Prediagnostic presentations of Parkinson's disease in primary care: a case-control study

Great to have been involved in this study. It is amazing the see the symptoms and relative incidence of early features preceding diagnosis, played out in single cohort...

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(14)70287-X/fulltext

Lancet Neurol. 2014 Nov 26. pii: S1474-4422(14)70287-X. doi: 10.1016/S1474-4422(14)70287-X. [Epub ahead of print]

Schrag A, Horsfall L, Walters K, Noyce A, Petersen I.

BACKGROUND:

Parkinson's disease has an insidious onset and is diagnosed when typical motor features occur. Several motor and non-motor features can occur before diagnosis, early in the disease process. We aimed to assess the association between first presentation of several prediagnostic features in primary care and a subsequent diagnosis of Parkinson's disease, and to chart the timeline of these first presentations before diagnosis.

METHODS:

We identified individuals with a first diagnosis of Parkinson's disease and those without Parkinson's disease from Jan 1, 1996, to Dec 31, 2012, from The Health Improvement Network UK primary care database. Codes were extracted for a range of possible prediagnostic or early symptoms, comprising motor features (tremor, rigidity, balance impairments, neck pain or stiffness, and shoulder pain or stiffness), autonomic features (constipation, hypotension, erectile dysfunction, urinary dysfunction, and dizziness), neuropsychiatric disturbances (memory problems, late-onset anxiety or depression, cognitive decline, and apathy), and additional features (fatigue, insomnia, anosmia, hypersalivation and rapid-eye-movement sleep behaviour disorder) in the years before diagnosis. We report the incidence of symptoms recorded in more than 1% of cases per 1000 person-years and incidence risk ratios (RRs) for individuals with and without Parkinson's disease at 2, 5, and 10 years before diagnosis.

FINDINGS:

8166 individuals with and 46 755 individuals without Parkinson's disease were included in the study. Apathy, REM sleep behaviour disorder, anosmia, hypersalivation, and cognitive decline were all reported in less than 1% of people per 1000 person-years and were excluded from further analyses. At 2 years before Parkinson's disease diagnosis, the incidence of all studied prediagnostic features except neck pain or stiffness was higher in patients who went on to develop Parkinson's disease (n=7232) than in controls (n=40 541). At 5 years before diagnosis, compared with controls (n=25 544), patients who went on to develop Parkinson's disease (n=4769) had a higher incidence of tremor (RR 13·70, 95% CI 7·82-24·31), balance impairments (2·19, 1·09-4·16), constipation (2·24, 2·04-2·46), hypotension (3·23, 1·85-5·52), erectile dysfunction (1·30, 1·11-1·51), urinary dysfunction (1·96, 1·34-2·80), dizziness (1·99, 1·67-2·37), fatigue (1·56, 1·27-1·91), depression (1·76, 1·41-2·17), and anxiety (1·41, 1·09-1·79). At 10 years before diagnosis of Parkinson's disease, the incidence of tremor (RR 7·59, 95% CI 1·11-44·83) and constipation (2·01, 1·62-2·49) was higher in those who went on to develop Parkinson's disease (n=1680) than in controls (n=8305).

INTERPRETATION:

A range of prediagnostic features can be detected several years before diagnosis of Parkinson's disease in primary care. These data can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease for inclusion in future trials and to help understand progression in the earliest phase of Parkinson's disease.

FUNDING:

Parkinson's UK.

GBA-associated Parkinson's disease: Reduced survival and more rapid progression in a prospective longitudinal study.

Further insight into GBA related Parkinson's...

Mov Disord. 2014 Dec 1. doi: 10.1002/mds.26071. [Epub ahead of print]

Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, Maetzler W, Gasser T, Berg D.

BACKGROUND:

Parkinson's disease (PD) patients with GBA mutations show an earlier age at onset and more severe non-motor symptoms compared with PD patients without GBA mutations.

OBJECTIVE:

This study was undertaken to evaluate progression of motor and non-motor symptoms in sporadic PD patients depending on the mutational GBA status.

METHODS:

We used regression analysis to evaluate independent effects of the mutational GBA status, age at onset, age at examination, and disease duration on motor (Unified Parkinson's Disease Rating Scale [UPDRS]-III, Hoehn and Yahr [H&Y] stage, Levodopa [l-dopa]-equivalent-dosage) and non-motor characteristics (cognition and mood). Disease progression was assessed prospectively over 3 years.

RESULTS:

The GBA-associated PD patients compared with non-mutation PD patients, although younger and with an earlier age at onset, show (1) a more rapid disease progression of motor impairment and cognitive decline and (2) reduced survival rates.

CONCLUSIONS:

The mutational GBA status, rather than older age and age at onset, presents an important predictor for disease progression in this specific subgroup of PD patients.

Are Sleep Disturbances Preclinical Markers of Parkinson's Disease?

Neurochem Res. 2014 Nov 30. [Epub ahead of print]

Dos Santos AB, Kohlmeier KA, Barreto GE.

Abstract

Parkinson's disease (PD) is a neurobehavioral disorder characterized by motor symptoms and signs, and non-motor abnormalities such as olfactory dysfunction, pain, sleep disorders and cognitive impairment. Amongst these alterations, sleep disturbances play an important role in the pathology, but presence of disturbed sleep is not currently considered in diagnosis. However, sleeping problems may precede by many years the classic motor abnormalities of PD and should be clinically evaluated as a potential marker before disease onset. The first disturbance reported with this potential was the disorder REM sleep behaviour and currently several other disturbances have gained importance as potential markers, such as excessive daytime sleepiness, restless legs syndrome and new evidence also points to changes in circadian rhythms. Here we present a brief review of the major evidence indicating that sleep disturbances precede the motor symptoms in PD and neurodegeneration occurs in regions that could underlie these phenomena in order to provide support for the conclusion that disturbances of sleep should be considered as valuable preclinical markers for PD.

Sonography for diagnosis of Parkinson disease-from theory to practice: a study on 300 participants

Good results using a Toshiba...

J Ultrasound Med. 2014 Dec;33(12):2069-74. doi: 10.7863/ultra.33.12.2069.

Alonso-Cánovas A, López-Sendón JL, Buisán J, deFelipe-Mimbrera A, Guillán M, García-Barragán N, Corral I, Matute-Lozano MC, Masjuan J, Martínez-Castrillo JC, Walter U.

OBJECTIVES:

Hyperechogenicity of the substantia nigra on transcranial sonography is used for diagnosing Parkinson disease (PD). Cutoff values for the substantia nigra echogenic area, defining substantia nigra hyperechogenicity, vary among ultrasound systems from different manufacturers. In this study we wanted to determine the cutoff criterion for a Toshiba (Tokyo, Japan) system and to assess its diagnostic value.

METHODS:

Three hundred participants (controls, n = 138; patients with PD, n = 105; and patients with essential tremor, n = 57) underwent transcranial sonography following a standardized protocol.

RESULTS:

The substantia nigra was assessable in 92.7% of all participants. The substantia nigra echogenic area (larger of bilateral measurements) was larger in patients with PD (mean ± SD, 0.24 ± 0.05 cm(2)) than controls (0.14 ± 0.05 cm(2); P < .001) and patients with essential tremor (0.14 ± 0.04 cm(2); P < .001). Substantia nigra echogenicity was larger in male participants (0.20 ± 0.07 cm(2)) than female participants (0.15 ± 0.06 cm(2); P< .001). Age did not correlate with substantia nigra echogenicity in any group. Frontal horn width was larger and lenticular nucleus hyperechogenicity and a discontinuous raphe were more frequent in the PD group than the other groups. On multivariate analysis, only substantia nigra hyperechogenicity was associated with the diagnosis of PD. The 90th-percentile substantia nigra echogenic area in the control group, which defined marked substantia nigra hyperechogenicity, also represented the optimum cutoff value for discrimination of PD from non-PD participants on receiver operating characteristic curve analysis (area under the curve, 0.913; Youden index, 0.73). This cutoff value (≥0.21 cm(2), larger of bilateral measurements) yielded sensitivity of 83% and specificity of 90% for the diagnosis of PD.

CONCLUSIONS:

Transcranial sonography shows good diagnostic validity for diagnosis of PD when implemented according to a strictly standardized protocol.

Physical activity and risk of Parkinson's disease in the Swedish National March Cohort

http://brain.oxfordjournals.org/content/early/2014/11/16/brain.awu323.long

Brain. 2014 Nov 18. pii: awu323. [Epub ahead of print]

Yang F, Trolle Lagerros Y, Bellocco R, Adami HO, Fang F, Pedersen NL, Wirdefeldt K.

Physical exercise has been associated with neuroprotective effects in the nigrostriatal dopaminergic system. To examine the impact of physical activity on Parkinson's disease risk prospectively, we followed 43 368 individuals who provided extensive information on physical activity at baseline. We estimated hazard ratios with 95% confidence intervals using Cox proportional hazards regression. During an average of 12.6 years of follow-up, 286 incident Parkinson's disease cases were identified. In males, there was an inverse association with Parkinson's disease for total physical activity (hazard ratio 0.55, 95% confidence interval 0.35-0.87 for medium versus low level), for sum of household, commuting and leisure time exercise (hazard ratio 0.53, 95% confidence interval 0.33-0.85 for high versus low level), and for household and commuting physical activity specifically (hazard ratio 0.50, 95% confidence interval 0.31-0.81 for >6 versus <2 h per week). No association was observed for leisure time exercise or occupational physical activity with Parkinson's disease, among either males or females. Meta-analysis of the present study and five previous prospective studies showed a pooled hazard ratio of 0.66 (95% confidence interval 0.57-0.78) for highest versus lowest physical activity level. Our results indicate that a medium level of physical activity lowers Parkinson's disease risk.

CSF biomarkers and clinical progression of Parkinson disease

Neurology. 2014 Nov 19. pii: 10.1212/WNL.0000000000001098. [Epub ahead of print]

Hall S, Surova Y, Ohrfelt A, Zetterberg H, Lindqvist D, Hansson O.

OBJECTIVE:

To investigate whether certain CSF biomarkers at baseline can predict future progression of motor symptoms and cognitive decline in patients with Parkinson disease (PD).

METHODS:

Patients and controls were recruited from hospitals in southern Sweden as part of the prospective and longitudinal Swedish BioFinder Study. In the present study, we included 42 patients with PD and 69 controls who had clinical assessment and lumbar puncture at baseline. Baseline CSF samples were analyzed for α-synuclein (αSyn), β-amyloid 1-42 (Aβ42), tau, phosphorylated tau, and neurofilament light. Associations between CSF markers at baseline and change in clinical characteristics after 2 years of follow-up were investigated using multivariate models adjusting for age, sex, disease duration, and levodopa-equivalent daily dose.

RESULTS:

Higher levels of αSyn within the PD group were associated with progression of motor symptoms and cognitive decline over 2 years, indicated by significant relationships between αSyn and change in Hoehn and Yahr (β = 0.394, p = 0.043), Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III) (β = 0.449, p = 0.013), Timed Up and Go (β = 0.406, p = 0.023), and A Quick Test of Cognitive Speed (β = 0.423, p = 0.018). Lower levels of Aβ42 were associated with worsening of performance on delayed memory recall (F = 5.834, p = 0.022). Finally, high levels of phosphorylated tau were associated with worsening in motor symptoms (UPDRS-III, β = 0.350, p = 0.045; Hoehn and Yahr, β = 0.366, p = 0.038).

CONCLUSION:

We found evidence of a link between higher levels of αSyn at baseline and worsening of motor symptoms and cognitive speed over 2 years in PD. Increased αSyn might be a marker of more intense synaptic degeneration in PD. The results indicate that cortical amyloid pathology (low CSF Aβ42) is associated with memory decline.

A Novel 6-Item Screening Questionnaire for Parkinsonism: Validation and Comparison Between Different Instruments

Neuroepidemiology. 2014 Nov 13;43(3-4):178-193. [Epub ahead of print]

Fereshtehnejad SM, Shafieesabet M, Rahmani A, Farhadi F, Hadizadeh H, Shahidi GA, Delbari A, Lökk J.

Background: Several instruments have been developed to screen Parkinson's disease (PD); yet, there is no consensus on the items, number of questions, and diagnostic accuracy. We aimed to develop a new questionnaire combining the best items with highest validity to screen parkinsonism and to compare its diagnostic value with that of the previous instruments using the same database. 

Methods: 157 patients with parkinsonism and 110 healthy controls completed a comprehensive screening questionnaire consisting of 25 items on different PD symptoms used in previous studies. To select the optimal items, clinical utility index (CUI) was calculated and those who met at least good negative utility (CUI ≥0.64) were selected. Receiver operating characteristics (ROC) curves analysis was used to compare the area under the curve (AUC) of different screening instruments. 

Results: Six items on 'stiffness & rigidity', 'tremor & shaking', 'troublesome buttoning', 'troublesome arm swing', 'feet stuck to floor' and 'slower daily activity' demonstrated good CUI. The new screening instrument had the largest AUC (0.977) compared to other instruments. 

Conclusions: We selected a new set of six items to screen parkinsonism, which showed higher diagnostic values compared to the previously developed questionnaires. This screening instrument could be used in population-based PD surveys in poor-resource settings.

Higher Frequency of Certain Cancers in LRRK2 G2019S Mutation Carriers With Parkinson DiseaseA Pooled Analysis

http://archneur.jamanetwork.com/article.aspx?articleid=1934716

JAMA Neurology

Ilir Agalliu, MD, ScD¹; Marta San Luciano, MD²; Anat Mirelman, MD³; Nir Giladi, MD^3,4; Bjorg Waro, MD^5,6; Jan Aasly, MD, PhD^5,6; Rivka Inzelberg, MD^4,7; Sharon Hassin-Baer, MD^7,8; Eitan Friedman, MD^7,8; Javier Ruiz-Martinez, MD^9,10,11; Jose Felix Marti-Masso, MD^9,10,11; Avi Orr-Urtreger, MD^8,12; Susan Bressman, MD^13,14,15; Rachel Saunders-Pullman, MD^13,14,15

Importance  Patients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies.

Objectives  To analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies.

Design, Setting, and Participants  Clinical, demographic, and genotyping data as well as cancer outcomes were pooled from 1549 patients with PD recruited across 5 movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95% CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect.

Main Outcomes and Measures  All cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer.

Results  The overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers.

Conclusions and Relevance  This multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.

DNAJC13 genetic variants in parkinsonism

http://onlinelibrary.wiley.com/doi/10.1002/mds.26064/full

Mov Disord. 2014 Nov 12. doi: 10.1002/mds.26064. [Epub ahead of print]

Gustavsson EK, Trinh J, Guella I, Vilariño-Güell C, Appel-Cresswell S, Stoessl AJ, Tsui JK, McKeown M, Rajput A, Rajput AH, Aasly JO, Farrer MJ.

BACKGROUND:

A novel mutation (p.N855S) in DNAJC13 has been linked to familial, late-onset Lewy body parkinsonism in a Dutch-German-Russian Mennonite multi-incident kindred.

METHODS:

DNAJC13 was sequenced in 201 patients with parkinsonism and 194 controls from Canada. Rare (minor allele frequency < 0.01) missense variants identified in patients were genotyped in two Parkinson's disease case-controls cohorts.

RESULTS:

Eighteen rare missense mutations were identified; four were observed in controls, three were observed in both patients and controls, and eleven were identified only in patients. Subsequent genotyping showed p.E1740Q and p.L2170W to be more frequent in patients, and p.R1516H being more frequent in controls. Additionally, p.P336A, p.V722L, p.N855S, p.R1266Q were seen in one patient each, and p.T1895M was found in two patients.

CONCLUSION:

Although the contribution of rare genetic variation in DNAJC13 to parkinsonisms remains to be further elucidated, this study suggests that, in addition to p.N855S, other rare variants might affect disease susceptibility.

A feasibility study of conducting the Montreal Cognitive Assessment remotely in individuals with movement disorders

Hugely interesting to me, for obvious reasons...

Health Informatics J. 2014 Nov 11. pii: 1460458214556373. [Epub ahead of print]

Abdolahi A, Bull MT, Darwin KC, Venkataraman V, Grana MJ, Dorsey ER, Biglan KM.

Abstract

Remote assessments of individuals with a neurological disease via telemedicine have the potential to reduce some of the burdens associated with clinical care and research participation. We aim to evaluate the feasibility of conducting the Montreal Cognitive Assessment remotely in individuals with movement disorders. A pilot study derived from two telemedicine trials was conducted. In total, 17 individuals with movement disorders (8 with Parkinson disease and 9 with Huntington disease) had Montreal Cognitive Assessment examinations evaluated in-person and remotely via web-based video conferencing to primarily determine feasibility and potential barriers in its remote administration. Administering the Montreal Cognitive Assessment remotely in a sample of movement disorder patients with mild cognitive impairment is feasible, with only minor common complications associated with technology, including delayed sound and corrupted imaging for participants with low connection speeds. The Montreal Cognitive Assessment has the potential to be used in remote assessments of patients and research participants with movement disorders.

PERFORM: A System for Monitoring, Assessment and Management of Patients with Parkinson's Disease

Wearable technology certainly in-vogue right now in PD and movement disorders. Quite a few groups working on solutions - interesting to speculate on whose is best. I have my own thoughts, which for now I'll hold on to...

http://www.mdpi.com/1424-8220/14/11/21329

Sensors (Basel). 2014 Nov 11;14(11):21329-57. doi: 10.3390/s141121329.

Tzallas AT, Tsipouras MG, Rigas G, Tsalikakis DG, Karvounis EC, Chondrogiorgi M, Psomadellis F, Cancela J, Pastorino M, Waldmeyer MT, Konitsiotis S, Fotiadis DI.

Abstract

In this paper, we describe the PERFORM system for the continuous remote monitoring and management of Parkinson's disease (PD) patients. The PERFORM system is an intelligent closed-loop system that seamlessly integrates a wide range of wearable sensors constantly monitoring several motor signals of the PD patients. Data acquired are pre-processed by advanced knowledge processing methods, integrated by fusion algorithms to allow health professionals to remotely monitor the overall status of the patients, adjust medication schedules and personalize treatment. The information collected by the sensors (accelerometers and gyroscopes) is processed by several classifiers. As a result, it is possible to evaluate and quantify the PD motor symptoms related to end of dose deterioration (tremor, bradykinesia, freezing of gait (FoG)) as well as those related to over-dose concentration (Levodopa-induced dyskinesia (LID)). Based on this information, together with information derived from tests performed with a virtual reality glove and information about the medication and food intake, a patient specific profile can be built. In addition, the patient specific profile with his evaluation during the last week and last month, is compared to understand whether his status is stable, improving or worsening. Based on that, the system analyses whether a medication change is needed¾always under medical supervision¾and in this case, information about the medication change proposal is sent to the patient. The performance of the system has been evaluated in real life conditions, the accuracy and acceptability of the system by the PD patients and healthcare professionals has been tested, and a comparison with the standard routine clinical evaluation done by the PD patients' physician has been carried out. The PERFORM system is used by the PD patients and in a simple and safe non-invasive way for long-term record of their motor status, thus offering to the clinician a precise, long-term and objective view of patient's motor status and drug/food intake. Thus, with the PERFORM system the clinician can remotely receive precise information for the PD patient's status on previous days and define the optimal therapeutical treatment.