Intracerebral Hemorrhage Recurrence in Patients with and without Cerebral Amyloid Angiopathy.

BACKGROUND: Intracerebral hemorrhage (ICH) recurrence risk is known to be higher in patients with cerebral amyloid angiopathy (CAA) as compared to other causes of ICH. Risk factors for ICH recurrence are not completely understood, and our goal was to study specific imaging microangiopathy markers. METHODS: Retrospective case-control study of patients with non-traumatic ICH admitted to a single center between 2014 and 2017 who underwent magnetic resonance imaging (MRI). Clinical characteristics of the index event and occurrence of death and ICH recurrence were collected from clinical records. MRI images were independently reviewed by 2 neuroradiologists. Groups of patients with CAA-related and CAA-unrelated ICH defined were compared. Presence of CAA was defined according to the Boston modified criteria. Survival analysis with Kaplan-Meier curves and Cox-regression analyses was performed to analyze ICH recurrence-free survival. RESULTS: Among 448 consecutive patients with non-traumatic ICH admitted during the study period, 104 were included in the study, mean age 64 years (±13.5), median follow-up of 27 months (interquartile range, IQR 16-43), corresponding to 272 person-years of total follow-up. CAA-related ICH patients presented higher burden of lobar microbleeds (p < 0.001), higher burden of enlarged perivascular spaces (EPVS) in centrum semiovale (p < 0.001) and more frequently presented cortical superficial siderosis (cSS; p < 0.001). ICH recurrence in patients with CAA was 12.7 per 100 person-years, and no recurrence was observed in patients without CAA. Variables associated with ICH recurrence in the whole population were age (hazard ratio [HR] per 1-year increment = 1.05, 95% CI 1.00-1.11, p = 0.046), presence of disseminated cSS (HR 3.32, 95% CI 1.09-10.15, p = 0.035) and burden of EPVS in the centrum semiovale (HR per 1-point increment = 1.80, 95% CI 1.04-3.12, p = 0.035). CONCLUSIONS: This study confirms a higher ICH recurrence risk in patients with CAA-related ICH and suggests that age, disseminated cSS, and burden of EPVS in the centrum semiovale are associated with ICH recurrence.

Long-Term Follow-Up of Cerebral Amyloid Angiopathy-Associated Intracranial Hemorrhage Reveals a High Prevalence of Atrial Fibrillation.

GOAL: Cerebral amyloid angiopathy (CAA) is the second-most common cause of nontraumatic intracerebral hemorrhages (ICH), surpassed only by uncontrolled hypertension. We characterized the percentage, risk factors, and comorbidities of patients suffering from CAA-related ICH in relation to long-term outcomes. MATERIAL AND METHODS: We performed retrospective analyses and clinical follow-ups of individuals suffering from ICH who were directly admitted to neurosurgery between 2002 and 2016. FINDINGS: Seventy-four of 174 (42%) spontaneous nontraumatic lobar ICH cases leastwise satisfied the modified Boston criteria definition for at least "possible CAA." Females suffered a higher risk of CAA-caused ICH (42 of 74, 56.8%, P= .035). Atrial fibrillation as a major comorbidity was observed in 19 patients (25.7%). Recovery (decrease of modified Rankin scale [mRS]) was highest during hospitalization in the acute clinic. One-year mortality was as follows: 14 of 25 patients (56%) with probable CAA without supporting pathology, 6 of 18, and 8 of 31 patients with supporting pathology and possible CAA, respectively. Only 10 of 74 (13.6%) had favorable long-term outcomes (mRS ≤2). Increasing numbers of lobar hemorrhages, low initial Glasgow Coma Scale, and subarachnoid hemorrhage were significantly associated with poor survivability, whereas statins, antithrombotic agents, an intraventricular hemorrhage, and midline shift played seemingly minor roles. CONCLUSIONS: Symptomatic ICH is a serious stage in CAA progression with high mortality. The high incidence of concurrent atrial fibrillation in these patients may support data on more widespread vascular pathology in CAA.

Risk of Intracerebral Hemorrhage and Mortality After Convexity Subarachnoid Hemorrhage in Cerebral Amyloid Angiopathy.

Background and Purpose- Convexity subarachnoid hemorrhage (cSAH) is an increasingly recognized presentation of cerebral amyloid angiopathy (CAA), usually revealed by transient symptoms, but data on its outcome are limited. We compared the risk of future intracerebral hemorrhage (ICH), cSAH, and death in patients with CAA after cSAH and after lobar ICH. Methods- Consecutive patients with probable CAA, based on the Boston criteria, presenting with cSAH (CAA-cSAH) or lobar ICH (CAA-ICH) were included. We obtained baseline clinical and magnetic resonance imaging data and follow-up information. Univariable and multivariable analyses were used to compare incidence rate for symptomatic ICH, symptomatic cSAH, and late-death (beyond 30 days) between patients with CAA-cSAH and CAA-ICH. Results- Among 105 patients (mean age, 76.7±7.5 years) enrolled, 44 participants presented with CAA-cSAH and 61 with CAA-ICH. The median follow-up was 22.2 months (interquartile range, 12.6-34.4). The symptomatic ICH rate (per person-year) was 10.5% (95% CI, 5.6-19.4) in patients with CAA-cSAH compared with 8.5% (95% CI, 4.4-16.4) in those with CAA-ICH (adjusted hazard ratio, 1.05; 95% CI, 0.32-3.43). The annual incidence rates of symptomatic cSAH (9.9% versus 3.8%; adjusted hazard ratio, 1.77; 95% CI, 0.43-7.28) and death (9.5% versus 17.8%; adjusted hazard ratio, 0.56; 95% CI, 0.22-1.43) were not significantly different between patients with CAA-cSAH and those with CAA-ICH. Conclusions- Patients with CAA-related cSAH have a poor outcome, with similar high risk of future ICH and long-term mortality than CAA patients after lobar ICH. Our findings may have important prognostic implication and guide management of patients with cSAH in CAA.

Subarachnoid and Subdural Hemorrhages in Lobar Intracerebral Hemorrhage Associated With Cerebral Amyloid Angiopathy.

Background and Purpose- Identifying underlying cerebral amyloid angiopathy (CAA) in patients with intracerebral hemorrhage (ICH) has important clinical implication. Convexity subarachnoid hemorrhage (cSAH) and subdural hemorrhage (SDH) are computed tomography features of CAA-related ICH. We explored whether cSAH and SDH could be additional magnetic resonance imaging markers of CAA in lobar ICH survivors. Methods- We analyzed data from consecutive patients with acute lobar ICH associated with CAA (CAA-ICH) or not attributed to CAA (non-CAA-ICH). Magnetic resonance imaging scans were analyzed for cSAH, SDH, and markers of small vessel disease. The associations of cSAH and SDH with the diagnosis of probable CAA based on the modified Boston criteria were explored using multivariable models. Results- We included 165 patients with acute lobar ICH (mean age 70±13 years): 72 patients with CAA-ICH and 93 with non-CAA-ICH. Patients with CAA-ICH had a higher prevalence of cSAH (73.6% versus 39.8%; P<0.001) and SDH (37.5% versus 21.5%; P=0.02) than non-CAA-ICH. In multivariate logistic regression analysis, the presence of cSAH was independently associated with CAA-ICH (odds ratio, 2.97; 95% CI, 1.26-6.99; P=0.013), whereas there was no association between SDH and CAA-ICH. Conclusions- Among survivors of acute lobar ICH, the presence of cSAH is associated with the magnetic resonance imaging-based diagnosis of CAA. Further studies should investigate whether cSAH help improve the sensitivity of magnetic resonance imaging for in vivo diagnosis of CAA.

Recurrent hemorrhage risk and mortality in hereditary and sporadic cerebral amyloid angiopathy.

OBJECTIVE: To determine whether hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a monogenetic disease model for the sporadic variant of amyloid angiopathy (sCAA), has a comparable recurrent intracerebral hemorrhage (ICH) risk and mortality after a first symptomatic ICH. METHODS: We included patients with HCHWA-D from the Leiden University Medical Center and patients with sCAA from the Massachusetts General Hospital in a cohort study. Baseline characteristics, hemorrhage recurrence, and short- and long-term mortality were compared. Hazard ratios (HRs) adjusted for age and sex were calculated with Cox regression analyses. RESULTS: We included 58 patients with HCHWA-D and 316 patients with sCAA. Patients with HCHWA-D had fewer cardiovascular risk factors (≥1 risk factor 24% vs 70% in sCAA) and were younger at the time of presenting hemorrhage (mean age 54 vs 72 years in sCAA). Eight patients (14%) with HCHWA-D and 46 patients (15%) with sCAA died before 90 days. During a mean follow-up time of 5 ± 4 years (total 1,550 person-years), the incidence rate of recurrent ICH in patients with HCHWA-D was 20.9 vs 8.9 per 100 person-years in sCAA. Patients with HCHWA-D had a long-term mortality of 8.2 vs 8.4 per 100 person-years in patients with sCAA. After adjustments, patients with HCHWA-D had a higher risk of recurrent ICH (HR 2.8; 95% confidence interval 1.6-4.9; p < 0.001) and a higher long-term mortality (HR 2.8; 95% confidence interval 1.5-5.2; p = 0.001). CONCLUSIONS: Patients with HCHWA-D have worse long-term prognosis after a first ICH than patients with sCAA. The absence of cardiovascular risk factors in most patients with HCHWA-D suggests that vascular amyloid is responsible for the recurrent hemorrhages. HCHWA-D is therefore a pure form of cerebral amyloid angiopathy with an accelerated clinical course and provides a good model to study the pathophysiology and future therapeutic interventions of amyloid-related hemorrhages.

Cerebral amyloid angiopathy-related atraumatic convexal subarachnoid hemorrhage: an ARIA before the tsunami.

Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Aß40 and Aß42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-ɛ2 overrepresentation and CAAo had an APOE-ɛ4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology.

Dementia is strongly associated with 90-day mortality in lobar cerebral amyloid angiopathy related intra-cerebral haemorrhage.

BACKGROUND: While evidence suggests that lobar intracerebral haemorrhage (ICH) is linked with dementia and cognitive impairment, the association between cognition and mortality risk from ICH is unclear. AIMS: To examine the association between dementia or cognitive impairment and short- and medium-term mortality post ICH. METHODS: Patients with primary ICH were classified into lobar and non-lobar ICH using radiological criteria. Patients' characteristics and radiological measures were collected at the baseline along with history of dementia and cognitive impairment. Mortality risks at 7, 30, 60, and 90 days were assessed using multiple logistic regression adjusting for potential confounders identified as significant associates in univariate models. RESULTS: A total of 136 patients (males 50%, mean age 77 years, SD 10) were included in this study. Out of 53 (39%) patients with lobar ICH 47 (89%) were classified as having possible and 6 (11%) as probable cerebral amyloid angiopathy (CAA). In lobar ICH the prevalence of history of dementia or cognitive impairment, confusion at presentation, previous ICH, multiple haemorrhages, and initial haematoma volume were significantly higher (p<0.05). In lobar ICH the significant mortality predictors (p<0.05) were history of dementia or cognitive impairment (90 days), prior antiplatelet use (60 and 90 days), initial haematoma volume (60 days), male sex (30 and 60 days), age (30, 60, 90 days), and low Glasgow Coma Scale (GCS) (7 and 30 days). In non-lobar ICH prior use of anticoagulation, initial haematoma volume, low GCS and age were significant mortality predictors (p<0.05). CONCLUSION: A history of dementia or cognitive impairment is more common in lobar CAA-related ICH and it is a medium-term mortality predictor in lobar ICH but not in deep non-lobar ICH.

A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries.

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.

Effect of liver transplantation on transthyretin Tyr114Cys-related cerebral amyloid angiopathy.

OBJECTIVE: Patients with amyloidogenic transthyretin (ATTR) Tyr114Cys develop amyloid deposits in cerebral blood vessels, cerebral hemorrhage, and rapidly progressive dementia that presents with hereditary cerebral amyloid angiopathy (CAA). However, no treatment has been identified for CAA. Although liver transplantation has become an acceptable treatment of TTR-related amyloidosis, liver transplantation may not successfully treat CNS manifestations of the disorder. In this study, we examined the effect of liver transplantation on these manifestations of TTR-related CAA. METHODS: We compared clinical courses of three patients with CAA associated with ATTR Tyr114Cys who underwent liver transplantation with those of five patients with the disorder who did not undergo liver transplantation. RESULTS: The mortality and occurrence of cerebral hemorrhage and dementia in patients having transplantations were reduced compared with those in patients not having transplantations. The two groups did not differ with regard to the frequency of episodes of fluctuating consciousness and TIAs. The group undergoing transplantations had significantly smaller volumes of intracranial hemorrhage than did the no-transplantation group. CONCLUSION: Liver transplantation was effective for CNS manifestations of cerebral amyloid angiopathy associated with amyloidogenic transthyretin Tyr114Cys.

Microvasculopathy is associated with the number of cerebrovascular lesions in hereditary cerebral hemorrhage with amyloidosis, Dutch type.

BACKGROUND AND PURPOSE: Microvascular changes such as microaneurysms and fibrinoid necrosis have been found in the presence of cerebral amyloid angiopathy (CAA). These CAA-associated microvasculopathies (CAA-AM) may contribute to the development of CAA-associated hemorrhages and/or infarcts, hereafter referred to as "cerebrovascular lesions." Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) is an autosomal dominant form of CAA, in which the amyloid angiopathy is pathologically and biochemically similar to sporadic CAA associated with aging and Alzheimer disease. To determine the significance of CAA-AM for CAA-associated cerebrovascular complications, we investigated the association between CAA-AM and cerebrovascular lesions in HCHWA-D patients. METHODS: In a previous autopsy study we semiquantitatively scored CAA-AM in 29 HCHWA-D patients. In the present study we reviewed clinical charts and autopsy protocols of these same patients. We investigated whether CAA-AM was associated with age at death, number of cerebrovascular lesions, duration of clinical illness, hypertension, and atherosclerosis. RESULTS: An association was found between CAA-AM and the number of cerebrovascular lesions (P = 0.009). The presence of microaneurysmal degeneration was most strongly associated with the number of cerebrovascular lesions (P < 0.001). In addition, we found an association between atherosclerosis and the CAA-AM score (P = 0.047). Hypertension was not associated with CAA-AM. CONCLUSIONS: Our findings support previous reports suggesting an important role of secondary microvascular degenerative changes in CAA-associated cerebrovascular lesions and suggest an aggravating effect of systemic atherosclerosis, but not hypertension, on the evolution of CAA-AM. These findings may be of relevance to understanding cerebrovascular complications of sporadic or Alzheimer disease-associated CAA.

Mortality from hereditary cerebral haemorrhage with amyloidosis--Dutch type. The impact of sex, parental transmission and year of birth.

Hereditary cerebral haemorrhage with amyloidosis--Dutch type (HCHWA-D) is an autosomal dominant disorder, caused by a single base mutation in the amyloid beta precursor protein (beta PP) gene located on chromosome 21, resulting in recurrent haemorrhagic strokes and dementia. Though HCHWA-D is caused by a dominant mutation, the phenotypic expression varies widely, suggesting modulation of the phenotypic expression by additional factors. In this study we investigated the influence of sex, parental transmission and year of birth on mortality from HCHWA-D. Since the early sixties, clinical and genealogical data of patients with HCHWA-D have been collected. The standardized mortality rate (relative to the general population) was calculated to compare the mortality within the pedigrees with the mortality in the Dutch population. The influence of sex, parental transmission and year of birth on survival were studied using Cox's proportional hazard model. By December 1, 1995, a total of 187 cases were identified belonging to four large families. Mortality rate in affected individuals was fourfold increased compared with the Dutch population (relative mortality 4.0; 95% confidence interval 3.4-4.7) and higher in females than in males (relative mortality risk 8.0 and 2.6, respectively). Mortality rate was lower when HCHWA-D was maternally transmitted (mortality relative to paternal transmission 0.7; 95% confidence interval 0.5-1.0). Year of birth had no effect on the mortality of the affected individuals. Survival of HCHWA-D has not yet increased, in spite of higher standards of general medicine, i.e. the mortality rate did not decline over the years. Female sex was a major factor increasing mortality rate in HCHWA-D. Paternal transmission had a just significant effect on mortality rate in HCHWA-D. The possible mechanisms behind these phenomena remain unexplained by this clinical study.

The molecular pathology of hereditary cystatin C amyloid angiopathy causing brain hemorrhage.

Knowledge about molecular pathology of hereditary cystatin C amyloid angiopathy (HCCAA), also called hereditary cerebral hemorrhage with amyloidosis, Icelandic type, has increased greatly in the last decade. The disorder has an autosomal dominant mode of inheritance and causes fatal brain hemorrhage in normotensive young adults. It is due to a mutation in the gene encoding the cysteine proteinase inhibitor, cystatin C.A single nucleotide is substituted, A for T, in the codon 68, resulting in glutamine replacing leucine in the protein sequence. This variant protein has an increased tendency to aggregate and forms heavy depositions of amyloid in the walls of the small arteries and arterioles of the brain. The amyloid deposition leads to arterial damage with single or multiple strokes. In the following review the clinical features, family studies, pathology, biochemistry and molecular genetics of HCCAA are addressed.

Influence of apolipoprotein E genotype on cerebral amyloid angiopathy in the elderly.

BACKGROUND AND PURPOSE: The inheritance of the epsilon 4 allele of the apolipoprotein E gene (APOE) is associated with increased risk of developing dementia of the Alzheimer type (DAT). We have investigated whether the APOE genotype influences the severity of cerebral amyloid angiopathy (CAA) in elderly individuals with or without DAT. METHODS: From a consecutive autopsy series, we studied 88 patients (85.2 +/- 8.1 years) without degenerative disorders other than DAT. The percentages of amyloid-laden vessels in the occipital lobes were calculated and compared between APOE genotypes. RESULTS: For epsilon 3/3 and epsilon 3/4 genotypes, there was a trend toward increased CAA in epsilon 3/4 individuals for non-DAT and conversely in epsilon 3/3 individuals for DAT patients, but these did not achieve significance. CONCLUSIONS: The present study suggests that the epsilon 4 allele is not a strong risk factor for CAA in elderly people.