Saturday, 28 May 2016

Inflammatory profile in LRRK2-associated prodromal and clinical PD.

Interesting results on the inflammatory profile of LRRK2 and non-LRRK2 PD here... but no evidence for inflammation in non-manifesting LRRK2 carriers with prodromal features... speaks to the notion that the events that initiate and those that drive the disease may not be the same...

J Neuroinflammation. 2016 May 24;13(1):122. doi: 10.1186/s12974-016-0588-5.
Brockmann K, Apel A, Schulte C, Schneiderhan-Marra N, Pont-Sunyer C, Vilas D, Ruiz-Martinez J, Langkamp M, Corvol JC, Cormier F, Knorpp T, Joos TO, Gasser T, Schüle B, Aasly JO, Foroud T, Marti-Masso JF, Brice A, Tolosa E, Marras C, Berg D, Maetzler W

There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson's disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.

We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium.

A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.


Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.

Friday, 27 May 2016

Profiling cognitive and neuropsychiatric heterogeneity in Parkinson's disease

A disorder of great heterogeneity - here is one groups attempt to cluster sub-types of PD according to cognitive and neuropsychiatric symptoms... these may well represent different disease sub-types too. The first and second cluster are recognisable, although caution should be taken over the second group given its small size. The third and fourth cluster are also recognisable. It would be interesting to see how sleep fits in to all this...

Parkinsonism Relat Disord. 2016 May 15. pii: S1353-8020(16)30166-3. doi: 10.1016/j.parkreldis.2016.05.014. [Epub ahead of print]
van Balkom TD, Vriend C, Berendse HW, Foncke EM, van der Werf YD, van den Heuvel OA, Klein M.

Parkinson's disease (PD) is a highly heterogeneous disease, in which motor symptom subtypes are often-described. While it is recognized that motor, cognitive and affective neuropsychiatric symptoms negatively influence the patients' quality of life, it is currently unknown how these symptoms contribute to phenotypic subtypes. The objective of this study was to assess subtypes of motor, cognitive and affective symptoms in PD.

A hierarchical cluster analysis was conducted on clinical data of 226 PD patients screened at the VU University Medical Center using comprehensive assessment of cognitive, affective and motor symptoms. Subsequent linear discriminant analyses were conducted to investigate discriminating constructs between clusters.

The cluster analysis yielded four clusters: (1) a young-age (59.9 years), mildly affected cluster (N = 86), (2) an old-age (72.3 years) cluster with severe motor and non-motor symptoms (N = 15), (3) a cluster (age 64.7 years) with mild motor symptoms, below-average executive functioning and affective symptoms (N = 46) and (4) a cluster (age 64.8 years) with severe motor symptoms, affective symptoms and below-average verbal memory (N = 79).


Cluster 1 and 2 seem to represent opposite ends of the PD disease stages. Patients in clusters 3 and 4 had similar age, educational level and disease duration but different symptom profiles - we therefore suggest that these clusters represent different pathways of disease progression, presumably with distinct underlying pathology localization. Future research on the neuropathophysiological characteristics of these two clusters and monitoring of disease progression is required.

Sunday, 22 May 2016

Low frequency of GCH1 and TH mutations in Parkinson's disease

Mutations in GCH1 are believed to be a risk factor for PD... the results of this study do not confirm this. However the numbers of participants was too low and the study was underpowered... there was a difference between cases and controls in terms of the number that had mutations in TH (also involved in dopamine synthesis) but again the study was underpowered to test the null hypothesis...

Parkinsonism Relat Disord. 2016 May 7. pii: S1353-8020(16)30148-1. doi: 10.1016/j.parkreldis.2016.05.010. [Epub ahead of print]
Rengmark A, Pihlstrøm L, Linder J, Forsgren L, Toft M.

The causes of Parkinson's disease (PD) are unknown in the majority of patients. The GCH1 gene encodes GTP-cyclohydrolase I, an important enzyme in dopamine synthesis. Co-occurrence of dopa-responsive dystonia (DRD) and a PD phenotype has been reported in families with GCH1 mutations. Recently, rare coding variants in GCH1 were found to be enriched in PD patients, indicating a role for the enzyme in the neurodegenerative process.

To further elucidate the contribution of GCH1 mutations to sporadic PD, we examined its coding exons in a targeted deep sequencing study of 509 PD patients (mean age at onset 56.7 ± 12.0 years) and 230 controls. We further included the tyrosine hydroxylase gene TH, also known to cause DRD. Gene dose assessments were performed to screen for large copy number variants in a subset of 48 patients with early-onset PD.

No putatively pathogenic GCH1 mutations were found. The frequency of rare heterozygous variants in the TH gene was 0.69% (7/1018) in the patient group and 0.22% (1/460) in the control group (p = 0.45).

Previous studies have found that coding variants in the GCH1 gene may be considered a risk factor for PD. Our study indicates that mutations in GCH1 are rare in late-onset PD. Several patients carried heterozygous variants in the TH gene that may affect protein function. Our study was not designed to determine with certainty if any of these variants play a role as risk factors for late-onset PD.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Friday, 20 May 2016

Trends in the Incidence of Parkinson Disease in the General Population: The Rotterdam Study

This is an interesting result particularly when many projections indicate that the burden of PD is increasing... there are number of potential explanations for a true decline or spurious reduction in incidence. The effect they report is also clearly greater in women, which if true, should mean that the gender gap for PD is increasing...

Am J Epidemiol. 2016 Apr 29. pii: kwv271. [Epub ahead of print]
Darweesh SK, Koudstaal PJ, Stricker BH, Hofman A, Ikram MA.

We investigated trends in the incidence of parkinsonism and Parkinson disease (PD) by comparing data from the first 2 subcohorts of the Rotterdam Study, a prospective, population-based cohort study (first subcohort: baseline 1990 with 10 years of follow-up; second subcohort, baseline 2000 with 10 years of follow-up). From the baseline years, we observed differences in the second subcohort that were associated with a lower risk of PD for some but not all baseline risk factors. Participants in both subcohorts were followed for a maximum of 10 years and monitored for the onset of parkinsonism, the onset of dementia, or death, until January 1, 2011. We used Poisson regression models to compare the incidences of parkinsonism, both overall and by cause (PD and secondary causes), and competitive events (incident dementia and death) as well as the mortality of parkinsonism patients in the 2 subcohorts. In the 1990 subcohort, there were 182 cases of parkinsonism (84 of which were PD) during 57,052 person-years. In the 2000 subcohort, we observed 28 cases of parkinsonism (10 with PD) during 22,307 person-years. The overall age- and sex-adjusted incidence of parkinsonism was lower in the 2000 subcohort (incidence rate ratio = 0.55, 95% confidence interval: 0.36, 0.81), and PD incidence declined sharply (incidence rate ratio = 0.39, 95% confidence interval: 0.19, 0.72). Competitive event rates were lower in the 2000 subcohort, and mortality rates among persons with parkinsonism remained stable. These findings suggest that the incidence of parkinsonism in general, and of PD in particular, decreased between 1990 and 2011.

Thursday, 19 May 2016

Cancer incidence among Parkinson's disease patients in a 10-yrs time-window around disease onset: A large-scale cohort study

Much of the published literature in the past has seemed to suggest that patients with PD are less likely to get cancer than those without (except melanoma and maybe prostate cancer). The results presented here are against that and suggest no difference between those with and without PD...

Parkinsonism Relat Disord. 2016 Apr 30. pii: S1353-8020(16)30132-8. doi: 10.1016/j.parkreldis.2016.04.028. [Epub ahead of print]
Peretz C, Gurel R, Rozani V, Gurevich T, El-Ad B, Tsamir J, Giladi N.

To compare the incidences of any cancer and specific types among patients with Parkinson's disease (PD) in a 10-yrs time window around diagnosis, to that of the general population.

We conducted a population-based, retrospective large-scale cohort study on 7125 newly diagnosed PD patients who had just initiated anti-parkinsonian medications between 1.1.2000 and 12.31.2012; all members of Maccabi Health Services (MHS), a large Israeli HMO. Cancer incidence during the same period was collected from MHS cancer-registry. Standardized-Incidence-Ratio (SIR) accounting for age, chronological-year and sex were calculated to compare cancer risks of PD patients to that of MHS population.

The PD cohort (54% males) had a mean age at initiation of anti-parkinsonian medications of 71.2 ± 10.3years. In a time-window of 6.6 ± 3.4years before and 4.0 ± 3.9years after PD was first treated, 21% of the men and 15% of the women were diagnosed with incident-cancer. We found no-difference in any cancer risk for the PD cohort compared to the reference population: SIR = 0.99 (95%CI: 0.92-1.06) for males and 0.98 (95%CI: 0.89-1.07) for females. Risks for lung and colon cancers in the PD cohort were significantly lower for both sexes compared to the reference population. Risks for breast, central nervous system, kidney, leukemia, lymphoma, melanoma, ovarian, pancreatic, prostatic, rectal and thyroid were similar for the two populations. The SIRs did not differ between the sexes.

We found no difference in the risk of any-type of cancer among PD patients compared to the general population, focusing on 10yrs time-window around the initiation of anti-parkinsonian medications.

Copyright © 2016. Published by Elsevier Ltd.

Wednesday, 18 May 2016

Night-time sleep in Parkinson's disease - the potential use of Parkinson's KinetiGraph: a prospective comparative study

This is a great use for the PKG and something I have been thinking about for a while. Devices like this have so much potential to tell us more about how PD is behaving away from the clinic... screening for those that might be suitable for PSG is a great further avenue for study...

Eur J Neurol. 2016 May 10. doi: 10.1111/ene.13015. [Epub ahead of print]
Klingelhoefer L, Rizos A, Sauerbier A, McGregor S, Martinez-Martin P, Reichmann H, Horne M, Chaudhuri KR.

Night-time sleep disturbances are important non-motor symptoms and key determinants of health-related quality of life (HRQoL) in patients with Parkinson's disease (PD). The Parkinson's KinetiGraph (PKG) can be used as an objective measure of different motor states and periods of immobility may reflect episodes of sleep. Our aim was to evaluate whether PKG can be used as an objective marker of disturbed night-time sleep in PD.

In this prospective comparative study, data from PKG recordings over six consecutive 24 h periods are compared with Hauser diaries and scales focusing on motor state, sleep and HRQoL in PD patients. Thirty-three 'non-sleepy' PD patients (PD-NS) were compared with 30 PD patients presenting with excessive daytime sleepiness (PD-EDS). The groups were matched for age, gender and Hoehn and Yahr state.

In the PD-EDS group subjective sleep reports correlated with the PKG's parameters for quantity and quality night-time sleep, but not in the PD-NS group. There were no significant correlations of the night-time sleep quantity parameters of the Hauser diary with subjective sleep perception, neither in the PD-EDS nor in the PD-NS group.

This first PKG based study of night-time sleep in PD suggests that PKG could be used to provide an easy to use and rough evaluation of aspects of night-time sleep and one that could flag patients where polysomnography may be required. In sleepy PD patients for instance, quantity and quality PKG parameters correlate with different aspects of sleep such as insomnia, parasomnia and restless legs syndrome.

© 2016 EAN.

Tuesday, 17 May 2016

Monitoring of 30 marker candidates in early Parkinson disease as progression markers.

Here we have important results from a longitudinal study aiming to define progression markers in early PD. The results are not surprising in many ways (at least to me). As expected there is progression in non-motor symptoms in the patients with early PD, but most of these (except for RBD) are not objectively measured. Previous studies have warned of the wide heterogeneity and variability of CSF markers, but I was surprised that there was no significant change on cognitive measures. As time passes I suspect detailed structural and functional MRI will give the best read outs of progression...

Neurology. 2016 May 6. pii: 10.1212/WNL.0000000000002651. [Epub ahead of print]
Mollenhauer B, Zimmermann J, Sixel-Döring F, Focke NK, Wicke T, Ebentheuer J, Schaumburg M, Lang E, Trautmann E, Zetterberg H, Taylor P, Friede T, Trenkwalder; DeNoPa Study Group.

This was a longitudinal single-center cohort study to comprehensively explore multimodal progression markers for Parkinson disease (PD) in patients with recently diagnosed PD (n = 123) and age-matched, neurologically healthy controls (HC; n = 106).

Thirty tests at baseline and after 24 months covered nonmotor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers. Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95% confidence intervals (CI).

A composite panel of 10 informative markers was identified. Significant relative worsening (PD vs HC) was seen with the following markers: the Unified Parkinson's Disease Rating Scale I (d 0.39; CI 0.09-0.70), the Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25; CI 0.06-0.46), the Epworth Sleepiness Scale (d 0.47; CI 0.24-0.71), the RBD Screening Questionnaire (d 0.44; CI 0.25-0.64), and RBD by PSG (d 0.37; CI 0.19-0.55) as well as VBM units of cortical gray matter (d -0.2; CI -0.3 to -0.09) and hippocampus (d -0.15; CI -0.27 to -0.03). Markers with a relative improvement included the Nonmotor Symptom (Severity) Scale (d -0.19; CI -0.36 to -0.02) and 2 depression scales (Beck Depression Inventory d -0.18; CI -0.36 to 0; Montgomery-Åsberg Depression Rating Scale d -0.26; CI -0.47 to -0.04). Unexpectedly, cognitive measures and select laboratory markers were not significantly changed in PD vs HC participants.

Current CSF biomarkers and cognitive scales do not represent useful progression markers. However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression.

© 2016 American Academy of Neurology.

Lifetime occupational and leisure time physical activity and risk of Parkinson's disease

After a 3 week break away from the blog, I am back again...

This study sets out to explore whether physical activity protects you against Parkinson's. These types of study are always tricky to interpret because a reduction in physical activity can occur as a result of Parkinson's that is (as yet) undiagnosed. We call this reverse causation - when something looks like a risk factor or protective factor but instead the presence of the disease is driving a change in behaviour.

Here the authors take steps to avoid this situation, by looking at physical activity early in life and they still observe a protective effect.

Clinical trials of physical activity in Parkinson's disease are ongoing...

Parkinsonism Relat Disord. 2016 May 3. pii: S1353-8020(16)30145-6. doi: 10.1016/j.parkreldis.2016.05.007. [Epub ahead of print]
Shih IF, Liew Z, Krause N, Ritz B.

While regular exercise has been shown to alleviate the motor symptoms of Parkinson's disease (PD), it remains unclear whether a physically active lifestyle may prevent PD.

To examine physical activities across the lifespan and risk of PD, we relied on data from a population-based case-control study that enrolled 357 incident PD cases and 341 controls. We assessed physical activity levels via self-report of (1) overall physical activity (PA) over 4 age periods; (2) competitive sports; and (3) occupational histories.

PD risks were lower comparing the overall PA highest quartile (moderate to vigorous activities ≥180 metabolic equivalent task-hours/week (MET-h/wk)) with the lowest quartile (<47.8 MET-h/wk) in age-period 18-24 years (adjusted odds ratio (OR) 0.64, 95% confidence interval (CI) 0.40-1.02), and 45-64 years (OR 0.50, 95%CI 0.31-0.83) but not in age-period 25-44. Individuals who consistently engaged in overall PA at high levels (before age 65 years) had a 51% lower PD risk than those with low levels. Also, having participated in competitive sports prior to age 25 was inversely associated with PD (OR 0.53, 95% CI 0.31-0.91 for high level versus never). There was no association for measures of occupational physical activity though.

The long prodromal stage of PD makes it difficult to conclude whether insidious disease leads to a reduction of physical activity years before motor symptom onset and PD diagnosis. However, sports activities and high levels of overall PA in youth appear protective unless they are markers for biologic or genetic factors that lower PD risk.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Plain English - LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

This research study compared patients with Parkinson's who carry the commonest gene mutation associated with the disease (called LRRK2),...