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Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch type (HCHWA‐D): II ‐ A Review of Histopathological Aspects

Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch type (HCHWA‐D): II ‐ A Review of... From the Departments of Neurology1 and Pathologyz, Leiden University Hospital, and the Department of Neurology3, Rilnland Hospital. Leiderdorp, The Netherlands Cerebral amyloid-R (AR) angiopathy is the histopathological hallmark of hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D). A13 deposits are found mainly in the cerebral and cerebellar meningocortical blood vessels and as plaques throughout the cerebrocortical gray matter. AR deposition in arteries and arterioles starts at the junction of media and adventitia and proceeds t o involve the media causing degeneration of the vascular smooth muscle cells. Cerebrocortical arterioles often show one or t w o layers of radial AR around a layer of homogenous AR that replaces the media. Degenerating neurites, reactive astrocytes and microglial cells may surround cerebrocortical angiopathic arterioles and capillaries, probably in reaction t o invasion of the perivascular neuropil by AR fibrils. Furthermore, clusters of coarse extracelM a r matrix deposits may be found near AS-laden cerebrocortical arterioles. The amyloid-associated proteins, cystatin C and RPP colocalize diffusely , w i t h Dutch vascular AR, whereas HLA-DR immunoreactivity is found only in the periphery of the diseased vessel wall. The latter phenomenon may be related t o the presence of perivascular cells. Angiopathic blood vessels frequently show structural changes. The relation of the described pathology t o the development of hemorrhage, infarction and leukoencephalopathy needs further elucidation. Introduction presence of degenerating neurites, evidenced by synaptophysin, Ai3 precursor protein (BPP), and ubiquitin immunohistochemistry (15,16). Neurofibrillary (NF) degeneration is only observed to a minor degree in the hippocampus and the cerebral, particularly the temporal cortex of some of the older HCHWA-D patients (personal observation). Extracranial localizations of Ai3 have not been demonstrated thus far in HCHWA-D (46). This paper will review histopathological aspects of cerebral amyloid angiopathy (CAA) in HCHWA-D. Distribution and Morphology Cerebral amyloid-i3 (An) angiopathy is the histopathological hallmark of hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D). In addition, diffuse plaques are found in the cerebrocortical gray matter. In particular in older patients, a number of plaques may show congophilia and the Corresponding author: MLC Maat-Schieman MD, Department of Neurology K5Q-116, Leiden University Hospital, Postbox 9600, 2300 RC Leiden, The Netherlands Tel31 (71)5262197 Fax 31 (71) 5248253 Amyloid angiopathy in HCHWA-D preferentially affects the meningocortical blood vessels of the cerebral hemispheres and to a lesser extent of the cerebellum. In advanced cases blood vessels of the hippocampus, basal ganglia and brain stem may be involved as well. As far as studied (46), CAA has not been observed in the spinal cord or its meninges. Ai3 is immunohistochemically demonstrable in arteries, arterioles and veins of the meninges. In the cerebral and cerebellar gray matter Ai3 is localized in the walls of arterioles and in more advanced cases also in capillaries. The superficial course of the perforating cortical arterioles is first affected by A13 deposition. White matter blood vessels are almost consistently spared. The meningeal arteries display focal or circular homogenous AB deposits localized in the outer media at the border with the adventitia. Ai3 deposits are occasionally observed in the arterial adventitia and seem to be distinct from Af3 in the media. Also in Alzheimer’s disease (AD) CAA, arterial and arteriolar Ali deposits are first detectable in the outer part of the media (13, see below). Ultrastructural studies of CAA in AD have demonstrated that Af3 fibrils appear first of all in the abluminal basement membrane of meningeal and cerebrocortical blood vessels (54, see below). Likewise, amyloid fibrils accumulate in this location in HCHWA-D CAA (personal observation). In HCHWA-D meningocortical arterioles, most of or the entire media is usually replaced by homogenous Ai3 (congophilic angiopathy of Pantelakis (22)). Besides, HCHWA-D cerebrocortical arterioles frequently show a ring of radially arranged Af3 around the homogenous Af3 that replaces the media (Fig.1). Foci of radial A13 may again project from this ring. In M.L.C. Maat-Schieman e t al: HCHWA-D: Histopathological Aspects Figure 1. Paraffin section from a patient w i t h HCHWA-D showing an A 3 immunoreactive cortical arteriole with an inner 1 layer of homogenous A 3 and an outer layer of radial A13. x250 1 aged patients a complete second radial layer is sometimes observed. A single layer of radial Ai3 may project from the wall of affected cortical capillaries. Radial A& is virtually absent i n angiopathic meningeal blood vessels or cerebellar cortical arterioles. The occurrence of one or two radial layers of amyloid around homogenous cerebrocortical arteriolar amyloid has been noticed before in not further specified patients with CAA (32,33). Ultrastructural studies showed that the radial layers develop within the confines of the vessel wall, but amyloid fibrils may reach the surrounding neuropil in places where the outermost adventitial collagenous fibers and the parenchymal basement membrane have disappeared (32). Like in AD CAA (13), accumulation of AB in the vascular wall in HCHWA-D is accompanied by degeneration of the smooth muscle cells in the .media, as evidenced by disappearance of a-smooth muscle actin immunoreactivity (Fig. 2a-b). Colocalization with Amyloid-Associated Proteins (Amyloid P-Component, Proteoglycans and Apolipoprotein El, al-Antichymotrypsin, Cystatin C, RPP, and HLA-DR Amyloid P-component (protein AP) and highly sulfated glycosaminoglycans are constituents of all forms of amyloidosis, including AD vascular Al3 (24,25,35-37). They likely play a fundamental, but not yet defined role in amyloidogenesis. Accordingly, HCHWA-D vascular A13 shows irnmunostaining with antibodies against protein AP (40). A t variance with AD vascular An, Dutch vascular amyloid appears t o be unreactive or only weakly reactive with antibodies against t h e basement membrane component heparan sulfate proteoglycan (HSPG) (6). The same pattern was observed for two other basement membrane components, laminin and collagen type IV, suggesting that these extracellular matrix (ECM) compo- nents are present only in low quantities in HCHWAD CAA ( 6 ) .Apolipoprotein E (apoE) immunoreactivity has been found in a variety of amyloids, including HCHWA-D and AD parenchymal and vascular Ai3 (12,49). It has been shown that apoE enhances polymerization of A13 into fibrils in vitro. Of the common isoforms, ApoE-4 has t h e strongest effect in this respect (14,47). Recently, the immunohistochemical colocalization of A13 and cystatin C, reported before in CAA in AD and in SCAA (21,43,44), has been demonstrated in cortical blood vessels of patients with HCHWA-D (10). The presence of cystatin C immunoreactivity i n Al3 laden blood vessels has been correlated with the occurrence of fatal hemorrhage (21). The serine protease inhibitor al-antichymotrypsin (al-ACT), possibly derived from astrocytes, has been identified in the plaque-amyloid of the cerebral Al3 diseases, including HCHWA-D, but not in other chemical types of cerebral amyloid or i n extracerebral amyloid deposits (1,29,26). Like apoE, al-ACT promotes A& fibril formation (14). Conflicting results concerning the presence of alACT in vascular A S have emerged (1,26,28). Rozemuller et al. (28) reported the absence of al-ACT immunostaining in AD vascular A&. It was postulated that the use of fresh-frozen in stead of formalin-fixed tissue may account for t h e difference with other studies (1,26). In HCHWA-D, intense al-ACT immunostaining of vascular amyloid was reported in formalin-fixed tissue (40). Angiopathic blood vessels in HCHWA-D exhibit pronounced diffuse BPP immunoreactivity i n contrast to weak &PP staining of angiopathic vessels in AD (30). Differences i n the process of vascular amyloid formation in HCHWA-D and AD and the severity of the angiopathy in HCHWA-D as compared t o AD have been suggested as possible factors accounting for this difference (30). In contrast t o t h e diffuse immunostaining of Dutch vascular A13 with antibodies against the amyloid-associated proteins, cystatin C, and BPP, immunostaining for class I1 major histocompatibility antigen HLA-DR is found only in the periphery of the wall of a subset of angiopathic cerebrocortical blood vessels (17). It has been suggested that this HLA-DR immunoreactivity reflects activity from perivascular cells in reaction to Al3 fibrils penetrating between the vascular and parenchymal basement membranes. Alternatively, perivascular cells, implicated in AD in the production of Ai3 in (pre)capillaries (52, see below), may have a function in the formation of (HCHWA-D) radial amyloid (17). Perivascular Neuropil Pathology Degenerating neurites as revealed by synaptophysin, BPP, and ubiquitin immunohistochemistry, as well as reactive astrocytes and microglial cells, demonstrated by anti-GFAP antibodies and mono- M.L.C. Maat-Schieman et al: HCHWA-0: Histopathological Aspects Figure 2. Paraffin section from a patient with HCHWA-D showing A 3 immunoreactive meningeal blood vessels (a), which demon1 strate partial to complete loss of a-smooth muscle actin immunoreactivity in an adjacent section (b).x25 cyte/macrophage markers respectively, are present around a subset of cerebrocortical AB-laden blood vessels in HCHWA-D (16 and personal observation). Perivascular neurites showing NF degeneration are encountered in cortical areas with NF tangles (personal observation). Similar neuritic and glial pathology has been observed around angiopathic blood vessels in AD and in sporadic CAA (4,5,19,23). It has been suggested that the perivascular pathology is provoked by amyloid fibrils invading the neuropil after breaching the parenchymal basement membrane (19,23,52). Thus, it appears that neuronal processes degenerate and astrocytes and microglia show reactive changes upon the appearance of amyloid fibrils in the perivascular neuropil. Consequently, one may speculate with respect to the issue of plaque-formation that the presence of degenerating neurites, astrocytes, and microglia in plaques likewise represents a secondary phenomenon. Diffuse AB immunoreactivity may be found, though infrequently, in the neuropil adjacent to angiopathic cerebrocortical arterioles, but dyshoric angiopathy (39), is not a feature of the vascular pathology of HCHWA-D. Recently, ill-defined clusters of coarse deposits showing strong immunoreactivity for several extracellular matrix (ECM) components (HSPG, laminin, collagen type 111 and IV) have been demonstrated in the neuropil in the vicinity of or around a minority of the angiopathic cerebrocortical arterioles (6). The deposits were not spatially associated with AB immunoreactive plaques. Furthermore, they were not observed in control or AD patients. Their site of origin, possibly the perivascular neuropil or the diseased vessel wall, as well as their significance are a matter of speculation. Moreover, the specificity of the coarse deposits for HCHWA-D remains to be established, since none of the control or AD patients in this study had severe CAA (6). Hemorrhages, infarcts, and Leukoencephaiopathy in Relation to Structural Changes of the Blood Vessel Wall Both recent and old hemorrhages and infarcts, the latter either hemorrhagic or not, are characteristically found in the cerebra1 cortex and subcortical white matter in HCHWA-D (?1,46). The meninges may show fresh hemorrhage and hemosiderosis. M.L.C. Maat-Schieman et al: HCHWA-D: Histopathological Aspects Furthermore, the subcortical white matter shows varying degrees of demyelination, axonal loss and gliosis (11). The angiopathic blood vessels frequently show structural changes. These include glomerular formations, double barreling, obliterative fibrous or hyaline intimal thickening, and aneurysmal dilatation. Fibrinoid necrosis of the vascular wall may be present. Perivascular and intramural chronic inflammatory infiltrates are often found. Perivascular multinucleated giant cells are occasionally observed. The walls of angiopathic vessels may show extensive calcification. These findings confirm those reported for CAA in general (20). It has been postulated that hypoperfusion of the deep white matter due t o stenosis of the long perforating arterioles causes the demyelination, axonal loss and gliosis of the subcortical white matter or leukoencephalopathy (9). Furthermore, it has been suggested that severe CAA accompanied by microaneurysm-formation and fibrinoid necrosis must be considered an important factor in the pathogenesis of cerebral hemorrhage (18,45,53). HCHWA-D and the Pathogenesis of CAA Finally, it should be noted that comparative studies of biochemically different cerebral amyloid angiopathies may contribute to the unraveling of the pathogenesis of CAA in general. For instance, degeneration of vascular smooth muscle cells, as observed in AD and HCHWA-D CAA, may not be specifically related t o Ai3 deposition in the cerebral vessel wall, but may also occur as a result of the deposition o f amyloid fibrils composed of variant cystatin C (Acys) or transthyretin (ATTR), both presumably derived from circulating precursors. Furthermore, focal deposits of ATTR (Fig. 1 A in 41), are recognizable in the outer media of meningeal arteries. If the abluminal basement membrane turns out t o be the site of initial A?TR and Acys fibril deposition, the role of the basement membrane in the pathogenesis of cerebrovascular amyloid is not limited to An. Concluding Remarks Several observations have implicated vascular smooth muscle cells in the production of l3PP and Ai3 in arteries and arterioles. For example, immunohistochemical studies have localized BPP t o vascular smooth muscle cells (13,34) and initial A13 deposits in AD meningocortical blood vessels to the abluminal portion of the media (13). The latter phenomenon is also observed in HCHWA-D. In addition, it has been suggested that non-fibrillar An accumulates between and within vascular smooth muscle cells in the early stages of vascular Ai3-formation (7). Furthermore, cultured human vascular smooth muscle cells have been shown to secrete BPP (42). and non-fibrillar and fibrillar Ai3 have been reported to accumulate in canine vascular smooth muscle in culture (48). Lastly, the basement membrane is a product of vascular smooth muscle cells and ultrastructurally A& fibrils appear to arise within that basement membrane in close proximity t o the vascula1 smooth muscle cells (51,54). Perivascular cells constitutively express GPP (2) and ultrastructural studies have suggested that these cells are the producers of (pre)capillary AB (52). The role, if any, of perivascular cells in the formation of radial arteriolar Ai3 in HCHWA-D needs further clarification (see above). In vitro studies have suggested that the Dutch mutation has no effect on the secretory cleavage of B I T (31), but that it accelerates amyloid fibril formation (3,47) and increases the stability of the fibrils (8,38). Notably, Dutch vascular amyloid contains both the mutated and the non-mutated An (27). The variant Ai3 putatively acts as a template, converting normal An to an abnormal configuration. HCHWA-D is an autosomal dominant disease of the cerebral vasculature characterized by extensive deposition of Ai3 i n the vessel walls. Furthermore, numerous Ai3-immunoreactive deposits are found in the cortical gray matter. Vascular AB deposition leads to structural changes of the vessels themselves and to reactive changes i n t h e perivascular neuropil. It remains to be elucidated in which way the vascular and neuropil pathology relate to the development of cerebral hemorrhages and infarcts and the clinical picture of stroke and dementia. Although clinicopathological differences exist with other cerebral AP diseases, most importantly with Alzheimer's disease, HCHWA-D may serve as a model t o study i3-amyloidogenesis and in particular the mechanism and consequences of cerebrovascular Ai3 deposition. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Pathology Wiley

Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch type (HCHWA‐D): II ‐ A Review of Histopathological Aspects

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Publisher
Wiley
Copyright
Copyright © 1996 Wiley Subscription Services, Inc., A Wiley Company
ISSN
1015-6305
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1750-3639
DOI
10.1111/j.1750-3639.1996.tb00794.x
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Abstract

From the Departments of Neurology1 and Pathologyz, Leiden University Hospital, and the Department of Neurology3, Rilnland Hospital. Leiderdorp, The Netherlands Cerebral amyloid-R (AR) angiopathy is the histopathological hallmark of hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D). A13 deposits are found mainly in the cerebral and cerebellar meningocortical blood vessels and as plaques throughout the cerebrocortical gray matter. AR deposition in arteries and arterioles starts at the junction of media and adventitia and proceeds t o involve the media causing degeneration of the vascular smooth muscle cells. Cerebrocortical arterioles often show one or t w o layers of radial AR around a layer of homogenous AR that replaces the media. Degenerating neurites, reactive astrocytes and microglial cells may surround cerebrocortical angiopathic arterioles and capillaries, probably in reaction t o invasion of the perivascular neuropil by AR fibrils. Furthermore, clusters of coarse extracelM a r matrix deposits may be found near AS-laden cerebrocortical arterioles. The amyloid-associated proteins, cystatin C and RPP colocalize diffusely , w i t h Dutch vascular AR, whereas HLA-DR immunoreactivity is found only in the periphery of the diseased vessel wall. The latter phenomenon may be related t o the presence of perivascular cells. Angiopathic blood vessels frequently show structural changes. The relation of the described pathology t o the development of hemorrhage, infarction and leukoencephalopathy needs further elucidation. Introduction presence of degenerating neurites, evidenced by synaptophysin, Ai3 precursor protein (BPP), and ubiquitin immunohistochemistry (15,16). Neurofibrillary (NF) degeneration is only observed to a minor degree in the hippocampus and the cerebral, particularly the temporal cortex of some of the older HCHWA-D patients (personal observation). Extracranial localizations of Ai3 have not been demonstrated thus far in HCHWA-D (46). This paper will review histopathological aspects of cerebral amyloid angiopathy (CAA) in HCHWA-D. Distribution and Morphology Cerebral amyloid-i3 (An) angiopathy is the histopathological hallmark of hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D). In addition, diffuse plaques are found in the cerebrocortical gray matter. In particular in older patients, a number of plaques may show congophilia and the Corresponding author: MLC Maat-Schieman MD, Department of Neurology K5Q-116, Leiden University Hospital, Postbox 9600, 2300 RC Leiden, The Netherlands Tel31 (71)5262197 Fax 31 (71) 5248253 Amyloid angiopathy in HCHWA-D preferentially affects the meningocortical blood vessels of the cerebral hemispheres and to a lesser extent of the cerebellum. In advanced cases blood vessels of the hippocampus, basal ganglia and brain stem may be involved as well. As far as studied (46), CAA has not been observed in the spinal cord or its meninges. Ai3 is immunohistochemically demonstrable in arteries, arterioles and veins of the meninges. In the cerebral and cerebellar gray matter Ai3 is localized in the walls of arterioles and in more advanced cases also in capillaries. The superficial course of the perforating cortical arterioles is first affected by A13 deposition. White matter blood vessels are almost consistently spared. The meningeal arteries display focal or circular homogenous AB deposits localized in the outer media at the border with the adventitia. Ai3 deposits are occasionally observed in the arterial adventitia and seem to be distinct from Af3 in the media. Also in Alzheimer’s disease (AD) CAA, arterial and arteriolar Ali deposits are first detectable in the outer part of the media (13, see below). Ultrastructural studies of CAA in AD have demonstrated that Af3 fibrils appear first of all in the abluminal basement membrane of meningeal and cerebrocortical blood vessels (54, see below). Likewise, amyloid fibrils accumulate in this location in HCHWA-D CAA (personal observation). In HCHWA-D meningocortical arterioles, most of or the entire media is usually replaced by homogenous Ai3 (congophilic angiopathy of Pantelakis (22)). Besides, HCHWA-D cerebrocortical arterioles frequently show a ring of radially arranged Af3 around the homogenous Af3 that replaces the media (Fig.1). Foci of radial A13 may again project from this ring. In M.L.C. Maat-Schieman e t al: HCHWA-D: Histopathological Aspects Figure 1. Paraffin section from a patient w i t h HCHWA-D showing an A 3 immunoreactive cortical arteriole with an inner 1 layer of homogenous A 3 and an outer layer of radial A13. x250 1 aged patients a complete second radial layer is sometimes observed. A single layer of radial Ai3 may project from the wall of affected cortical capillaries. Radial A& is virtually absent i n angiopathic meningeal blood vessels or cerebellar cortical arterioles. The occurrence of one or two radial layers of amyloid around homogenous cerebrocortical arteriolar amyloid has been noticed before in not further specified patients with CAA (32,33). Ultrastructural studies showed that the radial layers develop within the confines of the vessel wall, but amyloid fibrils may reach the surrounding neuropil in places where the outermost adventitial collagenous fibers and the parenchymal basement membrane have disappeared (32). Like in AD CAA (13), accumulation of AB in the vascular wall in HCHWA-D is accompanied by degeneration of the smooth muscle cells in the .media, as evidenced by disappearance of a-smooth muscle actin immunoreactivity (Fig. 2a-b). Colocalization with Amyloid-Associated Proteins (Amyloid P-Component, Proteoglycans and Apolipoprotein El, al-Antichymotrypsin, Cystatin C, RPP, and HLA-DR Amyloid P-component (protein AP) and highly sulfated glycosaminoglycans are constituents of all forms of amyloidosis, including AD vascular Al3 (24,25,35-37). They likely play a fundamental, but not yet defined role in amyloidogenesis. Accordingly, HCHWA-D vascular A13 shows irnmunostaining with antibodies against protein AP (40). A t variance with AD vascular An, Dutch vascular amyloid appears t o be unreactive or only weakly reactive with antibodies against t h e basement membrane component heparan sulfate proteoglycan (HSPG) (6). The same pattern was observed for two other basement membrane components, laminin and collagen type IV, suggesting that these extracellular matrix (ECM) compo- nents are present only in low quantities in HCHWAD CAA ( 6 ) .Apolipoprotein E (apoE) immunoreactivity has been found in a variety of amyloids, including HCHWA-D and AD parenchymal and vascular Ai3 (12,49). It has been shown that apoE enhances polymerization of A13 into fibrils in vitro. Of the common isoforms, ApoE-4 has t h e strongest effect in this respect (14,47). Recently, the immunohistochemical colocalization of A13 and cystatin C, reported before in CAA in AD and in SCAA (21,43,44), has been demonstrated in cortical blood vessels of patients with HCHWA-D (10). The presence of cystatin C immunoreactivity i n Al3 laden blood vessels has been correlated with the occurrence of fatal hemorrhage (21). The serine protease inhibitor al-antichymotrypsin (al-ACT), possibly derived from astrocytes, has been identified in the plaque-amyloid of the cerebral Al3 diseases, including HCHWA-D, but not in other chemical types of cerebral amyloid or i n extracerebral amyloid deposits (1,29,26). Like apoE, al-ACT promotes A& fibril formation (14). Conflicting results concerning the presence of alACT in vascular A S have emerged (1,26,28). Rozemuller et al. (28) reported the absence of al-ACT immunostaining in AD vascular A&. It was postulated that the use of fresh-frozen in stead of formalin-fixed tissue may account for t h e difference with other studies (1,26). In HCHWA-D, intense al-ACT immunostaining of vascular amyloid was reported in formalin-fixed tissue (40). Angiopathic blood vessels in HCHWA-D exhibit pronounced diffuse BPP immunoreactivity i n contrast to weak &PP staining of angiopathic vessels in AD (30). Differences i n the process of vascular amyloid formation in HCHWA-D and AD and the severity of the angiopathy in HCHWA-D as compared t o AD have been suggested as possible factors accounting for this difference (30). In contrast t o t h e diffuse immunostaining of Dutch vascular A13 with antibodies against the amyloid-associated proteins, cystatin C, and BPP, immunostaining for class I1 major histocompatibility antigen HLA-DR is found only in the periphery of the wall of a subset of angiopathic cerebrocortical blood vessels (17). It has been suggested that this HLA-DR immunoreactivity reflects activity from perivascular cells in reaction to Al3 fibrils penetrating between the vascular and parenchymal basement membranes. Alternatively, perivascular cells, implicated in AD in the production of Ai3 in (pre)capillaries (52, see below), may have a function in the formation of (HCHWA-D) radial amyloid (17). Perivascular Neuropil Pathology Degenerating neurites as revealed by synaptophysin, BPP, and ubiquitin immunohistochemistry, as well as reactive astrocytes and microglial cells, demonstrated by anti-GFAP antibodies and mono- M.L.C. Maat-Schieman et al: HCHWA-0: Histopathological Aspects Figure 2. Paraffin section from a patient with HCHWA-D showing A 3 immunoreactive meningeal blood vessels (a), which demon1 strate partial to complete loss of a-smooth muscle actin immunoreactivity in an adjacent section (b).x25 cyte/macrophage markers respectively, are present around a subset of cerebrocortical AB-laden blood vessels in HCHWA-D (16 and personal observation). Perivascular neurites showing NF degeneration are encountered in cortical areas with NF tangles (personal observation). Similar neuritic and glial pathology has been observed around angiopathic blood vessels in AD and in sporadic CAA (4,5,19,23). It has been suggested that the perivascular pathology is provoked by amyloid fibrils invading the neuropil after breaching the parenchymal basement membrane (19,23,52). Thus, it appears that neuronal processes degenerate and astrocytes and microglia show reactive changes upon the appearance of amyloid fibrils in the perivascular neuropil. Consequently, one may speculate with respect to the issue of plaque-formation that the presence of degenerating neurites, astrocytes, and microglia in plaques likewise represents a secondary phenomenon. Diffuse AB immunoreactivity may be found, though infrequently, in the neuropil adjacent to angiopathic cerebrocortical arterioles, but dyshoric angiopathy (39), is not a feature of the vascular pathology of HCHWA-D. Recently, ill-defined clusters of coarse deposits showing strong immunoreactivity for several extracellular matrix (ECM) components (HSPG, laminin, collagen type 111 and IV) have been demonstrated in the neuropil in the vicinity of or around a minority of the angiopathic cerebrocortical arterioles (6). The deposits were not spatially associated with AB immunoreactive plaques. Furthermore, they were not observed in control or AD patients. Their site of origin, possibly the perivascular neuropil or the diseased vessel wall, as well as their significance are a matter of speculation. Moreover, the specificity of the coarse deposits for HCHWA-D remains to be established, since none of the control or AD patients in this study had severe CAA (6). Hemorrhages, infarcts, and Leukoencephaiopathy in Relation to Structural Changes of the Blood Vessel Wall Both recent and old hemorrhages and infarcts, the latter either hemorrhagic or not, are characteristically found in the cerebra1 cortex and subcortical white matter in HCHWA-D (?1,46). The meninges may show fresh hemorrhage and hemosiderosis. M.L.C. Maat-Schieman et al: HCHWA-D: Histopathological Aspects Furthermore, the subcortical white matter shows varying degrees of demyelination, axonal loss and gliosis (11). The angiopathic blood vessels frequently show structural changes. These include glomerular formations, double barreling, obliterative fibrous or hyaline intimal thickening, and aneurysmal dilatation. Fibrinoid necrosis of the vascular wall may be present. Perivascular and intramural chronic inflammatory infiltrates are often found. Perivascular multinucleated giant cells are occasionally observed. The walls of angiopathic vessels may show extensive calcification. These findings confirm those reported for CAA in general (20). It has been postulated that hypoperfusion of the deep white matter due t o stenosis of the long perforating arterioles causes the demyelination, axonal loss and gliosis of the subcortical white matter or leukoencephalopathy (9). Furthermore, it has been suggested that severe CAA accompanied by microaneurysm-formation and fibrinoid necrosis must be considered an important factor in the pathogenesis of cerebral hemorrhage (18,45,53). HCHWA-D and the Pathogenesis of CAA Finally, it should be noted that comparative studies of biochemically different cerebral amyloid angiopathies may contribute to the unraveling of the pathogenesis of CAA in general. For instance, degeneration of vascular smooth muscle cells, as observed in AD and HCHWA-D CAA, may not be specifically related t o Ai3 deposition in the cerebral vessel wall, but may also occur as a result of the deposition o f amyloid fibrils composed of variant cystatin C (Acys) or transthyretin (ATTR), both presumably derived from circulating precursors. Furthermore, focal deposits of ATTR (Fig. 1 A in 41), are recognizable in the outer media of meningeal arteries. If the abluminal basement membrane turns out t o be the site of initial A?TR and Acys fibril deposition, the role of the basement membrane in the pathogenesis of cerebrovascular amyloid is not limited to An. Concluding Remarks Several observations have implicated vascular smooth muscle cells in the production of l3PP and Ai3 in arteries and arterioles. For example, immunohistochemical studies have localized BPP t o vascular smooth muscle cells (13,34) and initial A13 deposits in AD meningocortical blood vessels to the abluminal portion of the media (13). The latter phenomenon is also observed in HCHWA-D. In addition, it has been suggested that non-fibrillar An accumulates between and within vascular smooth muscle cells in the early stages of vascular Ai3-formation (7). Furthermore, cultured human vascular smooth muscle cells have been shown to secrete BPP (42). and non-fibrillar and fibrillar Ai3 have been reported to accumulate in canine vascular smooth muscle in culture (48). Lastly, the basement membrane is a product of vascular smooth muscle cells and ultrastructurally A& fibrils appear to arise within that basement membrane in close proximity t o the vascula1 smooth muscle cells (51,54). Perivascular cells constitutively express GPP (2) and ultrastructural studies have suggested that these cells are the producers of (pre)capillary AB (52). The role, if any, of perivascular cells in the formation of radial arteriolar Ai3 in HCHWA-D needs further clarification (see above). In vitro studies have suggested that the Dutch mutation has no effect on the secretory cleavage of B I T (31), but that it accelerates amyloid fibril formation (3,47) and increases the stability of the fibrils (8,38). Notably, Dutch vascular amyloid contains both the mutated and the non-mutated An (27). The variant Ai3 putatively acts as a template, converting normal An to an abnormal configuration. HCHWA-D is an autosomal dominant disease of the cerebral vasculature characterized by extensive deposition of Ai3 i n the vessel walls. Furthermore, numerous Ai3-immunoreactive deposits are found in the cortical gray matter. Vascular AB deposition leads to structural changes of the vessels themselves and to reactive changes i n t h e perivascular neuropil. It remains to be elucidated in which way the vascular and neuropil pathology relate to the development of cerebral hemorrhages and infarcts and the clinical picture of stroke and dementia. Although clinicopathological differences exist with other cerebral AP diseases, most importantly with Alzheimer's disease, HCHWA-D may serve as a model t o study i3-amyloidogenesis and in particular the mechanism and consequences of cerebrovascular Ai3 deposition.

Journal

Brain Pathology – Wiley

Published: Apr 1, 1996

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