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Title: A pathological investigation of the frontal lobe in post-stroke dementia and other ageing-related dementias
Author: Foster, Vincent
ISNI:       0000 0004 5924 4122
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2015
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Approximately 30% of elderly stroke survivors develop post-stroke dementia (PSD). The mechanisms underlying this cognitive decline following stroke are unclear. Vascular pathology is associated with the frontal lobe, damage to which may result in executive dysfunction; a common clinical outcome of PSD. Previous pathological studies in PSD subjects have found that pyramidal neurons in the CA1 region of the hippocampus were particularly vulnerable, with atrophy of these cells associated with cognitive impairment. In this study we test the hypothesis that similar changes in pyramidal neurons in the three prefrontal circuits which control executive function may be related to executive dysfunction. The three circuits are; the dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC). Histological and immunohistochemical staining with three dimensional morphometric analysis and quantitative image analysis was carried out in fixed paraffin-embedded prefrontal brain sections from the MRC funded CogFAST study (a long-term prospective study designed to investigate delayed dementia after stroke) as well as frontal brain tissue from aged-matched controls and pathologically defined dementia groups: vascular dementia (VaD), Alzheimer’s disease (AD), and those with mixed Alzheimer’s disease and vascular dementia (mixed). Pyramidal neuron volumes were significantly reduced in PSD, VaD, mixed, and AD when compared to aged-controls and post-stroke non demented (PSND) subjects in layer III, with layer V following a similar pattern. The neuronal changes in PSD correlated with global and executive function scores and were associated with markers for mitochondrial function, though did not correlate with tau or amyloid burden. Neuronal volumes in the ACC and the OFC did not significantly vary between groups; however pyramidal neurons within the OFC were significantly smaller in all groups (controls and disease) when compared to controls in dlPFC and ACC. There were no significant changes in pyramidal neuron densities between PSND and PSD in any of the three frontal regions. Analysis of the interneuronal densities revealed no significant differences between inhibitory neurons in PSND and PSD subjects. Pyramidal neuron ii volume changes did not appear to be associated with white matter (WM) pathology in post-stroke subjects. These findings suggest that pyramidal neuronal volume loss in the dlPFC is associated with cognitive decline in post-stroke and ageing-related dementia. The lack of relationship between AD type pathology, WM pathology, or interneuronal changes suggests dysfunction of the pyramidal neurons in the dlPFC play an important role in the development of executive dysfunction in PSD.
Supervisor: Not available Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available