Temporal Biomarker Model
We proposed a preclinical AD biomarker model in a recent publication (Leal and Yassa, 2013) based on cross-species investigations in aged rodents and aged humans with subclinical memory impairments as well as patients with MCI. We propose that the first synaptic degradation occurs in the perforant path, the loss of which is tightly coupled to CA3/DG dysfunction (indexed by fMRI). Decline in this pathway has retrograde effects (loss of EC neurons) that precede anterograde effects (loss of hippocampal neurons). We are now testing various aspects of this model using high-resolution structural and functional MRI, ultrahigh-resolution diffusion tensor imaging (hr-DTI), as well as high angular resolution diffusion imaging (HARDI).
Perforant path degradation as the earliest synapse loss in AD
The perforant path connects layer II EC neurons to the hippocampal DG and CA3 and is critical for normal hippocampal function. This pathway is reduced in aged rats with memory loss (Geinisman et al., 1992; Smith et al., 2000). Perforant path lesions also result in layer II EC neuronal loss (Peterson et al., 1994), one of the earliest hallmark features of AD. Thus, attempts to evaluate perforant path alterations are critical to understanding the extent of AD pathophysiology. We developed a novel in vivo ultra-high resolution (0.66 mm in-plane) microstructural DTI technique that we used to assess the perforant path (Yassa et al., 2010; Yassa et al., 2011). We demonstrated that (1) perforant path declines with age, (2) decline was tightly linked to cognitive performance on a pattern separation task and word list delayed recall, and (3) decline was also coupled to CA3/DG fMRI signals. We have since improved these methods, reduced scanning time, improved signal-to-noise ratio and conducted tractography to quantify the perforant path, which was consistent with post-mortem data (Augustinack et al., 2010). Based on these results, we propose that the perforant path lesion is the earliest indication of synapse loss, which subsequently leads to neurodegeneration in AD.
Hippocampal Hyperactivity in Mild Cognitive Impairment
One critical advantage to the study of neurocognitive aging is that we additionally gain a more complete understanding of the processes that change with healthy aging and changes that could potentially lead to pathology.This can be done by studying individuals with mild cognitive impairment (MCI), a preclinical phase that is associated with a high risk of conversion to Alzheimer’s disease. We have found that individuals with amnestic MCI (aMCI), a form of MCI where the hallmark cognitive features include memory loss, show a further degradation in pattern separation abilities, coupled with a decreased target recognition ability, suggesting that their memory system as a whole is compromised. In high-resolution fMRI studies, we observed that their CA3/dentate activity during a separation task is elevated beyond that of healthy aging (Yassa et al., 2010). In addition, we found that activity in the entorhinal cortex was decreased compared to controls, also suggesting that this region, which is the first to suffer from cellular loss in the course of AD, may be functionally impaired earlier on in the disease process. Based on this work and work in the rodent, we conducted a clinical trial where low dose levetiracetam was used to reduce hippocampal activity levels and rescue memory deficits (Bakker et al., 2012). This trial initiated a course of research into the disease-modifying effects of low-dose anti-epileptics that have also been corroborated in the aged rodent (Koh et al., 2011; Koh et al., 2013) and in AD mouse models (Sanchez et al., 2012).