Microbleeds in hereditary cerebral hemorrhage with amyloidosis-Dutch type

In a hereditary variant of cerebral amyloid angiopathy (CAA), cerebral hemorrhage with amyloidosis-Dutch type, supratentorial microbleeds were found to occur independently of the presence of hypertension, whereas hypertension probably contributed to the development of cerebellar microbleeds. This predictable hereditary variant of CAA may be a useful model to study microbleeds in relation to CAA.     

Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles.

Cerebral amyloid angiopathy is frequently found in demented and nondemented elderly persons, but its contribution to the causation of dementia is unknown. Therefore, we investigated the relation between the amount of cerebral amyloid angiopathy and the presence of dementia in 19 patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type. The advantage of studying hereditary cerebral hemorrhage in amyloidosis-Dutch type is that patients with this disease consistently have severe cerebral amyloid angiopathy with minimal neurofibrillary pathology. The amount of cerebral amyloid angiopathy, as quantified by computerized morphometry, was strongly associated with the presence of dementia independent of neurofibrillary pathology, plaque density, or age. The number of cortical amyloid beta-laden severely stenotic vessels, vessel-within-vessel configurations, and cerebral amyloid angiopathy-associated microvasculopathies was associated with the amount of cerebral amyloid angiopathy and dementia. A semiquantitative score, based on the number of amyloid beta-laden severely stenotic vessels, completely separated demented from nondemented patients. These results suggest that extensive (more than 15 amyloid beta-laden severely stenotic vessels in five frontal cortical sections) cerebral amyloid angiopathy alone is sufficient to cause dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type. This may have implications for clinicopathological correlations in Alzheimer's disease and other dementias with cerebral amyloid angiopathy.     

Hereditary cerebral hemorrhage with amyloidosis-Dutch type: a study of fibrinolysis.

In view of reported associations between increased bleeding tendency and systemically decreased alpha 2-antiplasmin in patients with systemic amyloid deposition we studied alpha 2-antiplasmin, fibrinogen, C-reactive protein and blood levels of locally produced endothelial hemostasis factors in the acute and quiescent phase in 16 patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). None of the factors measured in the quiescent phase of the disease was abnormal. In the acute phase, shortly after a stroke, only factor VIII:Ag was evidently elevated. We concluded that systemic abnormalities in the part of the fibrinolysis system studied are not likely to be responsible for multifocal and recurrent cerebral hemorrhages in HCHWA-D. The role of an elevated factor VIII:Ag level in the acute phase is unclear.     

Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type share a decrease in cerebrospinal fluid levels of amyloid beta-protein precursor.

The amyloid beta-protein is a 39-42 amino acid peptide that is deposited in senile plaques and in cerebral vessel walls in individuals with Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and, to a much lesser extent, normal aging. It is derived from abnormal proteolytic processing of its parent protein, the amyloid beta-protein precursor. Here we show that individuals with the HCHWA-D mutation and clinically manifesting the disease have markedly decreased cerebrospinal fluid levels of soluble amyloid beta-protein precursor (0.7 +/- 0.4 micrograms/ml) compared with age-matched normal subjects (3.0 +/- 0.2 micrograms/ml) as determined by quantitative immunoblotting and enzyme-linked immunosorbent assays. Similarly, age-matched patients diagnosed with probable Alzheimer's disease also have decreased cerebrospinal fluid levels of soluble amyloid beta-protein precursor (1.0 +/- 0.3 micrograms/ml). These parallel findings suggest a common biochemical marker for these two diseases and further establish the pathogenic relatedness of HCHWA-D and Alzheimer's disease.     

Hereditary cerebral hemorrhage with amyloidosis-Dutch type. Clinical and computed tomographic analysis of 24 cases

Clinical and computed tomographic findings in 24 patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type were reviewed. The common initial symptoms were headache and vomiting. Computed tomographic scans showed 50 hypodense and 49 hyperdense cortical lesions and in 20 patients the scans also showed generalized white matter hypodensity. Impairment of consciousness was related to the size of the hemorrhagic lesion. Dementia, seen in 11 patients, was related to the duration of the disease and the number of focal lesions on the computed tomographic scans, but not to the presence of white matter hypodensity. It is concluded that in hereditary cerebral hemorrhage with amyloidosis-Dutch type, lobar hemorrhages account predominantly for the acute clinical syndromes. The hemorrhages often have an irregular shape and are responsible for progression of the symptoms after an acute onset. Furthermore, cerebral amyloid angiopathy leads to a generalized abnormality of the white matter, probably due to chronic hypoperfusion.     

Amyloid beta protein (Abeta) starts to deposit as plasma membrane-bound form in diffuse plaques of brains from hereditary cerebral hemorrhage with amyloidosis-Dutch type, Alzheimer disease and nondemented aged subjects

To clarify where and how beta-amyloid begins to deposit in senile plaques, we examined the ultrastructural localization of amyloid beta protein (Abeta) in diffuse plaques of brains with hereditary cerebral hemorrhage with amyloidosis-Dutch type. Alzheimer disease (AD), and from nondemented aged subjects. Serial ultrathin sections of osmium-plastic blocks were immunogold-labeled for Abetax-42 (Abeta42), and sections on grids were observed under the electron microscope (EM) after observing the exact localization of the diffuse plaques in sections on glass slides by the reflection contrast microscope. Abeta42 deposition, which was decollated with gold particles, appeared in 3 forms in all subjects under the EM: 1) Scattered small bundles of amyloid fibrils between cell processes, frequently seen in the densely stained area of diffuse plaques. 2) Scattered small foci of nonfibrillar materials between cell processes as a relatively minor form. 3) Abeta42 on a part of the cell surface plasma membrane of normal appearing cell processes, a major form in weakly immunostained areas. The last form was not associated with degenerative neurites or reactive glia. Abeta42 deposition on the cell surface plasma membrane appears to be an initial event in diffuse plaques, and then it develops into amorphous/fibrillar amyloid between cell processes.     

Morphology of cerebral plaque-like lesions in hereditary cerebral hemorrhage with amyloidosis (Dutch)

Summary We studied the presence and morphology of plaque-like lesions in the frontal cortex of six patients, aged 40 to 76 years, with hereditary cerebral hemorrhage with amyloidosis — Dutch type (HCHWA-D), using /A4 immuno-, silver, Congo red and thioflavin S staining. Two types of /A4 immunoreactive and Congo red-negative plaques were detected. The first type was composed of argyrophilic fibrous material in periodic acid-methenamine silver (PAM) and modified Bielschowsky staining and lacked silver-stained degenerating neurites. Therefore, this type of plaque has the same staining properties as the diffuse plaque described in Alzheimer's disease, Down's syndrome and nondemented elderly. The second type of plaque, occurring only in the three oldest patients and numerically increasing with age, consisted of a spherical non-argyrophilic area of granular texture with a rim of PAM-positive material. The PAM-positive fibrous material of both types of plaques was mingled with coarser and compact, irregular-shaped argyrophilic structures in the oldest patient. The described plaques did not show bright fluorescence with thioflavin S staining. These results indicate, that the morphology of plaques, encountered in HCHWA-D, is diverse and changes with age.No reprints available     

Progressive dementia, without cerebral hemorrhage, in a patient with hereditary cerebral amyloid angiopathy

A now 58-year-old female patient, carrier of the point-mutation in the β-amyloid gene on chromosome 21 which causes hereditary cerebral hemorrhage with amyloidosis — Dutch type, developed progressive dementia after the age of 55 years. She never suffered from a cerebral hemorrhage. Dementia has been described as a feature of hereditary amyloid angiopathy before, but only in patients who also suffer from strokes. The clinical manifestation of the patient described here underlines the relation between the Dutch type of hereditary amyloid angiopathy and (familial) Alzheimer's disease.     

Secondary microvascular degeneration in amyloid angiopathy of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D)

Various secondary microvascular degenerative and inflammatory alterations may complicate cerebral amyloid angiopathy (CAA) and contribute to the morbidity of CAA-associated stroke. We have investigated the severity of CAA-associated microangiopathy in a genetically determined Dutch form of CAA (HCHWA-D) that has major similarities to the type of CAA that more commonly occurs with aging or Alzheimer’s disease (AD). The presence and extent of the following vascular abnormalities was assessed: (1) hyalinization/fibrosis, (2) microaneurysm formation, (3) chronic (especially lymphocytic) inflammation, (4) perivascular multinucleated giant cells/granulomatous angiitis, (5) macrophages/histiocytes within the vessel wall, (6) vessel wall calcification, (7) fibrinoid necrosis, and (8) mural or occlusive thrombi. (Of these, calcification of CAA-affected vessel walls has, to our knowledge, been described in only a single patient with CAA-associated cerebral hemorrhage.) Some of the changes, such as histiocytes in blood vessel walls and the relationship of vascular hyalinosis to amyloid β/A4 protein deposition, were highlighted by immunohistochemistry. By assessing the numbers of sections in which the changes were present for each case, a ‘score’ reflective of CAA-associated angiopathy could be obtained. This ‘score’ was reproducible among several observers. We suggest that it might also be applicable to quantifying severe CAA and related microvascular degenerative changes in patients with AD. β/A4 immunoreactivity was often sparse and adventitial (or almost absent) in severely hyalinized arterioles and microaneurysms. However, macrophages were prominent in the walls of such vessels and may play a role in the pathogenesis and progression of CAA-related microvasculopathy. Received: 18 June 1997 / Revised, accepted: 22 September 1997     

Hereditary cerebral hemorrhage with amyloidosis‐Dutch type

The amyloid β‐protein (Aβ) 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 Aβ production but may alter the Aβ1–42:Aβ1–40 ratio, and affect the proteolytic degradation of Aβ and its transport across the blood–brain barrier. Aβ E22Q aggregates faster into more stable amyloid‐like fibrils than wild‐type Aβ. Non‐fibrillar Aβ(x‐42) deposits precede the appearance of fibrils and the deposition of Aβ(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 Aβ deposition is also enhanced in the HCHWA‐D brain with non‐fibrillar membrane‐bound Aβ(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 Aβ‐related factors for cognitive deterioration in HCHWA‐D remains to be determined.     

Fatal hemorrhage in a cerebral pilocytic astrocytoma-adult type

Summary A 69-year-old female presented with a 6-week history of left-sided weakness and a large cerebral mass on computed tomographic scan and magnetic resonance imaging. The patient subsequently had an acute intracerebral hemorrhage with uncal and tonsillar herniation. Postmortem examination revealed an acute cerebral hemorrhage from a pilocytic astrocytoma-adult type. These cerebral neoplasms are rarely associated with hemorrhage.     

Cerebral vascular accumulation of Dutch-type Abeta42, but not wild-type Abeta42, in hereditary cerebral hemorrhage with amyloidosis, Dutch type

Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is an autosomal dominant disorder caused by the Dutch mutation (E693Q) in the beta-amyloid precursor protein. This mutation produces an aberrant amyloid beta (Abeta) species (AbetaE22Q) and causes severe meningocortical vascular Abeta deposition. We analyzed the Abeta composition of the vascular amyloid in the brains of HCHWA-D patients. Immunohistochemistry demonstrated that the vascular amyloid contained both Abeta40 and Abeta42, with a high Abeta40/Abeta42 ratio. In Western blotting of cerebral microvessel fractions isolated from the brains, both wild-type and Dutch-type Abeta40 were observed as major species. Reverse-phase HPLC-mass spectrometric analysis of the fractions revealed both wild-type and Dutch-type Abeta38 as the other main components of the vascular amyloid. Moreover, we detected peaks corresponding to Dutch-type Abeta42 but not to wild-type Abeta42. These results suggest a pathogenic role for the mutant Abeta42 in addition to the mutant Abeta40 in the cerebral amyloid angiopathy of HCHWA-D.     

Cerebrovascular amyloidosis with cerebral hemorrhage

Summary More than 1400 necropsies performed on patients with either a non-traumatic cerebral hemorrhage (400 cases) or with dementia over the age of 55 (1010 cases), or both, have been reviewed. There were 15 cases in which a cerebral hemorrhage had occurred together with cerebral amyloid angiopathy all of whom had been demented. Eight of the 15 patients were hypertensive. The 7 non-hypertensives showing only the amyloid change included two cases of atypical Alzheimer's disease with acute neurological features, and 5 cases of senile dementia (aged 72 to 78 years) coupled with focal neurological disorders. In the hypertensive patients, aged 67 to 86 years, with a progressive dementing syndrome and acute neurological signs, multiple ball-like hemorrhages (7 cases) and/or cerebral hematomas (3 cases) were associated with a combination of amyloid and hyalinar (hypertensive) angiopathy, often affecting segments of the same pial and cortical vessels. From these data and recent reports on lethal cerebral hemorrhage occurring spontaneously or after neurosurgical procedures in demented old people, cerebral amyloid angiopathy, which is not necessarily associated with systemic amyloidosis or severe (pre)senile cerebral degeneration, may be considered a rare but important cause of cerebral hemorrhage in the aged. The vascular type of presenile dementia, occasionally complicated by focal cerebrovascular lesions or bleeds, is considered a variant of Alzheimer's disease. The mechanism leading to formation of cerebral amyloid is unknown.Dedicated to Prf. St. Környey on the occasion of his 75th anniversary     

高血压脑出血手术时间及方式对手术效果的影响

目的观察高血压脑出血手术时间及方式对手术治疗效果的影响。方法 120例高血压脑出血患者根据手术时间、手术方式不同分为观察组和对照组,观察组接受超早期微创血肿清除术,对照组接受延期开颅血肿清除术,比较2组手术情况、炎症应激指标以及神经功能恢复情况。结果观察组手术时间、术中出血量、术后意识恢复时间、术后引流量、住院总时间、ACTH、Cor、NE、CRP、TNF-α、CSS评分、NIHSS评分均明显低于对照组(P0.05)。结论超早期微创血肿清除术有助于减小手术创伤,促进术后恢复,缓解炎症应激反应,改善神经功能,是高血压脑出血理想的手术方式。     

Immunohistochemical characterization of the amyloid deposits and quantitation of pertinent cerebrospinal fluid proteins in hereditary cerebral hemorrhage with amyloidosis

Cystatin C, a protein inhibitor of lysosomal cysteine proteinases, was demonstrated by immunohistochemical techniques to be present in the birefringent amyloid deposits of the small arteries in the cerebrum, cerebellum, and leptomeninges of 10 Icelandic individuals with hereditary cerebral hemorrhage with amyloidosis. Specimens from other organs were investigated in one of the patients, and amyloid angiopathy characterized by an immunoreactivity of cystatin C was found in a submandibular lymph node. No immunoreactivity of amyloid fibril protein AA, kappa or lambda immunoglobulin light chain, or prealbumin was observed. Significantly low cerebrospinal fluid concentrations of cystatin C were found in all 9 investigated individuals with hereditary cerebral hemorrhage with amyloidosis. The concentrations of beta 2-microglobulin, albumin, and IgG in the cerebrospinal fluid were within normal limits. Isoelectric focusing showed that cystatin C from the cerebrospinal fluid of 9 patients with hereditary cerebral hemorrhage with amyloidosis had an isoelectric point identical to that of normal individuals. This investigation demonstrates that hereditary cerebral hemorrhage with amyloidosis may be diagnosed by two laboratory methods: immunohistochemical investigation of cystatin C in brain tissue specimens and quantitation of cystatin C in cerebrospinal fluid.     

Hereditary cerebral hemorrhage with amyloidosis--Dutch type: its importance for Alzheimer research.

Alzheimer's disease is now commonly regarded as a form of 'amyloid encephalopathy'. Amyloid deposits in the cerebral blood vessels and parenchyma consist mainly of a unique protein called amyloid beta protein (A beta P), which has a molecular weight of 4 kDa and is 42 amino acids long. These deposits are thought to be of pathogenetic importance in Alzheimer's disease. Recently, therefore, attention has been focused on the process of turnover of the precursor of A beta P to amyloid fibrils, and the deposition and persistence of A beta P in this disease. The study of several other diseases with cerebral A beta P deposition can be informative in this respect, because they allow the comparison of different pathogenetic mechanisms that lead to this type of deposition. One of these diseases is hereditary cerebral hemorrhage with amyloidosis- Dutch type (HCHWA-D), which is the subject of this review.