Immunohistochemical study of cerebral amyloid angiopathy. II. Enhancement of immunostaining using formic acid pretreatment of tissue sections.

Cerebral amyloid angiopathy (CAA) is a biochemically heterogeneous entity most commonly associated with stroke syndromes, Alzheimer's disease (AD), Down's syndrome, and miscellaneous neurologic conditions. The authors have applied and extended (using formic acid pretreatment of histologic sections) an immunocytochemical technique that used antibody to a synthetic 28-amino acid peptide representing a segment of the AD amyloid precursor, to study CAA and related parenchymal amyloid deposits in brain tissues originally derived from: 1) patients with CAA with or without typical clinicopathologic features of AD, cerebral hemorrhage, and infarcts; 2) a young boy with angiocentric brain amyloid; 3) patients with familial (Icelandic, Dutch) forms of cerebral hemorrhage caused by CAA; and 4) Japanese patients with nonfamilial CAA-related brain hemorrhage, sometimes associated with histopathology characteristic of AD. Formic acid pretreatment of sections resulted in markedly enhanced staining of senile plaque core and microvascular, especially capillary, amyloid, and some apparent staining of the neuritic component of senile plaques. Perivascular halos of immunoreactive material were observed frequently. Neurofibrillary tangles were not immunolabeled, nor were blood vessels or any parenchymal components within cerebral white matter. CAA in Japanese patients with nonfamilial encephalic hemorrhages appeared immunocytochemically identical to AD-related CAA. Arterioles in brains that had severe CAA frequently showed significant stenosis of their lumina by nonamyloid hyaline or cellular material.     

Sporadic and familial cerebral amyloid angiopathies

Cerebral amyloid angiopathy (CAA) is the term used to describe deposition of amyloid in the walls of arteries, arterioles and, less often, capillaries and veins of the central nervous system. CAAs are an important cause of cerebral hemorrhage and may also result in ischemic lesions and dementia. A number of amyloid proteins are known to cause CAA. The most common sporadic CAA, caused by A beta deposition, is associated with aging and is a common feature of Alzheimer disease (AD). CAA occurs in several familial conditions, including hereditary cerebral hemorrhage with amyloidosis of Icelandic type caused by deposition of mutant cystatin C, hereditary cerebral hemorrhage with amyloidosis Dutch type and familial AD with deposition of either A beta variants or wild-type A beta, the transthyretin-related meningo-vascular amyloidoses, gelsolin as well as familial prion disease-related CAAs and the recently described BRI2 gene-related CAAs in familial British dementia and familial Danish dementia. This review focuses on the morphological, biochemical, and genetic aspects as well as the clinical significance of CAAs with special emphasis on the BRI2 gene-related cerebrovascular amyloidoses. We also discuss data relevant to the pathomechanism of the different forms of CAA with an emphasis on the most common A beta-related types.     

Subcortical vascular dementia

Subcortical vascular dementia (SVD) is a small vessel disease with dementia that exhibits relatively uniform clinical and pathological features and constitutes approximately half of vascular dementia (VaD) cases. This subtype is further classified into Binswanger's disease and multiple lacunar infarctions. The former is characterized by diffuse white matter lesions, and the latter is characterized by lacunar infarctions. Both of these entities are related to hypertensive small vessel changes. Subcortical vascular dementia may exhibit slowly progressive vascular Parkinsonism and dementia but can be differentiated from Alzheimer's disease because it is associated with more extensive white matter lesions, less severe hippocampal atrophy and the absence of cerebral amyloid angiopathy (CAA), which may be indicated radiologically by lobar microbleeds, cortical subarachnoid hemorrhage (SAH) and cortical microinfarctions. Cerebral amyloid angiopathy may manifest as dementia and constitute the cortical type counterpart of SVD in small vessel disease with dementia.This paper provides an overview of the clinical features, pathogenesis and treatment for SVD, as well as its relationship to CAA and Alzheimer's disease.     

Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis

The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.     

皮质下缺血性脑血管病的磁共振波谱研究

目的:检测皮质下缺血性脑血管病(SIVD)患者和正常对照组不同脑区脑组织的代谢水平,探讨其与认知功能损害的关系。方法:采用多体素磁共振波谱(1 H-MRS)技术评测SIVD患者(SIVD组,n=32例)和体检健康人(对照组,n=21)额叶及顶叶皮质、白质的代谢物N-乙酰天门冬氨酸(NAA)、胆碱(Cho)、肌酸(Cr);计算有关比值NAA/Cr、Cho/Cr,分析有无认知功能损害SIVD患者上述比值的变化。结果:(1)SIVD组额叶皮质、白质及顶叶皮质、白质各体素NAA/Cr比值明显低于对照组(P0.01);(2)SIVD组顶叶皮质及白质的Cho/Cr比值明显高于对照组(P0.01);(3)SIVD组有认知功能损害患者的额叶皮质和顶叶皮质、白质NAA/Cr比值显著低于无认知功能损害者(P值分别0.01、0.01、0.05),Cho/Cr比值的两者间差异无统计学意义(P0.05)。结论:SIVD患者脑组织存在NAA/Cr、Cho/Cr比值改变,且额叶皮质和顶叶皮质、白质NAA/Cr的下降与认知损害有关。     

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology.     

Cerebral amyloid angiopathy: major contributor or decorative response to Alzheimer's disease pathogenesis

Amyloid deposition within cerebral vessels, or cerebral amyloid angiopathy (CAA), is common in advanced age and even more common in Alzheimer's disease. CAA may be complicated by lobar intracerebral hemorrhage, while rare kindreds of autosomal dominant CAA also show propensity for intracerebral hemorrhage, due to germline mutations in specific amyloidogenic precursor proteins and apparent compromise of structural integrity of the blood vessel wall due to marked amyloid deposition. The relationship between cerebral amyloid angiopathy and cognitive dysfunction, however, is less clear. While cognitive dysfunction in familial CAA is likely related to prodigious amyloid deposits and vascular luminal compromise (e.g., hereditary cerebral hemorrhage with angiopathy-Dutch type (HCHWA-D)), cerebral amyloid angiopathy with intracerebral hemorrhage often presents sporadically in cognitively intact elderly patients. Moreover, while about 80% of subjects with Alzheimer's disease have demonstrable amyloid beta within blood vessel walls at autopsy, the vast majority of these fail to suffer clinically relevant intracerebral hemorrhage during life. The remaining 20% manage to progress and die of their disease with virtual no amyloid within blood vessels. Thus, the role of amyloid beta deposits in cerebral vessels as regards cognitive function on the one hand, and tendency for hemorrhage on the other, remain to be resolved for sporadic late onset Alzheimer's disease and CAA. Recent studies on transgenic APP23 mice suggest a relationship between passive immunization and amyloid angiopathy-associated cerebral hemorrhage, although the mechanism of hemorrhage was unclear from the data presented. We suggest that amyloid accumulation represents a response to chronic stress, and that the neurodegenerative process occurs at the neuronal level, encompassing oxidative stress and aberrant cell cycle activation. As such, CAA represents tissue homeostasis, such that an abrupt perturbation of this balance (e.g., amyloid beta immunization) is deleterious.     

Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations

Pigmented orthochromatic leukodystrophy and hereditary diffuse leukoencephalopathy with spheroids are two adult onset leukodystrophies with neuroaxonal spheroids presenting with prominent neurobehavioral, cognitive and motor symptoms. These are familial or sporadic disorders characterized by cerebral white matter degeneration including myelin and axonal loss, gliosis, macrophages and axonal spheroids. We report clinical, neuroimaging and pathological correlations of four women ages 34–50 years with adult onset leukodystrophy. Their disease course ranged from 1.5–8 years. Three patients had progressive cognitive and behavioral changes; however, one had acute onset. Neuroimaging revealed white matter abnormalities characterized by symmetric, bilateral, T2 hyperintense and T1 hypointense Magnetic Resonance Imaging signal involving frontal lobe white matter in all patients. Extensive laboratory investigations were negative apart from abnormalities in some mitochondrial enzymes and immunologic parameters. Autopsies demonstrated severe leukodystrophy with myelin and axonal loss, axonal spheroids and macrophages with early and severe frontal white matter involvement. The extent and degree of changes outside the frontal lobe appeared to correlate with disease duration. The prominent neurobehavioral deficits and frontal white matter disease provide clinical-pathologic support for association pathways linking distributed neural circuits sub-serving cognition. These observations lend further support to the notion that white matter disease alone can account for dementia.     

Osteopontin and phospho‐SMAD2/3 are associated with calcification of vessels in D‐CAA,an hereditary cerebral amyloid angiopathy

In severe forms of cerebral amyloid angiopathy (CAA) pathology, vascular calcification has been observed in the cerebral cortex, both in vivo on MRI and CT, and post‐mortem using histopathology. However, the pathomechanisms leading to calcification of CAA‐laden arteries are unknown. Therefore, we investigated the correlation between calcification of cortical arterioles and several potential modulators of vascular calcification using immunohistochemistry in a unique collection of brain material of patients with a hereditary form of CAA, namely hereditary cerebral hemorrhage with amyloidosis‐Dutch type (HCHWA‐D or D‐CAA). We show a topographical association of osteopontin (OPN) and TGFβ signaling factor phospho‐SMAD2/3 (pSMAD2/3) in calcified CAA vessel walls. OPN and pSMAD2/3 gradually accumulate in vessels prior to calcification. Moreover, we found that the vascular accumulation of Collagen 1 (Col1), OPN and pSMAD2/3 immunomarkers correlated with the CAA severity. This was independently of the vessel size, including capillaries in the most severe cases. We propose that calcification of CAA vessels in the observed HCHWA‐D cases may be induced by extracellular OPN trapped in the fibrotic Col1 vessel wall, independently of the presence of vascular amyloid.     

Hippocampal volume is an independent predictor of cognitive performance in CADASIL

Recent evidence suggests that hippocampal changes are present in vascular cognitive impairment but their importance and relationship with ischaemic mechanisms remain controversial. To investigate these issues we performed MRI and cognitive assessment in a large cohort (n=144) of patients with CADASIL, a hereditary small vessel disease and model of pure vascular cognitive impairment. Dementia status was ascribed according to DSM-IV and global cognitive function assessed with the Minimental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS). Hippocampal volume (HV) correlated with age (r=-0.33, p<0.001), brain volume (r=0.39, p<0.001) and lacunar lesion volume (r=-0.23, p=0.008), but not white matter lesions or microhaemorrhages. HV was reduced in dementia (2272+/-333 mm(3) versus 2642+/-349 mm(3), p<0.001) in the whole cohort and the subgroup progressing to dementia before age 60. HV correlated with MMSE (r=0.30, p<0.001), MDRS (r=0.40, p<0.001) and in a multivariate model predicted cognition independent of typical vascular lesions and whole brain atrophy. These findings strengthen the view that hippocampal atrophy is an important pathway of cognitive impairment in vascular as well as degenerative disease.     

Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease.

The presence of apolipoprotein E-epsilon4 (APOE-epsilon4) allele has been implicated as a risk factor for Alzheimer's disease (AD). We examined the frequencies of APOE-epsilon4 alleles in age-matched controls and subgroups of 190 AD subjects exhibited cerebral amyloid angiopathy (CAA) and other frequently associated lesions. CAA was evident in 96% of the AD subjects, which were divided into two groups, one bearing mild or no apparent CAA and the other with moderate to severe CAA. APOE-epsilon4 allele frequency (48%) in the latter advanced CAA group was six times higher than in those who exhibited mild CAA. In the advanced CAA subjects, the occurrence of an epsilon4 allele was increased by a factor of 17 (95% confidence interval, 7.56 to 38.9). This was despite the fact that neocortical amyloid-beta plaque densities in the two groups were similar and that all of the AD subjects had met the accepted neuropathological criteria. We also observed that the degree of CAA severity was greatest in the group of subjects with the epsilon4/epsilon4 genotype. The association between CAA and APOE-epsilon4 was further implicated in two non-AD subjects among neurological controls with severe CAA. These two subjects, both homozygous for the APOE-epsilon4 allele, were primarily diagnosed as having Creutzfeldt-Jakob disease and Pick's disease in the absence of significant neocortical amyloid deposition. Allele frequency comparisons between neurological control subjects with CAA and those without likewise accorded a strong relationship between the APOE-epsilon4 allele and the presence of CAA. More remarkably, the epsilon4 allele frequency was highly associated with AD subjects exhibiting lobar or intracerebral hemorrhage, all of whom had advanced CAA. We observed that 36% of the AD subjects had concomitant cerebrovascular pathology resulting from single infarcts, multiple microinfarcts, ischemic white matter lesions, or petechial hemorrhages. Although the difference in APOE genotype distribution between subjects with and without cerebrovascular lesions did not reach statistical significance, we did note that the frequency of the epsilon4 allele was significantly higher in subjects with such pathology as compared with those without. However, we found no evidence to suggest that the acquisition of an APOE-epsilon4 allele or one of the alleles, epsilon2 or epsilon3, was a factor in the occurrence of atherosclerosis localized in the basal surface arteries. Analyses of our sample also confirm that there was a lower frequency of the APOE-epsilon2 allele in AD subjects and that the frequency of the epsilon4 allele in AD subjects with concomitant diffuse Lewy body disease was intermediate between controls and AD subjects. Our results suggest that the APOE-epsilon4 allele is a significant factor in the development of CAA in AD and reveal the possibility that APOE is an independent factor in CAA and other vascular abnormalities associated with AD.     

White Matter Hypoperfusion and Damage in Dementia: Post‐Mortem Assessment

Neuroimaging has revealed a range of white matter abnormalities that are common in dementia, some that predict cognitive decline. The abnormalities may result from structural diseases of the cerebral vasculature, such as arteriolosclerosis and amyloid angiopathy, but can also be caused by nonstructural vascular abnormalities (eg, of vascular contractility or permeability), neurovascular instability or extracranial cardiac or vascular disease. Conventional histopathological assessment of the white matter has tended to conflate morphological vascular abnormalities with changes that reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. However, histopathology is being supplemented by biochemical approaches, including the measurement of proteins involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage, vessel‐associated proteins that allow rapid measurement of microvessel density, markers of blood–brain barrier dysfunction and axonal injury, and mediators of white matter damage. By combining neuroimaging with histopathology and biochemical analysis, we can provide reproducible, quantitative data on the severity of white matter damage, and information on its etiology and pathogenesis. Together these have the potential to inform and improve treatment, particularly in forms of dementia to which white matter hypoperfusion makes a significant contribution.     

Vascular depressions

The notion of vascular depression (VD) includes depressive disorders resulting from organic cerebral lesions of vascular genesis. Two types of VD are distinguished: post-stroke VD (PSD) and VD proper (SDP). VD develops in case of clinically manifest (neurologic) lesions in cerebral vessels that simultaneously act as psychogenic (nosogenic) factors. SDP is associated with clinically latent vascular disorders ("silent" infarctions and white matter ischemia). VD is characterized by multiple phenomenological convergence of vascular signs and symptoms inherent in both PSD and SDP. Whatever the type of VDs, they are associated with frequent cognitive problems with a variety of dynamic patterns, viz. reversible, relatively stable, and progressing.     

Imaging of cerebrovascular disease in sickle cell anemia

Cerebral vascular disease is a common and serious complication of sickle cell disease that mainly involves the large blood vessels of the skull base. Because recurrences are common and residual deficits severe, attention has turned to detection of preclinical cerebral involvement with the goal of preventing clinical damage. Magnetic resonance imaging (MRI), an extremely sensitive tool for detecting cerebral infarction/ischemia, has shown that 10% of asymptomatic patients exhibit white matter lesions that seem to be associated with impaired cognitive function and may be predictive of stroke; magnetic resonance angiography demonstrates occlusions of skull base arteries but is not reliable for the diagnosis of stenosis because of artifacts generated by rapid turbulent flow. Transcranial Doppler is sensitive and specific for the detection of arterial stenosis and occlusion, even in asymptomatic patients. Digitized cerebral angiography remains the gold standard investigation for pretreatment confirmation of lesions detected by Doppler and/or MRI.     

The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models

A variant of the cysteine protease inhibitor, cystatin C, forms amyloid deposited in the cerebral vasculature of patients with hereditary cerebral hemorrhage with amyloidosis, Icelandic type (HCHWA-I), leading to cerebral hemorrhages early in life. However, cystatin C is also implicated in neuronal degenerative diseases in which it does not form the amyloid protein, such as Alzheimer disease (AD). Accumulating data suggest involvement of cystatin C in the pathogenic processes leading to amyloid deposition in cerebral vasculature and most significantly to cerebral hemorrhage in patients with cerebral amyloid angiopathy (CAA). This review focuses on cell culture and animal models used to study the role of cystatin C in these processes.     

1H MRS in stroke patients with and without cognitive impairment

The pathophysiological basis of cognitive impairment in patients with cerebrovascular disease (CVD) is not well understood, particularly in relation to the role of non-infarction ischemic change and associated Alzheimer-type pathology. We used single voxel 1H MRS to determine the differences in brain neurometabolites in non-infarcted frontal white matter and occipito-parietal gray matter of 48 stroke patients with or without cognitive impairment and 60 elderly controls. The results showed that there were no significant neurometabolite differences between the stroke cohort and healthy elderly controls, but there was a difference in NAA/H2O between the stroke patients that had cognitive impairment (vascular dementia (VaD) and vascular cognitive impairment (VCI)) compared with those patients with no impairment. This was significant in the occipito-parietal gray matter, but not in the frontal white matter, although the results were in the same direction for the latter. This suggests that cognitive impairment in stroke patients may be related to cortical neuronal dysfunction rather than purely subcortical change. Moreover, cortical regions not obviously infarcted may have dysfunctional neurons, the pathophysiological basis for which needs further study.     

Effects of cerebrovascular disease and amyloid beta burden on cognition in subjects with subcortical vascular cognitive impairment

Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB–positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment.     

The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy

Vascular dementia appears rarer than previously thought, but the contribution of vascular lesions to cognitive impairment in Alzheimer's disease (AD) affected patients (mixed dementias) is now recognized as frequent. The role of strategic areas of the brain involved in the cognitive decline induced by vascular lesions and their relative contributions to the severity of the dementing process remain poorly understood. We determined the relationship between the severity of clinical dementia and the volume of different brain areas affected by infarcts in a prospective clinicopathological study in elderly patients. A volumetric study of the functional zones of Mesulam's human brain map affected by vascular lesions was made and correlations between quantified neuropathological data and the severity of dementia were performed in cases with large vascular lesions only, pure AD, and both lesions. The severity of cognitive impairment was significantly correlated with the total volume of infarcts but in a multi-variate model the volume destroyed in the limbic and heteromodal association areas, including the frontal cortex and in the white matter explained 50% of the variability in MMSE and GDS. The total volume of ischemic lesions explained only 0.1-5% of the variability in MMSE and GDS. Age only explained an extra of 0.1-1.6%. This study confirms that infarcts located in strategic areas have a role in the mechanism of cognitive impairment and brings a key for their quantification. It may be useful for developing neuropathological criteria in multi-infarct and mixed dementias.     

Selective white matter abnormalities in a novel rat model of vascular dementia

Rats subjected to bilateral common carotid artery (CCA) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia. However, this model possesses an inherent limitation in that cerebral blood flow (CBF) drops too sharply and substantially after ligation of CCAs. To circumvent such hypoxic-ischemic conditions, we tested implantation of the ameroid constrictor device on bilateral CCAs of male Wistar-Kyoto rats and more precisely replicated chronic cerebral hypoperfusion by gradual narrowing of the CCAs (2-vessel gradual occlusion; 2VGO). The acute cerebral blood flow reduction and resultant inflammatory responses observed in the 2VO rats were eliminated in the 2VGO rats. Thus, chronic cerebral hypoperfusion was segregated, and induced selective white matter changes with relatively preserved neurovascular coupling and substantially less metabolic and histological derangements in the gray matter including the hippocampus. This led to significant spatial working memory impairment of a magnitude similar to the 2VO rats at 28 days postoperation. The 2VGO model may more closely mimic cognitive impairment subsequent to selective white matter damage.     

Introduction: Non-atherosclerotic cerebrovascular disorders

Non-atherosclerotic cerebrovascular disorders are considered to occur less frequently than those caused by embolic or thrombotic disease. Such sporadic disorders resulting from direct effects on the cerebral or peripheral vasculature include hypertensive small vessel disease, vascular inflammatory conditions, aneurysms and arteriovenous malformations. Remarkably, some of these are also inherited in an autosomal dominant manner and appear to entail degeneration or abnormal differentiation of blood vessel wall elements such as smooth muscle, endothelial cells, pericytes and the perivascular nerve plexus. Two intensively investigated examples of these include the cerebral amyloid angiopathies and distinct primary arteriopathies such as CADASIL. The identification of novel genes associated with the hereditary forms of cerebrovascular disorders has been invaluable to understanding of the pathogenesis and management of sporadic disease.