It was therefore, previously, hypothesized that topographical memory impairment would be sensitive and specific for early AD. This constellation of affected regions (MTL, posterior cingulate, retrosplenial cortex, posterior parietal lobe) is homologous with the network activated when healthy volunteers navigate in functional magnetic resonance imaging (MRI) paradigms ( Ghaem et al., 1997 Maguire et al., 1998 Burgess et al., 2001 Ino et al., 2002 Shelton and Gabrieli, 2002 Rosenbaum et al., 2004 Wolbers et al., 2004 Wolbers and Buchel, 2005 Ekstrom and Bookheimer, 2007 Iaria et al., 2007 Ino et al., 2007). Indeed, the earliest hypometabolic region identified in AD is the posterior cingulate/retrosplenial cortex ( Minoshima et al., 1997 Nestor et al., 2003a) with posterior temporoparietal hypometabolism emerging as the next most affected isocortical region with disease progression ( Nestor et al., 2003b Chetelat et al., 2005).
This is also true of the MCI-stage of sporadic AD in which there is comparable atrophy of retrosplenial cortex, posterior cingulate cortex and hippocampus ( Choo et al., 2010 Pengas et al., 2010a). Furthermore, it is now well documented that prodromal AD is not simply a “hippocampal” disease: at a presymptomatic stage, carriers of familial, autosomal dominant AD mutations had both accelerated hippocampal and posterior cingulate volume loss ( Scahill et al., 2002). For instance, Braak and Braak (1991) used NFTs for their proposed staging protocol, precisely because they observed that NFT pathology followed a progressive pattern in AD it is therefore expected that NFTs will correlate with other measures of disease severity. Such reasoning, however, might be an oversimplification. The reasons for this are self-evident: neurofibrillary tangle (NFT) pathology in AD begins in the MTL ( Braak and Braak, 1991) NFT load correlates with cognition in AD ( Giannakopoulos et al., 2003) and the hippocampus is known to be atrophic in AD ( Jack et al., 1997), including those at the mild cognitive impairment (MCI) stage whose deficit is restricted to memory ( Pengas et al., 2010a). Memory impairment in Alzheimer's disease (AD) is often assumed to be a consequence of mesial temporal lobe (MTL) degeneration. The results also emphasize that structures beyond the mesial temporal lobe (MTL) contribute to memory impairment in AD-it is too simplistic to view memory impairment in AD as a synonym for hippocampal degeneration. These results offer strong evidence that topographical memory impairment in AD relates to damage across a network, in turn offering complimentary lesion evidence to previous studies in healthy volunteers for the neural basis of topographical memory. It also identified right medio-dorsal thalamus (part of the limbic-diencephalic hypometabolic network of early AD) and right caudate nucleus (activated during normal route learning).
The multivariate analysis revealed a significant, right hemisphere-predominant, network level correlation with cerebral metabolism this comprised areas common to both activation in normal route learning and early degeneration in AD (retrosplenial and lateral parietal cortices). Univariate analyses of GM density, metabolism and WM axial diffusion converged on the vicinity of the retrosplenial/posterior cingulate cortex, isthmus and, possibly, hippocampal tail. GM density and cerebral metabolism were then submitted to a multivariate analysis to examine whether there was a network associated with task performance. VRLT score in a mild AD cohort was regressed against gray matter (GM) density and diffusion tensor metrics of white matter (WM) ( n = 30), and, cerebral glucose metabolism ( n = 26), using a mass univariate approach.
This study investigated the neural basis of VRLT performance in AD to test whether impairment was underpinned by a network or by the widely held explanation of hippocampal degeneration.
This inspired the virtual route learning test (VRLT) in which patients learn routes in a virtual reality environment. The network activated during normal route learning shares considerable homology with the network of degeneration in the earliest symptomatic stages of Alzheimer's disease (AD). 2Neuroscience Research Australia, Sydney, NSW, Australia.1Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.Hong 1, David Izquierdo-Garcia 1†, Tim D. Williams 1, Julio Acosta-Cabronero 1, Tom W.