Imaging of static brain lesions in vascular dementia: Implications for clinical trials

Vascular dementia (VaD) relates to different vascular mechanisms and change s in the brain and has different causes and clinical manifestations, reflec ting complex interactions between vascular etiologies, changes in the brain , host factors, and cognition. Critical elements to the concept and diagnos is of VaD are defining the vascular causes, the vascular etiologies, and ch anges in the brain. Verifying the relation between brain lesions and cognit ion (i.e., the extent to which brain changes cause, compound or coexist wit h cognitive impairment) and establishing the types, extent, side, site, and tempo of brain lesions that relate to incident cognitive impairment are ma jor diagnostic challenges. Previous work on interactions between brain lesi on and cognition in to cerebrovascular disease (CVD) have shown variation i n the definitions and measures of cognitive impairment, in the techniques a nd methods used to reveal different brain changes, and in the selection of patient populations. Furthermore, small sample sizes and the absence of mul tivariate statistics have been design limitations. Accordingly, the differe nt sets of criteria used and methods applied identify different numbers and clusters of subjects and different distribution of brain changes. Furtherm ore, this heterogeneity is reflected in variation in natural history such a s the rate of progression of decline in different cognitive domains over ti me. All these factors have hampered optimal designs of clinical drug trials . A summary of generalizations regarding lesion and cognition interaction i n VaD can be made. (1) Not a single feature, but a combination of infarct f eatures-extent and type of white matter lesions (WMLs), degree and site of atrophy, and host factor characteristics-constitues correlates of VaD. (2) Infarct features favoring VaD include bilaterality, multiplicity (>1), loca tion in the dominant hemisphere, and location in the limbic structures (fro nto- and mediolimbic). (3) WML features favoring VaD are extensive Whits (e xtensive periventricular WMLs and confluent to extensive WMLs in the deep W M). (4) It is doubtful that only a single small lesion could provide imagin g evidence for a diagnosis of VaD. (5) Absence of CVD lesions on computed t omography or magnetic resonance imaging is strong evidence against a diagno sis of VaD. In forthcoming protocols on CVD-associated cognitive impairment , the following brain imaging features should be specified: detailed charac terization of brain changes; use of possible predefined subtypes based on b rain imaging; use of rating of vascular burden; defining the type and exten t of WMLs favoring a diagnosis of VaD; defining the extent of medial tempor al lobe atrophy disfavoring a diagnosis of VaD; and technical harmonization of methods of scanning and analysis.