Imaging in familial dementias

Abstract

Background Though rare, early onset familial Alzheimer’s disease (FAD) provides strong support for the theory that beta-amyloid (Aβ) is involved in the pathogenesis of sporadic Alzheimer’s disease (AD). Mutations in the APP, presenilin 1 ( PSEN1 ), and presenilin 2 ( PSEN2 ) genes lead to increased Aβ 42 levels, even before symptoms arise. Magenetic resonance imaging (MRI) and FDG positron emission tomography (PET) shows the expected development of hippocampal atrophy and parietotemporal hypometabolism predating symptoms in carriers of these mutations consistent with findings in sporadic AD. However, beta-amyloid imaging with the PET tracer C-11 PiB has revealed that the distribution of binding is markedly different from that seen in sporadic AD. We evaluated the PiB retention pattern in individuals carrying either PSEN1 or APP mutations. Methods Six PSEN1 and one APP mutation carriers underwent 11 C-PiB and 18 F-FDG PET scans. Aβ burden was quantified using Standardised Uptake Value normalised to whole brain. PET results were compared against a well-characterised cohort of healthy controls (HC; n = 60) and AD ( n = 30) patients. Results All mutation carriers had very high PiB retention in the striatum, with variable cortical PiB retention in orbitofrontal and posterior cingulate/precuneus areas. The striatal pattern of PiB retention was similar in the PSEN1 and APP mutation carriers. Neither striatal nor cortical Aβ burden was related to cognitive status. Conclusions In contrast to sporadic AD where maximal PiB binding is seen in the frontal and precuneus/posterior cingulate cortex, binding in FAD is maximal in the striatum and thalamus with some subjects showing little binding in cortex despite the presence of dementia and severe cortical atrophy and hypometabolism. To further explore the relationship between Aβ deposition and cognitive decline in FAD, a NIH sponsored longitudinal study of at risk persons called DIAN (Dominantly Inherited Alzheimers Network) has commenced at sites in the USA, Australia and the UK that will utilise MRI, FDG PET, PiB PET and CSF and blood analyses at regular intervals.