Research theme #3

Alzheimer/semantic dementia

Understanding the paradoxical uncoupling between episodic amnesia and hippocampal atrophy

Hippocampal atrophy is a key feature of AD, and has been shown to correlate with episodic memory deficits. This makes a lot of sense given the major role of this structure in episodic memory, largely demonstrated in patients with focal hippocampal lesions or using functional neuroimaging in healthy controls.

However, it has been suggested that patients with semantic dementia – SD, a rather rare and specific subtype of FrontoTemporal Lobar Degeneration – also experience hippocampal atrophy while their memory deficits clearly differ from AD patients. Indeed, they have (relatively) spared day-to-day episodic memory but major semantic memory impairments (Nestor et al., 2006). Considering autobiographical memory, AD and SD patients have reverse temporal gradients of deficits: SD patients have specific difficulties retrieving oldest memories while AD patients have global deficits, with the most remote period being better preserved than the others (Piolino et al., 2003).

COMPARING AD AND SD: A CLINICAL IMAGING PARADOX. in both cases, hippocampal atrophy is detectable while episodic memory deficits are only major in AD.

In a first step, we aimed at objectively assess the similarity – and highlight potential differences – between the patterns of brain and hippocampal atrophy associated with AD and SD.

In an exploratory, hypothesis-free analysis of whole brain atrophy performed on 18 AD patients, 13 SD patients and 58 healthy elders using Voxel Based Morphometry, we showed that patterns of gray matter atrophy associated with the two disorders partially overlapped, notably in the (medial) temporal lobe (see Figure below and La Joie et al., Neuron 2014).


GRAY MATTER ATROPHY IN AD AND SD. Voxel-based morphometry (VBM) analyses of gray matter atrophy in AD and SD, as well as the overlap of these patterns, showing common atrophy in the temporal lobe, including the hippocampus (derived from La Joie et al., Neuron 2014).

We then focused on the hippocampus, using a specific MR sequence we had previously developed to assess hippocampal subfields in vivo (La Joie et al., Neuroimage 2010).


SPECIFIC ANALYSIS OF HIPPOCAMPAL (SUBREGIONAL) ATROPHY. AD and SD patients have comparable hippocampal atrophy (left), which predominates in the CA1 subfield in both groups. However, the anterior-posterior gradient of atrophy is stronger in SD, indicating that the anterior hippocampus is disproportionately atrophied (derived from La Joie et al., Neuroimage clinical 2013).

After careful manual delineation, we showed that AD and SD patients:

– have quantitatively comparable hippocampal atrophy when considering the whole structure,

– both have predominant CA1 and Subicular atrophy,

– only slightly differ in terms of asymmetry and anterior-posterior gradient, atrophy being more asymmetric and anterior-predominant in SD.
(See opposite Figure and La Joie et al., Neuroimage Clinical 2013)

Given that these slight differences were unlikely to account for the major cognitive differences between AD and SD alone, we decided to move from a very hippocampal-centric regional point of view to a broader network-based perspective. As a matter of fact, recent evidence suggests that neurodegenerative diseases do not develop randomly in the cortex, but rather target large-scale networks that preexist in the normal brain (Seeley et al., Neuron 2009; Zhou et al., Neuron 2009; See Alzforum’s 2009 News story and 2012 webminar).

In line with this idea, we hypothesized that AD and SD mechanisms target two partly overlapping networks that both encompass the hippocampus but have distinct functions in the normal brain.

To identify these networks in the normal brain, we first compared FDG-PET data between AD and SD patients (see Image below, top pannel) and used resultant cluster peaks as seeds for intrinsic connectivity analyses in healthy controls using resting-state fMRI (see Figure below, bottom panel). Interestingly, all the connectivity patterns converged to the medial temporal lobe, indicating that the hippocampus is connected to regions that are specifically altered in AD and SD.

NETWORKS ASSOCIATED WITH AD AND SD. Top panel shows hypometabolism (FDG-PET) differences between AD and SD patients, indicating that some cortical regions are specifically involved in each disease. Bottom panel represents intrinsic connectivity analyses (resting-state fMRI) of these SD and AD-specific regions performed in a group of healthy elders. It shows that all regions that are specifically altered in AD or SD is functionally connected to the hippocampus in the normal brain as indicated by the region of overlap between the 6 networks, see bottom right (derived from La Joie et al., Neuron 2014).

In further analyses, we showed that:
– in the normal brain, connectivity between the hippocampus and AD-specific regions only underlies episodic memory abilities
– there are variations in terms of cortical connectivity along the anterior-posterior axis of the hippocampus in the normal brain, and that these regions that are more tightly connected to the anterior hippocampus are those that undergo stronger degeneration in SD than in AD. This is in line with our previous result of a stronger anterior-predominance of hippocampal atrophy in SD than in AD.


 Overall, we have shown that the hippocampus is at the crossroad of two large-scale networks in the normal brain and that these network have different functions and different vulnerability to disease.
This  helps us understand how two different diseases can impair the same region, and at the same time have very distinct cognitive deficits.

Papers I (co)authored: La Joie et al., Neuroimage Clinical 2013; La Joie et al., Neuron 2014
Main collaborators: Alexandre Bejanin, Gaël Chételat, Béatrice Desgranges, Vincent de La Sayette, Serge Belliard.
Further reading:
– on the AD/SD comparison: Piolino et al., Brain 2003; Nestor et al., Neuroimage 2006; Drzezga et al., Neuroimage 2008; Han et al., Brain 2014.
– on hippocampal networks and network-based theories of neurodegeneration propagation: Seeley et al., Neuron 2009; Ranganath & Ritchey, Nature Review Neuroscience 2012.

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