Background to Hippocampal Volume in Alzheimer's Disease

Why look at the Hippocampus?

Atrophy is an extremely well established downstream effect of dementia. The hippocampus - a part of the brain associated with memory - is affected especially early in the disease course and the rate of atrophy is considerably higher for the hippocampus than for the brain as a whole. Changes in other regions of the brain including the amydala, the parahippocampal gyrus and the lateral ventricles are also associated with dementia.

Measurement of hippocampal volume (HCV) from structural MRI scans is a well-established biomarker in dementias including Alzheimer’s Disease (AD), correlating with disease stage (Fox et al 2000, Jack et al 2000), cognitive performance (Soininen et al 1994, van Petten 2004, Schuff et al 2009, Wolz et al 2010b), post-mortem Braak stage (Braak and Braak 1991) and local neuronal density (Bobinski et al 1999). In the Alzheimer’s pathological cascade (Jack et al. 2010), hippocampal atrophy accelerates before the transition to clinical dementia (Jack et al 2011b).

Indeed, low hippocampal volume has been shown to be a predictive marker of Alzheimer’s disease (AD) in subjects with mild cognitive impairment (MCI) (Convit et al. 1997, Jack et al. 1999, Gosche et al. 2002). It is proposed as a screening criterion to select a more homogeneous prodromal patient population of increased risk for rapid imminent clinical progression (Hampel et al. 2010), and has recently been qualified by the European Medicines Agency (EMA) as a biomarker to enrich prodromal AD clinical trials (EMA 2011) . Low hippocampal volume has also been proposed for new diagnostic criteria for MCI patients at high risk of converting to AD. (Albert 2011).

Other Structures Affected by Dementia

While the volume of research is greatest for AD, which is the most common dementia, atrophy of the hippocampus isn't just associated with Alzheimer's Disease. In frontal temporal dementia, the hippocampus often undergoes asymmetrical atrophy, and measuring this assymetry can assist with the differential diagnosis. Measurement of amydala volume can improve the quality of this differential diagnosis (Barnes et al 2006).

Automating the Assessment of Regional Brain Volumes

Manual volumetry of structures in the brain such as the hippocampus is a time-consuming task (Frisoni et al 2011), calling for automated methods to allow routine use. Multiple methods for the automated extraction of hippocampal volume have been proposed in recent years, e.g., (Fischl et al. 2002, Owen et al. 2005, Chupin et al. 2007, Leung et al. 2010, Wolz et al. 2010).

Accounting for Normal Variation in the Population

Measures of the volume of brain structures such as the hippocampus and amygdala are influenced by overall cranial cavity size, and natural age-related volume shrinkage. Therefore the measurement is often combined with some measurement of head size (such as total intracranial volume or affine scaling factors) and age is used as a covariate in order to reduce this variability.