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

Clinical and neuropathological findings are reported in 63 patients with hereditary cerebral haemorrhage with amyloid angiopathy. Patients had mostly recurrent strokes, and at least 80% of these were haemorrhages. Almost a third of the 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 cerebellar 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 of plaque 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.     

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.     

Hereditary cerebral hemorrhage with amyloidosis (Dutch): a model for congophilic plaque formation without neurofibrillary pathology

Plaque-like lesions and amyloid angiopathy were investigated in the frontal cerebral cortex of four patients with hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D), using immunohistochemical [antibodies to amyloid protein (A), protein precursor (PP), synaptophysin, ubiquitin (UBQ), cathepsin D, paired helical filaments (PHF) and glial fibrillary acidic protein (GFAP)], enzymehistochemical (acid phosphatase) and silver [methenamine silver (MS) and Palmgren] staining methods. Whereas A-and MS-positive diffuse plaques were found in all patients, only the three older patients showed neuritic or congophilic plaques, which were acid phosphatase and cathepsin D positive and contained PP-, synaptophysin-and UBQ-positive, but PHF-negative neurites. These plaques were surrounded by reactive astrocytes. Similar immuno-and enzymereactivity was found around congophilic blood vessels. Thus, apart from neuronal degeneration in a subset of plaque-like lesions and around blood vessels, this study shows an age-related morphology of the plaques in HCHWA-D, corresponding to that in Down's syndrome (DS), with the difference that neurofibrillary (NF) pathology is absent in HCHWA-D in contrast to DS. HCHWA-D may be considered as a model for congophilic plaque formation not associated with NF pathology.     

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     

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.     

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: 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.     

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.     

血浆N端脑钠肽前体浓度变化与脑出血患者预后的相关分析

目的：探讨血浆N端脑钠肽前体浓度变化与脑出血患者预后的关系。方法选择我院2011-02-2013-02收治的52例脑出血患者的临床资料,并选择本院同期38例健康的体检人员作为对照组,探讨血浆N端脑钠肽前体浓度变化与脑出血患者预后的关系。结果脑出血患者组的NT-proBNP水平均明显高于对照组,且组间差异具有统计学意义（P＜0.05）,且大量出血组患者的血浆 NT-proBNP水平明显高于中量和少量出血组,死亡患者的血浆 NT-proBNP水平达（1688.32±234.98）pg/mL ,明显高于好转组,且组间差异具有统计学意义（P＜0.05）;而在好转的45例患者中,NIHSS评分＞6分的患者其血浆NT-proBNP水平达（677.09±102.34）pg/mL ,明显高于 NIHSS评分≤6分的患者,且差异具有统计学意义（P＜0.05）。结论脑出血患者的血浆NT-proBNP水平明显增高对判断脑出血患者的预后恢复具有十分重要的意义,可作为临床脑出血诊断和治疗的重要参考指标。     

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.     

Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta

Familial Danish dementia (FDD) is pathologically characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal protein deposits, and neurofibrillary degeneration. FDD is associated with a mutation of the BRI2 gene located on chromosome 13. In FDD there is a decamer duplication, which abolishes the normal stop codon, resulting in an extended precursor protein and the release of an amyloidogenic fragment, ADan. The aim of this study was to describe the major neuropathological changes in FDD and to assess the distribution of ADan lesions, neurofibrillary pathology, glial, and microglial response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non-fibrillary) lesions was found. Abeta was also present in a proportion of both vascular and parenchymal lesions. There was severe neurofibrillary pathology, and tau immunoblotting revealed a triplet electrophoretic migration pattern comparable with PHF-tau. FDD is a novel form of CNS amyloidosis with extensive neurofibrillary degeneration occurring with parenchymal, predominantly pre-amyloid rather than amyloid, deposition. These findings support the notion that parenchymal amyloid fibril formation is not a prerequisite for the development of neurofibrillary tangles. The significance of concurrent ADan and Abeta deposition in FDD is under further investigation.     

载脂蛋白E基因和脑血管淀粉样变在高血压脑出血中的作用

目的研究载脂蛋白E基因(APOE)与脑血管淀粉样变(CAA)在高血压脑出血(HICH)中的作用。方法随机收集HICH患者236例,其中行手术治疗的108例;采用聚合酶链反应限制性片段长度多态性法(PCRRFLP)检测所有研究对象的APOE基因型;比较两组临床特征、APOE基因型及等位基因频率分布的差异;并进一步分析手术组中发生脑血管淀粉样变与临床特征、APOE基因型及等位基因频率相关因素的关系。结果 HICH组与手术组在临床特征、等位基因及基因型分布上均无统计学差异。108例进行了手术治疗的HICH患者当中,有28例发生脑血管淀粉样改变。CAA(+)的患者发生浅部出血的比例明显高于CAA(-)的患者。CAA(+)的患者中APOEε3/4基因型及APOEε4等位基因的比例明显高于CAA(-)患者,且单因素和多因素Logistic回归分析均发现APOEε4是HICH患者发生CAA的危险因素。结论 APOEε3/4基因型和APOEε4等位基因可能是HICH发生的危险因素,也是HICH患者发生CAA的危险因素;APOE可能通过对CAA的发生和发展产生影响,进而对HIGH的发生产生作用。     

Hereditary cystatin C (γ-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage

Hereditary CNS amyloid angiopathy occurring in Icelanders is the first human disorder known to be caused by deposition of cystatin C amyloid fibrils in the walls of the brain arteries leading to single or or multiple strokes with fatal outcome. One or more affected members have been verified by histological examination in 8 families containing 127 affected. These originated from the same geographic area. Abnormally low value of cystatin C found in the cerebrospinal fluid of those affected can be used to support or make diagnosis of this disease, also in asymptomatic relatives. By amino acid sequence analysis the amyloid fibrils in the patients are found to be a variant of cystatin C (gamma-trace), a major cysteine proteinase inhibitor. The variant protein has an amino acid substitution (glutamine for leucine) at position 58 in the amyloid molecule. It is postulated that a point mutation has occurred leading to production of amyloidogenic protein causing the disorder.     

Hereditary cerebellar atrophy (Holmes type) with optic atrophy

Summary A family with a dominantly inherited progressive cerebellar ataxia is described; four members of successive generations were affected. Neuropathological examination of one family member classified this disorder as hereditary cerebellar atrophy of Holmes type. An associated optic atrophy has not been previously reported in this disease.     

Familial British dementia (FBD): a cerebral amyloidosis with systemic amyloid deposition

Introduction:  FBD is an autosomal dominant disease with neuropathological similarities to Alzheimer's disease (AD) as it is characterized by amyloid angiopathy, parenchymal amyloid plaque deposition and neurofibrillary degeneration. FBD is associated with a stop codon mutation in the BRI2 gene encoding a type II transmembrane protein, BriPP. Mutation results in an extended precursor protein, ABriPP, from which a C-terminal 34 amino acid peptide (ABri) is generated by furin-like proteolytic cleavage and deposited as amyloid and preamyloid in the central nervous system. Despite the morphological parallels with AD the sequences of the amyloidogenic peptides, ABri in FBD and Aβ in AD, are completely different. We examined systemic tissues in FBD for ABri deposition.
Materials and methods:  Immunohistochemistry using an ABri-specific antibody, Ab338, counterstained with Thioflavin S and Ab338 immuno-electron microscopy identified ABri deposits and determined whether these were amyloid or preamyloid in nature.
Results:  Amyloid bearing blood vessels stained positively for ABri in myocardium, uterus, bladder, spleen, pancreas, lung and skeletal muscle. ABri was also identified in either amyloid or preamyloid conformation in the parenchyma of myocardium, adrenal, pancreas and skeletal muscle.
Conclusion:  This study demonstrates that FBD is the first described cerebral amyloidosis with neurofibrillary pathology and dementia to be accompanied by systemic amyloid deposition.     

Two Dutch siblings with congenital muscular dystrophy (Fukuyama type)

Two Dutch siblings are described suffering from muscular weakness, hypotonia, severe joint contractures, mental retardation and epileptic fits. E.M.G. showed a characteristic myopathic pattern. Muscle biopsy revealed changes consistent with congenital muscular dystrophy. On CT marked hypodensities of the cerebral white matter were noticed. These findings are consistent with congenital muscular dystrophy of the Fukuyama type, a peculiar form of congenital muscular dystrophy, extremely rare outside Japan.     

Hereditary gelsolin amyloidosis (HGA): a neglected cause of bilateral progressive or recurrent facial palsy

We report the first Italian family affected by hereditary gelsolin amyloidosis (HGA), a rare autosomal dominant disease characterized by adult‐onset slowly progressive cranial neuropathy, lattice corneal dystrophy, and cutis laxa. The index case was a 39‐year‐old male with a 9‐year history of progressive bilateral facial nerve palsy. His mother had two episodes of acute facial palsy, and his maternal aunt and grandfather were also affected. Electrophysiological studies confirmed bilateral facial nerve involvement, without signs of peripheral polyneuropathy, and ophthalmological examination showed bilateral lattice corneal dystrophy, in both the index case and his mother. Gelsolin‐gene sequencing revealed the heterozygous c.640G>A mutation (p.Asp187Asn) in the proband, his mother and aunt and also in three apparently asymptomatic relatives. The majority of HGA patients come from Finland, although several cases have been reported from other countries. HGA should be considered in the differential diagnosis of progressive or recurrent bilateral facial neuropathy.     

Co-localization of β/A4 and cystatin C in cortical blood vessels in Dutch, but not in Icelandic hereditary cerebral hemorrhage with amyloidosis

Based on the recent discovery of co-localization of β/A4 and cystatin C in cortical blood vessels of patients with cerebral hemorrhages due to sporadic amyloid angiopathy and patients with Alzheimer's disease we investigated the presence of these two proteins in the cortical blood vessels of patients suffering from hereditary cerebral hemorrhage with amyioidosis of the Dutch (n = 11) and the Icelandic (n = 2) type. The brains of three patients with sporadic cerebral amyloid angiopathy were also investigated. Blood vessels of the Dutch patients clearly showed immunostaining with β/A4 as well as with cystatin C antibodies, whereas the blood vessels of Icelandic patients showed only staining with cystatin C. In one of the three sporadic amyloid angiopathy patients co-localization was shown as well. The co-localization of mutated β/A4 with normal cystatin C in the Dutch patients suggests that cystatin C deposition occurs secondarily to β/A4 deposition. This is probably also the case in sporadic amyloid angiopathy and Alzheimer's disease. Cystatin C deposition may play a role in the development of cerebral hemorrhages and leukoencephalopathy.     

Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation

The contribution of mutations in the amyloid precursor protein (APP) gene known as Flemish (APP/A692G) and Dutch (APP/E693Q) to the pathogenesis of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type, respectively, was studied in transgenic mice that overexpress the mutant APP in brain. These transgenic mice showed the same early behavioral disturbances and defects and increased premature death as the APP/London (APP V717I), APP/Swedish (K670N, M671L), and other APP transgenic mice described previously. Pathological changes included intense glial reaction, extensive microspongiosis in the white matter, and apoptotic neurons in select areas of the brain, while amyloid deposits were absent, even in mice over 18 months of age. This contrasts with extensive amyloid deposition in APP/London transgenic mice and less pronounced amyloid deposition in APP/Swedish transgenic mice generated identically. It demonstrated, however, that the behavioral deficiencies and the pathological changes in brain resulting from an impaired neuronal function are caused directly by APP or its proteolytic derivative(s). These accelerate or impinge on the normal process of aging and amyloid deposits per se are not essential for this phenotype.