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Title: Investigating mechanisms of pain in Alzheimer's disease
Author: Aman, Yahyah
ISNI:       0000 0004 7232 0396
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Experience of pain is a key contributor to challenge of care in Alzheimer’s disease (AD) individuals and is often associated with age-related medical comorbidities, commonly musculoskeletal conditions such as osteoarthritis (OA). Significant alteration in perception of pain is an important clinical issue in patients with AD and its effective treatment is increasingly recognised as a critical unmet clinical need. Currently, management of pain has been hindered by difficulties in the assessment of pain partly due to the impaired ability to communicate sensations as well as the inadequate understanding of the underlying mechanisms of pain in this susceptible patient group. Animal models of AD recapitulate many of the clinical and pathological features of the human AD and thereby offer to be a powerful tool in order to delineate mechanisms in AD. This thesis aims to investigate possible alterations of nociceptive sensitivity, in acute and chronic pain models, using the transgenic double-mutant APPswe×PS1.M146V (TASTPM) mouse model of AD. Furthermore, it aims to elucidate the associated plastic changes along the pain pathway (i.e. spinal cord and thalamus) of the preclinical TASTPM model and evaluate its translational implication using human post-mortem tissue obtained from AD patients with chronic pain conditions. This thesis provides preclinical evidence for alterations in nocifensive behaviour that are associated with dysfunction of the opioidergic system in TASTPM mice compared to age- and gender-matched wild-type (WT) controls. Specifically, TASTPM mice display reduced sensitivity to acute noxious thermal stimulation and impaired persistent pain-like behaviour in a model of OA induced by an intra-articular administration of monosodium iodoacetate (MIA). These changes coincide with impairment of cognition, development of amyloid plaques in the brain, and intraneuronal accumulation of amyloid precursor protein/β-amyloid (APP/Aβ) in the spinal cord of TASTPM mice. Increase in expression of endogenous inhibitory peptides: enkephalins in the dorsal horn and β-endorphins in plasma correlate with the attenuated nociceptive sensitivity to noxious thermal stimulation and persistent pain, respectively, in TASTPM mice. Administration of naloxone, an opioid antagonist, re-establishes normal sensory thermal thresholds and unmasks the reduced MIA-induced mechanical allodynia exhibited by the TASTPM mice. Subsequent administration of the analgesic morphine, an opioid agonist, induces heightened responsiveness in the TASTPM mice compared to WT controls. Together, these findings implicate the disruption of the opioidergic system as a common mechanism underlying the reduced acute nocifensive and impaired persistent pain-like behaviour in TASTPM model of AD. In parallel to these observations, alteration in the neuro-immune plasticity along the pain pathway is also identified as a possible mechanism that underlies impaired persistent pain-like behaviour exhibited by AD mice. In particular, diminished spinal microgliosis in response MIA administration in the periphery coupled to inability of gabapentin to induce analgesia were evident in TASTPM. These data indicate blunted central sensitisation in the model of AD. Intriguingly, increase in the extent of neuroinflammation is observed in the thalamus of TASTPM mice compared to WT, in the model of OA. However, no change in APP/Aβ pathology was detected in both the spinal cord and brain of TASTPM mice. Analyses of human post-mortem tissue obtained from AD individuals lend support to preclinical observations in TASTPM mice of intraneuronal accumulation of APP/Aβ and amyloid plaque deposition in the spinal cord. The other pathological hallmark of AD, neurofibrillary tangles (NFT), was not detected in the spinal cord of AD patients. Assessment of supraspinal structures involved in pain processing, including the thalamus, reveal presence of both amyloid plaques and NFT, which increased in abundance with progression of AD. Moreover, evaluation of AD-associated pathology in AD individuals with a clinical history of chronic pain and/or persistent analgesic use displays no alteration in deposition of amyloid plaques and NFT. However, increase in microglial activation was observed in both the spinal cord and supraspinal regions compared to AD subjects with no clinical pain record. These data provide additional support for the exacerbation of ongoing neuroinflammation identified in the preclinical TASTPM mice in a model of OA. Such observations from human post-mortem tissue reinforce the advantage of utilising the TASTPM model of AD in order to delineate mechanisms of pain in AD as it recapitulates some of the key features that are observed in human AD patients. Taken together, the findings of this thesis have important clinical implications for the care of patients with AD who have deteriorating cognitive function along with reduced sensitivity to pain. Altered pain sensitivity could be considered in assessing clinical risk as it may be associated with neuropsychiatric symptoms as well as an increased risk of injury during daily routine activities. Finally, these data highlight the need to re-evaluate current treatments, such as opioids, or develop novel therapeutic strategies for management of pain in individuals with AD.
Supervisor: Malcangio, Marzia Anna Maria ; Ballard, Clive Gerald Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available