Search Results (107)

Background: Cerebral amyloid angiopathy (CAA) represents a progressive cerebrovascular disorder, characterized by aberrant accumulation of beta-amyloid isoforms in cortical and leptomeningeal vessel walls of cerebrum and cerebellum. Methods: We sought to investigate the clinical manifestations, current different diagnostic tools, various therapeutic strategies and most uncommon subtypes of the disease. Results: The vast majority of CAA remains sporadic, with increasing prevalence with age and very frequent coexistence with Alzheimer’s disease. Clinically, CAA can present with spontaneous lobar intracerebral hemorrhage, transient focal neurologic episodes attributed to convexity subarachnoid hemorrhage or cortical superficial siderosis, and progressive cognitive decline leading to dementia. Inflammatory CAA subtype should be recognized early and treated promptly so that better functional outcomes may be achieved. Moreover, genetic and iatrogenic CAA forms are rare, yet increasingly recognized during the last years. Therapeutic management remains challenging for clinicians, especially when markers indicative of higher bleeding risk are present. A targeted therapy does not currently exist. However, various clinical trials are in progress, focusing on offering new promising insights into the disease treatment. Conclusions: This review aims to deepen our understanding of CAA diagnosis and therapeutic approach but also summarizes current evidence on the most uncommon subtypes of this cerebral small-vessel disease. Full article

The molecular imaging of α-synuclein (α-syn) pathology in Parkinson’s disease (PD) and related movement disorders is a clinically unmet need. The aim of this study was to discover and characterize in vitro a radioligand for imaging α-syn pathology. A library of 78 small molecules was developed and screened using recombinant α-syn fibrils and brain homogenates from Alzheimer’s disease (AD) donors. The selection criteria were as follows: Ki_α-syn < 30 nM, Ki_tau and Ki_A-β > 200 nM. Three compounds, GMC-073 (K_iα-syn: 8 nM), GMC-098 (Ki_α-syn: 9.7 nM), and GMC-058 (Ki_α-syn: 22.5 nM), fulfilled the criteria and were radiolabeled with ³H. [³H]GMC-058 was the only compound with negligible binding in controls, and was further evaluated using tissue microarrays, autoradiography on fresh-frozen brain slices, and in vitro saturation binding assay on brain homogenates. [³H]GMC-058 binding co-localized with α-syn inclusions in Parkinson’s disease (PD) and multiple-system atrophy (MSA), with dense A-β plaques in cerebral amyloid angiopathy and AD and with p-tau inclusions in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Specific binding was highest in PSP and CBD. In vitro K_D was highest in AD (5.4 nM), followed by PSP (41 nM) and CBD (75 nM). The K_D in MSA, PD, and controls was >100 nM. [³H]GMC-058 is a novel radioligand displaying a low affinity for aggregated α-syn in tissue, with an in vitro profile also suitable for detecting tau pathology in 4R tauopathies. Full article

Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) sequence sensitive to substances that alter the local magnetic field, such as calcium and iron, allowing phase information to distinguish between them. SWI is a 3D gradient–echo sequence with high spatial resolution that leverages both phase and magnitude effects. The interaction of paramagnetic (such as hemosiderin and deoxyhemoglobin), diamagnetic (including calcifications and minerals), and ferromagnetic substances with the local magnetic field distorts it, leading to signal changes. Neurodegenerative diseases are typically characterized by the progressive loss of neurons and their supporting cells within the neurovascular unit. This cellular decline is associated with a corresponding deterioration of both cognitive and motor abilities. Many neurodegenerative disorders are associated with increased iron accumulation or microhemorrhages in various brain regions, making SWI a valuable diagnostic tool in clinical practice. Suggestive SWI findings are known in Parkinson’s disease, Lewy body dementia, atypical parkinsonian syndromes, multiple sclerosis, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, hereditary ataxias, Huntington’s disease, neurodegeneration with brain iron accumulation, and chronic traumatic encephalopathy. This review will assist radiologists in understanding the technical framework of SWI sequences for a correct interpretation of currently established MRI findings and for its potential future clinical applications. Full article

Background: Cerebral amyloid angiopathy-related inflammation (CAA-RI) is a rare subtype of cerebral amyloid angiopathy (CAA), which presents mostly as a subacute and reversible encephalopathy. Primary symptoms include behavioral changes and cognitive decline in the form of rapidly progressive dementia, headache, seizures, and focal neurological deficits. It can also manifest as a varied range of typical and atypical presentations. Misdiagnosis is common because it shares symptoms with other infectious, ischemic and autoimmune pathologies and there is also a significant overlap of MRI findings. Methods: Gold standard diagnosis requires brain biopsy in appropriate clinical setting, but diagnostic criteria is established for probable and possible CAA-RI using clinical symptoms and MRI findings in the absence of other inflammatory, infectious or autoimmune processes. Immunomodulatory therapy is the mainstay of treatment, with variable response. Results: We present a case series of three patients with CAA-RI highlighting disease course, neuroradiological manifestation, treatment response, and clinical outcomes. We also provide a literature review to increase insight into this rare pathology. Conclusions: Early diagnosis and prompt initiation of immunosuppressive therapy is beneficial in most cases. Full article

Background/Objectives: A subtype of cerebral amyloid angiopathy (CAA), iatrogenic CAA (iCAA), has been increasingly reported. iCAA occurs primarily in patients who underwent surgery during childhood and is caused by the prion-like propagation of amyloid beta. This subtype of CAA tends to develop at a younger age than age-related CAA, usually before the age of 55. After a latency period of 20–40 years following surgery, it manifests as lobar intracerebral hemorrhage (ICH), cognitive impairment, or transient focal neurological episodes. Between 2023 and 2024, we observed four cases of possible iCAA, all of which had a history of neurosurgery during childhood. Case presentation: MRI findings for all cases revealed multiple lobar microbleeds. Two cases also showed cortical superficial siderosis and lobar ICH. Notably, contrast-enhanced 3D FLAIR demonstrated sulcal enhancement in two cases, and CT demonstrated cortical calcification in the bilateral posterior lobes in one case. Conclusions: Sulcal enhancement on contrast-enhanced 3D FLAIR and cortical calcification in the bilateral posterior lobes on CT may suggest advanced CAA in the present cases. Full article

Vascular basement membranes (BMs), composed of laminins, collagen IV, fibronectin, and perlecan, are secreted by endothelial cells, pericytes, smooth muscle cells (SMCs), and astrocytes. In the brain, amyloid beta (Aβ) is eliminated along cerebrovascular BMs of capillaries and arteries as intramural periarterial drainage (IPAD). Ageing modifies vascular BMs, impairing IPAD and leading to Aβ deposition as cerebral amyloid angiopathy. To better understand the molecular determinants of IPAD in ageing, we quantified the relative abundance of BMs secreted by human-derived cerebral endothelial cells, pericytes, brain vascular SMCs, and astrocytes in vitro. We then assessed BM protein levels in SMCs under hypercapnia (8% CO₂) as a model of vascular ageing, with and without Aβ exposure. Of the four cell types, we found SMCs secreted the highest levels of fibronectin, laminin, and perlecan, whilst pericytes secreted the highest levels of collagen IV. Hypercapnia increased the expression of collagen IV and fibronectin in SMCs but decreased the expression of laminin. The expression of perlecan increased under hypercapnia, but only in the presence of Aβ. This work highlights the varying compositions of vascular BMs and the dynamic differential responses of SMCs to Aβ and hypercapnia, helping to elucidate the age-related changes that impair IPAD in cerebral vessels. Full article

Exposure to aflatoxin (AF) triggers the production of inflammatory molecules and free radicals, leading to chronic inflammation, cancer, and neurodegenerative diseases. This systematic review evaluated the effects of AFB1 on the nervous system, particularly focusing on Alzheimer’s disease (AD). A comprehensive search was conducted in Scopus, Cochrane Library, PubMed, and Web of Science databases up to 1 June 2024, without restrictions. From 993 records retrieved, 16 articles were included in the systematic review. AFB1 participates in various biochemical processes and pathological conditions. The study highlights that AFB1 contributes to AD by inducing DNA damage, oxidative stress, and endoplasmic reticulum (ER) stress, impairing DNA repair mechanisms. This results in neuronal damage, cognitive decline, and neurodegeneration. AFB1 also affects key signaling pathways, reduces sodium–potassium pump activity, and disrupts cell cycle regulation involving p53, leading to neurotoxicity, inflammation, and the formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. Additionally, network analysis revealed 309 genes associated with AD, inflammation, angiopathy, and aflatoxin B1 (AFB1). Among these, ESR1 exhibited the highest number of direct connections to other nodes within the network. The gene TP53 played a pivotal role in mediating communication among genes, while the EP300 gene significantly influenced the overall network structure. Additionally, KEGG enrichment analysis demonstrated that these 309 genes are substantially involved in pathways related to cancer, the FoxO signaling pathway, apoptosis, and AD. In summary, the study highlights that AFB1 causes DNA damage and stress, leading to cognitive decline and neurodegeneration. It disrupts signaling pathways, damages neurons, and affects DNA repair, contributing to neurotoxicity and inflammation. PROSPERO registration number: CRD420250651007. Full article

Cerebral microbleeds (CMBs) are increasingly detected in patients with aortic and cardiac diseases following transcatheter aortic valve implantation (TAVI), thoracic endovascular aortic repair (TEVAR), or cardiac surgery. CMBs can be observed in magnetic resonance imaging (MRI) when susceptibility-weighted imaging (SWI) or T2*-Gradient-Echo (GRE) sequences are used. Differential diagnosis of CMBs from other causes, such as cerebral amyloid angiopathy (CAA), is crucial because of its clinical implications, particularly for anticoagulation management. A literature search was conducted using publicly available online databases to identify relevant studies for this review. The selection criteria focused on publications utilizing MRI with T2*-GRE or SWI sequences to detect CMBs in patients following cardiac or endovascular procedures. The extracted data included study characteristics, lesion distribution, and associated clinical factors. Ten studies were included in this review, with 50% analyzing a prospective cohort. Cerebral T2*-GRE or SWI hypointensities after cardiac and vascular procedures often showed a lobar distribution, thus complicating the differential diagnosis with “probable” CAA. However, CMBs seem predominantly located in subcortical white matter (SWM), unlike CAA, and commonly not associated with other alterations. Furthermore, CMBs seem to correlate with prolonged procedural duration, especially in the case of cardiopulmonary bypass, and anticoagulation therapy. Regarding etiology, various hypotheses have been proposed, with the most widely accepted being microhemorrhagic. CMBs are a common finding following cardiac procedures, either surgical or endovascular. Their distribution patterns may aid in differentiating from CAA-related lesions, with important implications for anticoagulation strategies. Identifying and characterizing these lesions is essential for optimizing postoperative management. Full article

Traumatic brain injury (TBI) has been linked to the development of neurodegenerative diseases, particularly Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). This review critically assesses the relationship between TBI and cerebral amyloid angiopathy (CAA), highlighting the complexities of diagnosing CAA in the context of prior head trauma. While TBI has been shown to facilitate the accumulation of amyloid plaques and tau pathology, the interplay between neurodegenerative processes and vascular contributions remains underexplored. Epidemiological studies indicate that TBI increases the risk of various dementias, not solely AD, emphasizing the need for a comprehensive understanding of TBI-related neurodegeneration as a polypathological condition. This review further delineates the mechanisms by which TBI can lead to CAA, particularly focusing on the vascular changes that occur post-injury. It discusses the challenges associated with diagnosing CAA after TBI, particularly due to the overlapping symptoms and pathologies that complicate clinical evaluations. Notably, this review includes a clinical case that exemplifies the diagnostic challenges posed by TBI in patients with subsequent cognitive decline and vascular pathology. By synthesizing current research on TBI, CAA, and associated neurodegenerative conditions, this review aims to foster a more nuanced understanding of how these conditions interact and contribute to long-term cognitive outcomes. The findings underscore the importance of developing standardized diagnostic criteria and imaging techniques to better elucidate the relationship between TBI and vascular pathology, which could enhance clinical interventions and inform therapeutic strategies for affected individuals. Full article

Background/Objectives: Cerebral amyloid angiopathy (CAA) is one of the most prevalent small vessel diseases (SVDs). Its diagnostic criteria rely mainly on neuroimaging markers, in particular using Magnetic Resonance Imaging (MRI), as pathology-based diagnoses are only occasionally available. Amyloid PET is frequently used to assess parenchymal amyloid deposition in Alzheimer’s disease (AD), but amyloid tracers are not specific to vascular and parenchymal amyloids. The aim of this scoping review is to assess the usefulness of amyloid PET imaging in CAA. Methods: A systematic literature search was performed, aiming to assess amyloid PET performance in the following situations: (I) CAA-related intracerebral hemorrhage (ICH) and convexal subarachnoid hemorrhage; (II) pathology-proven CAA; (III) CAA-related inflammation; (IV) hereditary CAA. Results: A total of 52 studies were retrieved, including three systematic reviews, and from these, a specific selection was taken according to each objective, confirming the diagnostic value of amyloid PET added to MRI and clinical information in all the selected situations, although with some limitations. Conclusions: Amyloid PET reliably detects increased global and region-specific amyloid deposition in CAA patients, with a characteristic occipital-predominant pattern. Continued advancements in tracer development and imaging methodologies are needed to increase specificity. Full article

Within the phenotypic spectrum of Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD) and cerebral amyloid angiopathy (CAA), dementia that is attributed to iatrogenic transmission has increasingly gained scientific attention recently. Newly recognized, this treatment-induced form of dementia may result from exposure to certain medical or surgical procedures. The present review aims to explore the distinct features of acquired dementia encompassing a history of potential exposure and relatively early age of onset, highlighting transmission potential with a rather prion-like pattern. Having reviewed all available relevant literature, dementia of iatrogenic etiology represents a new disease entity that requires an individualized investigation process and poses a great clinical challenge as far as patients with AD, CJD and CAA are concerned. Understanding the underlying pathophysiology of these rare forms of dementia may significantly enhance awareness within clinical field of neurodegenerative diseases and facilitate their prompt management. Full article

Many clinico-pathological studies point to the presence of multiple comorbidities/co-pathologies in the course of Parkinson disease (PD). Lewy body pathology, the morphological hallmark of PD, rarely exists in isolation, but is usually associated with other concomitant pathologies, in particular Alzheimer disease-related changes (ADNC), cerebrovascular pathologies (macro- and microinfarcts, cerebral small vessel disease, cerebral amyloid angiopathy), TDP-43 pathology as well as multiple pathological combinations. These include cardiovascular disorders, metabolic syndrome, diabetes mellitus, autoimmune and rheumatic diseases, myasthenia gravis, Sjögren’s syndrome, restless leg syndrome or other rare disorders, like Fabry disease. A combination of PD and multiple sclerosis (MS) may be due to the immune function of LRRK2 and its interrelation with α-synuclein. COVID-19 and HIV posed considerable impacts on patients with PD. Epidemiological evidence points to a decreased risk for the majority of neoplasms, except melanoma and other skin cancers, while some tumors (breast, brain) are increased. On the other hand, a lower frequency of malignancies preceding early PD markers may argue for their protective effect on PD risk. Possible pathogenetic factors for the association between PD and cancer are discussed. The tremendous heterogeneity of concomitant pathologies and comorbidities observed across the PD spectrum is most likely caused by the complex interplay between genetic, pathogenic and other risk factors, and further research should provide increasing insight into their relationship with idiopathic PD (and other parkinsonian disorders) in order to find better diagnostic tools and probable disease-modifying therapies. Full article

Cerebral amyloid angiopathy (CAA) is one of the most prevalent small vessel diseases (SVDs). Its neuroradiological hallmarks are both hemorrhagic and non-hemorrhagic ones. Among the clinical manifestations, transient focal neurological episodes (TFNEs) are associated with an increased risk of bleeding in a short time period and with convexal subarachnoid hemorrhage (SAH). The natural history of CAA is incompletely characterized in the literature, because the focus has been mostly on hemorrhagic events, while both clinical and non-hemorrhagic presentations are possible and sometimes underestimated. Furthermore, new diagnostic criteria have incorporated non-hemorrhagic Magnetic Resonance Imaging (MRI) markers and non-hemorrhagic clinical presentations. Disease trajectories are often individual and help provide food for thought and discussion on some issues, thus allowing for a greater and deeper evaluation. We, therefore, present a case that exemplifies how the natural history of CAA can be atypical compared to its expected course, which is long and not only hemorrhagic. Several episodes of CAA-related inflammation, with prevalent, but not exclusive, leptomeningeal involvement, were evaluated and treated in the presented case, in which the intraparenchymal cerebral hemorrhagic manifestation was the last in the patient’s history. CAA may have a very long natural history. During the disease’s course, inflammatory features might be prominent in neuroimaging but not strongly symptomatic, and intraparenchymal cerebral hemorrhage (ICH) may be a late event. The awareness of this subtype of the disease allows us to better explore the pathophysiology of CAA and to increase the level of clinical suspicion for the diagnosis. Furthermore, the distinction between different disease phenotypes can provide useful information for patient management in clinical practice. Full article

The prevalence of cerebral amyloid angiopathy (CAA) has been shown to increase with age, with rates reported to be around 50–60% in individuals over 80 years old who have cognitive impairment. The disease often presents as spontaneous lobar intracerebral hemorrhage (ICH), which carries a high risk of recurrence, along with transient focal neurologic episodes (TFNE) and progressive cognitive decline, potentially leading to Alzheimer’s disease (AD). In addition to ICH, neuroradiologic findings of CAA include cortical and subcortical microbleeds (MB), cortical subarachnoid hemorrhage (cSAH) and cortical superficial siderosis (cSS). Non-hemorrhagic pathologies include dilated perivascular spaces in the centrum semiovale and multiple hyperintense lesions on T2-weighted magnetic resonance imaging (MRI). A definitive diagnosis of CAA still requires histological confirmation. The Boston criteria allow for the diagnosis of a probable or possible CAA by considering specific neurological and MRI findings. The recent version, 2.0, which includes additional non-hemorrhagic MRI findings, increases sensitivity while maintaining the same specificity. The characteristic MRI findings of autoantibody-related CAA-related inflammation (CAA-ri) are similar to the so-called “amyloid related imaging abnormalities” (ARIA) observed with amyloid antibody therapies, presenting in two variants: (a) vasogenic edema and leptomeningeal effusions (ARIA-E) and (b) hemorrhagic lesions (ARIA-H). Clinical and MRI findings enable the diagnosis of a probable or possible CAA-ri, with biopsy remaining the gold standard for confirmation. In contrast to spontaneous CAA-ri, only about 20% of patients treated with monoclonal antibodies who show proven ARIA on MRI also experience clinical symptoms, including headache, confusion, other psychopathological abnormalities, visual disturbances, nausea and vomiting. Recent findings indicate that treatment should be continued in cases of mild ARIA, with ongoing MRI and clinical monitoring. This review offers a concise update on CAA and its associated consequences. Full article

Anti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer’s disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity. Full article