Sex- and Neuropsychiatric-Dependent Circadian Alterations in Daily Voluntary Physical Activity Engagement and Patterns in Aged 3xTg-AD Mice.

Alzheimer's disease (AD) patients suffer from circadian rhythm alterations affecting their daily physical activity patterns with less willingness to perform a voluntary exercise. In preclinical studies, there is no clarity on whether animal models of AD can replicate these impairments. Here, we provide a proof of concept of the performance and behavioral effects of four weeks of voluntary wheel running (VWR) in a group of 14-month-old male and female 3xTg-AD mice at advanced stages of AD and the daily variance (behavioral circadian rhythmicity) of VWR associated with sex and their neuropsychiatric-like phenotype. Higher levels of horizontal exploration in the open field (OF) test were found in mice submitted to exercise. A linear mixed effect model showed significant sex-dependent differences in the VWR activity performed on the first night of follow-up, with high-NIBI males running less than high-NIBI females. Thus, an influence of NPS-like symptoms on the circadian patterns of VWR may account for such differences. In addition, males remained more active than females during diurnal periods. We hypothesize that this increment in energy expenditure during resting periods may be related to hyperactive behavior, similar to that observed in humans' exacerbated agitation or sundowning behavior. These findings support the usage of the 3xTg-AD mouse as a reliable model for studying circadian rhythm alterations in AD and, at the translational level, the importance of tailored and individualized physical activity programs in clinical settings.

Clasping, ledge-score coordination and early gait impairments as primary behavioural markers of functional impairment in Alzheimer's disease.

Motor performance facilitates the understanding of the functional state related to the progression of Alzheimer's disease (AD). At the translational level, this brief report refines the characterization of the motor dysfunction of the 3xTg-AD mouse model in different motor tasks, focusing on the abnormal clasping reflex and coordination impairments measured through the Phenotype Scoring System four items screening originally developed for models of ataxia. We studied male 3xTg-AD mice at 6, 12, and 16 months of age (mimicking the early, advanced, and late stages of the disease, respectively) and their age-matched non-transgenic counterparts with normal aging. According to the score, incidence, or severity of the four items and the total score, the 3xTg-AD mice showed deficiencies in all score elements. Clasping was increased independently of age, and its severity worsened with repeated testing. In contrast, the impairment of coordination worsened with the progress of the disease. The gait score was sensitive to genotype since early stages, and the worse ledge score was evident at 16 months. Kyphosis and ledge scores were sensitive to age. The impairments and functional limitations of male 3xTg-AD mice related to the stages of AD provide a scenario that allows understanding the heterogeneity of non-cognitive symptoms.

Impact of Behavioral Assessment and Re-Test as Functional Trainings That Modify Survival, Anxiety and Functional Profile (Physical Endurance and Motor Learning) of Old Male and Female 3xTg-AD Mice and NTg Mice with Normal Aging.

Longitudinal approaches for disease-monitoring in old animals face survival and frailty limitations, but also assessment and re-test bias on genotype and sex effects. The present work investigated these effects on 56 variables for behavior, functional profile, and biological status of male and female 3xTg-AD mice and NTg counterparts using two designs: (1) a longitudinal design: naïve 12-month-old mice re-tested four months later; and (2) a cross-sectional design: naïve 16-month-old mice compared to those re-tested. The results confirmed the impact as (1) improvement of survival (NTg rested females), variability of gait (3xTg-AD 16-month-old re-tested and naïve females), physical endurance (3xTg-AD re-tested females), motor learning (3xTg-AD and NTg 16-month-old re-tested females), and geotaxis (3xTg-AD naïve 16-month-old males); but (2) worse anxiety (3xTg-AD 16-month-old re-tested males), HPA axis (3xTg-AD 16-month-old re-tested and naïve females) and sarcopenia (3xTg-AD 16-month-old naïve females). Males showed more functional correlations than females. The functional profile, biological status, and their correlation are discussed as relevant elements for AD-pathology. Therefore, repetition of behavioral batteries could be considered training by itself, with some variables sensitive to genotype, sex, and re-test. In the AD-genotype, females achieved the best performance in physical endurance and motor learning, while males showed a deterioration in most studied variables.

Kyphosis and bizarre patterns impair spontaneous gait performance in end-of-life mice with Alzheimer's disease pathology while gait is preserved in normal aging.

The shorter life spans of mice provide an exceptional experimental gerontology scenario. We previously described increased bizarre (disruptive) behaviors in the 6-month-old 3xTg-AD mice model for Alzheimer's disease (AD), compared to C57BL/6J wildtype (NTg), when confronting new environments. In the present work, we evaluated spontaneous gait and exploratory activity at old age, using 16-month-old mice. Male sex was chosen since sex-dependent psychomotor effects of aging are stronger in NTg males than females and, at this age, male 3 × Tg-AD mice are close to an end-of-life status due to increased mortality rates. Mice's behavior was evaluated in a transparent test box during the neophobia response. Stretching, jumping, backward movements and bizarre circling were identified during the gait and exploratory activity. The results corroborate that in the face of novelty and recognition of places, old 3xTg-AD mice exhibit increased bizarre behaviors than mice with normal aging. Furthermore, bizarre circling and backward movements delayed the elicitation of locomotion and exploration, in an already frail scenario, as shown by highly prevalent kyphosis in both groups. Thus, the translational study of co-occurrence of psychomotor impairments and anxiety-like behaviors can be helpful for understanding and managing the progressive functional deterioration shown in aging, especially in AD.

Modeling Functional Limitations, Gait Impairments, and Muscle Pathology in Alzheimer's Disease: Studies in the 3xTg-AD Mice.

Gait impairments in Alzheimer's disease (AD) result from structural and functional deficiencies that generate limitations in the performance of activities and restrictions in individual's biopsychosocial participation. In a translational way, we have used the conceptual framework proposed by the International Classification of Disability and Health Functioning (ICF) to classify and describe the functioning and disability on gait and exploratory activity in the 3xTg-AD animal model. We developed a behavioral observation method that allows us to differentiate qualitative parameters of psychomotor performance in animals' gait, similar to the behavioral patterns observed in humans. The functional psychomotor evaluation allows measuring various dimensions of gait and exploratory activity at different stages of disease progression in dichotomy with aging. We included male 3xTg-AD mice and their non-transgenic counterpart (NTg) of 6, 12, and 16 months of age (n = 45). Here, we present the preliminary results. The 3xTg-AD mice show more significant functional impairment in gait and exploratory activity quantitative variables. The presence of movement limitations and muscle weakness mark the functional decline related to the disease severity stages that intensify with increasing age. Motor performance in 3xTg-AD is accompanied by a series of bizarre behaviors that interfere with the trajectory, which allows us to infer poor neurological control. Additionally, signs of physical frailty accompany the functional deterioration of these animals. The use of the ICF as a conceptual framework allows the functional status to be described, facilitating its interpretation and application in the rehabilitation of people with AD.

Translational Modeling of Psychomotor Function in Normal and AD-Pathological Aging With Special Concerns on the Effects of Social Isolation.

One year after the start of the COVID-19 pandemic, its secondary impacts can be globally observed. Some of them result from physical distancing and severe social contact restrictions by policies still imposed to stop the fast spread of new variants of this infectious disease. People with Alzheimer's disease (AD) and other dementias can also be significantly affected by the reduction of their activity programs, the loss of partners, and social isolation. Searching for the closest translational scenario, the increased mortality rates in male 3xTg-AD mice modeling advanced stages of the disease can provide a scenario of "naturalistic isolation." Our most recent work has shown its impact worsening AD-cognitive and emotional profiles, AD-brain asymmetry, and eliciting hyperactivity and bizarre behaviors. Here, we further investigated the psychomotor function through six different psychomotor analysis in a set of 13-month-old 3xTg-AD mice and their non-transgenic counterparts with normal aging. The subgroup of male 3xTg-AD mice that lost their partners lived alone for the last 2-3 months after 10 months of social life. AD's functional limitations were shown as increased physical frailty phenotype, poor or deficient psychomotor performance, including bizarre behavior, in variables involving information processing and decision-making (exploratory activity and spontaneous gait), that worsened with isolation. Paradoxical muscular strength and better motor performance (endurance and learning) was shown in variables related to physical work and found enhanced by isolation, in agreement with the hyperactivity and the appearance of bizarre behaviors previously reported. Despite the isolation, a delayed appearance of motor deficits related to physical resistance and tolerance to exercise was found in the 3xTg-AD mice, probably because of the interplay of hyperactivity and mortality/survivor bias. The translation of these results to the clinical setting offers a guide to generate flexible and personalized rehabilitation strategies adaptable to the restrictions of the COVID-19 pandemic.

PasoDoble, a Proposed Dance/Music for People With Parkinson's Disease and Their Caregivers.

Managing the heterogeneity of Parkinson's disease symptoms and its progressive nature demands strategies targeting the hallmark disrupted neurotransmission but also the comorbid derangements and bolstering neuroprotection and regeneration. Strong efforts are done to find disease-modifying strategies, since slowing disease progression is not enough to hamper its burden and some motor symptoms are resistant to dopamine-replacement therapy. The inclusion of non-pharmacological strategies can provide such a multitarget umbrella approach. The silent long-term biological process that precedes the clinical onset of disease is a challenge but also an opportunity to reinforce healthy lifestyle known to exert preventive/therapeutic effects. These non-pharmacological strategies are foreseen as able to reduce the prevalence and the global impact of long-term diseases demanding strong management of patient-caregiver quality of life. In this regard, European guidelines for Parkinson's disease recommend physical-related activities such as aerobic exercise and dancing known to improve functional mobility and balance in patients. Here, we propose "PasoDoble," a novel dance/music patient-caregiver intervention with additional preventive value. The rationale is founded on evidence-based therapeutic benefits of dance/music therapy and the singular features of this widely extended Hispanic dance/music targeting motor symptoms, mood/cognition, and socialization: (i) As a dance, an easy and simple double-step pattern (back-and-forward and lateral movements) that evolves from a spontaneous individual dance to a partnered dancing, performed in social groups and involving dancing-figures of increasing complexity; (ii) "PasoDoble," as a music that can be sung, has musical rhythmicity with high groove and familiarity that will help to synchronize the steps to the rhythm of music; (iii) Widely extended (Spain, Mexico, Puerto Rico, Colombia, and USA) and easy-to-learn for others. As a regular dancing "PasoDoble" can improve and preserve function, mood and socialization, as an intervention the method is structured to improve gait and balance; facilitate movement, reaching and grasping; muscle power and joint mobility; reduce of risk of falls, and increase of aerobic capacity. Finally, this easy-to-implement into patient care and free-living environments (elderly social centers, home care) rehabilitation programs can promote positive emotions and self-esteem, with added general improvement of social attachment and recognition, thus improving the quality of life of patient-caregiver.

Indexes for flotation and circling, two non-search behaviors in the water maze, sensitive to d-galactose-induced accelerated aging and Alzheimer's disease.

The study of behavioral and psychological symptoms of dementia (BPSD) has been largely neglected in most experimental research on Alzheimer's disease (AD) classically focused on cognitive symptoms. The aquatic environment of the Morris water maze (MWM) implies a stressful condition for mice leading to cognitive performances with presence of other behaviors related to emotionality. This can be critical in models such as the 3xTg-AD mice that exhibit a noticeable BPSD-like profile. The present work is aimed to provide a quantitative (number of episodes and duration) and qualitative (prevalence) analysis of flotation and circling, the most common 'non-searching behaviors' elicited in the MWM. We studied the expression of these behaviors in 6-month-old gold-standard wildtype C57BL/6 mice (genetic background) and 3xTg-AD mice (onset of disease) and when both genotypes were submitted to chronic d-galactose induced accelerated aging. Elicitation of floating and circling was recorded during three standard MWM paradigms: visual perceptual learning, place task for spatial reference memory and a final probe trial for short-term memory. In view of the results, we demonstrate that the index of 'flotation', characteristic of non-transgenic performance, is sensitive (reduction) to accelerated aging and AD. Conversely, circling behavior, characteristic of 3xTg-AD mice, can be an additional tool for evaluating BPSD-like symptoms in AD-models while its index unveils bizarre behavior induced by d-galactose induced aging. These results can be useful in relation to preventive and/or therapeutical interventions targeting AD but they may also be suitable in the evaluation of the potential risk factors in animals with normal aging.

Efectos de 8 semanas de entrenamiento intervalado de alta intensidad sobre los niveles de glicemia basal, perfil antropométrico y VO 2 máx de jóvenes sedentarios con sobrepeso u obesidad.

Introducción: existe una alta prevalencia de sedentarismo, sobrepeso y obesidad en jóvenes universitarios. Objetivo: el propósito del estudio fue determinar los efectos de un programa de entrenamiento intervalado de alta intensidad (HIIT) sobre el perfil antropométrico, glicemia basal y VO 2 máx (consumo máximo de oxígeno) de jóvenes sedentarios con malnutrición por exceso. Material y métodos: 6 mujeres y 2 hombres (2 obesos y 6 con sobrepeso) se sometieron a un programa de entrenamiento de alta intensidad de 8 semanas de duración (3 sesiones/semana). Se evaluó en ayuno y posterior a 72 horas de la última intervención; peso, índice de masa corporal (IMC), contorno de cintura (CC), perímetro de cadera y glicemia de basal. El VO 2 máx fue evaluado en condiciones normales previo a la primera sesión. Resultados: las variables de estudio no presentaron cambios significativos (p > 0,05), pero reportaron disminuciones porcentuales. El peso disminuyó un 0,18%, el IMC un 0,27%, el CC 2,67%, el perímetro de cadera un 1,15%, y el VO 2 máx un 0,48%. La glicemia basal presentó la mayor disminución, pasó de 95,13 ± 23,91 a 89,88 ± 12,45 mg/dl (5,52%), estabilizando y mejorando sus niveles en cada uno de los participantes. Conclusiones: el programa de entrenamiento intervalado de alta intensidad fue factible de realizar sin resultados adversos para la salud de los participantes, la glicemia basal mostró la mayor variación, estabilizando sus valores en los participantes, lo que es un indicador positivo dentro del programa. Es necesario seguir investigando sobre esta metodología HIIT y aumentar los tiempos de estudio para ver los cambios que se pueden producir en distintos parámetros metabólicos, antropométricos y físicos en población con malnutrición por exceso.

Efectos de 8 semanas de entrenamiento intervalado de alta intensidad sobre los niveles de glicemia basal, perfil antropométrico y VO2 máx de jóvenes sedentarios con sobrepeso u obesidad / Effects of 8 weeks of high intensity interval training program on the levels of basal blood glucose, anthropometric profile and VO2 max of young sedentary with overweight or obesity

Introducción: existe una alta prevalencia de sedentarismo, sobrepeso y obesidad en jóvenes universitarios. Objetivo: el propósito del estudio fue determinar los efectos de un programa de entrenamiento intervalado de alta intensidad (HIIT) sobre el perfil antropométrico, glicemia basal y VO2 máx (consumo máximo de oxígeno) de jóvenes sedentarios con malnutrición por exceso. Material y métodos: 6 mujeres y 2 hombres (2 obesos y 6 con sobrepeso) se sometieron a un programa de entrenamiento de alta intensidad de 8 semanas de duración (3 sesiones/semana). Se evaluó en ayuno y posterior a 72 horas de la última intervención; peso, índice de masa corporal (IMC), contorno de cintura (CC), perímetro de cadera y glicemia de basal. El VO2 máx fue evaluado en condiciones normales previo a la primera sesión. Resultados: las variables de estudio no presentaron cambios significativos (p > 0,05), pero reportaron disminuciones porcentuales. El peso disminuyó un 0,18%, el IMC un 0,27%, el CC 2,67%, el perímetro de cadera un 1,15%, y el VO2 máx un 0,48%. La glicemia basal presentó la mayor disminución, pasó de 95,13 ± 23,91 a 89,88 ± 12,45 mg/dl (5,52%), estabilizando y mejorando sus niveles en cada uno de los participantes. Conclusiones: el programa de entrenamiento intervalado de alta intensidad fue factible de realizar sin resultados adversos para la salud de los participantes, la glicemia basal mostró la mayor variación, estabilizando sus valores en los participantes, lo que es un indicador positivo dentro del programa. Es necesario seguir investigando sobre esta metodología HIIT y aumentar los tiempos de estudio para ver los cambios que se pueden producir en distintos parámetros metabólicos, antropométricos y físicos en población con malnutrición por exceso (AU)

Introduction: There is a high prevalence sedentary, overweight and obesity in young college. Objective: The purpose of this study was to determine the effects of a program of high intensity interval training program (HIIT) on the anthropometric profile, basal blood glucose and VO2 max of young sedentary with malnutrition by excess. Material and methods: 6 women and 2 men (2 obese and 6 with overweight) were submitted to a training program for high intensity of 8 weeks duration (3 session/week). It was evaluated in fasting and later to 72 hours after the last intervention; weight, body mass index (BMI), contour waist (CW), perimeter hip and basal blood glucose. The VO2 max was assessed in normal conditions prior to the first meeting. Results: The study variables did not present significant changes (p > 0.05), but they brought percentage decreases. The weight decreased by 0.18%, the BMI 0.27%, the CW 2.67%, the perimeter hip a 1.15%, and the VO2 max 0.48%. The basal blood glucose presented the biggest decrease, from 95.13 ± 23.91 to 89.88 ± 12.45 mg/dl (5.52%), stabilizing and improving its levels in each of the participants. Conclusions: It was possible to use high intensity interval training program without adverse results for the health of the participants. The basal blood glucose showed the greatest variation, stabilizing their values in the participants, which is a positive indicator within the program. It is necessary to keep on investigating on this methodology HIIT and to increase the learning times to see the changes that can take place in different parameters metabolites, anthropometric, physical in population with malnutrition by excess (AU)