Florey Department of Neuroscience and Mental Health - Theses
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ItemThe nature of memory decline and learning dysfunction in preclinical Alzheimer’s disease( 2019)Background: In cognitively normal (CN) older adults, abnormal levels of amyloid-beta indicates that the pathophysiological process of Alzheimer’s disease (AD) has begun, although it may be up to 20 years before these individuals meet clinical criteria for dementia Measurement of episodic memory is a cornerstone of neuropsychological assessment in AD, which is consistent with clinicopathological studies showing that the earliest neuronal loss begins within the medial temporal lobe (MTL), a brain region crucial for learning and memory. Neuropsychological compendia detail many tests of episodic memory well validated for use in AD, however, there are fewer standardized neuropsychological tests of learning validated for use in AD. The overarching aim of this thesis was to investigate the relationship between AD pathological markers such as beta-amyloid, and trajectories of neuropsychological performance on memory and learning tasks in CN older adults. Methods: The nature and magnitude of cognitive impairment and decline associated with abnormal levels of amyloid beta in CN older adults was determined via meta-analysis of studies published from 2012 to 2016. Indices of memory and learning on computerised cognitive tests were examined in amyloid negative and amyloid positive CN older adults, with estimates of impairment and decline reported over periods of 18 and 36 months. Finally, a novel web-based learning task was designed and validated to enable the modelling of learning and memory in amyloid negative and amyloid positive CN older adults. Results: Meta-analytic estimates showed significant impairments of small to moderate magnitude (Cohen’s d’s 0.15-0.32) associated with abnormal amyloid in CN older adults in the domains of visuospatial function, processing speed, episodic memory, executive function, and global cognition. Significant decline of small-to-moderate magnitude associated with abnormal amyloid in CN older adults were found for semantic memory, visuospatial function, episodic memory, and global cognition (Cohen’s d’s 0.24-0.30). Rates of learning on the computerised cognitive tests at baseline were equivalent between the amyloid negative and amyloid positive CN groups, while significant differences in longitudinal trajectory of performance was evident. The amyloid negative group showed significant practice effects over time, which were absent in the amyloid positive group, suggesting an inability to learn from repeated exposure. Daily measurement of cognition via a remote, online assessment was sensitive to both age and pathology related changes in ability to learn new information over one week in CN older adults. The magnitude of this effect was very large (Cohen’s d = 1.50), approximately three times larger than current longitudinal estimates of cognitive decline in amyloid positive CN individuals over a year or more. Conclusions: Results indicated that the presence of abnormal amyloid in CN older adults has a significant, negative effect on a range of cognitive domains, although the magnitude of this effect is only small-to-moderate and is largest for memory. Furthermore, amyloid positive CN older adults display aberrant performance on memory and learning tasks over time in the form of a lack of practice effects. This suggests that in amyloid positive CN individuals, the processes by which learning occurs as a function of repeated exposure and presentation to stimuli may be compromised. The large magnitude of impairment in daily learning on the web-based task highlights that the ability to learn new information is dysfunctional in the preclinical stage of AD, and that a sensitive way of measuring cognition in very early disease stages is via repeatable learning assessments. This suggests the need for a paradigm shift towards understanding cognitive dysfunction in preclinical AD as dysfunctional learning, rather than memory.