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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 18F flutemetamol 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 18F flutemetamol 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: 18F Flutemetamol 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 18F flutemetamol PET can distinguish between CAA + arteriolosclerosis and arteriolosclerosis-predominant pathology.

Objective: To gain insight into different cerebral amyloid angiopathy (CAA) phenotypes and mechanisms, we investigated cortical superficial siderosis (CSS), a new imaging marker of the disease, and its relation with APOE genotype in patients with pathologically proven CAA, who presented with and without intracerebral hemorrhage (ICH)., Methods: MRI scans of 105 patients with CAA pathologic confirmation and MRI were analyzed for CSS (focal, ≤3 sulci; disseminates, ≥4 sulci) and other imaging markers. We compared pathologic, imaging, and APOE genotype data between subjects with vs without ICH, and investigated associations between CSS and APOE genotype., Results: Our cohort consisted of 54 patients with CAA with symptomatic lobar ICH and 51 without ICH. APOE genotype was available in 53 patients. More than 90% of pathology samples in both groups had neuritic plaques, whereas neurofibrillary tangles were more commonly present in the patients without ICH (87% vs 42%, p < 0.0001). There was a trend for patients with CAA with ICH to more commonly have APOE ε2 (48.7% vs 21.4%, p = 0.075), whereas patients without ICH were more likely to be APOE ε4 carriers (85.7% vs 53.9%, p = 0.035). Disseminated CSS was considerably commoner in patients with ICH (33.3% vs 5.9%, p < 0.0001). In logistic regression, disseminated CSS was associated with APOE ε2 (but not APOE ε4) (odds ratio 5.83; 95% confidence interval 1.49-22.82, p = 0.011)., Conclusions: This neuropathologically defined CAA cohort suggests that CSS and APOE ε2 are related to the hemorrhagic expression of the disease; APOE ε4 is enriched in nonhemorrhagic CAA. Our study emphasizes the concept of different CAA phenotypes, suggesting divergent pathophysiologic mechanisms., (© 2015 American Academy of Neurology.)

Cerebral amyloid angiopathy (CAA) is caused by the accumulation of amyloid fibrils on vascular walls and is a well-known cause of cerebral hemorrhages in the elderly. This disease manifests as recurrent or multiple simultaneous subcortical hematomas, occasionally leading to fatal hemorrhages. Additionally, it is noteworthy that CAA-related hemorrhages can develop in individuals aged around 50 years. Although a few different amyloid fibril proteins have been isolated from patients with CAA, the most common protein is Aβ, which is also the main component of senile plaques in Alzheimer's disease. Recent studies have suggested that corticosteroid therapy is effective for preventing the recurrence of CAA-related hemorrhages. Hereditary generalized amyloidosis usually manifests as familial amyloid polyneuropathy (FAP), showing severe involvement of peripheral somatic and autonomic nerves. Many variant forms of transthyretin (TTR) with a single amino acid substitution have been identified as causative amyloid precursor proteins in FAP. Moreover, a small number of TTR gene mutations causes a rare phenotype of systemic amyloidosis characterized by preferential deposition of TTR-derived amyloid proteins in the vitreous body in the eye, as well as the leptomeninges and subarachnoidal vessels in the central nervous system (CNS). This disorder is called familial oculoleptomeningeal or leptomeningeal amyloidosis and is characterized clinically by CNS symptoms, including progressive dementia, seizures, ataxia, spastic paresis, and stroke-like episodes. Since the variant forms of TTR in this amyloidosis are derived from the retinal epithelium or choroid plexus, liver transplantation-an effective treatment for FAP-is considered less effective for treating this rare form of TTR-related systemic amyloidosis.

Cerebral amyloid angiopathy (CAA) belongs to the group of amyloidoses and is characterised by the deposition and accumulation of beta-amyloid (Aβ) in small arterial vessels of the brain. Hereditary forms of CAA exist but sporadic CAA is much more frequent. Deposition of Aβ induces degenerative changes of the cerebral vascular system (thickening of the vessel wall, constriction of vascular lumen, microaneurysms, dissection) that trigger the development of the typical clinical presentation of CAA, that is spontaneous intracerebral haemorrhage. Apart from haemorrhages, also cerebral ischaemia, transient neurological symptoms, leukencephalopathy as well as cognitive decline and dementia can occur in association with CAA. The definite diagnosis of CAA is only possible by means of pathological examination, even though neuroimaging and clinical findings allow the diagnosis of a probable CAA. Currently, no specific causal therapy exists. Although CAA is located in the range of neurological diseases psychiatric symptoms might occur. In the review, we discuss epidemiological, pathogenetic, clinical and diagnostic aspects and possible psychiatric implications of CAA., (© Georg Thieme Verlag KG Stuttgart · New York.)

Cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid deposition and is related to stroke and dementia. CAA is classified into 6 types according to the biochemical properties of amyloid proteins, and among 6 types, the sporadic CAA of amyloid beta protein (Abeta) type is most frequently found in elderly people or patients with Alzheimer's disease (AD). In sporadic CAA of the Abeta type, the epsilon4 allele of the apolipoprotein E gene is associated with increased vascular Abeta deposition, while the epsilon2 allele is associated with CAA-related intracerebral hemorrhage. We have also reported that the genetic polymorphisms of presenilin-1, neprilysin, transforming growth factor beta-1, and alpha1-antichymotrypsin are associated with CAA. In the case of hereditary CAA of the Abeta type, mutations in the genes of amyloid precursor protein (APP) and presenilins have been reported. Interestingly, the missense mutations associated with CAA are located in the middle portion of Abeta, while those associated with familial AD (FAD) are near the N- or C- terminals of Abeta. Individuals with FAD with APP duplication have been reported to present with severe CAA. Some of the FAD patients with mutations in the presenilin genes and patients with Down syndrome also show CAA as a complication. Besides sporadic or hereditary CAA of the Abeta type, hereditary CAA with cerebrovascular deposition of cystatin C, transthyretin, gelsolin, prion protein, and ABri/ADan have also been reported in association with mutations in the genes of the precursor proteins. Better understanding of the genetic factors influencing CAA will lead to identification of novel diagnostic markers and the development of preventive for CAA and CAA-related disorders.

Objectives: To investigate the clinical pictures of patients with recurrent thunderclap headaches of unknown etiology and to field-test two relevant International Classification of Headache Disorders, 2nd edition (ICHD-II) criteria, i.e., primary thunderclap headache (Code 4.6) and benign (or reversible) angiopathy of the CNS (Code 6.7.3)., Methods: We prospectively recruited patients presenting with idiopathic recurrent thunderclap headaches from a hospital-based headache clinic. Detailed histories, neurologic examinations, and MRIs and magnetic resonance angiographies (MRAs) were performed in all patients to exclude secondary causes. Patients with cerebral vasoconstriction received serial MRA follow-up., Results: Fifty-six consecutive patients (51 female/5 male, mean age 49.6 +/- 9.8 [range 22 to 76] years) were enrolled. Segmental vasoconstriction (or benign CNS angiopathy) was found in 22 patients (39%). Thunderclap headache recurred in all patients with a median frequency of 0.7 times per day for a median period of 14 days (range 6 to 86 days). The median duration for each single attack was 3 hours. Most patients (84%) reported at least one trigger. Nimodipine effectively aborted further attacks in 83% of the treated patients. Headache attacks subsided within 3 months. Four patients (7%) developed ischemic complications. Patients with and without vasoconstriction based on MRA images were similar regarding demographics and headache profile. Except for the duration criterion, our patients generally mapped well into the proposed ICHD-II criteria., Conclusions: This study suggests that the two diagnostic entities proposed by the ICHD-II may present different spectra of the same disorder. The distinct headache profile may help physicians quickly recognize this disabling headache disorder with risk of stroke and provide timely treatment.

Objective: The purpose of this study was to differentiate between cerebral amyloid angiopathy (CAA) and hypertension (HTN) based on hemorrhage pattern interpretation., Methods: From June 1994 to Oct., 2000, 83 patients admitted to our service with acute intracerebral hemorrhage (ICH) were investigated retrospectively; 41 patients with histologically proven diagnosis of cerebral amyloid angiography and 42 patients with clear history of hypertension were investigated., Results: Patients with a CAA-related ICH were significantly older than patients with a HTN-related ICH (74.0 years vs 66.5 years, P < 0.05). There was a significantly higher number of hematomas > or = 30 ml in CAA (85.3%) when compared with HTN (59.5%). No basal ganglional hemorrhage was seen in CAA, but in 40.5% in HTN. In CAA-related ICH, subarachnoid hemorrhage (SAH) was seen in 26 patients (63.4%) compared to only 11 patients (26.2%) in HTN-related ICH. Intraventricular hemorrhage was seen in 24.4% in CAA, and in 26.2% in HTN. Typical features of CAA-related ICH included lobar distribution affecting mainly the lobar superficial areas, lobulated appearance, rupture into the subarachnoid space, and secondary IVH from the lobar hemorrhage. More specifically, multiplicity of hemorrhage, bilaterality, and repeated episodes also strongly suggest the diagnosis of CAA. Multiple hemorrhages, defined as 2 or more separate hematomas in multiple lobes, accounted for 17.1% in CAA-related ICH., Conclusion: There are certain features in CAA on CT and MRI and in clinical settings. To some extent, these features may contribute to distinguishing CAA from HTN related ICH.

Cerebral amyloid angiopathy (CAA) is a frequent finding on neuropathological examination of patients with Alzheimer's disease (AD). A recent study from our laboratory showed that CAA also frequently occurred in vascular dementia with additional mild Alzheimer encephalopathy (VaD-ae, i.e. Alzheimer pathology that does not fulfill criteria for AD). Because CAA is associated with cerebral hemorrhages and infarctions, it is of significant interest to confirm or dismiss the hypothesis that CAA contributes clinically in the many patients that present with VaD-ae. Therefore, we examined entire temporal lobes of 11 VaD-ae cases and 11 age-matched AD cases with Abeta immunohistochemistry. Six of 11 VaD-ae cases had severe CAA, more extensive than in any AD case. There was a trend toward more cortical infarctions in this group, indicating that CAA in VaD may be of clinical importance and an underestimated cause of dementia., (Copyright 2004 S. Karger AG, Basel)

Amyloidosis is a heterogeneous group of extracellular protein deposition diseases. Age-related amyloidosis may be systemic or localized. The systemic forms include associated-myeloma AL amyloidosis and senile systemic amyloidosis which is the only clear-cut systemic form related to age and derived from normal transthyretin. In localized amyloidosis, the fibril protein precursors are synthesized in the tissue involved by the amyloid. In most cases, localized age-related amyloidosis does not appear to cause clinical disease with the exception of amyloid associated with Alzeihmer's disease and type 2 diabetes mellitus. The significance of aortic amyloidosis, amyloidosis of seminal vesicles, amyloid of the endocrine glands, and articular amyloidosis remains unknown.

Dementia, defined as progressive cognitive decline, is a feature of a wide variety of genetic disorders. For example, a search of "dementia" in the Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/Omim) reveals 162 entries. Therefore this article cannot be encyclopedic and will be necessarily restricted to more prevalent or illustrative etiologies of familial dementia in adults. These disorders also have in common an initial and primarily dementing clinical presentation. Thus, this article is limited to: familial Alzheimer's disease (AD) and related amyloid angiopathies, frontotemporal dementias (FTD) and related tauopathies, familial prion diseases, British and Danish familial dementias, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral amyloid angiopathy (CAA) is a type of beta-amyloidosis that occurs in leptomeningeal and cortical vessels of the elderly. In a sample of 41 CAA cases including 16 Alzheimer disease (AD) cases and 28 controls, we show that 2 types of sporadic CAA exist: The first type is characterized by immunohistochemically detectable amyloid beta-protein (Abeta) in cortical capillaries, leptomeningeal and cortical arteries, arterioles, veins, and venules. It is referred to here as CAA-Type 1. The second type of CAA also exhibits immunohistochemically detectable Abeta deposits in leptomeningeal and cortical vessels, with the exception of cortical capillaries. This type is termed CAA-Type 2. In cases with CAA-Type 1, the frequency of the apolipoprotein E (ApoE) epsilon4 allele is more than 4 times greater than in CAA-Type 2 cases and in controls. CAA-Type 2 cases have a higher epsilon2 allele frequency than CAA-Type 1 cases and controls. The ratio of CAA-Type 2 to CAA-Type 1 cases does not shift significantly with respect to the severity of AD-related beta-amyloidosis, with respect to degrees of CAA-severity, or with increasing age. Therefore, CAA-Type 1 is unlikely to be the late stage of CAA-Type 2; rather, they represent 2 different entities. Since both the ApoE epsilon2 and the epsilon4 allele are known to be risk factors for CAA, we can assign the risk factor ApoE epsilon4 to a distinct morphological type of CAA. The ApoE epsilon4 allele constitutes a risk factor for CAA-Type 1 and, as such, for neuropil-associated dyshoric vascular Abeta deposition in capillaries, whereas the e2 allele does not. CAA-Type 2 is not associated with the epsilon4 allele as a risk factor but shows a higher epsilon2 allele frequency than CAA-Type 1 cases and controls in our sample.

Cerebral amyloid angiopathy (CAA) is characterized by amyloid deposition in cortical and leptomeningeal vessels. Several cerebrovascular amyloid proteins (amyloid beta-protein (Abeta), cystatin C (ACys), prion protein (AScr), transthyretin (ATTR), gelsolin (AGel), and ABri (or A-WD)) have been identified, leading to the classification of several types of CAA. Sporadic CAA of Abeta type is commonly found in elderly individuals and patients with Alzheimer's disease. Cerebral amyloid angiopathy is an important cause of cerebrovascular disorders including lobar cerebral hemorrhage, leukoencephalopathy, and small cortical hemorrhage and infarction. We review the clinicopathological and molecular aspects of CAA and discuss the pathogenesis of CAA with future perspectives.

Dementia is in addition to cerebral haemorrhage major symptom of cerebral amyloid angiopathy (CAa). In order to explore the pathological basis for dementia in CAa-related conditions, we made a clinicopathological analysis of CAa, with special attention to dementia. Among 150 patients (mean age 78.6 years) with autopsy-proven intracranial haemorrhage in Tokyo Metropolitan Geriatric Medical Center, CAa with cerebral haemorrhage accounted for 8.0% (12 cases), associated with hypertension and metastatic brain tumour. Among 38 patients with lobar haemorrhage, CAa represented the second most common cause (21.1%) of intracranial haemorrhage after hypertension. A total of 20 patients with CAa (mean age 82.5 years) were studies clinically and pathologically. Hypertension was present in 50%. Thirteen had a history of stroke and others had either ill-defined or no strokes. The average number of strokes 2.9. Fifteen patients (75%) had dementia. Based on the clinicopathological grounds for dementia, CAa-related conditions could be divided into three subtypes: "haemorrhagic", "dementia-haemorrhagic" and "dementia" type. Haemorrhagic type (30%, 6 cases) showed multiple recurrent lobar haemorrhages caused by CAa. Hypertension was present in only 1 patient. The incidence of senile plaques and neurofibrillary tangles was generally correlated with age. Only 1 patient had dementia. The dementia-haemorrhagic type (40%, 8 patients) had recurrent strokes with cerebral haemorrhage after preceding dementia. There were two different neuropathological subsets: CAa with atypical senile dementia of Alzheimer type (SDAT) and CAa with diffuse leucoencephalopathy. Patients with CAa with atypical SDAT had multiple cerebral haemorrhages caused by CAa combined with atypical Alzheimer-type pathology. Patients with CAa with diffuse leucoencephalopathy had cerebral haemorrhages in combination with diffuse white matter damage like Binswanger's subcortical vascular encephalopathy (BSVE). The incidence of senile changes correlated with age. Patients with the dementia type (30%, 6 patients) showed progressive dementia with or without haemorrhage. All had hypertension. They had a combined condition of Alzheimer-type pathology with conspicuous CAa with BSVE. Dementia in CAa-related conditions may be responsible for multiple factors including not Alzheimer-type degeneration, but also diffuse leucoencephalopathy like Binswanger's disease. We also found an asymptomatic type, an ischaemic type, a vasculitis type and an hereditary type in this condition.