PET studies on disease progression and treatment efficacy in Alzheimer’s disease and mild cognitive impairment

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. Mild cognitive impairment (MCI) is a transitional state between normal ageing and dementia. Positron emission tomography (PET) can detect the metabolic and neuro-chemical changes that occur in MCI and dementia. The aim of this thesis was to assess the use of PET as an in vivo biomarker for early disease detection, prognosis, and proof of treatment efficacy in AD and MCI. In study I, the prevalence of increased beta-amyloid deposition (assessed by 11C-PIB PET) and microglial activation (assessed by 11C-PK11195 PET) was studied in amnestic MCI (aMCI) subjects. 50% had raised amyloid deposition and 38% evidence of microglial activation. Subjects with increased PIB retention had significantly higher cortical PK11195 binding. In study II, rates at which aMCI subjects with and without increased amyloid load converted to AD were compared over one to three years of follow-up. 55% of aMCI subjects had significantly increased PIB retention at baseline and 82% of these converted to AD compared to 7% of aMCI cases with normal PIB uptake. Faster AD converters had higher PIB retention than slower converters. In study III, changes in regional cerebral Aβ deposition (assessed with 11C-PIB PET) and regional cerebral glucose metabolism (rCMRGlc) (assessed with 18F-FDG PET) were followed over three years in MCI and AD subjects. The MCI subjects demonstrated small but significant increases in 11C-PIB retention and parallel decreases in rCMRGlc. 11C-PIB retention in AD subjects remained unchanged, despite decreases in rCMRGlc and a decline in their MMSE. In study IV, the effects of passive immunisation with infusions of the anti-Aβ monoclonal antibody bapineuzumab on amyloid plaque load was assessed in AD subjects. After 78 weeks, subjects receiving bapineuzumab had reduced cortical 11C-PIB retention compared with their baseline and with placebo treated subjects. Through its detection of fibrillar Aβ, PET can detect the presence of Alzheimer pathology and provides a prognostic indicator of future progression of MCI to AD. However, PIB PET is not a marker of AD progression as the amyloid load remains relatively stable. 18F-FDG PET, a marker of synaptic activity, more closely mirrors cognitive decline as neurodegeneration progresses. Finally, PET allows the changes in glial activation in MCI to be monitored and provides a rationale for therapeutic trials of anti-inflammatory agents.