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.

http://link.springer.com/article/10.1007%2Fs00198-015-3390-9

Abstract

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.

INTRODUCTION:

The purpose of this study is to investigate risk factors for hip fracture among a representative sample of very old people.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

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.

Abstract

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.

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.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141694

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

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.

Abstract

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.

http://www.sciencedirect.com/science/article/pii/S0197458015004777

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.

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.

http://www.sciencedirect.com/science/article/pii/S1353802015004216

Abstract

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.

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.

http://www.karger.com/Article/FullText/439221

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

http://archneur.jamanetwork.com/article.aspx?articleid=2466582

IMPORTANCE:

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.

OBJECTIVE:

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

DESIGN, SETTING, AND PARTICIPANTS:

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.

INTERVENTIONS:

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.

MAIN OUTCOMES AND MEASURES:

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

RESULTS:

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).

CONCLUSIONS AND RELEVANCE:

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.

Pathogenesis of Parkinson disease-the gut-brain axis and environmental factors

Interesting article... that said there is plenty of evidence in favour of genetics explaining much of the risk and heterogeneity of PD... time to stop considering genes and the environment independently...?

Nat Rev Neurol. 2015 Oct 27. doi: 10.1038/nrneurol.2015.197. [Epub ahead of print]

Klingelhoefer L, Reichmann H.

Abstract

Parkinson disease (PD) follows a defined clinical pattern, and a range of nonmotor symptoms precede the motor phase. The predominant early nonmotor manifestations are olfactory impairment and constipation. The pathology that accompanies these symptoms is consistent with the Braak staging system: α-synuclein in the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the enteric nervous system (ENS) and the submandibular gland, each of which is a gateway to the environment. The neuropathological process that leads to PD seems to start in the ENS or the olfactory bulb and spreads via rostrocranial transmission to the substantia nigra and further into the CNS, raising the intriguing possibility that environmental substances can trigger pathogenesis. Evidence from epidemiological studies and animal models supports this hypothesis. For example, in mice, intragastric administration of the pesticide rotenone can almost completely reproduce the typical pathological and clinical features of PD. In this Review, we present clinical and pathological evidence to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS. We also consider how environmental factors might trigger pathogenesis, and the potential for therapeutically targeting the mechanisms of these initial stages.

Increased risk of brain tumor in patients with Parkinson's disease: a nationwide cohort study in Taiwan

Unfortunately from what I can see, the paper doesn't tell us what proportion of these subjects had brain scans. One can imagine that although a brain scan is not essential for the diagnosis of PD, people with PD are still more likely to have a brain scan than those in the background population. This could explain the excess numbers observed...

Acta Neurol Scand. 2015 Oct 28. doi: 10.1111/ane.12524. [Epub ahead of print]

Tang CF, Lu MK, Muo CH, Tsai CH, Kao CH.

OBJECTIVES:

Parkinson's disease (PD) is a neurodegenerative disease. A decreased risk of cancer, except for melanoma, has been observed in patients with PD. The aim of this study was to evaluate the association between brain tumor and PD in a Taiwanese population.

MATERIALS AND METHODS:

We used data from the National Health Insurance program of Taiwan. The PD cohort contained 2998 patients, and each patient was frequency-matched, based on age and sex, with 4 people without PD, who were randomly selected from the general population. Cox's proportional hazard regression analysis was conducted to estimate the effects of PD on the risk of brain tumor.

RESULTS:

The risk of developing brain tumor was significantly higher in patients with PD than in those without PD (adjusted hazard ratio = 2.11; 95% confidence interval (CI) = 1.24-3.59), and benign brain tumor exhibited a particularly elevated risk of 2.16-fold (95% CI = 1.26-3.68). The hazard ratio (HR) for developing a benign brain tumor was higher in female patients with PD than in female patients without PD, with the risk being 2.65-fold (95% CI = 1.30-5.43). An analysis of the two age groups, 50-64 years and ≥65 years, showed that the HR of only the 50-64-year group was significantly higher between the PD and non-PD groups (HR = 2.77, 95% CI = 1.07-7.14).

CONCLUSION:

The present study showed that Taiwanese patients with PD are at a higher risk of developing brain tumor than the general population. The exact underlying etiologies require further investigation.

Pisa syndrome in Parkinson disease: An observational multicenter Italian study

More common than one would expect, but important insights into this disabling feature of PD. Risk factors, preventive measures and treatments are really important for patients and their relatives...

Neurology. 2015 Oct 21. pii: 10.1212/WNL.0000000000002122. [Epub ahead of print]

Tinazzi M, Fasano A, Geroin C, Morgante F, Ceravolo R, Rossi S, Thomas A, Fabbrini G, Bentivoglio A, Tamma F, Cossu G, Modugno N, Zappia M, Volontè MA, Dallocchio C, Abbruzzese G, Pacchetti C, Marconi R, Defazio G, Canesi M, Cannas A, Pisani A, Mirandola R, Barone P, Vitale C; Italian Pisa Syndrome Study Group.

OBJECTIVE:

To estimate the prevalence of Pisa syndrome (PS) in patients with Parkinson disease (PD) and to assess the association between PS and demographic and clinical variables.

METHODS:

In this multicenter cross-sectional study, consecutive outpatients with PD attending 21 movement disorders Italian tertiary centers were enrolled and underwent standardized clinical evaluation. PS was defined as trunk lateral deviation ≥10°. Patients with PD were compared according to the presence of PS for several demographic and clinical variables.

RESULTS:

Among 1,631 enrolled patients with PD, PS was detected in 143 patients (8.8%, 95% confidence interval 7.4%-10.3%). Patients with PS were older, had lower body mass index, longer disease duration, higher disease stages, and poorer quality of life. Falls were more frequent in the PS group as well as occurrence of "veering gait" (i.e., the progressive deviation toward one side when patient walked forward and backward with eyes closed). Patients with PS received higher daily levodopa equivalent daily dose and were more likely to be treated with combination of levodopa and dopamine agonists. Osteoporosis and arthrosis were significantly the most frequent associated medical conditions in patients with PS. Multiple explanatory variable logistic regression models confirmed the association of PS with the following variables: Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, associated medical conditions, and presence of veering gait.

CONCLUSIONS:

Our results suggest that PS is a relatively frequent and often disabling complication in PD, especially in the advanced disease stages. The association is dependent on a number of potentially relevant demographic and clinical variables.