Primary and secondary signatures of psychomotor dysfunction in experimental models of normal aging and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder traditionally described through cognitive and neuropsychiatric/behavioural symptomatology. However, psychomotor motor dysfunctions and motor impairment remain under-explored. The 3xTg-AD model shows the neuropathological and cognitive alterations that characterise the disease similar to what occurs in humans, presenting β-amyloid plaques in the cortex and hippocampus at 12 months of age spread throughout the cortex. Subsequently, at 15 months, intraneuronal Tau tangles accompany this spread in the cerebral cortex. This research is based on the International Classification of Functioning and Disability, which is used worldwide in the rehabilitation of neurodegenerative pathologies, including AD, and from a life course approach associated with normal, accelerated and pathological ageing reproducible in different translational research contexts. For the study of AD, two research phases were included. In the first phase, the primary and secondary motor signatures of psychomotor dysfunction in normal ageing and Alzheimer's disease were characterised. Male 3xTg-AD and NTg mice aged 6 and 12 months were included in phase 1. In the second phase, the primary and secondary signatures were modulated and integrated under the exploration of external factors. Male 3xTg-AD and C57BL/6 mice were included between 13 and 16 months of age, and male and female 3xTg-AD and NTg mice aged 12 and 16 months were also included. Psychomotor tests assessed performance from spontaneous gait, exploratory activity, muscle strength, and physical endurance. In addition, frailty phenotype and specific phenotypes such as clasping reflex and geotaxis were included. Additionally, sarcopenia studies and HPA axis analysis were performed. For the first time, the results report the classification of primary and secondary signatures of psychomotor dysfunctions in the 3xTg-AD mice model. They were detected as primary signatures present in gait and exploratory activity from the study of quantitative and qualitative variables of psychomotor performance. They show a decrease in stride length, speed and cadence, modified by postural alterations such as structural kyphosis in 3xTg-AD mice. In addition, kyphosis is age-sensitive, changing from postural to structural in the ageing process. Also, the clasping reflex indicates the severity of AD, a primary signature like kyphosis. It includes the frailty phenotype that accompanies general psychomotor impairment in mice and increases with age. On the other hand, bizarre behaviour patterns that were evidenced in dry and water tests showed greater severity of affectation among 3xTg-AD mice. In addition, neophobia (freezing) alters performance, particularly exploration and locomotion. Also, bizarre patterns and kyphosis modify the performance of spontaneous gait and exploratory activity, which is preserved in normal ageing. Even secondary dysfunctions can be modulated by external factors such as isolation and a re-test of the behavioural battery, where 3xTg-AD mice improve motor performance in females and isolation in males. Also, physical endurance measured in rotarod was sex-sensitive, with 3xTg-AD and non-transgenic females performing better. However, they showed the highest indicators of frailty, sarcopenia and alteration of the HPA axis. Finally, functional impairments and alterations in 3xTg-AD mice are related to Alzheimer's disease stages, providing a scenario to understand the heterogeneity of non-cognitive symptoms of motor performance.

Date of Award	9 Sept 2022
Original language	English
Supervisor	Lidia Gimenez Llort (Director)