Cognitive and neuroimaging approaches to preclinical markers for Alzheimer's Disease.

In the absence of disease modifying therapies, early diagnosis of Alzheimer’s disease (AD) is imperative not only for drug development but also for the timely application of pharmaceutical and behavioural treatments that may ameliorate rapid decline and improve quality of life for both patients and caregivers. The present research, therefore, applied psychological and neuroimaging approaches for the identification of cognitive markers of the earliest stages of AD physiological degradation. Specifically, the first experiments focussed on clarifying neural correlates of semantic memory decline in prodromal and dementia stages of disease. These studies not only identified a significant relationship between semantic memory performance and discrete structural alterations, within structures known to be affected at the initial stages of the AD pathological cascade, but further confirmed that a quick and simple verbal fluency test may provide a meaningful marker for very early neurodegeneration. Experiments three and four applied a more novel graph theoretical approach to the quantification of AD cognitive change. Experiment three aimed to elucidate neuropsychological profiles characteristic of the various stages of ageing and disease. The topology of networks reflecting cognitive performance were outlined and compared revealing notable differences in network structure relating to age that were further altered in the presence of disease. These findings specifically highlighted a central role for semantic processing and abstract reasoning in neuropsychological performance among healthy older adults, which appeared to be lost among patient groups. Finally, experiment four sought to investigate underlying alterations in brain structural networks that may account for the differences seen in ageing and disease at the cognitive level. Findings indicated that, even in prodromal AD, significant differences in network topology, relating to volumetric covariance, are apparent when compared with healthy age-related change, and such differences in structural relationships may account, to some extent, for the observable contrast in neuropsychological profile.