Central Nervous System Diseases: Innovative Animal Models from Lab to Clinic

Central Nervous System Diseases: Innovative Animal Models from Lab to Clinic. Emerich DF, Dean RL 3rd, Sanberg PR, editors. Totowa (NJ): Humana Press; 2000. 512 pp with index. ISBN 0-896-03724-X (cloth). Can$145.

Medical research depends heavily on the use of nonhuman models, particularly in preclinical evaluations of interventions. However, the appropriate choice of animal model is not always obvious; it depends on the disorder of interest and on the appropriateness of the particular species for modelling that disorder. The validity of any given model is established by its similarity to the disorder, its similarity in underlying mechanisms and its ability to predict the effectiveness of interventions. Yet too often, model selection is based on practical considerations, independent of validity.

Central Nervous System Diseases: Innovative Animal Models from Lab to Clinic focuses on the development and utility of animal models for particular types of central nervous system (CNS) disorders. The focus is on disorders associated with obvious brain abnormalities. CNS disorders such as depression, which are not associated with obvious neurodegeneration, are not covered. Also lacking is coverage of disorders associated with infectious agents, such as human immunodeficiency virus. The editors’ stated goal is to provide practical information. To this end, the authors were encouraged to critically examine the various models and to discuss both their advantages and disadvantages.

Four of the 5 sections address specific types of neurodegenerative disorders: aging and Alzheimer’s disease; Parkinson’s disease; Huntington’s disease; and traumatic brain injury, stroke and hypertensive cerebrovascular disease. Section 5 looks at examples of animal models leading to clinical trials. Each of the first 4 sections starts with an article on behavioural analysis, which provides a useful overview of the types of behavioural techniques used in developing particular animal models.

In section 1, on aging and Alzheimer’s disease, all but 1 of the 7 chapters deal with rodent models, which is unfortunate, given that the types of cognitive deficits seen in aged rodents are only questionably comparable to those associated with either aging or Alzheimer’s disease. Similarly, rodents do not experience the neuroanatomic abnormalities seen in the human brain (e.g., neurotic plaques and neurofibrillary tangles). The problematic nature of the behavioural and neuroanatomic correlates warrants a greater focus on more advanced species. One chapter discusses age-related cognitive decline in the rhesus monkey. The authors point out that aged monkeys can be used to model human cognitive aging, but not Alzheimer’s disease. If a primate cannot adequately model Alzheimer’s disease, how likely is it that the rat will?

Section 2 deals with Parkinson’s disease, and again, all but 1 of the 6 chapters focuses on rodent models. The clinical relevance of the movement disorders seen in rodent models is questionable. Rotometry, the most commonly used rodent measure, does not model any symptoms of Parkinson’s disease. The models focus only on motor deficits, omitting modelling of the accompanying cognitive changes.

Section 3, which deals with Huntington’s disease, has 5 chapters. Several rodent models described in this section are based on damage to the striatum. None of these provide valid behavioural correlates, since rats do not exhibit choreiform movements. Furthermore, the rat striatum, unlike that of the primate, does not have a distinct caudate nucleus and putamen. The motor disorders of Huntington’s disease are better modelled by primates with damage to the striatum, which can be produced by either lesions or chronic treatment with 3-nitropropionic acid, a poison that disrupts cellular metabolism.

Section 4 deals with traumatic brain injury, stroke and hypertension. These disorders are fundamentally different from those discussed in the first 3 sections because of the broader range of behavioural and anatomic deficits seen clinically. Animal models are particularly useful in helping to establish how mechanical injury or stroke produces brain damage and how this damage can be prevented and treated.

The last section of the book discusses instances of animal models with clinical applications. These examples are probably most useful in showing how far we still have to go before animal models can reliably lead to therapeutics. Thus far, neither neural grafting nor gene therapy has been convincingly shown to be clinically effective for neurodegenerative disorders.

Overall, this is a useful volume for those involved in animal research on neurodegenerative disorders because it provides insight into the process of model development and selection. Such insight is particularly important for the development of interventions for CNS disorders. The articles are generally well written, and some of the models described are promising. But the selection of models is, of necessity, limited, with too much attention devoted to rodent models. Equally problematic is the failure in many instances to critically assess the validity of the model. The limited number of models discussed restricts the usefulness of the volume as a reference source.