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Robust reference group normative data for neuropsychological tests accounting for primary language use in Asian American older adults
- Arunima Kapoor, Jean K. Ho, Jung Yun Jang, Daniel A. Nation
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- Journal:
- Journal of the International Neuropsychological Society / Volume 30 / Issue 4 / May 2024
- Published online by Cambridge University Press:
- 01 March 2024, pp. 402-409
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Objective:
The present study aimed to develop neuropsychological norms for older Asian Americans with English as a primary or secondary language, using data from the National Alzheimer’s Coordinating Center (NACC).
Method:A normative sample of Asian American participants was derived from the NACC database using robust criteria: participants were cognitively unimpaired at baseline (i.e., no MCI or dementia) and remained cognitively unimpaired at 1-year follow-up. Clinical and demographic characteristics were compared between Primary and Secondary English speakers using analyses of variance for continuous measures and chi-square tests for categorical variables. Linear regression models compared neuropsychological performance between the groups, adjusting for demographics (age, sex, and education). Regression models were developed for clinical application to compute demographically adjusted z-scores.
Results:Secondary English speakers were younger than Primary English speakers (p < .001). There were significant differences between the groups on measures of mental status (Mini-Mental State Examination, p = .002), attention (Trail Making Test A, Digit Span Forward Total Score, p <.001), language (Boston Naming Test, Animal Fluency, Vegetable Fluency, p < .001), and executive function (Trail Making Test B, p = .02).
Conclusions:Separate normative data are needed for Primary vs. Secondary English speakers from Asian American backgrounds. We provide normative data on older Asian Americans to enable clinicians to account for English use in the interpretation of neuropsychological assessment scores.
6 Pulse Pressure and APOE ε4 Dose Interact to Affect Cerebral Blood Flow in Older Adults Without Dementia
- Lauren Edwards, Kelsey R Thomas, Alexandra J Weigand, Emily C Edmonds, Alexandra L Clark, Einat K Brenner, Daniel A Nation, Lisa Delano-Wood, Mark W Bondi, Katherine J Bangen
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 107-108
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Objective:
Alterations in cerebral blood flow (CBF) are associated with risk of cognitive decline and Alzheimer’s disease (AD). Although apolipoprotein E (APOE) ε4 and greater vascular risk burden have both been linked to reduced CBF in older adults, less is known about how APOE ε4 status and vascular risk may interact to influence CBF. We aimed to determine whether the effect of vascular risk on CBF varies by gene dose of APOE ε4 alleles (i.e., number of e4 alleles) in older adults without dementia.
Participants and Methods:144 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent arterial spin labeling (ASL) and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure assessment. Vascular risk was assessed using pulse pressure (systolic blood pressure -diastolic blood pressure), which is thought to be a proxy for arterial stiffening. Participants were classified by number of APOE ε4 alleles (n0 alleles = 87, m allele = 46, n2 alleles = 11). CBF in six FreeSurfer-derived a priori regions of interest (ROIs) vulnerable to AD were examined: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regression models tested the interaction between categorical APOE ε4 dose (0, 1, or 2 alleles) and continuous pulse pressure on CBF in each ROI, adjusting for age, sex, cognitive diagnosis (cognitively unimpaired vs. mild cognitive impairment), antihypertensive medication use, cerebral metabolism (FDG-PET composite), reference CBF region (precentral gyrus), and AD biomarker positivity defined using the ADNI-optimized phosphorylated tau/ß-amyloid ratio cut-off of > 0.0251 pg/ml.
Results:A significant pulse pressure X APOE ε4 dose interaction was found on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex (ps < .005). Among participants with two e4 alleles, higher pulse pressure was significantly associated with lower CBF (ps < .001). However, among participants with zero or one ε4 allele, there was no significant association between pulse pressure and CBF (ps > .234). No significant pulse pressure X APOE ε4 dose interaction was found in the inferior temporal cortex, rostral middle frontal gyrus, or medial orbitofrontal cortex (ps > .109). Results remained unchanged when additionally controlling for general vascular risk assessed via the modified Hachinski Ischemic Scale.
Conclusions:These findings demonstrate that the cross-sectional association between pulse pressure and region-specific CBF differs by APOE ε4 dose. In particular, a detrimental effect of elevated pulse pressure on CBF in AD-vulnerable regions was found only among participants with the e4/e4 genotype. Our findings suggest that pulse pressure may play a mechanistic role in neurovascular unit dysregulation for those genetically at greater risk for AD. Given that pulse pressure is just one of many potentially modifiable vascular risk factors for AD, future studies should seek to examine how these other factors (e.g., diabetes, high cholesterol) may interact with APOE genotype to affect cerebrovascular dysfunction.
32 Elevated Plasma pTau-181 is Associated with Lower Global Cognition and Executive Function in Older Adults
- Arunima Kapoor, Jean K Ho, Shubir Dutt, Yanrong Li, John P Alitin, Jung Yun Jang, Aimee Gaubert, Amy Nguyen, Belinda Yew, Anna E Blanken, Isabel J Sible, Anisa Marshall, Fatemah Shenasa, Alessandra Martini, Kathleen E Rodgers, Elizabeth Head, Daniel A Nation
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 907-908
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Objective:
Aggregation of phosphorylated tau (pTau) is a hallmark feature of Alzheimer’s disease (AD). Novel assays now allow pTau to be measured in plasma. Elevated plasma pTau predicts subsequent development of AD, cortical atrophy and AD-related pathologies in the brain. We aimed to determine whether elevated pTau is associated with cognitive functioning in older adults prior to the development of dementia.
Participants and Methods:Independently living older adults (N = 48, mean age = 70.0 years; SD = 7.7; age range 55-88 years; 35.4% male) free of dementia or clinical stroke were recruited from the community and underwent blood draw and neuropsychological assessment. Plasma was assayed using the Quanterix Simoa® pTau-181 V2 Advantage Kit to quantify pTau-181 levels and APOE genotyping was conducted on the blood cell pellet fraction obtained from plasma separation. Global cognition was assessed using the Dementia Rating Scale-2 (DRS-2) and executive function was assessed using the Stroop, D-KEFS-2 Fluency, and Trails Making Test. Diagnosis of mild cognitive impairment (MCI) was determined based on overall neuropsychological performance. Participants were diagnosed as MCI if they scored >1 SD below norm-referenced values on 2 or more tests within a domain (language, executive, memory) or on 3 tests across domains.
Results:Multiple linear regression analysis revealed a significant negative association between plasma pTau-181 levels and DRS-2 (B = -2.57, 95% CI (-3.68, -1.47), p <.001), Stroop Color-Word score (B = -2.64, 95% CI (-4.56, - 0.71), p = .009) and Fruits and Vegetables Fluency (B = -1.67, 95% CI (-2.84, -0.49), p = .007), adjusting for age, sex, education and APOE4 status. MCI diagnosis was determined for 43 participants, of which 8 (18.6%) met criteria. Logistic regression analysis revealed that pTau-181 levels are associated with increased odds of MCI diagnosis (OR = 2.18, 95% CI (1.01, 4.68), p = .046), after accounting for age, sex, education and APOE4 status.
Conclusions:Elevated plasma pTau-181 is associated with worse cognition, particularly executive function, and predicts MCI diagnosis in older adults. Higher plasma pTau-181 was associated with increased odds of MCI diagnosis. Detection of pTau-181 in plasma allows a novel, non-invasive method to detect burden of one form of AD pathology. These findings lend support to the use of plasma pTau-181 as a valuable marker in detecting even early cognitive changes prior to the development of AD. Additional longitudinal studies are warranted to explore the prognostic value of plasma pTau-181 over time.
5 Associations Between Regional Perfusion and Locus Coeruleus MRI Contrast are Moderated by Plasma Alzheimer’s Disease Biomarkers in Older Adults
- Shubir Dutt, Shelby L Bachman, Yanrong Li, Belinda Yew, Jung Y Jang, Jean K Ho, Kaoru Nashiro, Jungwon Min, Hyun Joo Yoo, Aimee Gaubert, Amy Nguyen, Isabel J Sible, Anna E Blanken, Anisa J Marshall, Arunima Kapoor, John P Alitin, Kim Hoang, Alessandra C Martini, Elizabeth Head, Xingfeng Shao, Danny J J Wang, Mara Mather, Daniel A Nation
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 610-611
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The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion and probed whether varying levels of plasma Alzheimer’s disease (AD) biomarkers (Aß42/40 ratio and ptau181) moderated these relationships.
Participants and Methods:64 dementia-free community-dwelling older adults (ages 55-87) recruited across two studies underwent structural and functional neuroimaging on the same MRI scanner. 3D-pCASL MRI measured regional cerebral blood flow in limbic and frontal cortical regions, while T1-FSE MRI quantified rostral LC-MRI contrast, a well-established proxy measure of LC structural integrity. A subset of participants underwent fasting blood draw to measure plasma AD biomarker concentrations (Aß42/40 ratio and ptau181). Multiple linear regression models examined associations between perfusion and LC integrity, with rostral LC-MRI contrast as predictor, regional CBF as outcome, and age and study as covariates. Moderation analyses included additional terms for plasma AD biomarker concentration and plasma x LC interaction.
Results:Greater rostral LC-MRI contrast was linked to lower regional perfusion in limbic regions, such as the amygdala (ß = -0.25, p = 0.049) and entorhinal cortex (ß = -0.20, p = 0.042), but was linked to higher regional perfusion in frontal cortical regions, such as the lateral (ß = 0.28, p = 0.003) and medial (ß = 0.24, p = 0.05) orbitofrontal (OFC) cortices. Plasma amyloid levels moderated the relationship between rostral LC and amygdala CBF (Aß42/40 ratio x rostral LC interaction term ß = -0.31, p = 0.021), such that as plasma Aß42/40 ratio decreased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and amygdala perfusion decreased. Plasma ptau181levels moderated the relationship between rostral LC and entorhinal CBF (ptau181 x rostral LC interaction term ß = 0.64, p = 0.001), such that as ptau181 increased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and entorhinal perfusion decreased. For frontal cortical regions, ptau181 levels moderated the relationship between rostral LC and lateral OFC perfusion (ptau181 x rostral LC interaction term ß = -0.54, p = .004), as well as between rostral LC and medial OFC perfusion (ptau181 x rostral LC interaction term ß = -0.53, p = .005), such that as ptau181 increased (i.e., greater pathology), the strength of the positive relationship between rostral LC integrity and frontal perfusion decreased.
Conclusions:LC integrity is linked to regional cortical perfusion in non-demented older adults, and these relationships are moderated by plasma AD biomarker concentrations. Variable directionality of the associations between the LC and frontal versus limbic perfusion, as well as the differential moderating effects of plasma AD biomarkers, may signify a compensatory mechanism and a shifting pattern of hyperemia in the presence of aggregating AD pathology. Linking LC integrity and cerebrovascular regulation may represent an important understudied pathway of dementia risk and may help to bridge competing theories of dementia progression in preclinical AD studies.
96 Short-Term Blood Pressure Variability and Cerebrovascular Health in OlderaAdults
- Isabel J Sible, Belinda Yew, Arunima Kapoor, Jung Y Jang, John Paul M Alitin, Shubir Dutt, Yanrong Li, Anna E Blanken, Jean K Ho, Anisa J Marshall, Fatemah Shenasa, Aimee Gaubert, Amy Nguyen, Kathleen E Rodgers, Virginia E Sturm, Daniel A Nation
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 195-196
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Objective:
Blood pressure variability (BPV), independent of traditionally targeted average blood pressure levels, is an emerging vascular risk factor for stroke, cerebrovascular disease, and dementia, possibly through links with vascular-endothelial injury. Recent evidence suggests visit-to-visit (e.g., over months, years) BPV is associated with cerebrovascular disease severity, but less is known about relationships with short-term (e.g., < 24 hours) fluctuations in blood pressure. Additionally, it is unclear how BPV may be related to angiogenic growth factors that play a role in cerebral arterial health.
Participants and Methods:We investigated relationships between short-term BPV, white matter hyperintensities on MRI, and levels of plasma vascular endothelial growth factor (VEGF) in a sample of community-dwelling older adults (n = 57, ages 55-88) without history of dementia or stroke. Blood pressure was collected continuously during a 5-minute resting period. BPV was calculated as variability independent of mean, a commonly used index of BPV uncorrelated with average blood pressure levels. Participants underwent T2-FLAIR MRI to determine severity of white matter lesion burden. Severity of lesions was classified as Fazekas scores (0-3). Participants also underwent venipuncture to determine levels of plasma VEGF. Ordinal logistic regression examined the association between BPV and Fazekas scores. Multiple linear regression explored relationships between BPV and VEGF. Models controlled for age, sex, and average blood pressure.
Results:Elevated BPV was related to greater white matter lesion burden (i.e., Fazekas score) (systolic: OR = 1.17 [95% CI 1.01, 1.37]; p = .04; diastolic: OR = 2.47 [95% CI 1.09, 5.90]; p = .03) and increased levels of plasma VEGF (systolic: ß = .39 [95% CI .11, .67]; adjusted R2 = .16; p = .007; diastolic: ß = .48 [95% CI .18, .78]; adjusted R2 = .18; p = .003).
Conclusions:Findings suggest short-term BPV may be related to cerebrovascular disease burden and angiogenic growth factors relevant to cerebral arterial health, independent of average blood pressure. Understanding the role of BPV in cerebrovascular disease and vascular-endothelial health may help elucidate the increased risk for stroke and dementia associated with elevated BPV.
Neuropsychological Profiles and Trajectories in Preclinical Alzheimer’s Disease
- Jean K. Ho, Daniel A. Nation, for the Alzheimer’s Disease Neuroimaging Initiative
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- Journal:
- Journal of the International Neuropsychological Society / Volume 24 / Issue 7 / August 2018
- Published online by Cambridge University Press:
- 30 April 2018, pp. 693-702
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Objectives: The present study investigated the independent and synergistic effects of amyloid beta (Aβ1-42) and phosphorylated tau (Ptau) pathologies on neuropsychological profiles and trajectories in cognitively normal older adults. Methods: Alzheimer’s Disease Neuroimaging Initiative participants identified as cognitively normal at baseline underwent longitudinal assessment (N=518; 0, 12, 24, 36 months), baseline lumbar puncture and follow-up cognitive exams. Cerebral spinal fluid (CSF) biomarker profiles (Aβ-Ptau-, Aβ+Ptau-, Aβ-Ptau+, Aβ+Ptau+) were compared on baseline profiles and trajectories for memory (Rey Auditory Verbal Learning Test), attention/executive function (Trail Making Test, A and B), language (Animal Fluency, Vegetable Fluency, Boston Naming Test) and processing speed (Digit Symbol) using multilevel models. Results: The Aβ+Ptau+ group exhibited significantly worse baseline performance on tests of memory and executive function relative to the Aβ-Ptau+ and Aβ-Ptau- groups. The Aβ+Ptau- group fell between the Aβ+Ptau+ participants and the Aβ-Ptau- and Aβ-Ptau+ groups on all three cognitive domains and exhibited worse baseline executive function. The Aβ-Ptau+ group performed worse than Aβ-Ptau- participants on processing speed. Over 36-month follow-up, the Aβ+Ptau+ group exhibited the greatest declines in memory and semantic fluency compared to all other groups. Conclusions: Cognitively normal older adults with both Aβ and Ptau pathology exhibited the weakest profile, marked by the worst memory decline compared to the other groups. Other subtle changes in this group included declines in executive function and semantic fluency. Those with Ptau pathology alone showed slowed processing speed, and those with Aβ pathology alone showed worse attention and executive function compared to biomarker negative participants. (JINS, 2018, 24, 1–10)
Mechanisms of Memory Dysfunction during High Altitude Hypoxia Training in Military Aircrew
- Daniel A. Nation, Mark W. Bondi, Ellis Gayles, Dean C. Delis
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- Journal of the International Neuropsychological Society / Volume 23 / Issue 1 / January 2017
- Published online by Cambridge University Press:
- 07 December 2016, pp. 1-10
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Objectives: Cognitive dysfunction from high altitude exposure is a major cause of civilian and military air disasters. Pilot training improves recognition of the early symptoms of altitude exposure so that countermeasures may be taken before loss of consciousness. Little is known regarding the nature of cognitive impairments manifesting within this critical window when life-saving measures may still be taken. Prior studies evaluating cognition during high altitude simulation have predominantly focused on measures of reaction time and other basic attention or motor processes. Memory encoding, retention, and retrieval represent critical cognitive functions that may be vulnerable to acute hypoxic/ischemic events and could play a major role in survival of air emergencies, yet these processes have not been studied in the context of high altitude simulation training. Methods: In a series of experiments, military aircrew underwent neuropsychological testing before, during, and after brief (15 min) exposure to high altitude simulation (20,000 ft) in a pressure-controlled chamber. Results: Acute exposure to high altitude simulation caused rapid impairment in learning and memory with relative preservation of basic visual and auditory attention. Memory dysfunction was predominantly characterized by deficiencies in memory encoding, as memory for information learned during high altitude exposure did not improve after washout at sea level. Retrieval and retention of memories learned shortly before altitude exposure were also impaired, suggesting further impairment in memory retention. Conclusions: Deficits in memory encoding and retention are rapidly induced upon exposure to high altitude, an effect that could impact life-saving situational awareness and response. (JINS, 2017, 23, 1–10)
Patterns of Cortical and Subcortical Amyloid Burden across Stages of Preclinical Alzheimer’s Disease
- Emily C. Edmonds, Katherine J. Bangen, Lisa Delano-Wood, Daniel A. Nation, Ansgar J. Furst, David P. Salmon, Mark W. Bondi, for the Alzheimer’s Disease Neuroimaging Initiative
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- Journal:
- Journal of the International Neuropsychological Society / Volume 22 / Issue 10 / November 2016
- Published online by Cambridge University Press:
- 01 December 2016, pp. 978-990
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Objectives: We examined florbetapir positron emission tomography (PET) amyloid scans across stages of preclinical Alzheimer’s disease (AD) in cortical, allocortical, and subcortical regions. Stages were characterized using empirically defined methods. Methods: A total of 312 cognitively normal Alzheimer’s Disease Neuroimaging Initiative participants completed a neuropsychological assessment and florbetapir PET scan. Participants were classified into stages of preclinical AD using (1) a novel approach based on the number of abnormal biomarkers/cognitive markers each individual possessed, and (2) National Institute on Aging and the Alzheimer’s Association (NIA-AA) criteria. Preclinical AD groups were compared to one another and to a mild cognitive impairment (MCI) sample on florbetapir standardized uptake value ratios (SUVRs) in cortical and allocortical/subcortical regions of interest (ROIs). Results: Amyloid deposition increased across stages of preclinical AD in all cortical ROIs, with SUVRs in the later stages reaching levels seen in MCI. Several subcortical areas showed a pattern of results similar to the cortical regions; however, SUVRs in the hippocampus, pallidum, and thalamus largely did not differ across stages of preclinical AD. Conclusions: Substantial amyloid accumulation in cortical areas has already occurred before one meets criteria for a clinical diagnosis. Potential explanations for the unexpected pattern of results in some allocortical/subcortical ROIs include lack of correspondence between (1) cerebrospinal fluid and florbetapir PET measures of amyloid, or between (2) subcortical florbetapir PET SUVRs and underlying neuropathology. Findings support the utility of our novel method for staging preclinical AD. By combining imaging biomarkers with detailed cognitive assessment to better characterize preclinical AD, we can advance our understanding of who is at risk for future progression. (JINS, 2016, 22, 978–990)
Are Empirically-Derived Subtypes of Mild Cognitive Impairment Consistent with Conventional Subtypes?
- Lindsay R. Clark, Lisa Delano-Wood, David J. Libon, Carrie R. McDonald, Daniel A. Nation, Katherine J. Bangen, Amy J. Jak, Rhoda Au, David P. Salmon, Mark W. Bondi
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- Journal:
- Journal of the International Neuropsychological Society / Volume 19 / Issue 6 / July 2013
- Published online by Cambridge University Press:
- 03 April 2013, pp. 635-645
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Given the importance of identifying dementia prodromes for future treatment efforts, we examined two methods of diagnosing mild cognitive impairment (MCI) and determined whether empirically-derived MCI subtypes of these diagnostic methods were consistent with one another as well as with conventional MCI subtypes (i.e., amnestic, non-amnestic, single-domain, multi-domain). Participants were diagnosed with MCI using either conventional Petersen/Winblad criteria (n = 134; >1.5 SDs below normal on one test within a cognitive domain) or comprehensive neuropsychological criteria developed by Jak et al. (2009) (n = 80; >1 SD below normal on two tests within a domain), and the resulting samples were examined via hierarchical cluster and discriminant function analyses. Results showed that neuropsychological profiles varied depending on the criteria used to define MCI. Both criteria revealed an Amnestic subtype, consistent with prodromal Alzheimer's disease (AD), and a Mixed subtype that may capture individuals in advanced stages of MCI. The comprehensive criteria uniquely yielded Dysexecutive and Visuospatial subtypes, whereas the conventional criteria produced a subtype that performed within normal limits, suggesting its susceptibility to false positive diagnostic errors. Whether these empirically-derived MCI subtypes correspond to dissociable neuropathologic substrates and represent reliable prodromes of dementia will require additional follow-up. (JINS, 2013, 19, 1–11)
Contributors
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- By Blair C. Armstrong, David A. Balota, Lawrence W. Barsalou, Jos J. A. Van Berkum, Lera Boroditsky, Gregory A. Bryant, Cristina Cacciari, Joana Cholin, Morten H. Christiansen, Stella Christie, Eve V. Clark, Herbert H. Clark, Eliana Colunga, John F. Connolly, Michael J. Cortese, Seana Coulson, George S. Cree, Christopher M. Crew, Gary S. Dell, Kevin Diependaele, Judit Druks, Thomas A. Farmer, Anne Fernald, Kelly Forbes, Carol A. Fowler, Michael Frank, Stephen J. Frost, Dedre Gentner, Raymond W. Gibbs, Monica Gonzalez-Marquez, Arthur C. Graesser, Jonathan Grainger, Zenzi M. Griffin, Mary Hare, Harlan D. Harris, Marc F. Joanisse, Leonard Katz, Albert Kim, Gina R. Kuperberg, Nicole Landi, Birte Loenneker-Rodman, Danielle S. MacNamara, James S. Magnuson, Ken McRae, W. Einar Mencl, Daniel Mirman, Jennifer B. Misyak, Srini Narayanan, Kate Nation, Randy L. Newman, Lee Osterhout, Roberto Padovani, Karalyn Patterson, Kenneth R. Pugh, Terry Regier, Douglas Roland, Jay G. Rueckl, Vasile Rus, Jenny R. Saffran, Sarah D. Sahni, Arthur G. Samuel, Rebecca Sandak, Dominiek Sandra, Sophie Scott, Mark S. Seidenberg, Linda B. Smith, Michael J. Spivey, Meghan Sumner, Daniel Tranel, Gabriella Vigliocco, Nicole L. Wilson, Anna Woollams
- Edited by Michael Spivey, Ken McRae, University of Western Ontario, Marc Joanisse, University of Western Ontario
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- The Cambridge Handbook of Psycholinguistics
- Published online:
- 05 November 2012
- Print publication:
- 20 August 2012, pp xi-xiv
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