Reaction-Diffusion Model of Cortical Atrophy Spread during Early Stages of Alzheimer’s Disease

1.AbstractThis study introduces a reaction-diffusion model of atrophy spread across the rhinal cortex during early stages of Alzheimer’s disease. Our finite elements model of atrophy spread is motivated by histological evidence of a spatio-temporally specific pattern of neurofibrillary tau accumulation, and evidence of grey matter atrophy correlating with sites of neurofibrillary tau accumulation. The goal is to estimate disease-related parameters such as the origin of atrophy, the speed at which atrophy spreads, and the stage of the disease. We solve a constrained optimization problem using the adjoint state method and gradient descent to match modeled cortical thickness to observed cortical thickness as calculated from 3T MRI scans. Simulation testing shows that disease-related parameters can be estimated accurately with as little as 2 years of annual observations, depending on the stage of the disease. Case studies of 3 subjects suggests that we can pinpoint the origin of atrophy to the anterior transentorhinal cortex, and that the speed of atrophy spread is less than 1 mm per year. In the future, this type of modeling could be useful to stage the progression of the disease prior to the onset of clinical symptoms.2.Author SummaryMisfolded tau proteins are associated with Alzheimer’s disease. They are known to accumulate and spread across the rhinal cortex, which is an area of the temporal lobe. Recent imaging studies suggest that we can detect grey matter thinning that occurs in pattern similar to tau spread. In this study, we introduce a model of disease spread to examine where thinning begins, how fast it spreads, and the stage of the disease. The results show that the origin of thinning corresponds with the earliest known location of tau accumulation, and spreads at a rate of less than 1 mm per year. Future work may focus on staging the progression of the disease using this type of model.

The effect of A1R agonist on epileptiform activity in organotypic slices

Epilepsy is a common neurological disorder but resistance to pharmacotherapy makes it necessary the development of novel antiepileptic drugs (AEDs). An A1 adenosine receptor (A1R) agonist, MRS5474, possesses anticonvulsant activity in an animal model (Tosh et al.,2012-J.Med.Chem., 55,8075), without the cardiac side effects common to other A1R agonists, leading us to hypothesise that it could operate through a mechanism different from classical A1R agonists. We thus tested this hypothesis in an ex vivo model of epileptogenesis in rhinal cortex -hippocampus organotypic slices (Magalhães et al., 2018-J.Neuroinflam.15:203). MRS5474 (250nM) was incubated during 1h with slices under depolarizing ([K + ] o =8.5mM) or non-depolarizing ([K + ] o =3mM) conditions. Interestingly, MRS5474 decreased by 6615% (n=4, P<0.05) the number of bursts from slices under high K + but not under normal K + . Event frequency, amplitude and burst duration were not affected. The canonical A1R agonist, N 6 -cyclopentyladenosine (30nM, n=4) prevented burst-like activity (number of bursts decreased to zero, spike amplitude markedly reduced) even under non-depolarizing conditions. Our results showing that MRS5474 prevents spontaneous neuronal firing only under depolarizing conditions, suggest that it may predominantly influence spontaneous synchronous firing of stressed neurons, sparing non-injured ones. This renders this compound with presumably less side effects than other A1R agonists and currently available AEDs.

Distinct Patterns of Hippocampal and Neocortical Evolution in Primates

Because of the central role of the hippocampus in representing spatial and temporal details of experience, comparative studies of its volume and structure are relevant to understanding the evolution of representational memory across species. The hippocampal formation, however, is organized into separate anatomical subregions with distinct functions, and little is known about the evolutionary diversification of these subregions. We investigate relative volumetric changes in hippocampal subregions across a large sample of primate species. We then compare the evolution of the hippocampal formation to the neocortex. Results across hippocampal subregions indicate that, compared to strepsirrhines, the anthropoid lineage displays a decrease in relative CA3, fascia dentata, subiculum, and rhinal cortex volume in tandem with an increase in relative neocortical volume. These findings indicate that hippocampal function in anthropoids might be substantially augmented by the executive decision-making functions of the neocortex. Humans are found to have a unique cerebral organization combining increased relative CA3, subiculum, and rhinal cortex with increased relative neocortical volumes, suggesting that these regions may play a role in behaviors that are uniquely specialized in humans.

Theta Phase Synchronization between the Human Hippocampus and Prefrontal Cortex Increases during Encoding of Unexpected Information: A Case Study

Events that violate predictions are thought to not only modulate activity within the hippocampus and PFC but also enhance communication between the two regions. Scalp and intracranial EEG studies have shown that oscillations in the theta frequency band are enhanced during processing of contextually unexpected information. Some theories suggest that the hippocampus and PFC interact during processing of unexpected events, and it is possible that theta oscillations may mediate these interactions. Here, we had the rare opportunity to conduct simultaneous electrophysiological recordings from the human hippocampus and PFC from two patients undergoing presurgical evaluation for pharmacoresistant epilepsy. Recordings were conducted during a task that involved encoding of contextually expected and unexpected visual stimuli. Across both patients, hippocampal–prefrontal theta phase synchronization was significantly higher during encoding of contextually unexpected study items, relative to contextually expected study items. Furthermore, the hippocampal–prefrontal theta phase synchronization was larger for contextually unexpected items that were later remembered compared with later forgotten items. Moreover, we did not find increased theta synchronization between the PFC and rhinal cortex, suggesting that the observed effects were specific to prefrontal–hippocampal interactions. Our findings are consistent with the idea that theta oscillations orchestrate communication between the hippocampus and PFC in support of enhanced encoding of contextually deviant information.

Perceptual processing in the ventral visual stream requires area TE but not rhinal cortex

There is an on-going debate over whether area TE, or the anatomically adjacent rhinal cortex, is the final stage of visual object processing. Both regions have been implicated in visual perception, but their involvement in non-perceptual functions, such as short-term memory, hinders clear-cut interpretation. Here, using a two-interval forced choice task without a short-term memory demand, we find that after bilateral removal of area TE, monkeys trained to categorize images based on perceptual similarity (morphs between dogs and cats), are, on the initial viewing, badly impaired when given a new set of images. They improve markedly with a small amount of practice but nonetheless remain moderately impaired indefinitely. The monkeys with bilateral removal of rhinal cortex are, under all conditions, indistinguishable from unoperated controls. We conclude that the final stage of the integration of visual perceptual information into object percepts in the ventral visual stream occurs in area TE.