Subcortical Vascular Dementia as a Specific Target for Clinical Trials DOMENICO INZITARI,a TIMO ERKINJUNTTI,b ANDERS WALLIN,c TEODORO DEL SER,d MARCO ROMANELLI,a AND LEONARDO PANTONIa,e aDepartment
of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy bDepartment
of Clinical Neurosciences, Helsinki University Central Hospital, Helsinki, Finland
cInstitute dSection
of Clinical Neuroscience, Götenberg University, Molndal, Sweden
of Neurology, “Severo Ochoa” Hospital, Madrid, Spain
ABSTRACT: Vascular cognitive impairment is considered the second most common form of mental deterioration in the elderly after degenerative dementias. Therapeutic approaches to vascular dementia mainly rely on the identification and treatment of risk factors. A number of drugs have also been tested with the aim of improving or slowing cognitive decline in patients affected by various forms of cerebrovascular disease. Most of these trials have yielded unsatisfactory results. We hypothesize that some of these failures depend on the inclusion of patients with pathophysiologically heterogeneous types of vascular cognitive decline. In this paper, we review some of the most important trials that tested drugs with a preventive or therapeutic aim in vascular dementia patients. Preliminary results suggest that some beneficial effects can be detected only when the trial population is homogeneous on a clinical and pathogenic basis. In particular, subcortical vascular dementia, a form with a rather univocal clinical, radiological, and pathological picture, seems a particularly apt choice as a target for future clinical studies. At present, only one therapeutic trial is being conducted in patients affected by this specific form of vascular dementia.
INTRODUCTION At present, no drug has been definitively accepted as effective in vascular dementia (VaD). We suggest that this mainly depends on the current definition of VaD itself. As the term VaD is now commonly used, it, in fact, encompasses different clinical–pathological subtypes, linked with selective pathophysiological mechanisms, which are considered and listed in the most recent classifications.1–3 Chui et al. classify the disorder into subtypes with the disclaimer, however, that their classification should serve only for research purposes. Different subtypes of VaD are defined according to location (cortical, deep or periventricular white matter, basal ganglia, thalamus), size (volume), distribution (large, small, or microvessel), severeAddress for correspondence: Leonardo Pantoni, M.D., Ph.D., Department of Neurological and Psychiatric Sciences, University of Florence, Viale Morgagni 85, 50134 Firenze, Italy. Tel.: #39-055-4277 995; fax: #39-055-4298 461. e-mail:
[email protected]
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ity (chronic ischemia vs. infarction), and etiology (embolism, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and hypoperfusion) of the lesions. The National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria listed the following pathophysiological causes that may be associated with VaD syndromes: (1) multiple large complete infarcts; (2) strategic single infarcts; (3) small-vessel disease; (4) hypoperfusion; (5) hemorrhage; and (6) other mechanisms. A definitive systematization has not yet been reached because, according to Nyenhuis and Gorelick,4 there has been little research comparing VaD subgroups on important variables such as the pattern and severity of cognitive or functional impairment, the relationship to stroke risk factors, demographic variables, and course of dementia. In fact, different VaD types share common risk factors, neurological findings, and clinical course. Moreover, different lesion types (for example, cortical territorial and small, deep infarcts, strategic infarcts, and hypoperfusion changes) may frequently occur in combination in the same patient. Modern imaging techniques have proved strongly supportive for a more detailed characterization of these subtypes. It has become more and more apparent that subcortical VaD, which is consistent with the NINDS-AIREN subtyping for both small-vessel and Binswanger’s dementia and is so recognized in the 10th revision of the International Classification of Disease (ICD-10), is probably one the most frequent forms of VaD. Neuroimaging and clinical studies have indicated that this type of VaD has rather univocal radiological and clinical characteristics,5,6 although a clinical–pathological correlation has not yet been established with precision.7–11 Finally, there are forms where vascular changes are combined with Alzheimer’s disease or other types of pathologic degeneration (mixed dementia). Unfortunately for these last cases, neither clinical nor laboratory tools exist that are sensitive enough to permit a unequivocal identification. Understanding the pathophysiological mechanism that causes cognitive impairment in individual cases is an essential step for choosing the proper treatments. Unlike what has been done so far, clinical trials should address a univocal pathophysiological setting, ascertain that a particular treatment has a rationale that fits with this setting, and include in the study patients homogeneously presenting a definite clinical–pathological condition. In this paper, treatments that have been proposed and tested in VaD are reviewed with the aim of disclosing clues to support the theory that failure of therapeutic trials in VaD, and lack of evidence for any effective treatment, may depend at least in part on the fact that these trials have not taken into account different subtypes of VaD.
PREVENTIVE TREATMENTS IN VASCULAR DEMENTIA Ideally, cognitive impairment of vascular origin should be treated in its earliest phase, at a time when the mental deficit has not achieved its most severe degree (i.e., dementia). Dementia is ultimately caused by more or less severe loss of brain tissue, which can be either extensive or very selective affecting crucial areas or circuits. In both cases, at present, we have no means to regenerate the damaged tissue. Unlike primary degenerative dementias in which the cause of the process is unknown, how-
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ever, in VaD we know enough about risk factors and pathogenic mechanisms to take preventive measures. Accordingly, the aim should be to identify subjects at risk, and, by treating their risk factors, to slow or even arrest the dementing process. Control of risk factors has a twofold objective: (a) prevention of cerebrovascular events; (b) slowing of the progression of underlying pathology. Blood hypertension (probably the main risk factor), diabetes mellitus, smoking, and hyperlipidemia, can all be effectively controlled. Several large therapeutic trials have been carried out over the last decades with different types of treatments, including interventions for risk-factor control, antithrombotic agents (antiplatelet or anticoagulant), or even surgery, with the aim of stroke prevention. It is quite surprising, and in some ways unexplainable, that these trials have omitted to include, among preventable outcomes, cognitive decline. It is suggested that future trials avoid this omission. Moreover, therapeutic trials for stroke prevention have not classified different stroke types (for example, large cortical vs. lacunar infarct, linked with the multiinfarct or the subcortical VaD forms, respectively) on entry or as outcome events. Consequently, it is impossible to evaluate, even if indirectly, the impact of selective treatments on VaD subtypes. For example, given the association of lacunar stroke with VaD (lacunar state, subcortical VaD), it would be interesting to know whether antiplatelet agents are specifically able to prevent recurrence in patients with this stroke type. Actually, only two trials provided evidence regarding the possible preventive effect of antiplatelet agents in patients presenting with lacunar infarcts. The Accidents Ischemic Cerebraux Lies a l’Atherosclerose (AICLA) trial examined the effect of aspirin, aspirin plus dypiradomole, or placebo in patients with lacunar stroke only, showing that these treatments also reduced the stroke recurrence in this subgroup.12 A significant benefit of ticlopidine for stroke prevention in patients with lacunar stroke was shown by the Canadian American Ticlopidine Study (CATS).13 Considering studies specifically addressing VaD, only small studies and hints are available. Meyer et al., following a small number of patients, showed that control of vascular risk factors, such as arterial hypertension and smoking, was able to stabilize or improve the cognitive status of patients diagnosed with multi-infarct dementia.14 The same authors observed that a too marked reduction in systolic blood pressure levels was associated with progression of mental deterioration.14 More recently, the Syst-Eur trial, a randomized, double-blind, placebo-controlled trial for treating systolic hypertension, has provided the first clear-cut evidence that controlling hypertension reduces the incidence of dementia.15 Using a treatment regimen consisting of nitrendipine, with the possible addition of enalapril, hydroclorothiazide, or both drugs titrated or combined to reduce the systolic blood pressure by at least 20 mmHg to reach a value
