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Background: Delirium is a serious acute neuropsychiatric condition associated with altered attention and arousal., Objective: To evaluate simple bedside tests for attention and arousal to detect delirium in those with and without Parkinson's disease (PD) and dementia., Methods: Participants from two prospective delirium studies were pooled comprising 30 with PD without cognitive impairment, 24 with Lewy body cognitive impairment (PD dementia or dementia with Lewy bodies), 16 with another dementia and 179 PD and dementia-free older adults. Participants completed standardised delirium assessments including tests of attention: digit span, Memorial Delirium Assessment Scale (MDAS) attention and months of the year backwards; and arousal: Glasgow Coma Scale (GSC), Observational Scale of Level of Arousal (OSLA), Modified Richmond Agitation Scale and MDAS consciousness. Delirium was diagnosed using the DSM-5 criteria., Results: On their first admission, 21.7%participants had prevalent delirium. Arousal measures accurately detected delirium in all participants (p < 0.01 for all), but only selected attention measures detected delirium in PD and dementia. In PD and dementia-free older adults, impaired digit span and OSLA were the optimal tests to detect delirium (area under the curve [AUC] = 0.838, p < 0.001) while in PD and dementia the optimal tests were MDAS attention and GCS (AUC=0.90 and 0.84, respectively, p < 0.001 for both)., Conclusion: Simple bedside tests of attention and arousal at a single visit could accurately detect delirium in PD, dementia and PD and dementia-free older adults; however, the optimal tests differed between groups. Combined attention and arousal scores increased accuracy, which could have clinical utility to aid the identification of delirium neurodegenerative disorders.

Background: Cognitive impairment is common in Parkinson's disease (PD), with 80% cumulatively developing dementia (PDD)., Objective: We sought to identify tests that are sensitive to change over time above normal ageing so as to refine the neuropsychological tests predictive of PDD., Methods: Participants with newly diagnosed PD (n = 211) and age-matched controls (n = 99) completed a range of clinical and neuropsychological tests as part of the ICICLE-PD study at 18-month intervals over 72 months. Impairments on tests were determined using control means (<1-2SD) and median scores. Mild cognitive impairment (PD-MCI) was classified using 1-2SD below normative values. Linear mixed effects modelling assessed cognitive decline, while Cox regression identified baseline predictors of PDD., Results: At 72 months, 46 (cumulative probability 33.9%) participants had developed PDD; these participants declined at a faster rate in tests of global cognition, verbal fluency, memory and attention (p < 0.05) compared to those who remained dementia-free. Impaired baseline global cognition, visual memory and attention using median cut-offs were the best predictors of early PDD (area under the curve [AUC] = 0.88, p < 0.001) compared to control-generated cut-offs (AUC = 0.76-0.84,p < 0.001) and PD-MCI (AUC = 0.64-0.81, p < 0.001). Impaired global cognition and semantic fluency were the most useful brief tests employable in a clinical setting (AUC = 0.79, p < 0.001)., Conclusion: Verbal fluency, attention and memory were sensitive to change in early PDD and may be suitable tests to measure therapeutic response in future interventions. Impaired global cognition, attention and visual memory were the most accurate predictors for developing a PDD. Future studies could consider adopting these tests for patient clinical trial stratification.

Background: Cognitive decline is a frequent complication of Parkinson's disease (PD) and the identification of predictive biomarkers for it would help in its management., Objective: Our aim was to analyse whether senescence markers (telomere length, p16 and p21) or their change over time could help to better predict cognitive and motor progression of newly diagnosed PD patients. We also compared these senescence markers to previously analysed markers of inflammation for the same purpose., Methods: This study examined the association of blood-derived markers of cell senescence and inflammation with motor and cognitive function over time in an incident PD cohort (the ICICLE-PD study). Participants (154 newly diagnosed PD patients and 99 controls) underwent physical and cognitive assessments over 36 months of follow up. Mean leukocyte telomere length and the expression of senescence markers p21 and p16 were measured at two time points (baseline and 18 months). Additionally, we selected five inflammatory markers from existing baseline data., Results: We found that PD patients had shorter telomeres at baseline and 18 months compared to age-matched healthy controls which also correlated to dementia at 36 months. Baseline p16 levels were associated with faster rates of motor and cognitive decline over 36 months in PD cases, while a simple inflammatory summary score at baseline best predicted cognitive score over this same time period in PD patients., Conclusion: Our study suggests that both inflammatory and senescence markers (p16) are valuable predictors of clinical progression in PD patients.

Background: Urate and homocysteine are potential biomarkers for disease progression in Parkinson's disease (PD). Baseline serum urate concentration has been shown to predict motor but not cognitive decline. The relationship between serum homocysteine concentration and cognitive and motor impairment is unknown., Objectives: The aim of this study was to examine the association between baseline serum urate and homocysteine, and prospective measures of disease progression and cognition over 54 months in early PD., Methods: 154 newly diagnosed PD participants and 99 age-matched controls completed a schedule of assessments at baseline, 18, 36 and 54 months. The Movement Disorders Society Unified Parkinson's Disease Scale Part III (MDS-UPDRS III) was used to assess motor severity. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Serum samples drawn at baseline were analysed for urate, homocysteine, red cell folate and vitamin B12 concentrations., Results: Baseline urate was 331.4±83.8 and 302.7±78.0μmol/L for control and PD participants, respectively (p = 0.015). Baseline homocysteine was 9.6±3.3 and 11.1±3.8μmol/L for controls and PD participants, respectively (p < 0.01). Linear mixed effects modelling showed that lower baseline urate (β= 0.02, p < 0.001) and higher homocysteine (β= 0.29, p < 0.05) predicted decline in motor function. Only higher homocysteine concentrations at baseline, however, predicted declining MoCA scores over 54 months (β= 0.11, p < 0.01)., Conclusions: Lower serum urate concentration is associated with worsening motor function; while higher homocysteine concentration is associated with change in motor function and cognitive decline. Therefore, urate and homocysteine may be suitable biomarkers for predicting motor and cognitive decline in early PD.

Recent guidance by the National Institute for Health and Care Excellence (NICE) focuses on the management of people with multimorbidity, including Parkinson's disease (PD). To date there has been little exploration of this in neurodegenerative diseases. This study aimed to explore the associations between multimorbidity, motor severity and quality of life (QoL) in early PD. Regression analyses determined whether multimorbidity was significantly associated with disease severity and QoL. Multimorbidity was a small but significant predictor of QoL in people with incident PD, but not motor severity, suggesting that they may benefit from a tailored multidisciplinary approach to care.

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.

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.

Background: The detection of prodromal Parkinson's disease (PD) is desirable to test drugs with neuroprotective potential, but will be affected by known disease variations., Objective: To assess the prevalence of four key non-motor prodromal PD markers, and evaluate the sensitivity of case detection when non-motor screening tools for prodromal PD are implemented in an early clinical PD cohort., Methods: Hyposmia (University of Pennsylvania smell identification test ≤15th centile or Sniffin' Sticks at or ≤10th centile corrected for age and sex), rapid-eye movement sleep behaviour disorder (RBD questionnaire >4), constipation (<1 daily spontaneous bowel motion) and depression (Leeds >6) were recorded in recent onset PD cases, and proposed non-motor screening criteria applied., Results: In 1,719 PD cases, mean age 68.6 years (SD 8.1), 65.5% male, mean disease duration 1.3 years (SD 0.9), 72.2% were hyposmic, 43.3% had RBD, 22.1% depression, and 21.5% constipation. 11.6% of cases had no key non-motor features, 38.8% one, 32.1% two, 15.5% three, and 2.0% all four. Increasing numbers of non-motor features were associated with younger age (p = 0.019), higher motor scores (p < 0.001), more postural instability gait difficulty (PIGD) (p < 0.001), greater cognitive impairment (p < 0.001) and higher total non-motor burden (p < 0.001). Cases with hyposmia alone were younger (p < 0.001), had less severe cognitive (p = 0.006) and other non-motor features (p < 0.001). All screening criteria selected younger patients (p = 0.001, p < 0.001), three of four greater overall non-motor burden (p = 0.005, p < 0.001), and inclusion of RBD more cognitive impairment (p = 0.003, p = 0.001) and PIGD (p = 0.004, p = 0.001)., Conclusions: Varying sensitivity levels, and age and phenotype selectivity, are found when different non-motor screening methods to detect prodromal PD are applied to an early clinical PD cohort.

Background: There is wide variation in the phenotypic expression of Parkinson's disease (PD), which is driven by both genetic and epidemiological influences., Objectives: To define and explain variation in the clinical phenotype of PD, in relation to genotypic variation., Methods: Tracking Parkinson's is a multicentre prospective longitudinal epidemiologic and biomarker study of PD. Patients attending specialist clinics in the United Kingdom with recent onset (<3.5 years) and young onset (diagnosed <50 years of age) PD were enrolled. Motor, non-motor and quality of life assessments were performed using validated scales. Cases are followed up 6 monthly up to 4.5 years for recent onset PD, and up to 1 year for young onset PD. We present here baseline clinical data from this large and demographically representative cohort., Results: 2247 PD cases were recruited (1987 recent onset, 260 young onset). Recent onset cases had a mean (standard deviation, SD) age of 67.6 years (9.3) at study entry, 65.7% males, with disease duration 1.3 years (0.9), MDS-UPDRS 3 scores 22.9 (12.3), LEDD 295 mg/day (211) and PDQ-8 score 5.9 (4.8). Young onset cases were 53.5 years old (7.8) at study entry, 66.9% male, with disease duration 10.2 years (6.7), MDS-UPDRS 3 scores 27.4 (15.3), LEDD 926 mg/day (567) and PDQ-8 score 11.6 (6.1)., Conclusions: We have established a large clinical PD cohort, consisting of young onset and recent onset cases, which is designed to evaluate variation in clinical expression, in relation to genetic influences, and which offers a platform for future imaging and biomarker research.

We evaluated the effect of anticholinergic burden on 219 participants with incident Parkinson's disease (PD) and 99 controls at study baseline and 18 months. Anticholinergic burden for each individual was calculated and summed according to the Anticholinergic Drug Scale (ADS). Medication with anticholinergic activity was more commonly prescribed in PD compared to controls, although mean ADS scores were not significantly different. Cognitive scores did not differ in PD participants taking medications with anticholinergic activity compared to those who were not. Low overall ADS scores due to increased awareness of adverse effects of medications and brevity of follow-up are potential explanations.

Dementia in Parkinson's disease (PD) is a serious health issue and a major concern for many patients. In most cases mild cognitive impairment (MCI) is considered a transitional stage between normal cognitive functioning and dementia which is of potential importance in the early identification of patients at risk for dementia. Recently, the Movement Disorder Society (MDS) proposed diagnostic criteria for MCI in PD (PD-MCI). These criteria comprise two operationalizations: Level I (based on an abbreviated assessment) and Level II (based on comprehensive neuropsychological evaluation permitting MCI subtyping). These criteria need to be validated. This paper describes a project aiming to validate the MDS PD-MCI criteria by pooling and analyzing cross-sectional and longitudinal neuropsychological databases comprising ≥5,500 PD patients and ≥1,700 controls. After applying the MDS PD-MCI Level I and Level II criteria, rates of conversion to PD-dementia and predictive variables for conversion to PD-dementia will be established. This study will also assist in identifying whether revisions of the PD-MCI criteria are required.

Background: Dopaminergic drugs are the primary risk factor for Impulse Control Behaviours (ICB) in Parkinson's disease (PD), others being early-onset disease and gender., Objective: This report further explores ICB symptom relationships with motor and mood phenotypes, the complex relationship with dopaminergic medications, and hypothesizes a model with potential clinical implications., Methods: Data from 500 PD patients were analyzed. Hypersexuality, gambling and shopping behaviour were assessed using selected questions from the Minnesota Impulsive Disorders Interview questionnaire. Local questions assessed hobbyism. Motor characteristics considered were akinetic-rigid/gait disturbance (PIGD) and 'non-PIGD' phenotypes, motor severity, motor progression, and presence/absence of motor fluctuations. Other variables included anxiety, depression, current levodopa and agonist use, age, gender and cognition., Results: Overall, ICB symptom frequency was 17.8%. There was no relationship between PIGD/non-PIGD motor phenotypes and ICB symptoms. Those with ICB symptoms had higher total combined levodopa/agonist equivalent intake, but not current agonist-only equivalent intake. ICB symptoms were reported by 23.1% of those taking combined levodopa and agonist compared to 19.2% on agonist monotherapy and 11.6% levodopa monotherapy. Compared with non-ICB patients, patients with ICB symptoms were more likely to show an anxious mood phenotype, reported more motor fluctuations, and were younger., Conclusions: Both PIGD and non-PIGD phenotypes are equally affected. Dose-related risk applies to total anti-parkinsonian medication and not just current agonist-only. Anxious mood phenotypes may carry increased risk. A role of anxiety, either as a marker of risk, indirect causal factor, or maintaining factor is incorporated into a preliminary model. We discuss implications for clinical management.

We evaluated the association between mild cognitive impairment (MCI) subtypes and quality of life (QoL) in 219 newly diagnosed Parkinson's disease (PD) patients without dementia. Participants completed neuropsychological tests of attention, executive function, visuospatial function, memory, and language, and reported QoL using the Parkinson's Disease Questionnaire. Impairments were most common in executive function, memory and attention. MCI subtypes were classified according to Movement Disorder Society Task Force criteria. More severe cognitive impairment was associated with poorer quality of life (p = 0.01), but subtype of impairment was not (p > 0.10), suggesting that the nature of cognitive impairment is less significant than its severity.

Background: Anxiety disorder and anxiety symptomatology are common in Parkinson's disease (PD), with up to 25% patients experiencing significant worry. There is no systematic evidence base for the management of anxiety or anxiety related symptoms such as worry in PD., Objectives: To investigate whether cognitive therapy, delivered as bibliotherapy, is an effective intervention for worry in PD., Methods: 54 participants were randomly allocated to a guided reading group and a control group. The guided reading group were given a CBT based self-help resource called What? Me Worry!?! to work through over eight weeks, with telephone support at two week intervals. Controls were given information about worry only, and one phone call. Measures of worry, intolerance of uncertainty, metacognitions and health status were taken at baseline and after 3 months., Results: Analysable data were obtained for 15 controls and 17 from the guided reading group. Worry and intolerance of uncertainty were significantly reduced in the guided reading group. However, no significant differences were found for the follow up measures between the groups., Conclusions: Bibliotherapy has the potential to be useful and cost effective as a management strategy for the treatment of worry in people with PD.