Systems Biology   |   Personalized Neurology

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Personalized Neurology

Science, 2017;357:891-898

Science, 2017;357:891-898.

β2-Adrenoreceptor is a Regulator of the α-Synuclein Gene Driving Risk of Parkinson's Disease
Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR

Abstract

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered the β2-adrenoreceptor (β2AR) as a regulator of the α-synuclein gene (SNCA). β2AR ligands modulate SNCA transcription via histone 3 lysine 27 acetylation of its promoter and enhancers. During 11 years of follow up in four million Norwegians, the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio = 0.66, 95% C.I. 0.58-0.76). Conversely, a β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR links to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.


Lancet Neurology, 2017; 16: 620-629

Lancet Neurology, 2017; 16: 620-629

Prediction of cognition in Parkinson's disease with a clinical–genetic score: a longitudinal analysis of nine cohorts
Ganqiang Liu, Joseph J Locascio, Jean-Christophe Corvol, Brendon Boot, Zhixiang Liao, Kara Page, Daly Franco, Kyle Burke, Iris E Jansen, Ana Trisini-Lipsanopoulos, Sophie Winder-Rhodes, Caroline M Tanner, Anthony E Lang, Shirley Eberly, Alexis Elbaz, Alexis Brice, Graziella Mangone, Bernard Ravina, Ira Shoulson, Florence Cormier-Dequaire, Peter Heutink, Jacobus J van Hilten, Roger A Barker, Caroline H Williams-Gray, Johan Marinus, Clemens R Scherzer

Summary

BACKGROUND Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical–genetic score to predict global cognitive impairment in patients with the disease.

METHODS In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.

FINDINGS 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6–4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β–glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1–7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82–0·90) and replication (95% CI 0·78–0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4–36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79–0·94) and a negative predictive value of 0·92 (95% 0·88–0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.

INTERPRETATION Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis.

FUNDING National Institutes of Health, US Department of Defense.


Ann Neurol. 2016

Ann Neurol. 2016 Nov;80(5):674-685. doi: 10.1002/ana.24781.

F1000Prime recommendedSpecifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.
Liu G, Boot B, Locascio JJ, Jansen IE, Winder-Rhodes S, Eberly S, Elbaz A, Brice A, Ravina B, van Hilten JJ, Cormier-Dequaire F, Corvol JC, Barker RA, Heutink P, Marinus J, Williams-Gray CH, Scherzer CR; International Genetics of Parkinson Disease Progression (IGPP) Consortium.

Abstract

OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates.
METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.
RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance.
Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685.

©2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.


 

Brain 2015

Brain. 2015 Jul 28. pii: awv202. [Epub ahead of print]

Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.
Locascio JJ, Eberly S, Liao Z, Liu G, Hoesing AN, Duong K, Trisini-Lipsanopoulos A, Dhima K, Hung AY, Flaherty AW, Schwarzschild MA, Hayes MT, Wills AM, Shivraj Sohur U, Mejia NI, Selkoe DJ, Oakes D, Shoulson I, Dong X, Marek K, Zheng B, Ivinson A, Hyman BT, Growdon JH, Sudarsky LR, Schlossmacher MG, Ravina B, Scherzer CR.

Abstract

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.

© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.


 

Ann Neurol 2013

Ann Neurol. 2013 Nov 16. doi: 10.1002/ana.24053. [Epub ahead of print]

Metallothioneins as dynamic markers for brain disease in lysosomal disorders.
Cesani M, Cavalca E, Macco R, Leoncini G, Terreni MR, Lorioli L, Furlan R, Comi G, Doglioni C, Zacchetti D, Sessa M, Scherzer CR, Biffi A.

San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, 20132, Milan, Italy; The Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, 02139, USA.

Abstract

Objective: To facilitate development of novel disease-modifying therapies for Lysosomal Storage Disorder (LSD) characterized by nervous system involvement such as Metachromatic Leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this goal we sought to identify blood transcripts associated with the progression of MLD. Methods: Genome-wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age- and sex-matched healthy controls. Genes associated with MLD were identified, confirmed on a quantitative PCR platform, and replicated in an independent patient cohort. mRNA and protein expression of the prioritized gene family of metallothioneins was evaluated in post-mortem patient brains and in mouse models representing six other LSDs. MT expression during disease progression and in response to specific treatment was evaluated in one of the tested LSD mouse models. Finally, a set of in vitro studies was planned to dissect the biological functions exerted by this class of molecules. Results: Metallothionein genes were significantly over-expressed in T lymphocytes and brain of patients with MLD and generally marked nervous tissue damage in the LSDs here evaluated. Over-expression of metallothioneins correlated with measures of disease progression in mice and patients, whereas their levels decreased in mice upon therapeutic treatment. In vitro studies indicated that metallothionein expression is regulated in response to oxidative stress and inflammation that are biochemical hallmarks of lysosomal storage diseases. Interpretation: Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs. ANN NEUROL 2013. © 2013 American Neurological Association.

Copyright © 2013 American Neurological Association.
PMID: 24242821 [PubMed - as supplied by publisher]


 

 

Neurology. 2013 Oct 22;81(17):1531-7. doi: 10.1212/WNL.0b013e3182a95818. Epub 2013 Sep 25.

Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study.
Ding H, Dhima K, Lockhart KC, Locascio JJ, Hoesing AN, Duong K, Trisini-Lipsanopoulos A, Hayes MT, Sohur US, Wills AM, Mollenhauer B, Flaherty AW, Hung AY, Mejia N, Khurana V, Gomperts SN, Selkoe DJ, Schwarzschild MA, Schlossmacher MG, Hyman BT, Sudarsky LR, Growdon JH, Scherzer CR.

From the Neurogenomics Laboratory (H.D., K.D., K.C.L., A.N.H., K.D., A.T.-L., C.R.S.), Harvard Medical School and Brigham & Women's Hospital, Cambridge; Biomarkers Program (K.D., K.C.L., A.N.H., K.D., A.T.-L., M.T.H., U.S.S., B.M., N.M., V.K., S.N.G., D.J.S., M.A.S., M.G.S., B.T.H., J.H.G., C.R.S.), Harvard NeuroDiscovery Center, Boston; Department of Neurology (J.J.L., U.S.S., A.-M.W., A.W.F., A.Y.H., N.M., V.K., S.N.G., M.A.S., B.T.H., J.H.G., C.R.S.), Massachusetts General Hospital, Boston; Department of Neurology (M.T.H., A.Y.H., D.J.S., L.R.S., C.R.S.), Brigham and Women's Hospital, Boston, MA; Paracelsus-Elena-Klinik (B.M.), Kassel, Germany; and Division of Neurology, the Ottawa Hospital, University of Ottawa (M.G.S.), Canada.

Abstract

OBJECTIVE: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD).

METHODS: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study.

RESULTS: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson's Disease Rating Scale scores at baseline and during follow-up.

CONCLUSIONS: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

PMID: 24068787 [PubMed - in process]


 

figure 1

Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17141-6. doi: 10.1073/pnas.1104409108. Epub 2011 Oct 3.

Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse.
Hu Y, Chopra V, Chopra R, Locascio JJ, Liao Z, Ding H, Zheng B, Matson WR, Ferrante RJ, Rosas HD, Hersch SM, Scherzer CR.

Laboratory for Neurogenomics, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA.

Abstract

Huntington disease (HD) is a progressive neurodegenerative disease that affects 30,000 individuals in North America. Treatments that slow its relentless course are not yet available, and biomarkers that can reliably measure disease activity and therapeutic response are urgently needed to facilitate their development. Here, we interrogated 119 human blood samples for transcripts associated with HD. We found that the dynamic regulator of chromatin plasticity H2A histone family, member Y (H2AFY) is specifically overexpressed in the blood and frontal cortex of patients with HD compared with controls. This association precedes the onset of clinical symptoms, was confirmed in two mouse models, and was independently replicated in cross-sectional and longitudinal clinical studies comprising 142 participants. A histone deacetylase inhibitor that suppresses neurodegeneration in animal models reduces H2AFY levels in a randomized phase II clinical trial. This study identifies the chromatin regulator H2AFY as a potential biomarker associated with disease activity and pharmacodynamic response that may become useful for enabling disease-modifying therapeutics for HD.

Comment in
Does chromatin modulation provide the first wet biomarker for Huntington's disease? [Mov Disord. 2012]
Chromatin plasticity and the pathogenesis of Huntington disease. [Proc Natl Acad Sci U S A. 2011]

PMID: 21969577 [PubMed - indexed for MEDLINE] PMCID: PMC3193232
Free PMC Article


 

 

Mov Disord. 2011 Oct;26(12):2283-6. doi: 10.1002/mds.23934. Epub 2011 Sep 23.

Association of SNCA with Parkinson: replication in the Harvard NeuroDiscovery Center Biomarker Study.
Ding H, Sarokhan AK, Roderick SS, Bakshi R, Maher NE, Ashourian P, Kan CG, Chang S, Santarlasci A, Swords KE, Ravina BM, Hayes MT, Sohur US, Wills AM, Flaherty AW, Unni VK, Hung AY, Selkoe DJ, Schwarzschild MA, Schlossmacher MG, Sudarsky LR, Growdon JH, Ivinson AJ, Hyman BT, Scherzer CR.

Center for Neurologic Diseases, Harvard Medical School and Brigham & Women's Hospital, Cambridge, Massachusetts, USA.

Abstract

BACKGROUND: Mutations in the α-synuclein gene (SNCA) cause autosomal dominant forms of Parkinson's disease, but the substantial risk conferred by this locus to the common sporadic disease has only recently emerged from genome-wide association studies.

METHODS: We genotyped a prioritized noncoding variant in SNCA intron 4 in 344 patients with Parkinson's disease and 275 controls from the longitudinal Harvard NeuroDiscovery Center Biomarker Study.

RESULTS: The common minor allele of rs2736990 was associated with elevated disease susceptibility (odds ratio, 1.40; P = .0032).

CONCLUSIONS: This result increases confidence in the notion that in many clinically well-characterized patients, genetic variation in SNCA contributes to "sporadic" disease.

Copyright © 2011 Movement Disorder Society.

PMID: 21953863 [PubMed - indexed for MEDLINE] PMCID: PMC3337217
Free PMC Article


 

Ann Neurol. 2012 Mar;71(3):370-84. doi: 10.1002/ana.22687.

Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2.
Pankratz N, Beecham GW, DeStefano AL, Dawson TM, Doheny KF, Factor SA, Hamza TH, Hung AY, Hyman BT, Ivinson AJ, Krainc D, Latourelle JC, Clark LN, Marder K, Martin ER, Mayeux R, Ross OA, Scherzer CR, Simon DK, Tanner C, Vance JM, Wszolek ZK, Zabetian CP, Myers RH, Payami H, Scott WK, Foroud T; PD GWAS Consortium.

Collaborators (739)

Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Abstract

OBJECTIVE: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility.

METHODS: A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).

RESULTS: Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.

INTERPRETATION: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.

Copyright © 2012 American Neurological Association

PMID: 22451204 [PubMed - indexed for MEDLINE] PMCID: PMC3354734
Free PMC Article


 

17215369

Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):955-60. Epub 2007 Jan 10.

Molecular markers of early Parkinson's disease based on gene expression in blood.
Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR.

Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA. cscherzer@rics.bwh.harvard.edu

Abstract

Parkinson's disease (PD) progresses relentlessly and affects five million people worldwide. Laboratory tests for PD are critically needed for developing treatments designed to slow or prevent progression of the disease. We performed a transcriptome-wide scan in 105 individuals to interrogate the molecular processes perturbed in cellular blood of patients with early-stage PD. The molecular multigene marker here identified is associated with risk of PD in 66 samples of the training set comprising healthy and disease controls [third tertile cross-validated odds ratio of 5.7 (P for trend 0.005)]. It is further validated in 39 independent test samples [third tertile odds ratio of 5.1 (P for trend 0.04)]. Insights into disease-linked processes detectable in peripheral blood are offered by 22 unique genes differentially expressed in patients with PD versus healthy individuals. These include the co-chaperone ST13, which stabilizes heat-shock protein 70, a modifier of alpha-synuclein misfolding and toxicity. ST13 messenger RNA copies are lower in patients with PD (mean +/- SE 0.59 +/- 0.05) than in controls (0.96 +/- 0.09) (P = 0.002) in two independent populations. Thus, gene expression signals measured in blood can facilitate the development of biomarkers for PD.

PMID: 17215369 [PubMed - indexed for MEDLINE] PMCID: PMC1766335
Free PMC Article


 

19285134

Neurobiol Dis. 2009 Aug;35(2):148-56. doi: 10.1016/j.nbd.2009.02.016. Epub 2009 Mar 10.

Chipping away at diagnostics for neurodegenerative diseases.
Scherzer CR.

Abstract

Biomarkers are needed to overcome critical roadblocks in the development of disease-modifying therapeutics for neurodegenerative diseases. Evolving genome-wide expression technologies can comprehensively search for molecular biomarkers and allow fascinating insights into the expanding complexity of the human transcriptome. The technology has matured to the point where some applications are deemed reliable enough for use in patient care. In the neurosciences, it has led to the discoveries of osteopontin in multiple sclerosis and SORL1/LR11 in Alzheimer's, and recent studies indicate its potential for identifying neurogenomic biomarkers. Advances in pre-analytical and analytical methods are improving search efficiency and reproducibility and may lead to a pipeline of biomarker candidates suitable for development into future neurologic diagnostics.

PMID: 19285134 [PubMed - indexed for MEDLINE] PMCID: PMC2753504
Free PMC Article

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