Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation

Abstract

Six young related pre-symptomatic carriers of a His163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucose metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an ¹¹C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterised by relentless cognitive decline, usually afflicting elderly individuals, and accounting for up to 60% of all dementia cases (Ferri et al., 2005). Its pathology has been suggested to base upon abnormal deposition of β-amyloid amongst other things (Hardy and Selkoe, 2002). Genetic predisposition is well-known as a risk factor for developing AD, as family histories involving an early age at onset (younger than 65 years) and a clear autosomal dominant pattern of inheritance of AD with virtually 100% penetrance was recognised as early as in the 1930s (Lowenberg and Waggoner, 1934, Schottky, 1932, Sjögren et al., 1952). Mutations in three genes—the amyloid precursor protein (APP) gene on chromosome 21 (Goate et al., 1991), the presenilin 1 (PSEN1) gene on chromosome 14 (Sherrington et al., 1995) and the presenilin 2 (PSEN2) gene on chromosome 1 (Levy-Lahad et al., 1995, Rogaev et al., 1995)—have been found to be pathogenic in families with early onset AD.

While the above-mentioned mutations leading to the early onset familial form of AD (eoFAD) occur in only about 1% of all AD cases (Pastor and Goate, 2004), it has been estimated that the majority of eoFAD patients under the age of 60 carry a mutation in the PSEN1 gene, and may constitute up to 75% of afflicted families (Campion et al., 1999, Cruts et al., 1998, Pastor and Goate, 2004). More than 170 disease-causing mutations in this gene have been identified to date (http://www.molgen.ua.ac.be/ADMutations). Alzheimer's disease caused by mutations in the PSEN1 gene has been reported to exhibit characteristic early onset within a relatively narrow range of ages (Farrer et al., 1990, Van Broeckhoven, 1995, Van Duijn et al., 1991), although later onset and differing onset ranges have also been observed (Axelman et al., 1998, Rossor et al., 1996). All show a short and intense course, reflecting its severity. One mutation in the PSEN1 gene (His163Tyr) has been identified in a large multi-generational family living in Sweden (Axelman et al., 1998, Clark et al., 1995).

Studies in pre-symptomatic carriers employing imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT) have revealed regional abnormalities in cerebral glucose metabolism (CMRglc) (Kennedy et al., 1995, Mosconi et al., 2006, Polinsky et al., 1987) and brain blood-flow (Johnson et al., 2001) prior to the development of clinically significant impairment. Likewise, very early pathological changes in terms of amyloid deposition have been shown in a study in young pre-symptomatic PSEN1 mutation carriers by using ¹¹C-PIB PET (Klunk et al., 2007).

In the present study, our goal was to determine whether an abnormal pattern of cerebral glucose metabolism as measured by ¹⁸F-Fluorodeoxyglucose (FDG) PET could be identified in young pre-symptomatic carriers of a mutation in the PSEN1 gene, compared to a control group over a period of 2 years. The baseline scans were thereby on average performed 20 years before the expected age of disease onset for this specific mutation.

Furthermore we examined longitudinal changes in CMRglc in one carrier over a period of 12 years, as well as amyloid deposition as studied by PIB PET in this carrier after having received a clinical diagnosis of AD.