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An 87-year-old woman was admitted to our hospital (day 0) because of acute disorientation caused by multiple acute intracerebral hemorrhages. T2*-weighted magnetic resonance imaging (MRI) at admission revealed multiple subcortical old microbleeds indicative of cerebral amyloid angiopathy. Microbleeds in the right cerebellar hemisphere and acute spotty ischemia in the left cerebellum were also identified. The patient had been afebrile, and blood examinations on day 7 were within normal limits of inflammatory findings without antibiotics. On day 11, she developed a high fever and blood culture was performed. Her fever resolved within 2 days of antibiotic administration, although subsequent findings revealed her blood culture was positive for Staphylococcus aureus. Echocardiogram revealed bacterial vegetation in the mitral valve and moderate mitral regurgitation, with a diagnosis of infectious endocarditis (IE). Follow-up MRI demonstrated multiple spotty acute infarctions and an increased number of microbleeds. The patient may have been infected via peripheral infusions administered during the first few days after admission. However, considering the coexistence of acute hemorrhagic and ischemic lesions on MRI, as well as the acute lesions in the cerebellum, it is possible that IE was already latent on admission, and that the multiple brain hemorrhages might have been caused by IE rather than by cerebral amyloid angiopathy.
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BACKGROUND: While several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted. METHODS: We prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer's Disease (AD) Assessment Scale's (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS. RESULTS: Patients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94-5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19-0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05-1.39) and 0.63 units (95% CI 0.19-1.08) more severe NPS. NPS number (MMSE mean difference - 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26-2.56) and severity (MMSE - 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57-1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect - 0.08, 95% CI -0.22 to -0.002). DISCUSSION: This study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA.
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Angiopatía Amiloide Cerebral , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Humanos , Femenino , Masculino , Anciano , Estudios Transversales , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/psicología , Persona de Mediana Edad , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Central nervous system dysfunction is common in longstanding hereditary transthyretin amyloidosis (ATTRv) caused by the V30M (p.V50M) mutation. Neuropathology studies show leptomeningeal amyloid deposition and cerebral amyloid angiopathy (CAA). Brain MRI is widely used in the assessment of Aß associated CAA but there are no systematic studies with brain MRI in ATTRv amyloidosis. METHODS: we performed 3 T brain MRIs in 16 patients with longstanding (>14 years) ATTRV30M. We additionally retrospectively reviewed 48 brain MRIs from patients followed at our clinic. CNS symptoms and signs were systematically accessed, and MRIs were blindly reviewed for ischaemic and haemorrhagic lesions. RESULTS: in the prospective cohort, we found white matter hyperintensities in 8/16 patients (50%, Fazekas score> =1). There were no relevant microbleeds, large ischaemic or haemorrhagic lesions or superficial siderosis. In the retrospective cohort, microbleeds were found in 5/48 patients (10,4%), two of which with > =20 microbleeds. White matter hyperintensities were found in 20/48 cases (41.7%). White matter lesions, microbleeds and cortical atrophy were not associated with disease duration. CONCLUSIONS: white matter hyperintensities are common in ATTRV30M, irrespective of disease duration. Haemorrhagic lesions are rare, even in patients with longstanding disease, suggesting the existence of other risk factors.
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Human brain aging is characterized by the production and deposition of ß-amyloid (Aß) in the form of senile plaques and cerebral amyloid angiopathy and the intracellular accumulation of hyper-phosphorylated tau (Hp-tau) to form neurofibrillary tangles (NFTs) and dystrophic neurites of senile plaques. The process progresses for years and eventually manifests as cognitive impairment and dementia in a subgroup of aged individuals. Aß is produced and deposited first in the neocortex in most aged mammals, including humans; it is usually not accompanied by altered behavior and cognitive impairment. Hp-tau is less frequent than Aß pathology, and NFTs are rare in most mammals. In contrast, NFTs are familiar from middle age onward in humans; NFTs first appear in the paleocortex and selected brain stem nuclei. NFTs precede for decades or years Aß deposition and correlate with dementia in about 5% of individuals at the age of 65 and 25% at the age of 85. Based on these comparative data, (a) Aß deposition is the most common Alzheimer's disease neuropathological change (ADNC) in the brain of aged mammals; (b) Hp-tau is less common, and NFTs are rare in most aged mammals; however, NFTs are the principal cytoskeletal pathology in aged humans; (c) NFT in aged humans starts in selected nuclei of the brain stem and paleocortical brain regions progressing to the most parts of the neocortex and other regions of the telencephalon; (d) human brain aging is unique among mammalian species due to the early appearance and dramatic progression of NFTs from middle age onward, matching with cognitive impairment and dementia in advanced cases; (e) neither mammalian nor human brain aging supports the concept of the amyloid cascade hypothesis.
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Envejecimiento , Enfermedad de Alzheimer , Ovillos Neurofibrilares , Proteínas tau , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Animales , Humanos , Envejecimiento/patología , Envejecimiento/metabolismo , Ovillos Neurofibrilares/patología , Ovillos Neurofibrilares/metabolismo , Proteínas tau/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Mamíferos/metabolismo , Placa Amiloide/patología , Placa Amiloide/metabolismoRESUMEN
Spontaneous convexity subarachnoid hemorrhage (cSAH) is a vascular disease different from aneurysmal SAH in neuroimaging pattern, causes, and prognosis. Several causes might be considered in individual patients, with a limited value of the patient's age for discriminating among these causes. Cerebral amyloid angiopathy (CAA) is the most prevalent cause in people > 60 years, but reversible cerebral vasoconstriction syndrome (RCVS) has to be considered in young people. CAA gained attention in the last years, but the most known manifestation of cSAH in this context is constituted by transient focal neurological episodes (TFNEs). CAA might have an inflammatory side (CAA-related inflammation), whose diagnosis is relevant due to the efficacy of immunosuppression in resolving essudation. Other causes are hemodynamic stenosis or occlusion in extracranial and intracranial arteries, infective endocarditis (with or without intracranial infectious aneurysms), primary central nervous system angiitis, cerebral venous thrombosis, and rarer diseases. The diagnostic work-up is fundamental for an etiological diagnosis and includes neuroimaging techniques, nuclear medicine techniques, and lumbar puncture. The correct diagnosis is the first step for choosing the most effective and appropriate treatment.
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BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with white matter damage and neurodegeneration. Gait is impaired in CAA; however, the neural basis of this impairment is unclear. RESEARCH QUESTION: Are gait impairments in patients with CAA associated with altered cerebral white matter diffusivity and/or atrophy of cortical and subcortical grey matter. METHODS: Participants with CAA (n=29), Alzheimer's disease (AD; n=16), and normal controls (n=47) were included. Gait was assessed using a 6â¯m walkway with parameters categorized into rhythm, pace, postural control, and variability domains. The dual-task cost (DTC) of gait speed was calculated for counting backwards, animal fluency, and serial sevens tasks. Whole-brain white matter disruption was quantified using the peak width of skeletonized mean diffusivity (PSMD), and thickness and volume of select cortical, subcortical, and cerebellar regions were quantified using FreeSurfer. RESULTS: In CAA participants, associations were found between PSMD and pace (standardized parameter estimate (ß), 95â¯% confidence interval (CI): 0.17, 0.03-0.32), and medial orbital frontal cortical thickness and counting backwards DTC (parameter estimate (PE), 95â¯% CI: -5.7â¯%/SD, -0.24 to -11.23). Across all groups, including CAA, associations were found between PSMD and pace, variability, counting backwards DTC, and animal fluency DTC; between frontal cortical thickness and pace, counting backwards DTC, and animal fluency DTC; between cortical regions affected by AD (inferior parietal cortex, inferior and middle temporal gyrus) and counting backwards DTC; and between thalamus volume and postural control. SIGNIFICANCE: Reduced white matter structural integrity and grey matter loss is associated with poor overall gait performance in CAA, AD, and normal controls.
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Angiopatía Amiloide Cerebral , Sustancia Gris , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Masculino , Femenino , Anciano , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/fisiopatología , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/fisiopatología , Enfermedad de Alzheimer/fisiopatología , Anciano de 80 o más Años , Estudios de Casos y Controles , Imagen de Difusión Tensora , Atrofia , Persona de Mediana EdadRESUMEN
BACKGROUND AND PURPOSE: Although the Boston criteria version 2.0 facilitates the sensitivity of cerebral amyloid angiopathy (CAA) diagnosis, there are only limited data about precursor symptoms. This study aimed to determine the impact of neurological and imaging features in relation to the time of CAA diagnosis. METHODS: Patients diagnosed with probable CAA according to the Boston criteria version 1.5, treated between 2010 and 2020 in our neurocentre, were identified through a keyword search in our medical database. Neuroimaging was assessed using Boston criteria versions 1.5 and 2.0. Medical records with primary focus on the clinical course and the occurrence of transient focal neurological episodes were prospectively evaluated. RESULTS: Thirty-eight out of 81 patients (46.9%) exhibited transient focal neurological episodes, most often sensory (13.2%) or aphasic disorders (13.2%), or permanent deficits at a mean time interval of 31.1 months (SD ±26.3; range 1-108 months) before diagnosis of probable CAA (Boston criteria version 1.5). If using Boston criteria version 2.0, all patients receiving magnetic resonance imaging (MRI) met the criteria for probable CAA, and diagnosis could have been made on average 44 months earlier. Four patients were younger than 50 years, three of them with supporting pathology. Cognitive deficits were most common (34.6%) at the time of diagnosis. CONCLUSIONS: Non-haemorrhagic MRI markers enhance the sensitivity of diagnosing probable CAA; however, further prospective studies are proposed to establish a minimum age for inclusion. As the neurological overture of CAA may occur several years before clinical diagnosis, early clarification by MRI including haemosensitive sequences are suggested.
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Angiopatía Amiloide Cerebral , Imagen por Resonancia Magnética , Neuroimagen , Humanos , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Masculino , Femenino , Anciano , Neuroimagen/métodos , Neuroimagen/normas , Anciano de 80 o más Años , Imagen por Resonancia Magnética/normas , Persona de Mediana EdadRESUMEN
Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rapid but reversible autoimmune encephalopathy where spontaneous autoantibody reaction against amyloid beta deposited in cerebral blood vessels produces characteristic neuroinflammatory changes such as vasogenic edema and microhemorrhages on MRI. The term amyloid-related imaging abnormalities (ARIA) is sometimes used to describe these changes but are more often reserved for similar MRI signal abnormalities seen after administration of anti-amyloid immunotherapy, using treatment exposure as an antecedent. It is unclear if there is any biological basis for this dichotomized distinction. We report a case of severe CAA-ri after exposure to SARS-CoV-2 vaccine and performed a literature review of CAA-ri related to vaccination. CAA-ri precipitated by immunogenic triggers other than anti-amyloid therapy would lend support to the hypothesis that ARIA seen on MRI may represent the same disease underpinned by a shared anti-Aß autoantibody response irrespective of etiology. A thorough history should be taken before labelling CAA-ri as spontaneous.
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Angiopatía Amiloide Cerebral , Anciano , Humanos , Angiopatía Amiloide Cerebral/inmunología , Angiopatía Amiloide Cerebral/diagnóstico por imagen , COVID-19/inmunología , COVID-19/complicaciones , Vacunas contra la COVID-19/efectos adversos , Inflamación/inmunología , Inflamación/etiología , Inflamación/inducido químicamente , Imagen por Resonancia Magnética , Vacunación/efectos adversosRESUMEN
High blood pressure (BP) and cerebral amyloid angiopathy (CAA) are two common risk factors for intracranial hemorrhage, potentially leading to cognitive impairment. Less is known about the relationship between BP and CAA, the examination of which was the objective of this study. We analyzed data from 2510 participants in the National Alzheimer's Coordinating Center (NACC) who had information on longitudinal BP measurements before death and on CAA from autopsy. Using the average of four systolic BPs (SBPs) prior to death, SBP was categorized into three groups: <120 mmHg (n = 435), 120-139 mmHg (n = 1335), and ≥140 mmHg (n = 740). CAA was diagnosed using immunohistochemistry in 1580 participants and categorized as mild (n = 759), moderate (n = 529), or severe (n = 292). When adjusted for age at death, sex, APOE genotype, Braak, CERAD, antihypertensive medication use, and microinfarcts, the odds ratios (95% CIs) for CAA associated with SBPs of 120-139 and ≥140 mmHg were 0.91 (0.74-1.12) and 1.00 (0.80-1.26), respectively. Findings from predictor effect plots show no variation in the probability of CAA between the three SBP categories. Microbleeds had no association with CAA, but among those with SBP ≥ 130 mmHg, the proportion of those with microbleeds was numerically greater in those with more severe CAA (p for trend, 0.084). In conclusion, we found no evidence of an association between SBP and CAA. Future studies need to develop non-invasive laboratory tests to diagnose CAA and prospectively examine this association and its implication on the pathophysiology and outcome of Alzheimer's disease.
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INTRODUCTION: MRI rating criteria for small vessel disease markers include definitions for microbleeds and macrobleeds but do not account for small (<10 mm) hemorrhages with a cystic cavity and/or irregular shape. Such hemorrhages, however, are often present in patients with cerebral amyloid angiopathy (CAA). In this study, we aimed to investigate the frequency, diameter, and volume distribution of these hemorrhages (which we called mesobleeds) in patients with CAA. METHODS: We selected participants with Dutch-type hereditary CAA (D-CAA) and sporadic CAA (sCAA) and scored microbleeds, mesobleeds, and macrobleeds on 3T susceptibility-weighted images MRI. Hemorrhage diameter and volume were calculated in a subset of participants using a semi-automatic tool; their distribution was evaluated on a logarithmic scale. RESULTS: We included 25 participants with D-CAA (mean age 56 years) and 25 with sCAA (mean age 73 years). In total, 11,007 microbleeds, 602 mesobleeds, and 195 macrobleeds were observed. Eighty-two percent of participants had ≥1 mesobleed. Hemorrhage diameter and volume were calculated in four participants with 272 microbleeds (median diameter 1.52 mm, volume 0.004 mL), 84 mesobleeds (median diameter 5.61 mm, volume 0.06 mL), and 37 macrobleeds (median diameter 19.58 mm, volume 1.33 mL). Mesobleed diameter and volume were larger than microbleeds (optimal cut-off 0.02 mL) but showed overlap with macrobleeds. CONCLUSION: Hemorrhages <10 mm with an irregular shape and/or cystic cavity are frequently found in participants with CAA and have a distinct diameter and volume distribution. We propose to name these hemorrhage mesobleeds and to rate them separately from micro- and macrobleeds. Future research is necessary to investigate their pathophysiology and prognostic value.
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Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare condition primarily driven by an autoimmune reaction against cerebrovascular amyloid beta protein. Accurate diagnosis hinges on recognizing characteristic clinical symptoms and imaging features, such as asymmetric cerebral white matter lesions often linked to angioedema. We report the case of a woman in her 70s with progressive, irreversible CAA-ri who initially presented with left homonymous hemianopia and experienced significant psychiatric and neurological deterioration following an epileptic seizure. Despite initiating corticosteroid therapy seven months after onset, her condition continued to worsen, ultimately leading to her death in the 11th month due to general decline. This report reviews the clinical progression and imaging findings of the case, discusses the diagnostic process for CAA-ri, differentiates it from related conditions, and evaluates the timing of corticosteroid treatment.
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The expansion of GGC repeats within NOTCH2NLC leads to the translation of the uN2CpolyG protein, the primary pathogenic factor in neuronal intranuclear inclusion disease (NIID). This study aims to explore the deposition of uN2CpolyG as an amyloid in the vessel wall, leading to uN2CpolyG cerebral amyloid angiopathy (CAA)-related cerebral microbleeds (CMBs). A total of 97 patients with genetically confirmed NIID were enrolled in this study. We analyzed the presence of CMBs using susceptibility-weighted imaging sequences and compared general clinical information, cerebrovascular risk factors, stroke history, antiplatelet medication use, and MRI features between NIID patients with and without CMBs. We further performed hematoxylin and eosin (H&E), Perl's, Congo red, and Thioflavin S staining, ubiquitin, p62 and uN2CpolyG immunostaining on brain tissue obtained from four NIID patients. A total of 354 CMBs were detected among 41 patients with NIID, with nearly half located in the deep brain, one-third in the lobes, and approximately 20% in the infratentorial area. No significant differences in cerebrovascular disease risk factors or history of antiplatelet drug use were observed between patients with and without CMBs. However, patients with CMBs suffered a higher incidence of previous ischemic and hemorrhagic stroke events. This group also had a higher incidence of recent subcortical infarcts and a higher proportion of white matter lesions in the external capsule and temporal pole. Conversely, patients without CMBs showed higher detection of high signals at the corticomedullary junction on diffusion-weighted imaging and more pronounced brain atrophy. H&E staining showed blood vessel leakage and hemosiderin-laden macrophage clusters, and Prussian blue staining revealed brain tissue iron deposition. CMBs occurred more frequently in small vessels lacking intranuclear inclusions, and extensive degeneration of endothelial cells and smooth muscle fibres was observed mainly in vessels lacking inclusions. Congo red-positive amyloid deposition was observed in the cerebral vessels of NIID patients, with disordered filamentous fibres appearing under an electron microscope. Additionally, the co-localization of Thioflavin S-labeled amyloid and uN2CpolyG protein in the cerebral vascular walls of NIID patients further suggested that uN2CpolyG is the main pathogenic protein in this form of amyloid angiopathy. In conclusion, we reviewed patients with GGC repeat expansion of NOTCH2NLC from a novel perspective, providing initial clinical, neuroimaging, and pathological evidence suggesting that uN2CpolyG may contribute to a distinct type of CAA.
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Alzheimer's disease (AD) is characterized by extracellular amyloid plaques containing amyloid-ß (Aß) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aß can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aß and tau pathologies in postmortem brain tissues across cases and Aß peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aß peptides with MS-brain imaging. While intraparenchymal Aß deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aß deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aß deposits in capillaries. Investigation of Aß peptide profiles showed a specific increase in Aßx-37, Aßx-38 and Aßx-40 but not Aßx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aß2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aß peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aß deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aß peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Encéfalo , Angiopatía Amiloide Cerebral , Síndrome de Down , Humanos , Síndrome de Down/patología , Síndrome de Down/metabolismo , Síndrome de Down/genética , Síndrome de Down/complicaciones , Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/patología , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Masculino , Femenino , Anciano , Persona de Mediana Edad , Encéfalo/patología , Encéfalo/metabolismo , Proteínas tau/metabolismo , Anciano de 80 o más Años , Placa Amiloide/patología , Placa Amiloide/metabolismoRESUMEN
A Nature Medicine paper published in January 2024 describes eight cases of iatrogenic Alzheimer's disease in individuals who received cadaveric pituitary-derived human growth hormone. The paper's conclusions argue for the transmissibility of Alzheimer's disease, which, if true, would create a significant public health crisis. For example, neurosurgical practices would require substantial revision, and many individuals who have undergone neurosurgical procedures would now be at considerable risk of Alzheimer's disease. A detailed review of the presented cases reveals that they do not have Alzheimer's disease, and there are alternative explanations for the cognitive decline described. In people with progressive cognitive decline, the diagnosis of Alzheimer's disease requires a demonstration of amyloid and tau pathology or amyloid and tau biomarkers. Extensive tau pathology is not demonstrated, and some also lack amyloid beta pathology. The cases described in this paper do not meet the criteria for dementia due to Alzheimer's disease by clinical and pathological standards. HIGHLIGHTS: Creutzfeldt-Jakob disease has been transmitted by cadaveric growth hormone. There is no evidence for the transmission of Alzheimer's disease by cadaveric growth hormone. There is no evidence that Alzheimer's disease is transmissible.
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Globally, cerebral microbleeds (CMBs) are increasingly being viewed not only as a marker for cerebral small vessel disease (SVD) but also as having an increased risk for the development of stroke (hemorrhagic/ischemic) and aging-related dementia. Recently, brain endothelial cell activation and dysfunction and blood-brain barrier dysfunction and/or disruption have been shown to be associated with SVD, enlarged perivascular spaces, and the development and evolution of CMBs. CMBs are a known disorder of cerebral microvessels that are visualized as 3-5 mm, smooth, round, or oval, and hypointense (black) lesions seen only on T2*-weighted gradient recall echo or susceptibility-weighted sequences MRI images. CMBs are known to occur with high prevalence in community-dwelling older individuals. Since our current global population is the oldest recorded in history and is only expected to continue to grow, we can expect the healthcare burdens associated with CMBs to also grow. Increased numbers (≥10) of CMBs should raise a red flag regarding the increased risk of large symptomatic neurologic intracerebral hemorrhages. Importantly, CMBs are also currently regarded as markers of diffuse vascular and neurodegenerative brain damage. Herein author highlights that it is essential to learn as much as we can about CMB development, evolution, and their relation to impaired cognition, dementia, and the exacerbation of neurodegeneration.
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Hereditary cystatin C amyloid angiopathy (HCCAA) is an Icelandic disease that belongs to a disease class called cerebral amyloid angiopathy, a group of heterogenous diseases presenting with aggregation of amyloid complexes and deposition predominantly in the central nervous system. HCCAA is dominantly inherited, caused by L68Q mutation in the cystatin C gene, leading to aggregation of the cystatin C protein. HCCAA is a very progressive and severe disease, with widespread cerebral and parenchymal cystatin C and collagen IV deposition within the central nervous system (CNS) but also in other organs in the body, for example, in the skin. Most L68Q carriers have clinical symptoms characterized by recurrent hemorrhages and dementia, between the age of 20-30 years. If the carriers survive the first hemorrhage, the frequency and severity of the hemorrhages tend to increase, resulting in death at average of 30 years with mean number of major hemorrhages ranging from 3.2 to 3.9 over a 5-year average life span. The pathogenesis of the disease in carriers is very similar in the CNS and in the skin based on autopsy studies, thus skin biopsies can be used to monitor the progression of the disease by quantifying the cystatin C immunoreactivity. The cystatin C deposition always colocalizes with collagen IV and fibroblasts in the skin are found to be the main cell type responsible for the deposition of both proteins. No therapy is available for this devastating disease.
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BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by amyloid-ß (Aß) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aß aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of ß-amyloidosis with prominent CAA. METHODS: Twenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aß levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings. RESULTS: rhApoJ-treated APP23 presented fewer cortical CMBs (50-300 µm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 µm) (p = 0.002) than saline-treated mice, independently of Aß brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036). CONCLUSIONS: Chronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.
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Angiopatía Amiloide Cerebral , Hemorragia Cerebral , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Transgénicos , Animales , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Humanos , Hemorragia Cerebral/sangre , Ratones , Masculino , Femenino , Péptidos beta-Amiloides , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/efectos de los fármacos , Anciano , Imagen por Resonancia Magnética , Proteínas Recombinantes/administración & dosificación , Precursor de Proteína beta-Amiloide/genética , ClusterinaRESUMEN
INTRODUCTION: Cerebral amyloid angiopathy-related inflammation (CAA-ri) derives from inflammatory response to ß-amyloid (Aß) protein deposition within the cerebral blood vessel walls. We report a case that accentuates those clinical and imaging features that can contribute to raise suspicion for the condition and lead to early treatment initiation. CASE PRESENTATION: A 72-year-old man was referred with one-month history of cognitive decline along with behavioral alterations. Brain MRI showed fluid attenuated inversion recovery (FLAIR) asymmetrical multifocal white matter hyperintensities (WMHs) along with multiple cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS) on T2*-weighted gradient-recalled echo (T2*-GRE) images. Metabolic, infectious, and neoplastic causes were excluded, and subsequently corticosteroids were administered to the patient resulting in clinical recovery. Imaging on follow-up disclosed remission of WMHs, while CMBs load increased significantly. DISCUSSION: Clinical neurologists' acquaintance with the clinical and imaging features of CAA-ri allows prompt diagnosis and medication initiation, that is essential for a conceivably treatable condition.
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INTRODUCTION: Dutch-type cerebral amyloid angiopathy (D-CAA) is an autosomal dominant hereditary form of CAA causing intracerebral hemorrhage (ICH) and cognitive decline. The age of onset of ICH in D-CAA mutation carriers is strikingly variable and ranges from late thirties up to 70 years. We investigated the presence of genetic anticipation and assessed the influence of parental age at onset and sex on age of ICH onset in offspring. METHODS: We included (potential) D-CAA mutation carriers from our prospective D-CAA family database. Participants were sent a questionnaire by mail and asked for the onset age of symptomatic ICH and the onset age of symptomatic ICH of their affected first-degree relative(s), their siblings and affected parent. We used a Cox regression model with the age of onset of the parent as the covariate and the sex of the offspring as the factor. Next, we replaced the sex of the offspring with a factor with four levels: mother/daughter, mother/son, father/daughter, and father/son. We used a random effect per household. RESULTS: A total of 66 respondents completed the questionnaire. Reported mean age of first symptomatic ICH was similar (both 52 years, p = 0.87) for D-CAA parents (n = 60) and their offspring (n = 100). Offspring with a mother with D-CAA seemed to have an earlier ICH onset (50 years, standard deviation [SD] ± 7) than offspring with a paternal inheritance (54 years, SD ± 6, p = 0.03). There was no association between onset of first ICH of the parent and offspring after adding sex of the offspring to the Cox regression model: hazard ratio 0.99, 95% CI: 0.94-1.03, p = 0.51. The interaction between parent's sex and child's sex was not significant (p = 0.70). The results with and without random effect were essentially identical. CONCLUSION: We found no indication for genetic anticipation in D-CAA in general, although maternal inheritance seemed to be associated with an earlier ICH onset.
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BACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-ß42 (Aß42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. RESULTS: NP with CAA had significantly lower CSF Aß42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aß42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CONCLUSIONS: CSF Aß42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.