Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Neuroimaging and plasma evidence of early white matter loss in Parkinson's disease with poor outcomes.

Parkinson's disease is a common and debilitating neurodegenerative disorder, with over half of patients progressing to postural instability, dementia or death within 10 years of diagnosis. However, the onset and rate of progression to poor outcomes is highly variable, underpinned by heterogeneity in underlying pathological processes. Quantitative and sensitive measures predicting poor outcomes will be critical for targeted treatment, but most studies to date have been limited to a single modality or assessed patients with established cognitive impairment. Here, we used multimodal neuroimaging and plasma measures in 98 patients with Parkinson's disease and 28 age-matched controls followed up over 3 years. We examined: grey matter (cortical thickness and subcortical volume), white matter (fibre cross-section, a measure of macrostructure; and fibre density, a measure of microstructure) at whole-brain and tract level; structural and functional connectivity; and plasma levels of neurofilament light chain and phosphorylated tau 181. We evaluated relationships with subsequent poor outcomes, defined as development of mild cognitive impairment, dementia, frailty or death at any time during follow-up, in people with Parkinson's disease. We show that extensive white matter macrostructural changes are already evident at baseline assessment in people with Parkinson's disease who progress to poor outcomes (n = 31): with up to 19% reduction in fibre cross-section in multiple tracts, and a subnetwork of reduced structural connectivity strength, particularly involving connections between right frontoparietal and left frontal, right frontoparietal and left parietal and right temporo-occipital and left parietal modules. In contrast, grey matter volumes and functional connectivity were preserved in people with Parkinson's disease with poor outcomes. Neurofilament light chain, but not phosphorylated tau 181 levels were increased in people with Parkinson's disease with poor outcomes, and correlated with white matter loss. These findings suggest that imaging sensitive to white matter macrostructure and plasma neurofilament light chain may be useful early markers of poor outcomes in Parkinson's disease. As new targeted treatments for neurodegenerative disease are emerging, these measures show important potential to aid patient selection for treatment and improve stratification for clinical trials.

Democratising access to dementia research.

As the UK population ages, dementia affects an increasing proportion of the population. There is a drive to accelerate dementia research, however access to research is not equitably distributed. We examine access to dementia research and discuss some enabling factors and barriers. High recruitment is frequently driven by a person (or people) dedicated to improving research participation. Barriers are commonly structural, rather than lack of willingness or knowledge. A recurring issue was lack of time and/or resources. Leveraging existing infrastructure, such as streamlined and efficient governance frameworks, is a clear part of the solution. Research teams need to ensure inclusion/exclusion criteria serve the target population, and that any intervention is accessible to a range of patients. An injection of resources is crucial to support the recruitment process on the ground.

Longitudinal Associations of Magnetic Susceptibility with Clinical Severity in Parkinson's Disease.

BACKGROUND: Dementia is common in Parkinson's disease (PD), but there is wide variation in its timing. A critical gap in PD research is the lack of quantifiable markers of progression, and methods to identify early stages of dementia. Atrophy-based magnetic resonance imaging (MRI) has limited sensitivity in detecting or tracking changes relating to PD dementia, but quantitative susceptibility mapping (QSM), sensitive to brain tissue iron, shows potential for these purposes. OBJECTIVE: The objective of the paper is to study, for the first time, the longitudinal relationship between cognition and QSM in PD in detail. METHODS: We present a longitudinal study of clinical severity in PD using QSM, including 59 PD patients (without dementia at study onset), and 22 controls over 3 years. RESULTS: In PD, increased baseline susceptibility in the right temporal cortex, nucleus basalis of Meynert, and putamen was associated with greater cognitive severity after 3 years; and increased baseline susceptibility in basal ganglia, substantia nigra, red nucleus, insular cortex, and dentate nucleus was associated with greater motor severity after 3 years. Increased follow-up susceptibility in these regions was associated with increased follow-up cognitive and motor severity, with further involvement of hippocampus relating to cognitive severity. However, there were no consistent increases in susceptibility over 3 years. CONCLUSIONS: Our study suggests that QSM may predict changes in cognitive severity many months prior to overt cognitive involvement in PD. However, we did not find robust longitudinal changes in QSM over the course of the study. Additional tissue metrics may be required together with QSM for it to monitor progression in clinical practice and therapeutic trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Herpes Zoster and Risk of Incident Parkinson's Disease in US Veterans: A Matched Cohort Study.

BACKGROUND: Although some systemic infections are associated with Parkinson's disease (PD), the relationship between herpes zoster (HZ) and PD is unclear. OBJECTIVE: The objective is to investigate whether HZ is associated with incident PD risk in a matched cohort study using data from the US Department of Veterans Affairs. METHODS: We compared the risk of PD between individuals with incident HZ matched to up to five individuals without a history of HZ using Cox proportional hazards regression. In sensitivity analyses, we excluded early outcomes. RESULTS: Among 198,099 individuals with HZ and 976,660 matched individuals without HZ (median age 67.0 years (interquartile range [IQR 61.4-75.7]); 94% male; median follow-up 4.2 years [IQR 1.9-6.6]), HZ was not associated with an increased risk of incident PD overall (adjusted HR 0.95, 95% CI 0.90-1.01) or in any sensitivity analyses. CONCLUSION: We found no evidence that HZ was associated with increased risk of incident PD in this cohort. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Embedding Patient Input in Outcome Measures for Long-Term Disease-Modifying Parkinson Disease Trials.

BACKGROUND: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. OBJECTIVES: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. METHODS: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. RESULTS: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. CONCLUSIONS: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Retinal Optical Coherence Tomography Features Associated With Incident and Prevalent Parkinson Disease.

BACKGROUND AND OBJECTIVES: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD); however, it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort. METHODS: This cross-sectional analysis used data from 2 studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and older attending secondary care ophthalmic hospitals in London, United Kingdom, between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea-centered OCT. Linear mixed-effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models. RESULTS: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 µm, 95% CI -3.17 to -1.07, p = 8.2 × 10-5) and INL (-0.99 µm, 95% CI -1.52 to -0.47, p = 2.1 × 10-4). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2,653 ± 851 days. Thinner GCIPL (hazard ratio [HR] 0.62 per SD increase, 95% CI 0.46-0.84, p = 0.002) and thinner INL (HR 0.70, 95% CI 0.51-0.96, p = 0.026) were also associated with incident PD. DISCUSSION: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD.

Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative.

BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

Understanding visual hallucinations: A new synthesis.

Despite decades of research, we do not definitively know how people sometimes see things that are not there. Eight models of complex visual hallucinations have been published since 2000, including Deafferentation, Reality Monitoring, Perception and Attention Deficit, Activation, Input, and Modulation, Hodological, Attentional Networks, Active Inference, and Thalamocortical Dysrhythmia Default Mode Network Decoupling. Each was derived from different understandings of brain organisation. To reduce this variability, representatives from each research group agreed an integrated Visual Hallucination Framework that is consistent with current theories of veridical and hallucinatory vision. The Framework delineates cognitive systems relevant to hallucinations. It allows a systematic, consistent, investigation of relationships between the phenomenology of visual hallucinations and changes in underpinning cognitive structures. The episodic nature of hallucinations highlights separate factors associated with the onset, persistence, and end of specific hallucinations suggesting a complex relationship between state and trait markers of hallucination risk. In addition to a harmonised interpretation of existing evidence, the Framework highlights new avenues of research, and potentially, new approaches to treating distressing hallucinations.

Clinical trials for cognition in Parkinson's disease: Where are we and how can we do better?

BACKGROUND: Cognitive impairment is common in Parkinson's disease (PD) and has a substantial impact on quality of life. Despite numerous trials targeting various PD features, we still lack effective treatments for cognition beyond cholinesterase inhibitors. OBJECTIVE: To identify the gaps in recent clinical trials with cognitive outcomes in PD and consider areas for improvement. METHODS: We examined recent clinical trials with cognitive outcomes in PD registered on ClinicalTrials.gov, excluding trials without cognitive outcomes, non-interventional studies, and in atypical Parkinsonian disorders. Included trials were categorized by treatment approach (investigational medicinal product, behavioral, physical activity, device-based). Details of trial design and outcomes were collected. RESULTS: 178 trials at different stages of trial completion were considered. 46 trials were completed, 25 had available results. Mean follow-up duration was 29.9 weeks. Most common cognitive measure was Montreal Cognitive Assessment. Most were performed in North America or Europe. Majority of the participants identified as non-Hispanic and White. Only eight trials showed improvement in cognition, none showed improvement beyond four months. These included trials of international medicinal products, cognitive and physical interventions and devices. GRADE certainty levels ranged from Moderate to Very Low. Only mevidalen had a Moderate certainty for potential clinical effectiveness. CONCLUSIONS: Amongst a large number of trials for cognition in PD, only a small proportion were completed. Few showed significant improvement, with no proven long-lasting effects. Trial design, lack of enrichment for at-risk groups, short follow-up duration, insensitive outcome measures likely contribute to lack of detectable benefit and should be considered in future trials.

Changes in both top-down and bottom-up effective connectivity drive visual hallucinations in Parkinson's disease.

Visual hallucinations are common in Parkinson's disease and are associated with a poorer quality of life and a higher risk of dementia. An important and influential model that is widely accepted as an explanation for the mechanism of visual hallucinations in Parkinson's disease and other Lewy body diseases is that these arise due to aberrant hierarchical processing, with impaired bottom-up integration of sensory information and overweighting of top-down perceptual priors within the visual system. This hypothesis has been driven by behavioural data and supported indirectly by observations derived from regional activation and correlational measures using neuroimaging. However, until now, there was no evidence from neuroimaging for differences in causal influences between brain regions measured in patients with Parkinson's hallucinations. This is in part because previous resting-state studies focused on functional connectivity, which is inherently undirected in nature and cannot test hypotheses about the directionality of connectivity. Spectral dynamic causal modelling is a Bayesian framework that allows the inference of effective connectivity-defined as the directed (causal) influence that one region exerts on another region-from resting-state functional MRI data. In the current study, we utilize spectral dynamic causal modelling to estimate effective connectivity within the resting-state visual network in our cohort of 15 Parkinson's disease visual hallucinators and 75 Parkinson's disease non-visual hallucinators. We find that visual hallucinators display decreased bottom-up effective connectivity from the lateral geniculate nucleus to primary visual cortex and increased top-down effective connectivity from the left prefrontal cortex to primary visual cortex and the medial thalamus, as compared with non-visual hallucinators. Importantly, we find that the pattern of effective connectivity is predictive of the presence of visual hallucinations and associated with their severity within the hallucinating group. This is the first study to provide evidence, using resting-state effective connectivity, to support a model of aberrant hierarchical predictive processing as the mechanism for visual hallucinations in Parkinson's disease.

Computer vision quantification of whole-body Parkinsonian bradykinesia using a large multi-site population.

Parkinson's disease (PD) is a common neurological disorder, with bradykinesia being one of its cardinal features. Objective quantification of bradykinesia using computer vision has the potential to standardise decision-making, for patient treatment and clinical trials, while facilitating remote assessment. We utilised a dataset of part-3 MDS-UPDRS motor assessments, collected at four independent clinical and one research sites on two continents, to build computer-vision-based models capable of inferring the correct severity rating robustly and consistently across all identifiable subgroups of patients. These results contrast with previous work limited by small sample sizes and small numbers of sites. Our bradykinesia estimation corresponded well with clinician ratings (interclass correlation 0.74). This agreement was consistent across four clinical sites. This result demonstrates how such technology can be successfully deployed into existing clinical workflows, with consumer-grade smartphone or tablet devices, adding minimal equipment cost and time.

Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design.

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

Changes in dynamic transitions between integrated and segregated states underlie visual hallucinations in Parkinson's disease.

Hallucinations are a core feature of psychosis and common in Parkinson's. Their transient, unexpected nature suggests a change in dynamic brain states, but underlying causes are unknown. Here, we examine temporal dynamics and underlying structural connectivity in Parkinson's-hallucinations using a combination of functional and structural MRI, network control theory, neurotransmitter density and genetic analyses. We show that Parkinson's-hallucinators spent more time in a predominantly Segregated functional state with fewer between-state transitions. The transition from integrated-to-segregated state had lower energy cost in Parkinson's-hallucinators; and was therefore potentially preferable. The regional energy needed for this transition was correlated with regional neurotransmitter density and gene expression for serotoninergic, GABAergic, noradrenergic and cholinergic, but not dopaminergic, receptors. We show how the combination of neurochemistry and brain structure jointly shape functional brain dynamics leading to hallucinations and highlight potential therapeutic targets by linking these changes to neurotransmitter systems involved in early sensory and complex visual processing.

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations.

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.

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.