Cerebral amyloid angiopathy

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Cerebral amyloid angiopathy
Other namesCongophilic angiopathy [1]
Cerebral amyloid angiopathy - very high mag.jpg
Micrograph of cerebral amyloid angiopathy using congo red stain
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
CausesCause of CAA is unknown [2]
Diagnostic method PET scan, CT scan [2]
TreatmentManagement can be physical, occupational, or speech therapy. [2]

Cerebral amyloid angiopathy (CAA) is a form of angiopathy in which amyloid beta peptide deposits in the walls of small to medium blood vessels of the central nervous system and meninges. [2] [3] The term congophilic is sometimes used because the presence of the abnormal aggregations of amyloid can be demonstrated by microscopic examination of brain tissue after staining with Congo red. The amyloid material is only found in the brain and as such the disease is not related to other forms of amyloidosis. [4]

Contents

Signs and symptoms

CAA is associated with brain hemorrhages, particularly microhemorrhages. The accumulation of amyloid beta peptide deposits in the blood vessel walls results in damage of the blood vessels and hindrance of normal blood flow, making blood vessels more prone to bleeding [5] Since CAA can be caused by the same amyloid protein that is associated with Alzheimer's dementia, brain bleeds [6] are more common in people who have a diagnosis of Alzheimer's disease. However, they can also occur in those who have no history of dementia. The bleeding within the brain is usually confined to a particular lobe [7] and this is slightly different compared to brain bleeds which occur as a consequence of high blood pressure (hypertension) – a more common cause of a hemorrhagic stroke (or bleeding in the brain). [8] The location of the cerebral microbleed determines whether it is more likely to have been caused by hypertension or CAA. Tsai et al. conducted amyloid PET imaging in an Asian population with cerebral amyloid angiopathy–intracerebral hemorrhage and noticed that superficial cerebellar microbleeds are related to CAA, whereas deep or mixed-location cerebellar microbleeds are more likely related to hypertension. [9]

Causes

Astrocyte Astrocyte5.jpg
Astrocyte

CAA has been identified as occurring either sporadically (generally in elderly populations) [10] or in familial forms such as Flemish, Iowa, and Dutch types. In all cases, it is defined by the deposition of amyloid beta (Aβ) in the leptomeningeal and cerebral vessel walls. [11] CAA occurring in the Flemish type has been observed to be linked to large dense-core plaques observed in this pedigree. [12]

The reason for increased deposition of Aβ in sporadic CAA is still unclear with both increased production of the peptide and abnormal clearance having been proposed as potential causes. [13] Under normal physiology Aβ is cleared from the brain by four pathways: (1) endocytosis by astrocytes and microglial cells, (2) enzymatic degradation by neprilysin or insulysin (3) cleared by way of the blood–brain barrier or (4) drained along periarterial spaces. Abnormalities in each of these identified clearance pathways have been linked to CAA. [14] [15]

In familial forms of CAA, the cause of Aβ build up is likely due to increased production rather than poor clearance. [16] Mutations in the amyloid precursor protein (APP), Presenilin (PS) 1 and PS2 genes can result in increased rates of cleavage of the APP into Aβ. An immune mechanism has also been proposed. [17] [18] apolipoprotein E (APOE) ε2 and ε4 are associated with increased risk of getting cerebral amyloid antipathy. The use of antiplatelet and anticoagulant therapy increases the risk of getting intracerebral haemorrhage in CAA. [19]

Types

Several familial variants exist. [20] The condition is usually associated with amyloid beta. [21] However, there are types involving other amyloid peptides:

Pathophysiology

The vascular amyloid pathology characteristic of CAA can be classified as either Type 1 or Type 2, the latter type being the more common. Type 1 CAA pathology entails detectable amyloid deposits within cortical capillaries as well as within the leptomeningeal and cortical arteries and arterioles. In type 2 CAA pathology, amyloid deposits are present in leptomeningeal and cortical arteries and arterioles, but not in capillaries. Deposits in veins or venules are possible in either type but are far less prevalent. [25]

Diagnosis

MRI showing low signal foci in cerebral amyloid angiopathy. Conventional gradient echo T2*-weighted image (left, TE=20ms), susceptibility weighted image (SWI) and SWI phase image (center and right, respectively, TE=40ms) at 1.5 Tesla. Compare SWI and GRE CAA.png
MRI showing low signal foci in cerebral amyloid angiopathy. Conventional gradient echo T2*-weighted image (left, TE=20ms), susceptibility weighted image (SWI) and SWI phase image (center and right, respectively, TE=40ms) at 1.5 Tesla.

CAA can only be definitively diagnosed by a post-mortem autopsy. [27] Biopsies can play a role in diagnosing probable cases. [28] When no tissue is available for biopsy, the Boston Criteria are used to determine probable CAA cases from MRI or CT scan data. The Boston Criteria require evidence of multiple lobar or cortical hemorrhages to label a patient as probably having CAA. [27] Susceptibility weighted imaging has been proposed as a tool for identifying CAA-related microhemorrhages. [29]

Imaging

Cerebral amyloid angiopathy can be presented with lobar intracerebral hemorrhage or microbleeds in the brain. The bleeding usually occurs on the surfaces of the brain in contrast with intracranial haemorrhage due to high blood pressure which occurs in deep locations of the brain such as basal ganglia and pons. In lobar intracerebral bleed, computed tomography (CT) scan would show hyperdense haemorrhage area and hypodense odema around the haemorrhagic site. [19]

MRI sequence of gradient echo and susceptibility weighted imaging (SWI) are useful in detecting microbleeds and deposition of iron on the brain cortex (cortical superficial siderosis). [19] Other MRI indicators of CAA include white matter hyperintensities and cortical thinning. [30]

Management

The aim in cerebral amyloid angiopathy is to treat the symptoms, as there is no current cure. Physical, occupational and/or speech therapy may be helpful in the management of this condition. [2]

History

Gustav Oppenheim was the first to report vascular amyloid β deposits on the vasculature of the central nervous system in 1909. The first paper focusing solely on what would come to be known as CAA was published in 1938 by WZ Scholz. In 1979, H. Okazaki published a paper implicating CAA in certain cases of lobar intracerebral hemorrhage. [24] The Boston Criteria for CAA originated in a 1995 paper from Harvard Medical School. [27]

Related Research Articles

Vascular dementia (VaD) is dementia caused by problems in the blood supply to the brain, resulting from a cerebrovascular disease. Restricted blood supply (ischemia) leads to cell and tissue death in the affected region, known as an infarct. The three types of vascular dementia are subcortical vascular dementia, multi-infarct dementia, and stroke related dementia. Subcortical vascular dementia is brought about by damage to the small blood vessels in the brain. Multi-infarct dementia is brought about by a series of mini-strokes where many regions have been affected. The third type is stroke related where more serious damage may result. Such damage leads to varying levels of cognitive decline. When caused by mini-strokes, the decline in cognition is gradual. When due to a stroke, the cognitive decline can be traced back to the event.

<span class="mw-page-title-main">Cerebrovascular disease</span> Condition that affects the arteries that supply the brain

Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The most common presentation of cerebrovascular disease is an ischemic stroke or mini-stroke and sometimes a hemorrhagic stroke. Hypertension is the most important contributing risk factor for stroke and cerebrovascular diseases as it can change the structure of blood vessels and result in atherosclerosis. Atherosclerosis narrows blood vessels in the brain, resulting in decreased cerebral perfusion. Other risk factors that contribute to stroke include smoking and diabetes. Narrowed cerebral arteries can lead to ischemic stroke, but continually elevated blood pressure can also cause tearing of vessels, leading to a hemorrhagic stroke.

<span class="mw-page-title-main">Cerebral edema</span> Excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain

Cerebral edema is excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compression of brain tissue and blood vessels. Symptoms vary based on the location and extent of edema and generally include headaches, nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, death.

<span class="mw-page-title-main">Intracranial hemorrhage</span> Hemorrhage, or bleeding, within the skull

Intracranial hemorrhage (ICH), also known as intracranial bleed, is bleeding within the skull. Subtypes are intracerebral bleeds, subarachnoid bleeds, epidural bleeds, and subdural bleeds.

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.

<span class="mw-page-title-main">Frontotemporal lobar degeneration</span> Medical condition

Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.

<span class="mw-page-title-main">Perivascular space</span>

A perivascular space, also known as a Virchow–Robin space, is a fluid-filled space surrounding certain blood vessels in several organs, including the brain, potentially having an immunological function, but more broadly a dispersive role for neural and blood-derived messengers. The brain pia mater is reflected from the surface of the brain onto the surface of blood vessels in the subarachnoid space. In the brain, perivascular cuffs are regions of leukocyte aggregation in the perivascular spaces, usually found in patients with viral encephalitis.

<span class="mw-page-title-main">Intracerebral hemorrhage</span> Type of intracranial bleeding that occurs within the brain tissue itself

Intracerebral hemorrhage (ICH), also known as hemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. An ICH is a type of bleeding within the skull and one kind of stroke. Symptoms can vary dramatically depending on the severity, acuity, and location (anatomically) but can include headache, one-sided weakness, numbness, tingling, or paralysis, speech problems, vision or hearing problems, memory loss, attention problems, coordination problems, balance problems, dizziness or lightheadedness or vertigo, nausea/vomiting, seizures, decreased level of consciousness or total loss of consciousness, neck stiffness, and fever.

<span class="mw-page-title-main">Intraparenchymal hemorrhage</span> Medical condition

Intraparenchymal hemorrhage (IPH) is one form of intracerebral bleeding in which there is bleeding within brain parenchyma. The other form is intraventricular hemorrhage (IVH).

<span class="mw-page-title-main">Proteinopathy</span> Medical condition

In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

<span class="mw-page-title-main">Hereditary cystatin C amyloid angiopathy</span> Medical condition

Hereditary cystatin C amyloid angiopathy (HCCAA) is a rare, fatal type of hereditary cerebral amyloid angiopathy found almost exclusively in Iceland. A mutation in the protein cystatin C leads to amyloid dispositions in arteries in the brain, resulting in repeated brain hemorrhages.

<span class="mw-page-title-main">Cerebral atherosclerosis</span> Medical condition

Cerebral atherosclerosis is a type of atherosclerosis where build-up of plaque in the blood vessels of the brain occurs. Some of the main components of the plaques are connective tissue, extracellular matrix, including collagen, proteoglycans, fibronectin, and elastic fibers; crystalline cholesterol, cholesteryl esters, and phospholipids; cells such as monocyte derived macrophages, T-lymphocytes, and smooth muscle cells. The plaque that builds up can lead to further complications such as stroke, as the plaque disrupts blood flow within the intracranial arterioles. This causes the downstream sections of the brain that would normally be supplied by the blocked artery to suffer from ischemia. Diagnosis of the disease is normally done through imaging technology such as angiograms or magnetic resonance imaging. The risk of cerebral atherosclerosis and its associated diseases appears to increase with increasing age; however there are numerous factors that can be controlled in attempt to lessen risk.

A microinfarct is a microscopic stroke generally ranging between 0.1 millimeter and 1 millimeter in size. Microinfarcts can be found in 25-50% of all elderly deceased persons. Microinfarcts may be the second most important cause of dementia, after Alzheimer's disease.

<span class="mw-page-title-main">Amyloid-related imaging abnormalities</span> Medical condition

Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in magnetic resonance imaging of the brain in patients with Alzheimer's disease. ARIA is associated with anti-amyloid drugs, particularly human monoclonal antibodies such as aducanumab. There are two types of ARIA: ARIA-E and ARIA-H. The phenomenon was first seen in trials of bapineuzumab.

<span class="mw-page-title-main">Intracerebroventricular injection</span> Injection into the cerebrospinal fluid

Intracerebroventricular injection is a route of administration for drugs via injection into the cerebral ventricles so that it reaches the cerebrospinal fluid (CSF). This route of administration is often used to bypass the blood-brain barrier because it can prevent important medications from reaching the central nervous system. This injection method is widely used in diseased mice models to study the effect of drugs, plasmid DNA, and viral vectors on the central nervous system. In humans, ICV injection can be used for the administration of drugs for various reasons. Examples include the treatment of Spinal Muscular Atrophy (SMA), the administration of chemotherapy in gliomas, and the administration of drugs for long-term pain management. ICV injection is also used in the creation of diseased animal models specifically to model neurological disorders.

Familial Danish Dementia is an extremely rare, neurodegenerative disease characterized by progressive cataracts, loss of hearing, cerebellar ataxia, paranoid psychosis, and dementia. Neuropathological hallmarks include extensive atrophy of all areas of the brain, chronic diffuse encephalopathy, and the presence of exceedingly thin and nearly totally demyelinated cranial nerves.

David John Werring is a British physician, neurologist, and academic specialising in stroke. He is professor of Neurology at the UCL Queen Square Institute of Neurology and current head of Stroke Research Centre and the department of Brain Repair & Rehabilitation at UCL.

The Boston criteria version 2.0 is a set of guidelines designed to diagnose cerebral amyloid angiopathy (CAA), a disease that affects small blood vessels in the brain, particularly those in the cortex and leptomeninges. Although the gold standard for diagnosis is histopathological examination, the Boston criteria provide clinicians with a probabilistic approach for diagnosis largely based on imaging characteristics.

References

  1. ↑ Exley C, Esiri MM (July 2006). "Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK". J. Neurol. Neurosurg. Psychiatry. 77 (7): 877–9. doi:10.1136/jnnp.2005.086553. PMC   2117501 . PMID   16627535.
  2. 1 2 3 4 5 "Cerebral amyloid angiopathy: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov. Retrieved 2015-05-27.
  3. ↑ "UpToDate". www.uptodate.com. Retrieved 2019-08-17.
  4. ↑ Newfoundland, FRCP William Pryse-Phillips MD, FRCP(C) Faculty of Medicine Health Sciences Centre Memorial University of Newfoundland St John's (2009-05-06). Companion to Clinical Neurology. Oxford University Press, USA. ISBN   9780199710041.{{cite book}}: CS1 maint: multiple names: authors list (link)
  5. ↑ "Exploring cerebral amyloid angiopathy: Insights into pathogenesis, diagnosis, and treatment".
  6. ↑ Godefroy, Olivier (2013-02-28). The Behavioral and Cognitive Neurology of Stroke. Cambridge University Press. ISBN   9781107310896.
  7. ↑ Coleman, William B.; Tsongalis, Gregory J. (2010-02-16). Essential Concepts in Molecular Pathology. Academic Press. ISBN   9780080922188.
  8. ↑ "Brain Basics: Preventing Stroke: National Institute of Neurological Disorders and Stroke (NINDS)". www.ninds.nih.gov. Retrieved 2015-05-27.
  9. ↑ Tsai, Hsin-Hsi; Pasi, Marco; Tsai, Li-Kai; Chen, Ya-Fang; Chen, Yu-Wei; Tang, Sung-Chun; Gurol, M. Edip; Yen, Ruoh-Fang; Jeng, Jiann-Shing (January 2020). "Superficial Cerebellar Microbleeds and Cerebral Amyloid Angiopathy". Stroke. 51 (1): 202–208. doi:10.1161/STROKEAHA.119.026235. PMID   31726962 . Retrieved 2023-11-17.
  10. ↑ Sirven, Joseph I.; Malamut, Barbara L. (2008). Clinical Neurology of the Older Adult. Lippincott Williams & Wilkins. ISBN   9780781769471.
  11. ↑ Ettinger, Alan B.; Weisbrot, Deborah M. (2014-04-17). Neurologic Differential Diagnosis: A Case-Based Approach. Cambridge University Press. ISBN   9781107014558.
  12. ↑ Kumar-Singh, S.; Cras, P.; et al. (2002). "Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric". American Journal of Pathology. 161 (2): 507–20. doi:10.1016/S0002-9440(10)64207-1. PMC   1850756 . PMID   12163376.
  13. ↑ Tolnay, Markus; Probst, Alphonse (2012-12-06). Neuropathology and Genetics of Dementia. Springer Science & Business Media. ISBN   9781461512493.
  14. ↑ Subramaniam, Rathan; Barrio, Jorge (2013-10-15). Novel Imaging Techniques in Neurodegenerative and Movement Disorders, an Issue of Pet Clinics. Elsevier Health Sciences. ISBN   9780323227353.
  15. ↑ Brain Extracellular Matrix in Health and Disease. Elsevier. 2014-10-30. ISBN   9780444634948.
  16. ↑ Hall, Tim (2013-09-17). PACES for the MRCP: with 250 Clinical Cases. Elsevier Health Sciences. ISBN   978-0702054662.
  17. ↑ Mental Disorders: New Insights for the Healthcare Professional: 2011 Edition. ScholarlyEditions. 2012-01-09. ISBN   9781464900853.
  18. ↑ Advances in Dementia Research and Treatment: 2012 Edition. ScholarlyEditions. 2012-12-26. ISBN   9781464991721.
  19. 1 2 3 Sharma, Rohit; Dearaugo, Stephanie; Infeld, Bernard; O'Sullivan, Richard; Gerraty, Richard P (August 2018). "Cerebral amyloid angiopathy: Review of clinico-radiological features and mimics". Journal of Medical Imaging and Radiation Oncology. 62 (4): 451–463. doi: 10.1111/1754-9485.12726 . PMID   29604173.
  20. ↑ Revesz, Tamas; Holton, Janice L.; Lashley, Tammaryn; Plant, Gordon; Rostagno, Agueda; Ghiso, Jorge; Frangione, Blas (July 2002). "Sporadic and familial cerebral amyloid angiopathies". Brain Pathology (Zurich, Switzerland). 12 (3): 343–357. doi:10.1111/j.1750-3639.2002.tb00449.x. ISSN   1015-6305. PMC   8095796 . PMID   12146803. S2CID   8930792.
  21. ↑ Dickson, Dennis; Weller, Roy O. (2011-09-09). Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. John Wiley & Sons. ISBN   9781444341232.
  22. ↑ Larner, A. J. (2008-04-24). Neuropsychological Neurology: The Neurocognitive Impairments of Neurological Disorders. Cambridge University Press. ISBN   9780521717922.
  23. ↑ Dening, Tom; Thomas, Alan (2013-09-26). Oxford Textbook of Old Age Psychiatry. OUP Oxford. ISBN   9780199644957.
  24. 1 2 Biffi, Alessandro; Greenburg, Steven M. (2011). "Cerebral Amyloid Angiopathy: A Systematic Review". Journal of Clinical Neurology. 7 (1): 1–9. doi:10.3988/jcn.2011.7.1.1. PMC   3079153 . PMID   21519520.
  25. ↑ Thal, Dietmar Rudolph; Ghebremidhin, Estifanos; Rüb, Udo; Haruyasu, Yamaguchi; Del Tredici, Kelly; Braak, Heiko (2002). "Two types of sporadic cerebral amyloid angiopathy". Journal of Neuropathology & Experimental Neurology. 61 (3): 282–293. doi: 10.1093/jnen/61.3.282 . PMID   11895043.
  26. ↑ Mittal, S.; Wu, Z.; Neelavalli, J.; Haacke, E. M. (2009). "Susceptibility-Weighted Imaging: Technical Aspects and Clinical Applications, Part 2". American Journal of Neuroradiology. 30 (2): 232–252. doi:10.3174/ajnr.A1461. ISSN   0195-6108. PMC   3805373 . PMID   19131406.
  27. 1 2 3 Greenberg, Steven; Charidimou, Andreas (2018). "Diagnosis of Cerebral Amyloid Angiopathy: Evolution of the Boston Criteria". Stroke. 49 (2): 491–497. doi:10.1161/STROKEAHA.117.016990. PMC   5892842 . PMID   29335334.
  28. ↑ Verbeek, M. M.; Waal, R. M. de; Vinters, Harry V. (2013). Cerebral Amyloid Angiopathy in Alzheimer's Disease and Related Disorders. Springer Science & Business Media. ISBN   9789401710077.
  29. ↑ Ellenbogen, Richard G.; Abdulrauf, Saleem I.; Sekhar, Laligam N. (2012). Principles of Neurological Surgery. Elsevier Health Sciences. ISBN   978-1437707014.
  30. ↑ Charidimou, Andreas; Boulouis, Gregoire; Gurol, M. Edip; Ayata, Cenk; Bacskai, Brian J.; Frosch, Matthew P.; Viswanathan, Anand; Greenberg, Steven M. (1 July 2017). "Emerging concepts in sporadic cerebral amyloid angiopathy". Brain. 140 (7): 1829–1850. doi:10.1093/brain/awx047. ISSN   0006-8950. PMC   6059159 . PMID   28334869.

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