Persistence and emergence of new neuropsychological deficits following SARS-CoV-2 infection: A follow-up assessment of the Geneva COVID-COG cohort.

Background: Despite numerous observations of neuropsychological deficits immediately following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, little is known about what happens to these deficits over time and whether they are affected by changes in fatigue and any psychiatric symptoms. We aimed to assess the prevalence of neuropsychological deficits at 6-9 months and again at 12-15 months after coronavirus disease 2019 (COVID-19) and to explore whether it was associated with changes in fatigue and psychiatric symptoms. Methods: We administered a series of neuropsychological tests and psychiatric questionnaires to 95 patients (mean age = 57.12 years, standard deviation (SD) = 10.68; 35.79% women) 222 (time point 1 (T1)) and 441 (time point 2 (T2)) days on average after infection. Patients were categorised according to the severity of their respiratory COVID-19 symptoms in the acute phase: mild (no hospitalisation), moderate (conventional hospitalisation), and severe (hospitalisation in intensive care unit (ICU) plus mechanical ventilation). We ran Monte-Carlo simulation methods at each time point to generate a simulated population and then compared the cumulative percentages of cognitive disorders displayed by the three patient subgroups with the estimated normative data. We calculated generalised estimating equations for the whole sample to assess the longitudinal associations between cumulative neuropsychological deficits, fatigue, and psychiatric data (anxiety, depressive symptoms, posttraumatic stress disorder, and apathy). Results: Most participants (>50%) exhibited a decrease in their neuropsychological impairments, while approximately 25% showed an escalation in these cognitive deficits. At T2, patients in the mild subgroup remained free of accumulated neuropsychological impairments. Patients with moderate severity of symptoms displayed a decrease in the magnitude of cumulative deficits in perceptual and attentional functions, a persistence of executive, memory and logical reasoning deficits, and the emergence of language deficits. In patients with severe symptoms, perceptual deficits emerged and executive deficits increased, while attentional and memory deficits remained unchanged. Changes in executive functions were significantly associated with changes in depressive symptoms, but the generalised estimating equations failed to reveal any other significant effect. Conclusion: While most cumulative neuropsychological deficits observed at T1 persisted and even worsened over time in the subgroups of patients with moderate and severe symptoms, a significant proportion of patients, mainly in the mild subgroup, exhibited improved performances. However, we identified heterogeneous neuropsychological profiles both cross-sectionally and over time, suggesting that there may be distinct patient phenotypes. Predictors of these detrimental dynamics have yet to be identified.

Similar odor discrimination behavior in head-restrained and freely moving mice.

A major challenge in neuroscience is relating neuronal activity to animal behavior. In olfaction limited techniques are available for these correlation studies in freely moving animals. To solve this problem, we developed an olfactory behavioral assay in head-restrained mice where we can monitor behavioral responses with high temporal precision. Mice were trained on a go/no-go operant conditioning paradigm to discriminate simple monomolecular odorants, as well as complex odorants such as binary mixtures of monomolecular odorants or natural odorants. Mice learned to discriminate both simple and complex odors in a few hundred trials with high accuracy. We then compared the discrimination performance of head-restrained mice to the performance observed in freely moving mice. Discrimination accuracies were comparable in both behavioral paradigms. In addition, discrimination times were measured while the animals performed well. In both tasks, mice discriminated simple odors in a few hundred milliseconds and took additional time to discriminate the complex mixtures. In conclusion, mice showed similar and efficient discrimination behavior while head-restrained compared with freely moving mice. Therefore, the head-restrained paradigm offers a relevant approach to monitor neuronal activity while animals are actively engaged in olfactory discrimination behaviors.

Early locus coeruleus degeneration and olfactory dysfunctions in Tg2576 mice.

Olfactory deficiency has been reported in the early stages of Alzheimer's disease (AD) in humans but is very poorly understood due to the lack of investigations in animal models of AD. Recent studies point to the noradrenergic system as an important target of the AD pathological process. In addition, noradrenalin has been shown to influence adult neurogenesis which is implicated in cognitive functions. We have therefore investigated the olfactory neurogenesis and cognitive performances in young transgenic Tg2576 mice in relation with the status of the noradrenergic and the cholinergic systems. Tg2576 showed a deficit in neurogenesis in the olfactory bulb evidenced by an increased death of newborn cells and a reduced expression of PSA-NCAM. The locus coeruleus degenerated in Tg2576 between the age of 6.5 and 8 months. These changes were associated with olfactory memory impairments. Our findings indicate that a noradrenergic deficiency could play a role in the early stages of the pathological process in this transgenic model and induce olfactory cognitive impairments through an alteration of olfactory neurogenesis.

Noradrenergic neuromodulation in the olfactory bulb modulates odor habituation and spontaneous discrimination.

Noradrenergic projections from the locus coeruleus (LC) project to the olfactory bulb (OB), a cortical structure implicated in odor learning and perceptual differentiation among similar odorants. The authors tested the role of OB noradrenaline (NA) in short-term olfactory memory using an animal model of LC degeneration coupled with intrabulbar infusions of NA. Specifically, the authors lesioned cortical noradrenergic fibers in mice with the noradrenergic neurotoxin N-Ethyl-N-(2-chloroethyl)-2-bromobenzylamine hydrochloride (DSP4) and measured the effects on an olfactory habituation/spontaneous discrimination task. DSP4-treated mice failed to habituate to repeated odor presentations, indicating that they could not remember odors over the 5-min intertrial interval. The authors then infused NA bilaterally into the OBs of both DSP4-treated and nonlesioned control animals at two concentrations (10(-3)M and 10(-5)M, 2 microl/side). In DSP4-treated animals, NA administration at either concentration restored normal habituation and spontaneous discrimination performance, indicating that noradrenergic neuromodulation mediates these aspects of perceptual learning and that its efficacy does not require activity-dependent local regulation of NA release. Functional OB learning mechanisms may be necessary for normal odor recognition and differentiation among physically similar odorants.