Development Of Cerebral Amyloid Angiopathy Research Articles

Hereditary cerebral hemorrhage with amyloidosis‐Dutch type

The amyloid beta-protein (Abeta) E22Q mutation of the rare disorder hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) causes severe cerebral amyloid angiopathy (CAA) with hemorrhagic strokes of mid-life onset and dementia. The mutation does not affect total Abeta production but may alter the Abeta1-42:Abeta1-40 ratio, and affect the proteolytic degradation of Abeta and its transport across the blood-brain barrier. Abeta E22Q aggregates faster into more stable amyloid-like fibrils than wild-type Abeta. Non-fibrillar Abeta(x-42) deposits precede the appearance of fibrils and the deposition of Abeta(x-40) in the vascular basement membrane. CAA severity tends to increase with age but may vary greatly among patients of comparable ages. Lumenal narrowing of affected blood vessels, leukoencephalopathy, CAA-associated vasculopathies, and perivascular astrocytosis, microgliosis, and neuritic degeneration complicate the development of HCHWA-D CAA. Parenchymal Abeta deposition is also enhanced in the HCHWA-D brain with non-fibrillar membrane-bound Abeta(x-42) deposits evolving into relatively fibrillar diffuse plaques variously associated with reactive astrocytes, activated microglia, and degenerating neurites. Plaque density tends to decrease with age. Neurofibrillary degeneration is absent or limited. HCHWA-D dementia is associated with CAA severity independently of Braak stage, age, and plaque density. Particularly, microaneurysms may contribute to the development of (small) hemorrhages/infarcts and the latter to cognitive decline in affected subjects. However, the relative importance of cerebral hemorrhages/infarcts, white matter damage and/or other CAA- or Abeta-related factors for cognitive deterioration in HCHWA-D remains to be determined.

Progression of Cerebral Amyloid Angiopathy in Transgenic Mouse Models of Alzheimer Disease

Cerebral amyloid angiopathy (CAA), the deposition of beta-amyloid (Abeta3) in cerebral vessels, has been implicated as a common cause of hemorrhagic stroke and other forms of vascular disease. CAA is also a frequent concomitant of Alzheimer disease (AD). While the longterm consequences of CAA are well recognized from clinical and pathologic studies, numerous questions remain unanswered regarding the progression of the disease. Examination of CAA in traditional histologic sections does not easily allow for characterization of CAA, particularly in leptomeningeal vessels. In order to approach this topic, we used low magnification imaging of intact, postmortem brains from transgenic mouse models of AD-like pathology to define the spatial and temporal characteristics of CAA in leptomeningeal vessels. Imaging of brains from 10- to 26-month-old animals demonstrated a stereotypical pattern to the development of CAA, with vessels over the dorsal surface of the brain showing an anterior-to-posterior and large-to-small vessel gradient of involvement. High magnification imaging revealed that CAA deposition began with a banding pattern determined by the organization of the vascular smooth muscle cells. Further analysis of the pattern of amyloid deposits showed shrinkage and disappearance of the gaps between clusters of amyloid bands, gradually reaching a confluent pattern. These data led to a classification system to describe the severity of CAA deposition and demonstrate the potential of using intact brains to generate maps defining the progression and kinetics of CAA. This approach should lead to more informed analysis of the consequences of evolving therapeutic options for AD on this related form of vascular pathology.

Cerebrovascular Amyloidosis and Dementia

Cerebrovascular amyloidosis occurs increasingly in older age. The amyloid β (Aβ) protein type of cerebral amyloid angiopathy (CAA) is the most common form of this microangiopathy, evident in virtually all cases of Alzheimers disease (AD). CAA may range from focal deposits to widespread infiltration of amyloid in walls of perforating and meningeal arteries, capillaries and diffuse perivascular plaques. Prior to their degeneration vascular smooth muscle cells may be sensitised and stimulated by the aggregated amyloid peptide itself and cytokines. Two patterns of CAA namely arteriolar and capillary types have recently been recognized. CAA also occurs in other dementing conditions including Downs syndrome and dementia with Lewy bodies. It is the principal feature of the hereditary amyloid angiopathies such as hereditary cerberal haemorrhage with amyloidosis of the Dutch type and familial British dementia. Varying degrees of CAA have been recorded in early onset familial AD. Mutations in the amyloid precursor protein (APP) gene that lie in codons within the Aβ domain may result in a phenotype characterised by severe CAA, cerebral infarction and white matter disease. The apolipoprotein E ε4 allele is a strong factor in the development of Aβ CAA, which may progress to lobar or intracerebral hemorrhages. At least two different transgenic mice models over-expressing human APP implicate neuronal origin of the Aβ within vascular deposits. CAA may largely develop due to lack of clearance by reduced proteolytic degradation and progressive blockage of the interstitial drainage pathways via the brain vascular routes superimposed by age-related arteriosclerotic changes. Current observations from both sporadic and familial cases suggest CAA to be an independent factor for cognitive impairment and dementia. Keywords: Amyloidosis, arteriosclerotic, apolipoprotein, phenotype

The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage.

Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is a risk factor for the development of CAA and the epsilon2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE epsilon2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid beta-protein (A beta), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for A beta, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p < 10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE epsilon2 allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may result from its association with fibrinoid necrosis.

Amyloid deposition in cerebrovascular angiopathy.

Recent evidence suggests that AD is associated with the development of cerebral amyloid angiopathy and with significant changes in the blood-brain barrier glucose transporter and basement membrane protein alterations. It is likely that these changes significantly contribute to chronic cerebral hypoperfusion, possibly resulting in progressive neural death in AD. To investigate the etiology of these changes, we have analyzed postmortem tissue sections of frontal cortex of moderately demented AD cases, stained using both single-label and double-label immunocytochemistry to detect vessels and beta-amyloid. The resultant color images are analyzed using HSV (hue-saturation-value) color image analysis, shape analysis, and histogram analysis techniques. These analyses let us segment the tissue images for further statistical analyses.