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BACKGROUND: Severe QT prolongation (SQTP) has been identified as a strong predictor of adverse cardiovascular events in acute drug overdose, but drug-specific causes of SQTP in the setting of acute drug overdose remain unclear. We aimed to perform the most definitive study to date describing drug-specific risk of SQTP following acute drug overdose. METHODS: This was a prospective multicenter cohort study at >50 hospital sites across the U.S. using the ToxIC Registry between 2015–18. Inclusion criteria were adults (≥18 years) receiving medical toxicology consultation for acute drug overdose. The primary outcome was SQTP, which was defined using the computer automated Bazett QT correction (QTc) on the ECG with the previously validated cut point of 500 milliseconds. Mean difference in QTc was also calculated for specific drugs. Drugs associated with SQTP were analyzed using multivariable logistic regression to control for known confounders of QT risk (age, sex, race, cardiac disease). RESULTS: From 25,303 patients screened, 6,473 met inclusion criteria with SQTP occurring in 825 (13%). Drugs associated with increased adjusted odds of SQTP included Class III antidysrhythmics (sotalol), sodium channel blockers (amitriptyline, diphenhydramine, doxepin, imipramine, nortriptyline), antidepressants (bupropion, citalopram, escitalopram, trazodone), antipsychotics (haloperidol, quetiapine), and the antiemetic serotonin antagonist ondansetron. CONCLUSIONS: This large U.S. cohort describes drug-specific risk of SQTP following acute drug overdose. Healthcare providers caring for acute drug overdoses from any of these implicated drugs should pay close attention to cardiac monitoring for occurrence of SQTP.

SUMMARY The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog cindr enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function., In Brief CD2AP is an Alzheimer’s disease susceptibility gene with uncertain brain function. Ojelade et al. discover that mutation of the Drosophila homolog cindr disrupts ubiquitin-proteasome system activity, causing calcium dyshomeostasis and impaired synaptic vesicle recycling and release. Cd2ap null mice and human brain proteomic studies support a conserved role in synaptic proteostasis., Graphical Abstract

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

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. National Foundation for Alzheimer's disease and related disorders Institut Pasteur de Lille Centre National de Genotypage Inserm FRC (fondation pour la recherche sur le cerveau) Rotary LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) MEDIALZ Project - ERDF (European Regional Development Fund) 11001003 Conseil Regional Nord Pas de Calais Fondation pour la Recherche Medicale Caisse Nationale Maladie des Travailleurs Salaries Direction Generale de la Sante MGEN Institut de la Longevite Agence Francaise de Securite Sanitaire des Produits de Sante Aquitaine and Bourgogne Regional Councils Fondation de France joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program Eisai Wellcome Trust British Heart Foundation Chief Scientist Office of the Scottish Executive NIA N01-AG-12100 National Heart, Lung and Blood Institute Contracts HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C R01HL70825 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute U01HG004402 NIH Roadmap for Medical Research Austrian Science Fond (FWF) P20545-P05 P13180 Intramural Research Program of the NIH, National Institute on Aging NHLBI HHSN268201200036C HHSN268200800007C N01HC55222 N01HC85079 N01HC85080 N01HC85081 N01HC85082 N01HC85083 N01HC850863 U01HL080295 R01HL087652 R01HL105756 R01HL103612 R01HL120393 National Institute of Neurological Disorders and Stroke (NINDS) National Institute on Aging (NIA) R01AG023629 R01AG15928 R01AG20098 R01AG027058 National Center for Advancing Translational Sciences CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) DK063491 Medical Research Council (UK) European Commission Framework 6 project EUROSPAN LSHG-CT-2006-018947 Republic of Croatia Ministry of Science, Education and Sports 108-1080315-0302 Netherlands Organization for Scientific Research (NWO) Internationale Stichting Alzheimer Onderzoek (ISAO) Hersenstichting Nederland (HSN) Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) Russian Foundation for Basic Research (RFBR) National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 U01 HL096917 R01 HL093029 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Neurological Disorders and Stroke NS17950 National Institute of Aging U01 AG049505 AG033193 AG008122 AG16495 Agence National de la Recherche Leducq Foundation National Heart, Lung and Blood Institute HL054464 HL054457 HL054481 HL071917 HL87660 HL043851 HL080467 National Institute of Neurological Disorders and Stroke of the National Institutes of Health NS041558 Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 Scottish Funding Council HR03006 Academy of Finland Finnish Diabetes Research Society Folkhalsan Research Foundation Novo Nordisk Foundation Finska Lakaresallskapet Signe and Ane Gyllenberg Foundation University of Helsinki Ministry of Education Ahokas Foundation Emil Aaltonen Foundation Juho Vainio Foundation Wellcome Trust WT089062 University of Newcastle's Strategic Initiative Fund Vincent Fairfax Family Foundation Hunter Medical Research Institute Italian Ministry of Health ICS 110.1RS97.71 US National Institute on Aging N01[AG]916413 N01[AG]821336 263 MD 9164 13 263 MD 821336 Intramural Research Program, National Institute on Aging, National Institutes of Health BBSRC Royal Society Chief Scientist Office of the Scottish Government Research Into Ageing UK Biotechnology and Biological Sciences Research Council (BBSRC) Engineering and Physical Sciences Research Council (EPSRC) Economic and Social Research Council (ESRC) MRC NHMRC 401184 Australian National Health & Medical Research Council 350833 568969 Capacity Building Grant 568940 NHMRC Project 525453 National Institutes of Health CA87969 CA49449 HL34594 U01HG004399 DK058845 CA65725 CA67262 CA50385 5UO1CA098233 EY09611 EY015473 HG004728 HL35464 CA55075 CA134958 DK070756 MRC Human Genetics Unit Arthritis Research UK European Union LSHG-CT-2006-018947 Bristol-Myers Squibb Netherlands Heart Foundation 2001 D 032 European commission 223004 Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) 050-060-810 Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission 49 (DG XII) Municipality of Rotterdam ZonMW Veni Grant 916.13.054 NIA Grants P30AG10161 R01AG15819 R01AG17917 R01AG30146 K08AG34290 K25AG41906 Federal Ministry of Education and Research 01ZZ9603 01ZZ0103 01ZZ0403 Ministry of Cultural Affairs Social Ministry of the Federal State of Mecklenburg-West Pomerania National Cancer Institute CA047988 Donald W Reynolds Foundation Fondation Leducq Amgen info:eu-repo/grantAgreement/EC/FP7/223004

Aims/hypothesis MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes. Methods Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic). Results We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3–5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p = 1.6 × 10−5). HNF1A showed the strongest enrichment of class 3–5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5. Conclusions/interpretation This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.

Heart transplantation in adults with congenital heart disease (CHD) has historically been associated with sub-optimal survival compared with other indications for transplantation. The purpose of this study was to evaluate survival outcomes after heart transplantation in a contemporary cohort of adults with CHD and to identify risk factors for mortality that may help guide recipient and donor selection.We performed a retrospective analysis of our adult heart transplant database, from January 2001 to February 2011, identifying 19 patients who underwent transplantation for CHD. These patients were compared with a control group of 428 patients who underwent transplantation for indications other than CHD. Kaplan-Meier survival analysis and Cox regression modeling were performed.The mean age for the CHD group was 39.4 ± 13 years vs 54.7 ± 12 years (p0.001). There was no significant difference in survival (CHD vs control) at 30 days (89% vs 92%, p = 0.5567), 1 year (84% vs 86%, p = 0.6976) or 5 years (70% vs 72%, p = 0.8478). The only significant predictor of death in the CHD group was donor organ ischemic time4 hours (HR 13.26, 95% CI 1.3 to 132.2, p = 0.028). There was no significant correlation with recipient age, history of failed Fontan surgery, pre-operative ventilator use, donor:recipient weight ratio0.8, donor:recipient CMV mismatch, model for end-stage liver disease (MELD) score or percent reactive antibody10%.In the modern era, with careful donor and recipient selection, adults with CHD have excellent early and mid-term survival after heart transplantation, rivaling that of recipients with other indications for transplantation.

SummaryCerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer’s disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10−9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10−8 and p = 3.22 × 10−9 for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10−8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10−4, 0.039, 4.86 × 10−5, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.

Background: Recent genetic studies of stroke and related risk factors have identified a growing number of susceptibility loci; however, the relationship of these alleles to ischemic stroke is unknown. The challenge in finding reproducible loci of ischemic stroke susceptibility may be in part related to the etiologic heterogeneity in clinically defined stroke subtypes. In this study, we tested whether known single nucleotide polymorphisms (SNPs) associated with stroke or putative stroke risk factors are associated with neuropathologically defined micro- or macroscopic infarcts and with arteriolosclerosis. Methods: Measures of neuropathology and genotyping were available from 755 deceased participants from the Religious Orders Study and the Rush Memory and Aging Project. All donated brains were examined by a board-certified neuropathologist using standardized protocol for the presence of microscopic infarct, macroscopic infarct and arteriolosclerosis (lipohyalinosis). In primary analysis, 74 candidate SNPs previously associated (p < 5 × 10-8) with ischemic stroke or known risk factors, including atrial fibrillation (AF), hypertension, diabetes, low-density lipoprotein (LDL) level and carotid artery stenosis, were evaluated for association with neuropathologic endpoints. We performed a secondary exploratory analysis to include 93 additional SNPs associated with putative ischemic stroke risk factors including SNPs associated with high-density lipoprotein (HDL), triglyceride serum levels, myocardial infarction (MI), coronary artery disease and cerebral white matter disease. Regression models relating SNPs to cerebrovascular neuropathology were adjusted for age at death, gender and cohort membership. Results: The strongest associations seen for both macroscopic and microscopic infarcts were risk variants associated with diabetes. The diabetes risk variant rs7578326 located near the IRS1 locus was associated with both macroscopic (OR = 0.73, p = 0.011) and microscopic (OR = 0.71, p = 0.009) infarct pathology. Another diabetes susceptibility locus (rs12779790) located between the calcium/calmodulin-dependent protein kinase ID (CAMK1D) and cell division cycle 123 homolog (CDC123) genes is also associated with both macroscopic (OR = 1.40, p = 0.0292) and microscopic infarcts (OR = 1.43, p = 0.0285). The diabetes risk variant rs864745 within JAZF1 was associated with arteriolosclerosis (OR = 0.80, p = 0.014). We observed suggestive associations with the diabetes risk variant rs7961581 (p = 0.038; between TSPAN8 and LGR5) and rs5215 (p = 0.043; KCNJ11), the LDL risk variant rs11206510 (p = 0.045; PCSK9), as well as the AF risk locus ZFHX3. The CDKN2A/B locus (rs2383207, 9p21), identified initially as a susceptibility allele for MI and recently implicated in large vessel stroke, was associated with macroscopic infarct pathology in our autopsy cohort (OR = 1.26, p = 0.031). Conclusion: Our results suggest replication of the candidate CDKN2A/B stroke susceptibility locus with directly measured macroscopic stroke neuropathology, and further implicate several diabetes and other risk variants with secondary, pleiotropic associations to stroke-related pathology in our autopsy cohort. When coupled with larger sample sizes, cerebrovascular neuropathologic phenotypes will likely be powerful tools for the genetic dissection of susceptibility for ischemic stroke.

Previous work has showed that nigral neuron density is related to the severity of parkinsonism proximate to death in older persons without a clinical diagnosis of Parkinson's disease (PD). We tested the hypothesis that neuron density in other brain stem aminergic nuclei is also related to the severity of parkinsonism. We studied brain autopsies from 125 deceased older adults without PD enrolled in the Memory and Aging Project, a clinicopathologic investigation. Parkinsonism was assessed with a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). We measured neuron density in the substantia nigra, ventral tegmental area, locus coeruleus, and dorsal raphe, along with postmortem indices of Lewy body disease, Alzheimer's disease and cerebrovascular pathologies. Mean age at death was 88.0 years, and global parkinsonism was 14.8 (SD, 9.50). In a series of regression models that controlled for demographics and neuron density in the substantia nigra, neuron density in the locus coeruleus (estimate, -0.261; SE, 0.117; P = .028) but not in the ventral tegmental area or dorsal raphe was associated with severity of global parkinsonism proximate to death. These findings were unchanged in models that controlled for postmortem interval, whole-brain weight, and other common neuropathologies including Alzheimer's disease and Lewy body pathology and cerebrovascular vascular pathologies. In older adults without a clinical diagnosis of PD, neuron density in locus coeruleus nuclei is associated with the severity of parkinsonism and may contribute to late-life motor impairments.

Cerebral amyloid angiopathy (CAA) related intracerebral hemorrhage (ICH) is a devastating form of stroke with no known therapies. Clinical, neuropathological, and genetic studies have suggested both overlap and divergence between the pathogenesis of CAA and the biologically related condition of Alzheimer's disease (AD). Among the genetic loci associated with AD are APOE and TOMM40, a gene in close proximity to APOE. We investigate here whether variants within TOMM40 are associated with CAA-related ICH and CAA neuropathology. Using cohorts from the Massachusetts General Hospital (MGH) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), we designed a comparative analysis of high-density SNP genotype data for CAA-related ICH and AD. APOE ε4 was associated with CAA-related ICH and AD, while APOE ε2 was protective in AD but a risk factor for CAA. A total of 14 SNPs within TOMM40 were associated with AD (p 0.05 after multiple testing correction), but not CAA-related ICH (all p 0.20); as a result, all AD-associated SNPs within TOMM40 showed heterogeneity of effect in CAA-related ICH (BD p 0.001). Analysis of CAA neuropathology in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), however, found that neuritic plaque, diffuse plaque burden, and vascular amyloid burden associated with all TOMM40 SNPs (p 0.02). These results suggest that alterations in TOMM40 can promote vascular as well as plaque amyloid deposition, but not the full pathogenic pathway leading to CAA-related ICH.

We have leveraged a Drosophila model relevant to Alzheimer disease (AD) for functional screening of findings from a genome-wide scan for loci associated with a quantitative measure of AD pathology in humans. In six of the 15 genomic regions evaluated, we successfully identified a causal gene for the association, on the basis of in vivo interactions with the neurotoxicity of Tau, which forms neurofibrillary tangles in AD. Among the top results, rs10845990 within SLC2A14, encoding a glucose transporter, showed evidence of replication for association with AD pathology, and gain and loss of function in glut1, the Drosophila ortholog, was associated with suppression and enhancement of Tau toxicity, respectively. Our strategy of coupling genome-wide association in humans with functional screening in a model organism is likely to be a powerful approach for gene discovery in AD and other complex genetic disorders.

Planar cell polarity signaling in Drosophila requires the receptor Frizzled and the cytoplasmic proteins Dishevelled and Prickle. From initial, symmetric subcellular distributions in pupal wing cells, Frizzled and Dishevelled become highly enriched at the distal portion of the cell cortex. We describe a Prickle-dependent intercellular feedback loop that generates asymmetric Frizzled and Dishevelled localization. In the absence of Prickle, Frizzled and Dishevelled remain symmetrically distributed. Prickle localizes to the proximal side of pupal wing cells and binds the Dishevelled DEP domain, inhibiting Dishevelled membrane localization and antagonizing Frizzled accumulation. This activity is linked to Frizzled activity on the adjacent cell surface. Prickle therefore functions in a feedback loop that amplifies differences between Frizzled levels on adjacent cell surfaces.

Importance Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. Objective To identify genetic variants contributing to disease risk in familial PD. Design, Setting, and Participants A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. Main Outcomes and Measures Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. Results The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes ( TNK2 and TNR ) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. Conclusions and Relevance TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

In Parkinson disease (PD), dopaminergic neuronal death within the substantia nigra generates characteristic motor manifestations, while synuclein pathology in cortical regions often causes additional symptoms, including cognitive impairment and dementia.1 Therefore, a comprehensive understanding of PD pathogenesis requires the evaluation of cell death mechanisms both within the brainstem and extranigral sites. In the current issue of Neurology ®, Jiang et al.2 begin to reveal the potential molecular pathways responsible for cortical degeneration in PD.

Importance Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored. Objective To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons. Design, Setting, and Participants Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies. Main Outcomes and Measures The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson’s Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss. Results Parkinson disease risk alleles in the MAPT (rs2942168; P = .0006) and CCDC62 (rs12817488; P = .004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson’s Disease Rating Scale subscores, MAPT ( P = .0002) and CCDC62 ( P = .003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P = .005) and gait impairment, SNCA (rs356220; P = .04) and rigidity, and GAK (rs1564282; P = .03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P = .03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies. Conclusions and Relevance In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human tau in the fruit fly Drosophila melanogaster . Transgenic flies showed key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary tangle formation that is seen in human disease and some rodent tauopathy models. This fly model may allow a genetic analysis of the cellular mechanisms underlying tau neurotoxicity.

Importance While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. Objectives To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. Design, Setting, and Participants Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. Main Outcomes and Measures A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. Results Besides the previously reportedAPOEandCR1loci, we found that theABCA7(rs3764650;P = .02) andCD2AP(rs9349407;P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10−6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition. Conclusions and Relevance These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at theAPPlocus in the earliest, presymptomatic stages of AD.

Recent genome-wide association studies have identified a number of susceptibility loci for Alzheimer disease (AD). To understand the functional consequences and potential interactions of the associated loci, we explored large-scale data sets interrogating the human genome for evidence of positive natural selection. Our findings provide significant evidence for signatures of recent positive selection acting on several haplotypes carrying AD susceptibility alleles; interestingly, the genes found in these selected haplotypes can be assembled, independently, into a molecular complex via a protein-protein interaction (PPI) network approach. These results suggest a possible coevolution of genes encoding physically-interacting proteins that underlie AD susceptibility and are coexpressed in different tissues. In particular, PICALM, BIN1, CD2AP, and EPHA1 are interconnected through multiple interacting proteins and appear to have coordinated evidence of selection in the same human population, suggesting that they may be involved in the execution of a shared molecular function. This observation may be AD-specific, as the 12 loci associated with Parkinson disease do not demonstrate excess evidence of natural selection. The context for selection is probably unrelated to AD itself; it is likely that these genes interact in another context, such as in immune cells, where we observe cis-regulatory effects at several of the selected AD loci.

Background We tested the hypothesis that harm avoidance, a trait associated with behavioral inhibition, is associated with the rate of change in parkinsonism in older adults. Methods At baseline harm avoidance was assessed with a standard self-report instrument in 969 older people without dementia participating in the Rush Memory and Aging Project, a longitudinal community-based cohort study. Parkinsonism was assessed annually with a modified version of the motor section of the Unified Parkinson’s Disease Rating Scale (mUPDRS). Results Average follow-up was 5 years. A linear mixed-effects model controlling for age, sex and education showed that for an average participant (female, 80 years old at baseline, with 14 years of education and a harm avoidance score of 10), the overall severity of parkinsonism increased by about 0.05 unit/ year (Estimate, 0.054, S.E., 0.007, p