MicroRNAs in Cerebrospinal Fluid as Potential Biomarkers for Parkinson's Disease and Multiple System Atrophy

Studying microRNA may be another avenue to identify and define biomarkers for diseases like Parkinson's.... the work below describes differences between PD and controls, and MSA and controls, which is very encouraging. However, what we really need are biomarkers that show clear differences in the early stages of PD and sensitivity to change, as well as biomarkers which differentiate PD from atypical parkinson's...

Mol Neurobiol. 2016 Nov 14. [Epub ahead of print]
Marques TM, Kuiperij HB, Bruinsma IB, van Rumund A, Aerts MB, Esselink RA, Bloem BR, Verbeek MM.

http://link.springer.com/article/10.1007%2Fs12035-016-0253-0

Parkinson's disease (PD) and multiple system atrophy (MSA) are both part of the spectrum of neurodegenerative movement disorders and α-synucleinopathies with overlap of symptoms especially at early stages of the disease but with distinct disease progression and responses to dopaminergic treatment. Therefore, having biomarkers that specifically classify patients, which could discriminate PD from MSA, would be very useful. MicroRNAs (miRNAs) regulate protein translation and are observed in biological fluids, including cerebrospinal fluid (CSF), and may therefore have potential as biomarkers of disease. The aim of our study was to determine if miRNAs in CSF could be used as biomarkers for either PD or MSA. Using quantitative PCR (qPCR), we evaluated expression levels of 10 miRNAs in CSF patient samples from PD (n = 28), MSA (n = 17), and non-neurological controls (n = 28). We identified two miRNAs (miR-24 and miR-205) that distinguished PD from controls and four miRNAs that differentiated MSA from controls (miR-19a, miR-19b, miR-24, and miR-34c). Combinations of miRNAs accurately discriminated either PD (area under the curve (AUC) = 0.96) or MSA (AUC = 0.86) from controls. In MSA, we also observed that miR-24 and miR-148b correlated with cerebellar ataxia symptoms, suggesting that these miRNAs are involved in cerebellar degeneration in MSA. Our findings support the potential of miRNA panels as biomarkers for movement disorders and may provide more insights into the pathological mechanisms related to these disorders.

Parkinson's disease and risk of prostate cancer: A Danish population-based case-control study, 1995-2010

Previous studies have suggested an increased risk of PD in those with prostate cancer. Although the exposure and outcome are the other way round here, this study suggests a negative association between the two diseases...

Cancer Epidemiol. 2016 Nov 10;45:157-161. doi: 10.1016/j.canep.2016.11.002. [Epub ahead of print]
Jespersen CG, Nørgaard M, Borre M.

INTRODUCTION: Prostate cancer growth and progression may be linked to neurogenesis and to medical anti- Parkinson treatment, but results are inconclusive. Therefore, we examined the association between Parkinson's disease and risk of prostate cancer in a population based case-control study.

METHODS: We identified 45,429 patients diagnosed with incident prostate cancer during 1997-2010 from the National Cancer Registry. Five age-matched population controls (n=227,145) were selected for each case. Odds ratios (ORs) adjusted for age and comorbidity for prostate cancer associated with Parkinson's disease were computed using conditional logistic regression. Analyses were stratified by duration of Parkinson's disease and stage of prostate cancer (localized and advanced).

RESULTS: In total, 245 patients (0,5%) and 1656 controls (0,7%) had Parkinson's disease. Overall, patients with Parkinson's disease had a 27% lower risk of prostate cancer compared with patients without Parkinson's disease (adjusted OR (ORa) 0.73; 95% confidence interval (CI), 0.63-0.83). Risk of prostate cancer decreased with increasing duration of Parkinson's disease. The odds ratios were slightly lower for advanced prostate cancer (ORa, 0.68; 95% CI, 0.52-0.88) than for localized prostate cancer (ORa 0.76; 95% CI, 0.61-0.93).

CONCLUSION: Parkinson's disease was associated with a risk reduction overall (27%), which decreased with increasing duration of Parkinson's disease.

Medulla oblongata damage and cardiac autonomic dysfunction in Parkinson disease

As time goes on there are more and more MRI correlates for PD in general and PD-specific features... some of these may well extend into the pre-diagnostic phase and we already suspect that autonomic dysfunction occurs prior to a diagnosis of PD in some, if not the majority of, patients...

Neurology. 2016 Nov 11. pii: 10.1212/WNL.0000000000003426. [Epub ahead of print] Pyatigorskaya N, Mongin M, Valabregue R, Yahia-Cherif L, Ewenczyk C, Poupon C, Debellemaniere E, Vidailhet M, Arnulf I, Lehéricy S.

http://www.neurology.org/content/early/2016/11/11/WNL.0000000000003426.long

OBJECTIVE: To characterize medulla oblongata damage using diffusion tensor imaging (DTI) in Parkinson disease (PD) and correlate it with dysfunction of the cardiac sympathetic/vagal balance.

METHODS: Fifty-two patients with PD and 24 healthy controls were included in the study. All participants underwent clinical examination and 3T MRI using 3D T1-weighted imaging and DTI. DTI metrics were calculated within manually drawn regions of interest. Heart rate variability was evaluated using spectral analysis of the R-R cardiac interval during REM and slow-wave sleep based on continuous overnight electrocardiographic monitoring. Respiratory frequency was measured in 30-second contiguous epochs of REM and slow-wave sleep. The relationships between imaging and cardiac variables were calculated using partial correlations followed by the multiple comparisons permutation approach.

RESULTS: The changes in heart rate and respiratory frequency variability from slow-wave sleep to REM sleep in healthy controls were no longer detectable in patients with PD. There were significant increases in the mean (p = 0.006), axial (p = 0.006), and radial diffusivities (p = 0.005) in the medulla oblongata of patients with PD. In PD, diffusion changes were specifically correlated with a lower heart rate and respiratory frequency variability during REM sleep.

CONCLUSIONS: This study provides evidence that medulla oblongata damage underlies cardiac sympathetic/vagal balance and respiratory dysfunction in patients with PD.

Calcium Channel Antagonists as Disease-Modifying Therapy for Parkinson's Disease: Therapeutic Rationale and Current Status

I saw James Surmeier (http://physio.northwestern.edu/research/research-areas/systems-neuroscience.html#surmeier) talking on this subject at the Parkinson's UK Research Conference in Leeds earlier this week... he was very inspiring. I was already aware of the epidemiological research on this topic, but not the animal studies that support it... exciting times for calcium channel blockers and PD...

CNS Drugs. 2016 Nov 8. [Epub ahead of print]
Swart T, Hurley MJ.

http://link.springer.com/article/10.1007%2Fs40263-016-0393-9

Parkinson's disease is a disabling hypokinetic neurological movement disorder in which the aetiology is unknown in the majority of cases. Current pharmacological treatments, though effective at restoring movement, are only symptomatic and do nothing to slow disease progression. Electrophysiological, epidemiological and neuropathological studies have implicated CaV1.3 subtype calcium channels in the pathogenesis of the disorder, and drugs with some selectivity for this ion channel (brain-penetrant dihydropyridine calcium channel blockers) are neuroprotective in animal models of the disease. Dihydropyridines have been safely used for decades to treat hypertension and other cardiovascular disorders. A phase II clinical trial found that isradipine was safely tolerated by patients with Parkinson's disease, and a phase III trial is currently underway to determine whether treatment with isradipine is neuroprotective and therefore able to slow the progression of Parkinson's disease. This manuscript reviews the current information about the use of dihydropyridines as therapy for Parkinson's disease and discusses the possible mechanism of action of these drugs, highlighting CaV1.3 calcium channels as a potential therapeutic target for neuroprotection in Parkinson's disease.

Usefulness of Cardiac MIBG Scintigraphy, Olfactory Testing and Substantia Nigra Hyperechogenicity as Additional Diagnostic Markers for Distinguishing between Parkinson's Disease and Atypical Parkinsonian Syndromes

Combining (relatively) cheap investigations to differentiate Parkinson's from atypical Parkinson's may prove fruitful... certainly in most centres it is difficult to differentiate these conditions using SPECT imaging... and many people are not confident with the MRI differences...

PLoS One. 2016 Nov 3;11(11):e0165869. doi: 10.1371/journal.pone.0165869. eCollection 2016. Fujita H1, Suzuki K1, Numao A1, Watanabe Y1, Uchiyama T1,2, Miyamoto T3, Miyamoto M4, Hirata K1.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165869

BACKGROUND: We aimed to evaluate the utility of the combined use of cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, olfactory testing, and substantia nigra (SN) hyperechogenicity on transcranial sonography (TCS) in differentiating Parkinson's disease (PD) from atypical parkinsonian syndromes (APSs), such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).

METHODS: Cardiac MIBG scintigraphy, card-type odor identification testing (Open Essence (OE), Wako, Japan), and TCS were performed with 101 patients with PD and 38 patients with APSs (MSA and PSP). Receiver operating characteristic (ROC) curve analysis was used to assess the sensitivity and specificity of these batteries for diagnosing PD from APSs. The diagnostic accuracy of the three tests was also assessed among patients at the early disease stage (drug-naïve patients with a disease duration of 3 years or less).

RESULTS: In differentiating PD from APSs, the area under the ROC curve was 0.74 (95% CI, 0.65-0.83), 0.8 (95% CI, 0.73-0.87), and 0.75 (95% CI, 0.67-0.82) for TCS, cardiac MIBG scintigraphy, and olfactory testing, respectively. The diagnostic sensitivity and specificity were 53.1% and 91.7%, respectively, for TCS, 70.3% and 86.8%, respectively, for cardiac MIBG scintigraphy, 58.4% and 76.3%, respectively, for OE. Among early-stage patients, sensitivity and specificity were 50.0% and 93.8%, respectively, for TCS, 57.1% and 87.5%, respectively, for cardiac MIBG scintigraphy, and 54.8% and 79.2%, respectively, for OE. At least one positive result from 3 tests improved sensitivity (86.1%) but decreased specificity (63.2%). In contrast, at least 2 positive results from 3 tests had good discrimination for both early-stage patients (50.0% sensitivity and 93.8% specificity) and patients overall (57.8% sensitivity and 95.8% specificity). Positive results for all 3 tests yielded 100% specificity but low sensitivity (25%).

CONCLUSIONS: At least 2 positive results from among TCS, cardiac MIBG scintigraphy, and olfactory testing can support clinical diagnosis in distinguishing PD from APSs.

Genome-wide association study in essential tremor identifies three new loci

Understanding the genetics of essential tremor has been difficult, but this is now a reasonably large GWAS study conducted by investigators who will have accurately characterise the phenotype... GWAS (like anything) depends on accurate diagnosis of the cases and ideally confident exclusion of the disease in controls... interestingly some of the previously reported 'hits' for essential tremor are not replicated here...

Brain. 2016 Oct 20. pii: aww242. [Epub ahead of print]

Müller SH, Girard SL, Hopfner F, Merner ND, Bourassa CV, Lorenz D, Clark LN, Tittmann L, Soto-Ortolaza AI, Klebe S, Hallett M, Schneider SA, Hodgkinson CA, Lieb W, Wszolek ZK, Pendziwiat M, Lorenzo-Betancor O, Poewe W, Ortega-Cubero S, Seppi K, Rajput A, Hussl A, Rajput AH, Berg D, Dion PA, Wurster I, Shulman JM, Srulijes K, Haubenberger D, Pastor P, Vilariño-Güell C, Postuma RB, Bernard G, Ladwig KH, Dupré N, Jankovic J, Strauch K, Panisset M, Winkelmann J, Testa CM, Reischl E, Zeuner KE, Ross OA, Arzberger T, Chouinard S, Deuschl G, Louis ED, Kuhlenbäumer G, Rouleau GA.

http://brain.oxfordjournals.org/content/early/2016/10/20/brain.aww242.long

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Additional Rare Variant Analysis in Parkinson's Disease Cases with and Without Known Pathogenic Mutations: Evidence for Oligogenic Inheritance

Great to see this paper published... it provides evidence for another layer of complexity to the genetics of Parkinson's, but also provides further explanation for this complexity... as time passes we realise there is not just genetic and non-genetic Parkinson's, but instead that genetic variability underpins a great deal of the heterogeneity of all Parkinson's disease...

Hum Mol Genet. 2016 Oct 18. pii: ddw348. [Epub ahead of print]

Lubbe SJ, Escott-Price V, Gibbs JR, Nalls MA, Bras J, Price TR, Nicolas A, Jansen IE, Mok KY, Pittman AM, Tomkins JE, Lewis PA, Noyce AJ, Lesage S, Sharma M, Schiff ER, Levine AP, Brice A, Gasser T, Hardy J, Heutink P, Wood NW, Singleton AB, Williams NM, Morris HR; for International Parkinson’s Disease Genomics Consortium.

http://hmg.oxfordjournals.org/content/early/2016/10/14/hmg.ddw348.abstract

Abstract

Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognized primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of no known mutation PD cases harbor a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of PD patients and their families.