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1.  Large-scale replication and heterogeneity in Parkinson disease genetic loci 
Sharma, Manu | Ioannidis, John P.A. | Aasly, Jan O. | Annesi, Grazia | Brice, Alexis | Van Broeckhoven, Christine | Bertram, Lars | Bozi, Maria | Crosiers, David | Clarke, Carl | Facheris, Maurizio | Farrer, Matthew | Garraux, Gaetan | Gispert, Suzana | Auburger, Georg | Vilariño-Güell, Carles | Hadjigeorgiou, Georgios M. | Hicks, Andrew A. | Hattori, Nobutaka | Jeon, Beom | Lesage, Suzanne | Lill, Christina M. | Lin, Juei-Jueng | Lynch, Timothy | Lichtner, Peter | Lang, Anthony E. | Mok, Vincent | Jasinska-Myga, Barbara | Mellick, George D. | Morrison, Karen E. | Opala, Grzegorz | Pramstaller, Peter P. | Pichler, Irene | Park, Sung Sup | Quattrone, Aldo | Rogaeva, Ekaterina | Ross, Owen A. | Stefanis, Leonidas | Stockton, Joanne D. | Satake, Wataru | Silburn, Peter A. | Theuns, Jessie | Tan, Eng-King | Toda, Tatsushi | Tomiyama, Hiroyuki | Uitti, Ryan J. | Wirdefeldt, Karin | Wszolek, Zbigniew | Xiromerisiou, Georgia | Yueh, Kuo-Chu | Zhao, Yi | Gasser, Thomas | Maraganore, Demetrius | Krüger, Rejko | Boyle, R.S | Sellbach, A | O'Sullivan, J.D. | Sutherland, G.T. | Siebert, G.A | Dissanayaka, N.N.W | Van Broeckhoven, Christine | Theuns, Jessie | Crosiers, David | Pickut, Barbara | Engelborghs, Sebastiaan | Meeus, Bram | De Deyn, Peter P. | Cras, Patrick | Rogaeva, Ekaterina | Lang, Anthony E | Agid, Y | Anheim, M | Bonnet, A-M | Borg, M | Brice, A | Broussolle, E | Corvol, JC | Damier, P | Destée, A | Dürr, A | Durif, F | Lesage, S | Lohmann, E | Pollak, P | Rascol, O | Tison, F | Tranchant, C | Viallet, F | Vidailhet, M | Tzourio, Christophe | Amouyel, Philippe | Loriot, Marie-Anne | Mutez, Eugénie | Duflot, Aurélie | Legendre, Jean-Philippe | Waucquier, Nawal | Gasser, Thomas | Riess, Olaf | Berg, Daniela | Schulte, Claudia | Klein, Christine | Djarmati, Ana | Hagenah, Johann | Lohmann, Katja | Auburger, Georg | Hilker, Rüdiger | van de Loo, Simone | Dardiotis, Efthimios | Tsimourtou, Vaia | Ralli, Styliani | Kountra, Persa | Patramani, Gianna | Vogiatzi, Cristina | Hattori, Nobutaka | Tomiyama, Hiroyuki | Funayama, Manabu | Yoshino, Hiroyo | Li, Yuanzhe | Imamichi, Yoko | Toda, Tatsushi | Satake, Wataru | Lynch, Tim | Gibson, J. Mark | Valente, Enza Maria | Ferraris, Alessandro | Dallapiccola, Bruno | Ialongo, Tamara | Brighina, Laura | Corradi, Barbara | Piolti, Roberto | Tarantino, Patrizia | Annesi, Ferdinanda | Jeon, Beom S. | Park, Sung-Sup | Aasly, J | Opala, Grzegorz | Jasinska-Myga, Barbara | Klodowska-Duda, Gabriela | Boczarska-Jedynak, Magdalena | Tan, Eng King | Belin, Andrea Carmine | Olson, Lars | Galter, Dagmar | Westerlund, Marie | Sydow, Olof | Nilsson, Christer | Puschmann, Andreas | Lin, JJ | Maraganore, Demetrius M. | Ahlskog, J, Eric | de Andrade, Mariza | Lesnick, Timothy G. | Rocca, Walter A. | Checkoway, Harvey | Ross, Owen A | Wszolek, Zbigniew K. | Uitti, Ryan J.
Neurology  2012;79(7):659-667.
Objective:
Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.
Methods:
Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.
Results:
In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.
Conclusion:
Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667
doi:10.1212/WNL.0b013e318264e353
PMCID: PMC3414661  PMID: 22786590
2.  Loss of ability to work and ability to live independently in Parkinson’s Disease 
Parkinsonism & related disorders  2011;18(2):130-135.
Objective
Ability to work and independent living capacity are of particular concern for patients with Parkinson’s disease (PD). We utilized a series of PD patients able to work or live independently at baseline, and evaluated potential risk factors for the two separate outcomes of loss of ability to work and loss of ability to live independently.
Methods
The series was comprised of 495 PD patients followed prospectively. Ability to work and ability to live independently were based on clinical interview and examination. Cox regression models adjusted for age and disease duration were used to evaluate associations of baseline characteristics with loss of ability to work and loss of ability to live independently.
Results
Higher UPDRS dyskinesia score, UPDRS instability score, UPDRS total score, Hoehn and Yahr stage, and presence of intellectual impairment at baseline were all associated with increased risk of future loss of ability to work and loss of ability to live independently (P≤0.0033). Five years after initial visit, for patients ≤70 years of age with a disease duration ≤4 years at initial visit, 88% were still able to work and 90% to live independently. These estimates worsened as age and disease duration at initial visit increased; for patients >70 years of age with a disease duration >4 years, estimates at 5 years were 43% and 57%, respectively.
Conclusions
The information provided in this study can offer useful information for PD patients in preparing for future loss of ability to perform activities of daily living.
doi:10.1016/j.parkreldis.2011.08.022
PMCID: PMC3977346  PMID: 21975262
Parkinson disease; work ability; independence
3.  Depression in Parkinson’s Disease 
Objective
To examine predictive factors associated with onset of depression among individuals diagnosed with Parkinson’s disease (PD).
Background
Depression may precede or follow symptomatic parkinsonism in PD. It is frequently treatable but often overlooked.
Methods
The clinical series comprised 685 individuals who were diagnosed with PD and followed by one neurologist (RJU) from 1994 to 2007. The primary outcome was time to depression following the onset of PD. Diagnosis of depression was based on clinical assessment of depressive symptoms from patients (and spouse/family/caregiver) and antidepressant usage. A number of demographic, historical and clinical predictive factors were examined, including gender, age at symptomatic onset, disease duration, onset characteristics, clinical ratings, antiparkinsonian medications, cognitive status, depression history, and familial history of PD and other neurodegenerative disorders.
Results
Seventy-two percent of patients developed depression within ten years of symptomatic PD onset, and the mean time to depression was 7.9 years (median: 5.7 years). Factors associated with depression included longer PD duration, greater impairment in activities of daily living, and positive family history of motor neuron disease (MND).
Conclusions
A high rate of individuals with PD develop depressive symptoms during the course of the disease. Based on first clinic visit characteristics, most factors examined were not helpful in identifying individuals with an increased risk of depression. However, disease duration, functional limitations and family history of MND should lead clinicians to an increased vigilance for identifying depression.
PMCID: PMC3907778  PMID: 20169775
4.  Clinicopathologic variability of the GRN A9D mutation, including amyotrophic lateral sclerosis 
Neurology  2013;80(19):1771-1777.
Objective:
We examined the clinical and pathologic phenotypes of GRN mutation carriers with the pathogenic A9D (g.26C>A) missense mutation.
Methods:
Three patients with GRN A9D mutations were evaluated clinically and came to autopsy with subsequent neuropathologic examination.
Results:
The clinical diagnoses of patients with GRN A9D mutations were amyotrophic lateral sclerosis, atypical extrapyramidal disorder, and behavioral variant frontotemporal dementia. Immunohistochemistry for TAR DNA-binding protein 43 (TDP-43) revealed variability in morphology and distribution of pathology. One patient had notable involvement of motor neurons in the spinal cord as well as type B TDP-43, whereas 2 other patients had type A TDP-43.
Conclusions:
The clinical presentation of the GRN A9D missense mutation is not restricted to behavioral variant frontotemporal dementia and may include aphasia, extrapyramidal features, and, notably, amyotrophic lateral sclerosis.
doi:10.1212/WNL.0b013e3182919059
PMCID: PMC3719429  PMID: 23596077
5.  A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia 
Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia.
doi:10.1002/mgg3.67
PMCID: PMC4049367  PMID: 24936516
Dystonia; DYT6; intronic variant; minigene assay; THAP1
6.  TARDBP mutations in Parkinson’s disease 
Parkinsonism & related disorders  2012;19(3):312-315.
Mutations of the TARDBP gene encoding TDP-43 protein have been shown to cause amyotrophic lateral sclerosis and have been reported to present with clinical heterogeneity including parkinsonism. In addition, TDP-43 pathology has been observed across a spectrum of neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Herein we report the presence of a TDP-43 mutation in a patient with a clinical diagnosis of Parkinson’s disease. The TDP-43 p.N267S substitution has been previously implicated in both amyotrophic lateral sclerosis and behavioral variant frontotemporal dementia. Our findings widen the phenotypic presentation for the TDP-43 p.N267S substitution and support a possible role for rare TDP-43 mutations presenting with Parkinson’s disease.
doi:10.1016/j.parkreldis.2012.11.003
PMCID: PMC3582838  PMID: 23231971
TDP-43; amyotrophic lateral sclerosis; Parkinson’s disease
7.  LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease 
Neurogenetics  2010;11(4):401-408.
Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n=95; PD, n=96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n=1,247; PD, n=633) and controls (n=642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR)=0.63; P=0.026) and PD (OR=0.54; P=0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P<0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P<0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.
doi:10.1007/s10048-010-0241-x
PMCID: PMC3930084  PMID: 20369371
Essential tremor; Parkinson disease; LINGO1; LINGO2; Genetic association
8.  Analysis of the C9orf72 repeat in Parkinson’s disease, essential tremor and restless legs syndrome 
Parkinsonism & related disorders  2012;19(2):198-201.
The hexanucleotide expanded repeat (GGGGCC) in intron 1 of the C9orf72 gene is recognized as the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, as part of the clinical phenotype, some patients present with parkinsonism. The present study investigated the potential expansion or association of the C9orf72 repeat length with susceptibility to Parkinson’s disease and related disorders, essential tremor and restless legs syndrome. One restless legs syndrome patient was shown to harbor a repeat expansion, however on clinical follow-up this patient was observed to have developed frontotemporal dementia. There was no evidence of association of repeat length on disease risk or age-at-onset for any of the three disorders. Therefore the C9orf72 hexanucleotide repeat expansion appears to be specific to TDP-43 driven amyotrophic lateral sclerosis and dementia.
doi:10.1016/j.parkreldis.2012.09.013
PMCID: PMC3570692  PMID: 23084342
C9orf72; expanded repeat; PD; ET; RLS; genetic association
9.  Anatomy of Disturbed Sleep in Pallido-Ponto-Nigral Degeneration 
Annals of neurology  2011;69(6):1014-1025.
Objective
Pallido-ponto-nigral degeneration (PPND), caused by an N279K mutation of the MAPT gene, is 1 of a family of disorders collectively referred to as frontotemporal dementia and parkinsonism linked to chromosome 17. This study aims to characterize the nature of the sleep disturbance in PPND and compare these findings to those in other progressive neurological illnesses. Pathological findings are also provided.
Methods
Ten subjects were recruited from the PPND kindred; 5 affected and 5 unaffected. The subjects underwent clinical assessment, polysomnography, and wrist actigraphy. Available sleep-relevant areas (pedunculopontine/laterodorsal tegmentum, nucleus basalis of Meynert, thalamus, and locus ceruleus) of affected subjects were analyzed postmortem.
Results
The affected group's total sleep time was an average of 130.8 minutes compared to 403.6 minutes in the control group (p < 0.01). Initial sleep latency was significantly longer in affected subjects (range, 58–260 minutes vs 3–34 minutes). Affected subjects also had an increase in stage I sleep (8.5% vs 1%), and less stage III/IV sleep (8.5% vs 17%). At the time of autopsy, all cases had severe neuronal tau pathology in wake-promoting nuclei, as well as decreases in thalamic cholinergic innervations. There was no difference in orexinergic fiber density in nucleus basalis of Meynert or locus ceruleus compared to controls.
Interpretation
The PPND kindred showed severe sleep disturbance. Sleep abnormalities are common in neurodegenerative illnesses, but this is the first study of sleep disorders in PPND. Unlike most neurodegenerative conditions, PPND is characterized by decreased total sleep time, increased sleep latency, and decreased sleep efficiency, without daytime hypersomnolence.
doi:10.1002/ana.22340
PMCID: PMC3905604  PMID: 21681797
10.  Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype 
Neurobiology of aging  2012;33(12):2950.e5-2950.e7.
Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers.
doi:10.1016/j.neurobiolaging.2012.07.005
PMCID: PMC3617405  PMID: 22840558
Amyotrophic lateral sclerosis; Frontotemporal Dementia; C9ORF72; Repeat-expansion disease; Association study
11.  GWAS risk factors in Parkinson’s disease: LRRK2 coding variation and genetic interaction with PARK16  
Parkinson’s disease (PD) is a multifactorial movement disorder characterized by progressive neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown. GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk within the associated loci and the interactions between them must be identified to fully comprehend their impact on the development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in our series of 1381 patients with PD and 1328 controls. BST1, SNCA, HLA-DRA, CCDC62/HIP1R and MAPT all showed a significant association with PD under different models of inheritance and LRRK2 showed a suggestive association. We then examined the role of coding LRRK2 variants in the GWAS association signal for that gene. The previously identified LRRK2 risk mutant p.M1646T and protective haplotype p.N551K-R1398H-K1423K did not explain the association signal of LRRK2 in our series. Finally, we investigated the gene-gene interaction between PARK16 and LRRK2 that has previously been proposed. We observed no interaction between PARK16 and LRRK2 GWAS variants, but did observe a non-significant trend toward interaction between PARK16 and LRRK2 variants within the protective haplotype. Identification of causal variants and the interactions between them is the crucial next step in making biological sense of the massive amount of data generated by GWAS studies. Future studies combining larger sample sizes will undoubtedly shed light on the complex molecular interplay leading to the development of PD.
PMCID: PMC3852568  PMID: 24319646
Association studies in genetics; Parkinson’s disease/Parkinsonism
12.  Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases 
Coppola, Giovanni | Chinnathambi, Subashchandrabose | Lee, Jason JiYong | Dombroski, Beth A. | Baker, Matt C. | Soto-Ortolaza, Alexandra I. | Lee, Suzee E. | Klein, Eric | Huang, Alden Y. | Sears, Renee | Lane, Jessica R. | Karydas, Anna M. | Kenet, Robert O. | Biernat, Jacek | Wang, Li-San | Cotman, Carl W. | DeCarli, Charles S. | Levey, Allan I. | Ringman, John M. | Mendez, Mario F. | Chui, Helena C. | Le Ber, Isabelle | Brice, Alexis | Lupton, Michelle K. | Preza, Elisavet | Lovestone, Simon | Powell, John | Graff-Radford, Neill | Petersen, Ronald C. | Boeve, Bradley F. | Lippa, Carol F. | Bigio, Eileen H. | Mackenzie, Ian | Finger, Elizabeth | Kertesz, Andrew | Caselli, Richard J. | Gearing, Marla | Juncos, Jorge L. | Ghetti, Bernardino | Spina, Salvatore | Bordelon, Yvette M. | Tourtellotte, Wallace W. | Frosch, Matthew P. | Vonsattel, Jean Paul G. | Zarow, Chris | Beach, Thomas G. | Albin, Roger L. | Lieberman, Andrew P. | Lee, Virginia M. | Trojanowski, John Q. | Van Deerlin, Vivianna M. | Bird, Thomas D. | Galasko, Douglas R. | Masliah, Eliezer | White, Charles L. | Troncoso, Juan C. | Hannequin, Didier | Boxer, Adam L. | Geschwind, Michael D. | Kumar, Satish | Mandelkow, Eva-Maria | Wszolek, Zbigniew K. | Uitti, Ryan J. | Dickson, Dennis W. | Haines, Jonathan L. | Mayeux, Richard | Pericak-Vance, Margaret A. | Farrer, Lindsay A. | Ross, Owen A. | Rademakers, Rosa | Schellenberg, Gerard D. | Miller, Bruce L. | Mandelkow, Eckhard | Geschwind, Daniel H.
Human Molecular Genetics  2012;21(15):3500-3512.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
doi:10.1093/hmg/dds161
PMCID: PMC3392107  PMID: 22556362
13.  TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease 
Background
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
Results
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Conclusions
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
doi:10.1186/1750-1326-8-19
PMCID: PMC3691612  PMID: 23800361
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
14.  Genetic variants of α-synuclein are not associated with essential tremor 
Background
Given the overlap between Parkinson disease and essential tremor, we examined genetic variants in α-synuclein (SNCA) as risk determinants for essential tremor.
Methods
Samples from 661 essential tremor subjects and 1,316 control subjects from four participating North American sites were included in this study. Parkinson disease samples (n=427) were compared against controls for two cohorts. Twenty variants were selected for association analysis within the SNCA locus. Individual logistic regression analyses against essential tremor diagnosis and then combined using meta-analysis was run for each variant.
Results
Our results do not show a significant association between variants in the SNCA locus and risk of essential tremor, while the established association of SNCA variants with Parkinson disease risk was observed.
Conclusions
While genetic factors are likely to play a large role in essential tremor pathogenesis our results do not support a role for common SNCA genetic variants in risk for essential tremor.
doi:10.1002/mds.23909
PMCID: PMC3677575  PMID: 22025277
tremor; essential tremor; association studies in genetics; Parkinson’s disease; parkinsonism; synuclein
15.  Angiogenin variation and Parkinson’s disease 
Annals of Neurology  2012;71(5):725-727.
doi:10.1002/ana.23586
PMCID: PMC3335436  PMID: 22522484
PD; ANG; genetic association; mutation
16.  DJ-1 and αSYN in LRRK2 CSF do not correlate with striatal dopaminergic function 
Neurobiology of Aging  2011;33(4):836.e5-836.e7.
Previous studies demonstrated decreased levels of DJ-1 and α-synuclein (αSYN) in human cerebrospinal fluid (CSF) in patients with Parkinson’s disease (PD), but neither marker correlated with PD severity, raising the possibility that they may be excellent progression markers during early or preclinical phases of PD. Individuals carrying the leucine-rich repeat kinase 2 (LRRK2) gene mutation are at increased risk for PD, and the phenotype of LRRK2 patients is almost identical to sporadic PD. To determine whether dopaminergic dysfunction in the basal ganglia, as determined by positron emission tomography (PET) scans, correlates with CSF levels of DJ-1 and αSYN during preclinical stages, Luminex assays were used to analyze CSF samples from asymptomatic LRRK2 mutation carriers, along with carriers who presented with a clinical diagnosis of PD. The data revealed no statistically significant relationship between PET scan evidence of loss of striatal dopaminergic function and the CSF biomarkers DJ-1 and αSYN, except for a weak correlation between DJ-1 and MP binding, suggesting that the use of these potential biomarkers on their own to screen LRRK2 gene mutation carriers for PD is not appropriate.
doi:10.1016/j.neurobiolaging.2011.09.015
PMCID: PMC3279603  PMID: 22019052
Parkinson’s Disease; LRRK2; gene mutation; biomarker; DJ-1; α-synuclein
17.  Mutations in CIZ1 cause adult-onset primary cervical dystonia 
Annals of Neurology  2012;71(4):458-469.
Objective
Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult-onset, primary cervical dystonia.
Methods
Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult-onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult-onset cervical dystonia and matching controls for sequence variants in this mutant gene.
Results
Exome sequencing led to the identification of an exonic splicing enhancer mutation in Exon 7 of CIZ1 (c.790A>G, p.S264G) which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21Cip1/Waf1-interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified two additional CIZ1 missense mutations (p.P47S and p.R672M).
Interpretation
Mutations in CIZ1 may cause adult-onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system.
doi:10.1002/ana.23547
PMCID: PMC3334472  PMID: 22447717
18.  Pathogenicity of exonic indels in fused in sarcoma in amyotrophic lateral sclerosis 
Neurobiology of aging  2010;33(2):424.e23-424.e24.
Insertion and deletion variants (indels) within poly glycine tracts of fused in sarcoma (FUS) were initially reported as causative of disease in amyotrophic lateral sclerosis (ALS). Subsequent studies identified similar indels in controls and suggested that these indels may confer susceptibility to ALS. We aimed to elucidate the role of previously published and novel exonic indels in FUS in an extensive cohort of 630 ALS patients and 1063 controls. We detected indels in FUS exons 5, 6, 12 and 14 with similar frequencies in patients (0.95%) and controls (0.75%). Exonic indels in poly glycine tracts were also observed with similar frequencies. The largest indel (p.Gly138_Tyr143del) was observed in one control. In one patient, a 3 base pair deletion in exon 14 (p.Gly475del) was identified, however in-vitro studies did not reveal abnormal localization of p.Gly475del mutant FUS. These findings suggest that not all exonic indels in FUS cause disease.
doi:10.1016/j.neurobiolaging.2010.09.029
PMCID: PMC3130814  PMID: 21074900
19.  Familial Parkinson's disease iPSCs show cellular deficits in mitochondrial responses that can be pharmacologically rescued 
Science translational medicine  2012;4(141):141ra90.
Parkinson's disease (PD) is a common neurodegenerative disease caused by genetic and environmental factors. We analyzed induced pluripotent stem cell (iPSC)-derived neural cells from PD patients and presymptomatic individuals carrying mutations in the PINK1 and LRRK2 genes, and healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial function in iPSC-derived neural cells from PD patients and at-risk individuals could be rescued with coenzyme Q10, rapamycin or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insights into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in PD.
doi:10.1126/scitranslmed.3003985
PMCID: PMC3462009  PMID: 22764206
20.  A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants 
Journal of Medical Genetics  2012;49(11):721-726.
Background
Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.
Methods and results
We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.
Conclusions
Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.
doi:10.1136/jmedgenet-2012-101155
PMCID: PMC3488700  PMID: 23125461
Parkinson-s disease; Genome-wide; Genetics; Genetic epidemiology; Complex traits
21.  Neuropathological features of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome 
Brain  2011;134(11):3264-3275.
Patients with corticobasal degeneration can present with several different clinical syndromes, making ante-mortem diagnosis a challenge. Corticobasal syndrome is the clinical phenotype originally described for corticobasal degeneration, characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus. Some patients do not develop these features, but instead have clinical features consistent with the Richardson syndrome presentation of progressive supranuclear palsy, characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia. The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical and neuropathological features. Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15). Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, while those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures. Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioural dysfunction. The results suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration. Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.
doi:10.1093/brain/awr234
PMCID: PMC3212714  PMID: 21933807
pathology; immunocytochemistry; progressive supranuclear palsy; tau protein; corticobasal degeneration
22.  LRRK2 exonic variants and susceptibility to Parkinson’s disease 
Lancet neurology  2011;10(10):898-908.
Background
Leucine-rich repeat kinase 2 (LRRK2) is known to harbor highly penetrant mutations linked to familial parkinsonism. However, its full polymorphic variability in relationship to Parkinson’s disease (PD) risk has not been systematically assessed.
Methods
We examined the frequency pathogenicity of 121 exonic LRRK2 variants in three ethnic series (Caucasian [N=12,590], Asian [N=2,338] and Arab-Berber [N=612]) consisting of 8,611 patients and 6,929 control subjects from 23 separate sites of the Genetic Epidemiology of Parkinson’s Disease Consortium.
Findings
Excluding carriers of previously known pathogenic mutations, new independent risk associations were found for polymorphic variants in Caucasian (p.M1646T, OR: 1.43, 95% CI: 1.15 – 1.78, P=0.0012) and Asian (p.A419V, OR: 2.27, 95% CI: 1.35 – 3.83, P=0.0011) populations. In addition, a protective haplotype was observed at >5% frequency (p.N551K-p.R1398H-p.K1423K) in the Caucasian and Asian series’, with a similar finding in the small Arab-Berber series that requires further study (combined 3-series OR: 0.82, 95% CI: 0.72 – 0.94, P=0.0043). Of the two previously reported Asian risk variants p.G2385R was found to be associated with disease (OR: 1.73, 95% CI: 1.20 – 2.49, P=0.0026) but no association was observed for p.R1628P (OR: 0.62, 95% CI: 0.36 – 1.07, P=0.087). Also in the Arab-Berber series, p.Y2189C showed potential evidence of risk association with PD (OR: 4.48, 95% CI: 1.33 – 15.09, P=0.012). Of note, two variants (p.I1371V and p.T2356I) which have been previously proposed as pathogenic were observed in patient and control subjects at the same frequency.
Interpretation
LRRK2 offers an example where multiple rare and common genetic variants in the same gene have independent effects on disease risk. Lrrk2, and the pathway in which it functions, is important in the etiology and pathogenesis of a greater proportion of patients with PD than previously believed.
Funding
The present study and original funding for the GEO-PD Consortium was supported by grants from Michael J. Fox Foundation. Studies at individual sites were supported by a number of funding agencies world-wide.
doi:10.1016/S1474-4422(11)70175-2
PMCID: PMC3208320  PMID: 21885347
Parkinson disease; LRRK2; genetics
23.  Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research 
PLoS ONE  2012;7(8):e43099.
Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
doi:10.1371/journal.pone.0043099
PMCID: PMC3428297  PMID: 22952635
24.  Ataxin-2 repeat-length variation and neurodegeneration 
Human Molecular Genetics  2011;20(16):3207-3212.
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31–33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
doi:10.1093/hmg/ddr227
PMCID: PMC3140823  PMID: 21610160
25.  Evaluation of the Role of SNCA Variants in Survival without Neurological Disease 
PLoS ONE  2012;7(8):e42877.
Background
A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability, or preservation of high physical and cognitive function. Many behavioral, biomedical, and psychological factors have been linked with these various measures of successful aging, however genetic predictors are less understood. Parkinson's disease (PD) is an age-related neurodegenerative disorder, and variants in the α-synuclein gene (SNCA) affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease.
Methods
We utilized 769 controls without neurological disease (Mean age: 79 years, Range: 33–99 years) and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk.
Results
There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021), from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025). A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD.
Conclusions
In addition to its documented roles in PD and α-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.
doi:10.1371/journal.pone.0042877
PMCID: PMC3418246  PMID: 22912757

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