脑小血管病

目的探讨伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)患者脑微出血(cerebral microbleeds,CMBs)的分布特征及临床意义。方法回顾性纳入2017年6月-2019年12月北京协和医院基因确诊的连续CADASIL患者21例(CADASIL组),以及性别匹配的高血压动脉硬化性脑小血管病患者21例(高血压脑小血管病组)。所有患者均行头MRI检查(含T2^*/SWI序列),盲法读片并记录CMBs的数量和部位,分析两组CMBs分布的差异。结果CADASIL组年龄和常见血管病危险因素比例均低于高血压脑小血管病组。CADASIL组47.6%患者检出CMBs(共计115个),而高血压脑小血管病组高达95.2%(共计218个)。CADASIL组CMBs分布以丘脑最常受累(45.2%),其次是脑叶(皮层/皮层下,35.7%)、基底节(11.3%)。高血压脑小血管病组则以丘脑以外的基底节CMBs最多见(35.3%),其次是脑叶(26.6%)、丘脑(19.2%)、脑干(16.1%)。CADASIL患者丘脑CMBs/总CMBs比例、丘脑CMBs/(基底节CMBs+脑干CMBs)比例均高于高血压脑小血管病组(均P<0.001)。结论CADASIL患者CMBs分布以丘脑最常见,其次是皮层/皮层下区域,而高血压脑小血管病患者则以丘脑以外的基底节、脑干更常见。     

Thrombophilic risk factors and unusual clinical features in three Italian CADASIL patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetically transmitted cerebrovascular disease. Typically, the first clinical manifestation is migraine and the full clinical spectrum of the disease with recurrent strokes of the subcortical type, cognitive, and mood disorders is seen during the fourth and fifth decades of life. Vascular risk factors are usually absent in CADASIL patients and the diagnosis of the disease is particularly suspected in young adults with cerebrovascular events of unknown cause, diffuse leukoencephalopathy on computed tomography or magnetic resonance imaging, and a history of cerebrovascular diseases or dementia in many family members. We describe three Italian CADASIL patients who presented to medical attention for cerebrovascular events occurred after the age of 55 and had, in addition to hypertension and hyperlipidemia, thrombophilic risk factors such as hyperhomocysteinemia, elevated levels of lipoprotein(a), and antiphospholipid antibodies. Symptoms possibly related to cortical involvement, such as dysphasia and visual field deficits, were reported by two of these patients. We conclude that a diagnosis of CADASIL should not be disregarded in patients with vascular risk factors and presenting with symptoms not immediately referable to subcortical damage at ages more advanced than commonly reported.     

CADASIL or CADVaSIL?

In the present study, morphological examination of patients from two unrelated Polish families with CADASIL was performed. Using light microscopy, there were evident changes characteristic to the disease. On electron microscopy, deposits of granular osmiophillic material (GOM) were found not only in cerebral arteries and veins but also in cerebral capillaries and vessels of the internal organs. These findings indicate that pathological process in CADASIL is generalized and involves also small vessels devoid of smooth muscle cells. Therefore, we propose to consider a replacement for the name CADASIL that better reflects the morphological picture of the disease like, for example, cerebral autosomal dominant vasculopathy with subcortical infarcts and leukoencephalopathy (CADVaSIL) or, to preserve the commonly known acronym, cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy.     

White Matter Changes in Dementia: Role of Impaired Drainage of Interstitial Fluid

White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease.     

Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer's disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI.     

CADASIL伴脑出血的临床和基因分析:3例报告

目的:评估常染色体显性遗传性皮质下梗死和白质脑病(CADASIL)伴脑出血(ICH)的临床表现、影像学和基因特征。方法:CADASIL伴ICH患者3例,在Pubmed数据库纳入另外25例有详细资料的患者,评估出血性CADASIL的临床表现、影像学特征和基因突变特点。结果:共纳入患者28例,男19例、女9例,平均年龄(54.2±13.4)岁。高血压病是最常见的危险因素(18例,64.3%),50%的患者曾接受抗栓治疗。10例患者以ICH为首发表现,最常见的出血部位是基底节和脑叶。11号外显子R544C位点是最常见的突变位点(46.2%)。18例患者(64.3%)发现数量不等的微出血灶。结论:CADASIL可发生ICH且可能是首发临床表现。严格控制高血压和谨慎使用抗血栓药可能有助于防止CADASIL患者发生ICH。     

Acute Confusional Migraine May Be a Presenting Feature of CADASIL

Objective.— Characterize the phenomenon of acute confusional migraine (ACM) among Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients and emphasize the possibility of CADASIL in adults with ACM.
Background.— ACM, well described in children, has rarely been reported in adults. Although 30-60% of CADASIL patients have migraine, acute confusional state during migraine has not been described. We describe 7 patients with ACM that complicated up to 50% of the migraine episodes.
Design/Methods.— Detailed neurologic evaluation was performed in 20 CADASIL patients; International Classification of Headache Disorders 2nd edition criteria were used to diagnose migraine.
Results.— The mean age was 51 years. Fourteen patients reported headache and 11 met the criteria for migraine (mean age of onset 25). Seven patients experienced concomitant confusion, within 3 years of migraine onset. Confusion occurred either abruptly or insidiously, at the onset of aura or headache, lasting for 2-48 hours, and ending abruptly. These episodes were stereotypic, characterized by disorientation with agitation, and retrograde amnesia for the episodes. Patients reported disorientation to time and place, inability to recognize friends and relatives, difficulty with finding directions home, fear of getting lost, inability to analyze traffic lights or tell time. Patients reliably predicted the episodes and felt the need to seek a safe place for protection. Severity of the episodes progressed, but a striking improvement occurred after the first stroke.
Conclusion.— ACM may be a presenting feature and important clue, enabling CADASIL to be recognized up to a decade or earlier than at present. Therefore, a brain MRI and/or testing for Notch3 mutations should be considered in adult patients with ACM.