Association of Anticoagulant Use With Hemorrhage Location and Etiology in Incident Spontaneous Intracerebral Hemorrhage.

BACKGROUND: It is unknown whether hypertensive microangiopathy or cerebral amyloid angiopathy (CAA) predisposes more to anticoagulant-associated intracerebral hemorrhage (AA-ICH). The purpose of our study was to determine whether AA-ICH is associated with lobar location and probable CAA. METHODS: This was a cross-sectional analysis of patients with first-ever spontaneous ICH admitted to a tertiary hospital in Boston, between 2008 and 2023. Univariable and multivariable logistic regression were used to investigate the association between anticoagulation use and both lobar hemorrhage location and probable CAA on magnetic resonance imaging (MRI) by Boston Criteria 2.0 or computed tomography by Simplified Edinburgh Criteria. RESULTS: A total of 1104 patients (mean [SD] age, 73 [12]; 499 females [45.0%]) were included. Of the 1104 patients, 268 (24.3%) had AA-ICH: 148 (55.2%) with vitamin K antagonists and 107 (39.9%) with direct oral anticoagulants. Brain MRI was performed in 695 (63.0%) patients. The proportion of patients with lobar hemorrhage was not different between those with and without AA-ICH (121/268 [45.1%] versus 424/836 [50.7%]; odds ratio [OR], 0.80 [95% CI, 0.61-1.05]; P=0.113). Patients with AA-ICH were less likely to have probable CAA on MRI (17/146 [11.6%] versus 127/549 [23.1%]; OR, 0.44 [95% CI, 0.25-0.75]; P=0.002) and probable CAA on MRI or computed tomography if MRI not performed (27/268 [10.0%] versus 200/836 [23.9%]; OR, 0.36 [95% CI, 0.23-0.55]; P<0.001). Among patients with AA-ICH, there were no differences in the proportion with lobar hemorrhage (63/148 [42.6%] versus 46/107 [43.0%]; OR, 1.02 [95% CI, 0.62-1.68]; P=0.946) or probable CAA on MRI (10/72 [13.9%] versus 7/69 [10.1%]; OR, 0.70 [95% CI, 0.25-1.96]; P=0.495) between vitamin K antagonists and direct oral anticoagulant users. CONCLUSIONS: AA-ICH was not associated with lobar hemorrhage location but was associated with reduced odds of probable CAA. These results suggest that hypertensive microangiopathy may predispose more toward incident AA-ICH than CAA and emphasize the importance of blood pressure control among anticoagulant users. These findings require replication in additional cohorts.

Cerebral Proteomic Changes in the rTg-D Rat Model of Cerebral Amyloid Angiopathy Type-2 With Cortical Microhemorrhages and Cognitive Impairments.

Cerebral amyloid angiopathy (CAA) is a common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a novel transgenic rat model (rTg-D) that produces human familial CAA Dutch E22Q mutant amyloid ß-protein (Aß) in brain and develops arteriolar CAA type-2. Here, we show that deposition of fibrillar Aß promotes arteriolar smooth muscle cell loss and cerebral microhemorrhages that can be detected by magnetic resonance imaging and confirmed by histopathology. Aged rTg-D rats also present with cognitive deficits. Cerebral proteomic analyses revealed 241 proteins that were significantly elevated with an increase of >50% in rTg-D rats presenting with CAA compared to wild-type rats. Fewer proteins were significantly decreased in rTg-D rats. Of note, high temperature requirement peptidase A (HTRA1), a proteinase linked to transforming growth factor beta 1 (TGF-ß1) signaling, was elevated and found to accumulate in cerebral vessels harboring amyloid deposits. Pathway analysis indicated elevation of the TGF-ß1 pathway and increased TGF-ß1 levels were detected in rTg-D rats. In conclusion, the present findings provide new molecular insights into the pathogenesis of CAA and suggest a role for interactions between HTRA1 and TGF-ß1 in the disease process.

Cognition in (pre)symptomatic Dutch-type hereditary and sporadic cerebral amyloid angiopathy.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is a main cause of cognitive dysfunction in the elderly. We investigated specific cognitive profiles, cognitive function in the stage before intracerebral hemorrhage (ICH), and the association between magnetic resonance imaging (MRI) based cerebral small vessel disease (cSVD) burden in CAA because data on these topics are limited. METHODS: We included Dutch-type hereditary CAA (D-CAA) mutation carriers with and without ICH, patients with sporadic CAA (sCAA), and age-matched controls. Cognition was measured with a standardized test battery. Linear regression was performed to assess the association between MRI-cSVD burden and cognition. RESULTS: D-CAA ICH- mutation carriers exhibited poorer global cognition and executive function compared to age-matched controls. Patients with sCAA performed worse across all cognitive domains compared to D-CAA ICH+ mutation carriers and age-matched controls. MRI-cSVD burden is associated with decreased processing speed. DISCUSSION: CAA is associated with dysfunction in multiple cognitive domains, even before ICH, with increased MRI-cSVD burden being associated with slower processing speed. HIGHLIGHTS: Cognitive dysfunction is present in early disease stages of cerebral amyloid angiopathy (CAA) before the occurrence of symptomatic intracerebral hemorrhage (sICH). Presymptomatic Dutch-type CAA (D-CAA) mutation carriers show worse cognition than age-matched controls. More early awareness of cognitive dysfunction in CAA before first sICH is needed. Increased cerebral small vessel disease CAA-burden on magnetic resonance imaging is linked to a decrease in processing speed.

[A case of young onset cerebral amyloid angiopathy associated with dural grafting].

A 47-year-old man was admitted to our hospital because of sudden-onset motor aphasia and right hemiplegia. His past medical history was notable for left craniotomy and hematoma evacuation following a traumatic brain hemorrhage approximately 40 years earlier, for which dural grafting was performed. He also had a history of three lobar hemorrhages in the left hemisphere since the age of 42 years. Brain CT imaging revealed an acute left frontal lobar hemorrhage. His initial brain MRI conducted at our hospital demonstrated hemorrhagic findings with left hemisphere dominance, including acute and old lobar hemorrhage, cortical superficial siderosis, and cerebral microbleeds. Cerebrospinal fluid analyses demonstrated reduced levels of cerebral amyloid-ß 42, and elevated total tau. His apolipoprotein E genotype was ε3/ε3. Whole-exome sequencing did not detect mutations in genes associated with Alzheimer's disease, including presenilin 1, presenilin 2, and amyloid precursor protein. These findings led to a clinical diagnosis of iatrogenic cerebral amyloid angiopathy (CAA) using recently proposed diagnostic criteria, which do not require pathological evaluation of the brain. Iatrogenic CAA should be considered as a cause of lobar hemorrhage in young patients, especially those with a past history of neurosurgery.

A case of multiple cerebral hemorrhages followed by shower emboli.

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.

Loss of TREM2 diminishes CAA despite an overall increase of amyloid load in Tg-SwDI mice.

INTRODUCTION: The microglial receptor triggering receptor expressed on myeloid cells 2 (TREM2) is a major risk factor for Alzheimer's disease (AD). Experimentally, Trem2 deficiency affects parenchymal amyloid beta (Aß) deposition. However, the role of TREM2 in cerebrovascular amyloidosis, especially cerebral amyloid angiopathy (CAA), remains unexplored. METHODS: Tg-SwDI (SwDI) mice, a CAA-prone model of AD, and Trem2 knockout mice were crossed to generate SwDI/TWT, SwDI/THet, and SwDI/TKO mice, followed by pathological and biochemical analyses at 16 months of age. RESULTS: Loss of Trem2 led to a dramatic decrease in CAA and microglial association, despite a marked increase in overall brain Aß load. Single nucleus RNA sequencing analysis revealed that in the absence of Trem2, microglia were activated but trapped in transition to the fully reactive state, with distinct responses of vascular cells. DISCUSSION: Our study provides the first evidence that TREM2 differentially modulates parenchymal and vascular Aß pathologies, offering significant implications for both TREM2- and Aß-targeting therapies for AD. HIGHLIGHTS: Triggering receptor expressed on myeloid cells 2 (TREM2) differentially modulates brain parenchymal and vascular amyloidosis. Loss of Trem2 markedly reduces cerebral amyloid angiopathy despite an overall increase of amyloid beta load in Tg-SwDI mice. Microglia are trapped in transition to the fully reactive state without Trem2. Perivascular macrophages and other vascular cells have distinct responses to Trem2 deficiency. Balanced TREM2-targeting therapies may be required for optimal outcomes.

Human iPSC-derived pericyte-like cells carrying APP Swedish mutation overproduce beta-amyloid and induce cerebral amyloid angiopathy-like changes.

BACKGROUND: Patients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aß) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis, and vessel stability. Despite the known impact of vascular dysfunction on the progression of neurodegenerative diseases, the specific role of pericytes in AD pathology remains to be elucidated. METHODS: To explore this, we generated pericyte-like cells from human induced pluripotent stem cells (iPSCs) harboring the Swedish mutation in the amyloid precursor protein (APPswe) along with cells from healthy controls. We initially verified the expression of classic pericyte markers in these cells. Subsequent functional assessments, including permeability, tube formation, and contraction assays, were conducted to evaluate the functionality of both the APPswe and control cells. Additionally, bulk RNA sequencing was utilized to compare the transcriptional profiles between the two groups. RESULTS: Our study reveals that iPSC-derived pericyte-like cells (iPLCs) can produce Aß peptides. Notably, cells with the APPswe mutation secreted Aß1-42 at levels ten-fold higher than those of control cells. The APPswe iPLCs also demonstrated a reduced ability to support angiogenesis and maintain barrier integrity, exhibited a prolonged contractile response, and produced elevated levels of pro-inflammatory cytokines following inflammatory stimulation. These functional changes in APPswe iPLCs correspond with transcriptional upregulation in genes related to actin cytoskeleton and extracellular matrix organization. CONCLUSIONS: Our findings indicate that the APPswe mutation in iPLCs mimics several aspects of CAA pathology in vitro, suggesting that our iPSC-based vascular cell model could serve as an effective platform for drug discovery aimed to ameliorate vascular dysfunction in AD.

Chronic Stress Exacerbates Cerebral Amyloid Angiopathy Through Promoting Neutrophil Extracellular Traps Formation.

Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in cerebral amyloid angiopathy patients but are usually considered as consequences of cerebral amyloid angiopathy pathology. Here, it is reported that chronic stress promotes cerebral amyloid angiopathy progression, which enhances deposition of amyloid protein beta (Aß) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in cerebral amyloid angiopathy development. Aß that accumulates in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. It is demonstrated that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate cerebral amyloid angiopathy severity in the context of chronic stress. Therefore, it is proposed that stress-associated psychological disorders and NETs are promising therapeutic targets in cerebral amyloid angiopathy.

Quality of life, depression and anxiety in cerebral amyloid angiopathy: A cross-sectional study.

BACKGROUND AND PURPOSE: Data on health-related quality of life (HRQoL) and mood in cerebral amyloid angiopathy (CAA), a disease characterized by stroke and cognitive decline, are limited. We aimed to investigate the impacted domains of life, value-based HRQoL and the prevalence of depression and anxiety in patients with CAA. METHODS: We conducted a cross-sectional study of patients with sporadic (s)CAA, lobar dominant mixed CAA and hypertensive arteriopathy (mixed CAA-HTA), or Dutch-type hereditary (D-)CAA, from prospective outpatient clinic cohorts. Participants completed four questionnaires: the EuroQoL 5 dimensions 5-level questionnaire (EQ-5D-5L; EQ-VAS for visual analogue scale; EQ-Index for index rating), the Short-Form 36 questionnaire (SF-36), the Center for Epidemiologic Studies-Depression scale (CES-D), and the Hospital Anxiety and Depression Scale (HADS; -D for depression and -A for anxiety subscales). The EQ-5D-5L assesses the domains mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The SF-36 domains are physical functioning, social functioning, physical role limitations, emotional role limitations, mental health, vitality, bodily pain, and general health perceptions. We compared age- and sex- adjusted HRQoL (SF-36 domain scores; EQ-VAS; EQ-Index) to the Dutch normative population, and estimated the prevalences of current depression (either: history of depression or current use of antidepressants, with high score on CES-D [≥16] and/or HADS-D [≥8]; or high score on both depression questionnaires) and anxiety (HADS-A ≥ 8). RESULTS: We included 179 patients: 77 with sCAA (mean age: 72 years, women: 36%), 31 with mixed CAA-HTA (68 years, women: 29%), and 71 with D-CAA (56 years, women: 52%, symptomatic: 35 [49%]). The SF-36 profiles of all patient groups were similar, negatively differing from the norm in emotional role functioning, social functioning and vitality. The EQ-VAS score of patients (mean [SD] sCAA: 76 [16], D-CAA: 77 [15]) was similar to the norm, as was the EQ-Index score. Fifteen patients with sCAA (23%; 95% confidence interval [CI] 13%-33%), seven with mixed CAA-HTA (27%; 95% CI 10%-44%) and eight with D-CAA (14%; 95% CI 5%-22%) were noted as having depression. The prevalences of anxiety and depression were equivalent. CONCLUSIONS: We found that CAA influenced emotional role functioning and aspects linked to social engagement consistently across its subtypes. One quarter of patients exhibited depressive or anxiety symptoms. Recognizing these impacted domains could enhance overall well-being.

Familial cerebral amyloid disorders with prominent white matter involvement.

Familial cerebral amyloid disorders are characterized by the accumulation of fibrillar protein aggregates, which deposit in the parenchyma as plaques and in the vasculature as cerebral amyloid angiopathy (CAA). Amyloid ß (Aß) is the most common of these amyloid proteins, accumulating in familial and sporadic forms of Alzheimer's disease and CAA. However, there are also a number of rare, hereditary, non-Aß cerebral amyloidosis. The clinical manifestations of these familial cerebral amyloid disorders are diverse, including cognitive or neuropsychiatric presentations, intracerebral hemorrhage, seizures, myoclonus, headache, ataxia, and spasticity. Some mutations are associated with extensive white matter hyperintensities on imaging, which may or may not be accompanied by hemorrhagic imaging markers of CAA; others are associated with occipital calcification. We describe the clinical, imaging, and pathologic features of these disorders and discuss putative disease mechanisms. Familial disorders of cerebral amyloid accumulation offer unique insights into the contributions of vascular and parenchymal amyloid to pathogenesis and the pathways underlying white matter involvement in neurodegeneration. With Aß immunotherapies now entering the clinical realm, gaining a deeper understanding of these processes and the relationships between genotype and phenotype has never been more relevant.

Neuropsychiatric symptoms and lifelong mental activities in cerebral amyloid angiopathy - a cross-sectional study.

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.

Clinical Presentation and Imaging Findings of Irreversible Cerebral Amyloid Angiopathy-Related Inflammation (CAA-ri): A Case Report and Literature Review.

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.

GGC repeat expansions in NOTCH2NLC cause uN2CpolyG cerebral amyloid angiopathy.

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.

Associations between white and grey matter damage and gait impairment in cerebral amyloid angiopathy.

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 6 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), 95 % confidence interval (CI): 0.17, 0.03-0.32), and medial orbital frontal cortical thickness and counting backwards DTC (parameter estimate (PE), 95 % CI: -5.7 %/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.

Late-Life Blood Pressure and Cerebral Amyloid Angiopathy: Findings from the U.S. National Alzheimer's Coordinating Center Uniform Dataset.

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.

Clinical and neuroimaging precursors in cerebral amyloid angiopathy: impact of the Boston criteria version 2.0.

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.

One Size Does Not Fit All: Micro-, Meso-, and Macrobleeds in Cerebral Amyloid Angiopathy.

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.

Spontaneous Non-Aneurysmal Convexity Subarachnoid Hemorrhage: A Scoping Review of Different Etiologies beyond Cerebral Amyloid Angiopathy.

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.

Alzheimer's Disease Neuropathological Change in Aged Non-Primate Mammals.

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.

Brain MRI in patients with V30M hereditary transthyretin amyloidosis.

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.