Medicine seminars

Despite the importance of early diagnosis of dementia for prognosis and personalised interventions, we still lack robust tools for predicting individual progression to dementia. We propose a trajectory modelling approach that mines multimodal data from patients at early dementia stages to derive individualised prognostic scores of cognitive decline Our approach has potential to facilitate effective stratification of individuals based on prognostic disease trajectories, reducing patient misclassification with important implications for clinical practice.

Pain has both a sensory and emotional component and is driven by activation of sensory neurones called nociceptors that are tuned to detect noxious stimuli in a process called nociception. Although nociception functions as a detect and protect mechanism. and is found in many organisms, this system becomes dysregulated in a number of conditions where chronic pain presents as a key symptom, for example osteoarthritis. Nociceptors do not innervate empty space though and do not act alone. Going beyond the neurone, other cell types, such as fibroblast-like synoviocytes interact with and modify the function of nociceptors, which is likely a key contributor to the chronification of pain. In this talk, I will look at how combining pre-clinical mouse work with human tissue and genetics might provide a way to accelerate new analgesics from bench to bedside, giving examples from our work in joint pain, bowel pain and labour pain.

ONS figures suggest that at least 10% of individuals suffering COVID -19 Infection continue to experience several weeks after testing positive, and other studies report the proportions as even higher (e.g. Logue et al., 2021). One of the most prevalent reported symptoms among these “Long Covid” sufferers is cognitive dysfunction (Davis et al., 2020). However, to date the cognitive sequelae of COVID -19 are little understood. There are a number of reasons why COVID -19 infection might be associated with cognitive impairment and mental illness (e.g. Bougakov et al., 2020). In particular, increasing evidence indicates inflammation (e.g. Huang et al., 2020) and dysfunctional clotting (e.g. Taquet et al., 2021) as issues of major concern, both of which have been previously linked to a range of cognitive deficits (e.g. Vintimilla et al., 2019; Cumming et al., 2013). Indeed, evidence is beginning to emerge that cognitive issues may be widespread in the post-infection period, particularly among hospitalised and ventilated patients (e.g. Hampshire et al., 2020; Alemanno et al,. 2020). Here I shall present “Hot off the [SPSS]Press” results from a study on memory and cognition following COVID infection in a non-hospitalized cohort.

In this talk series, addiction neuroscientists from across the world share their personal stories/experiences on the beauty of addiction neuroscience and how/why they have decided to invest their scientific life in this field. We hope that this talk series would encourage and support a new generation of young and passionate addiction neuroscientists in different countries to revolutionize the field of addiction medicine.

Alzheimer’s Disease is characterised by the accumulation of misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease. Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy[1] (rTg4510) and amyloidopathy[2] (J20). This revealed that pre- and post-synaptic components are differentially affected in both AD models in response to pathology. In the Tg4510 model, differences in the stability and turnover of axonal boutons and dendritic spines immediately prior to neurite degeneration was revealed. Moreover, the dystrophic neurites could be partially rescued by transgene suppression. Understanding the imbalance in the response of pre- and post-synaptic components is crucial for drug discovery studies targeting the synapse in Alzheimer’s Disease. To investigate how sub-types of synapses are affected in human tissue, the Multi-‘omics Atlas Project, a UKDRI initiative to comprehensively map the pathology in human AD, will determine the synaptome changes using imaging and synaptic proteomics in human post mortem AD tissue. The use of multiple brain regions and multiple stages of disease will enable a pseudotemporal profile of pathology and the associated synapse alterations to be determined. These data will be compared to data from preclinical models to determine the functional implications of the human findings, to better inform preclinical drug discovery studies and to develop a therapeutic strategy to target synapses in Alzheimer’s Disease[3].

L-DOPA-induced dyskinesia is a debilitating adverse effect of treating Parkinson’s disease with this drug. New therapeutic approaches that prevent or attenuate this side effect is clearly needed. Wistar adult male rats submitted to 6-hydroxydopamine-induced unilateral medial forebrain bundle lesions were treated with L-DOPA (oral or subcutaneous, 20 mg kg-1) once a day for 14 days. After this period, we tested if doxycycline (40 mg kg-1, intraperitoneal, a subantimicrobial dose) and COL-3 (50 and 100 nmol, intracerebroventricular) could reverse LID. In an additional experiment, doxycycline was also administered repeatedly with L-DOPA to verify if it would prevent LID development. A single injection of doxycycline or COL-3 together with L-DOPA attenuated the dyskinesia. Co-treatment with doxycycline from the first day of L-DOPA suppressed the onset of dyskinesia. The improved motor responses to L-DOPA remained intact in the presence of doxycycline or COL-3, indicating the preservation of L-DOPA-produced benefits. Doxycycline treatment was associated with decreased immunoreactivity of FosB, cyclooxygenase-2, the astroglial protein GFAP and the microglial protein OX-42 which are elevated in the basal ganglia of rats exhibiting dyskinesia. Doxycycline also decreased metalloproteinase-2/-9 activity, metalloproteinase-3 expression and reactive oxygen species production. Metalloproteinase-2/-9 activity and production of reactive oxygen species in the basal ganglia of dyskinetic rats showed a significant correlation with the intensity of dyskinesia. The present study demonstrates the anti-dyskinetic potential of doxycycline and its analog compound COL-3 in hemiparkinsonian rats. Given the long-established and safe clinical use of doxycycline, this study suggests that these drugs might be tested to reduce or to prevent L-DOPA-induced dyskinesia in Parkinson’s patients.