New animal models of progressive neurodegeneration: tools for identifying targets in predictive diagnostics and presymptomatic treatment

Abstract

Mental and neurological disorders are increasingly prevalent and constitute a major societal and economic burden worldwide. Many of these diseases and disorders are characterized by progressive deterioration over time, that ultimately results in identifiable symptoms that in turn dictate therapy. Disease-specific symptoms, however, often occur late in the degenerative process. A better understanding of presymptomatic events could allow for the development of new diagnostics and earlier interventions that could slow or stop the disease process. Such studies of progressive neurodegeneration require the use of animal models that are characterized by delayed or slowly developing disease phenotype(s). This brief review describes several examples of such animal models that have recently been developed with relevance to various neurological diseases and disorders, and delineates the potential of such models to aid in predictive diagnosis, early intervention and disease prevention.

Fig. 1

Prevalence in the USA of several important neurological diseases characterized by progressive neurodegeneration. Numbers are expressed in thousands (000 s) of persons affected. Data derived from [2]

Fig. 2

Representation of the concept of progressive neurodegeneration and presymptomatic therapeutic intervention. Events, often unidentified, initiate a progressive deterioration of brain health that continues for some time prior to the appearance of symptoms associated with a particular neurological disease. Traditionally therapy is initiated at the time of symptom onset and diagnosis, but earlier detection of deteriorating brain health would allow for presymptomatic intervention that could slow or prevent disease progression

Fig. 3

Preliminary schematic depiction of identified changes over time in a neurodevelopmental rat model of temporal lobe epilepsy. Low doses of domoic acid during the second postnatal week lead to a progressive series of changes in hippocampal neurotrophin signaling, astrogliosis, sprouting of dentate granule cell axons and cell loss, that are accompanied by changes in cognition, seizure threshold and EEG although the precise time of onset of each is currently unknown. Changes depicted are correlative only and not necessarily causally related. Data derived from [–36]