Thursday, 26 November 2015

Systematic review and meta-analysis of salivary protein concentration in Parkinson's disease

Our new meta published as a letter in Movement Disorders, therefore no abstract. Of the published studies thus far, it appears that total protein concentration is increased in the saliva of patients with PD. We have to use a method called Standardized Mean Difference (see figure below) because of differences in the way protein concentration was measured. The next question is... what are these proteins?

Mov Disord. 2015 Nov 19. doi: 10.1002/mds.26462. [Epub ahead of print]
Masters JM, Bestwick J, Warner TT, Giovannoni G, Proctor GB, Noyce AJ.

MDS research criteria for prodromal Parkinson's disease

Hmmm Bayesian methods using likelihood ratios to update age related odds of PD... where have I heard that approach before?? Nonetheless very important to formalise this approach and I think these criteria will be used widely...

Mov Disord. 2015 Oct;30(12):1600-11. doi: 10.1002/mds.26431.

Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G.

This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease-modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individual's risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available. © 2015 International Parkinson and Movement Disorder Society.

Wednesday, 25 November 2015

REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers.

Not sure I arrive at the same conclusions here... which should be suffixed with 'in LRRK2 mutation carriers'. There are differences between LRRK2 patients and patients with iPD and these differences likely extend into the pre-diagnostic phase too. That said, I think the RBDSQ is prone to significant inaccuracy... at least that is our experience.

Mov Disord. 2015 Sep 14. doi: 10.1002/mds.26413. [Epub ahead of print]

Saunders-Pullman R, Alcalay RN, Mirelman A, Wang C, Luciano MS, Ortega RA, Glickman A, Raymond D, Mejia-Santana H, Doan N, Johannes B, Yasinovsky K, Ozelius L, Clark L, Orr-Utreger A, Marder K, Giladi N, Bressman SB; AJ LRRK2 Consortium.

Rapid eye movement sleep behavior disorder occurs with idiopathic Parkinson's disease (PD) and often precedes PD. Its frequency in LRRK2-PD and utility as a preclinical marker has not been established.

One hundred forty-four idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related noncarriers, and 40 healthy controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire.

Cut scores were met by 30.6% idiopathic PD, 19.7% LRRK2-PD, 6% nonmanifesting carriers, 20.4% related noncarriers, and 15% controls. The likelihood of abnormal scores was decreased in LRRK2-PD versus idiopathic PD (odds ratio = 0.55, P = 0.03), nonmanifesting carriers versus related noncarriers (OR = 0.25, P < 0.01), and PD of less than 3 years' duration, 1 of 19 LRRK2-PD versus 14 of 41 idiopathic PD (P < 0.05).

A lower frequency of abnormal questionnaire scores is seen in LRRK2-PD, especially in early LRRK2-PD, and in nonmanifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a preclinical marker for phenoconversion to PD. © 2015 International Parkinson and Movement Disorder Society.

Saturday, 14 November 2015

Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson’s Disease Patients

Once potential biomarkers of a disease are discovered, it is important that they are 'validated' in a group of patients and controls different from the group in which the biomarker was initially discovered.

In this study, the researchers test for the presence of 10 candidate biomarkers (discovered in previous work) in the blood of patients very recently diagnosed with PD and controls.

A particular strength of this study is that the newly diagnosed patients had not yet been prescribed any treatments for Parkinson's. This removes the possibility that PD medications might be having an effect on the biomarker levels and suggests that the biomarkers are reflective of the underlying diseas process.

The researchers makes use of samples from the Parkinson's Progression Markers Initiative (PPMI) demonstrating, how large collaborative projects can help accelerate biomarker discovery. Santiago JA, & Potashkin JA (2015). Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson's Disease Patients. PloS one, 10 (11) PMID: 26566043


Early diagnosis of Parkinson’s disease (PD) continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinson’s Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009) when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA) score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI). Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naïve PD patients. Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted.

Risk factors for hip fracture in very old people: a population-based study

Once again PD shown to be a major risk factor for hip fracture in older persons...

Osteoporos Int. 2015 Nov 4. [Epub ahead of print]
Wiklund R, Toots A, Conradsson M, Olofsson B, Holmberg H, Rosendahl E, Gustafson Y, Littbrand H.

Knowledge of risk factors for hip fracture among very old people is limited. Walking indoors with help from ≤1 person, Parkinson's disease, currently smoking, delirium in the previous month, underweight, and age were associated with increased risk of hip fracture and could be important for preventive strategy development.
The purpose of this study is to investigate risk factors for hip fracture among a representative sample of very old people.
In total, 953 participants from the Umeå 85+/Gerontological Regional Database population-based cohort study were interviewed and assessed during home visits. Associations of baseline characteristics with hip fracture during the maximum 5-year follow-up period were analyzed using Cox proportional hazards regression.
Participants had a mean age of 89.3 ± 4.7 years; 65.8 % were women, 36.8 % lived in residential care facilities, 33.6 % had dementia, and 20.4 % had histories of hip fracture. During a mean follow-up period of 2.7 years, 96 (10.1 %) individuals sustained hip fracture. Walking indoors with help from no more than one person (hazard ratio [HR] = 8.57; 95 % confidence interval [CI], 1.90-38.71), Parkinson's disease (HR = 5.12; 95 % CI, 1.82-14.44), currently smoking (HR = 4.38; 95 % CI 2.06-9.33), delirium in the previous month (HR = 2.01; 95 % CI, 1.15-3.49), underweight (body mass index <22; HR = 1.74, 95 % CI, 1.09-2.77), and age (HR = 1.09; 95 % CI, 1.04-1.14) were associated independently with an increased risk of hip fracture. Hip prosthesis at baseline decreased the risk of hip fracture (HR = 0.37; 95 % CI, 0.15-0.91), but only for those with bilateral hip prostheses.

Seven factors were associated independently with incident hip fracture during follow-up in this sample of very old people. These factors could have important clinical implications in identifying persons at high risk of hip fracture, as well as in the development of effective preventive strategies.

Friday, 13 November 2015

Coenzyme Q10 for Patients with Parkinson's disease: A Systematic Review and Meta-analysis

No effect in meta-analysis... but this could mean that it is ineffective or that rating scales don't reflect underlying disease.... 

CNS Neurol Disord Drug Targets. 2015 Nov 10. [Epub ahead of print]
Negida A, Menshawy A, El Ashal G, Elfouly Y, Hani Y, Hegazy Y, El Ghonimy S, Fouda S, Rashad Y.


Introduction Coenzyme Q10 (CoQ10) is an antioxidant that enhances the activity of complex I and II in the Electron Transport Chain. Many preclinical and clinical studies evaluated CoQ10 for neuroprotection against Parkinson's disease (PD). The aim of this study is to synthesize evidence from published randomized controlled trials (RCTs) about the benefit of CoQ10 supplementation for patients with Parkinson's disease. Methods We followed the PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. A computer literature search for (PubMed, EBSCO, Web of science and Ovid Midline) was carried out. We included RCTs comparing CoQ10 with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, UPDRS III and Schwab and England scores were pooled as standardized mean difference (SMD) between two groups from baseline to the endpoint. Results Five RCTs (981 patients) were included in this study. The overall effect did not favor either of the two groups in terms of: total UPDRS score (SMD -0.05, 95%CI [-0.10, 0.15]), UPDRS I (SMD -0.03, 95% CI [-0.23, 0.17]), UPDRS II (SMD -0.10, 95%CI [-0.35, 0.15]), UPDRS III (SMD -0.05, 95%CI [-0.07, 0.17]) or Schwab and England score (SMD 0.08, 95%CI [-0.13, 0.29]). Conclusion CoQ10 supplementation does not slow functional decline nor provide any symptomatic benefit for patients with Parkinson's disease.

Saturday, 7 November 2015

A Validated Smartphone-Based Assessment of Gait and Gait Variability in Parkinson's Disease.

More smart phone tech for PD monitoring...

PLoS One. 2015 Oct 30;10(10):e0141694. doi: 10.1371/journal.pone.0141694. eCollection 2015.
Ellis RJ, Ng YS, Zhu S, Tan DM, Anderson B, Schlaug G, Wang Y.

A well-established connection exists between increased gait variability and greater fall likelihood in Parkinson's disease (PD); however, a portable, validated means of quantifying gait variability (and testing the efficacy of any intervention) remains lacking. Furthermore, although rhythmic auditory cueing continues to receive attention as a promising gait therapy for PD, its widespread delivery remains bottlenecked. The present paper describes a smartphone-based mobile application ("SmartMOVE") to address both needs.

The accuracy of smartphone-based gait analysis (utilizing the smartphone's built-in tri-axial accelerometer and gyroscope to calculate successive step times and step lengths) was validated against two heel contact-based measurement devices: heel-mounted footswitch sensors (to capture step times) and an instrumented pressure sensor mat (to capture step lengths). 12 PD patients and 12 age-matched healthy controls walked along a 26-m path during self-paced and metronome-cued conditions, with all three devices recording simultaneously.

Four outcome measures of gait and gait variability were calculated. Mixed-factorial analysis of variance revealed several instances in which between-group differences (e.g., increased gait variability in PD patients relative to healthy controls) yielded medium-to-large effect sizes (eta-squared values), and cueing-mediated changes (e.g., decreased gait variability when PD patients walked with auditory cues) yielded small-to-medium effect sizes-while at the same time, device-related measurement error yielded small-to-negligible effect sizes.


These findings highlight specific opportunities for smartphone-based gait analysis to serve as an alternative to conventional gait analysis methods (e.g., footswitch systems or sensor-embedded walkways), particularly when those methods are cost-prohibitive, cumbersome, or inconvenient.

Friday, 6 November 2015

Increased CSF biomarkers of angiogenesis in Parkinson disease

The authors of this study have found increased biomarkers of angiogenesis (proteins related to new blood vessel formation) in the CSF of patients with PD and PD with dementia (PDD).

The authors also detected increased CSF/plasma albumin ratio in the patients with PD, which suggests a loss of integrity in the blood-brain barrier in patients with PD. Interestingly, the biomarkers of angiogenesis were correlated with CSF/plasma albumin ratio, leading the authors to suggest that angiogenic factors might contribute to cerebral microbleeds and reduced blood brain barrier function, which could in be involved in the pathogenesis of PD.

This idea that angiogenesis and reduced blood-brain barrier function might contribute to the disease process in PD is not entirely new. A few studies of animal models of PD and post-mortem studies of PD patients' brains have also found increased levels of VEGF (one of the markers of angiogenesis identified by this paper) and signs of vascular proliferation. However, it is a relatively unexplored area.

The study methodology seems robust. The the validation of the associations in a separate validation cohort, is particularly good practice; this helps ensure the initial findings are not due to chance.

I think the paper is a nice example of how biomarker research, though normally aimed at helping improve diagnosis of the condition, can lead to insights into how the disease process actually works and potentially even reveal new targets for disease modifying treatment.


Objective: To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood–brain barrier (BBB) permeability, and cerebrovascular disease.

Methods: In this cross-sectional analysis, 38 elderly controls and 100 patients with PD (82 without dementia and 18 with dementia) were included from the prospective Swedish BioFinder study. CSF samples were analyzed for the angiogenesis biomarkers vascular endothelial growth factor (VEGF); its receptors, VEGFR-1 and VEGFR-2; placental growth factor (PlGF); angiopoietin 2 (Ang2); and interleukin-8. BBB permeability, white matter lesions (WMLs), and cerebral microbleeds (CMB) were assessed. CSF angiogenesis biomarkers were also measured in 2 validation cohorts: (1) 64 controls and 87 patients with PD with dementia; and (2) 35 controls and 93 patients with neuropathologically confirmed diagnosis of PD with and without dementia.

Results: Patients with PD without dementia displayed higher CSF levels of VEGF, PlGF, and sVEGFR-2, and lower levels of Ang2, compared to controls. Similar alterations in VEGF, PlGF, and Ang2 levels were observed in patients with PD with dementia. Angiogenesis markers were associated with gait difficulties and orthostatic hypotension as well as with more pronounced BBB permeability, WMLs, and CMB. Moreover, higher levels of VEGF and PlGF levels were associated with increased CSF levels of neurofilament light (a marker of neurodegeneration) and monocyte chemotactic protein–1 (a marker of glial activation). The main results were validated in the 2 additional cohorts.

Conclusions: CSF biomarkers of angiogenesis are increased in PD, and they are associated with gait difficulties, BBB dysfunction, WMLs, and CMB. Abnormal angiogenesis may be important in PD pathogenesis and contribute to dopa-resistant symptoms. Janelidze S, Lindqvist D, Francardo V, Hall S, Zetterberg H, Blennow K, Adler CH, Beach TG, Serrano GE, van Westen D, Londos E, Cenci MA, & Hansson O (2015). Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology PMID: 26511451

Analysis of the genetic variability in Parkinson's disease from Southern Spain

Interesting to see the contribution of known PD genes (and some novel mutations) in this diverse region...

Neurobiol Aging. 2015 Oct 8. pii: S0197-4580(15)00477-7. doi: 10.1016/j.neurobiolaging.2015.09.020. [Epub ahead of print]
Bandrés-Ciga S, Mencacci NE, Durán R, Barrero FJ, Escamilla-Sevilla F, Morgan S, Hehir J, Vives F, Hardy J, Pittman AM.

To date, a large spectrum of genetic variants has been related to familial and sporadic Parkinson's disease (PD) in diverse populations worldwide. However, very little is known about the genetic landscape of PD in Southern Spain, despite its particular genetic landscape coming from multiple historical migrations. We included 134 PD patients in this study, of which 97 individuals were diagnosed with late-onset sporadic PD (LOPD), 28 with early-onset sporadic PD (EOPD), and 9 with familial PD (FPD). Genetic analysis was performed through a next-generation sequencing panel to screen 8 PD-related genes (LRRK2, SNCA, PARKIN, PINK1, DJ-1, VPS35, GBA, and GCH1) in EOPD and FPD groups and direct Sanger sequencing of GBA exons 8-11 and LRRK2 exons 31 and 41 in the LOPD group. In the EOPD and FPD groups, we identified 11 known pathogenic mutations among 15 patients (40.5 %). GBA (E326K, N370S, D409H, L444P) mutations were identified in 7 patients (18.9 %); LRRK2 (p.R1441G and p.G2019S) in 3 patients (8.1 %); biallelic PARK2 mutations (p.N52fs, p.V56E, p.C212Y) in 4 cases (10.8%) and PINK1 homozygous p.G309D in 1 patient (2.7 %). An EOPD patient carried a single PARK2 heterozygous mutation (p.R402C), and another had a novel heterozygous mutation in VPS35 (p.R32S), both of unknown significance. Moreover, pathogenic mutations in GBA (E326K, T369M, N370S, D409H, L444P) and LRRK2 (p.R1441G and p.G2019S) were identified in 13 patients (13.4 %) and 4 patients (4.1 %), respectively, in the LOPD group. A large number of known pathogenic mutations related to PD have been identified. In particular, GBA and LRRK2 mutations appear to be considerably frequent in our population, suggesting a strong Jewish influence. Further research is needed to study the contribution of the novel found mutation p.R32S in VPS35 to the pathogenesis of PD.

Thursday, 5 November 2015

The relationship between essential tremor and Parkinson's disease

We see this occasionally in the clinic... and there are lots of lines of evidence to suggest an association...

Parkinsonism Relat Disord. 2015 Oct 9. pii: S1353-8020(15)00421-6. doi: 10.1016/j.parkreldis.2015.09.032. [Epub ahead of print]
Thenganatt MA, Jankovic J.


Essential tremor (ET) and Parkinson's disease (PD) are the two most common tremor disorders encountered in a movement disorders clinic. Although distinct clinical-pathological entities, both disorders may share overlapping features in addition to rest and postural tremor, such as bradykinesia, rigidity, gait and balance impairment and some non-motor signs. A subset of patients may have a combination of long-standing ET with subsequent PD (ET-PD). There are several lines of evidence from clinical, epidemiologic, imaging, genetic and pathologic studies supporting a link between ET and PD, greater than by chance alone. In this review we will discuss the latest data supporting a relationship between ET and PD and the implications for possible pathogenic link and treatment.

Wednesday, 4 November 2015

Methods in Neuroepidemiology Characterization of European Longitudinal Cohort Studies in Parkinson's Disease - Report of the JPND Working Group BioLoC-PD

Neuroepidemiology. 2015 Nov 3;45(4):282-297. [Epub ahead of print]
Lerche S, Liepelt-Scarfone I, Alves G, Barone P, Behnke S, Ben-Shlomo Y, Berendse H, Burn D, Dodel R, Grosset D, Heinzel S, Hu M, Kasten M, Krüger R, Maetzler W, Moccia M, Mollenhauer B, Oertel W, Roeben B, Sünkel U, Walter U, Wirdefeldt K, Berg D.

Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinson's disease (PD). An impressive number of PD patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used.

Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires.

Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts.


The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes.

Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned

No significant improvement in 'off' time using preladenant... but the investigators raise questions about the study design and conduct, which may have obscured benefits...

JAMA Neurol. 2015 Nov 2:1-10. doi: 10.1001/jamaneurol.2015.2268. [Epub ahead of print]
Hauser RA, Stocchi F, Rascol O, Huyck SB, Capece R, Ho TW, Sklar P, Lines C, Michelson D, Hewitt D.

Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials.

To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations.

Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations.

In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio.

The primary outcome measure was change in off time from baseline to week 12.

In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo).


In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials.