Investigating Imaging Biomarkers of Neuroinflammation and Neurodegeneration in Rodent Models of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in alterations in memory, language, executive function and emotional behaviour. Although it can be characterised by symptoms, by the time they arise significant pathological alterations have already emerged in the central nervous system, namely increased amyloid plaques, neurofibrillary tangles and neuronal loss. Despite known pathological hallmarks the exact aetiology of AD is poorly understood and no current treatments are available. However, there is growing interest in the role of neuroinflammation in AD, with increases observed in the early stages of disease and with disease progression. Moreover, it has been suggested that peripheral inflammation can influence neuroinflammation and worsen neurodegeneration. Using Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRS) we can non-invasively measure biomarkers of neuroinflammation and degeneration allowing multi-modal investigation of its role in normal aging and AD. Considering this the objectives of this study were to (i) Use PET and MRS to investigate neuroinflammatory and metabolite alterations in transgenic (TG) models of AD and their wildtype (WT) animals. (ii) Assess rates of cognitive decline in these models using memory based tests. (iii) Investigate relatively new TgF344AD rat as an AD model by characterising younger time-points than previously reported. (iv) Investigate the contribution of peripheral inflammation on AD progression. PET and MRS imaging was carried out longitudinally in the APPswe×PS1de9 mouse. Neuroinflammation was confirmed ex vivo and cognitive ability was assessed by behavioural tests. Results revealed significantly increase hippocampal and thalamic neuoinflammation in old TG mice as assessed by [18F]DPA-714 PET and supported by immunohistochemistry. Reduced neuronal marker N-acetlyaspartate was seen with age and was exacerbated in the TG mice. Accelerated cognitive decline was also seen in TG mice.PET and MRS imaging was carried out at 6 and 12 months in the TgF344AD model, which expresses amyloid and tau pathology as well as neuronal loss. No cognitive decline was observed in TG rats; however increased anxiety behaviour was seen. Increased [18F]DPA-714 PET was observed as an effect of gene in the thalamus at 6 months and the hypothalamus at 12 months. Increases in glutamate were seen with age in the TG rats but not the WTs. Increased inflammation and metabolite alterations were seen with aging. The effect of peripheral urinary tract infection (UTI) on cognition and imaging out was assessed. Imaging was carried out prior to and after re-current UTI. Infection induced cognitive decline in infected TG but not WT rats. Infection had an increasing effect on hypothalamic neuroinflammation in WT rats but a decreasing effect on TG rats, which masked the original gene differences. This thesis is set out in the alternative format with each experimental study represented as a chapter. Results in this thesis implicate neuroinflammation in AD development and progression. In addition, we report systemic infection-CNS interactions accelerating cognitive decline in AD and highlight the importance of understanding the effects of comorbidities in disease.

Keyword(s)

Alzheimer’s disease; Magnetic resonance spectroscopy; Neuroinflammation; Positron emission tomography

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