ABSTRACT
Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aß) deposition in cerebrovasculature. It is prevalent with aging and Alzheimer's disease (AD), associated with intracerebral hemorrhage, and contributes to cognitive deficits. To better understand molecular mechanisms, CAA(+) and CAA(-) vessels were microdissected from paraffin-embedded autopsy temporal cortex of age-matched Control (n = 10), mild cognitive impairment (MCI; n = 4), and sporadic AD (n = 6) cases, followed by label-free quantitative mass spectrometry. 257 proteins were differentially abundant in CAA(+) vessels compared to neighboring CAA(-) vessels in MCI, and 289 in AD (p < 0.05, fold-change > 1.5). 84 proteins changed in the same direction in both groups, and many changed in the same direction among proteins significant in at least one group (p < 0.0001, R2 = 0.62). In CAA(+) vessels, proteins significantly increased in both AD and MCI were particularly associated with collagen-containing extracellular matrix, while proteins associated with ribonucleoprotein complex were significantly decreased in both AD and MCI. In neighboring CAA(-) vessels, 61 proteins were differentially abundant in MCI, and 112 in AD when compared to Control cases. Increased proteins in CAA(-) vessels were associated with extracellular matrix, external encapsulating structure, and collagen-containing extracellular matrix in MCI; collagen trimer in AD. Twenty two proteins were increased in CAA(-) vessels of both AD and MCI. Comparison of the CAA proteome with published amyloid-plaque proteomic datasets identified many proteins similarly enriched in CAA and plaques, as well as a protein subset hypothesized as preferentially enriched in CAA when compared to plaques. SEMA3G emerged as a CAA specific marker, validated immunohistochemically and with correlation to pathology levels (p < 0.0001; R2 = 0.90). Overall, the CAA(-) vessel proteomes indicated changes in vessel integrity in AD and MCI in the absence of Aß, and the CAA(+) vessel proteome was similar in MCI and AD, which was associated with vascular matrix reorganization, protein translation deficits, and blood brain barrier breakdown.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Cognitive Dysfunction , Proteome , Humans , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Cognitive Dysfunction/pathology , Cognitive Dysfunction/metabolism , Male , Female , Proteome/metabolism , Aged , Aged, 80 and over , Proteomics/methodsABSTRACT
OBJECTIVES: Cerebral amyloid angiopathy (CAA)-related features on neuroimaging often coexist with signs of arteriolosclerosis-small vessel disease on neuroimaging in people with intracranial hemorrhage (ICH). This study aimed at defining the value of amyloid pathology detected by 18Fflutemetamol PET in reclassification and stratification of risk of bleeding in people with mixed CAA-arteriolosclerosis features. METHODS: We included consecutive patients admitted to 2 institutions (2018-2023) with spontaneous symptomatic ICH, subarachnoid hemorrhage (SAH), transient focal neurologic episodes (TFNE), or cognitive impairment and MRI showing CAA hallmarks. All patients underwent brain magnetic resonance imaging (MRI) with susceptibility weighted imaging and 18Fflutemetamol PET imaging and were followed up for at least 1 year. We compared cases with CAA and arteriolosclerosis + CAA features and defined long-term outcomes (composite outcome including death, ICH, ischemic stroke, SAH, TFNE) depending on PET status (CAA/amyloid pathology vs arteriolosclerosis-predominant groups). RESULTS: Among 47 patients, according to PET and MRI imaging, 38 patients were reclassified in the CAA/amyloid pathology group and 9 in the arteriolosclerosis-predominant group, with similar cardiovascular risk factors but a significantly higher lobar microbleed burden for the former group. The CAA/amyloid pathology group had higher rates of composite outcome (43.9 vs 11.1 events per 100 patient-year; p = 0.039) and ICH (36.5 vs 5.6 events per 100 patient-years; p = 0.04) compared with the arteriolosclerosis-predominant group. DISCUSSION: 18FFlutemetamol PET imaging can help in reclassification of mixed arteriolosclerosis + CAA into CAA/amyloid pathology and arteriolosclerosis-predominant, with implications on long-term risk of recurrent events. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that 18Fflutemetamol PET can distinguish between CAA + arteriolosclerosis and arteriolosclerosis-predominant pathology.
Subject(s)
Aniline Compounds , Cerebral Amyloid Angiopathy , Magnetic Resonance Imaging , Positron-Emission Tomography , Humans , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/classification , Cerebral Amyloid Angiopathy/complications , Male , Female , Aged , Positron-Emission Tomography/methods , Middle Aged , Benzothiazoles , Aged, 80 and over , Intracranial Hemorrhages/diagnostic imagingABSTRACT
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.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Amyloid beta-Protein Precursor , Brain , Cerebral Amyloid Angiopathy , Down Syndrome , Humans , Down Syndrome/pathology , Down Syndrome/metabolism , Down Syndrome/genetics , Down Syndrome/complications , Amyloid beta-Peptides/metabolism , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/genetics , Cerebral Amyloid Angiopathy/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Male , Female , Aged , Middle Aged , Brain/pathology , Brain/metabolism , tau Proteins/metabolism , Aged, 80 and over , Plaque, Amyloid/pathology , Plaque, Amyloid/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS. METHODS: Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk. RESULTS: This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS (p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04). CONCLUSION: Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.
Subject(s)
Cerebral Amyloid Angiopathy , Vasculitis, Central Nervous System , Humans , Female , Male , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/complications , Aged , Middle Aged , Vasculitis, Central Nervous System/diagnostic imaging , Vasculitis, Central Nervous System/pathology , Retrospective Studies , Biopsy , Magnetic Resonance Imaging , Aged, 80 and over , Brain/pathology , Brain/diagnostic imaging , Adult , RecurrenceABSTRACT
Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aß) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers (APOE4) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aß immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene (APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aß deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aß, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.
Subject(s)
Alzheimer Disease , Disease Models, Animal , Mice, Transgenic , Animals , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/genetics , Mice , Humans , Female , Male , Amyloid beta-Peptides/metabolism , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Cerebral Amyloid Angiopathy/metabolism , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/genetics , Brain/metabolism , Brain/pathologyABSTRACT
Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-ß (Aß) deposition in the cerebral blood vessel walls. CAA is associated with an increased risk for intracerebral hemorrhages (ICH). Insight into the molecular mechanisms associated with CAA pathology is urgently needed, to develop additional diagnostic tools to allow for reliable and early diagnosis of CAA and to obtain novel leads for the development of targeted therapies. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) is associated with cardiovascular functioning and disease and has been linked to vascular dementia. Using immunohistochemistry, we studied occipital brain tissue samples of 57 patients with CAA (39 without ICH and 18 with ICH) and 42 controls, and semi-quantitatively assessed expression levels of TIMP4. Patients with CAA had increased vascular expression of TIMP4 compared to controls (p < 0.001), and in these patients, TIMP4 expression correlated with CAA severity (τb = 0.38; p = 0.001). Moreover, TIMP4 expression was higher in CAA-ICH compared to CAA-non-ICH cases (p = 0.024). In a prospective cross-sectional study of 38 patients with CAA and 37 age- and sex-matched controls, we measured TIMP4 levels in cerebrospinal fluid (CSF) and serum using ELISA. Mean CSF levels of TIMP4 were decreased in patients with CAA compared to controls (3.36 ± 0.20 vs. 3.96 ± 0.22 ng/ml, p = 0.033), whereas median serum levels were increased in patients with CAA (4.51 ng/ml [IQR 3.75-5.29] vs 3.60 ng/ml [IQR 3.11-4.85], p-9.013). Moreover, mean CSF TIMP4 levels were lower in CAA patients who had experienced a symptomatic hemorrhage compared to CAA patients who did not (2.13 ± 0.24 vs. 3.57 ± 0.24 ng/ml, p = 0.007). CSF TIMP4 levels were associated with CSF levels of Aß40 (spearman r (rs) = 0.321, p = 0.009). In summary, we show that TIMP4 is highly associated with CAA and CAA-related ICH, which is reflected by higher levels in the cerebral vasculature and lower levels in CSF. With these findings we provide novel insights into the pathophysiology of CAA, and more specifically in CAA-associated ICH.
Subject(s)
Brain , Cerebral Amyloid Angiopathy , Tissue Inhibitor of Metalloproteinase-4 , Tissue Inhibitor of Metalloproteinases , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Brain/metabolism , Brain/pathology , Cerebral Amyloid Angiopathy/cerebrospinal fluid , Cerebral Amyloid Angiopathy/pathology , Cerebral Hemorrhage/cerebrospinal fluid , Cerebral Hemorrhage/metabolism , Tissue Inhibitor of Metalloproteinases/cerebrospinal fluid , Tissue Inhibitor of Metalloproteinases/metabolismABSTRACT
Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid protein in the walls of cerebral blood vessels. This deposition of amyloid causes damage to the cerebral vasculature, resulting in blood-brain barrier disruption, cerebral hemorrhage, cognitive decline, and dementia. The role of the immune system in CAA is complex and not fully understood. While the immune system has a clear role in the rare inflammatory variants of CAA (CAA related inflammation and Abeta related angiitis), the more common variants of CAA also have immune system involvement. In a protective role, immune cells may facilitate the clearance of beta-amyloid from the cerebral vasculature. The immune system can also contribute to CAA pathology, promoting vascular injury, blood-brain barrier breakdown, inflammation, and progression of CAA. In this review, we summarize the role of the immune system in CAA, including the potential of immune based treatment strategies to slow vascular disease in CAA and associated cognitive impairment, white matter disease progression, and reduce the risk of cerebral hemorrhage. HIGHLIGHTS: The immune system has a role in cerebral amyloid angiopathy (CAA) which is summarized in this review. There is an inflammatory response to beta-amyloid that may contribute to brain injury and cognitive impairment. Immune cells may facilitate the clearance of beta-amyloid from the cerebral vasculature. Improved understanding of the immune system in CAA may afford novel treatment to improve outcomes in patients with CAA.
Subject(s)
Amyloid beta-Peptides , Cerebral Amyloid Angiopathy , Cerebral Amyloid Angiopathy/pathology , Humans , Amyloid beta-Peptides/metabolism , Immune System , Inflammation/immunology , Blood-Brain Barrier , Animals , Brain/pathology , Brain/immunologyABSTRACT
Cerebral amyloid angiopathy (CAA) is a progressive neurodegenerative small vessel disease that is associated with intracranial hemorrhage and cognitive impairment in the elderly. The clinical and radiographic presentations have many overlapping features with vascular cognitive impairment, hemorrhagic stroke, and Alzheimer disease (AD). Amyloid-ß-related angiitis (ABRA) is a form of primary CNS vasculitis linked to CAA, with the development of spontaneous autoimmune inflammation against amyloid in the vessel wall with resultant vasculitis. The diagnosis of ABRA and CAA is important. ABRA is often fatal if untreated and requires prompt immunosuppression. Important medical therapies such as anticoagulation and antiamyloid agents for AD are contraindicated in CAA. Here, we present a biopsy-proved case of ABRA with underlying occult CAA. Initial 1.5T and 3T MR imaging did not suggest CAA per the Boston Criteria 2.0. ABRA was not included in the differential diagnosis due to the lack of any CAA-related findings on conventional MR imaging. However, a follow-up 7T MR imaging revealed extensive cortical/subcortical cerebral microbleeds, cortical superficial siderosis, and intragyral hemorrhage in extensive detail throughout the supratentorial brain regions, which radiologically supported the diagnosis of ABRA in the setting of CAA. This case suggests an increased utility of high-field MR imaging to detect occult hemorrhagic neuroimaging findings with the potential to both diagnose more patients with CAA and diagnose them earlier.
Subject(s)
Cerebral Amyloid Angiopathy , Magnetic Resonance Imaging , Vasculitis, Central Nervous System , Humans , Magnetic Resonance Imaging/methods , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Amyloid Angiopathy/pathology , Vasculitis, Central Nervous System/diagnostic imaging , Aged , Male , Female , Neuroimaging/methods , Amyloid beta-Peptides/metabolism , Diagnosis, DifferentialABSTRACT
This study investigated the correlation of newly identified inflammatory and insulin resistance indices with cerebral amyloid angiopathy (CAA), and explored their potential to differentiate CAA from hypertensive arteriopathy (HA). We retrospectively analyzed 514 consecutive patients with cerebral small vessel disease (CSVD)-related haemorrhage, comparing the differences in novel inflammatory and insulin resistance indices between patients with CAA and HA. Univariate regression, LASSO and multivariate regression were used to screen variables and construct a classification diagnosis nomogram. Additionally, these biomarkers were explored in patients with mixed haemorrhagic CSVD. Inflammatory indices were higher in CAA patients, whereas insulin resistance indices were higher in HA patients. Further analysis identified neutrophil-to-lymphocyte ratio (NLR, OR 1.17, 95% CI 1.07-1.30, P < 0.001), and triglyceride-glucose index (TyG, OR = 0.56, 95% CI 0.36-0.83, P = 0.005) as independent factors for CAA. Therefore, we constructed a CAA prediction nomogram without haemorrhagic imaging markers. The nomogram yielded an area under the curve (AUC) of 0.811 (95% CI 0.764-0.865) in the training set and 0.830 (95% CI 0.718-0.887) in the test set, indicating an ability to identify high-risk CAA patients. These results show that CSVD patients can be phenotyped using novel inflammatory and insulin resistance indices, potentially allowing identification of high-risk CAA patients without haemorrhagic imaging markers.
Subject(s)
Biomarkers , Cerebral Amyloid Angiopathy , Inflammation , Insulin Resistance , Humans , Male , Female , Cerebral Amyloid Angiopathy/pathology , Aged , Retrospective Studies , Biomarkers/blood , Inflammation/pathology , Middle Aged , Neutrophils/metabolism , Cerebral Small Vessel Diseases/pathology , Cerebral Small Vessel Diseases/blood , Nomograms , Lymphocytes/metabolism , Triglycerides/bloodABSTRACT
BACKGROUND AND OBJECTIVES: Updated criteria for the clinical-MRI diagnosis of cerebral amyloid angiopathy (CAA) have recently been proposed. However, their performance in individuals without symptomatic intracerebral hemorrhage (ICH) presentations is less defined. We aimed to assess the diagnostic performance of the Boston criteria version 2.0 for CAA diagnosis in a cohort of individuals ranging from cognitively normal to dementia in the community and memory clinic settings. METHODS: Fifty-four participants from the Mayo Clinic Study of Aging or Alzheimer's Disease Research Center were included if they had an antemortem MRI with gradient-recall echo sequences and a brain autopsy with CAA evaluation. Performance of the Boston criteria v2.0 was compared with v1.5 using histopathologically verified CAA as the reference standard. RESULTS: The median age at MRI was 75 years (interquartile range 65-80) with 28/54 participants having histopathologically verified CAA (i.e., moderate-to-severe CAA in at least 1 lobar region). The sensitivity and specificity of the Boston criteria v2.0 were 28.6% (95% CI 13.2%-48.7%) and 65.3% (95% CI 44.3%-82.8%) for probable CAA diagnosis (area under the receiver operating characteristic curve [AUC] 0.47) and 75.0% (55.1-89.3) and 38.5% (20.2-59.4) for any CAA diagnosis (possible + probable; AUC 0.57), respectively. The v2.0 Boston criteria were not superior in performance compared with the prior v1.5 criteria for either CAA diagnostic category. DISCUSSION: The Boston criteria v2.0 have low accuracy in patients who are asymptomatic or only have cognitive symptoms. Additional biomarkers need to be explored to optimize CAA diagnosis in this population.
Subject(s)
Cerebral Amyloid Angiopathy , Magnetic Resonance Imaging , Humans , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Amyloid Angiopathy/pathology , Aged , Female , Male , Magnetic Resonance Imaging/standards , Aged, 80 and over , Sensitivity and Specificity , Brain/diagnostic imaging , Brain/pathology , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/pathologyABSTRACT
The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.
Subject(s)
Amyloid beta-Peptides , Brain , Cerebral Amyloid Angiopathy , Humans , Brain/metabolism , Brain/pathology , Cerebral Amyloid Angiopathy/metabolism , Cerebral Amyloid Angiopathy/pathology , Animals , Amyloid beta-Peptides/metabolism , Glymphatic System/metabolism , Glymphatic System/pathology , Alzheimer Disease/metabolism , Alzheimer Disease/pathologyABSTRACT
Therapeutic antibodies have been developed to target amyloid-beta (Aß), and some of these slow the progression of Alzheimer's disease (AD). However, they can also cause adverse events known as amyloid-related imaging abnormalities with edema (ARIA-E). We investigated therapeutic Aß antibody binding to cerebral amyloid angiopathy (CAA) fibrils isolated from human leptomeningeal tissue to study whether this related to the ARIA-E frequencies previously reported by clinical trials. The binding of Aß antibodies to CAA Aß fibrils was evaluated in vitro using immunoprecipitation, surface plasmon resonance, and direct binding assay. Marked differences in Aß antibody binding to CAA fibrils were observed. Solanezumab and crenezumab showed negligible CAA fibril binding and these antibodies have no reported ARIA-E cases. Lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA-E frequency of 12.6%, while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA-E frequencies (25-35%). An ARIA-E frequency of 24% was reported for donanemab, and its binding to CAA fibrils correlated with the amount of pyroglutamate-modified Aß present. The findings of this study support the proposal that Aß antibody-CAA interactions may relate to the ARIA-E frequency observed in patients treated with Aß-based immunotherapies.
Subject(s)
Amyloid beta-Peptides , Cerebral Amyloid Angiopathy , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/immunology , Alzheimer Disease/pathology , Amyloid/metabolism , Amyloid/immunology , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Amyloid Angiopathy/immunology , Cerebral Amyloid Angiopathy/pathology , Protein Binding , Surface Plasmon ResonanceABSTRACT
Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.
Subject(s)
Alzheimer Disease , Hispanic or Latino , Lewy Bodies , White People , Humans , Alzheimer Disease/pathology , Alzheimer Disease/ethnology , Female , Male , Aged , Aged, 80 and over , Cohort Studies , Lewy Bodies/pathology , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/ethnology , alpha-Synuclein/metabolism , Brain/pathology , Cerebral Small Vessel Diseases/pathology , Cerebral Small Vessel Diseases/ethnology , Arteriolosclerosis/pathologyABSTRACT
Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer's disease (AD). While it is known that vascular fibrillar amyloid ß (Aß) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-ß1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-ß1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Rats , Animals , Amyloid beta-Peptides/metabolism , Transforming Growth Factor beta1/metabolism , Proteomics , Cerebral Amyloid Angiopathy/pathology , Alzheimer Disease/metabolism , Brain/metabolism , Inflammation/pathologyABSTRACT
BACKGROUND: Cortical microinfarcts (CMI) were attributed to cerebrovascular disease and cerebral amyloid angiopathy (CAA). CAA is frequent in Down syndrome (DS) while hypertension is rare, yet no studies have assessed CMI in DS. METHODS: We included 195 adults with DS, 63 with symptomatic sporadic Alzheimer's disease (AD), and 106 controls with 3T magnetic resonance imaging. We assessed CMI prevalence in each group and CMI association with age, AD clinical continuum, vascular risk factors, vascular neuroimaging findings, amyloid/tau/neurodegeneration biomarkers, and cognition in DS. RESULTS: CMI prevalence was 11.8% in DS, 4.7% in controls, and 17.5% in sporadic AD. In DS, CMI increased in prevalence with age and the AD clinical continuum, was clustered in the parietal lobes, and was associated with lacunes and cortico-subcortical infarcts, but not hemorrhagic lesions. DISCUSSION: In DS, CMI are posteriorly distributed and related to ischemic but not hemorrhagic findings suggesting they might be associated with a specific ischemic CAA phenotype. HIGHLIGHTS: This is the first study to assess cortical microinfarcts (assessed with 3T magnetic resonance imaging) in adults with Down syndrome (DS). We studied the prevalence of cortical microinfarcts in DS and its relationship with age, the Alzheimer's disease (AD) clinical continuum, vascular risk factors, vascular neuroimaging findings, amyloid/tau/neurodegeneration biomarkers, and cognition. The prevalence of cortical microinfarcts was 11.8% in DS and increased with age and along the AD clinical continuum. Cortical microinfarcts were clustered in the parietal lobes, and were associated with lacunes and cortico-subcortical infarcts, but not hemorrhagic lesions. In DS, cortical microinfarcts are posteriorly distributed and related to ischemic but not hemorrhagic findings suggesting they might be associated with a specific ischemic phenotype of cerebral amyloid angiopathy.
Subject(s)
Alzheimer Disease , Down Syndrome , Magnetic Resonance Imaging , Humans , Down Syndrome/pathology , Down Syndrome/complications , Down Syndrome/diagnostic imaging , Female , Male , Middle Aged , Alzheimer Disease/pathology , Alzheimer Disease/diagnostic imaging , Adult , Aged , Cerebral Infarction/diagnostic imaging , Cerebral Infarction/pathology , Prevalence , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/complications , Risk Factors , Cerebral Cortex/pathology , Cerebral Cortex/diagnostic imagingABSTRACT
Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02âM V2O5 1âh, 3/week for 6 months) groups (nâ=â10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.
Subject(s)
Alzheimer Disease , Brain , Disease Models, Animal , Spatial Memory , Vanadium Compounds , Animals , Male , Administration, Inhalation , Alzheimer Disease/chemically induced , Alzheimer Disease/pathology , Amygdala/drug effects , Amygdala/pathology , Brain/drug effects , Brain/pathology , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/pathology , Cerebral Amyloid Angiopathy/chemically induced , Cerebral Amyloid Angiopathy/pathology , Dendritic Spines/drug effects , Dendritic Spines/pathology , Entorhinal Cortex/drug effects , Entorhinal Cortex/pathology , Frontal Lobe/drug effects , Frontal Lobe/pathology , Maze Learning/drug effects , Neurofibrillary Tangles/drug effects , Neurofibrillary Tangles/pathology , Plaque, Amyloid/chemically induced , Plaque, Amyloid/pathology , Rats, Wistar , Spatial Memory/drug effects , Vanadium Compounds/administration & dosage , Vanadium Compounds/toxicityABSTRACT
Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aß peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer's disease (AD). We investigate the structure of human-derived Aß40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro Aß40 fibril structures. One population has an ordered N-terminal fold comprised of two ß-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations can guide fibril formation.
Subject(s)
Amyloid beta-Peptides , Cerebral Amyloid Angiopathy , Static Electricity , Humans , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/chemistry , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/genetics , Cerebral Amyloid Angiopathy/metabolism , Cryoelectron Microscopy/methods , Amyloid/metabolism , Amyloid/chemistry , Amyloid/genetics , Peptide Fragments/genetics , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Mutation , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Alzheimer Disease/metabolismABSTRACT
Dementia is characterized by acquired cognitive dysfunction caused by various neurological disorders. Many neurological conditions can cause dementia, including neurodegenerative diseases, vascular disorders, infections, inflammation, demyelination, intoxication, metabolic disorders, tumors, and head trauma. Despite recent developments in biomarkers and imaging techniques, neuropathological examination is necessary for the final diagnosis. Moreover, approximately 11% of the patients with dementia have dual or triple pathological conditions. The coexistence of neurological diseases makes it difficult for neurologists to diagnose patients accurately. Degenerative diseases are characterized by neuronal loss with gliosis in distinct parts of the brain, the presence of neuronal or glial inclusions, and abnormal protein accumulation. Senile plaques and neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease. These findings are characterized by the presence of amyloid ß protein (Aß) and phosphorylated tau protein, respectively. Although vascular dementia is common, it may be difficult to identify the relationship between vascular lesions and cognitive impairment. The incidence of sporadic Aß-type cerebral amyloid angiopathy (CAA) tends to increase with age and causes dementia due to vascular dysfunction and leukoencephalopathy. Furthermore, patients with CAA can develop inflammation. Clinical neurologists should possess a neuropathological perspective for the appropriate diagnosis and management of patients with dementia.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Humans , Amyloid beta-Peptides , Alzheimer Disease/pathology , Cerebral Amyloid Angiopathy/pathology , Brain/pathology , InflammationABSTRACT
BACKGROUND AND OBJECTIVES: Epilepsy is 1 of the 3 most common neurologic diseases of older adults, but few studies have examined its underlying pathologies in older age. We examined the associations of age-related brain pathologies with epilepsy in older persons. METHODS: Clinical and pathologic data came from 2 ongoing clinical pathologic cohort studies of community-dwelling older adults. Epilepsy was ascertained using Medicare fee-for-service Parts A and B claims data that were linked to data from the cohort studies. The postmortem pathologic assessment collected indices of 9 pathologies including Alzheimer disease, hippocampal sclerosis, macroinfarcts, and cerebral amyloid angiopathy. The fixed brain hemisphere was imaged using 3T MRI scanners before the pathologic assessments in a subgroup of participants. RESULTS: The participants (n = 1,369) were on average 89.3 (6.6) years at death, and 67.0% were women. Epilepsy was identified in 58 (4.2%) participants. Cerebral amyloid angiopathy (odds ratio [OR] = 2.21, 95% CI 1.24-3.95, p = 0.007) and cortical macroinfarcts (OR = 2.74, 95% CI 1.42-5.28, p = 0.003) were associated with a higher odds of epilepsy. Of note, hippocampal sclerosis and Alzheimer disease pathology were not associated with epilepsy (both p's > 0.25), although hippocampal sclerosis was not common and thus hard to examine with the modest number of epilepsy cases here. In 673 participants with MRI data, the association of cerebral amyloid angiopathy and cortical macroinfarcts with epilepsy did not change after controlling for cortical gray matter atrophy, which was independently associated with a higher odds of epilepsy (OR = 1.06, 95% CI 1.02-1.10, p = 0.003). By contrast, hippocampal volume was not associated with epilepsy. DISCUSSION: Cerebrovascular pathologies and cortical atrophy were associated with epilepsy in older persons.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Epilepsy , Hippocampal Sclerosis , United States/epidemiology , Humans , Female , Aged , Aged, 80 and over , Male , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Medicare , Cerebral Amyloid Angiopathy/pathology , Autopsy , Epilepsy/diagnostic imaging , Epilepsy/epidemiology , Epilepsy/pathology , Atrophy/pathology , Brain/diagnostic imaging , Brain/pathologyABSTRACT
INTRODUCTION: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. METHODS: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. RESULTS: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). DISCUSSION: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. HIGHLIGHTS: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.