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Supplemental material, sj-docx-2-cpa-10.1177_07067437221147443 for Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function by Daniel Kapustin, Shadi Zarei, Wei Wang, Malcolm A. Binns, Paula M. McLaughlin, Agessandro Abrahao, Sandra E. Black, Michael Borrie, David Breen, Leanna Casaubon, Dar Dowlatshahi, Elizabeth Finger, Corinne E Fischer, Andrew Frank, Morris Freedman, David Grimes, Ayman Hassan, Mandar Jog, Donna Kwan, Anthony Lang, Brian Levine, Jennifer Mandzia, Connie Marras, Mario Masellis, Joseph B. Orange, Stephen Pasternak, Alicia Peltsch, Bruce G. Pollock, Tarek K. Rajji, Angela Roberts, Demetrios Sahlas, Gustavo Saposnik, Dallas Seitz, Christen Shoesmith, Alisia Southwell, Thomas D.L. Steeves, Kelly Sunderland, Richard H Swartz, Brian Tan, David F. Tang-Wai, Maria Carmela Tartaglia, Angela Troyer, John Turnbull, Lorne Zinman, and Sanjeev Kumar in The Canadian Journal of Psychiatry

Supplemental material, sj-pdf-1-cpa-10.1177_07067437221147443 for Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function by Daniel Kapustin, Shadi Zarei, Wei Wang, Malcolm A. Binns, Paula M. McLaughlin, Agessandro Abrahao, Sandra E. Black, Michael Borrie, David Breen, Leanna Casaubon, Dar Dowlatshahi, Elizabeth Finger, Corinne E Fischer, Andrew Frank, Morris Freedman, David Grimes, Ayman Hassan, Mandar Jog, Donna Kwan, Anthony Lang, Brian Levine, Jennifer Mandzia, Connie Marras, Mario Masellis, Joseph B. Orange, Stephen Pasternak, Alicia Peltsch, Bruce G. Pollock, Tarek K. Rajji, Angela Roberts, Demetrios Sahlas, Gustavo Saposnik, Dallas Seitz, Christen Shoesmith, Alisia Southwell, Thomas D.L. Steeves, Kelly Sunderland, Richard H Swartz, Brian Tan, David F. Tang-Wai, Maria Carmela Tartaglia, Angela Troyer, John Turnbull, Lorne Zinman, and Sanjeev Kumar in The Canadian Journal of Psychiatry

Supplemental material, sj-docx-3-cpa-10.1177_07067437221147443 for Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function by Daniel Kapustin, Shadi Zarei, Wei Wang, Malcolm A. Binns, Paula M. McLaughlin, Agessandro Abrahao, Sandra E. Black, Michael Borrie, David Breen, Leanna Casaubon, Dar Dowlatshahi, Elizabeth Finger, Corinne E Fischer, Andrew Frank, Morris Freedman, David Grimes, Ayman Hassan, Mandar Jog, Donna Kwan, Anthony Lang, Brian Levine, Jennifer Mandzia, Connie Marras, Mario Masellis, Joseph B. Orange, Stephen Pasternak, Alicia Peltsch, Bruce G. Pollock, Tarek K. Rajji, Angela Roberts, Demetrios Sahlas, Gustavo Saposnik, Dallas Seitz, Christen Shoesmith, Alisia Southwell, Thomas D.L. Steeves, Kelly Sunderland, Richard H Swartz, Brian Tan, David F. Tang-Wai, Maria Carmela Tartaglia, Angela Troyer, John Turnbull, Lorne Zinman, and Sanjeev Kumar in The Canadian Journal of Psychiatry

Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer’s disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson’s disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00539-x.

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 (

There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

INTRODUCTION: Immune markers are altered in Parkinson's disease (PD), but relationships between cerebrospinal fluid (CSF) and plasma cytokines and associations with neurodegeneration-associated proteins remain unclear. METHODS: CSF and plasma samples and demographic/clinical measures were obtained from 35 PD patients. CSF samples were analyzed for cytokines (together with plasma) and for α-synuclein, amyloid β(1-42) peptide, total tau, and phospho(Thr231)-tau. RESULTS: There were no CSF-plasma cytokine correlations. Interleukin (IL)-8 was higher and interferon-γ, IL-10, and tumor necrosis factor-α were lower in CSF versus plasma. In CSF, total tau correlated positively with IL-8 and IL-1β, whereas α-synuclein correlated positively with amyloid β(1-42) and negatively with semantic fluency (a known marker of PD dementia risk). DISCUSSION: CSF and peripheral cytokine profiles in PD are not closely related. Associations between CSF IL-8 and IL-1β and tau suggest that CSF inflammatory changes may relate to tau pathology within PD. CSF α-synuclein/amyloid β may reflect the risk of developing PD dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. OBJECTIVES: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. METHODS: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. RESULTS: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. CONCLUSIONS: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

Inspired by the chemotaxis interaction of living cells, we have developed an agent-based approach for self-organizing shape formation. Since all our simulations begin with a different uniform random configuration and our agents move stochastically, it has been observed that the self-organization process may form two or more stable final configurations. These differing configurations may be characterized via statistical moments of the agents' locations. In order to direct the agents to robustly form one specific configuration, we generate biased initial conditions whose statistical moments are related to moments of the desired configuration. With this approach, we are able to successfully direct the aggregating swarms to produced a desired macroscopic shape, starting from randomized initial conditions with controlled statistical properties.

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.

Background: Symptomatic gastro-oesophageal reflux disease (GORD) has been associated with increased exacerbations and reduced quality of life in bronchiectasis (BR). We aimed to evaluate the prevalence of a BR-GORD phenotype, utilising the multi-domain Bronchiectasis Severity Index (BSI), to determine associations with disease severity and mortality. Methods: A retrospective cohort study in 212 consecutive BR patients attending our institution over a 2-year period was performed. A diagnosis of GORD was based on standardised definitions following full review of electronic records, review of prescriptions and investigator definitions. Results: 72 (19.8%) BR patients were confirmed to have co-existent GORD treated with proton pump inhibitors. These patients were predominantly male, older and with higher BMIs than their counterparts (p= Conclusion: BR-GORD patients have an increased disease severity and mortality risk compared with BR patients without GORD. Increased recognition of this BR-GORD phenotype and its potential for targeted therapy is needed.

Background and objectiveHiatal hernias (HH) are associated with gastro-oesophageal reflux and may contribute to lung disease severity. We aimed to evaluate the prevalence of HH among stable non-cystic fibrosis bronchiectasis (NCFB) patients and determine associations with disease severity. MethodsA retrospective cross-sectional cohort study of 100 consecutive NCFB patients in our institution was performed. Data were collected on baseline variables, microbiology, lung function and radiology, according to the modified Bhalla score. Disease severity was assessed using the Bronchiectasis Severity Index (BSI) and FACED severity scores. ResultsFollowing expert radiological review, 81 patients were deemed suitable for study inclusion (mean age (SD) 62.6 (12.4), females 55 (67.9%), body mass index (BMI) 26.9 (5.7)); 29 (35.8%) were HH positive (HH+). HH+ patients had a trend towards higher BMI (P=0.07), and a significantly higher proportion had reflux symptoms (HH+ 62.1% vs HH- 28.8%, P

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

Pleural infection is a major problem that affects 80000 cases per year in the UK and USA. It is increasing in incidence, and in an ageing population, it presents a complex challenge that requires a combination of medical therapies and may lead to the need for surgery. This article focuses on the role of the interventional pulmonologist in the diagnosis and management of pleural infection. In particular, we examine the role of pleural ultrasound in diagnostics, thoracocentesis and real-time guided procedures, and the current management strategies, including the controversial role of medical thoracoscopy.

BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.

OBJECTIVE: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. METHODS: We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed. RESULTS: We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69-6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04-20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16-1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19-2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (-0.72 [-1.21 to -0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21-1.03]). CONCLUSIONS: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

Funder: Foundation for the National Institutes of Health; FundRef: http://dx.doi.org/10.13039/100000009, Funder: Van Geest Foundation, Funder: Patrick Berthoud Charitable Trust; FundRef: http://dx.doi.org/10.13039/501100004218, Funder: Cure Parkinson's Trust, Funder: Michael J Fox Foundation, Funder: Innovate UK; FundRef: http://dx.doi.org/10.13039/501100006041, Funder: Dooley LLC, Funder: American Parkinson's disease association, Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265, Funder: Cambridge Centre for Parkinson-Plus, Funder: Parkinson's UK; FundRef: http://dx.doi.org/10.13039/501100000304, Funder: John Black charitable foundation, Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440, Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272, Funder: Van Andel Research Institute; FundRef: http://dx.doi.org/10.13039/100006019, Introduction: Variants in the GBA1 gene have been identified as a common risk factor for Parkinson’s disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of ‘non-pathogenic’ variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of ‘non-pathogenic’ GBA1 variants on PD course is less clear. In this study, we report the effect of GBA1 variants in incident PD patients with long-term follow-up. Methods: The study population consisted of patients in the Cambridgeshire Incidence of Parkinson’s disease from General Practice to Neurologist and Parkinsonism: Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire cohorts. Patients were grouped into non-carriers, carriers of ‘non-pathogenic’ GBA1 variants and carriers of pathogenic GBA1 mutations. Survival analyses for time to development of dementia, postural instability and death were carried out. Cox regression analysis controlling for potential confounders were used to determine the impact of GBA1 variants on these outcome measures. Results: GBA1 variants were identified in 14.4% of patients. Pathogenic and ‘non-pathogenic’ GBA1 variants were associated with the accelerated development of dementia and a more aggressive motor course. Pathogenic GBA1 variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia. Discussion: GBA1 variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course.

INTRODUCTION: Variants in the GBA1 gene have been identified as a common risk factor for Parkinson's disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of 'non-pathogenic' variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of 'non-pathogenic' GBA1 variants on PD course is less clear. In this study, we report the effect of GBA1 variants in incident PD patients with long-term follow-up. METHODS: The study population consisted of patients in the Cambridgeshire Incidence of Parkinson's disease from General Practice to Neurologist and Parkinsonism: Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire cohorts. Patients were grouped into non-carriers, carriers of 'non-pathogenic' GBA1 variants and carriers of pathogenic GBA1 mutations. Survival analyses for time to development of dementia, postural instability and death were carried out. Cox regression analysis controlling for potential confounders were used to determine the impact of GBA1 variants on these outcome measures. RESULTS: GBA1 variants were identified in 14.4% of patients. Pathogenic and 'non-pathogenic' GBA1 variants were associated with the accelerated development of dementia and a more aggressive motor course. Pathogenic GBA1 variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia. DISCUSSION: GBA1 variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course.