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Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Dewan, Ramita; Chia, Ruth; Ding, Jinhui; Hickman, Richard A; Stein, Thor D; Abramzon, Yevgeniya; Ahmed, Sarah; Sabir, Marya S; Portley, Makayla K; Tucci, Arianna; Ibáñez, Kristina; Shankaracharya, F N U; Keagle, Pamela; Rossi, Giacomina; Caroppo, Paola; Tagliavini, Fabrizio; Waldo, Maria L; Johansson, Per M; Nilsson, Christer F; Rowe, James B; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Jabbari, Edwin; Viollet, Coralie; Glass, Jonathan D; Singleton, Andrew B; Silani, Vincenzo; Ross, Owen A; Ryten, Mina; Torkamani, Ali; Tanaka, Toshiko; Ferrucci, Luigi; Resnick, Susan M; Pickering-Brown, Stuart; Brady, Christopher B; Kowal, Neil; Hardy, John A; Van Deerlin, Vivianna; Vonsattel, Jean Paul; Harms, Matthew B; Morris, Huw R; Ferrari, Raffaele; Landers, John E; Chiò, Adriano; Gibbs, J Raphael; Dalgard, Clifton L; Scholz, Sonja W; Traynor, Bryan J; Adeleye, Adelani; Alba, Camille; Bacikova, Dagmar; Hupalo, Daniel N; Martinez, Elisa McGrath; Pollard, Harvey B; Sukumar, Gauthaman; Soltis, Anthony R; Tuck, Meila; Zhang, Xijun; Wilkerson, Matthew D; Smith, Bradley N; Ticozzi, Nicola; Fallini, Claudia; Gkazi, Athina Soragia; Topp, Simon D; Kost, Jason; Scotter, Emma L; Kenna, Kevin P; Miller, Jack W; Tiloca, Cinzia; Vance, Caroline; Danielson, Eric W; Troakes, Claire; Colombrita, Claudia; Al-Sarraj, Safa; Lewis, Elizabeth A; King, Andrew; Calini, Daniela; Pensato, Viviana; Castellotti, Barbara; de Belleroche, Jacqueline; Baas, Frank; Ten Asbroek, Anneloor L M A; Sapp, Peter C; McKenna-Yasek, Diane; McLaughlin, Russell L; Polak, Meraida; Asress, Seneshaw; Esteban-Pérez, Jesús; Muñoz-Blanco, José Luis; Stevic, Zorica; D'Alfonso, Sandra; Mazzini, Letizia; Comi, Giacomo P; Del Bo, Roberto; Ceroni, Mauro; Gagliardi, Stella; Querin, Giorgia; Bertolin, Cinzia; van Rheenen, Wouter; Diekstra, Frank P; Rademakers, Rosa; van Blitterswijk, Marka; Boylan, Kevin B; Lauria, Giuseppe; Duga, Stefano; Corti, Stefania; Cereda, Cristina; Corrado, Lucia; Sorarù, Gianni; Williams, Kelly L; Nicholson, Garth A; Blair, Ian P; Leblond-Manry, Claire; Rouleau, Guy A; Hardiman, Orla; Morrison, Karen E; Veldink, Jan H; van den Berg, Leonard H; Al-Chalabi, Ammar; Pall, Hardev; Shaw, Pamela J; Turner, Martin R; Talbot, Kevin; Taroni, Franco; García-Redondo, Alberto; Wu, Zheyang; Gellera, Cinzia; Ratti, Antonia; Brown, Robert H Jr; Shaw, Christopher E; Ambrose, John C; Arumugam, Prabhu; Baple, Emma L; Bleda, Marta; Boardman-Pretty, Freya; Boissiere, Jeanne M; Boustred, Christopher R; Brittain, H; Caulfield, Mark J; Chan, Georgia C; Craig, Clare E H; Daugherty, Louise C; de Burca, Anna; Devereau, Andrew; Elgar, Greg; Foulger, Rebecca E; Fowler, Tom; Furió-Tarí, Pedro; Hackett, Joanne M; Halai, Dina; Hamblin, Angela; Henderson, Shirley; Holman, James E; Hubbard, Tim J P; Jackson, Rob; Jones, Louise J; Kasperaviciute, Dalia; Kayikci, Melis; Lahnstein, Lea; Lawson, Kay; Leigh, Sarah E A; Leong, Ivonne U S; Lopez, Javier F; Maleady-Crowe, Fiona; Mason, Joanne; McDonagh, Ellen M; Moutsianas, Loukas; Mueller, Michael; Murugaesu, Nirupa; Need, Anna C; Odhams, Chris A; Patch, Christine; Perez-Gil, Daniel; Polychronopoulos, Dimitris; Pullinger, John; Rahim, Tahrima; Rendon, Augusto; Riesgo-Ferreiro, Pablo; Rogers, Tim; Savage, Kevin; Sawant, Kushmita; Scott, Richard H; Siddiq, Afshan; Sieghart, Alexander; Smedley, Damian; Smith, Katherine R; Sosinsky, Alona; Spooner, William; Stevens, Helen E; Stuckey, Alexander; Sultana, Razvan; Thomas, Ellen R A; Thompson, Simon R; Tregidgo, Carolyn; Walsh, Emma; Watters, Sarah A; Welland, Matthew J; Williams, Eleanor; Witkowska, Katarzyna; Wood, Suzanne M; Zarowiecki, Magdalena; Arepalli, Sampath; Auluck, Pavan; Baloh, Robert H; Bowser, Robert; Brice, Alexis; Broach, James; Camu, William; Chiò, Adriano; Cooper-Knock, John; Corcia, Philippe; Drepper, Carsten; Drory, Vivian E; Dunckley, Travis L; Faghri, Faraz; Farren, Jennifer; Feldman, Eva; Floeter, Mary Kay; Fratta, Pietro; Gerhard, Glenn; Gibson, Summer B; Goutman, Stephen A; Heiman-Patterson, Terry D; Hernandez, Dena G; Hoover, Ben; Jansson, Lilja; Kamel, Freya; Kirby, Janine; Kowall, Neil W; Laaksovirta, Hannu; Landi, Francesco; Le Ber, Isabelle; Lumbroso, Serge; MacGowan, Daniel Jl; Maragakis, Nicholas J; Mora, Gabriele; Mouzat, Kevin; Myllykangas, Liisa; Nalls, Mike A; Orrell, Richard W; Ostrow, Lyle W; Pamphlett, Roger; Pioro, Erik; Pulst, Stefan M; Ravits, John M; Renton, Alan E; Robberecht, Wim; Robey, Ian; Rogaeva, Ekaterina; Rothstein, Jeffrey D; Sendtner, Michael; Shaw, Pamela J; Sidle, Katie C; Simmons, Zachary; Stone, David J; Tienari, Pentti J; Trojanowski, John Q; Troncoso, Juan C; Valori, Miko; Van Damme, Philip; Van Den Bosch, Ludo; Zinman, Lorne; Albani, Diego; Borroni, Barbara; Padovani, Alessandro; Bruni, Amalia; Clarimon, Jordi; Dols-Icardo, Oriol; Illán-Gala, Ignacio; Lleó, Alberto; Danek, Adrian; Galimberti, Daniela; Scarpini, Elio; Serpente, Maria; Graff, Caroline; Chiang, Huei-Hsin; Khoshnood, Behzad; Öijerstedt, Linn; Morris, Christopher M; Nacmias, Benedetta; Sorbi, Sandro; Nielsen, Jorgen E; Hjermind, Lynne E; Novelli, Valeria; Puca, Annibale A; Pastor, Pau; Alvarez, Ignacio; Diez-Fairen, Monica; Aguilar, Miquel; Perneczky, Robert; Diehl-Schimd, Janine; Rogaeva, Ekaterina; Rossi, Mina; Ruiz, Agustin; Boada, Mercè; Hernández, Isabel; Moreno-Grau, Sonia; Schlachetzki, Johannes C; Aarsland, Dag; Alba, Camille; Albert, Marilyn S; Al-Sarraj, Safa; Attems, Johannes; Bacikova, Dagmar; Barrett, Matthew J; Beach, Thomas G; Bekris, Lynn M; Bennett, David A; Besser, Lilah M; Bigio, Eileen H; Black, Sandra E; Boeve, Bradley F; Bohannan, Ryan C; Brett, Francesca; Brice, Alexis; Brunetti, Maura; Caraway, Chad A; Palma, Jose-Alberto; Calvo, Andrea; Canosa, Antonio; Clarimon, Jordi; Dickson, Dennis; Diez-Fairen, Monica; Duyckaerts, Charles; Faber, Kelley; Ferman, Tanis; Flanagan, Margaret E; Floris, Gianluca; Foroud, Tatiana M; Fortea, Juan; Gan-Or, Ziv; Gentleman, Steve; Ghetti, Bernardino; Gibbs, Jesse Raphael; Goate, Alison; Goldstein, David; González-Aramburu, Isabel; Graff-Radford, Neill R; Hodges, Angela K; Hu, Heng-Chen; Hupalo, Daniel; Infante, Jon; Iranzo, Alex; Kaiser, Scott M; Kaufmann, Horacio; Keith, Julia; Kim, Ronald C; Klein, Gregory; Krüger, Rejko; Kukull, Walter; Kuzma, Amanda; Lage, Carmen; Lesage, Suzanne; Lleó, Alberto; Leverenz, James B; Logroscino, Giancarlo; Lopez, Grisel; Love, Seth; Mao, Qinwen; Marti, Maria Jose; Martinez-McGrath, Elisa; Masellis, Mario; Masliah, Eliezer; May, Patrick; McKeith, Ian; Mesulam, Marek-Marsel; Monuki, Edwin S; Morris, Christopher M; Newell, Kathy L; Norcliffe-Kaufmann, Lucy; Palmer, Laura; Pastor, Pau; Perkins, Matthew; Pletnikova, Olga; Molina-Porcel, Laura; Renton, Alan E; Reynolds, Regina H; Rodríguez-Rodríguez, Eloy; Rogaeva, Ekaterina; Rohrer, Jonathan D; Sanchez-Juan, Pascual; Scherzer, Clemens R; Serrano, Geidy E; Shakkottai, Vikram; Sidransky, Ellen; Tayebi, Nahid; Thomas, Alan J; Tilley, Bension S; Troakes, Claire; Troncoso, Juan C; Walton, Ronald L; Woltjer, Randy; Wszolek, Zbigniew K; Xiromerisiou, Georgia; Zecca, Chiara; Phatnani, Hemali; Kwan, Justin; Sareen, Dhruv; Broach, James R; Simmons, Zachary; Arcila-Londono, Ximena; Lee, Edward B; Shneider, Neil A; Fraenkel, Ernest; Ostrow, Lyle W; Baas, Frank; Zaitlen, Noah; Berry, James D; Malaspina, Andrea; Fratta, Pietro; Cox, Gregory A; Thompson, Leslie M; Finkbeiner, Steve; Dardiotis, Efthimios; Miller, Timothy M; Chandran, Siddharthan; Pal, Suvankar; Hornstein, Eran; MacGowan, Daniel J; Heiman-Patterson, Terry; Hammell, Molly G; Patsopoulos, Nikolaos A; Butovsky, Oleg; Dubnau, Joshua; Nath, Avindra; Bowser, Robert; Harms, Matt; Aronica, Eleonora; Poss, Mary; Phillips-Cremins, Jennifer; Crary, John; Atassi, Nazem; Lange, Dale J; Adams, Darius J; Stefanis, Leonidas; Gotkine, Marc; Baloh, Robert H; Babu, Suma; Raj, Towfique; Paganoni, Sabrina; Shalem, Ophir; Smith, Colin; Zhang, Bin; Harris, Brent; Broce, Iris; Drory, Vivian; Ravits, John; McMillan, Corey; Menon, Vilas; Wu, Lani; Altschuler, Steven; Amar, Khaled; Archibald, Neil; Bandmann, Oliver; Capps, Erica; Church, Alistair; Coebergh, Jan; Costantini, Alyssa; Critchley, Peter; Ghosh, Boyd Cp; Hu, Michele T M; Kobylecki, Christopher; Leigh, P Nigel; Mann, Carl; Massey, Luke A; Morris, Huw R; Nath, Uma; Pavese, Nicola; Paviour, Dominic; Sharma, Jagdish; Vaughan, Jenny
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
PMID: 33242422
ISSN: 1097-4199
CID: 5429222

Achieving Wellness: Monitoring the Success and Challenges of the Youth Health Indicator Program for Youth Treated in Outpatient Psychiatric Settings

Radigan, Marleen; Wang, Rui; Calderwood, Christina; Perkins, Matthew B; Lanzara, Carol; Sederer, Lloyd
The youth health indicator (YHI) program was developed to improve health and reduce risk behaviors for youth treated in clinic and day treatment psychiatric settings. This study examined implementation of the YHI program and factors associated with BMI % change for youth participating in the program. Outpatient facilities which implemented the YHI program were surveyed (N = 10) and lessons learned were summarized. Mixed random effects repeated measures analysis was used to examine BMI % trajectory for youth admitted during 2010-2014 with BMI % measured (N = 6403). Treatment settings indicated a variety of strategies to undertake and sustain the YHI program. Factors associated with BMI % change over time were identified. The YHI program resulted in the development of a wide variety of programmatic innovations targeted at improving youth health. Continued work needs to be done to improve the health outcomes for youth in these treatment settings.
PMID: 27600389
ISSN: 1573-6709
CID: 4809752

Access to Care for Youth in a State Mental Health System: A Simulated Patient Approach

Olin, Su-Chin Serene; O'Connor, Briannon C; Storfer-Isser, Amy; Clark, Lisa J; Perkins, Matthew; Hudson Scholle, Sarah; Whitmyre, Emma D; Hoagwood, Kimberly; Horwitz, Sarah McCue
OBJECTIVE: To examine access to psychiatric care for adolescents with depression in outpatient specialty clinics within a state mental health system, using a simulated patient approach. METHOD: Trained callers posed as the mother of a 14-year-old girl with depression, following a script. A stratified random sample (n = 264) of 340 state-licensed outpatient mental health clinics that serve youth was selected. Clinics were randomly assigned to season and insurance condition. We examined whether access varied by season, clinic characteristics, and caller insurance type. Weighted logistic and linear mixed effects regression models were fitted to examine associations with appointment availability and wait times. RESULTS: Among clinics at which a treatment appointment could be scheduled, appointment availability differed by season. Clinics that had participated in state-sponsored trainings targeting access were more available. Wait times for treatment appointments varied by season and region. Wait times in New York City were shorter than in some other regions. Although callers were 4.1 times more likely to be able to schedule a psychiatry appointment in the spring, wait times for psychiatry appointments were significantly longer in the spring than in the summer (49.9 vs. 36.7 days). Wait times for therapy appointments were significantly shorter in community than in hospital clinics (19.1 days vs. 35.3 days). CONCLUSION: Access to psychiatric care for youth with depression was found to be variable in a state system. State-sponsored trainings on strategies to reduce wait times appear to improve care access. The simulated patient approach has promise for monitoring the impact of health care policy reforms on care quality measures.
PMCID:4970515
PMID: 27126853
ISSN: 1527-5418
CID: 2092652

Detection and Treatment of Mental Health Issues by Pediatric PCPs in New York State: An Evaluation of Project TEACH

Kerker, Bonnie D; Chor, Ka Ho Brian; Hoagwood, Kimberly E; Radigan, Marleen; Perkins, Matthew B; Setias, Jade; Wang, Rui; Olin, S Serene; Horwitz, Sarah M
OBJECTIVE: The authors evaluated Project TEACH (PT), a statewide training and consultation program for pediatric primary care providers (PCPs) on identification and treatment of mental health conditions. METHODS: An intervention group of 176 PCPs who volunteered for PT training was compared with a stratified random sample of 200 PCPs who did not receive PT training. Data on prescription practices, diagnoses, and follow-up care were from New York State Medicaid files (2009-2013) for youths seen by the trained (N=21,784) and untrained (N=46,607) PCPs. RESULTS: The percentage of children prescribed psychotropic medication increased after PT training (9% to 12%, p<.001), a larger increase than in the untrained group (4% to 5%, p<.001) (comparison, p<.001). Fewer differences were noted in diagnoses and in medication use and follow-up care among children with depression. CONCLUSIONS: This intervention may have an impact on providers' behaviors, but further research is needed to clarify its effectiveness.
PMCID:4384126
PMID: 25828984
ISSN: 1557-9700
CID: 1519382

Applying theory-driven approaches to understanding and modifying clinicians' behavior: what do we know?

Perkins, Matthew B; Jensen, Peter S; Jaccard, James; Gollwitzer, Peter; Oettingen, Gabriele; Pappadopulos, Elizabeth; Hoagwood, Kimberly E
OBJECTIVE: Despite major recent research advances, large gaps exist between accepted mental health knowledge and clinicians' real-world practices. Although hundreds of studies have successfully utilized basic behavioral science theories to understand, predict, and change patients' health behaviors, the extent to which these theories-most notably the theory of reasoned action (TRA) and its extension, the theory of planned behavior (TPB)-have been applied to understand and change clinician behavior is unclear. This article reviews the application of theory-driven approaches to understanding and changing clinician behaviors. METHODS: MEDLINE and PsycINFO databases were searched, along with bibliographies, textbooks on health behavior or public health, and references from experts, to find article titles that describe theory-driven approaches (TRA or TPB) to understanding and modifying health professionals' behavior. RESULTS: A total of 19 articles that detailed 20 studies described the use of TRA or TPB and clinicians' behavior. Eight articles describe the use of TRA or TPB with physicians, four relate to nurses, three relate to pharmacists, and two relate to health workers. Only two articles applied TRA or TPB to mental health clinicians. The body of work shows that different constructs of TRA or TPB predict intentions and behavior among different groups of clinicians and for different behaviors and guidelines. CONCLUSIONS: The number of studies on this topic is extremely limited, but they offer a rationale and a direction for future research as well as a theoretical basis for increasing the specificity and efficiency of clinician-targeted interventions.
PMID: 17325107
ISSN: 1075-2730
CID: 167926

Pharmacotherapy of aggression in children and adolescents: efficacy and effect size

Pappadopulos, Elizabeth; Woolston, Sophie; Chait, Alanna; Perkins, Matthew; Connor, Daniel F; Jensen, Peter S
INTRODUCTION/BACKGROUND:The treatment of pediatric aggression often involves psychotropic agents. Despite growing research on pediatric psychopharmacology, however, clinical issues regarding medication management of persistent behavioral problems remain poorly addressed. METHOD/METHODS:A review of the literature from 1980 to November, 2005 yielded 45 randomized, placebo-controlled trials that addressed the treatment of aggression as either a primary or secondary outcome variable. Effect sizes (ES) (Cohen's d) were calculated for studies that met inclusion criteria. RESULTS:Overall ES for psychotropic agents in treating aggression was 0.56. Despite variability in psychiatric diagnoses, select agents showed moderate to large effects on maladaptive aggression. Most studies focused on younger children (mean age = 10.4 years), and were of short duration (7 to 70 days). Largest effects were noted with methylphenidate for co-morbid aggression in ADHD (mean ES = 0.9, combined n = 844) and risperidone for persistent behavioral disturbances in youth with conduct disorder and sub-average IQ (mean ES = 0.9, combined n = 875). CONCLUSION/CONCLUSIONS:A growing literature supports the use of certain medications for managing pediatric aggression. Future studies should distinguish between impulsive and predatory aggression, and examine the efficacy of agents over longer treatment periods.
PMCID:2277275
PMID: 18392193
ISSN: 1719-8429
CID: 4809742