Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D): clinicopathological studies.

Abstract

Clinical and neuropathological findings are reported in 63 patients with hereditary cerebral haemorrhage with amyloid angiopathy. Patients hadf mostly recurrent strokes, and at least 80% of these were haemorrhages. Almost a third ofthe patients died within a year of their first and only recorded haemorrhage, half of them within two weeks. This angiopathy was restricted to the cerebral and cerebeliar cortex and its covering leptomeninges. As the most important consequence, haemorrhagic infarcts and haemorrhages occurred in the subcortical white matter-that is, the region most vulnerable to impaired cortical circulation. Further development of these subcortical lesions gives rise to the fatal haemorrhages seen at necropsy. In so far as dementia occurs this is likely to result from multiple microinfarcts or haemorrhages. In most cases preamyloid lesions or diffuse plaques and early plaques were seen. No other type ofplaque or neurofibrillary degeneration was found. The plaques occur in conjunction with the angiopathy, but may not occur even when the angiopathy is severe. In one patient plaques were totally absent. Angiopathy and plaques may be the result of the same mutation, the expression of which is governed by tissue factors or phenotypic differences between individual subjects. (7 Neurol Neurosurg Psychiatry 1995;59:699-705)

Amyloid β-Protein Stimulates the Expression of Urokinase-type Plasminogen Activator (uPA) and Its Receptor (uPAR) in Human Cerebrovascular Smooth Muscle Cells

“…These findings suggest that chronic activation of plasminogen can undermine HCSM cell attachment by degradation of cell adhesion components. DISCUSSION CAA is a common pathological feature of most patients with Alzheimer's disease and is prominently found in several rare hereditary cerebrovascular amyloidosis disorders involving mutations within A␤ (1,16,19). The reasons for the accumulation of A␤ in cerebral blood vessels remain unresolved although recent studies (47,48) suggest that it may involve the flow of parenchymal A␤ through interstitial fluid drainage pathways and ineffective transport into the circulation.…”

“…The reasons for the accumulation of A␤ in cerebral blood vessels remain unresolved although recent studies (47,48) suggest that it may involve the flow of parenchymal A␤ through interstitial fluid drainage pathways and ineffective transport into the circulation. A profound deleterious consequence of CAA, particularly in the hereditary forms, is cerebral hemorrhage that can result in serious debilitation or death (19,49,50). Although the mechanisms responsible for the development of hemorrhage in CAA are unclear proteolytic activities may contribute to this pathologic event.…”

“…The degenerating smooth muscle cells have been implicated in the overproduction of A␤PP and A␤ in the cerebral vessel wall further suggesting the active involvement of these cells in the progression of this cerebrovascular pathology (17)(18)(19). Similar to these in vivo observations, we have reported that A␤42, the more pathogenic form of the wild-type peptide, causes cellular degeneration accompanied by a marked increase in the level of cell-associated A␤PP in cultured human cerebrovascular smooth muscle (HCSM) cells, an in vitro model of CAA (20 -22).…”

Localization of a Fibrillar Amyloid β-Protein Binding Domain on Its Precursor

“…These degenerating smooth muscle cells have been implicated in the overproduction of A␤PP and A␤ in the cerebral vessel wall further suggesting the active involvement of these cells in the progression of this cerebrovascular pathology (17)(18)(19). Similar to these in vivo observations, we have reported that A␤- , the more pathogenic form of the wild-type peptide, causes severe cellular degeneration accompanied by a marked increase in the level of cell-associated A␤PP in cultured human cerebrovascular smooth muscle (HCSM) cells (20 -22).…”

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

“…HCHWA-D patients suffer from hemorrhagic strokes, infarcts, and vascular dementia (Wattendorff et al, 1995). Life expectancy is reduced: the first stroke occurs between the ages of 40 and 65 and is fatal in two thirds of the patients (Wattendorff et al, 1982;.…”