Longitudinal decline in striatal dopamine transporter binding in Parkinson’s disease: associations with apathy and anhedonia

Background: Motivational symptoms such as apathy and anhedonia are common in Parkinson’s disease (PD), respond poorly to treatment, and are hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in PD but the association has never been examined longitudinally. We investigated whether progression of dopaminergic dysfunction was associated with emergent apathy and anhedonia symptoms in PD. Methods: Longitudinal cohort study of 412 newly diagnosed patients with PD followed over 5 years as part of the Parkinson’s Progression Markers Initiative cohort. Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item Geriatric Depression Scale (GDS-15) and part I of the MDS-Unified Parkinson’s Disease Rating Scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging. Results: Linear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio (SBR) and apathy/anhedonia symptoms, which emerged as PD progressed (interaction:β=−0.09, 95% CI (−0.15 to 0.03), p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average 2 years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) (β=−0.06, 95% CI (−0.13 to 0.01)) or motor symptoms (β=0.20, 95% CI (−0.25 to 0.65)). Conclusions: Our findings support a central role for dopaminergic dysfunction in motivational symptoms in PD. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies

Lack of Association of Group A Streptococcal Infections and Onset of Tics: European Multicenter Tics in Children Study

Background and objectives: The goal of this work was to investigate the association between group A streptococcal (GAS) infections and tic incidence among unaffected children with a family history of chronic tic disorders (CTDs). Methods: In a prospective cohort study, children with no history for tics who were 3 to 10 years of age with a first-degree relative with a CTD were recruited from the European Multicentre Tics in Children Study (EMTICS) across 16 European centers. Presence of GAS infection was assessed with throat swabs, serum anti-streptolysin O titers, and anti-DNAse titers blinded to clinical status. GAS exposure was defined with 4 different definitions based on these parameters. Cox regression analyses with time-varying GAS exposure were conducted to examine the association of onset of tics and GAS exposure during follow-up. Sensitivity analyses were conducted with Cox regression and logistic regression analyses. Results: A total of 259 children were recruited; 1 child was found to have tic onset before study entry and therefore was excluded. Sixty-one children (23.6%) developed tics over an average follow-up period of 1 (SD 0.7) year. There was a strong association of sex and onset of tics, with girls having an ≈60% lower risk of developing tics compared to boys (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2-0.7). However, there was no statistical evidence to suggest an association of any of the 4 GAS exposure definitions with tic onset (GAS exposure definition 1: HR 0.310, 95% CI 0.037-2.590; definition 2: HR 0.561, 95% CI 0.219-1.436; definition 3: HR 0.853, 95% CI 0.466-1.561; definition 4: HR 0.725, 95% CI 0.384-1.370). Discussion: These results do not suggest an association between GAS exposure and development of tics. Classification of evidence: This study provides Class I evidence that group A streptococcal exposure does not associate with the development of tics in children with first-degree relatives with chronic tic disorder

Lack of Association of Group A Streptococcal Infections and Onset of Tics: European Multicenter Tics in Children Study

ObjectiveTo investigate the association between Group-A streptococcal (GAS) infections and tic incidence among unaffected children with a family history of chronic tic disorders (CTD).MethodsIn a prospective cohort study, children with no history for tics aged 3 to 10 years with a first-degree relative with CTD were recruited from the European Multicentre Tics in Children Study (EMTICS) across 16 European centres. Presence of GAS infection was assessed using throat swabs, serum Anti-streptolysin O titres (ASOT) and Anti-DNAse B (ADB) titres blinded to clinical status. GAS exposure was defined using four different definitions based on these parameters. Cox regression analyses with time-varying GAS exposure were conducted to examine the association of onset of tics and GAS exposure during follow-up. Sensitivity analyses were conducted using Cox regression and logistic regression analyses.ResultsA total of 260 children were recruited whilst one subject was found to have tic onsets before study entry and therefore was excluded. 61 children (23.6%) developed tics over an average follow-up period of 1 (SD 0.7) year. There was a strong association of sex and onset of tics, with girls having an approximately 60% lower risk of developing tics compared to boys (HR: 0.4, 95% CI 0.2-0.7). However, there was no statistical evidence to suggest an association of any of the four GAS exposure definitions with tic onset (GAS exposure definition 1: HR=0.310, 95% CI: 0.037-2.590; definition 2: HR=0.561, 95% CI: 0.219-1.436; definition 3: HR=0.853, 95% CI: 0.466-1.561; definition 4: HR=0.725, 95% CI: 0.384-1.370).ConclusionThese results do not suggest an association of GAS exposure and development of tics.Classification of EvidenceThis study provides Class I evidence that Group-A streptococcal exposure does not associate with the development of tics in children with first-degree relatives with chronic tic disorder

Accuracy of Screening Instruments for Detection of Neuropsychiatric Syndromes in Parkinson’s Disease

Parkinson's disease includes neuropsychiatric manifestations, such as depression, anxiety, apathy, psychosis, and impulse control disorders, which often are unreported by patients and caregivers or undetected by doctors. Given their substantial impact on patients and caregivers as well as the existence of effective therapies for some of these disorders, screening for neuropsychiatric symptoms is important. Instruments for screening have a particular methodology for validation, and their performance is expressed in terms of accuracy compared with formal diagnostic criteria. The present study reviews the attributes of the screening instruments applied for detection of the aforementioned major neuropsychiatric symptoms in Parkinson's disease. A quasi-systematic review (including predefined selection criteria, but not evaluating the quality of the reviewed studies) was carried out on the basis of previous systematic reviews (commissioned by the American Academy of Neurology and the Movement Disorder Society) and made current by conducting a literature search (2005-2014). For depression, 11 scales and questionnaires were shown to be valid for Parkinson's disease screening. The recently developed Parkinson Anxiety Scale and the Geriatric Anxiety Inventory demonstrate satisfactory properties as screening instruments for anxiety, and the Lille Apathy Rating Scale for detection of apathy. No scale adequately screens for psychosis, so a specific psychosis instrument should be developed. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (Questionnaire and Rating Scale) are valid for comprehensive screening of impulse control disorders, and the Parkinson's Disease-Sexual Addiction Screening Test for hypersexuality specifically

Late onset depression: Dopaminergic deficit and clinical features of prodromal Parkinson's disease: A cross-sectional study

Background: Late onset depression (LOD) may precede the diagnosis of Parkinson's disease (PD) or dementia with Lewy bodies (DLB). We aimed to determine the rate of clinical and imaging features associated with prodromal PD/DLB in patients with LOD. Methods: In a cross-sectional design, 36 patients with first onset of a depressive disorder (Diagnostic and Statistical Manual of Mental Disorders IV criteria) diagnosed after the age of 55 (LOD group) and 30 healthy controls (HC) underwent a detailed clinical assessment. In addition, 28/36 patients with LOD and 20/30 HC underwent a head MRI and 29/36 and 25/30, respectively, had dopamine transporter imaging by 123I-ioflupane single-photon emission computed tomography (SPECT) imaging. Image analysis of both scans was performed by a rater blind to the participant group. Results of clinical assessments and imaging results were compared between the two groups. Results: Patients with LOD (n=36) had significantly worse scores than HC (n=30) on the PD screening questionnaire (mean (SD) 1.8 (1.9) vs 0.8 (1.2); p=0.01), Movement Disorder Society Unified Parkinson's Disease Rating Scale total (mean (SD) 19.2 (12.7) vs 6.1 (5.7); p<0.001), REM-sleep behaviour disorder screening questionnaire (mean (SD) 4.3 (3.2) vs 2.1 (2.1); p=0.001), Lille Apathy Rating Scale (mean (SD)-23.3 (9.6) vs-27.0 (4.7); p=0.04) and the Scales for Outcomes in PD-Autonomic (mean (SD) 14.9 (8.7) vs 7.7 (4.9); p<0.001). Twenty-four per cent of patients with LOD versus 4% HC had an abnormal 123I-ioflupane SPECT scan (p=0.04). Conclusions: LOD is associated with increased rates of motor and non-motor features of PD/DLB and of abnormal 123I-ioflupane SPECTs. These results suggest that patients with LOD should be considered at increased risk of PD/DLB

Caregiver burden in late-stage Parkinsonism and its associations

Copyright © 2020, © SAGE PublicationsBackground: Patients in the late stages of parkinsonism are highly dependent on others in their self-care and activities of daily living. However, few studies have assessed the physical, psychological and social consequences of caring for a person with late-stage parkinsonism. Patients and methods: Five hundred and six patients and their caregivers from the Care of Late Stage Parkinsonism (CLaSP) study were included. Patients’ motor and non-motor symptoms were assessed using the UPDRS and Non-motor symptom scale (NMSS), Neuropsychiatric inventory (NPI-12), and caregivers’ health status using the EQ-5D-3 L. Caregiver burden was assessed by the Zarit Burden Interview (ZBI). Results: The majority of caregivers were the spouse or life partner (71.2%), and were living with the patient at home (67%). Approximately half of caregivers reported anxiety/depression and pain/discomfort (45% and 59% respectively). The factors most strongly associated with caregiver burden were patients’ neuropsychiatric features on the total NPI score (r = 0.38, p < 0.0001), total NMSS score (r = 0.28, p < 0.0001), caring for male patients and patients living at home. Being the spouse, the hours per day assisting and supervising the patient as well as caregivers’ EQ-5D mood and pain scores were also associated with higher ZBI scores (all p < 0.001). Conclusion: The care of patients with late stage parkinsonism is associated with significant caregiver burden, particularly when patients manifest many neuropsychiatric and non-motor features and when caring for a male patient at home.The study was funded by the European Commission (Joint Programme-Neurodegenerative Disease Research “European research projects for the evaluation of health care policies, strategies and interventions for Neurodegenerative Diseases”) through national funding bodies in all 6 countries (Economic and Social Research Council ES/L009250/1; BMBF, Marburg, Germany 01ED1403A, Munich, Germany 01ED1403B, Bordeaux, France: ANR-13-JPHC-0001-07, Lisbon, Portugal: HC/0002/2012, Lund, Sweden: HC-559-002, Nijmegen, Holland, 733051003). AS was supported by the National Institute for Health Research UCL/UCLH Biomedical Research Centre. AH was supported by co-funding of Groenhuysen organization and Stichting Beroepsopleiding Huisartsen.info:eu-repo/semantics/publishedVersio

Functional (conversion) neurological symptoms: research since the millennium

Functional neurological symptoms (FNS) are commonly encountered but have engendered remarkably little academic interest. ‘UK-Functional Neurological Symptoms (UK-FNS)’ was an informal inaugural meeting of UK based clinicians in March 2011 with a variety of research and clinical interests in the field. This narrative review reflects the content of the meeting, and our opinion of key findings in the field since the turn of the millennium

The prediagnostic phase of Parkinson's disease

Abstract The field of prediagnostic Parkinson's disease (PD) is fast moving with an expanding range of clinical and laboratory biomarkers, and multiple strategies seeking to discover those in the earliest stages or those ‘at risk’. It is widely believed that the highest likelihood of securing neuroprotective benefit from drugs will be in these subjects, preceding current point of diagnosis of PD. In this review, we outline current knowledge of the prediagnostic phase of PD, including an up-to-date review of risk factors (genetic and environmental), their relative influence, and clinical features that occur prior to diagnosis. We discuss imaging markers across a range of modalities, and the emerging literature on fluid and peripheral tissue biomarkers. We then explore current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials, what we are learning from these initiatives, and how these studies will bring the field closer to realistically commencing primary or secondary preventive trials for PD. Further progress in this field hinges on greater clinical and biological description, and understanding of the prediagnostic, peridiagnostic and immediate postdiagnostic stages of PD. Identifying subjects 3–5 years before they are currently diagnosed may be an ideal group for neuroprotective trials. At the very least, these initiatives will help clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of disease.Parkinson's UK (career development award for AJN, reference F-1201)