72.1 Clinical and Laboratory Findings
Cerebral amyloid angiopathy (CAA) was recognized as a disease entity at the beginning of the twentieth century. The first reports appeared in the German lit- erature in 1907 and 1909. In 1935 a familial form of this disease was reported from Iceland, later followed by the description of a Dutch family (1964), a Flemish variant (1992), and a British type (1996). In the latter variant hemorrhage is not a prominent feature, as it is in the Icelandic and Dutch type.Apart from the famil- ial forms, there are also sporadic forms.
The classic presentation of CAA is lobar hemor- rhage, often multiple, associated with an acute neuro- logical presentation. CAA is responsible for 5–20% of nontraumatic cerebral hemorrhages and 30% of lo- bar hemorrhages. The most frequent locations are:
frontal (35%), parietal (26%), temporal (14%), and occipital (19%). Cerebellar and basal ganglia hemor- rhages are infrequent; brain stem hemorrhages are extremely rare. Sporadic CAA may present with a va- riety of symptoms other than lobar hemorrhage.
There may be petechial hemorrhages in cortical and subcortical areas and these may produce either recur- rent transient neurological symptoms or rapidly pro- gressive dementia. Dementia is estimated to occur in about 40% of patients with CAA. The progression of dementia is as a rule much faster than in Alzheimer disease.
The familial forms of CAA have an autosomal dominant inheritance. There are differences in pre- sentation between the affected families. The Icelandic form presents in the third decade with multiple in- tracerebral hemorrhages and infarctions. The disease progresses rapidly to dementia, paralysis, and early death. The Dutch form has a later onset, in the fourth to fifth decade of life. Chronic migrainous headache, as in CADASIL, may precede the onset by years. The presenting symptom is most often intracerebral hemorrhage, sometimes ischemic strokes. Neuro- psychiatric symptoms and dementia are constant features. The Flemish variant presents with intracere- bral hemorrhage and dementia. The British variant shows progressive dementia, spasticity, and ataxia (Worster–Drought syndrome). In this form the entire CNS is involved, including cerebral white matter, cere- bellum, brain stem, and spinal cord. Hemorrhage is not prominent. Other families from Japan, Italy, and North America have been reported with oculo-
leptomeningeal amyloidosis. They vary in presenta- tion but dementia, hemiplegic migraine, spasticity, blindness, and deafness are usually present. These patients have amyloid deposition in the vitreous and retinal vessels, leptomeningeal vessels, and other organs.
The incidence of sporadic CAA increases with age.
The differentiation from other conditions with small vessel disease may be difficult. There is a relationship with sporadic Alzheimer disease. Amyloid deposition in vessel walls is also a factor of importance in spo- radic and familial forms of Alzheimer disease. CAA is found in 92% of postmortem studies of brains of pa- tients with Alzheimer disease. Amyloid deposition is accepted as one of the hallmarks of Alzheimer dis- ease. CAA, however, can occur without any other sign of Alzheimer disease, and Alzheimer disease can occur without CAA. If CAA is present there is risk of lobar hemorrhage. There is no obvious relation with the occurrence, location, and severity of neuritic plaques or neurofibrillary tangles.
Apart from a relationship with Alzheimer disease, CAA is reported to occur in transmissible spongiform encephalopathies (prion diseases), especially in Ger- stmann–Sträussler–Scheinker disease, and, less com- monly, in Creutzfeldt–Jakob disease; in malignant neoplasms treated with irradiation, parkinsonism–
dementia complex of Guam, and dementia pugilisti- ca. A few cases of primary angiitis of the CNS have been reported in combination with CAA.
Routine laboratory tests are unrevealing. The diag- nosis of CAA should be suspected on the basis of typ- ical clinical and neuroimaging findings. The diagno- sis may be confirmed by a leptomeningeal biopsy, but this is only done in exceptional cases. In familial CAA histological confirmation in one patient is necessary, whereas in other affected family members suggestive clinical and neuroimaging findings suffice for a diag- nosis. The Boston group for research of CAA has come up with criteria for the diagnosis of CAA-relat- ed hemorrhage (see Knudsen et al. 2001). Patients fulfilling these criteria, however, have a hemorrhage, so that patients without hemorrhage are excluded.
The MR criteria mentioned in this set of criteria also do not specify the mandatory inclusion of gradient echo techniques, which would help to identify pa- tients with and without hemorrhages with CAA, in addition to being helpful to demonstrate other possible causes.
Cerebral Amyloid Angiopathy
72.2 Pathology
Gross inspection of brain sections reveals a combina- tion of larger and smaller hemorrhages, most often in the cortex and subcortical regions; small infarctions, mainly affecting the cerebral cortex; and extensive white matter abnormalities, mainly involving the deep and periventricular white matter, usually spar- ing the U fibers. Lacunae may also be present in the basal ganglia. Ventricular dilatation is usually also present.
On microscopic examination the lesions in the white matter consist of patchy gliosis and myelin loss, the latter in particular in the parieto-occipital areas.
U fibers, corpus callosum, internal capsule, and optic radiation are usually spared. Perivascular spaces are enlarged and contain mononuclear cells and hemo- siderin-laden macrophages. Around the ventricles Rosenthal fibers may be found.
The most striking finding in CAA is that smooth muscle in the vessel wall of small blood vessels is replaced by a hyaline, eosinophilic material. The de- posits stain with Congo red, hence the name “con- gophilic angiopathy.” The term “amyloid” is applied to a number of proteins sharing the property of Congo red staining, which then exhibits green birefringence under polarized light. This latter property is depen- dent upon the configuration of a twisted b-pleated sheet. This is a feature of amyloid laid down under different circumstances and in different organs of the body, which, despite identical staining properties, may have different amino acid sequences in the con- stituent polypeptide chains. Specific antibodies against amyloid b peptide (Ab), cystatin C, and thyre- ostatin can be used for immunohistochemical char- acterization. It is of interest that in patients with a combination of CAA and Alzheimer disease the de- posits in the vessel wall are immunoreactive with both anti-Ab and anti-cystatin C. Fibrinoid necrosis and hyaline changes in vessel walls are usually also present in sporadic cases of CAA and larger cortical vessels are often thrombosed. Ultrastructurally, amy- loid fibrils in blood vessels appear as interwoven bun- dles of 10-nm filaments, short and disarranged. In early CAA only the outer part of the vessel wall is involved, but when the deposits become larger, they occupy the abluminal part of the basement mem- brane and adjacent smooth muscle cells show degen- erative features. When severely affected, the walls of blood vessels may be replaced entirely by bundles of fibrils with loss of smooth muscle cells and with radi- ation of fibrils into the surrounding neuropil.
72.3 Pathogenetic Considerations
The central biochemical event in the pathophysiology of CAA is the polymerization of soluble subunit pro- teins into insoluble amyloid fibrils. Several different forms of amyloid subunit proteins are deposited in the vasculature leading to amyloid angiopathy, including Ab protein, cystatin C, transthyretin, and gelsolin.
Ab protein is a hydrophobic, nonglycosylated pep- tide of 39–43 amino acids. Ab protein is derived from the amyloid precursor protein (APP) encoded by the gene APP located on chromosome 21q22.1. APP is one of the genes for familial Alzheimer disease, AD1. In sporadic CAA, CAA with sporadic Alzheimer disease, familial Alzheimer disease, Down syndrome, and the Dutch type of CAA, the vascular amyloid is composed of Ab protein subunits. Subtle differences exist be- tween the vascular amyloid in CAA and amyloid parenchymal deposits, such as in amyloid plaques in Alzheimer disease. Vascular amyloid is composed mainly of the 39-amino-acid Ab species, plaque amy- loid predominantly of a 42-amino-acid Ab species.
Different point mutations in APP, causing an amino acid substitution in the Ab protein, have been found in the Dutch type of hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) and in Italian families with similar clinicopathological findings to those in HCHWA-D.
Additionally, the e4 allele (apoEe4) of apolipopro- tein E (apoE) is a risk factor for CAA and Alzheimer disease and the e2 allele has been linked to greater risk of CAA and cerebral hemorrhage. The mecha- nism underlying this increased risk is not completely clear, but there is increasing evidence that the ability of apoE to interact with Ab and influence its confor- mation and clearance plays a major role. ApoE ap- pears critically involved in the conversion of Ab into forms which have a high b-sheet content with associ- ated cellular toxicity.
In the Icelandic form of CAA, HCHWA-I, the vas- cular amyloid is composed of a mutated form of cys- tatin C, a cysteine proteinase inhibitor, playing a role in intracellular catabolism of peptides and proteins.
Cystatin C is encoded by the gene CST3, located on chromosome 20p11.2.
In the familial oculo-leptomeningeal amyloidoses
the vascular amyloid is transthyretin, a prealbumin
that is also present in hereditary peripheral amyloi-
doses. Transthyretin is an amino acid residue carrier
protein for thyroid hormone and retinol binding
protein in plasma and CSF. The gene encoding
transthyretin is TTR, located on chromosome
18q12.1. In CAA related to transthyretin most of the
families (Japan, Portugal) have an association with
the same point mutation in TTR, but other mutations
have also been reported.
In the British form of CAA a novel 4-kDa protein fragment called amyloid-bri (ABri) was identified in isolated amyloid fibrils. ABri is a fragment of a pre- cursor protein (BriPP), a putative type II single-span- ning transmembrane precursor that is encoded by the gene BRI, located on chromosome 13. A mutation in the stop codon of this gene generates a longer open reading frame, resulting in a larger, 277-amino-acid protein, whereas the wild-type protein is 266 amino acids. Cleavage of 34 amino acids at the C-terminal end of the extended protein generates the amyloido- genic fragment, ABri.
The Finnish, gelsolin-related type of CAA is noted worldwide in relatives carrying the same mutation in the gelsolin gene on chromosome 9.
Amyloidosis is a phenomenon in which native globular proteins form long fibrils with a characteris- tic three-dimensional structure. Although emerging from different proteins, amyloid fibrils show a com- mon X-ray diffraction pattern, indicative of a cross-b structure, where the b-sheets run parallel to the fibril axis and the b-strands forming the sheets are perpen- dicular to this axis. Well studied amyloidogenic pro- teins include the Ab protein. The tendency to self-ag- gregate into insoluble fibrils is stronger in Ab 42 frag- ments of APP than in Ab 39 or Ab 40 fragments. Fac- tors promoting in vivo Ab-amyloid formation are:
∑ Overproduction, increased levels of APP (in gene overdose and trisomy 21)
∑ A highly amyloidogenic sequence (as in the codon 693 mutation of the Dutch variant of CAA)
∑ Altered proteolysis of APP (as in familial Alzheimer disease due to codon 692 mutation)
∑ A seeding nucleation event, analogous to seeding in crystal formation
∑ Time/patient age
Many theories describe the detailed process of amy- loid deposition in the parenchyma or the vessel wall.
In Alzheimer disease the amyloid cascade is a good example. It describes the stepwise progression in the deposition of amyloid in Alzheimer disease, starting with either the genetic influence of the APP or prese- nilin 1 and 2 genes, or the failure of clearance of Ab because of the apoEe4 allele, increasing the Ab42 lev- els, followed by oligomerization of Ab42 in limbic and association cortices, with gradual deposition of Ab42 oligomers, activation of microglia, complement, as- trocytes, altering neuronal ionic homeostasis, leading to oxidative injury, production of changes in tau pro- teins, and formation of tangles and plaques, leading to neuronal dysfunction, dementia, and death. Other theories try to explain why vascular amyloidosis in the absence of other risk factors leads to hemorrhage, an important feature in CAA. One of these theories suggests a cascade starting with amyloid deposition in the media and adventitia of cortical arteries, lead-
ing to loss of smooth muscle cells of the media, fol- lowed by vascular dilatation, spindle-shaped microan- eurysms, intimal thickening with thinning and dis- ruption of media and adventitia, changes in vascular permeability, invasion of plasma components into the vascular wall (fibrinoid necrosis), possible additional factors (e.g., hypertension, Ab-induced production of superoxide free radicals from endothelial cells), activation of fibrinolytic systems by Ab, infiltration of inflammatory cells with production of cytokines, and the ApoEe2 allele), ending in hemorrhage.
The frequency of sporadic congophilic angiopathy in the normal aging subject is variable. In patients over the age of 60 years presenting with lobar hemor- rhage, the incidence is high. In stroke patients, too, with the proper techniques, MRI detects microhem- orrhages in more than 20% of patients. In individuals without hemorrhage or other clinical symptoms, the percentages in population studies differ. There is little evidence of the disorder under the age of 60. In the population over 60 years of age there is evidence of congophilic angiopathy in about 30% of individuals.
In normal aging the changes are usually mild and limited to the cerebral cortex, most often in the pari- eto-occipital region. The presence of microhemor- rhages in a high percentage of normal aging people can induce false positives when brain biopsies are considered to obtain a histological diagnosis.
72.4 Therapy
There is no effective treatment for the underlying dis- ease process of CAA. Once a patient is diagnosed with CAA, measures can be taken to prevent brain hemor- rhage as much as possible. High blood pressure should be treated. Blood thinners such as Coumadin (warfarin), antiplatelet agents such as aspirin, or medications designed to dissolve blood clots may cause hemorrhage in patients with CAA, and should be avoided if possible. If these medications are re- quired for other conditions, such as heart disease, the potential benefits must be carefully weighed against the increased risks. Seizures should be treated with antiepileptic drugs, although some drugs should be avoided because of their antiplatelet effect. Once a he- morrhage has occurred, supportive and symptomatic medical care is important. Sometimes neurosurgical intervention is necessary to reduce the pressure with- in the brain.
72.5 Magnetic Resonance Imaging
In patients presenting with an intracerebral hemor-
rhage, both CT and MRI will show the hemor-
rhage(s), together with its secondary effects, such as
Fig. 72.1. A 54-year-old female with a familial history of amy- loid angiopathy. The first row demonstrates T
1-weighted parasagittal images of the left hemisphere with a parietal lobar hemorrhage. The second and third rows represent T
2*- (GE-)weighted images revealing smaller and larger spots
of very low signal intensity, dispersed throughout the brain.
The low signal intensity is caused by hemosiderin residues of microhemorrhages. The combination of lobar hemorrhage with multiple spot-like microhemorrhages is characteristic of CAA
Fig. 72.2. Transverse FLAIR images of a 72-year-old man with slowly progressive cognitive deterioration (first and second rows). The images show slightly asymmetrical confluent areas of hyperintensity in the deep and periventricular white matter, in some places extending into the U fibers. The underlying
cause of the white matter changes is not evident from these images.The images made with a T
2*-weighted sequence (third and fourth rows) reveal multiple spots with very low signal intensity, representing microhemorrhages. These images sug- gest that the patient is suffering from a sporadic form of CAA
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