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3. Towards AI-Assisted Synthesis of Verified Dafny Methods

Author

Misu, Md Rakib Hossain, Lopes, Cristina V., Ma, Iris, and Noble, James

Subjects
Computer Science - Software Engineering, Computer Science - Programming Languages
Abstract

Large language models show great promise in many domains, including programming. A promise is easy to make but hard to keep, and language models often fail to keep their promises, generating erroneous code. A promising avenue to keep models honest is to incorporate formal verification: generating programs' specifications as well as code so that the code can be proved correct with respect to the specifications. Unfortunately, existing large language models show a severe lack of proficiency in verified programming. In this paper, we demonstrate how to improve two pretrained models' proficiency in the Dafny verification-aware language. Using 178 problems from the MBPP dataset, we prompt two contemporary models (GPT-4 and PaLM-2) to synthesize Dafny methods. We use three different types of prompts: a direct Contextless prompt; a Signature prompt that includes a method signature and test cases, and a Chain of Thought (CoT) prompt that decomposes the problem into steps and includes retrieval augmentation generated example problems and solutions. Our results show that GPT-4 performs better than PaLM-2 on these tasks and that both models perform best with the retrieval augmentation generated CoT prompt. GPT-4 was able to generate verified, human-evaluated, Dafny methods for 58% of the problems, however, GPT-4 managed only 19% of the problems with the Contextless prompt, and even fewer (10%) for the Signature prompt. We are thus able to contribute 153 verified Dafny solutions to MBPP problems, 50 that we wrote manually, and 103 synthesized by GPT-4. Our results demonstrate that the benefits of formal program verification are now within reach of code generating large language models..., Comment: This is an author provided preprint. The final version will be published at Proc. ACM Softw. Eng; FSE 2024, in July 2024

Published
2024
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4. Reference Capabilities for Flexible Memory Management: Extended Version

Author

Arvidsson, Ellen, Castegren, Elias, Clebsch, Sylvan, Drossopoulou, Sophia, Noble, James, Parkinson, Matthew J., and Wrigstad, Tobias

Subjects
Computer Science - Programming Languages
Abstract

Verona is a concurrent object-oriented programming language that organises all the objects in a program into a forest of isolated regions. Memory is managed locally for each region, so programmers can control a program's memory use by adjusting objects' partition into regions, and by setting each region's memory management strategy. A thread can only mutate (allocate, deallocate) objects within one active region -- its "window of mutability". Memory management costs are localised to the active region, ensuring overheads can be predicted and controlled. Moving the mutability window between regions is explicit, so code can be executed wherever it is required, yet programs remain in control of memory use. An ownership type system based on reference capabilities enforces region isolation, controlling aliasing within and between regions, yet supporting objects moving between regions and threads. Data accesses never need expensive atomic operations, and are always thread-safe., Comment: 87 pages, 10 figures, 5 listings, 4 tables. Extended version of paper to be published at OOPSLA 2023

Published
2023
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7. Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Author

Johnson, Erik CB, Bian, Shijia, Haque, Rafi U, Carter, E Kathleen, Watson, Caroline M, Gordon, Brian A, Ping, Lingyan, Duong, Duc M, Epstein, Michael P, McDade, Eric, Barthélemy, Nicolas R, Karch, Celeste M, Xiong, Chengjie, Cruchaga, Carlos, Perrin, Richard J, Wingo, Aliza P, Wingo, Thomas S, Chhatwal, Jasmeer P, Day, Gregory S, Noble, James M, Berman, Sarah B, Martins, Ralph, Graff-Radford, Neill R, Schofield, Peter R, Ikeuchi, Takeshi, Mori, Hiroshi, Levin, Johannes, Farlow, Martin, Lah, James J, Haass, Christian, Jucker, Mathias, Morris, John C, Benzinger, Tammie LS, Roberts, Blaine R, Bateman, Randall J, Fagan, Anne M, Seyfried, Nicholas T, and Levey, Allan I

Subjects
Biomedical and Clinical Sciences, Health Sciences, Brain Disorders, Dementia, Alzheimer's Disease, Acquired Cognitive Impairment, Aging, Neurodegenerative, Biotechnology, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Neurological, Humans, Alzheimer Disease, Biomarkers, Proteomics, Male, Female, Adult, Middle Aged, Mutation, Age of Onset, Dominantly Inherited Alzheimer Network, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.

Published
2023

8. Necessity Specifications for Robustness

Author

Mackay, Julian, Drossopoulou, Sophia, Noble, James, and Eisenbach, Susan

Subjects
Computer Science - Programming Languages
Abstract

Robust modules guarantee to do only what they are supposed to do - even in the presence of untrusted, malicious clients, and considering not just the direct behaviour of individual methods, but also the emergent behaviour from calls to more than one method. Necessity is a language for specifying robustness, based on novel necessity operators capturing temporal implication, and a proof logic that derives explicit robustness specifications from functional specifications. Soundness and an exemplar proof are mechanised in Coq.

Published
2022

9. A rapid environmental risk assessment of the Kakhovka Dam breach during the Ukraine conflict

Author

Spears, Bryan M., Harpham, Quillon, Brown, Emma, Barnett, Catherine L., Barwell, Louise, Collell, Marta Roca, Davison, Mark, Dixon, Harry, Elliott, J. Alex, Garbutt, Angus, Hazlewood, Caroline, Hofmann, Barbara, Lanyon, James, Lofts, Stephen, MacKechnie, Colin, Medinets, Sergiy, Noble, James, Ramsbottom, David, Redhead, John W., Riera, Alberto, Spurgeon, David J., Svendsen, Claus, Taylor, Philip, Thackeray, Stephen J., Turvey, Katharine, and Wood, Michael D.

Published
2024
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10. Biomarker clustering in autosomal dominant Alzheimers disease.

Author

Luckett, Patrick, Chen, Charlie, Gordon, Brian, Wisch, Julie, Berman, Sarah, Chhatwal, Jasmeer, Cruchaga, Carlos, Fagan, Anne, Farlow, Martin, Fox, Nick, Jucker, Mathias, Levin, Johannes, Masters, Colin, Mori, Hiroshi, Noble, James, Salloway, Stephen, Schofield, Peter, Brickman, Adam, Brooks, William, Cash, David, Fulham, Michael, Ghetti, Bernardino, Jack, Clifford, Vöglein, Jonathan, Klunk, William, Koeppe, Robert, Su, Yi, Weiner, Michael, Wang, Qing, Marcus, Daniel, Koudelis, Deborah, Joseph-Mathurin, Nelly, Cash, Lisa, Hornbeck, Russ, Xiong, Chengjie, Perrin, Richard, Karch, Celeste, Hassenstab, Jason, McDade, Eric, Morris, John, Benzinger, Tammie, Bateman, Randall, and Ances, Beau

Subjects
Autosomal dominant Alzheimers disease, biomarkers, machine learning, Humans, Alzheimer Disease, Amyloid beta-Peptides, Amyloidogenic Proteins, Biomarkers, Cross-Sectional Studies, Inflammation, tau Proteins
Abstract

INTRODUCTION: As the number of biomarkers used to study Alzheimers disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

Published
2023

12. Rusty Links in Local Chains

Author

Noble, James, Mackay, Julian, and Wrigstad, Tobias

Subjects
Computer Science - Programming Languages
Abstract

Rust successfully applies ownership types to control memory allocation. This restricts the programs' topologies to the point where doubly-linked lists cannot be programmed in Safe Rust. We sketch how more flexible "local" ownership could be added to Rust, permitting multiple mutable references to objects, provided each reference is bounded by the object's lifetime. To maintain thread-safety, locally owned objects must remain thread-local; to maintain memory safety, local objects can be deallocated when their owner's lifetime expires.

Published
2022

13. More Programming Than Programming: Teaching Formal Methods in a Software Engineering Programme

Author

Noble, James, Streader, David, Gariano, Isaac Oscar, and Samarakoon, Miniruwani

Subjects
Computer Science - Software Engineering, Computer Science - Logic in Computer Science
Abstract

Formal methods for software correctness are critical to the future of software engineering - and so must be an essential part of software engineering education. Unfortunately, formal methods are often resisted by students due to perceived difficulty, mathematicity, and practical irrelevance. We redeveloped our software correctness course by taking a programming intensive approach, using the solver-aided language Dafny to provide instant formative feedback via automated assessment. Our redeveloped course increased student retention and resulted in the best evaluation for the course for at least ten years.

Published
2022

14. Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology

Author

Morris, John C, Weiner, Michael, Xiong, Chengjie, Beckett, Laurel, Coble, Dean, Saito, Naomi, Aisen, Paul S, Allegri, Ricardo, Benzinger, Tammie LS, Berman, Sarah B, Cairns, Nigel J, Carrillo, Maria C, Chui, Helena C, Chhatwal, Jasmeer P, Cruchaga, Carlos, Fagan, Anne M, Farlow, Martin, Fox, Nick C, Ghetti, Bernardino, Goate, Alison M, Gordon, Brian A, Graff-Radford, Neill, Day, Gregory S, Hassenstab, Jason, Ikeuchi, Takeshi, Jack, Clifford R, Jagust, William J, Jucker, Mathias, Levin, Johannes, Massoumzadeh, Parinaz, Masters, Colin L, Martins, Ralph, McDade, Eric, Mori, Hiroshi, Noble, James M, Petersen, Ronald C, Ringman, John M, Salloway, Stephen, Saykin, Andrew J, Schofield, Peter R, Shaw, Leslie M, Toga, Arthur W, Trojanowski, John Q, Vöglein, Jonathan, Weninger, Stacie, Bateman, Randall J, and Buckles, Virginia D

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Alzheimer's Disease, Clinical Research, Brain Disorders, Dementia, Genetics, Clinical Trials and Supportive Activities, Acquired Cognitive Impairment, Biomedical Imaging, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Neurodegenerative, 2.1 Biological and endogenous factors, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, Magnetic Resonance Imaging, Amyloidosis, Biomarkers, Alzheimer pathophysiology, biomarkers, rates of change, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

Published
2022

16. CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

Author

Noble, James M., Day, Gregory S., Graff-Radford, Neill R., Voglein, Jonathan, Allegri, Ricardo, Mendez, Patricio Chrem, Surace, Ezequiel, Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh, Lopera, Francisco, Ramirez, Laura, Aguillon, David, Leon, Yudy, Ramos, Claudia, Alzate, Diana, Baena, Ana, Londono, Natalia, Mathias Jucker, Sonia Moreno, Laske, Christoph, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Preische, Oliver, Hofmann, Anna, Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Ishii, Kenji, Senda, Michio, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Fox, Nick, Cash, Dave, Lee, Jae-Hong, Roh, Jee Hoon, Riddle, Meghan, Menard, William, Bodge, Courtney, Surti, Mustafa, Takada, Leonel Tadao, Farlow, Martin, Chhatwal, Jasmeer P., Sanchez-Gonzalez, V.J., Orozco-Barajas, Maribel, Goate, Alison, Renton, Alan, Esposito, Bianca, Karch, Celeste M., Marsh, Jacob, Cruchaga, Carlos, Fernandez, Victoria, Gordon, Brian A., Fagan, Anne M., Jerome, Gina, Herries, Elizabeth, Llibre-Guerra, Jorge, Levey, Allan I., Johnson, Erik C.B., Seyfried, Nicholas T., Schofield, Peter R., Brooks, William, Bechara, Jacob, Bateman, Randall J., McDade, Eric, Hassenstab, Jason, Perrin, Richard J., Franklin, Erin, Benzinger, Tammie L.S., Chen, Allison, Chen, Charles, Flores, Shaney, Friedrichsen, Nelly, Hantler, Nancy, Hornbeck, Russ, Jarman, Steve, Keefe, Sarah, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, McKay, Nicole, Nicklaus, Joyce, Pulizos, Christine, Wang, Qing, Mishall, Sheetal, Sabaredzovic, Edita, Deng, Emily, Candela, Madison, Smith, Hunter, Hobbs, Diana, Scott, Jalen, Levin, Johannes, Xiong, Chengjie, Wang, Peter, Xu, Xiong, Li, Yan, Gremminger, Emily, Ma, Yinjiao, Bui, Ryan, Lu, Ruijin, Martins, Ralph, Sosa Ortiz, Ana Luisa, Daniels, Alisha, Courtney, Laura, Mori, Hiroshi, Supnet-Bell, Charlene, Xu, Jinbin, Ringman, John, Shen, Yuanyuan, Timsina, Jigyasha, Heo, Gyujin, Beric, Aleksandra, Ali, Muhammad, Wang, Ciyang, Yang, Chengran, Wang, Yueyao, Western, Daniel, Liu, Menghan, Gorijala, Priyanka, Budde, John, Do, Anh, Liu, Haiyan, Gordon, Brian, Llibre-Guerra, Jorge J., Joseph-Mathurin, Nelly, Maschi, Dario, Wyss-Coray, Tony, Pastor, Pau, Renton, Alan E., Surace, Ezequiel I., Alvarez, Ignacio, Ringman, John M., Allegri, Ricardo Francisco, Seyfried, Nicholas, Day, Gregg S., Wu, Qisi, Fernández, M. Victoria, Tarawneh, Rawan, Morris, John C., Ibanez, Laura, and Sung, Yun Ju

Published
2024
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17. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Author

Aguillon, David, Allegri, Ricardo F., Aschenbrenner, Andrew J., Baker, Bryce, Barthelemy, Nicolas, Bechara, Jacob A., Berman, Sarah B., Brooks, William S., Cash, David M., Chen, Allison, Chrem Mendez, Patricio, Courtney, Laura, Cruchaga, Carlos, Daniels, Alisha J., Fagan, Anne M., Flores, Shaney, Fox, Nick C., Franklin, Erin, Goate, Alison M., Graber-Sultan, Susanne, Graff-Radford, Neill R., Gremminger, Emily, Herries, Elizabeth, Hofmann, Anna, Holtzman, David M., Hornbeck, Russ, Huey, Edward D., Ibanez, Laura, Ikeuchi, Takeshi, Ikonomovic, Snezana, Jackson, Kelley, Jarman, Steve, Jerome, Gina, Johnson, Erik C.B, Kasuga, Kensaku, Keefe, Sarah, Koudelis, Deborah, Kuder-Buletta, Elke, Laske, Christoph, Leon, Yudy Milena, Levey, Allan I., Li, Yan, Llibre-Guerra, Jorge J., Lopera, Francisco, Lu, Ruijin, Marsh, Jacob, Martins, Ralph, Massoumzadeh, Parinaz, Masters, Colin, McCullough, Austin, McKay, Nicole, Minton, Matthew, Mori, Hiroshi, Morris, John C., Nadkarni, Neelesh K., Nicklaus, Joyce, Niimi, Yoshiki, Noble, James M., Obermueller, Ulrike, Picarello, Danielle M., Pulizos, Christine, Ramirez, Laura, Renton, Alan E., Ringman, John, Rizzo, Jacqueline, Roedenbeck, Yvonne, Roh, Jee Hoon, Rosa-Neto, Pedro, Ryan, Natalie S., Sabaredzovic, Edita, Salloway, Stephen, Sanchez-Valle, Raquel, Scott, Jalen, Seyfried, Nicholas T., Simmons, Ashlee, Smith, Jennifer, Smith, Hunter, Stauber, Jennifer, Stout, Sarah, Supnet-Bell, Charlene, Surace, Ezequiel, Vazquez, Silvia, Vöglein, Jonathan, Wang, Guoqiao, Wang, Qing, Xu, Xiong, Xu, Jinbin, Schultz, Stephanie A, Liu, Lei, Schultz, Aaron P, Fitzpatrick, Colleen D, Levin, Raina, Bellier, Jean-Pierre, Shirzadi, Zahra, Joseph-Mathurin, Nelly, Chen, Charles D, Benzinger, Tammie L S, Day, Gregory S, Farlow, Martin R, Gordon, Brian A, Hassenstab, Jason J, Jack, Clifford R, Jr, Jucker, Mathias, Karch, Celeste M, Lee, Jae-Hong, Levin, Johannes, Perrin, Richard J, Schofield, Peter R, Xiong, Chengjie, Johnson, Keith A, McDade, Eric, Bateman, Randall J, Sperling, Reisa A, Selkoe, Dennis J, and Chhatwal, Jasmeer P

Published
2024
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18. Dala: A Simple Capability-Based Dynamic Language Design For Data Race-Freedom

Author

Fernandez-Reyes, Kiko, Gariano, Isaac Oscar, Noble, James, Greenwood-Thessman, Erin, Homer, Michael, and Wrigstad, Tobias

Subjects
Computer Science - Programming Languages, Computer Science - Distributed, Parallel, and Cluster Computing
Abstract

Dynamic languages like Erlang, Clojure, JavaScript, and E adopted data-race freedom by design. To enforce data-race freedom, these languages either deep copy objects during actor (thread) communication or proxy back to their owning thread. We present Dala, a simple programming model that ensures data-race freedom while supporting efficient inter-thread communication. Dala is a dynamic, concurrent, capability-based language that relies on three core capabilities: immutable values can be shared freely; isolated mutable objects can be transferred between threads but not aliased; local objects can be aliased within their owning thread but not dereferenced by other threads. Objects with capabilities can co-exist with unsafe objects, that are unchecked and may suffer data races, without compromising the safety of safe objects. We present a formal model of Dala, prove data race-freedom and state and prove a dynamic gradual guarantee. These theorems guarantee data race-freedom when using safe capabilities and show that the addition of capabilities is semantics preserving modulo permission and cast errors.

Published
2021

19. Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Author

Noble, James M., Day, Gregory S., Graff-Radford, Neill R., Voglein, Jonathan, Levin, Johannes, Allegri, Ricardo F., Mendez, Patricio Chrem, Surace, Ezequiel, Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh K., Lopera, Francisco, Ramirez, Laura, Aguillon, David, Leon, Yudy, Ramos, Claudia, Alzate, Diana, Baena, Ana, Londono, Natalia, Moreno, Sonia, Jucker, Mathias, Laske, Christoph, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Preische, Oliver, Hofmann, Anna, Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Ishii, Kenji, Senda, Michio, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Fox, Nick C., Cash, Dave, Lee, Jae-Hong, Roh, Jee Hoon, Salloway, Stephen, Riddle, Meghan C., Menard, William, Bodge, Courtney, Surti, Mustafa, Takada, Leonel Tadao, Farlow, Martin, Chhatwal, Jasmeer P., Sanchez-Gonzalez, V.J., Orozco-Barajas, Maribel, Goate, Alison M., Renton, Alan E., Esposito, Bianca T., Karch, Celeste M., Marsh, Jacob, Cruchaga, Carlos, Fernanadez, Victoria, Gordon, Brian A., Fagan, Anne M., Jerome, Gina, Herries, Elizabeth, Llibre-Guerra, Jorge, Levey, Allan I., Johnson, Erik C.B., Seyfried, Nicholas T., Schofield, Peter R., Brooks, William S., Bechara, Jacob A., Bateman, Randall, McDade, Eric, Hassenstab, Jason, Perrin, Richard J., Franklin, Erin E., Benzinger, Tammie, Chen, Allison, Chen, Charles, Flores, Shaney, Friedrichsen, Nelly, Gordon, Brian, Hantler, Nancy, Hornbeck, Russ, Jarman, Steve, Keefe, Sarah, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, McKay, Nicole, Nicklaus, Joyce, Pulizos, Christine, Wang, Qing, Mishall, Sheetal, Sabaredzovic, Edita, Deng, Emily, Candela, Madison, Smith, Hunter, Hobbs, Diana, Scott, Jalen, Xiong, Chengjie, Wang, Peter, Xu, Xiong, Li, Yan, Gremminger, Emily, Ma, Yinjiao, Bui, Ryan, Lu, Ruijin, Martins, Ralph, Sosa Ortiz, Ana Luisa, Daniels, Alisha, Courtney, Laura, Mori, Hiroshi, Supnet-Bell, Charlene, Xu, Jinbin, Ringman, John, Barthelemy, Nicolas, Morris, John, Smith, Jennifer, Doering, Stephanie, Chen, Charles D., Jarman, Stephen, Jackson, Kelley, Hornbeck, Russ C., Ances, Beau M., Aschenbrenner, Andrew J., Bateman, Randall J., Morris, John C., and Benzinger, Tammie L.S.

Published
2024
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20. Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study

Author

Aizenstein, Howard J., Andrews, Howard F., Bell, Karen, Birn, Rasmus M., Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D., Constantino, John N., Doran, Eric W., Feingold, Eleanor, Foroud, Tatiana M., Hartley, Sigan L., Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D., Johnson, Sterling C., Jordan, Courtney, Kamboh, M. Ilyas, Keator, David, Klunk, William E., Kofler, Julia K., Kreisl, William C., Krinsky-McHale, Sharon J., Lao, Patrick, Laymon, Charles, Lott, Ira T., Lupson, Victoria, Mathis, Chester A., Minhas, Davneet S., Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C., Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N., Schupf, Nicole, Tudorascu, Dana L., Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A., Yassa, Michael A., Zaman, Shahid, Zhang, Fan, Bateman, Randall, Daniels, Alisha J., Courtney, Laura, McDade, Eric, Llibre-Guerra, Jorge J., Supnet-Bell, Charlene, Xiong, Chengie, Xu, Xiong, Lu, Ruijin, Wang, Guoqiao, Li, Yan, Gremminger, Emily, Perrin, Richard J., Franklin, Erin, Ibanez, Laura, Jerome, Gina, Herries, Elizabeth, Stauber, Jennifer, Baker, Bryce, Minton, Matthew, Cruchaga, Carlos, Goate, Alison M., Renton, Alan E., Picarello, Danielle M., Benzinger, Tammie, Gordon, Brian A., Hornbeck, Russall, Hassenstab, Jason, Smith, Jennifer, Stout, Sarah, Aschenbrenner, Andrew J., Karch, Celeste M., Marsh, Jacob, Morris, John C., Holtzman, David M., Barthelemy, Nicolas, Xu, Jinbin, Noble, James M., Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh K., Day, Gregory, Graff-Radford, Neill R., Farlow, Martin, Chhatwal, Jasmeer P., Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Huey, Edward D., Salloway, Stephen, Schofield, Peter R., Brooks, William S., Bechara, Jacob A., Martins, Ralph, Fox, Nick C., Cash, David M., Ryan, Natalie S., Jucker, Mathias, Laske, Christoph, Hofmann, Anna, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Obermueller, Ulrike, Levin, Johannes, Roedenbeck, Yvonne, Vöglein, Jonathan, Lee, Jae-Hong, Roh, Jee Hoon, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Allegri, Ricardo F., Chrem Mendez, Patricio, Surace, Ezequiel, Vazquez, Silvia, Lopera, Francisco, Leon, Yudy Milena, Ramirez, Laura, Aguillon, David, Levey, Allan I., Johnson, Erik C.B, Seyfried, Nicholas T., Ringman, John, Mori, Hiroshi, Wisch, Julie K, McKay, Nicole S, Boerwinkle, Anna H, Kennedy, James, Flores, Shaney, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O’Bryant, Sid E, Price, Julie C, Laymon, Charles M, Krinsky-McHale, Sharon J, Lai, Florence, Rosas, H Diana, Hartley, Sigan L, Lott, Ira T, Tudorascu, Dana, Zammit, Matthew, Brickman, Adam M, Lee, Joseph H, Bird, Thomas D, Cohen, Annie, Chrem, Patricio, Daniels, Alisha, Chhatwal, Jasmeer P, Karch, Celeste M, Day, Gregory S, Llibre-Guerra, Jorge, Ringman, John M, van Dyck, Christopher H, Xiong, Chengjie, Morris, John C, Bateman, Randall J, Benzinger, Tammie L S, Gordon, Brian A, and Ances, Beau M

Published
2024
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21. Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN)

Author

McKay, Nicole S., Gordon, Brian A., Hornbeck, Russ C., Dincer, Aylin, Flores, Shaney, Keefe, Sarah J., Joseph-Mathurin, Nelly, Jack, Clifford R., Koeppe, Robert, Millar, Peter R., Ances, Beau M., Chen, Charles D., Daniels, Alisha, Hobbs, Diana A., Jackson, Kelley, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, Nickels, Michael L., Rahmani, Farzaneh, Swisher, Laura, Wang, Qing, Allegri, Ricardo F., Berman, Sarah B., Brickman, Adam M., Brooks, William S., Cash, David M., Chhatwal, Jasmeer P., Day, Gregory S., Farlow, Martin R., la Fougère, Christian, Fox, Nick C., Fulham, Michael, Ghetti, Bernardino, Graff-Radford, Neill, Ikeuchi, Takeshi, Klunk, William, Lee, Jae-Hong, Levin, Johannes, Martins, Ralph, Masters, Colin L., McConathy, Jonathan, Mori, Hiroshi, Noble, James M., Reischl, Gerald, Rowe, Christopher, Salloway, Stephen, Sanchez-Valle, Raquel, Schofield, Peter R., Shimada, Hiroyuki, Shoji, Mikio, Su, Yi, Suzuki, Kazushi, Vöglein, Jonathan, Yakushev, Igor, Cruchaga, Carlos, Hassenstab, Jason, Karch, Celeste, McDade, Eric, Perrin, Richard J., Xiong, Chengjie, Morris, John C., Bateman, Randall J., and Benzinger, Tammie L. S.

Published
2023
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22. Contemporary Neuroscience Core Curriculum for Medical Schools

Author

Gelb, Douglas J, Kraakevik, Jeff, Safdieh, Joseph E, Agarwal, Sachin, Odia, Yazmin, Govindarajan, Raghav, Quick, Adam, Soni, Madhu, Bickel, Jennifer, Gamaldo, Charlene, Hannon, Peter, Hatch, Hayden AM, Hernandez, Christian, Merlin, Lisa R, Noble, James M, Reyes-Iglesias, Yolanda, Marie E Salas, Rachel, Sandness, David James, Treat, Lauren, Benameur, Karima, Brown, Robert D, DeLuca, Gabriele C, Garg, Neeta, Goldstein, Larry B, Gutmann, Laurie, Henchcliffe, Claire, Hessler, Amy, Jordan, Justin T, Kilgore, Shannon M, Khan, Jaffar, Levin, Kerry H, Mohile, Nimish A, Nevel, Kathryn S, Roberts, Kirk, Said, Rana R, Simpson, Ericka P, Sirven, Joseph I, Smith, A Gordon, Southerland, Andrew Mebane, and Wilson, Rujuta Bhatt

Subjects
Neurosciences, Quality Education, AAN Undergraduate Education Subcommittee, AAN Education Committee, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also, because the nervous system plays such a critical role in the function of every organ system. Due to the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the pre-clerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are re-assessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the pre-clerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors.

Published
2021

24. Holistic Specifications for Robust Programs

Author

Drossopoulou, Sophia, Noble, James, Mackay, Julian, and Eisenbach, Susan

Subjects
Computer Science - Programming Languages, 68, 68N19, 68Q60, 68Q65
Abstract

Functional specifications describe what program components do: the sufficient conditions to invoke a component's operations. They allow us to reason about the use of components in the closed world setting, where the component interacts with known client code, and where the client code must establish the appropriate pre-conditions before calling into the component. Sufficient conditions are not enough to reason about the use of components in the open world setting, where the component interacts with external code, possibly of unknown provenance, and where the component itself may evolve over time. In this open world setting, we must also consider the necessary} conditions, i.e, what are the conditions without which an effect will not happen. In this paper we propose the language Chainmail for writing holistic specifications that focus on necessary conditions (as well as sufficient conditions). We give a formal semantics for \Chainmail. The core of Chainmail has been mechanised in the Coq proof assistant., Comment: 44 pages, 1 Table, 11 Figures

Published
2020

26. Which of My Transient Type Checks Are Not (Almost) Free?

Author

Gariano, Isaac Oscar, Roberts, Richard, Marr, Stefan, Homer, Michael, and Noble, James

Subjects
Computer Science - Programming Languages
Abstract

One form of type checking used in gradually typed language is transient type checking: whenever an object 'flows' through code with a type annotation, the object is dynamically checked to ensure it has the methods required by the annotation. Just-in-time compilation and optimisation in virtual machines can eliminate much of the overhead of run-time transient type checks. Unfortunately this optimisation is not uniform: some type checks will significantly decrease, or even increase, a program's performance. In this paper, we refine the so called "Takikawa" protocol, and use it to identify which type annotations have the greatest effects on performance. In particular, we show how graphing the performance of such benchmarks when varying which type annotations are present in the source code can be used to discern potential patterns in performance. We demonstrate our approach by testing the Moth virtual machine: for many of the benchmarks where Moth's transient type checking impacts performance, we have been able to identify one or two specific type annotations that are the likely cause. Without these type annotations, the performance impact of transient type checking becomes negligible. Using our technique programmers can optimise programs by removing expensive type checks, and VM engineers can identify new opportunities for compiler optimisation.

Published
2019
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27. Towards Gradual Checking of Reference Capabilities

Author

Fernandez-Reyes, Kiko, Gariano, Isaac Oscar, Noble, James, and Wrigstad, Tobias

Subjects
Computer Science - Programming Languages
Abstract

Concurrent and parallel programming is difficult due to the presence of memory side-effects, which may introduce data races. Type qualifiers, such as reference capabilities, can remove data races by restricting sharing of mutable data. Unfortunately, reference capability languages are an all-in or nothing game, i.e., all the types must be annotated with reference capabilities. In this work in progress, we propose to mix the ideas from the reference capability literature with gradual typing, leading to gradual reference capabilities., Comment: draft

Published
2019

28. CallE: An Effect System for Method Calls

Author

Gariano, Isaac Oscar, Noble, James, and Servetto, Marco

Subjects
Computer Science - Programming Languages
Abstract

Effect systems are used to statically reason about the effects an expression may have when evaluated. In the literature, such effects include various behaviours as diverse as memory accesses and exception throwing. Here we present CallE, an object-oriented language that takes a flexible approach where effects are just method calls: this works well because ordinary methods often model things like I/O operations, access to global state, or primitive language operations such as thread creation. CallE supports both flexible and fine-grained control over such behaviour, in a way designed to minimise the complexity of annotations. CallE's effect system can be used to prevent OO code from performing privileged operations, such as querying a database, modifying GUI widgets, exiting the program, or performing network communication. It can also be used to ensure determinism, by preventing methods from (indirectly) calling non-deterministic primitives like random number generation or file reading.

Published
2019
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30. The biological and pharmacological allosteric modulation of inositol monophosphatase

Author

Noble, James William

Subjects
572, QP0772.I5 Inositol
Abstract

The purpose of this project was to develop novel pharmacological tools against Inositol Monophosphatase (IMPase) and gain new insights into the Calbindin-IMPase interaction. IMPase is an enzyme that has been of significant therapeutic interest since the development of the inositol depletion hypothesis of lithium's efficacy in the treatment of bipolar disorder. More recent studies have implicated IMPase inhibition in the induction of autophagy and the clearance of peptides involved in the pathogenesis of neurodegenerative diseases. Despite this there is a lack of specific inhibitors and those that have been developed lack favorable physiochemical properties to explore specific IMPase inhibition in vivo. My aim was to find novel inhibiters and binding chemical fragments that could later be developed into potent specific inhibitors of IMPase that would allow for the specific evaluation of IMPase inhibition in vivo. To achieve this, two approaches were tried: first a crystallographic fragment soaking screen was used to identify novel binding sites and chemical matter. This resulted in the discovery of a novel fragment binding site at the homodimer interface and mutagenesis at this site inhibited IMPase activity, indicating that the site could be therapeutically relevant. The second approach was to screen a specially curated isothiazolone library based on the previously identified covalent inhibitor Ebselen. Here I identified a new class of isothiazolone inhibitors of IMPase. The calcium binding protein Calbindin-D28k can allosterically modulate IMPase, this results in the increase in the catalytic activity of IMPase. I aimed to explore this interaction by fusing the proteins using a flexible amino acid linker. The resulting complexes had activity in excess of that of the wild type IMPase, confirming that Calbindin-D28k activated IMPase. Low resolution structural analysis using small angle X-ray scattering (SAXS) revealed a V-shaped IMPase-calbindin complex which was in contrast to the more linear shape predicted by computational docking models. Here we also obtained the first crystal structure of Calbindin-D28k. This crystal structure gave the first direct visualization of the calcium binding sites of the protein and is a better model of Calbindin-D28k in solution than the previous NMR structure.

Published
2020

31. Analysis of Self-Efficacy for Stroke Recognition and Action from a Cluster Randomised Trial Evaluating the Effects of Stroke Education Pamphlets versus a 12-Minute Culturally Tailored Stroke Film among Black and Hispanic Churchgoers in New York

Author

Ilunga Tshiswaka, Daudet, Teresi, Jeanne, Eimicke, Joseph P., Kong, Jian, Noble, James M., Ogedegbe, Gbenga, and Williams, Olajide

Abstract

Background: Because early recognition of symptoms and timely treatment of stroke can reduce mortality and the longterm effects of such events, efforts to make many people both aware of these symptoms and knowledgeable about what to do when recognising them are critical for reducing impacts from stroke. Objectives: To assess the impact of a stroke preparedness film (intervention) and stroke preparedness pamphlets (usual care) on self-efficacy for stroke recognition and action. Design: Two-arm cluster randomised trial conducted between July 2013 and August 2018. Setting: A total of 13 church sites located in economically disadvantaged urban neighbourhoods in New York. Of the 883 churchgoers approached, 503 expressed interest, 375 completed eligibility screening and 312 were randomised. Participant inclusion criteria were Black or Hispanic churchgoers, aged 34years or older, without stroke history, but at a high risk for stroke. The intervention consisted of two 12-minute stroke films: "Gospel of Stroke," in English for Black participants, and "Derrame Cerebral," in Spanish for Hispanic participants. Method: Participants were pre-post-tested (at baseline, 6-month follow-up and 12-month follow-up) for self-efficacy. Descriptive analysis, a linear mixed model and "t" tests were used to assess the effects of a stroke preparedness film and stroke preparedness pamphlets on self-efficacy. Results: Findings are based on intention-to-treat analysis. A total of 310 participants completed the study (99% retention rate). About half (53.8%) of participants were Black and 46.2% Hispanic in the intervention group; 48.3% were Black and 51.7% were Hispanic in the usual care group. Overall, both groups evidenced higher self-efficacy (i.e. lower predicted means) over time (p < 0.0001), although a significant benefit was not observed for the intervention relative to usual care. Conclusion: Both stroke preparedness films and stroke preparedness pamphlets improved self-efficacy with respect to stroke recognition and action among minority churchgoers.

Published
2021
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32. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Aizenstein, Howard J, Andrews, Howard F, Bell, Karen, Birn, Rasmus M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D, Constantino, John N, Doran, Eric W, Feingold, Eleanor, Foroud, Tatiana M, Hartley, Sigan L, Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk MD, William E, Kofler, Julia K, Kreisl, William C, Krinsky- McHale, Sharon J, Lao, Patrick, Laymon, Charles, Lott, Ira T, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet S, Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C, Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N, Schupf, Nicole, Tudorascu, Dana L, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Yassa, Michael A, Zaman, Shahid, Zhang, Fan, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Mendez, Patricio C, Chua, Jasmin, Chui, Helena, Courtney, Laura, Day, Gregory, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häslerc, Lisa, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal S, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John C, Mountz, James, Mummery, Catherine, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Boerwinkle, Anna H, Gordon, Brian A, Wisch, Julie, Flores, Shaney, Henson, Rachel L, Butt, Omar H, McKay, Nicole, Chen, Charles D, Benzinger, Tammie L S, Fagan, Anne M, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O'Bryant, Sid, Lai, Florence, Rosas, H Diana, Lee, Joseph H, Silverman, Wayne, Brickman, Adam M, Chhatwal, Jasmeer P, Cruchaga, Carlos, Perrin, Richard J, Xiong, Chengjie, Hassenstab, Jason, McDade, Eric, Bateman, Randall J, and Ances, Beau M

Published
2023
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33. Transient Typechecks are (Almost) Free

Author

Roberts, Richard, Marr, Stefan, Homer, Michael, and Noble, James

Subjects
Computer Science - Programming Languages
Abstract

Transient gradual typing imposes run-time type tests that typically cause a linear slowdown in programs' performance. This performance impact discourages the use of type annotations because adding types to a program makes the program slower. A virtual machine can employ standard just-in-time optimizations to reduce the overhead of transient checks to near zero. These optimizations can give gradually-typed languages performance comparable to state-of-the-art dynamic languages, so programmers can add types to their code without affecting their programs' performance., Comment: Draft

Published
2018

35. Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

Author

Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bateman, Randall, Bechara, Jacob, Benzinger, Tammie, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William (Bill), Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Mendez, Patricio Chrem, Chua, Jasmin, Chui, Helena, Courtney, Laura, Cruchaga, Carlos, Day, Gregory S, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Fagan, Anne, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gordon, Brian, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häsler, Lisa, Hassenstab, Jason, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John, Mountz, James, Mummery, Cath, Nadkarni, N eelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Millar, Peter R., Luckett, Patrick H., Gordon, Brian A., Benzinger, Tammie L.S., Schindler, Suzanne E., Fagan, Anne M., Bateman, Randall J., Lee, Jae-Hong, Mori, Hiroshi, Salloway, Stephen P, Yakushev, Igor, Morris, John C., and Ances, Beau M.

Published
2022
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37. CSF Tau phosphorylation at Thr205 is associated with loss of white matter integrity in autosomal dominant Alzheimer disease

Author

Strain, Jeremy F., Barthelemy, Nicolas, Horie, Kanta, Gordon, Brian A., Kilgore, Collin, Aschenbrenner, Andrew, Cruchaga, Carlos, Xiong, Chengjie, Joseph-Mathurin, Nelly, Hassenstab, Jason, Fagan, Anne M., Li, Yan, Karch, Celeste M., Perrin, Richard J., Berman, Sarah B., Chhatwal, Jasmeer P., Graff-Radford, Neill R., Mori, Hiroshi, Levin, Johannes, Noble, James M., Allegri, Ricardo, Schofield, Peter R., Marcus, Daniel S., Holtzman, David M., Morris, John C., Benzinger, Tammie L.S., McDade, Eric M., Bateman, Randall J., and Ances, Beau M.

Published
2022
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38. Beyond electronic health record data: leveraging natural language processing and machine learning to uncover cognitive insights from patient-nurse verbal communications.

Author

Zolnoori, Maryam, Zolnour, Ali, Vergez, Sasha, Sridharan, Sridevi, Spens, Ian, Topaz, Maxim, Noble, James M, Bakken, Suzanne, Hirschberg, Julia, Bowles, Kathryn, Onorato, Nicole, and McDonald, Margaret V

Abstract

Background Mild cognitive impairment and early-stage dementia significantly impact healthcare utilization and costs, yet more than half of affected patients remain underdiagnosed. This study leverages audio-recorded patient-nurse verbal communication in home healthcare settings to develop an artificial intelligence-based screening tool for early detection of cognitive decline. Objective To develop a speech processing algorithm using routine patient-nurse verbal communication and evaluate its performance when combined with electronic health record (EHR) data in detecting early signs of cognitive decline. Method We analyzed 125 audio-recorded patient-nurse verbal communication for 47 patients from a major home healthcare agency in New York City. Out of 47 patients, 19 experienced symptoms associated with the onset of cognitive decline. A natural language processing algorithm was developed to extract domain-specific linguistic and interaction features from these recordings. The algorithm's performance was compared against EHR-based screening methods. Both standalone and combined data approaches were assessed using F1-score and area under the curve (AUC) metrics. Results The initial model using only patient-nurse verbal communication achieved an F1-score of 85 and an AUC of 86.47. The model based on EHR data achieved an F1-score of 75.56 and an AUC of 79. Combining patient-nurse verbal communication with EHR data yielded the highest performance, with an F1-score of 88.89 and an AUC of 90.23. Key linguistic indicators of cognitive decline included reduced linguistic diversity, grammatical challenges, repetition, and altered speech patterns. Incorporating audio data significantly enhanced the risk prediction models for hospitalization and emergency department visits. Discussion Routine verbal communication between patients and nurses contains critical linguistic and interactional indicators for identifying cognitive impairment. Integrating audio-recorded patient-nurse communication with EHR data provides a more comprehensive and accurate method for early detection of cognitive decline, potentially improving patient outcomes through timely interventions. This combined approach could revolutionize cognitive impairment screening in home healthcare settings. [ABSTRACT FROM AUTHOR]

Published
2025
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39. Decoding disparities: evaluating automatic speech recognition system performance in transcribing Black and White patient verbal communication with nurses in home healthcare.

Author

Zolnoori, Maryam, Vergez, Sasha, Xu, Zidu, Esmaeili, Elyas, Zolnour, Ali, Briggs, Krystal Anne, Scroggins, Jihye Kim, Ebrahimabad, Seyed Farid Hosseini, Noble, James M, Topaz, Maxim, Bakken, Suzanne, Bowles, Kathryn H, Spens, Ian, Onorato, Nicole, Sridharan, Sridevi, and McDonald, Margaret V

Published
2024
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40. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study

Author

Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William (Bill), Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Chrem, Patricio, Chua, Jasmin, Chui, Helena, Cruchaga, Carlos, Day, Gregory S, De La Cruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Friedrichsen, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Häsler, Lisa, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William (Bill), Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Lopez, Oscar, Marsh, Jacob, Martinez, Rita, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, Mejia, Arlene, MountzMD, James, Mummery, Cath, Nadkarni, Neelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, O'Connor, Antoinette, Obermüller, Ulricke, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nick, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Morenas-Rodríguez, Estrella, Li, Yan, Franzmeier, Nicolai, Xiong, Chengjie, Suárez-Calvet, Marc, Fagan, Anne M, Schultz, Stephanie, Gordon, Brian A, Benzinger, Tammie L S, Hassenstab, Jason, McDade, Eric, Feederle, Regina, Karch, Celeste M, Schlepckow, Kai, Morris, John C, Kleinberger, Gernot, Nellgard, Bengt, Vöglein, Jonathan, Blennow, Kaj, Zetterberg, Henrik, Ewers, Michael, Jucker, Mathias, Levin, Johannes, Bateman, Randall J, and Haass, Christian

Published
2022
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41. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease

Author

Preische, Oliver, Schultz, Stephanie A, Apel, Anja, Kuhle, Jens, Kaeser, Stephan A, Barro, Christian, Gräber, Susanne, Kuder-Buletta, Elke, LaFougere, Christian, Laske, Christoph, Vöglein, Jonathan, Levin, Johannes, Masters, Colin L, Martins, Ralph, Schofield, Peter R, Rossor, Martin N, Graff-Radford, Neill R, Salloway, Stephen, Ghetti, Bernardino, Ringman, John M, Noble, James M, Chhatwal, Jasmeer, Goate, Alison M, Benzinger, Tammie LS, Morris, John C, Bateman, Randall J, Wang, Guoqiao, Fagan, Anne M, McDade, Eric M, Gordon, Brian A, and Jucker, Mathias

Subjects
Dementia, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, Neurosciences, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Clinical Research, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Neurological, Good Health and Well Being, Alzheimer Disease, Disease Progression, Humans, Mutation, Nerve Degeneration, Neurofilament Proteins, Dominantly Inherited Alzheimer Network, Medical and Health Sciences, Immunology
Abstract

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.

Published
2019

42. Variant-dependent heterogeneity in amyloid β burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study

Author

Chhatwal, Jasmeer P, Schultz, Stephanie A, McDade, Eric, Schultz, Aaron P, Liu, Lei, Hanseeuw, Bernard J, Joseph-Mathurin, Nelly, Feldman, Rebecca, Fitzpatrick, Colleen D, Sparks, Kathryn P, Levin, Johannes, Berman, Sarah B, Renton, Alan E, Esposito, Bianca T, Fernandez, Maria Vitoria, Sung, Yun Ju, Lee, Jae Hong, Klunk, William E, Hofmann, Anna, Noble, James M, Graff-Radford, Neill, Mori, Hiroshi, Salloway, Steven M, Masters, Colin L, Martins, Ralph, Karch, Celeste M, Xiong, Chengjie, Cruchaga, Carlos, Perrin, Richard J, Gordon, Brian A, Benzinger, Tammie L S, Fox, Nick C, Schofield, Peter R, Fagan, Anne M, Goate, Alison M, Morris, John C, Bateman, Randall J, Johnson, Keith A, and Sperling, Reisa A

Published
2022
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