Publications
250 results found
Vellas B, Scrase D, Rosenberg GA, et al., 2018, WHO Guidelines on Community-Level Interventions to Manage Declines in Intrinsic Capacity: The Road to Prevention Cognitive Decline in Older Age?, JPAD-JOURNAL OF PREVENTION OF ALZHEIMERS DISEASE, Vol: 5, Pages: 165-167, ISSN: 2274-5807
Mansur A, Comley R, Lewis Y, et al., 2018, Imaging of Mitochondrial Complex 1 with <SUP>18</SUP>F-BCPP-EF in the Healthy Human Brain, Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging (SNMMI), Publisher: SOC NUCLEAR MEDICINE INC, ISSN: 0161-5505
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- Citations: 4
Woerman AL, Kazmi SA, Patel S, et al., 2017, MSA prions exhibit remarkable stability and resistance to inactivation., Acta Neuropathologica, Vol: 135, Pages: 49-63, ISSN: 1432-0533
In multiple system atrophy (MSA), progressive neurodegeneration results from the protein α-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human α-synuclein (TgM83(+/-)), inducing neurological disease following intracranial inoculation with brain homogenate from deceased patient samples. Noting the similarities between α-synuclein prions and PrP scrapie (PrP(Sc)) prions responsible for Creutzfeldt-Jakob disease (CJD), we investigated MSA transmission under conditions known to result in PrP(Sc) transmission. When peripherally exposed to MSA via the peritoneal cavity, hind leg muscle, and tongue, TgM83(+/-) mice developed neurological signs accompanied by α-synuclein prions in the brain. Iatrogenic CJD, resulting from PrP(Sc) prion adherence to surgical steel instruments, has been investigated by incubating steel sutures in contaminated brain homogenate before implantation into mouse brain. Mice studied using this model for MSA developed disease, whereas wire incubated in control homogenate had no effect on the animals. Notably, formalin fixation did not inactivate α-synuclein prions. Formalin-fixed MSA patient samples also transmitted disease to TgM83(+/-) mice, even after incubating in fixative for 244 months. Finally, at least 10% sarkosyl was found to be the concentration necessary to partially inactivate MSA prions. These results demonstrate the robustness of α-synuclein prions to denaturation. Moreover, they establish the parallel characteristics between PrP(Sc) and α-synuclein prions, arguing that clinicians should exercise caution when working with materials that might contain α-synuclein prions to prevent disease.
Petrova D, Hurley M, Prokopenko I, et al., 2017, Clinico-neuropathological classification of Parkinson's disease subtypes, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Ikram MA, Bersano A, Manso-Calderon R, et al., 2017, Genetics of vascular dementia - review from the ICVD working group, BMC MEDICINE, Vol: 15, ISSN: 1741-7015
Background:Vascular dementia is a common disorder resulting in considerable morbidity and mortality. Determining the extent to which genes play a role in disease susceptibility and their pathophysiological mechanisms could improve our understanding of vascular dementia, leading to a potential translation of this knowledge to clinical practice.Discussion:In this review, we discuss what is currently known about the genetics of vascular dementia. The identification of causal genes remains limited to monogenic forms of the disease, with findings for sporadic vascular dementia being less robust. However, progress in genetic research on associated phenotypes, such as cerebral small vessel disease, Alzheimer’s disease, and stroke, have the potential to inform on the genetics of vascular dementia. We conclude by providing an overview of future developments in the field and how such work could impact patients and clinicians.Conclusion:The genetic background of vascular dementia is well established for monogenic disorders, but remains relatively obscure for the sporadic form. More work is needed for providing robust findings that might eventually lead to clinical translation.
Woerman AL, Watts JC, Aoyagi A, et al., 2017, α-Synuclein: Multiple System Atrophy Prions., Cold Spring Harbor Perspectives in Medicine, ISSN: 2157-1422
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in oligodendrocytes, where it forms glial cytoplasmic inclusions (GCIs). Several years of studying synthetic α-synuclein fibrils has provided critical insight into the ability of α-synuclein to template endogenous protein misfolding, giving rise to fibrillar structures capable of propagating from cell to cell. However, more recent studies with MSA-derived α-synuclein aggregates have shown that they have a similar ability to undergo template-directed propagation, like PrP prions. Almost 20 years after α-synuclein was discovered as the primary component of GCIs, α-synuclein aggregates isolated from MSA patient samples were shown to infect cultured mammalian cells and also to transmit neurological disease to transgenic mice. These findings argue that α-synuclein becomes a prion in MSA patients. In this review, we discuss the in vitro and in vivo data supporting the recent classification of MSA as a prion disease.
Udeh-Momoh CT, Price G, Su B, et al., 2016, THE CHARIOT COGNITIVE RESERVE COMPOSITE: A CONSTRUCT AND PREDICTIVE VALIDITY STUDY, The 13th International Conference on Alxheimer's and Parkinson's Disease
Perneczky R, Tene O, Attems J, et al., 2016, Is the time ripe for new diagnostic criteria of cognitive impairment due to cerebrovascular disease? Consensus report of the International Congress on Vascular Dementia working group, BMC Medicine, Vol: 14, ISSN: 1741-7015
BACKGROUND: Long before Alzheimer's disease was established as the leading cause of dementia in old age, cerebrovascular lesions were known to cause cognitive deterioration and associated disability. Since the middle of the last century, different diagnostic concepts for vascular dementia and related syndromes were put forward, yet no widely accepted diagnostic consensus exists to date. DISCUSSION: Several international efforts, reviewed herein, are ongoing to define cognitive impairment due to cerebrovascular disease in its different stages and subtypes. The role of biomarkers is also being discussed, including cerebrospinal fluid proteins, structural and functional brain imaging, and genetic markers. The influence of risk factors, such as diet, exercise and different comorbidities, is emphasised by population-based research, and lifestyle changes are considered for the treatment and prevention of dementia. CONCLUSION: To improve the diagnosis and management of vascular cognitive impairment, further progress has to be made in understanding the relevant pathomechanisms, including shared mechanisms with Alzheimer's disease; bringing together fragmented research initiatives in coordinated international programs; testing if known risk factors are modifiable in prospective interventional studies; and defining the pre-dementia and pre-clinical stages in line with the concept of mild cognitive impairment due to Alzheimer's disease.
Bellou V, Belbasis L, Tzoulaki I, et al., 2016, Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses, Alzheimers & Dementia, Vol: 13, Pages: 406-418, ISSN: 1552-5279
INTRODUCTION: Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors. METHODS: We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance. RESULTS: A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease. DISCUSSION: Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.
Guella I, Evans DM, Szu-Tu C, et al., 2016, alpha-synuclein genetic variability: a biomarker for dementia in parkinson disease, Annals of Neurology, Vol: 79, Pages: 991-999, ISSN: 0364-5134
ObjectiveThe relationship between Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB) has long been debated. Although PD is primarily considered a motor disorder, cognitive impairment is often present at diagnosis, and only ∼20% of patients remain cognitively intact in the long term. Alpha-synuclein (SNCA) was first implicated in the pathogenesis of the disease when point mutations and locus multiplications were identified in familial parkinsonism with dementia. In worldwide populations, SNCA genetic variability remains the most reproducible risk factor for idiopathic PD. However, few investigators have looked at SNCA variability in terms of cognitive outcomes.MethodsWe have used targeted high-throughput sequencing to characterize the 135kb SNCA locus in a large multinational cohort of patients with PD, PDD, and DLB and healthy controls.ResultsAn analysis of 43 tagging single nucleotide polymorphisms across the SNCA locus shows 2 distinct association profiles for symptoms of parkinsonism and/or dementia, respectively, toward the 3′ or the 5′ of the SNCA gene. In addition, we define a specific haplotype in intron 4 that is directly associated with PDD. The PDD risk haplotype has been interrogated at single nucleotide resolution and is uniquely tagged by an expanded TTTCn repeat.InterpretationOur data show that PD, PDD, and DLB, rather than a disease continuum, have distinct genetic etiologies albeit within one genomic locus. Such results may serve as prognostic biomarkers to these disorders, to inform physicians and patients, and to assist in the design and stratification of clinical trials aimed at disease modification.
Gallo V, Vanacore N, Bueno-de-Mesquita HB, et al., 2016, Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study, European Journal of Epidemiology, Vol: 31, Pages: 255-266, ISSN: 1573-7284
Previous case–control studies have suggested a possible increased risk of Amyotrophic Lateral Sclerosis (ALS) with physical activity (PA), but this association has never been studied in prospective cohort studies. We therefore assessed the association between PA and risk of death from ALS in the European Prospective Investigation into Cancer and Nutrition. A total of 472,100 individuals were included in the analysis, yielding 219 ALS deaths. At recruitment, information on PA was collected thorough standardised questionnaires. Total PA was expressed by the Cambridge Physical Activity Index (CPAI) and analysed in relation to ALS mortality, using Cox hazard models. Interactions with age, sex, and anthropometric measures were assessed. Total PA was weakly inversely associated with ALS mortality with a borderline statistically significant trend across categories (p = 0.042), with those physically active being 33 % less likely to die from ALS compared to those inactive: HR = 0.67 (95 % CI 0.42–1.06). Anthropometric measures, sex, and age did not modify the association with CPAI. The present study shows a slightly decreased—not increased like in case–control studies—risk of dying from ALS in those with high levels of total PA at enrolment. This association does not appear confounded by age, gender, anthropometry, smoking, and education. Ours was the first prospective cohort study on ALS and physical activity.
Parkkinen L, Haytural H, Guella I, et al., 2016, Alpha-synuclein genetic variability: a biomarker for dementia in Parkinson's disease, 117th Meeting of the British-Neuropathological-Society, Publisher: WILEY-BLACKWELL, Pages: 24-24, ISSN: 0305-1846
Lindqvist D, Prokopenko I, Londos E, et al., 2016, Associations between TOMM40 Poly-T Repeat Variants and Dementia in Cases with Parkinsonism., Journal of Parkinsons Disease, Vol: 6, Pages: 99-108, ISSN: 1877-7171
BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of Parkinson's disease (PD)-related pathologies. OBJECTIVE: To investigate the role of the Translocase of the Outer Mitochondrial Membrane 40 homolog (TOMM40) variants in PD without dementia (PDND), PD with dementia (PDD) and in Dementia with Lewy bodies (DLB). METHODS: 248 individuals, including 92 PDND, 55 PDD, and 101 DLB, were included. The rs10524523 locus in the TOMM40 gene (TOMM40 poly-T repeat) is characterized by a variable number of T residues that were classified into three groups based on length; short (S), long (L), and very long (VL). We tested log-additive genetic model of association with dementia and adjusted for age, sex, and APOEɛ4 carrier status. We analyzed cerebrospinal fluid (CSF) levels of Aβ42 and Tau, biomarkers related to Alzheimer's disease (AD). RESULTS: PDD/DBL status and abnormal CSF AD biomarkers (Aβ42 and Aβ42/Tau ratio) were both associated with the APOEɛ4 allele (p < 0.014) and the L allele of TOMM40 poly-T repeat (p < 0.008). The VL allele was less frequently observed in the PDD/DLB group (p = 0.013). In APOE-ɛ4 adjusted analyses, the relationships between the L and VL alleles and dementia status as well as CSF AD biomarkers were not significant. When adjusting for APOE-ɛ4, however, there were associations between S carrier status and PDD/DLB (p = 0.019) and abnormal CSF levels of Aβ42/Tau ratio (p = 0.037) although these were not significant after adjustment for multiple comparisons. CONCLUSION: Our results do not support the notion that TOMM40 poly-T repeat variants have independent effects on PDD and DLB pathology. This relationship seems to be driven by APOE-ɛ4.
Gauthier S, Albert M, Fox N, et al., 2015, Why has therapy development for dementia failed in the last two decades?, Alzheimers & Dementia, Vol: 12, Pages: 60-64, ISSN: 1552-5279
The success rate of the pharmaceutical research and development (R&D) for dementia drugs has been abysmally low, in the last two decades. Also low has been the number of pipeline drugs in development, compared to other therapy areas. However, the rationale of early terminations has not been reported in the majority of trials. These are key findings of the recently published pharmaceutical pipeline analysis by the UK-based Office of Health Economics (OHE). Our understanding of main challenges include (1) the significant gaps of knowledge in the nosology and complexity of the underpinning biological mechanisms of the commonest, not familial, forms of late onset dementias; (2) low signal-to-noise ratio, notwithstanding the lack of validated biomarkers as entry and/or end-point criteria; (3) recruitment and retention, particularly in the asymptomatic and early disease stages. A number of current and future strategies aimed at ameliorating drug development are outlined and discussed.
Larsen M, Curry L, Mastellos N, et al., 2015, Development of the CHARIOT Research Register for the Prevention of Alzheimer’s Dementia and Other Late Onset Neurodegenerative Diseases, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundIdentifying cognitively healthy people at high risk of developing dementia is an ever-increasing focus. These individuals are essential for inclusion in observational studies into the natural history of the prodromal and early disease stages and for interventional studies aimed at prevention or disease modification. The success of this research is dependent on having access to a well characterised, representative and sufficiently large population of individuals. Access to such a population remains challenging as clinical research has, historically, focussed on patients with dementia referred to secondary and tertiary services. The primary care system in the United Kingdom allows access to a true prodromal population prior to symptoms emerging and specialist referral. We report the development and recruitment rates of the CHARIOT register, a primary care-based recruitment register for research into the prevention of dementia. The CHARIOT register was designed specifically to support recruitment into observational natural history studies of pre-symptomatic or prodromal dementia stages, and primary or secondary prevention pharmaceutical trials or other prevention strategies for dementia and other cognitive problems associated with ageing.MethodsParticipants were recruited through searches of general practice lists across the west and central London regions. Invitations were posted to individuals aged between 60 and 85 years, without a diagnosis of dementia. Upon consent, a minimum data set of demographic and contact details was extracted from the patient’s electronic health record.ResultsTo date, 123 surgeries participated in the register, recruiting a total of 24,509 participants–a response rate of 22.3%. The age, gender and ethnicity profiles of participants closely match that of the overall eligible population. Higher response rates tended to be associated with larger practices (r = 0.34), practices with a larger older population (r = 0.27), le
Ruffmann C, Calboli FC, Bravi I, et al., 2015, Cortical Lewy bodies and Aβ burden are associated with prevalence and timing of dementia in Lewy body diseases., Neuropathology and Applied Neurobiology, Vol: 42, Pages: 436-450, ISSN: 1365-2990
AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: 121 cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aβ plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, p<0.001). The total cortical Aβ plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (p=0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (p=0.02), particularly in the neocortical frontal, parietal, and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aβ plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele. This article is protected by copyright. All rights reserved.
Tran T, Akram A, Mastellos N, et al., 2015, Engaging older individuals with CHARIOT, Cognitive Health in Ageing Register, 1st International Conference of Primary Care & Public Health Medicine
Dementia affects over 850,000 people in the UK (one in three people over the age of 65). Dementia is not an inevitable part of ageing, and the CHARIOT Register aims to facilitate the involvement of elderly people in dementia prevention research. The CHARIOT Register is a research register of cognitively healthy individuals between the ages of 60 and 85 who are interested and willing to participate in future studies in relation to dementia prevention. Recruitment to the CHARIOT Register is primarily conducted through primary care facilities. The CHARIOT register team approaches General Practices (GPs) throughout greater London to seek their cooperation in identifying eligible individuals. Eligible individuals are sent an invitation letter with an information sheet and consent form via post. Upon consenting to join the Register, their details are collected and securely stored in the CHARIOT Register. Participants are then invited to join studies focusing on the prevention of cognitive decline and dementia. The Register currently consists of 25,000+ individuals from 130 GPs. At present, three studies are being conducted with over 1,000 Register participants. In addition to being at the forefront of dementia prevention research, participants also benefit from regular newsletters with up-to-date information on current studies and new research.
Wain LV, Shrine N, Miller S, et al., 2015, Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank, Lancet Respiratory Medicine, Vol: 3, Pages: 769-781, ISSN: 2213-2619
BackgroundUnderstanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health.MethodsWe sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10−8.FindingsUK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50 008 unique samples: 10 002 individuals with low FEV1, 10 000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2·29 × 10−16) and between individuals with and without doctor-diagnosed asthma (p=6·06 × 10−11). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also show
Prusiner SB, Woerman AL, Mordes DA, et al., 2015, Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 112, Pages: E5308-E5317, ISSN: 0027-8424
Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/− mice expressing α-synuclein (A53T). The TgM83+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.
Woerman AL, Stoehr J, Aoyagi A, et al., 2015, Propagation of prions causing synucleinopathies in cultured cells, Proceedings of the National Academy of Sciences of the United States of America, Vol: 112, Pages: E4949-E4958, ISSN: 1091-6490
Increasingly, evidence argues that many neurodegenerative diseases,including progressive supranuclear palsy (PSP), are causedby prions, which are alternatively folded proteins undergoing selfpropagation.In earlier studies, PSP prions were detected byinfecting human embryonic kidney (HEK) cells expressing a taufragment [TauRD(LM)] fused to yellow fluorescent protein (YFP).Here, we report on an improved bioassay using selective precipitationof tau prions from human PSP brain homogenatesbefore infection of the HEK cells. Tau prions were measured bycounting the number of cells with TauRD(LM)–YFP aggregates usingconfocal fluorescence microscopy. In parallel studies, we fusedα-synuclein to YFP to bioassay α-synuclein prions in the brains ofpatients who died of multiple system atrophy (MSA). Previously,MSA prion detection required ∼120 d for transmission into transgenicmice, whereas our cultured cell assay needed only 4 d. Variationin MSA prion levels in four different brain regions fromthree patients provided evidence for three different MSA prionstrains. Attempts to demonstrate α-synuclein prions in brain homogenatesfrom Parkinson’s disease patients were unsuccessful,identifying an important biological difference between the twosynucleinopathies. Partial purification of tau and α-synucleinprions facilitated measuring the levels of these protein pathogensin human brains. Our studies should facilitate investigationsof the pathogenesis of both tau and α-synuclein prion disordersas well as help decipher the basic biology of those prions thatattack the CNS.
Peyrot WJ, Lee SH, Milaneschi Y, et al., 2015, The association between lower educational attainment and depression owing to shared genetic effects? Results in ∼ 25 000 subjects, MOLECULAR PSYCHIATRY, Vol: 20, Pages: 735-743, ISSN: 1359-4184
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- Citations: 45
Maier R, Moser G, Chen G-B, et al., 2015, Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 96, Pages: 283-294, ISSN: 0002-9297
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- Citations: 163
O'Dushlaine C, Rossin L, Lee PH, et al., 2015, Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways, NATURE NEUROSCIENCE, Vol: 18, Pages: 199-209, ISSN: 1097-6256
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- Citations: 536
Gallo V, Brayne C, Forsgren L, et al., 2015, Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study, NEURODEGENERATIVE DISEASES, Vol: 15, Pages: 331-338, ISSN: 1660-2854
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- Citations: 13
Hung C-F, Rivera M, Craddock N, et al., 2014, Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study, BRITISH JOURNAL OF PSYCHIATRY, Vol: 205, Pages: 24-28, ISSN: 0007-1250
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- Citations: 49
Dexter DT, Gveric D, Gentleman S, et al., 2014, Parkinson's UK Tissue Bank: A unique tissue resource for fostering Parkinson's disease research, 18th International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY-BLACKWELL, Pages: S8-S9, ISSN: 0885-3185
Kakkos SK, Nicolaides AN, Charalambous I, et al., 2014, Predictors and clinical significance of progression or regression of asymptomatic carotid stenosis, JOURNAL OF VASCULAR SURGERY, Vol: 59, Pages: 956-+, ISSN: 0741-5214
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- Citations: 112
Votsi C, Zamba-Papanicolaou E, Middleton LT, et al., 2014, A Novel GBA2 Gene Missense Mutation in Spastic Ataxia, ANNALS OF HUMAN GENETICS, Vol: 78, Pages: 13-22, ISSN: 0003-4800
Watts JC, Giles K, Oehler A, et al., 2013, Transmission of multiple system atrophy prions to transgenic mice, Proceedings of the National Academy of Sciences, Vol: 110, Pages: 19555-19560, ISSN: 1091-6490
Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson’s disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83+/+ mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83+/− mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83+/− mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83+/− mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83+/+ mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.
Thorgeirsson TE, Gudbjartsson DF, Sulem P, et al., 2013, A common biological basis of obesity and nicotine addiction, Translational Psychiatry, Vol: 3, ISSN: 2158-3188
Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34 216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10−7). These findings replicate in a second large data set (N=127 274, thereof 76 242 smokers) for both SI (P=1.2 × 10−5) and CPD (P=9.3 × 10−5). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
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