The genetic background of Parkinson's disease: current progress and future prospects

Current update on the state of knowledge of PD genetics...

Acta Neurol Scand. 2016 Feb 12. doi: 10.1111/ane.12563. [Epub ahead of print]

Kalinderi K, Bostantjopoulou S, Fidani L.

http://onlinelibrary.wiley.com/doi/10.1111/ane.12563/abstract;jsessionid=C963B8F50B1B317C8F8DFDB77BB5C89C.f03t02

Almost two decades of genetic research in Parkinson's disease (PD) have remarkably increased our knowledge regarding the genetic basis of PD with numerous genes and genetic loci having been found to cause familial PD or affect the risk for PD. Approximately 5-10% of PD patients have monogenic forms of the disease, exhibiting a classical Mendelian type of inheritance, however, the majority PD cases are sporadic, probably caused by a combination of genetic and environmental risk factors. Nowadays, six genes, alpha synuclein, LRRK2, VPS35, Parkin, PINK1 and DJ-1, have definitely been associated with an autosomal dominant or recessive PD mode of inheritance. The advent of genome-wide association studies (GWAS) and the implementation of new technologies, like next generation sequencing (NGS) and exome sequencing has undoubtedly greatly aided the identification on novel risk variants for sporadic PD. In this review, we will summarize the current progress and future prospects in the field of PD genetics.

A cumulative genetic risk score predicts progression in Parkinson's disease

Starting to see more of these initiatives... genetic variability clearly underlies at least some, if not a large proportion, of disease heterogeneity. This is not limited to simply getting PD alone but also contributes to the disease course....

Mov Disord. 2016 Feb 8. doi: 10.1002/mds.26505. [Epub ahead of print]

Pihlstrøm L, Morset KR, Grimstad E, Vitelli V, Toft M.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26505/abstract;jsessionid=71FA86C376E70BD8198E9DCADF7C742A.f04t02

BACKGROUND:

The contribution of genetic variability to clinical heterogeneity in Parkinson's disease is insufficiently understood. We aimed to investigate the effect of cumulative genetic risk on clinical outcomes.

METHODS:

In a single-center study of 336 patients we genotyped 19 independent susceptibility variants identified in genome-wide association studies of Parkinson's disease. We tested for association between a cumulative genetic risk score and 3 outcome measures: survival, time until progression to Hoehn and Yahr stage 3, and Unified Parkinson's Disease Rating Scale motor score severity.

RESULTS:

Genetic risk score was significantly associated with time from diagnosis to Hoehn and Yahr stage 3 in a Cox regression model (P = 0.010). We observed no clear association for the other outcomes.

CONCLUSIONS:

We present results linking cumulative genetic risk to a motor outcome in Parkinson's disease. Our findings provide a valuable starting point for future large-scale efforts to map the genetic determinants of phenotypic variability.

Migraine is related to an increased risk of Parkinson's disease: A population-based, propensity score-matched, longitudinal follow-up study

I have not seen much on migraine and PD in the past... I wonder if the authors adjusted for smoking, coffee and alcohol, which are negatively associated with PD and can trigger headaches in those with migraine...

Cephalalgia. 2016 Feb 6. pii: 0333102416630577. [Epub ahead of print]

Wang HI, Ho YC, Huang YP, Pan SL.

http://cep.sagepub.com/content/early/2016/02/04/0333102416630577.abstract

BACKGROUND:

The association between migraine and Parkinson's disease (PD) remains controversial. The purpose of the present population-based, propensity score-matched follow-up study was to investigate whether migraineurs are at a higher risk of developing PD.

METHODS:

A total of 41,019 subjects aged between 40 and 90 years with at least two ambulatory visits with a diagnosis of migraine in 2001 were enrolled in the migraine group. A logistic regression model that included age, sex, pre-existing comorbidities and socioeconomic status as covariates was used to compute the propensity score. The non-migraine group consisted of 41,019 propensity score-matched, randomly sampled subjects without migraine. The PD-free survival rate were estimated using the Kaplan-Meier method. Stratified Cox proportional hazard regression was used to estimate the effect of migraine on the risk of developing PD.

RESULTS:

During follow-up, 148 subjects in the migraine group and 101 in the non-migraine group developed PD. Compared to the non-migraine group, the hazard ratio of PD for the migraine group was 1.64 (95% confidence interval: 1.25-2.14, p = 0.0004). The PD-free survival rate for the migraine group was significantly lower than that for the non-migraine group (p = 0.0041).

CONCLUSIONS:

This study showed an increased risk of developing PD in patients with migraine.

The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: Mechanisms of action

Interesting review on GLP-1 agonists... the results of these clinical trials are eagerly awaited...

Drug Discov Today. 2016 Feb 3. pii: S1359-6446(16)30001-0. doi: 10.1016/j.drudis.2016.01.013. [Epub ahead of print]

Athauda D, Foltynie T.

http://www.sciencedirect.com/science/article/pii/S1359644616300010

Growing evidence suggests that agonists of the glucagon-like peptide 1 (GLP-1) receptor provide neuroprotection across a range of experimental models of Parkinson's disease (PD) and, recently, a small proof-of-concept, open-label human trial of exenatide in the treatment moderate severity PD appeared to show persistent improvements in motor and cognitive function. The underlying mechanisms of action remain unclear, but as evidence for the potential use of GLP-1 agonists in treating several neurodegenerative disease mounts, and with several clinical trials of GLP-1 analogues in PD and Alzheimer's disease (AD) currently underway, here we review the molecular mechanisms underlying the neuroprotective effects of GLP-1 analogues in the laboratory and their potential therapeutic utility with particular relevance to PD and PD dementia (PDD).

Course and risk factors for excessive daytime sleepiness in Parkinson's disease

Interesting to look at things associated with excessive daytime somnolence in PD... what is particular interesting to me is the finding that EDS is non-persistent. This has been a concern of mine for a while, particularly in the pre-diagnostic phase of PD. Strategies that aim to identifying those at risk may miss people with fluctuating or non-persistent symptoms at the early stage. This is one reason why strategies that involve repeat testing may be more effective...

Parkinsonism Relat Disord. 2016 Jan 22. pii: S1353-8020(16)30020-7. doi: 10.1016/j.parkreldis.2016.01.020. [Epub ahead of print]

Zhu K, van Hilten JJ, Marinus J.

http://www.prd-journal.com/article/S1353-8020(16)30020-7/abstract

INTRODUCTION:

Excessive daytime sleepiness (EDS) is a common feature of Parkinson's disease (PD) that contributes to the disease burden and increases risk of harm. The aim of this study was to examine persistency, cross-sectional and longitudinal associations, and risk factors for EDS in patients with PD.

METHODS:

Analyses were performed on data from the SCOPA-PROPARK cohort, a 5-year hospital-based longitudinal cohort of over 400 PD patients who were examined annually. Cross-sectional analyses were conducted to evaluate differences between patients with and without EDS at baseline, while linear mixed models using data of all patients were used to identify factors associated with longitudinal changes in SCOPA-SLEEP-Daytime Sleepiness (SCOPA-SLEEP-DS) scores. A survival analysis was done using data of patients without EDS at baseline to identify risk factors for future EDS.

RESULTS:

EDS proved a non-persistent symptom, although persistency and the proportion of patients with EDS increased with longer follow-up. At baseline 43% of patients had EDS, while 46% of patients without EDS at baseline developed this symptom during follow-up. Male gender, poorer nighttime sleep, cognitive and autonomic dysfunction, hallucinations, less severe dyskinesias, dose of dopamine agonists and use of antihypertensives were associated with higher EDS scores over time, while use of benzodiazepines was associated with lower scores. Baseline SCOPA-SLEEP-DS score and PIGD phenotype were risk factors for future EDS.

CONCLUSION:

With longer disease duration a large proportion of patients develop EDS. Some risk factors are modifiable and patients should be monitored to improve quality of life and reduce risk of harm.

Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease.

The authors of this study have developed a new technique for identifying oligomeric alpha-synuclein in CSF (the form of alpha-synuclein which is thought to be responsible for causing neuronal damage in PD). Although the ability of this new assay to classify patients and controls is only modest, and has yet to be validated in an independent cohort, the methodological advance this paper represents is in itself significant.

Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease.

Majbour NK, Vaikath NN, van Dijk KD, Ardah MT, Varghese S, Vesterager LB Montezinho et al.
Mol Neurodegener. 2016 Jan 19;11(1):7. doi: 10.1186/s13024-016-0072-9.

Abstract
BACKGROUND:
Despite decades of intensive research, to date, there is no accepted diagnosis for Parkinson's disease (PD) based on biochemical analysis of blood or CSF. However, neurodegeneration in the brains of PD patients begins several years before the manifestation of the clinical symptoms, pointing to serious flaw/limitations in this approach.

RESULTS:
To explore the potential use of alpha-synuclein (α-syn) species as candidate biomarkers for PD, we generated specific antibodies directed against wide array of α-syn species, namely total-, oligomeric- and phosphorylated-Ser129-α-syn (t-, o- and p-S129-α-syn). Next we sought to employ our antibodies to develop highly specific ELISA assays to quantify α-syn species in biological samples. Finally we verified the usefulness of our assays in CSF samples from 46 PD patients and 48 age-matched healthy controls. We also assessed the discriminating power of combining multiple CSF α-syn species with classical Alzheimer's disease biomarkers. The combination of CSF o-/t-α-syn, p-S129-α-syn and p-tau provided the best fitting predictive model for discriminating PD patients from controls. Moreover, CSF o-α-syn levels correlated significantly with the severity of PD motor symptoms (r = -0.37).

CONCLUSION:
Our new ELISA assays can serve as research tools to address the unmet need for reliable CSF biomarkers for PD and related disorders.

The prediagnostic phase of Parkinson's disease

This has been online for a couple of weeks but just indexed for Pubmed today... hope you enjoy!!

J Neurol Neurosurg Psychiatry. 2016 Jan 11. pii: jnnp-2015-311890. doi: 10.1136/jnnp-2015-311890. [Epub ahead of print]

Noyce AJ, Lees AJ, Schrag AE.

http://jnnp.bmj.com/content/early/2016/02/04/jnnp-2015-311890

Abstract

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

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

KEYWORDS:

EPIDEMIOLOGY; MOVEMENT DISORDERS; PARKINSON'S DISEASE

α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models

This is important stuff... evidence that alpha-syn accumulation affecting lysosomal degradation... lysosomes are responsible for much of the clearance of abnormal proteins from cells... so impairing lysosomal function could start a cycle of events leading to further accumulation and dysfunction... what's particularly exciting here is that the investigators show it is modifiable. Human midbrain models sound like a good idea too... this is the most affected part of the brain in PD!!

Proc Natl Acad Sci U S A. 2016 Feb 2. pii: 201520335. [Epub ahead of print]

Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D.

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

Substantia nigra echogenicity correlated with clinical features of Parkinson's disease

This is a large study looking at TCS in PD patients... the association with male gender has been reported before by some but not all investigators. However the association with markers of disease severity is unexpected and will require further replication....

Parkinsonism Relat Disord. 2016 Jan 26. pii: S1353-8020(16)30021-9. doi: 10.1016/j.parkreldis.2016.01.021. [Epub ahead of print]

Zhou HY, Sun Q, Tan YY, Hu YY, Zhan WW, Li DH, Wang Y, Xiao Q, Liu J, Chen SD.

BACKGROUND:

Transcranial sonography can display structural alterations in the substantia nigra (SN) of patients with Parkinson's disease (PD), and is considered to be a potential useful tool for the diagnosis of PD. The aim of this study was to assess the correlation between SN echogenicity and clinical features in Chinese patients with PD.

METHODS:

A total of 420 subjects including 290 patients with PD and 130 controls were recruited from the neurological clinic or the community. Transcranial sonographic evaluations of the SN were performed in all subjects, and motor and non-motor symptoms were thoroughly assessed by a series of rating scales in PD patients.

RESULTS:

Two hundred and one patients were successfully assessed by transcranial sonography. SN hyperechogenicity was found to be associated with male sex (p = 0.004), higher scores on the Unified Parkinson's Disease Rating Scale (UPDRS) part II (p = 0.001) and autonomic symptoms scores (p = 0.003). Moreover, regression analysis revealed that UPDRS part II scores (odds ratio = 1.141, p < 0.001) and gender (odds ratio = 2.409, p = 0.007) could be the independent predictors for SN hyperechogenicity; in addition, among all items of UPDRS part II, speech, dressing, hygiene, and turning in bed and adjusting bed clothes significantly correlated with SN hyperechogenicity.

CONCLUSIONS:

This is the first report suggesting the correlation between SN echogenicity and UPDRS part II, and we conclude that increased SN echogenicity might reflect more severe disease disability or poorer medical response.

Circadian system - A novel diagnostic and therapeutic target in Parkinson's disease?

I first started wondering about circadian rhythm in PD about three years ago when I attended an excellent talk at Barts and the London School of Medicine and Dentistry and the idea came up. It seems may of the pre and post diagnosis symptoms of PD could be accounted for (at least in part) by altered circadian rhythm... I anticipate this will be an area of further focus in the coming years!

Mov Disord. 2016 Jan 30. doi: 10.1002/mds.26509. [Epub ahead of print]

Videnovic A, Willis GL.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26509/abstract;jsessionid=661D8F51842DC0A7A208F9EFEA8B0E24.f03t01

The circadian system regulates biological rhythmicity in the human body. The role of the circadian system in neurological disorders is a theme that is attracting an increasing amount of interest from the scientific community. This has arisen, in part, from emerging evidence that disorders such as Parkinson's disease (PD) are multifactorial with many features exhibiting diurnal fluctuations, thereby suggestive of circadian involvement. Although the importance of fluctuating motor and nonmotor manifestations in PD have been well acknowledged, the role of the circadian system has received little attention until recently. It is proposed that intervening with circadian function provides a novel research avenue down which new strategies for improving symptomatic treatment and slowing of the progressive degenerative process can be approached to lessen the burden of PD. In this article we review the literature describing existing circadian research in PD and its experimental models. © 2016 International Parkinson and Movement Disorder Society.

Risk of Injurious Fall and Hip Fracture up to 26 y before the Diagnosis of Parkinson Disease: Nested Case-Control Studies in a Nationwide Cohort

Notwithstanding the issues around case ascertainment and differentiation from atypical Parkinson's this is really interesting. In fact even if atypical Parkinson's did explain some of the association, one would not expect the effect to be present up to 10 years before diagnosis. 

Certainly prominent falling should still raise the possibility of atypical Parkinson's in individual patients, but this study suggests the presence of motor features many years before eventual diagnosis. We have been saying this for some time... subtle motor dysfunction ought to be present if looked for and the notion of 'premotor' PD may not hold true. Only if you have looked at people with prodromal or pre-diagnostic disease (without bias) and can find no hint of motor problems, then waited to see motor dysfunction subsequently emerge can one be confident of a premotor phase.

Whether the association with fracture risk suggests common disease mechanisms between osteoporosis and PD, or whether subtle reduction in mobility increases fracture risk will remain unclear... but given the lag time between fracture and PD, l-dopa, undernutrition and lack of sunlight exposure should not be playing a role...

PLoS Med. 2016 Feb 2;13(2):e1001954. doi: 10.1371/journal.pmed.1001954. eCollection 2016.

Nyström H, Nordström A, Nordström P.

BACKGROUND:

Low muscle strength has been found in late adolescence in individuals diagnosed with Parkinson disease (PD) 30 y later. This study investigated whether this lower muscle strength also may translate into increased risks of falling and fracture before the diagnosis of PD.

METHODS AND FINDINGS:

Among all Swedish citizens aged ≥50 y in 2005, two nested case-control cohorts were compiled. In cohort I, individuals diagnosed with PD during 1988-2012 (n = 24,412) were matched with up to ten controls (n = 243,363), and the risk of fall-related injuries before diagnosis of PD was evaluated. In cohort II, individuals with an injurious fall in need of emergency care during 1988-2012 (n = 622,333) were matched with one control (n = 622,333), and the risk of PD after the injurious fall was evaluated. In cohort I, 18.0% of cases and 11.5% of controls had at least one injurious fall (p < 0.001) prior to PD diagnosis in the case. Assessed by conditional logistic regression analysis adjusted for comorbid diagnoses and education level, PD was associated with increased risks of injurious fall up to 10 y before diagnosis (odds ratio [OR] 1.19, 95% CI 1.08-1.31; 7 to <10 y before diagnosis) and hip fracture ≥15 y before diagnosis (OR 1.36, 95% CI 1.10-1.69; 15-26 y before diagnosis). In cohort II, 0.7% of individuals with an injurious fall and 0.5% of controls were diagnosed with PD during follow-up (p < 0.001). The risk of PD was increased for up to 10 y after an injurious fall (OR 1.18, 95% CI 1.02-1.37; 7 to <10 y after diagnosis). An important limitation is that the diagnoses were obtained from registers and could not be clinically confirmed for the study.

CONCLUSIONS:

The increased risks of falling and hip fracture prior to the diagnosis of PD may suggest the presence of clinically relevant neurodegenerative impairment many years before the diagnosis of this disease.