Impact of Social Isolation on the Behavioral, Functional Profiles, and Hippocampal Atrophy Asymmetry in Dementia in Times of Coronavirus Pandemic (COVID-19): A Translational Neuroscience Approach

Abstract

The impact of COVID-19 on the elderly is devastating, and nursing homes are struggling to provide the best care to the most fragile. The urgency and severity of the pandemic forces the use of segregation in restricted areas and confinement in individual rooms as desperate strategies to avoid the spread of disease and the worst-case scenario of becoming a deadly trap. The conceptualization of the post–COVID-19 era implies strong efforts to redesign all living conditions, care/rehabilitation interventions, and management of loneliness forced by social distance measures. Recently, a study of gender differences in COVID-19 found that men are more likely to suffer more severe effects of the disease and are over twice as likely to die. It is well-known that dementia is associated with increased mortality, and males have worse survival and deranged neuro-immuno-endocrine systems than females. The present study examines the impact of long-term isolation in male 3xTg-AD mice modeling advanced stages of Alzheimer's disease (AD) and as compared to age-matched counterparts with normal aging. We used a battery of ethological and unconditioned tests resembling several areas in nursing homes. The main findings refer to an exacerbated (two-fold increase) hyperactivity and emergence of bizarre behaviors in isolated 3xTg-AD mice, worrisome results since agitation is a challenge in the clinical management of dementia and an important cause of caregiver burden. This increase was consistently shown in gross (activity in most of the tests) and fine (thermoregulatory nesting) motor functions. Isolated animals also exhibited re-structured anxiety-like patterns and coping-with-stress strategies. Bodyweight and kidney weight loss were found in AD-phenotypes and increased by isolation. Spleen weight loss was isolation dependent. Hippocampal tau pathology was not modified, but asymmetric atrophy of the hippocampus, recently described in human patients with dementia and modeled here for the first time in an animal model of AD, was found to increase with isolation. Overall, the results show awareness of the impact of isolation in elderly patients with dementia, offering some guidance from translational neuroscience in these times of coronavirus and post–COVID-19 pandemic. They also highlight the relevance of personalized-based interventions tailored to the heterogeneous and complex clinical profile of the individuals with dementia and to consider the implications on caregiver burden.

Digging Signatures in 13-Month-Old 3xTg-AD Mice for Alzheimer's Disease and Its Disruption by Isolation Despite Social Life Since They Were Born

“…Thus, despite the current brief report could be considered preliminary, our precedent data describing the consistency of digging in males studied in a social paradigm (Torres-Lista and Giménez-Llort, 2019 ) and of increased nest-building in animals under a long-term isolation (Muntsant and Giménez-Llort, 2020a ) support the consistent observations during housing routines that lead to this work and the present results showing disruptions in the subgroup under isolation. Still, the limitations of the current work must be noted and are mainly due to the naturalistic scenario, since the natural death of home-cage partners at this age only affects to 3xTg-AD mice (Giménez-Llort et al, 2008 ).…”

“…In the present work, the effects of a short-isolation did not modify the general motor activity pattern nor the anxiety-like profile of 3xTg-AD mice. However, as we have shown recently (Muntsant and Giménez-Llort, 2020a ), a longer isolation regime induced re-structured negative valence system with the emergence of bizarre behaviors and flight copying-with-stress strategies were found. More importantly, with regards of the present work, the long-term period induced a prominent hyperactive pattern in both gross (general motor activity in most tests) and fine-motor functions (increased nesting-behavior) that were correlated to hippocampal tau pathology (Muntsant and Giménez-Llort, 2020a ).…”

“…However, as we have shown recently (Muntsant and Giménez-Llort, 2020a ), a longer isolation regime induced re-structured negative valence system with the emergence of bizarre behaviors and flight copying-with-stress strategies were found. More importantly, with regards of the present work, the long-term period induced a prominent hyperactive pattern in both gross (general motor activity in most tests) and fine-motor functions (increased nesting-behavior) that were correlated to hippocampal tau pathology (Muntsant and Giménez-Llort, 2020a ). Activation of cortical and striatal regions during the expression of a naturalistic compulsive-like behavior in the rabbit have been described (Cano-Ramírez and Hoffman, 2018 ), so these are also our target areas in our current investigations.…”

“…In contrast, in 3xTg-AD mice, limited impact was found when long-term isolation was implemented from postweaning to adulthood (Pietropaolo et al, 2009 ). However, in our most recent work with these new Spanish colonies of 3xTg-AD mice, and also studying naturally occurring long-term isolation due to loss of partners in an aged scenario, we found that tau pathology of 3xTg-AD mice was enhanced, albeit did not reach the statistical significance, probably due to a celing effect (Muntsant and Giménez-Llort, 2020a ). Nevertheless, the hippocampal atrophy asymmetry found in human patients with AD (Wachinger et al, 2016 ) was modeled for the first time in mice and allowed us to show its worsening after long-term isolation.…”

“…In a social paradigm, elicitation of digging behavior was similar among males independently of their genotype but early expressed in female 3xTg-AD mice (Torres-Lista and Giménez-Llort, 2019 ). In our most recent work, in male 3xTg-AD mice under a long-term isolation (Muntsant and Giménez-Llort, 2020a ) increased gross and fine motor activity was recorded, with enhanced nest-building. This is also a species-specific natural behavior that, when disrupted, some authors consider a homologous to hoarding in humans with OCD (Warneke, 1993 ) and modeling compulsive-like behavior in mice (Greene-Schloesser et al, 2011 ).…”