A meta-analysis of hippocampal atrophy rates in Alzheimer's disease

Abstract

Hippocampal atrophy rates are useful in both diagnosing and tracking Alzheimer's disease (AD). However, cohorts and methods used to determine such rates are heterogeneous, leading to differences in reported annualised rates. We performed a meta-analysis of hippocampal atrophy rates in AD patients and matched controls from studies reported in the peer-reviewed literature. Studies reporting longitudinal volume change in hippocampi in AD subjects together with controls were systematically identified and appraised. All authors were contacted either to confirm the results or to provide missing data. Meta-analysis and meta-regression were then performed on this data. Nine studies were included from seven centres, with data from a total of 595 AD and 212 matched controls. Mean (95% CIs) annualised hippocampal atrophy rates were found to be 4.66% (95% CI 3.92, 5.40) for AD subjects and 1.41% (0.52, 2.30) for controls. The difference between AD and control subject in this rate was 3.33% (1.73, 4.94).

Introduction

Alzheimer's disease (AD) is a large and growing problem with increasing financial and social burdens to the individual, carers and society. AD affects over 5% of the population over 60 years (Dawbarn and Allen, 2001) and its prevalence doubles every 5–10 years above that age (Small et al., 1997). A definitive diagnosis of AD can only be given following pathologic examination of the brain, usually at post-mortem. The disease is pathologically characterised by the presence of microscopic extracellular neuritic plaques and intracellular neurofibrillary tangles. AD tangle pathology progresses from medial temporal lobe structures such as the entorhinal cortex and hippocampus, to encompass the whole cortex, whereas plaque pathology is largely cortical and increases with disease severity (Braak et al., 1993). One of the results of this pathology is cerebral atrophy which can be visualised using structural MRI (Scheltens et al., 2002). The atrophy can be seen even at a single time-point, as brain structures in Alzheimer's subjects are smaller on average compared with controls. In addition, loss of tissue volume over time can also be detected in large regions such as the whole brain (Jack et al., 2004) and in smaller temporal areas such as the hippocampus (Jack et al., 2004) and entorhinal cortex (Du et al., 2004). This has led to a number of studies that have suggested that hippocampal atrophy rates may be useful both diagnostically, and to track disease progression.

Many studies assessing longitudinal hippocampal change have been reported in the literature (Fox et al., 1996, Jack et al., 2004, Kaye et al., 2005). Different methods have been used to generate these rates of atrophy including automated (Wang et al., 2003, Du et al., 2004) and manual techniques (Jack et al., 2004, Barnes et al., 2005). In addition, different populations of patients have also been included. To the best of our knowledge, no statistical review of the hippocampal atrophy rate literature has been conducted to date. Such a review is required to assess heterogeneity of reported studies, to better understand how age and disease severity affect the calculated atrophy rates, and to pool the results from these studies to more accurately estimate the rate of atrophy of the hippocampus in AD and matched control groups. This type of analysis may also be useful in identifying outlier results where the methodology employed may deserve critical review. In addition measuring the inter-site variance in hippocampal atrophy rates may be useful for anyone planning a multi-site trial, as it may define the level of consistency to expect in the imaging measures across sites.

The objective of this study is to perform a meta-analysis of hippocampal atrophy rates in patients with AD and matched controls from studies reported in the peer-reviewed literature.