Microbleeds (less than 5 mm in diameter) occur at the gray-white matter junction in the cerebral hemispheres and cerebellum and do not occur in the thalamus, basal ganglia, or brainstem
Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive ... Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (Revesz et al., 2003, 2009).
Wattendorff et al. (1982) reported a Dutch family in which 11 members had cerebral and cerebellar hemorrhage and infarction at ages ranging from 44 to 58 years. Affected family members comprised 5 sibships spanning 2 generations. The principal ... Wattendorff et al. (1982) reported a Dutch family in which 11 members had cerebral and cerebellar hemorrhage and infarction at ages ranging from 44 to 58 years. Affected family members comprised 5 sibships spanning 2 generations. The principal clinical characteristic was recurring cerebral hemorrhages, sometimes preceded by migrainous headaches or mental changes. Of the 11 who presented with acute stroke, all who survived eventually developed dementia. In addition, there were 5 family members who developed dementia, with or without accompanying stroke. Neuropathology showed hyaline thickening of the walls of cortical arterioles in 6 autopsied cases and 1 biopsy specimen. The arteries of the arachnoid showed marked tortuosity, concentric proliferation, and focal hyalinization. Amyloid was demonstrated in the hyalinized vessels but was not found outside the nervous system. The kindred of Wattendorff et al. (1982) was from Scheveningen, the patients were descendants of a couple who married in 1871. Luyendijk and Bots (1986) wrote: 'As the hereditary disease is well-known to the co-members of the respective families they usually inform the doctors on the probable diagnosis themselves, when such a patient is admitted into the hospital. Besides which they usually add all kinds of genealogical information.' The disorder was referred to as HCHWAD for 'hereditary cerebral hemorrhage with amyloidosis, Dutch type.' In studies of the Dutch form of hereditary cerebral hemorrhage with amyloidosis, van Duinen et al. (1987) demonstrated that the vascular amyloid deposits were related to the beta-protein associated with Alzheimer disease and Down syndrome (190685). The findings indicated that the 'Dutch type' is genetically distinct from the 'Icelandic type' of cerebroarterial amyloidosis (105150), which is due to a defect in cystatin C (CST3; 604312). Luyendijk et al. (1988) described 136 patients with hereditary cerebral hemorrhage, all belonging to families originally resident in Katwijk, Netherlands. No genealogic connection had been established between the Dutch and Icelandic pedigrees. Moreover, the findings in all of the Dutch cases were identical and differed from the findings in the Icelandic cases in age at onset and involvement of cystatin C. Among 78 males and 58 females with HCHWAD, Luyendijk et al. (1988) found that the sex ratio for the proven cases was nearly equal (29 males and 26 females). There were numerous examples of father-to-son transmission. Roosen et al. (1985) and Smith et al. (1985) provided case reports of patients with intracerebral hemorrhage or transient ischemic attacks, respectively, resulting from cerebral amyloid angiopathy. Cosgrove et al. (1985) reviewed 24 cases of autopsy-proven cerebral amyloid angiopathy; death was caused by intracranial hemorrhage in 16. None had systemic amyloidosis. Haan et al. (1990) found that all 16 patients they examined with the Dutch type of hereditary cerebral hemorrhage with amyloidosis had psychiatric abnormalities; dementia was present in 12. Three patients tested twice at an interval of some years exhibited progressive intellectual deterioration and memory disturbance; in 2 of them there was no evidence of intercurrent strokes. Fernandez-Madrid et al. (1991) reported a 63-year-old woman of Dutch extraction living in the United States with HCHWA confirmed by molecular analysis. The patient was normotensive and was well until age 47 years, when she began to have attacks approximately every 2 weeks. Iglesias et al. (2000) reported a patient of Spanish descent who presented at age 62 years with intracerebral hemorrhage in a background of progressive mental deterioration. Neuroimaging revealed fine tram-line bilateral occipital calcifications, extensive leukoencephalopathy, and bilateral external carotid artery dysplasia. Skin biopsy with ultrastructural study revealed novel changes in the basal lamina of capillaries, with multilayered appearance and round-shaped microcalcifications. Of 19 next of kin who survived beyond 60 years of age, 6 had brain disorders; 4 of the 6 presented at least 3 components of the syndrome. The proband's mother had died at age 83 with profound dementia; one sister, who was diagnosed with dementia with occipital calcifications and leukoencephalopathy at age 67, died 2 years later from intracranial hemorrhage; a brother had an occipital hemorrhage at age 58, at which time occipital calcifications and leukoencephalopathy were discovered; and another brother died after a minor stroke at age 70 with dementia, occipital calcifications, and external carotid artery dysplasia. Iglesias et al. (2000) suggested that this represented a novel familial cerebrovascular entity with widespread microvascular calcifications and presumably autosomal dominant inheritance. They suggested the acronym FOCHS-LADD, for 'familial occipital calcifications, hemorrhagic strokes, leukoencephalopathy, arterial dysplasia, and dementia.' Iglesias et al. (2000) emphasized that subjects had no seizures, facial angioma, or intracranial vascular malformation, and that arterial hypertension was neither constant nor severe. Grabowski et al. (2001) reported a 3-generation Iowa family with autosomal dominant dementia beginning in the sixth or seventh decade of life. The proband and an affected brother had progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Neither had intracerebral hemorrhage. Neuropathologic examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and extensive distribution of beta-amyloid-40 in plaques. Using T2 gradient-echo MRI, van den Boom et al. (2005) identified microbleeds (less than 5 mm in diameter) in 18 (69%) of 27 patients with HCHWAD confirmed by genetic analysis. Three of the patients with microbleeds were asymptomatic. The microbleeds occurred at the gray-white matter junction in the cerebral hemispheres or in the cerebellum; none were found in the basal ganglia, thalamus, or brainstem. Mutation carriers with hypertension had more microbleeds in the cerebellum than those without hypertension, but there was no association between number of microbleeds and hypertension. Twenty-two (81%) mutation carriers had white matter hyperintensities, and 16 (62%) had intracranial hemorrhages. All hemorrhages were supratentorial and spared the thalamus and basal ganglia. The number of microbleeds correlated with increasing age, possibly reflecting disease progression. Obici et al. (2005) reported an Italian family with autosomal dominant cerebral amyloid angiopathy. Clinically, the patients had multiple intracerebral hemorrhages, but only 1 affected family member had cognitive impairment. Neuropathologic analysis of 2 patients showed severe selective cerebroarterial amyloidosis in leptomeningeal and cortical vessel walls with secondary microvascular degeneration and 'vessel-within-vessel' changes. There were no parenchymal amyloid plaques or neurofibrillary tangles. Bugiani et al. (2010) reported 4 unrelated Italian families with autosomal dominant hereditary cerebral hemorrhage with amyloidosis caused by a heterozygous mutation in the APP gene (E693K; 104760.0014). Affected individuals presented with recurrent headache and multiple hemorrhagic strokes between age 44 and 63, followed by epilepsy and cognitive decline in most of them. Several affected individuals became comatose or bedridden, and some died as a result of cerebral hemorrhage. Neuroimaging demonstrated small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, multi-infarct encephalopathy, and leukoaraiosis. Multiple brain regions were involved, including both gray and white matter. Postmortem examination of 1 patient showed many small vessels with thickened and/or split walls due to a hyaline congophilic material that was immunoreactive for beta-amyloid-40. Most of the abnormal vessels were in the leptomeninges, in the cerebral and cerebellar cortex, and in the white matter close to the cortex. Beta-amyloid-40 was also detectable in cortical capillaries, and beta-amyloid-42 was found in neuropil of the gray structures. Neurofibrillary tangles and neuritic plaques were not present. The progression of the clinical phenotype correlated with that pathologic findings.
In 2 patients from presumably unrelated Dutch families with hereditary cerebral hemorrhage with amyloidosis, Levy et al. (1990) identified a glu693-to-gln mutation in the APP gene (E693Q; 104760.0001). The authors noted that amyloid precursor proteins in the Dutch ... In 2 patients from presumably unrelated Dutch families with hereditary cerebral hemorrhage with amyloidosis, Levy et al. (1990) identified a glu693-to-gln mutation in the APP gene (E693Q; 104760.0001). The authors noted that amyloid precursor proteins in the Dutch and Icelandic forms of cerebroarterial amyloidosis are both protease inhibitors and both have been found to have a substitution in their genes that give rise to a substitution of glutamine (see 604312.0001). Prelli et al. (1990) demonstrated that both the normal and the variant alleles were expressed in vascular amyloid in this disorder. Graffagnino et al. (1994) failed to find the amyloid mutation in any of 48 consecutive patients with sporadic intracerebral hemorrhage admitted to Duke University Hospital. No pathologic examinations were made to determine if any of these patients had amyloid deposition. In 4 affected members of an Italian family with cerebral amyloid angiopathy, Obici et al. (2005) identified a mutation in the APP gene (104760.0019). In 2 brothers from an extensive Iowa kindred with progressive dementia and cerebroarterial amyloidosis, Grabowski et al. (2001) identified a heterozygous mutation in the APP gene (N694D; 104760.0016). Greenberg et al. (2003) identified the N694D mutation in 2 affected members of the Spanish family reported by Iglesias et al. (2000). Rovelet-Lecrux et al. (2006) identified duplication of the APP gene (104760.0020) in affected members of a family with early-onset Alzheimer disease and prominent cerebral amyloid angiopathy. - Modifier Genes The majority of beta-amyloid CAA is sporadic, affecting elderly individuals who may or may not have accompanying Alzheimer disease pathology. The incidence of both diseases steadily increases with age, with the incidence of CAA reaching 50% in those older than 70 years (Revesz et al., 2009). Greenberg et al. (1995) found that the presence of apolipoprotein E4 (107741) significantly increased the odds ratio for moderate or severe cerebral amyloid angiopathy, even after controlling for the presence of Alzheimer disease. Yamada et al. (1996) reported a lack of association between the E4 allele and cerebral amyloid angiopathy in elderly Japanese patients. Nicoll et al. (1996, 1997) did not find an association between the E4 allele and CAA-related hemorrhage. However, they did find a high frequency of the E2 allele in patients with CAA-related hemorrhage, regardless of the presence of AD. The authors suggested that patients with the E2 allele may be protected from parenchymal AD but may be susceptible to the rupture of amyloid-laden vessels. In a postmortem study, Greenberg et al. (1998) found an association between apolipoprotein E2 and vasculopathy in cerebral amyloid angiopathy. Of 75 brains with complete amyloid replacement of vessel walls, only 23 had accompanying signs of hemorrhage in cracks of the vessel wall. The frequency of apolipoprotein E2 was significantly higher in the group with vasculopathy. The authors suggested that apolipoprotein E2 and E4 might promote hemorrhage through separate mechanisms: E4 by enhancing amyloid deposition and E2 by promoting rupture. Hemorrhages related to amyloid angiopathy generally occur in the cortical and cortico-subcortical (lobar) brain regions where vascular amyloid deposits are most frequent, and occur less commonly in the cerebellum. Most patients recover from an initial lobar hemorrhage. Recurrent lobar hemorrhages are relatively common, however, and may cause greater morbidity and mortality than first hemorrhages. O'Donnell et al. (2000) identified a specific apolipoprotein E genotype as a risk factor for early recurrence: carriers of the E2 (107741.0001) or E4 (107741.0016) allele had an increased risk for early recurrence compared to individuals with the E3/E3 (107741.0015) genotype.