Can small-vessel disease-related cerebral abnormalities be used as a surrogate marker for vascular dementia trials?
Clinical scales for measuring the effectiveness of disease modifying therapies in patients with vascular dementia are of limited sensitivity. Moreover, they cannot serve to directly probe the potential of a drug in slowing further progression of vascular damage. Assessment of morphologic babormalities that reflect ischemia-related cerebral tissue changes and have a bearing on cognitive function could serve to address both of these aspects and, if sensitive enough, could constitute an ideal surrogate for measuring progresssion of the disease. For drug licensing agencies a validated surrogate has to meet several requirements: First, the surrogate must predict the future clinical course. Second, the effect of treatment on the disease must be explained by the effect of the treatment on the surrogate; the treatment needs to affect clinical outcome by working through mechanisms related to the surrogate. Third, evidence must exist that treatments of various classes affect the surrogate in the same and predictable manner. Apart from these requirements, regulatory guidelines may also allow the use of even an unvalidated surrogate if it is considered reasonably likely to predict future clinical outcome or disease activity. Various morphologic measures, particularly those using conventional or more sophisticated MRI techniques have already shown a close correlation to neuropsychologic functions. If these associations can also be confinned in longitudinal studies and following specific treatments, morphologic markers will play a major role in future clinical trials of vascular dementia.
KeywordsVascular Dementia White Matter Hyperintensities Vascular Cognitive Impairment High Cortical Function Poststroke Dementia
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- Erkinjuntti T, Inzitari D, Pantoni L, Wallin A, Scheltens P, Rockwood K, Desmond D (2000) Limitations of clinical criteria for the diagnossis of vascular dementia in clinical trials: is focus on subcortical vascular dementia a solution? Ann NY Acad Sci 90: 3262–3272Google Scholar
- Fazekas F, Ropele S, Bammer R, Kapeller P, Stollberger R, Schmidt R (2000) Novel imaging technologies in the assessment of cerebral ageing and vascular dementia. J Neural Transm [Suppl] 59: 45–52Google Scholar
- Filippi M, Horsfield M, Ader H, Barkhof F, Bruzzi P, Evans A, Frank J, Grossman R, McFarland H, Molyneux P, Paty D, Simon J, Tofts P, Wolinsky J, Miller D (1998) Guidelines for using quantitative measures of brain magnetic resonance imaging abnomrmalities in monitoring the treatment of multiple sclerosis. Ann Neurol 43: 499–506PubMedCrossRefGoogle Scholar
- Inzitari D, Erkinjuntti T, Wallin A, Del Ser T, Romanelli M, Pantoni L (2000) Subcortical vascular dementia as a specific target for clinical trials. Ann NY Acad Sci 90: 3510–3521Google Scholar
- Pohjasvaara T, Mantyla R, Ylikoski R, Kaste M, Erkinjuntti T (2000) Comparison of different clinical criteria (DSM-II1, ADDTC, ICD~lO, NINDS-AIREN, DSM-IV) for the diagnosis of vascular dementia. National Institute of Neurological Disorders and Stroke-Associahtion Internationale pour la Recherche et l’Enseignement en Neurosciences. Stroke 31: 2952–2957PubMedCrossRefGoogle Scholar
- Roman G, Tatemichi T, Erkinjuntti T, Cummings J, Masdeu J, Garcia J, Arnaducci L, Orgogozo J, Brun A, Hofman A, Moody D, O’Brien M, Yamaguchi T, Grafman J, Drayer B, Bennett D, Fisher M, Ogata J, Kokmen E, et al (1993) Vascular dementia:Small-vessel disease-related cerebral abnormalities 67 diagnostic criteria for research studies. Report of the NINDS-AIREN International Work Group. Neurology 43: 250–260PubMedCrossRefGoogle Scholar