Review: Vascular dementia: clinicopathologic and genetic considerations.

The incidence and severity of cerebrovascular disease (CVD) increase with advancing age, as does the risk of developing Alzheimer's disease (AD). Not surprisingly, heterogeneous forms of CVD may coexist with AD changes in the 'ageing brain'. These include angiopathies (affecting both large and small arteries) that result from 'classical' risk factors (hypertension, smoking and diabetes) and others (cerebral amyloid angiopathy) that are biochemically closely linked to AD. The morphologic consequences of these various vascular diseases are infarcts and/or haemorrhages of varying sizes within the brain, which lead to neurocognitive decline that may mimic AD - though the vascular abnormalities are usually detectable by neuroimaging. More subtle effects of CVD may include neuroinflammation and biochemical 'lesions' that have no reliable morphologic correlate and thus escape the attention of even an experienced Neuropathologist. The pathogenesis of hippocampal injury resembling ischaemic change - commonly seen in the brains of geriatric subjects - remains controversial. In recent years, genetically determined forms of microangiopathy (e.g. CADASIL, CARASIL, Trex1-related microangiopathies, CARASAL, familial forms of cerebral amyloid angiopathy or CAA) have provided interesting cellular and molecular clues to the pathogenesis of sporadic microvascular disease such as arteriolosclerosis and AD-related CAA.

Endogenous and exogenous DNA lesions recognized by N-alkylpurine-DNA glycosylases.

The combined action of glycosylases and abasic site-specific endonucleases on damaged bases in DNA results in single strand breaks. In plasmid DNA, as a consequence, the covalently closed circular (ccc) form is converted to the open circular (oc) form, and this can be quantitated by agarose gel electrophoresis. We studied DNA lesions sensitive to E. coli 3-methyladenine-DNA glycosylase II (AlkA) and cloned human N-alkylpurine-DNA glycosylase (ANPG-40) which are known to excise alkylated bases and etheno adducts. pBR322 and pAlk10 plasmids not pretreated with mutagens were cleaved by both glycosylases in the presence of enzymes possessing endonucleolytic activity, which indicates that plasmids contain unknown, endogenously formed adducts. Plasmids pretreated with chloroacetaldehyde, a mutagen forming etheno adducts, exhibited enhanced sensitivity to both glycosylases. Adducts formed by acrolein and croton aldehyde were excised by AlkA, but not by ANPG-40, whereas malondialdehyde adducts were not excised by either glycosylase. Bulky p-benzochinone adducts were not excised by AlkA, however, the plasmid pretreated with this mutagen was incised by endonucleases, possibly without prior generation of an abasic site. These examples show that examination of conformational changes of plasmid DNA can be taken advantage of to study the specificity of N-alkylpurine-DNA-glycosylases.

The induction of adaptive response to alkylating agents in Escherichia coli reduces the frequency of specific C-->T mutations in chloroacetaldehyde-treated M13 glyU phage.

The mutagenicity and repair of cytosine adducts formed in reactions of chloroacetaldehyde (CAA), a metabolite of the human carcinogen vinyl chloride, have been studied. The treatment of single-stranded DNA M13 JCM15472 (glyU313) phage with CAA and subsequent transfection of Escherichia coli K-12 JC15419 (trpA461) tester strain resulted in a dose-dependent increase of phage C-->T transitions and a decrease of phage survival. The induction of the adaptive response to alkylating agents in bacterial cells significantly decreased the frequency of examined C-->T transitions and increased phage survival. The results indicate that both CAA adducts to cytosine, the initially formed 3,N4-(N4-alpha-hydroxyethano)cytosine and the product of its dehydration, 3,N4-ethenocytosine, provoke C-->T transitions and are repaired in adapted bacteria. The role of 3-methyladenine-DNA glycosylase II, which is a part of the adaptive response system in E. coli, in excision of CAA adducts to cytosine, is discussed.