Age-related cognitive impairment : phenotypes, progression and prefrontal plasticity

Abstract

As a result of rapid aging trends, increasing numbers will be afflicted with age-related cognitive impairment and consequently escalating into a healthcare crisis. The role of research is critical in preparing ourselves for this crisis. Despite decades of research, there are still gaps in our understanding within the three broad areas of diagnosis/classification, disease progression tracking and treatment. This thesis sought to address some of these gaps across five studies. First, the existing diagnostic nosology for early age-related cognitive impairment is perhaps too broadly classified in the dichotomy of memory and non-memory impairment and may not adequately reflect the profiles of early cognitive impairments in reality. The first study (Chapter 2) sought a finer delineation on the early phenotypes of cognitive impairment. Using latent class analysis, four different profiles were discovered, each was characterized by different memory or executive functions (EF) impairment, or a combination of both. Furthermore, memory-impaired profiles tend to be associated with worse functional outcomes. Next, disease progression tracking and prediction is critical for informing diagnostic and treatment decisions. There is a growing interest in using diffusion tensor imaging (DTI) to track the progression of cognitive decline. Three studies were executed to explore this possibility in various neurocognitive disorders. A meta-analysis (Chapter 3) was first carried out on DTI studies of amnestic mild cognitive impairment (aMCI). It revealed significant white matter (WM) alterations in aMCI, especially in the fornix region. Relatedly, the subsequent study (Chapter 4) hypothesized that these fornix alterations would predict subsequent hippocampal atrophy and memory decline, alluding to the idea that the fornix is compromised much earlier than the hippocampus in Alzheimer’s disease. The results suggested otherwise; fornix alterations are likely to appear relatively late since memory impairments and hippocampal atrophy predicted subsequent fornix integrity but not vice-versa. The next study (Chapter 5) examined the longitudinal WM alterations and its association with EF decline in behavioral-variant frontotemporal dementia (bvFTD). Widespread WM alterations were observed in bvFTD; among them, alterations in the corpus callosum and anterior corona radiata were significantly associated with EF decline. Moving on to treatment, previous experiments have suggested the possibility of enhancing EF by modulating prefrontal plasticity via transcranial direct current stimulation (tDCS). The final study (Chapter 6) examined the effects of multi-session prefrontal tDCS on EF in a sham-controlled intervention and then across studies in a meta-analysis. No significant tDCS-associated gains in any EF outcomes were observed in the intervention. In the meta-analysis, the pooled tDCS treatment effect on overall EF was not significant. Within the EF domains, a significant, but small pooled tDCS treatment effect was observed only for working memory. Taken together, cognitive impairment, evident from its multiple phenotypes, is a heterogeneous condition. Various relationships between white matter and cognitive abilities may be observed in these different phenotypes. At least for EF, the accumulated evidence revealed that tDCS only resulted in somewhat limited gains in cognitive abilities. These findings present important implications, in the diagnosis/classification, disease progression tracking and treatment of age-related cognitive impairment.