The effect of exercise on early sensorimotor performance alterations in the 3xTg-AD model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a progressive decline in cognitive function; however, recent evidence suggests that non-cognitive sensorimotor and psychomotor symptoms accompany early stages of the disease in humans and AD models. Although exercise is emerging as an important therapeutic to combat AD progression, little is known about the effect of exercise on sensorimotor domain functions. The purpose of this study was to determine if early sensorimotor symptoms accompany deficits in Morris water maze (MWM) performance in the 3xTg-AD model, and investigate if exercise could protect against early behavioral decline. 3xTg-AD and wild-type (WT) control mice were subjected to 12 weeks of moderate intensity wheel running or remained sedentary. At 6 months of age, animals underwent a series of sensorimotor and MWM testing. 3xTg-AD mice displayed deficits in sensorimotor function (beam traversal, spontaneous activity, and adhesive removal) and MWM performance. Interestingly, 3xTg-AD animals exhibited increased freezing and unusual shaking/tremoring behaviors not displayed by WT controls. Exercise improved beam traversal, adhesive removal, and reduced the unusual motor-related behaviors in 3xTg-AD mice. Our study shows that sensorimotor symptoms coincide with deficits in MWM performance, and suggest that exercise may mitigate deficits associated with early disease in 3xTg-AD mice.

Evaluation of pain knowledge and attitudes and beliefs from a pre-licensure physical therapy curriculum and a stand-alone pain elective.

BACKGROUND: Adequate pain education of health professionals is fundamental in the management of pain. Although an interprofessional consensus of core competencies for health professional pre-licensure education in pain have been established, the degree of their incorporation into physical therapy curriculum varies greatly. The purpose of this study was to 1. Assess students' pain knowledge and their attitudes and beliefs in a pre-licensure physical therapy curriculum using a cross sectional comparison, and 2. Using a sub-sample of this population, we evaluated if an elective course on pain based on International Association for the Study of Pain (IASP) guidelines had an effect on students' knowledge and beliefs. METHODS: The Neurophysiology of Pain Questionnaire (NPQ) and the Pain Attitudes and Beliefs Scale for Physiotherapists (PABS-PT) was completed by first semester (n = 72) and final (n = 56) semester doctor of physical therapy (DPT) students. Final semester students completed surveys before and after participation in an elective course of their choosing (pain elective (PE) or other electives (OE)). RESULTS: Participation rate was > 90% (n = 128/140). We found mean differences in NPQ scores between final semester (3rd year) students (76.9%) compared to first semester students (64%), p < 0.001. Third year students showed a mean difference on PABS-PT subscales, showing decreased biomedical (p < 0.001) and increased biopsychosocial (p = 0.005) scores compared to first semester students. Only final semester students that participated in the PE improved their NPQ scores (from 79 to 86%, p < 0.001) and demonstrated a significant change in the expected direction on PABS-PT subscales with increased biopsychosocial (p = 0.003) and decreased biological scores (p < 0.001). CONCLUSIONS: We suggest that although core pre-licensure DPT education improves students' pain knowledge and changes their attitudes towards pain, taking a IASP based pain elective continues to improve their pain neurobiology knowledge and also further changes their attitudes and beliefs towards pain. Therefore, a stand-alone course on pain in addition to pain concepts threaded throughout the curriculum may help ensure that entry-level DPT students are better prepared to effectively work with patients with pain.

Physical Training and Activity in People With Diabetic Peripheral Neuropathy: Paradigm Shift.

Diabetic peripheral neuropathy (DPN) occurs in more than 50% of people with diabetes and is an important risk factor for skin breakdown, amputation, and reduced physical mobility (ie, walking and stair climbing). Although many beneficial effects of exercise for people with diabetes have been well established, few studies have examined whether exercise provides comparable benefits to people with DPN. Until recently, DPN was considered to be a contraindication for walking or any weight-bearing exercise because of concerns about injuring a person's insensitive feet. These guidelines were recently adjusted, however, after research demonstrated that weight-bearing activities do not increase the risk of foot ulcers in people who have DPN but do not have severe foot deformity. Emerging research has revealed positive adaptations in response to overload stress in these people, including evidence for peripheral neuroplasticity in animal models and early clinical trials. This perspective article reviews the evidence for peripheral neuroplasticity in animal models and early clinical trials, as well as adaptations of the integumentary system and the musculoskeletal system in response to overload stress. These positive adaptations are proposed to promote improved function in people with DPN and to foster the paradigm shift to including weight-bearing exercise for people with DPN. This perspective article also provides specific assessment and treatment recommendations for this important, high-risk group.

Early alterations in blood and brain RANTES and MCP-1 expression and the effect of exercise frequency in the 3xTg-AD mouse model of Alzheimer's disease.

Exercise has been shown to protect against cognitive decline and Alzheimer's disease (AD) progression, however the dose of exercise required to protect against AD is unknown. Recent studies show that the pathological processes leading to AD cause characteristic alterations in blood and brain inflammatory proteins that are associated with the progression of AD, suggesting that these markers could be used to diagnosis and monitor disease progression. The purpose of this study was to determine the impact of exercise frequency on AD blood chemokine profiles, and correlate these findings with chemokine brain expression changes in the triple transgenic AD (3xTg-AD) mouse model. Three month old 3xTg-AD mice were subjected to 12 weeks of moderate intensity wheel running at a frequency of either 1×/week or 3×/week. Blood and cortical tissue were analyzed for expression of monocyte chemotactic protein-1 (MCP-1) and regulated and normal T cell expressed and secreted (RANTES). Alterations in blood RANTES and MCP-1 expression were evident at 3 and 6 month old animals compared to WT animals. Three times per week exercise but not 1×/week exercise was effective at reversing serum and brain RANTES and MCP-1 expression to the levels of WT controls, revealing a dose dependent response to exercise. Analysis of these chemokines showed a strong negative correlation between blood and brain expression of RANTES. The results indicate that alterations in serum and brain inflammatory chemokines are evident as early signs of Alzheimer's disease pathology and that higher frequency exercise was necessary to restore blood and brain inflammatory expression levels in this AD mouse model.

PI3K mediated activation of GSK-3ß reduces at-level primary afferent growth responses associated with excitotoxic spinal cord injury dysesthesias.

BACKGROUND: Neuropathic pain and sensory abnormalities are a debilitating secondary consequence of spinal cord injury (SCI). Maladaptive structural plasticity is gaining recognition for its role in contributing to the development of post SCI pain syndromes. We previously demonstrated that excitotoxic induced SCI dysesthesias are associated with enhanced dorsal root ganglia (DRG) neuronal outgrowth. Although glycogen synthase kinase-3ß (GSK-3ß) is a known intracellular regulator neuronal growth, the potential contribution to primary afferent growth responses following SCI are undefined. We hypothesized that SCI triggers inhibition of GSK-3ß signaling resulting in enhanced DRG growth responses, and that PI3K mediated activation of GSK-3ß can prevent this growth and the development of at-level pain syndromes. RESULTS: Excitotoxic SCI using intraspinal quisqualic acid (QUIS) resulted in inhibition of GSK-3ß in the superficial spinal cord dorsal horn and adjacent DRG. Double immunofluorescent staining showed that GSK-3ß(P) was expressed in DRG neurons, especially small nociceptive, CGRP and IB4-positive neurons. Intrathecal administration of a potent PI3-kinase inhibitor (LY294002), a known GSK-3ß activator, significantly decreased GSK-3ß(P) expression levels in the dorsal horn. QUIS injection resulted in early (3 days) and sustained (14 days) DRG neurite outgrowth of small and subsequently large fibers that was reduced with short term (3 days) administration of LY294002. Furthermore, LY294002 treatment initiated on the date of injury, prevented the development of overgrooming, a spontaneous at-level pain related dysesthesia. CONCLUSIONS: QUIS induced SCI resulted in inhibition of GSK-3ß in primary afferents and enhanced at-level DRG intrinsic growth (neurite elongation and initiation). Early PI3K mediated activation of GSK-3ß attenuated QUIS-induced DRG neurite outgrowth and prevented the development of at-level dysesthesias.

Excitotoxic spinal cord injury induced dysesthesias are associated with enhanced intrinsic growth of sensory neurons.

Sensory dysesthesias and pain are common sequelae following spinal cord injury (SCI). While efforts to understand the mechanisms involved in SCI pain syndromes have focused on spinal and supraspinal regions, recent evidence suggests that SCI induces pathological responses in primary afferent neurons that may contribute to the development of sensory abnormalities. The purpose of this study was to investigate if excitotoxic spinal lesions lead to abnormal growth responses of cultured dorsal root ganglia (DRG) neurons, and to examine if the degree of neurite growth correlated with the presence of dysesthesias. Long-Evans rats underwent excitotoxic spinal cord lesions by injection of quisqualic acid at spinal level T12. Animals were examined daily for overgrooming behavior. Fourteen days after injury, DRG neurons were removed from at and below the level of injury, cultured and analyzed for soma size and neurite length. Grooming animals showed robust neurite growth in small, medium, and large neurons compared to nongrooming and control animals. Enhanced neuronal growth responses also occurred several segments caudal to the level of injury. This study provides the first evidence that excitotoxic spinal lesions result in DRG neurite outgrowth that correlated with the presence of sensory dysesthesias, providing support for the role of maladaptive peripheral afferent responses contributing to SCI pain syndromes.