Hereditary Cerebral amyloid angiopathy

Hereditary Cerebral amyloid angiopathy are vascular diseases caused by the accumulation of an amyloid substance in the walls of the small blood vessels in the meninges and cerebral cortex.

The term «amyloid » is used to describe the accumulation of insoluble proteins with a pleated beta-sheet configuration and a fibrillary structure that produces specific colour in the vessel walls with the use of congo red stains.). Various types of protein have these physical characteristics and can cause the formation of amyloid deposits in the blood vessels.

Amyloid deposits can sometimes result in very serious damage to the wall of the blood vessel and particularly to the smooth muscle cells of the media layer. Such structural changes can cause arterial rupture or lumen narrowing, associated with a decrease of the blood supply to the brain. These features explain the appearance of the cerebral lesions associated with severe forms of amyloid angiopathy i.e. major and minor haemorrhages, lesions in the white matter and small-infarcts. These cerebral lesions are responsible for the majority of neurological symptoms.

Within the cerebral amyloid angiopathy (CAA), there are sporadic (or non-familial) forms in the vast majority of case and characterised by the accumulation of Aß protein in the arterial wall. I

The familial forms of CAA are unusual. They are autosomal dominant and result from errors in various genes that code for a range of proteins leading to amyloid vascular deposits:

Hereditary Aß CAA(Dutch, Flemish and Iowa type):

• Type of amyloid peptide = peptide Aß
• Mutations of the APP gene (Aß precursor protein) on chromosome 21

Hereditary cystatin-C CAAs(Icelandic type):

• Nature of the amyloid peptide = cystatin-C
• Mutation of the cystatin-C gene, chromosome 20

Familial oculoleptomeningeal amyloidosis:

• Nature of the amyloid peptide = transthyretin
• Mutation of the transthyretin gene, chromosome 18

Gelsolin amyloidosis(Finnish type):

• Type of amyloid peptide = gelsolin
• Mutation of the gelsolin gene, chromosome 9

Hereditary British-type CAAs:

• Nature of the amyloid peptide = Bri protein
• Mutation of the BRI gene, chromosome 13

Definition

Hereditary Cerebral amyloid angiopathy (CAA) are vascular diseases caused by the accumulation of an amyloid substance in the wall of the small blood vessels in the meninges and cerebral cortex.

The term « amyloid » is used to describe the accumulation of insoluble proteins with a pleated beta-sheet configuration and a fibrillary structure that produces specific colour in the vessel walls with the use of congo red stains. Various types of protein have these physical characteristics and can cause the formation of amyloid deposits in the blood vessels. 

Amyloid deposits can sometimes resulting very serious damage to the wall of blood vessels and particularly to the smooth muscle cells within the media layer. Such structural changes can cause structural changes can cause arterial rupture or lumen narrowing associated with a decrease of blood supply to the brain. These features explain the appearance of cerebral lesions associated with the severe forms of amyloid angiopathy i.e. major or minor intra cranial haemorrhages (ICHs), lesions in the white matter and small infarcts. These cerebral lesions that are responsible for the majority of neurological symptoms.

Within the group of (CAA), the vast majority of cases are sporadic (or non-familial) forms characterised by the accumulation of Aß protein in the arterial wall.

The familial forms of CAA are unusual. They are usually autosomal dominant and result from errors in various genes that code for a range of proteins which lead to amyloid vascular deposits:

• Hereditary Aß CAA (Dutch, Flemish and Iowa type) :
  • Ttype of amyloid peptide = peptide Aß
  • Mutations of the APP gene (Aß precursor protein) on chromosome 21
• Hereditary cystatin-C CAAs (Icelandic type) :
  • Nature of the amyloid peptide = cystatin-C
  • Mutation of the cystatin-C gene, chromosome 20
• Familial oculoleptomeningeal amyloidosis :
  • Nature of the amyloid peptide = transthyretin
  • Mutation of the transthyretin gene, chromosome 18
• Gelsolin amyloidosis (Finnish type) :
  • Type of amyloid peptide = gelsolin
  • Mutation of the gelsolin gene, chromosome 9
• Hereditary British-type CAAs :
  • Nature of the amyloid peptide = Bri protein
  • Mutation of the BRI gene, chromosome 13

Epidemiology

The prevalence of sporadic CAA found at autopsy can be as high as 30% over the age of 60. The presence of abnormalities suggestive of amyloid angiopathy in the wall of small cerebral arteries is, however, only rarely associated with clinical signs. It is estimated that the frequency of ICHs is 2% in patients with amyloid angiopathy, based on histological criteria. Sporadic CAAs are thought to be implicated in the occurrence of approximately one-third of ICHs in the elderly. The main risk factor for sporadic CAAs is age.

Familial forms of CAA are rare and their prevalence is probably still widely underestimated. They have been identified in several dozen families in Europe:

• Hereditary AB CAAs:
  • Dutch form: 2 Dutch families (> 200 patients)
  • Flemish form: 2 families, one Dutch and the other British.
  • Iowa form: 2 American families (Iowa)
• Hereditary cystatin C CAAs:9 families in Iceland (>200 patients)
• Familial oculoleptomeningeal amyloidosis:12 families worldwide including 2 families in France
• Gelsolin amyloidosis:600 cases of gelsolin amyloidosis have been reported, 500 of them in Finland. Gelsolin amyloidosis is rarely accompanied by symptomatic CAAs. Some 10 families have been reported.   
• Hereditary British-type CAAs:4 families

Clinical Description

The average age for the onset of symptoms of sporadic CAA is approximately75 years.

Sporadic amyloid angiopathy can be responsible for:

• lobar ICHs(i.e. located at the periphery of the brain). It most frequently causes neurological symptoms of sudden onset (weakness of one side of the body, language difficulty, homonymous lateral hemianopia etc.) sometimes associated with headache, epileptic seizures and/or coma (depending on the location and size of the haematoma),
• Small cortical infarctsfrequently silent or sometimes responsible for transient neurological abnormalities,
• Cognitive deficits (memory loss, difficulties with concentration)as a result of the accumulation of cerebral haemorrhage(s) or cerebral infarct(s). In some cases, the deficits may be due to degenerative neuronal loss resulting from concomitant Alzheimer’s disease.

The clinical picture for familial forms of CAA may differ in several ways from that observed with sporadic CAAs: 1) age at onset, 2) severity of symptoms, 3) occasional combination of cognitive deficits suggestive of Alzheimer’s disease, and 4) in some cases, extra cerebral damage (peripheral nerves, eyes, skin).

The clinical picture for familial CAA varies depending on the genetic abnormality responsible for it.

Diagnosis (criteria – method)

CAA is most frequently diagnosed after one or more ICHs in the cerebral lobes when tests for blood clotting disorders or cerebral vascular malformation have proved negative.

Sporadic CAAs are more frequently diagnosed in elderly patients with a lobar ICH when no other cause of cerebral haemorrhage has been found.

CT- scan or MRI scan of the brain can be used to visualize the ICH responsible for the recent symptoms and can also locate the haematoma in superficial areas of the brain (lobar haematoma).

The MRI « gradient echo » sequence is the most effective technique  for the detection of previous, sometimes very small, haemorrhages (micro bleeds), which have remained silent (i.e. giving no symptoms because of their tiny size). A FLAIR sequence visualizes hypersignals (white spots) in the brain’s white matter (leukoencephalopathy). The abnormalities are fairly non-specific and are frequent in elderly patients, especially those suffering from hypertension. In sporadic CAAs, abnormalities in the white matter are more severe or extensive than those commonly observed in normal aging. Sometimes the diagnosis of CAA is given only after surgery to evacuate the cerebral haemorrhage. Microscopic examination of brain tissue reveals the amyloid deposit in the wall of the blood vessel. This is associated with the loss of smooth muscle cells from the vessel wall. 

A diagnosis of sporadic CAA based on the « Boston criteria » requires the presence of the following:

• Definite CAA
  • Full post-mortem examination of brain shows   lobare ICH and severe CAA and no other diagnostic lesion
• Probable CAA with supporting pathologic evidence
  • Clinical data and pathologic tissue (evacuated hematoma or cortical biopsy specimen) showing some lobar CAA in patthologic specimen
  • sNo other diagnostic lesion
• Probable CAA
  • Clinical data and MRI or CT demonstration of two or more haemorrhages lesions restricted to lobar regions (cerebellar hemorrhage allowed)
  • Age > 55 years
  • No other cause of haemorrhage
• Possible CAA
  • Clinical data and MRI or CT demonstration of single lobar ICH
  • Age > 55 years
  • No of other cause of haemorrhage

In familial forms, diagnosis requires a specialist consultation. Detailed study of family history and information obtained from doctors treating other members of the family may be undertaken. A neurological examination will include memory and cognitive function and will be completed by a detailed general examination, especially of the skin and eyes. As in the case of sporadic CAA, a cerebral MRI should be done to complete the examination and determine the number and location of cerebral haemorrhages (including silent haemorrhages) and the presence of lesions within the white matter, cerebral infarcts or other related lesions. When familial amyloid angiopathy is deemed to be very likely (at least two relatives with a clinical picture and/or cerebral imaging suggestive of the disease), gene analysis may be carried out to search for known abnormalities in the genes implicated in familial forms.

Pathophysiology – Etiology

In sporadic CAA, the amyloid protein corresponds to the Aß peptide that results from the fragmentation of a precursor: APP or A-ß beta peptide precursor protein. The affected arteries are mainly the small arteries, the arterioles the capillaries in the cerebral cortex but the arteries in the leptomeninges and cerebellum may be also concerned. In the arterial wall, an accumulation of amyloid deposits predominates in the media (intermediate layer of the arterial wall). In some cases, this accumulation makes the wall more fragile (destruction of the muscle cells, formation of micro-aneurysms, inflammation or splitting of the wall) and, at a more advanced stage, this can lead to the rupture of the artery and to a cerebral haemorrhage.

The accumulation of Aß protein is also observed in patients suffering from Alzheimer’s disease. However, unlike CAA, Alzheimer’s causes the deposits to accumulate   mainly within the   cerebral tissue (in senile plaques) and less in the vessels wall. In Alzheimer’s disease, senile plaques are associated with neurofibrillary degeneration corresponding to the aggregation of a protein (tau protein) within the nerve cells. The connections between vascular damage (amyloid angiopathy) and the amyloid deposits observed in the cerebral tissue of Alzheimer patients remain controversial.

Familial forms of CAA are associated with the accumulation of varying types of amyloid deposits (A beta peptide, gelsolin, transthyretin and c-cystatin). The location of these deposits is partly responsible for the types of complications and symptoms resulting from the disease. Thus, in the Flemish form of A beta CAA, the frequency of cognitive deficits is explained by the preponderant accumulation of amyloid deposits within the cerebral tissue in the form of very large senile plaques. In other forms of familial CAA, the amyloid deposits are seen mainly in the blood vessels of the meninges and they increase the risk of meningeal haemorrhage. They may sometimes extend to structures other than the central nervous system, such as the peripheral nerves, the retinal arteries, the vitreous, the cornea, the spleen and the lymph nodes.

• Hereditary Aß CAAs  : 
  • Dutch type
    • Clinical DescriptionThe most frequent complication is recurrent and sometimes fatal lobare ICH (30% of cases). The average age for clinical onset is 50. There may be symptomatic cerebral infarcts but they are more uncommon. Cognitive disorders, especially amnesia, frequently follow cerebral haemorrhages and they either evolve in stages after one or more cerebral haemorrhages or evolve gradually as they do in Alzheimer patients. The onset of epilepsy is also frequent in patients who have had one or more cerebral haemorrhages (50%).
    • MRI: An MRI reveals early-onset leukoencephalopathy, predominantly in posterior regions, microbleeds (especially at the junction of the cortex and the white matter), larger ICH and, in a few rare cases, cerebral infarcts.
    • Pathology: Severe amyloid angiopathy is found in the leptomeningeal arteries and in the arterioles supplying the cerebral cortex, especially in the posterior regions (occipital lobe). Vascular damage is associated with the presence (to a lesser extent) of senile plaques in the cerebral parenchyma. Neurofibrillary degeneration is rare.
    • Genetic: The mutation is located in codon 693 of the APP gene(chromosome 21). Penetrance is complete  (all the carriers of the genetic abnormality have symptoms)
  • Flemish Type
    • Clinical DescriptionMost patients have early-onset cognitive disorders evolving into dementia with symptoms starting between age 35 and 61. Lobar ICH are uncommon, affecting approximately 10% of patients.
    • Pathology: The amyloid deposits are diffuse within the cerebral vessels and in the cerebral parenchyma, forming very dense, large senile plaques that seem to have come from the affected vessels. Neurofibrillary degeneration is frequent, extensive and diffuse and is associated with severe cerebral atrophy.
    • Genetics: The mutation is located in codon 693 of the APP gene. Despite its proximity to the location of the mutation in the Dutch form, the clinical expression of the disease appears to be quite different.
  • Iowa Type
    • Clinical DescriptionThe most frequent symptoms are memory loss and language disorders, personality changes, myoclonia (minor muscle tremors) and loss of balance. Again, ICH are possible but appear in a secondary stage.
    • MRI: Leukoencephalopathy predominates in the superficial white matter, sometimes associated with gyriform calcifications in the occipital regions. In some cases, there are minor cortical or juxta-subcortical haemorrhages.
    • Pathology: Pathological examinations reveal that the calcifications correspond to the meningeal vessels containing significant amyloid deposits.
    • Genetic: The mutation is located in codon 693 of the APP gene.

• Hereditary cystatin-C CAAs (Icelandic form):
  
  
  • Clinical DescriptionOnset is noted at an early age (25, on average). The early symptoms of the disease are, in most cases, linked to recurrent lobar or deep ICH, sometimes stimulated by intense physical activity. Recurrent haemorrhages may be accompanied by the appearance of cognitive dysfunction, leading sometimes to dementia. The early onset of amnesia is possible but much less common.
  • Pathology: The accumulation of amyloid deposits is diffuse and situated in the walls of cerebral blood vessels (superficial and deep) as well as leptomeningeal vessels, with significant damage to distal and capillary microcirculation. There are no senile plaques or neurofibrillary degeneration. The lymph nodes, spleen, salivary glands, seminal glands, testicles and skin may also contain amyloid deposits without producing any symptoms.
  • Genetic : The mutation responsible for the disease (mutation L68Q) is located in exon 2 of the Cystatin-c gene (chromosome 20)

• Familial oculoleptomeningeal amyloidosis:
  
  
  • Clinical Description Hereditary transthyretin CAA causes visual disorders, epileptic seizures, migraines with aura (occasionally hemiplegic), meningeal haemorrhage and dementia.
  • MRI: A MRI brain scan gadolinium may reveal an abnormal thickening or contrast within the meninges, sometimes with cerebral atrophy. 
  • Pathology: The amyloid deposits predominate in the vitreous and in the meningeal blood vessels. The vessels in the cerebral parenchyma are usually spared.
  • Genetic: More than 90 mutations of the transthyretin gene have been reported. In most cases, the mutations give rise to Type 1 familial amyloid neuropathy, very occasionally accompanied by lesions suggestive of cerebral amyloid angiopathy. In most cases, vascular damage remains silent. Nine mutations in the transthyretin genehave been associated with familial oculoleptomeningeal amyloidosis.

• Gelsolin amyloidosis:
  
  
  • Clinical DescriptionThe main symptoms of gelsolin amyloidosis affect the eyes (lattice dystrophy of the cornea, cataract and glaucoma) and skin (cutis laxa, or loss of skin elasticity). Symptoms usually begin between the ages of 40 and 60. If the nervous system is affected, the symptoms may consist of a combination of   cranial nerve palsy (facial palsy, bulbar palsy with difficulty in swallowing as its main symptom), peripheral neuropathy  or damage to the posterior columns of the spinal cord (deep sensory disorders and loss of balance when walking), cognitive disorders (dementias rare) or behavioural problems (especially depression).
  • MRI : MRI scan of the brain may reveal leukoencephalopathy, predominantly in the deep white matter, and diffuse cerebral atrophy
  • Pathology: Damage to the nervous system produces deposits in the wall of the cerebral arteries within the white matter and grey matter, in the cranial nerves, in the spinal cord (posterior column) and the anterior and posterior roots of the spinal cord.
  • Genetic : The mutations implicated are located in codon 654 of the gelsolin gene (chromosome 9)

• Hereditary British-type CAAs: 
  • British type :
    • Clinical Description: Onset occurs most commonly between the ages of 40 and 50 and the disease develops over 10 years on average. The symptoms are mainly a combination of cognitive dysfunctiongradually leading to dementia and cerebellar ataxia. The appearance of spastic tetraparesis and pseudobulbar palsy is frequent.
    • MRI: MRI scan may reveal small, deep, ICH and lacunar infarcts. Leukoencephalopathy predominates in the deep white matter of the periventricular regions.
    • Pathology: Amyloid angiopathy affects mainly the small blood vessels (diameter < 150 microns) within the white matter and grey matter in the brain, the meninges and the spinal cord. Amyloid plaques and neurofibrillary degeneration are frequently observed in the cerebral parenchyma.
    • Genetics: The mutation (stop Arg) responsible for the disease is located in codon 267of the BRI 2 gene (chromosome 13). It generates a longer than normal APP.
  • Danish type :
    • Clinical DescriptionThis form of CAA usually becomes apparent before the age of 30 with development of cataract followed, on average 10 years later, by the onset of deafness. At about the age of 40, there is a gradual development of ataxia and dementia.
    • MRI : Leukoencephalopathy is observed, predominantly in the deep white periventricular matter
    • Pathology: There are amyloid deposits in blood vessels in the brain, spinal cord and retina. There are no senile plaques but neurofibrillary degeneration is observed. The cranial nerves are thin and demyelinated.
    • Genetic: The genetic abnormality responsible for the disease is a duplication and insertion after codon 265 in the BRI2 gene. It generates a longer than normal APP.

Treatment

The treatment of ICH and cognitive deficits in familial forms of CAA is not different to the treatment of sporadic CAA.

Following a cerebral haemorrhage, the aims of treatment during the first few hours and days are firstly to stem the progression of the haemorrhage and limit the cerebral complications resulting from it (intracranial hypertension, epilepsy) and the complications that may affect the patient’s general condition.

These therapeutic measures may consist of a combination of the following:

• Cessation of antithrombotic treatment(platelet antagonists or anticlotting medication) and sometimes the use of antagonists to suppress the effect of anticoagulant treatment (protamine sulphate, vitamin K)
• Steps are taken to counter intracranial hypertension :half-sitting position, restriction of fluid intake, analgesics and, in some cases, sedation
• Monitoring of blood pressure levels and glycaemia
• Antiepileptic treatmentif epilepsy occurs 
• Insertion of a ventricular shuntin cases of acute hydrocephalus and surgical evacuation in cases of haematoma in the cerebellum or extensive but superficial cerebral haemorrhage
• Preventive measures are taken to avoid complications resulting from the decubitus position(venous thrombosis in the lower limbs, pulmonary embolism): anticoagulation agents administered at a preventive dose 3 days after stabilisation of the size of the haematoma, insertion of a vena cava filter in the case of venous thrombosis in the lower limbs

The patient should be helped to mobilize and start physiotherapy and cognitive therapy if required (treatment of language difficulty and speech loss) as soon as possible.

No specific treatment able to decrease the risk of recurrent haemorrhage is available at the present time. Anticoagulant medication should be avoided because of the high risk of recurrent haemorrhage in patients suffering from CAA. However, in some situations, it may be necessary to prescribe such treatment (mechanical valve prosthesis, for example) and the decision should then be based on the risk/benefit ratio of anticoagulant treatment.  To a lesser extent, aspirin and platelet antagonists should also be avoided whenever possible.

When the patient is also suffering from cognitive disorders, the treatment can include anticholinesterase medication to reduce the severity of the symptoms in the associated Alzheimer’s disease. Specific cognitive therapy, measures to help the patient stay in their own home and assistance for the family are then offered.

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