude to that associated with Alzheimer's disease neuropathology. Within our study population, 63% of individuals given the 'gold-standard' neuropathological diagnosis of Alzheimer's disease in fact possessed either TDP-43 proteinopathy or cerebral amyloid angiopathy of sufficient severity to independently explain the majority of their cognitive impairment. This suggests that many individuals diagnosed with Alzheimer's disease may actually suffer from a mixed dementia, and therapeutics targeting only Alzheimer's disease-related processes may have severely limited efficacy in these co-morbid populations.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Angiopatía Amiloide Cerebral/patología , Trastornos del Conocimiento/patología , Cuerpos de Lewy/patología , Proteinopatías TDP-43/patología , Anciano , Enfermedad de Alzheimer/patología , Estudios de Casos y Controles , Angiopatía Amiloide Cerebral/etiología , Trastornos del Conocimiento/etiología , Femenino , Humanos , Masculino , Estudios Retrospectivos , Proteinopatías TDP-43/etiologíaRESUMEN
BACKGROUND: Cortical superficial siderosis (cSS) is a hemorrhagic marker of blood-brain barrier disruption detected in brain MRI. Together with cerebral microbleeds (CMB), they are recognized as a small vessel disease marker associated with cerebral amyloid angiopathy. OBJECTIVE: This study aims to determine the prevalence and the characteristics of cSS in a memory clinic population. METHODS: Cross-sectional retrospective analysis of 613 patients from Geneva University Hospitals memory clinic. All patients underwent standardized brain MRI and neuropsychological assessment with diagnosis confirmed by an expert. The presence of cSS was visually assessed and classified as focal (restricted to 3 sulci) or disseminated within the correspondent topography. CMB were classified according to the Microbleed Anatomical Rating Scale. RESULTS: cSS was detected in 26/613 patients (4.2%), classified as disseminated in 5/26 cases (19%). Alzheimer's disease (AD) and AD associated with a significant vascular component were the diagnoses more frequently related to cSS (18/26; 69%). Patients with cSS had an increased prevalence of both hypertension (81% versus 57%; pâ=â0.015) and WMH burden (pâ=â0.012). The overall prevalence of cerebral microbleeds (69% versus 32%; pâ<â0.01), as well as their mean number (0.69±0.47 versus 0.32±0.46; pâ<â0.01) were both increased in patients with cSS. In the logistic regression model, the presence of 5 or more CMB (OR 11.35; 95% CI 4.68-27.55; pâ<â0.01) and hypertension (OR 3.31; 95% CI 1.19-9.15; pâ=â0.021) were significantly associated with cSS. CONCLUSIONS: cSS is observed in patients diagnosed with AD and AD with a vascular component, being independently associated with multiple CMB and hypertension.
Asunto(s)
Siderosis/psicología , Anciano , Anciano de 80 o más Años , Barrera Hematoencefálica/diagnóstico por imagen , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/epidemiología , Angiopatía Amiloide Cerebral/etiología , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/etiología , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/epidemiología , Estudios Transversales , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Imagen por Resonancia Magnética , Masculino , Memoria , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Siderosis/diagnóstico por imagen , Siderosis/epidemiología , Suiza/epidemiología , Sustancia Blanca/diagnóstico por imagenRESUMEN
The aim of this study was to determine the interaction between cerebral amyloid angiopathy (CAA) and Braak staging on cognition in the elderly. The study used a total of 141 subjects consisting of 72 non-cognitively impaired (NCI), 33 mild cognitive impairment (MCI), 36 Alzheimer's disease (AD) cases displaying Braak stages 0-II and III from the Rush Religious Order Study cohort. The association between Braak stage and CAA status and cognition was evaluated using a series of regression models that adjusted for age at death, sex, education, APOEÉ4 status, and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological diagnosis. Individuals with CAA were more likely to be classified as Braak stage III relative to those without CAA [ORâ=â2.33, 95% CI (1.06, 5.14), pâ=â0.04]. A significant interaction was found between Braak stage and CAA status on a global cognitive score (ßâ=â-0.58, SEâ=â0.25, pâ=â0.02). Episodic memory also showed a significant association between Braak stage and CAA (ß=â-0.75, SEâ=â0.35, pâ=â0.03). These data suggest that there is a significant interaction between tau pathology and cerebrovascular lesions on cognition within the AD clinical spectrum.
Asunto(s)
Enfermedad de Alzheimer/psicología , Angiopatía Amiloide Cerebral/psicología , Disfunción Cognitiva/psicología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Autopsia , Angiopatía Amiloide Cerebral/etiología , Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/psicología , Disfunción Cognitiva/etiología , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Pruebas Neuropsicológicas , Sistema de Registros , Tauopatías/patología , Tauopatías/psicologíaAsunto(s)
Encéfalo/fisiopatología , Angiopatía Amiloide Cerebral/terapia , Enfermedades de los Pequeños Vasos Cerebrales/terapia , Disfunción Cognitiva/terapia , Encéfalo/diagnóstico por imagen , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/etiología , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Enfermedades de los Pequeños Vasos Cerebrales/etiología , Disfunción Cognitiva/diagnóstico por imagen , Hemorragia/etiología , Humanos , Imagen por Resonancia Magnética/métodosRESUMEN
Cerebral amyloid angiopathy (CAA) is commonly found in older people and in patients with Alzheimer's disease (AD) accompanying cerebrovascular disorders and dementia. Early-onset CAA cases generally have been found only in rare genetic forms of CAA. Interestingly, however, CAA-related hemorrhages have been recently reported in younger people who had histories of neurosurgery with or without evidence of cadaveric dura mater grafts in childhood. It has been established in experimental settings that amyloid ß-protein (Aß) pathology can be transmitted inter-individually with Aß seeds. Incidental Aß pathology, predominantly Aß-CAA, has been recognized in recipients of cadaveric dura mater grafts or cadaveric human growth hormone. These findings suggest that transmission of Aß seeds through dura mater grafts and other contaminated materials could lead to development of CAA. In addition, neurosurgery or brain injury may contribute to cerebrovascular Aß deposition through the disturbance of vascular Aß drainage pathways. Thus, a novel concept, "acquired CAA," has emerged.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/etiología , Animales , Angiopatía Amiloide Cerebral/patología , HumanosAsunto(s)
Péptidos beta-Amiloides/metabolismo , Lesiones Traumáticas del Encéfalo/cirugía , Encéfalo/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/etiología , Procedimientos Neuroquirúrgicos/efectos adversos , Fragmentos de Péptidos/metabolismo , Adulto , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Angiopatía Amiloide Cerebral/patología , Humanos , Enfermedad Iatrogénica , MasculinoRESUMEN
Our objective is to study a 53-year-old woman with Down syndrome presented with massive lobar hematoma in the left fronto-parietal lobe, and who underwent craniotomy and hematoma evacuation. Histopathological diagnosis of surgical specimen was amyloid angiopathy. Postoperative magnetic resonance studies were performed. The lesion this time showed mixed intensity on susceptibility-weighted imaging. In addition, multiple hypointense lesions were evident. An old previously unidentified hemorrhage in the right temporo-parietal lobe was accompanied by superficial cortical siderosis. Old bleeds were apparent in subcortical areas. These various kinds of hemorrhagic lesion were consistent with findings of amyloid angiopathy reported in the elderly. Most reported cases of Down syndrome associated with intracerebral hemorrhage have involved middle-aged patients. Magnetic resonance studies for Down syndrome patients before old age may disclose the degree to which amyloid angiopathy progresses in the brain of these patients.
Asunto(s)
Angiopatía Amiloide Cerebral/diagnóstico por imagen , Hemorragia Cerebral/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética , Síndrome de Down/complicaciones , Factores de Edad , Angiopatía Amiloide Cerebral/etiología , Hemorragia Cerebral/etiología , Hemorragia Cerebral/cirugía , Craneotomía , Progresión de la Enfermedad , Síndrome de Down/diagnóstico , Femenino , Hematoma/diagnóstico por imagen , Hematoma/etiología , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most common form of dementia coming along with cerebral amyloid angiopathy (CAA) in more than 70% of all cases. However, CAA occurs also in pure form without AD pathology. Vascular life style risk factors such as obesity, hypertension, hypercholesterolemia, diabetes, stress or an old age play an important role in the progression of CAA. So far, no animal model for sporadic CAA has been reported, thus the aim of the present study was to create and characterize a new mouse model for sporadic CAA by treatment with different vascular risk factors. Healthy C57BL6 mice were treated with lifestyle vascular risk factors for 35 or 56â¯weeks: lipopolysaccharide, social stress, streptozotozin, high cholesterol diet and copper in the drinking water. Four behavioral tests (black-white box, classical maze, cheeseboard maze and plus-maze discriminative avoidance task) showed impaired learning, memory and executive functions as well as anxiety with increased age. The treated animals exhibited increased plasma levels of cortisol, insulin, interleukin-1ß, glucose and cholesterol, confirming the effectiveness of the treatment. Confocal microscopy analysis displayed severe vessel damage already after 35â¯weeks of treatment. IgG positive staining points to a severe blood-brain barrier (BBB) disruption and furthermore, cerebral bleedings were observed in a much higher amount in the treatment group. Importantly, inclusions of beta-amyloid in the vessels indicated the development of CAA, but no deposition of beta-amyloid plaques and tau pathology in the brains were seen. Taken together, we characterized a novel sporadic CAA mouse model, which offers a strategy to study the progression of the disease and therapeutic and diagnostic interventions.
Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Angiopatía Amiloide Cerebral/etiología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Angiopatía Amiloide Cerebral/patología , Hemorragia Cerebral/patología , Diabetes Mellitus , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Hipercolesterolemia , Hipertensión , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Obesidad , Placa Amiloide , Factores de Riesgo , Estrés PsicológicoRESUMEN
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
BACKGROUND: Patients with Down syndrome carry a third copy of the amyloid precursor protein gene, which is localized on chromosome 21. Consequently, these patients are prone to develop early-onset Alzheimer disease and cerebral amyloid angiopathy. Post-mortem studies suggest increased amyloid deposition to be already detectable in children with Down syndrome. The aim of our study was to evaluate if amyloid-related changes in pediatric Down syndrome patients can be detected in vivo using MRI biomarkers of cerebral microbleeds and cortical superficial siderosis. MATERIALS AND METHODS: This retrospective study included 12 patients with Down syndrome (mean age = 5.0 years) and 12 age-matched control subjects (mean age = 4.8 years). Frequency and location of microbleeds and siderosis were assessed on blood-sensitive MRI sequences in a consensus reading by two radiologists applying a modified Microbleed Anatomical Rating Scale. RESULTS: Down syndrome patients showed a significantly higher mean microbleeds count and likelihood of siderosis than age-matched controls. Across groups, the highest microbleeds count was found in lobar regions (gray and white matter of frontal, parietal, temporal, and occipital lobes, and the insula), while fewer microbleeds were located in subcortical and infratentorial regions. The number of microbleeds increased over time in all three Down syndrome patients with a follow-up exam. CONCLUSION: In vivo MRI biomarkers can support the diagnosis of early-onset cerebral amyloid angiopathy, which might already be present in pediatric Down syndrome patients. This might contribute to clinical decision-making and potentially to the development of therapeutic and prophylactic approaches, as cerebral amyloid angiopathy increases the risk for intracranial hemorrhage and may be associated with increased risk of developing Alzheimer disease.