Hereditary cerebral amyloid angiopathy, Piedmont-type mutation

ObjectiveWe present here a case report of a patient with a family history of intracerebral hemorrhages (ICHs) who presented with multiple large lobar hemorrhages in rapid succession, with cognitive sparing, who was found to have a mutation in the β-amyloid coding sequence of amyloid precursor protein (Leu705Val), termed the Piedmont-type mutation, the second ever reported case of this form of hereditary cerebral amyloid angiopathy (CAA).MethodsTargeted pathologic examination was performed aided by the use of ex vivo MRI.ResultsSevere CAA was observed mainly involving the leptomeningeal vessels and, to a far lesser extent, cortical vessels, with no amyloid plaques or neurofibrillary tangles.ConclusionsThis leptomeningeal pattern of β-amyloid deposition coupled with multiple large hemorrhages demonstrates unique pathophysiologic characteristics of CAA associated with the Piedmont-type mutation, suggesting a potential association between leptomeningeal CAA and larger ICHs.

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Abstract W MP89: Validation of Clinical-Radiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy-related Inflammation

Stroke ◽

10.1161/str.45.suppl_1.wmp89 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Eitan Auriel ◽

Mahmut Edip Gurol ◽

Jun Ni ◽

Ellis Van Etten ◽

Sergi Martinez-Remirez ◽

...

Keyword(s):

Sensitivity And Specificity ◽

Cerebral Amyloid Angiopathy ◽

Vascular Inflammation ◽

Brain Biopsy ◽

Control Group ◽

Amyloid Angiopathy ◽

Radiological Criteria ◽

Disease Subtype ◽

History Of ◽

Cerebral Amyloid

Introduction: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a disease subtype characterized by rapidly progressive cognitive decline, seizures, headaches, T2-hyperintense MRI lesions, and neuropathologic evidence of CAA-associated vascular inflammation. CAA-ri is an important diagnosis to reach in clinical practice, as many patients respond to immunosuppressive therapy. Definitive diagnosis of CAA-ri generally requires brain biopsy, however, highlighting the importance of developing noninvasive diagnostic criteria. Objectives: To test the sensitivity and specificity of modified criteria (Table 1) for possible and probable CAA-ri in groups of subjects with histologically proven CAA-ri and non-CAA-ri. Methods: After refining previously proposed clinical- radiological criteria we retrospectively analyzed clinical charts and MRI FLAIR and gradient-echo scans obtained from 17 subjects with pathologically confirmed CAA-ri and 37 control subjects with pathologic diagnosis of non-inflammatory CAA. The control group was further divided into those with past intracerebral hemorrhage (ICH) (n=21) and those with cerebral microbleeds (CMB) only and no history of ICH (n=16). Results: In the CAA-ri group 14/17 (82.4%) met criteria for both probable and possible CAA-ri. One (4.7%) of the subjects in the control CAA-ICH group (n=21) met the criteria for possible and none met criteria for probable CAA-ri. In the control CAA-no ICH group 1/16 (6.25%) and 11/16 (68.75%) met criteria for probable and possible CAA-ri respectively. This yields sensitivity and specificity of 82% and of 97.3% respectively for the probable criteria and sensitivity and specificity of 82% and 67.6% respectively for the possible criteria. Conclusions: Our data suggest that a reliable diagnosis of CAA-ri can be reached from basic clinical and radiographic information alone with good sensitivity and excellent specificity.

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Familial Cerebral Cavernous Malformation Mimicking Cerebral Amyloid Angiopathy

Neurology Clinical Practice ◽

10.1212/cpj.0000000000001055 ◽

2021 ◽

pp. 10.1212/CPJ.0000000000001055

Author(s):

Mohamed Ridha ◽

Yasmin Aziz ◽

Joseph Broderick

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Cavernous Malformation ◽

Pathogenic Mutation ◽

Cerebral Cavernous Malformation ◽

Amyloid Angiopathy ◽

History Of ◽

Cerebral Amyloid ◽

Cerebral Microhemorrhages ◽

Familial Cerebral Cavernous Malformation ◽

Work Up

A 67-year-old man was referred from ophthalmology for possible cerebral amyloid angiopathy (CAA) discovered during work-up of possible optic neuropathy. MRI (figure 1) demonstrated innumerable periventricular, brainstem, and cortical cerebral microhemorrhages (CMH). Scattered, non-specific white matter hyperintensities was seen on T2-weighted imaging without surrounding hypointense rim. He had no hypertension, and the distribution was uncharacteristic for CAA. Despite absent family history of stroke or seizure, testing for familial cerebral cavernous malformation (FCCM) identified a pathogenic mutation of KRIT1 (c.382G>T).

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Predictors of localization, outcome, and etiology of spontaneous intracerebral hemorrhages: focus on cerebral amyloid angiopathy

Journal of Neural Transmission ◽

10.1007/s00702-020-02174-2 ◽

2020 ◽

Vol 127 (6) ◽

pp. 963-972 ◽

Cited By ~ 1

Author(s):

Bernadett Fakan ◽

Zita Reisz ◽

Denes Zadori ◽

Laszlo Vecsei ◽

Peter Klivenyi ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Intracerebral Hemorrhages ◽

Cerebral Amyloid

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Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques

Genes Brain & Behavior ◽

10.1111/j.1601-183x.2007.00380.x ◽

2008 ◽

Vol 7 ◽

pp. 67-82 ◽

Cited By ~ 49

Author(s):

S. Kumar-Singh

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Amyloid Plaques ◽

Amyloid Angiopathy ◽

Pathogenetic Mechanisms ◽

Cerebral Amyloid

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Reducing Available Soluble β-Amyloid Prevents Progression of Cerebral Amyloid Angiopathy in Transgenic Mice

Journal of Neuropathology & Experimental Neurology ◽

10.1097/nen.0b013e3182729845 ◽

2012 ◽

Vol 71 (11) ◽

pp. 1009-1017 ◽

Cited By ~ 7

Author(s):

Julia L. Gregory ◽

Claudia M. Prada ◽

Sara J. Fine ◽

Monica Garcia-Alloza ◽

Rebecca A. Betensky ◽

...

Keyword(s):

Transgenic Mice ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Β Amyloid ◽

Cerebral Amyloid

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Cerebral amyloid angiopathy as a cause of multiple intracerebral hemorrhages

Neurology ◽

10.1212/wnl.34.6.730 ◽

1984 ◽

Vol 34 (6) ◽

pp. 730-730 ◽

Cited By ~ 68

Author(s):

C. Gilles ◽

J. M. Brucher ◽

P. Khoubesserian ◽

J. J. Vanderhaeghen

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Intracerebral Hemorrhages ◽

Cerebral Amyloid

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O4-02-04: Selective targeting of perivascular macrophages for β -amyloid clearance in cerebral amyloid angiopathy

Alzheimer s & Dementia ◽

10.1016/j.jalz.2009.05.525 ◽

2009 ◽

Vol 5 (4S_Part_5) ◽

pp. P152-P152 ◽

Cited By ~ 1

Author(s):

JoAnne McLaurin ◽

Cheryl Hawkes

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Selective Targeting ◽

Perivascular Macrophages ◽

Β Amyloid ◽

Cerebral Amyloid

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Spatial and temporal intracerebral hemorrhage patterns in Dutch-type hereditary cerebral amyloid angiopathy

International Journal of Stroke ◽

10.1177/17474930211057022 ◽

2021 ◽

pp. 174749302110570

Author(s):

Sabine Voigt ◽

Siham Amlal ◽

Emma A Koemans ◽

Ingeborg Rasing ◽

Ellis S van Etten ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Temporal Pattern ◽

Occipital Lobe ◽

Time Interval ◽

Amyloid Angiopathy ◽

Degree Relative ◽

Amyloid Load ◽

Intracerebral Hemorrhages ◽

Cerebral Amyloid ◽

Histopathological Studies

Aim To investigate whether there is a topographical and temporal pattern of index and recurrent intracerebral hemorrhages (ICH) in Dutch-type hereditary Cerebral Amyloid Angiopathy (D-CAA) to increase our understanding on CAA-related ICH development. Methods We included patients with DNA confirmed D-CAA or a history with ≥1 lobar ICH and ≥1 first-degree relative with D-CAA. Topographical pattern was studied by location (proportion frontal/parietal/temporal/occipital; infra/supratentorial and occurrence ratios relative to lobe volume) and volume of index and recurrent ICHs were determined on CT. Temporal pattern was examined by time between recurrent ICHs was retrieved from medical records. Results We included 72 patients with D-CAA (mean age at index ICH 55 years) with in total 214 ICH. The median follow-up time was 7 years (range 0.8 to 28 years). All ICH were lobar and supratentorial. The index ICH was most frequently located in the occipital lobe (34% vs. 22% in the other three lobes; with index ICH occurrence ratios relative to lobe volume of 1.9 for occipital, 1.0 for temporal, 1.2 for parietal, and 0.5 for frontal, p = 0.001). In 16/47 (34%) patients with multiple ICH, the second ICH was located in the same lobe as the index ICH. The median time-interval between subsequent ICH was #1-2 ICH 27 months, #2-3 ICH 14 months, and #3-4 ICH 7 months (p = 0.6) There was no difference in volume between index and recurrent ICHs. Conclusions We found that index and recurrent ICHs in D-CAA have a preference for the occipital lobe and are least frequent in the frontal lobe, which adds to the existing knowledge of histopathological studies on amyloid load in CAA. Surprisingly, there was no acceleration in time nor gradual increase of hematoma volume between subsequent ICHs.

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Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy–Related Inflammation: A Multicenter Prospective Longitudinal Cohort Study

Neurology ◽

10.1212/wnl.0000000000012778 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012778

Author(s):

Laura Antolini ◽

Jacopo C. DiFrancesco ◽

Marialuisa Zedde ◽

Gianpaolo Basso ◽

Andrea Arighi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Amyloid Angiopathy ◽

Pulse Therapy ◽

Amyloid Angiopathy ◽

Longitudinal Cohort ◽

History Of ◽

Corticosteroid Pulse Therapy ◽

Cerebral Amyloid

Background and Objectives:To investigate the natural history and outcomes following treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri).Methods:A multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria, recruited through the iCAβ International Network, in the period January 2013 - March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, GRE-T2*, fluid-suppressed T2-weighted (FLAIR), and T1 post-gadolinium contrast-enhancement images aquired on 1.5T MRI, was employed at 3, 6, 12, 24-months follow-up. Centralized reads of MRI images were performed blinded to clinical, therapeutic, and time-points information. Main outcomes were survival, clinical and radiological recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri.Results:The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri), mean age 72.9 years, 43.4% female, 37.1% APOEε4 carriers. 36.3% had a history of Alzheimer’s disease, 33.6% of ICH. A history of ICH, as well as the occurrence of new ICH at follow-up, was more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%; p< 0.0001 and 19.3% vs 3.6%; p<0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% CI, 61.6-78.5) and 84.1% (95% CI, 76.2-90.6) clinically recovered within three and twelve months, followed by radiological recovery in 45.1% (95% CI, 36.4 - 54.8) and 77.4% (95% CI, 67.7 - 85.9), respectively. After clinicoradiological resolution of the first-ever episode, 38,3% (95% CI, 22.9 - 59.2) had at least one recurrence within the following 24 months. Recurrence was more likely if intravenous high dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering-off (Hazard Ratio 4.68; 95% CI, 1.57-13.93; p=0.006).Discussion:These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiological acute manifestations of the disease and the effectiveness of slow oral tapering-off after intravenous corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in Aβ-driven diseases, including treatment-related ARIA in Alzheimer’s disease patients exposed to immunotherapy drugs.

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