Medicine: Centre for Neuroscience, Imperial College London
Doi
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