Zerebrale Amyloidangiopathie

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the accumulation of cerebral amyloid-β (Aβ) in the tunica media and adventitia of leptomeningeal and cortical vessels of the brain. The resultant vascular fragility tends to manifest in normotensive elderly patients as lobar intracerebral hemorrhage. It is, along with Alzheimer disease, a common cerebral amyloid deposition disease.

Epidemiology 

Cerebral amyloid angiopathy can be divided into sporadic (spontaneous) and familial forms.

Sporadic CAA

Cerebral amyloid angiopathy is a frequent incidental finding, found on screening gradient-recalled echo imaging in up to 16% of asymptomatic elderly patients . Autopsy studies have found a prevalence of approximately 5-9% in patients between 60 and 69 years, and 43-58% in patients over the age of 90 .

Autopsies of patients who have evidence of Alzheimer disease have found cerebral amyloid angiopathy in the vast majority of cases (90%). This rate is still high (20-40%) in non-demented elderly individuals .

Importantly it is usually not associated with systemic amyloidoses.

Familial CAA

Familial cerebral amyloid angiopathy describes a group of very rare disorders that are usually encountered as autosomal dominant conditions . Many of these disorders are only isolated to only a few families and they mainly differ from spontaneous CAA in an earlier age of onset, typically in middle to late middle age . Furthermore, they may also be part of multi-system or other central nervous system genetic disorders .

Examples of familial CAA include :

• Aß peptide with precursor protein APP (chromosome 21):
  • CAA related to familial Alzheimer disease
  • CAA in Down syndrome
  • hereditary cerebral hemorrhage with amyloidosis (Dutch, Italian, Flemish, Iowa, Piedmont, Arctic types)
• ACys peptide with ​precursor protein cystatin C (chromosome 20): hereditary cerebral hemorrhage with amyloidosis Icelandic type
• ATTR peptide with precursor protein transthyretin (chromosome 18): meningovascular amyloidosis (see cerebral transthyretin-associated amyloidoses)
• AGel peptide with precursor protein gelsolin (chromosome 9): familial amyloidosis - Finnish type
• PrPSc peptide with precursor prion protein (chromosome 20): Gerstmann-Straussler-Scheinker disease
• ABri peptide with precursor protein ABri precursor protein (chromosome 13): familial British dementia (see case 17)
• ADan peptide with precursor protein ADan precursor protein (chromosome 13): familial Danish dementia

Clinical presentation

Manifestations of cortical vessel involvement:

• lobar hemorrhages or cerebellar hemorrhages: present as stroke, often with headache, focal neurological symptoms, seizures, and decreased conscious state
• cognitive impairment: occurs in three main patterns
  • gradual decline: a vascular dementia thought to be secondary to lobar cerebral microhemorrhages, ischemic leukoencephalopathy, microinfarcts, and lobar lacunes , and occurs independently to cognitive impairment of Alzheimer disease 
  • step-wise decline: due to recurrent lobar hemorrhages 
  • rapidly-progressive decline: may be present in inflammatory cerebral amyloid angiopathy , which is discussed separately

The primary manifestation of leptomeningeal vessel involvement is due to convexity subarachnoid hemorrhage, which can present with transient focal neurological symptoms (TFNS) or "amyloid spells" . These TFNS are classically described as recurrent, stereotyped, spreading paresthesias lasting several minutes but there is a wide spectrum of presentations encompassing both positive (spreading paresthesia or visual symptoms) and negative (paresis, aphasia or dysphagia) phenomenology . These symptoms are most prominent with the convexity subarachnoid hemorrhage is localized to the central sulcus , which is in close proximity to the primary motor and sensory cortices .

Other manifestations of CAA, which are discussed separately, include:

• inflammatory cerebral amyloid angiopathy: an umbrella description for inflammatory reactions that present with rapidly-progressive cognitive decline, seizures, headache and stroke-like episodes (without hemorrhage)  
• cerebral amyloidoma: mass-like lesions that have a varied presentation depending on the location of the amyloidoma

Pathology

Cerebral amyloid angiopathy is characterized by the deposition of amyloid in the tunica media and/or tunica adventitia of small and medium-sized arteries of the cerebral cortex and leptomeninges . This is associated with fibrinoid degeneration with separation of the tunica media and tunica intima, and microaneurysm formation .

There are a number of different proteins that can lead to intravascular amyloid deposition, however, the most common, as is the case in sporadic CAA, is Aß which is a short 42 amino acid peptide cleaved from amyloid precursor protein (APP) which is encoded on chromosome 21 .

Aß is an eosinophilic, insoluble protein, located in the extracellular space. It stains with Congo red yielding classic apple-green birefringence when viewed with polarized light . When staining with thioflavin T and illuminated with ultraviolet light, the Aß deposits emit bright green fluorescence .

Associations

• Alzheimer disease
  • pathological cerebral amyloid angiopathy changes are seen in ~80% of those with Alzheimer disease (Aß-42)  
  • ~40% of those with cerebral amyloid angiopathy have Alzheimer dementia type symptoms
• Down syndrome 
• chronic traumatic encephalopathy
• spongiform encephalitis
• other familial syndromes (as discussed above)

Radiographic features

Findings reflect the various manifestations of the disease:

• hemorrhage
  • intracerebral hemorrhage
    • usually cortico-subcortical, in a so-called lobar location , but can also be seen in the cerebellum (especially in the cerebellar cortex or vermis) , may have finger-like projections
      • tend to spare the basal ganglia and pons (cf. hypertensive 'deep' intracerebral hemorrhage)
    • CT: initially hyperdense with hypodense perihaematomal edema, often exerts positive mass-effect
    • MRI: appearance will vary according to age of bleed (see blood on MRI) 
  • cerebral microhemorrhage
    • defined as 2-10 millimeter, round or ovoid areas of hemorrhage, and tend to be corticosubcortical (grey-white matter junction) in distribution, but can also be in the cerebellum
      • tend to spare the basal ganglia and pons (cf. hypertensive microhemorrhages) 
    • CT: not appreciated
    • MRI: only seen on T2* sequences (GRE, echo-planar, SWI) as regions of low-signal blooming artefact , not seen on conventional T1 and T2/FLAIR sequences
  • convexity subarachnoid hemorrhage
    • hemorrhage that is localized to one or more adjacent cortical sulci at the convexity of the brain
      • tend to spare the basal cisterns, the Sylvian fissure, the interhemispheric fissure or the ventricles (cf. aneurysmal subarachnoid hemorrhage or perimesencephalic subarachnoid hemorrhage) 
    • CT: hyperdensity localized to one or more adjacent sulci, can be subtle
    • MRI: appearance will vary according to the age of the bleed (see blood on MRI), but is best acutely seen on T2 FLAIR as a hyperintensity
  • cortical superficial siderosis
    • a chronic sequela of convexity subarachnoid hemorrhage, including of hemorrhage that is asymptomatic
      • not present infratentorially (cf. superficial siderosis of the CNS) 
    • CT: not appreciated
    • MRI: curvilinear regions of signal drop-out localized to one or more sulci best seen on T2* sequences (GRE, echo-planar, SWI) 
• ischemia
  • ischemic leukoencephalopathy 
    • chronic lesions, indistinguishable from leukoaraiosis due to other etiologies, but tends to have a periventricular and posterior predominance
    • CT: diffuse hypodensity of the white matter
    • MR: T2 hyperintensity of the white matter without involvement of subcortical U-fibers (cf. cerebral amyloid angiopathy related inflammation) 
  • microinfarcts and lobar lacunes
    • acute cortico-subcortical lesions; lobar lacunes are 3-15 millimeters in size while microinfarcts are smaller
    • CT: not appreciated
    • MRI: same signal changes as in acute ischemic stroke, most pronounced on DWI
• others
  • dilated perivascular spaces of the centrum semiovale
    • dilation of normal perivascular spaces in the centrum semiovale
      • tend to spare the basal ganglia and pons (cf. hypertensive dilated perivascular spaces) 
    • CT: not appreciated
    • MRI: best appreciated on T2 images as CSF-signal structures with a varied appearance depending on the orientation of their draining vessel
  • cortical atrophy
    • CT: not appreciated
    • MRI: not readily appreciated on conventional sequences, requires cortical surface reconstructions

Radiographic features of inflammatory cerebral amyloid angiopathy and cerebral amyloidoma are discussed separately.

Diagnostic criteria

The Boston criteria and newer Modified Boston criteria are a combination of clinical, radiographic and pathological criteria which are used to assess the probability of cerebral amyloid angiopathy. These criteria require patients to have either biopsy specimens and/or brain MRI data available . Additionally, the Edinburgh criteria for lobar intracerebral hemorrhage associated with cerebral amyloid angiopathy can be utilized, especially for patients with a lobar intracerebral hemorrhage without an MRI .

Treatment and prognosis

There is currently no disease-modifying treatment available . Additionally, there are no guidelines regarding use of antiplatelet, anticoagulant, or thrombolytic drugs in patients with CAA, all medications which have been shown to increase the risk of disabling hemorrhage in this patient group .

Differential diagnosis

Radiological differential diagnosis, particularly of cerebral microhemorrhages, includes:

• hypertensive microangiopathy
  • hemorrhages, including microhemorrhages, are typically located in basal ganglia, pons and cerebellum
  • not associated with subarachnoid hemorrhage or superficial siderosis
• multiple cavernoma syndrome
  • lesions have a random distribution
  • random size, although Zabramski classification type IV cavernous malformations are indistinguishable from cerebral microhemorrhages related to CAA
  • often characteristic cavernous malformations can be identified
• hemorrhagic metastases (e.g. melanoma)
  • lesions have a variable size and can often be larger than microhemorrhages
  • enhancing
• diffuse axonal injury
  • lesions are typically located at the grey-white matter junction, in the corpus callosum and in more severe cases, in the brainstem
• neurocysticercosis
  • nodular calcified stage visible on CT or phase-filtered SWI
  • random distribution 
• fat embolism syndrome
  • 'starfield' pattern of distribution
  • lesions also show restricted diffusion on DWI and are likely visible on other sequences
• radiation-induced vasculopathy
  • microhemorrhages have a very similar appearance (similar pathophysiology)
  • distribution related to the treatment field

Siehe auch:

• Intrazerebrale Blutung
• Amyloidose
• CADASIL
• Amyloidangiopathie
• Inflammatory cerebral amyloid angiopathy
• Boston criteria
• Mikroblutungen
• intrazerebrale Blutung bei Amyloidangiopathie
• blood on MRI
• Amyloidosis zerebral
• Morbus Alzheimer
• cerebral amyloid angiopathy with superficial siderosis
• cerebral haemorrhage

und weiter:

• Intrakranielle Blutung
• zerebrale Kavernome
• zerebrale Mikroblutungen
• Lobärblutung
• familial multiple cavernous malformation syndrome
• boston criteria for cerebral amyloid angiopathy
• cerebral lobar haematoma secondary to amyloid angiopathy
• zerebrale Mikroangiopathie bei Hypertonus
• neurodegenerative Erkrankung
• zerebrale ATTR-Amyloidose