Predicting cognitive impairment in Parkinson's disease using neurophysiology and biochemical parameters as biomarkers

PhD ThesisParkinson’s disease (PD) is a common neurodegenerative condition with multiple associated non-motor symptoms. Of these, dementia is a frequent debilitating complication of the disorder, with significant morbidity and mortality. Some forms of mild cognitive impairment in PD (PD-MCI) may represent a pre-dementia state and certain clinical, laboratory and neurophysiological parameters may increase the accuracy of prediction of cognitive decline. If validated, these markers would offer the opportunity for disease modification and therapeutic intervention at a critical early stage of the illness, when the viable neuronal population is greater. The key aim of this thesis was to characterise cognitive impairment in PD in a cohort of newly diagnosed cases, and evaluate how a panel of biomarkers correlated with cognitive phenotypes to predict risk of future cognitive decline. The main findings were that PD-MCI was common, and was associated with a distinct clinical phenotype. Memory impairment was the most common single domain affected, although the majority of those with PD-MCI were classified as nonamnestic single domain subtype. A significant correlation was found between pattern recognition memory, sensitive to temporal lobe impairments, and cerebrospinal amyloid-β 1-42 levels, thought to represent amyloid-β metabolism and deposition Both amyloid-β 1-42 and 1-40 levels were significantly lower in those with impaired cognition. In addition, short latency afferent inhibition, a neurophysiological in vivo non-invasive measurement of cholinergic function, was also reduced in participants with mild cognitive impairment. These findings suggest that cholinergic dysfunction and amyloid deposition may contribute to the underlying pathophysiology of early PD- MCI. The major conclusion from this thesis is that PD-MCI is heterogeneous and more frequent than previously reported in early disease. This is associated with abnormalities of amyloid processing and cholinergic dysfunction, and may highlight those at risk of developing dementia. Longitudinal assessment of these individuals will enable us to determine and better model those measures predictive of cognitive decline at an early disease stage.Parkinson’s UK, The Michael J Fox Foundation, Newcastle University Lockhart Fun

Natural history of falls in an incident cohort of Parkinson’s disease: early evolution, risk and protective features

The natural history of falls in early Parkinson’s disease (PD) is poorly understood despite the profound effect of falls on outcome. The primary aim of this study was to describe the natural history of falls, and characterise fallers over 54 months in 99 newly diagnosed people with PD. Seventy-nine (79.7%) participants fell over 54 months and 20 (20.3%) remained falls-naïve. Twenty six (26.2%) reported retrospective falls at baseline. Gait outcomes, disease severity and self-efficacy significantly discriminated across groups. Subjective cognitive complaints emerged as the only significant cognitive predictor. Without exception, outcomes were better for non-fallers compared with fallers at any time point. Between group differences for 54 month fallers and non-fallers were influenced by the inclusion of retrospective fallers and showed a broader range of discriminant characteristics, notably stance time variability and balance self-efficacy. Single fallers (n = 7) were significantly younger than recurrent fallers (n = 58) by almost 15 years (P = 0.013). Baseline performance in early PD discriminates fallers over 54 months, thereby identifying those at risk of falls. Clinical profiles for established and emergent fallers are to some extent distinct. These results reiterate the need for timely interventions to improve postural control and gait

Natural history of falls in an incident cohort of Parkinson’s disease: early evolution, risk and protective features

The natural history of falls in early Parkinson’s disease (PD) is poorly understood despite the profound effect of falls on outcome. The primary aim of this study was to describe the natural history of falls, and characterise fallers over 54 months in 99 newly diagnosed people with PD. Seventy-nine (79.7%) participants fell over 54 months and 20 (20.3%) remained falls-naïve. Twenty six (26.2%) reported retrospective falls at baseline. Gait outcomes, disease severity and self-efficacy significantly discriminated across groups. Subjective cognitive complaints emerged as the only significant cognitive predictor. Without exception, outcomes were better for non-fallers compared with fallers at any time point. Between group differences for 54 month fallers and non-fallers were influenced by the inclusion of retrospective fallers and showed a broader range of discriminant characteristics, notably stance time variability and balance self-efficacy. Single fallers (n = 7) were significantly younger than recurrent fallers (n = 58) by almost 15 years (P = 0.013). Baseline performance in early PD discriminates fallers over 54 months, thereby identifying those at risk of falls. Clinical profiles for established and emergent fallers are to some extent distinct. These results reiterate the need for timely interventions to improve postural control and gait

Poor sleep quality and progression of gait impairment in an incident Parkinson’s disease cohort

Abnormal sleep may associate with cognitive decline in Parkinson's disease (PD). Furthermore, sleep dysfunction may associate with worse motor outcome. We hypothesised that PD patients with poor quality sleep would have greater progression in gait dysfunction, due to structural and functional overlap in networks subserving sleep and gait regulation. 12 PD patients and 12 age-matched controls completed longitudinal follow-up over 36 months. Poor sleep efficiency and greater sleep fragmentation correlated significantly with progression of step-width variability, a gait characteristic mediated by postural control, providing evidence that poor sleep in PD is associated with a more rapid deterioration in gait

The Role of Movement Analysis in Diagnosing and Monitoring Neurodegenerative Conditions: Insights from Gait and Postural Control

Quantifying gait and postural control adds valuable information that aids in understanding neurological conditions where motor symptoms predominate and cause considerable functional impairment. Disease-specific clinical scales exist; however, they are often susceptible to subjectivity, and can lack sensitivity when identifying subtle gait and postural impairments in prodromal cohorts and longitudinally to document disease progression. Numerous devices are available to objectively quantify a range of measurement outcomes pertaining to gait and postural control; however, efforts are required to standardise and harmonise approaches that are specific to the neurological condition and clinical assessment. Tools are urgently needed that address a number of unmet needs in neurological practice. Namely, these include timely and accurate diagnosis; disease stratification; risk prediction; tracking disease progression; and decision making for intervention optimisation and maximising therapeutic response (such as medication selection, disease staging, and targeted support). Using some recent examples of research across a range of relevant neurological conditions—including Parkinson’s disease, ataxia, and dementia— we will illustrate evidence that supports progress against these unmet clinical needs. We summarise the novel ‘big data’ approaches that utilise data mining and machine learning techniques to improve disease classification and risk prediction, and conclude with recommendations for future direction

Safety and tolerability of adjunct non-invasive vagus nerve stimulation in people with parkinson’s:a study protocol

Abstract Background Parkinson’s disease (PD) is the fastest growing neurological condition worldwide. Recent theories suggest that symptoms of PD may arise due to spread of Lewy-body pathology where the process begins in the gut and propagate transynaptically via the vagus nerve to the central nervous system. In PD, gait impairments are common motor manifestations that are progressive and can appear early in the disease course. As therapies to mitigate gait impairments are limited, novel interventions targeting these and their consequences, i.e., reducing the risk of falls, are urgently needed. Non-invasive vagus nerve stimulation (nVNS) is a neuromodulation technique targeting the vagus nerve. We recently showed in a small pilot trial that a single dose of nVNS improved (decreased) discrete gait variability characteristics in those receiving active stimulation relative to those receiving sham stimulation. Further multi-dose, multi-session studies are needed to assess the safety and tolerability of the stimulation and if improvement in gait is sustained over time. Design This will be an investigator-initiated, single-site, proof-of-concept, double-blind sham-controlled randomised pilot trial in 40 people with PD. Participants will be randomly assigned on a 1:1 ratio to receive either active or sham transcutaneous cervical VNS. All participants will undergo comprehensive cognitive, autonomic and gait assessments during three sessions over 24 weeks, in addition to remote monitoring of ambulatory activity and falls, and exploratory analyses of cholinergic peripheral plasma markers. The primary outcome measure is the safety and tolerability of multi-dose nVNS in PD. Secondary outcomes include improvements in gait, cognition and autonomic function that will be summarised using descriptive statistics. Discussion This study will report on the proportion of eligible and enrolled patients, rates of eligibility and reasons for ineligibility. Adverse events will be recorded informing on the safety and device tolerability in PD. This study will additionally provide us with information for sample size calculations for future studies and evidence whether improvement in gait control is enhanced when nVNS is delivered repeatedly and sustained over time. Trial registration This trial is prospectively registered at www.isrctn.com/ISRCTN19394828 . Registered August 23, 2021

Categorising Visual Hallucinations in Early Parkinson's Disease.

BACKGROUND: Visual hallucinations (VHs) are common in Parkinson's disease (PD), with prevalence ranging from 27-50% in cross-sectional cohorts of patients with well-established disease. However, minor hallucinations may occur earlier in the disease process than has been previously reported. OBJECTIVE: We sought to categorise VHs in a cohort of newly diagnosed PD patients and establish their relationship to other clinical features. METHODS: Newly diagnosed PD participants (n = 154) were recruited as part of the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in PD (ICICLE-PD) study. Participants completed the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS III), Montreal Cognitive Assessment (MoCA) and Parkinson's Disease Questionnaire (PDQ-39) to assess motor severity, cognition and quality of life (QoL), respectively. VHs were classified using the North East Visual Hallucinations Inventory. Hierarchical regression was used to build predictive models of motor severity, QoL and cognition. RESULTS: 22% (n = 34) of participants experienced recurrent VHs with minor VHs being most frequently reported (64.7% of hallucinators). Complex VHs were present in 32.4% of hallucinating participants. Linear regression showed VHs predicted poorer PDQ-39 and MoCA scores (β= 0.201, p = 0.006 and β= - 0.167, p = 0.01, respectively) but not motor severity (p > 0.05). CONCLUSIONS: Over a fifth of people with newly diagnosed PD reported recurrent VHs; minor hallucinations were the most common, although a small proportion reported complex VHs. Recurrent VHs were found to be a significant independent predictor of cognitive function and QoL but not motor severity. Our findings highlight the importance of screening for VHs at diagnosis.ICICLE-PD was funded by Parkinson’s UK (J-0802, G-1301, G-1507). The research was supported by the Lockhart Parkinson’s Disease Research Fund, the National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University and a NIHR Biomedical Research Centre award to the University of Cambridge/Addenbrooke’s Hospital

Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease

A survey of people with Parkinson’s and their carers: The management of pain in Parkinson’s

Background: Pain in Parkinson’s is problematic but under treated in clinical practice. Healthcare professionals must understand the impact of pain in Parkinson’s and patient preferences for management. Objective: To understand the impact of pain in Parkinson’s and to understand current management and preferences for pain management. Methods: We conducted a national survey with 115 people with Parkinson’s (PwP) and 10 carers. Both closed and open questions were used. The questions focused on how pain affected the individual, healthcare professional involvement in supporting pain management, current pain management strategies and views on future pain management interventions. We used descriptive statistics to summarize closed responses and thematic analysis to summarize open question responses. Results: 70% of participants reported pain impacted their daily life. Pain had a multifactorial impact on participants, affecting movement, mood and quality of life. Improved pain management was viewed to have the potential to address each of these challenges. Pain affected a number of different sites, with low back pain and multiple sites being most frequently reported. Exercise was the most frequently noted strategy (38%) recommended by healthcare professionals for pain management. PwP would value involvement from healthcare professionals for future pain management, but also would like to self-manage the condition. Medication was not suggested as a first line strategy. Conclusions: Despite reporting engagement in some strategies to manage pain, pain still has a wide-ranging impact on the daily life of PwP. Results from this survey highlight the need to better support PwP to manage the impact of pain