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Background: Common genetic variance in apolipoprotein E (APOE), β‐glucocerebrosidase (GBA), microtubule‐associated protein tau (MAPT), and α‐synuclein (SNCA) has been linked to cognitive decline in Parkinson’s disease (PD), although studies have yielded mixed results. Objectives: To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non‐selective, population‐based cohorts of newly diagnosed PD patients. Methods: 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE ‐ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini‐Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini−Hochberg corrections. Results: Carriers of APOE‐ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE‐ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non‐carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. Conclusions: GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Funder: GE Healthcare; Id: http://dx.doi.org/10.13039/100006775, Funder: Alzheimer's Research UK; Id: http://dx.doi.org/10.13039/501100002283, Funder: NIHR Newcastle Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012295, Objectives: Autonomic symptoms are a common feature of the synucleinopathies, and may be a distinguishing feature of prodromal Lewy body disease. We aimed to assess whether the cognitive prodrome of dementia with Lewy bodies, mild cognitive impairment (MCI) with Lewy bodies (MCI‐LB), would have more severe reported autonomic symptoms than cognitively healthy older adults, with MCI due to Alzheimer's disease (MCI‐AD) also included for comparison. We also aimed to assess the utility of an autonomic symptom scale in differentiating MCI‐LB from MCI‐AD. Methods: Ninety‐three individuals with MCI and 33 healthy controls were assessed with the Composite Autonomic Symptom Score 31‐item scale (COMPASS). Mild cognitive impairment patients also underwent detailed clinical assessment and differential classification of MCI‐AD or MCI‐LB according to current consensus criteria. Differences in overall COMPASS score and individual symptom sub‐scales were assessed, controlling for age. Results: Age‐adjusted severity of overall autonomic symptomatology was greater in MCI‐LB (Ratio = 2.01, 95% CI: 1.37–2.96), with higher orthostatic intolerance and urinary symptom severity than controls, and greater risk of gastrointestinal and secretomotor symptoms. MCI‐AD did not have significantly higher autonomic symptom severity than controls overall. A cut‐off of 4/5 on the COMPASS was sensitive to MCI‐LB (92%) but not specific to this (42% specificity vs. MCI‐AD and 52% vs. healthy controls). Conclusions: Mild cognitive impairment with Lewy bodies had greater autonomic symptom severity than normal ageing and MCI‐AD, but such autonomic symptoms are not a specific finding. The COMPASS‐31 may therefore have value as a sensitive screening test for early‐stage Lewy body disease.

Funder: Academy of Medical Sciences; Id: http://dx.doi.org/10.13039/501100000691, Funder: American Parkinson Disease Association Center for Advanced Parkinson Research, Funder: BMA Doris Hillier award, Funder: Bupa Foundation; Id: http://dx.doi.org/10.13039/501100000355, Funder: Cure Parkinson's Trust, Funder: Erling‐Persson Foundation, Funder: European Research Council; Id: http://dx.doi.org/10.13039/501100000781, Funder: Hjärnfonden; Id: http://dx.doi.org/10.13039/501100003792, Funder: John and Lucille Van Geest Foundation; Id: http://dx.doi.org/10.13039/501100020410, Funder: Kempestiftelserna; Id: http://dx.doi.org/10.13039/501100007067, Funder: Knut och Alice Wallenbergs Stiftelse; Id: http://dx.doi.org/10.13039/501100004063, Funder: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; Id: http://dx.doi.org/10.13039/501100006129, Funder: Lockhart Parkinson's Disease Research Fund, Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100007155, Funder: Medicinska Forskningdet, Funder: NIHR Newcastle Biomedical Research Unit and Centre, Funder: NHS Grampian endowments, Funder: Norwegian Health Association; Id: http://dx.doi.org/10.13039/501100013263, Funder: Norwegian Parkinson's Research Foundation, Funder: Patrick Berthoud Trust, Funder: Rebergs Legacy, Funder: RS Macdonald Trust, Funder: SPRING; Id: http://dx.doi.org/10.13039/100001869, Funder: Swedish Parkinson Foundation, Funder: Umeå Universitet; Id: http://dx.doi.org/10.13039/501100004885, Funder: Västerbotten Läns Landsting; Id: http://dx.doi.org/10.13039/501100002960, Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269, Background: Common genetic variance in apolipoprotein E (APOE), β‐glucocerebrosidase (GBA), microtubule‐associated protein tau (MAPT), and α‐synuclein (SNCA) has been linked to cognitive decline in Parkinson’s disease (PD), although studies have yielded mixed results. Objectives: To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non‐selective, population‐based cohorts of newly diagnosed PD patients. Methods: 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE ‐ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini‐Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini−Hochberg corrections. Results: Carriers of APOE‐ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE‐ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non‐carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. Conclusions: GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Funder: National Institute for Health Research Biomedical Research Centre in Ageing and Chronic Disease and Biomedical Research Unit in Lewy Body Dementia at Newcastle, Funder: National Institute for Health Research Dementia Biomedical Research Unit at Cambridge, Background: Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear. Objective: To investigate spatial covariance patterns of cholinergic muscarinic M1/M4 receptors in PD and their relationship with cognition and motor symptoms. Methods: Some 19 PD and 24 older adult controls underwent 123I‐iodo‐quinuclidinyl‐benzilate (QNB) (M1/M4 receptor) and 99mTc‐exametazime (perfusion) single‐photon emission computed tomography (SPECT) scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of intercorrelated voxels across individuals. Linear regression analyses derived specific M1/M4 spatial covariance patterns associated with PD. Results: A cholinergic M1/M4 pattern that converged onto key hubs of the default, auditory–visual, salience, and sensorimotor networks fully discriminated PD patients from controls (F1,41 = 135.4, P < 0.001). In PD, we derived M1/M4 patterns that correlated with global cognition (r = −0.62, P = 0.008) and motor severity (r = 0.53, P = 0.02). Both patterns emerged with a shared topography implicating the basal forebrain as well as visual, frontal executive, and salience circuits. Further, we found a M1/M4 pattern that predicted global cognitive decline (r = 0.46, P = 0.04) comprising relative decreased binding within default and frontal executive networks. Conclusions: Cholinergic muscarinic M1/M4 modulation within key brain networks were apparent in PD. Cognition and motor severity were associated with a similar topography, inferring both phenotypes possibly rely on related cholinergic mechanisms. Relative decreased M1/M4 binding within default and frontal executive networks could be an indicator of future cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

BACKGROUND: Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear. OBJECTIVE: To investigate spatial covariance patterns of cholinergic muscarinic M1 /M4 receptors in PD and their relationship with cognition and motor symptoms. METHODS: Some 19 PD and 24 older adult controls underwent 123 I-iodo-quinuclidinyl-benzilate (QNB) (M1 /M4 receptor) and 99m Tc-exametazime (perfusion) single-photon emission computed tomography (SPECT) scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of intercorrelated voxels across individuals. Linear regression analyses derived specific M1 /M4 spatial covariance patterns associated with PD. RESULTS: A cholinergic M1 /M4 pattern that converged onto key hubs of the default, auditory-visual, salience, and sensorimotor networks fully discriminated PD patients from controls (F1,41 = 135.4, P < 0.001). In PD, we derived M1 /M4 patterns that correlated with global cognition (r = -0.62, P = 0.008) and motor severity (r = 0.53, P = 0.02). Both patterns emerged with a shared topography implicating the basal forebrain as well as visual, frontal executive, and salience circuits. Further, we found a M1 /M4 pattern that predicted global cognitive decline (r = 0.46, P = 0.04) comprising relative decreased binding within default and frontal executive networks. CONCLUSIONS: Cholinergic muscarinic M1 /M4 modulation within key brain networks were apparent in PD. Cognition and motor severity were associated with a similar topography, inferring both phenotypes possibly rely on related cholinergic mechanisms. Relative decreased M1 /M4 binding within default and frontal executive networks could be an indicator of future cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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 (

Supplemental Material, sj-pdf-1-jgp-10.1177_08919887211023592 for A Survey of People With Parkinson’s and Their Carers: The Management of Pain in Parkinson’s by Jenni Naisby, Anneesa Amjad, Natasha Ratcliffe, Alison J. Yarnall, Lynn Rochester, Richard Walker and Katherine Baker in Journal of Geriatric Psychiatry and Neurology

INTRODUCTION: Functional dependency in basic activities of daily living (ADLs) is a key outcome in Parkinson's disease (PD). We aimed to define dependency in PD, using the original and MDS versions of the Unified Parkinson's Disease Rating Scale (UPDRS). METHODS: We developed two algorithms to define dependency from items of UPDRS Part 2 and MDS-UPDRS Part 2 relating to basic ADLs (feeding, dressing, hygiene and walking, and getting out of a chair). We validated both algorithms using data from 1110 patients from six community-based PD incidence cohorts, testing concurrent validity, convergent validity, and predictive validity. RESULTS: Our optimal algorithm showed high specificity and moderate to high sensitivity versus Schwab & England

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.

Participating in habitual physical activity (HPA) may slow onset of dependency and disability for people with Parkinson’s disease (PwP). While cognitive and physical determinants of HPA are well understood, psychosocial influences are not. This pilot study aimed to identify psychosocial factors associated with HPA to guide future intervention development. Sixty-four PwP participated in this study; forty had carer informants. PwP participants wore a tri-axial accelerometer on the lower back continuously for seven days at two timepoints (18 months apart), measuring volume, pattern and variability of HPA. Linear mixed effects analysis identified relationships between demographic, clinical and psychosocial data and HPA from baseline to 18 months. Key results in PwP with carers indicated that carer anxiety and depression were associated with increased HPA volume (p < 0.01), while poorer carer self-care was associated with reduced volume of HPA over 18 months (p < 0.01). Greater carer strain was associated with taking longer walking bouts after 18 months (p < 0.01). Greater carer depression was associated with lower variability of HPA cross-sectionally (p = 0.009). This pilot study provides preliminary novel evidence that psychosocial outcomes from PwP’s carers may impact HPA in Parkinson’s disease. Interventions to improve HPA could target both PwP and carers and consider approaches that also support psychosocial wellbeing.

BACKGROUND: Cumulative dementia incidence in Parkinson's disease (PD) is significant, with major personal and socioeconomic impacts on individuals with PD and their carers. Early identification of dementia risk is vital to ensuring optimal intervention. Saccadic deficits often distinguish neurodegenerative disorders and cognitive impairment, but their ability to predict cognitive decline in PD has yet to be determined. The aims of this study were to (1) evaluate baseline (6.4 ± 6.1 months since PD diagnosis) differences in pro-saccadic metrics between those with early PD and healthy age-matched adults; and (2) assess the ability of baseline pro-saccades to predict subsequent cognitive decline over 4.5 years. METHODS: One hundred and forty-one PD and 90 age-matched participants recruited at diagnosis underwent saccadometric assessment of pro-saccades at baseline and had cognition assessed at baseline, 18, 36, and 54 months. Pro-saccadic characteristics included latency, duration, amplitude, peak, and average velocity. Cognitive assessment included executive function, attention, fluctuating attention, and memory. Linear mixed-effects models examined pro-saccadic metrics as predictors of cognitive decline over 54 months. RESULTS: Pro-saccades were significantly impaired at baseline in PD compared with controls. Pro-saccadic characteristics of latency, duration, peak, and average velocity predicted decline in global cognition, executive function, attention, and memory over 54 months in PD. In addition, only reduction in global cognition and attention were predicted by pro-saccadic metrics in age-matched adults, indicating that PD findings were not purely age related. CONCLUSIONS: Saccadic characteristics are impaired in early PD and are predictive of cognitive decline in several domains. Assessment of saccades may provide a useful non-invasive biomarker for long-term PD cognitive decline in early disease. © 2019 International Parkinson and Movement Disorder Society.

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.

OBJECTIVE: To investigate whether white matter microstructural changes can be used as a predictor of worsening of motor features or cognitive decline in patients with Parkinson's disease and verify whether white matter microstructural longitudinal changes differ between patients with Parkinson's disease with normal cognition and those with mild cognitive impairment. METHODS: We enrolled 120 newly diagnosed patients with early stage Parkinson's disease (27 with mild cognitive impairment and 93 with normal cognition) along with 48 controls. Participants were part of the incidence of cognitive impairment in cohorts with longitudinal evaluation in Parkinson's disease study and were assessed at baseline and 18 months later with cognitive, motor tests and diffusion tensor imaging. The relationships between fractional anisotropy and mean diffusivity with disease status, cognitive and motor function were investigated. RESULTS: At baseline, patients with early stage Parkinson's disease had significantly higher widespread mean diffusivity relative to controls, regardless of cognitive status. In patients with Parkinson's disease/mild cognitive impairment, higher mean diffusivity was significantly correlated with lower attention and executive function scores. At follow-up frontal mean diffusivity increased significantly when comparing patients with Parkinson's disease/mild cognitive impairment with those with normal cognition. Baseline mean diffusivity was a significant predictor of worsening of motor features in Parkinson's disease. CONCLUSIONS: Mean diffusivity represents an important correlate of cognitive function and predictor of motor impairment in Parkinson's disease: DTI is potentially a useful tool in stratification of patients into clinical trials and to monitor the impact of treatment on motor function.

INTRODUCTION: Anxiety and mild cognitive impairment (MCI) are prevalent non-motor manifestations of Parkinson's disease (PD). While few studies have demonstrated a possible link between cognitive dysfunction and anxiety in PD, to our knowledge, no studies have directly examined the association between them. This study investigated the association between anxiety and cognitive deficits in newly diagnosed PD patients.METHODS: Patients with newly diagnosed PD (N = 185) were recruited from community and outpatient clinics. Anxiety was assessed using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) clinician rated anxiety item, which has previously been validated against a standardized criteria for the diagnosis of anxiety disorders in PD. Participants scoring ≥2 were classified as anxious. A threshold of 1 SD below normative values (obtained from controls) was used to define cognitive impairment. Impairments in specific cognitive domains were identified as being >1 SD below controls in ≥1 test per domain.RESULTS: After controlling for age, education and motor severity, patients with anxiety were three times more likely to have cognitive impairment compared to those without anxiety (OR = 3.0, 95% CI = 1.2-7.3, p < 0.05). Patients with anxiety were more than twice as likely to be classified as having cognitive impairment due to impairment in the memory domain compared with PD without anxiety (OR = 2.3, 95% CI = 1.0-5.1, p < 0.05), whilst no associations were found between anxiety and performance on other cognitive domains.CONCLUSION: This study shows an association between anxiety and cognitive impairment (specifically memory impairment). Examining the neural basis of this association warrants future research in this developing field.

INTRODUCTION: Parkinson's disease dementia (PDD) is associated with poorer quality of life (QoL). Prior to the onset of PDD, many patients experience progressive cognitive impairment. There is a paucity of longitudinal studies investigating the effects of cognitive decline on QoL. This study aimed to determine the longitudinal impact of cognitive change on QoL in an incident PD cohort. METHODS: Recently diagnosed patients with PD (n = 212) completed a schedule of neuropsychological assessments and QoL measures; these were repeated after 18 (n = 190) and 36 months (n = 158). Mild cognitive impairment (PD-MCI) was classified with reference to the Movement Disorder Society criteria. Principal component analysis was used to reduce 10 neuropsychological tests to three cognitive factors: attention, memory/executive function, and global cognition. RESULTS: Baseline PD-MCI was a significant contributor to QoL (β = 0.2, p < 0.01). For those subjects (9%) who developed dementia, cognitive function had a much greater impact on QoL (β = 10.3, p < 0.05). Multivariate modelling showed attentional deficits had the strongest predictive power (β = -2.3, p < 0.01); brief global tests only modestly predicted decline in QoL (β = -0.4, p < 0.01). CONCLUSIONS: PD-MCI was associated with poorer QoL over three years follow up. Cognitive impairment had a greater impact on QoL in individuals who developed dementia over follow-up. Impaired attention was a significant determinant of QoL in PD. Interventions which improve concentration and attention in those with PD could potentially improve QoL.

Mild cognitive impairment in Parkinson’s disease (PDMCI) is associated with progression to dementia in a majority of patients. Mak et al. reveal accelerated cortical thinning in patients with PDMCI compared to non-cognitively impaired patients and healthy controls. Patterns of cortical thinning may constitute biomarkers for increased dementia risk., Mild cognitive impairment in Parkinson’s disease is associated with progression to dementia (Parkinson’s disease dementia) in a majority of patients. Determining structural imaging biomarkers associated with prodromal Parkinson’s disease dementia may allow for the earlier identification of those at risk, and allow for targeted disease modifying therapies. One hundred and five non-demented subjects with newly diagnosed idiopathic Parkinson’s disease and 37 healthy matched controls had serial 3 T structural magnetic resonance imaging scans with clinical and neuropsychological assessments at baseline, which were repeated after 18 months. The Movement Disorder Society Task Force criteria were used to classify the Parkinson’s disease subjects into Parkinson’s disease with mild cognitive impairment (n = 39) and Parkinson’s disease with no cognitive impairment (n = 66). Freesurfer image processing software was used to measure cortical thickness and subcortical volumes at baseline and follow-up. We compared regional percentage change of cortical thinning and subcortical atrophy over 18 months. At baseline, cases with Parkinson’s disease with mild cognitive impairment demonstrated widespread cortical thinning relative to controls and atrophy of the nucleus accumbens compared to both controls and subjects with Parkinson’s disease with no cognitive impairment. Regional cortical thickness at baseline was correlated with global cognition in the combined Parkinson’s disease cohort. Over 18 months, patients with Parkinson’s disease with mild cognitive impairment demonstrated more severe cortical thinning in frontal and temporo-parietal cortices, including hippocampal atrophy, relative to those with Parkinson’s disease and no cognitive impairment and healthy controls, whereas subjects with Parkinson’s disease and no cognitive impairment showed more severe frontal cortical thinning compared to healthy controls. At baseline, Parkinson’s disease with no cognitive impairment converters showed bilateral temporal cortex thinning relative to the Parkinson’s disease with no cognitive impairment stable subjects. Although loss of both cortical and subcortical volume occurs in non-demented Parkinson’s disease, our longitudinal analyses revealed that Parkinson’s disease with mild cognitive impairment shows more extensive atrophy and greater percentage of cortical thinning compared to Parkinson’s disease with no cognitive impairment. In particular, an extension of cortical thinning in the temporo-parietal regions in addition to frontal atrophy could be a biomarker in therapeutic studies of mild cognitive impairment in Parkinson’s disease for progression towards dementia.

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.

Funder: Lockhart Parkinson's Disease Research Fund, Funder: Newcastle Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012295, BACKGROUND: Gait impairments are characteristic motor manifestations and significant predictors of poor quality of life in Parkinson's disease (PD). Neuroimaging biomarkers for gait impairments in PD could facilitate effective interventions to improve these symptoms and are highly warranted. OBJECTIVE: The aim of this study was to identify neural networks of discrete gait impairments in PD. METHODS: Fifty-five participants with early-stage PD and 20 age-matched healthy volunteers underwent quantitative gait assessment deriving 12 discrete spatiotemporal gait characteristics and [18 F]-2-fluoro-2-deoxyglucose-positron emission tomography measuring resting cerebral glucose metabolism. A multivariate spatial covariance approach was used to identify metabolic brain networks that were related to discrete gait characteristics in PD. RESULTS: In PD, we identified two metabolic gait-related covariance networks. The first correlated with mean step velocity and mean step length (pace gait network), which involved relatively increased and decreased metabolism in frontal cortices, including the dorsolateral prefrontal and orbital frontal, insula, supplementary motor area, ventrolateral thalamus, cerebellum, and cuneus. The second correlated with swing time variability and step time variability (temporal variability gait network), which included relatively increased and decreased metabolism in sensorimotor, superior parietal cortex, basal ganglia, insula, hippocampus, red nucleus, and mediodorsal thalamus. Expression of both networks was significantly elevated in participants with PD relative to healthy volunteers and were not related to levodopa dosage or motor severity. CONCLUSIONS: We have identified two novel gait-related brain networks of altered glucose metabolism at rest. These gait networks could serve as a potential neuroimaging biomarker of gait impairments in PD and facilitate development of therapeutic strategies for these disabling symptoms. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.