The role of the mammalian prion protein in the control of sleep

Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases where it can be the defining dysfunction, as in the case of the “eponymous” fatal familial insomnia, or an early-stage symptom as in certain types of Creutzfeldt-Jakob disease. It is important to establish the role of the cellular prion protein (PrPC), the key molecule involved in prion pathogenesis, within the sleep-wake system in order to understand fully the mechanisms underlying its contribution to both healthy circadian rhythmicity and sleep dysfunction during disease. Although severe disruption to the circadian rhythm and melatonin release is evident during the pathogenic phases of some prion diseases, untangling whether PrPC plays a role in circadian rhythmicity, as suggested in mice deficient for PrPC expression, is challenging given the lack of basic experimental research. We provide a short review of the small amount of direct literature focused on the role of PrPC in melatonin and circadian rhythm regulation, as well as suggesting mechanisms by which PrPC might exert influence upon noradrenergic and dopaminergic signaling and melatonin synthesis. Future research in this area should focus upon isolating the points of dysfunction within the retino-pineal pathway and further investigate PrPC mediation of pinealocyte GPCR activity

A Time Series Approach to Parkinson's Disease Classification from EEG

Firstly, we present a novel representation for EEG data, a 7-variate series of band power coefficients, which enables the use of (previously inaccessible) time series classification methods. Specifically, we implement the multi-resolution representation-based time series classification method MrSQL. This is deployed on a challenging early-stage Parkinson's dataset that includes wakeful and sleep EEG. Initial results are promising with over 90% accuracy achieved on all EEG data types used. Secondly, we present a framework that enables high-importance data types and brain regions for classification to be identified. Using our framework, we find that, across different EEG data types, it is the Prefrontal brain region that has the most predictive power for the presence of Parkinson's Disease. This outperformance was statistically significant versus ten of the twelve other brain regions (not significant versus adjacent Left Frontal and Right Frontal regions). The Prefrontal region of the brain is important for higher-order cognitive processes and our results align with studies that have shown neural dysfunction in the prefrontal cortex in Parkinson's Disease

Investigating light sensitivity in bipolar disorder (HELIOS-BD)

Many people with bipolar disorder have disrupted circadian rhythms. This means that the timing of sleep and wake activities becomes out-of-sync with the standard 24-hour cycle. Circadian rhythms are strongly influenced by light levels and previous research suggests that people with bipolar disorder might have a heightened sensitivity to light, causing more circadian rhythm disruption, increasing the potential for triggering a mood switch into mania or depression. Lithium has been in clinical use for over 70 years and is acknowledged to be the most effective long-term treatment for bipolar disorder. Lithium has many reported actions in the body but the precise mechanism of action in bipolar disorder remains an active area of research. Central to this project is recent evidence that lithium may work by stabilising circadian rhythms of mood, cognition and rest/activity. Our primary hypothesis is that people with bipolar disorder have some pathophysiological change at the level of the retina which makes them hypersensitive to the visual and non-visual effects of light, and therefore more susceptible to circadian rhythm dysfunction. We additionally hypothesise that the mood-stabilising medication lithium is effective in bipolar disorder because it reduces this hypersensitivity, making individuals less vulnerable to light-induced circadian disruption. We will recruit 180 participants into the HELIOS-BD study. Over an 18-month period, we will assess visual and non-visual responses to light, as well as retinal microstructure, in people with bipolar disorder compared to healthy controls. Further, we will assess whether individuals with bipolar disorder who are being treated with lithium have less pronounced light responses and attenuated retinal changes compared to individuals with bipolar disorder not being treated with lithium. This study represents a comprehensive investigation of visual and non-visual light responses in a large bipolar disorder population, with great translational potential for patient stratification and treatment innovation.</p

Inaccurate self-report of olfactory dysfunction in REM Sleep Behaviour Disorder and implications for prognosis

Introduction: The earliest stages of alpha-synucleinopathies are accompanied by non-specific prodromal symptoms such as diminished sense of smell, constipation and depression, as well as more specific prodromal conditions including REM Sleep Behaviour Disorder (RBD). While the majority of RBD patients will develop an alpha-synucleinopathy, one of the greatest clinical challenges is determining whether and when individual patients will phenoconvert. Clinical evaluation of a patient presenting with RBD should therefore include robust and objective assessments of known alpha-synucleinopathy prodromes. Methods: This study compared olfactory function self-report measures with psychophysical ‘Sniffin’ Stick 16-item Identification’ test scores in Control (n = 19), RBD (n = 16) and PD (n = 17) participants. Results: We confirm that olfactory test scores are significantly diminished in RBD and PD groups compared to Controls (p < 0.001, One-Way ANOVA with Tukey-Kramer Post-Hoc, effect size = 0.401). However, RBD participants were only 56 % accurate when self-reporting olfactory dysfunction, hence markedly less likely to perceive or acknowledge their own hyposmia compared to Controls (p = 0.045, Fisher’s Exact Test, effect-size = 0.35). Conclusion: When isolated RBD presents with hyposmia, there is an increased likelihood of phenoconversion to Parkinson’s Disease (PD) or Dementia with Lewy Bodies (DLB); unawareness of olfactory dysfunction in an individual with isolated RBD may therefore confound differential diagnosis and prognosis. Our results evidence the fallibility of olfactory function self-report in the context of RBD prognosis, indicating that clinical assessments of RBD patients should include more reliable measures of olfactory status