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64 Neuroimaging Evidence of Neurodegenerative Disease in Former Professional American Football Players Who “Fail” Validity Testing: A Case Series
- Ranjani Shankar, Julia Culhane, Leonardo Iaccarino, Chris Nowinski, Nidhi Mundada, Karen Smith, Jeremy Tanner, Charles Windon, Yorghos Tripodis, Gustavo Mercier, Thor D Stein, Anne C McKee, Robert A Stern, Neil Kowall, Bruce L Miller, Jesse Mez, Ron Killiany, Gil D Rabinovici, Michael L Alosco, Breton M Asken
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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. 574-575
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Objective:
Former professional American football players have a high relative risk for neurodegenerative diseases like chronic traumatic encephalopathy (CTE). Interpreting low cognitive test scores in this population occasionally is complicated by performance on validity testing. Neuroimaging biomarkers may help inform whether a neurodegenerative disease is present in these situations. We report three cases of retired professional American football players who completed comprehensive neuropsychological testing, but “failed” performance validity tests, and underwent multimodal neuroimaging (structural MRI, Aß-PET, and tau-PET).
Participants and Methods:Three cases were identified from the Focused Neuroimaging for the Neurodegenerative Disease Chronic Traumatic Encephalopathy (FIND-CTE) study, an ongoing multimodal imaging study of retired National Football League players with complaints of progressive cognitive decline conducted at Boston University and the UCSF Memory and Aging Center. Participants were relatively young (age range 55-65), had 16 or more years of education, and two identified as Black/African American. Raw neuropsychological test scores were converted to demographically-adjusted z-scores. Testing included standalone (Test of Memory Malingering; TOMM) and embedded (reliable digit span, RDS) performance validity measures. Validity cutoffs were TOMM Trial 2 < 45 and RDS < 7. Structural MRIs were interpreted by trained neurologists. Aß-PET with Florbetapir was used to quantify cortical Aß deposition as global Centiloids (0 = mean cortical signal for a young, cognitively normal, Aß negative individual in their 20s, 100 = mean cortical signal for a patient with mild-to-moderate Alzheimer’s disease dementia). Tau-PET was performed with MK-6240 and first quantified as standardized uptake value ratio (SUVR) map. The SUVR map was then converted to a w-score map representing signal intensity relative to a sample of demographically-matched healthy controls.
Results:All performed in the average range on a word reading-based estimate of premorbid intellect. Contribution of Alzheimer’s disease pathology was ruled out in each case based on Centiloids quantifications < 0. All cases scored below cutoff on TOMM Trial 2 (Case #1=43, Case #2=42, Case #3=19) and Case #3 also scored well below RDS cutoff (2). Each case had multiple cognitive scores below expectations (z < -2.0) most consistently in memory, executive function, processing speed domains. For Case #1, MRI revealed mild atrophy in dorsal fronto-parietal and medial temporal lobe (MTL) regions and mild periventricular white matter disease. Tau-PET showed MTL tau burden modestly elevated relative to controls (regional w-score=0.59, 72nd%ile). For Case #2, MRI revealed cortical atrophy, mild hippocampal atrophy, and a microhemorrhage, with no evidence of meaningful tau-PET signal. For Case #3, MRI showed cortical atrophy and severe white matter disease, and tau-PET revealed significantly elevated MTL tau burden relative to controls (w-score=1.90, 97th%ile) as well as focal high signal in the dorsal frontal lobe (overall frontal region w-score=0.64, 74th%ile).
Conclusions:Low scores on performance validity tests complicate the interpretation of the severity of cognitive deficits, but do not negate the presence of true cognitive impairment or an underlying neurodegenerative disease. In the rapidly developing era of biomarkers, neuroimaging tools can supplement neuropsychological testing to help inform whether cognitive or behavioral changes are related to a neurodegenerative disease.
73 Sex Differences in Verbal Memory and Alzheimer’s Disease Biomarkers in Clinically Normal Older Adults: Role of SNAP-25 Genetics
- Rowan Saloner, Emily W Paolillo, Kevin J Wojta, Corrina Fonseca, Eva Q Gontrum, Argentina Lario-Lago, Gil D Rabinovici, Jennifer S Yokoyama, Jessica E Rexach, Joel H Kramer, Kaitlin B Casaletto
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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. 377-378
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Objective:
Females outperform males on verbal memory tests across the lifespan. Females also exhibit greater Alzheimer’s disease (AD) pathology at preclinical stages and faster atrophy and memory decline during disease progression. Synaptic factors influence the accumulation of AD proteins and may underpin cognitive resilience against AD, though their role in sex-related cognitive and brain aging is unknown. We tested interactive effects of sex and genetic variation in SNAP-25, which encodes a presynaptic protein that is dysregulated in AD, on cognition and AD-related biomarkers in cognitively unimpaired older adults.
Participants and Methods:Participants included a discovery cohort of 311 cognitively unimpaired older adults (age mean [range]=70 [44-100]; 56% female; education mean=17.3 years; 24% APOE-e4+), and an independent, demographically-comparable replication cohort of 82 cognitively unimpaired older adults. All participants completed neurological examination, informant interview (CDR=0), neuropsychological testing, and blood draw. Participants were genotyped for the SNAP-25 rs105132 (T→C) single-nucleotide polymorphism via Sequenom (discovery cohort) or Omni 2.5M (replication cohort). In vitro models show the C-allele is associated with increased SNAP-25 expression compared to T/T genotype. A subset of the discovery cohort completed structural MRI (n=237) and florbetapir Aβ-PET (n=97). Regression analyses across cohorts examined the interaction of sex and SNAP-25 genotype (T/T homozygotes [53% prevalence] vs. C-carriers [47% prevalence]) on cognitive z-scores (verbal memory, visual memory, executive function, language), adjusting for age, education, APOE-e4, and APOE-e4 x sex. Discovery cohort models also examined sex-dependent effects of SNAP-25 on temporal lobe volumes and Aβ-PET positivity.
Results:SNAP-25 T/T vs. C-carriers did not differ on demographics or APOE-e4 status across cohorts or within sexes. Sex interacted with SNAP-25 to predict verbal memory (p=.024) and language (p=.008) in the discovery cohort, with similar verbal memory differences observed in the replication cohort. In sex-stratified analyses, C-carriers exhibited better verbal memory than T/T carriers among females (d range: 0.41 to 0.64, p range: .008 to .046), but not males (d range: 0.03 to 0.12, p range: .499 to .924). In SNAP-25-stratified analyses, female verbal memory advantages were larger among C-carriers (d range: 0.74 to 0.89, p range: <.001 to .034) than T/T (d range: 0.13 to 0.36, p range: .022 to .682). Sex also interacted with SNAP-25 to predict Aβ-PET positivity (p=.046) such that female C-carriers exhibited the lowest prevalence of Aβ-PET positivity (13%) compared to other groups (23% to 35%). C-carriers exhibited larger temporal lobe volumes across sex, yet this effect only reached statistical significance among females (females: d=0.41, p=.018; males: d=0.26, p=.179). In post-hoc analyses, larger temporal lobe volumes were selectively associated with better verbal memory in female C-carriers (β=0.36, p=.026; other groups: |βs|<0.10, ps>.538).
Conclusions:Among clinically normal older adults, we demonstrate female-specific advantages of carrying the SNAP-25 rs105132 C-allele across cognitive, neural, and molecular markers of AD. The rs105132 C-allele putatively reflects higher endogenous levels of SNAP-25. Our findings suggest a female-specific pathway of cognitive and neural resistance, whereby higher genetically-driven expression of SNAP-25 may reduce likelihood of amyloid plaque formation and support verbal memory, possibly through fortification of temporal lobe structure.
Visuospatial Functioning in the Primary Progressive Aphasias
- Christa L. Watson, Katherine Possin, I. Elaine Allen, H. Isabel Hubbard, Marita Meyer, Ariane E. Welch, Gil D. Rabinovici, Howard Rosen, Katherine P. Rankin, Zachary Miller, Miguel A. Santos-Santos, Joel H. Kramer, Bruce L. Miller, Maria Luisa Gorno-Tempini
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- Journal of the International Neuropsychological Society / Volume 24 / Issue 3 / March 2018
- Published online by Cambridge University Press:
- 17 October 2017, pp. 259-268
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Objectives: The aim of this study was to identify whether the three main primary progressive aphasia (PPA) variants would show differential profiles on measures of visuospatial cognition. We hypothesized that the logopenic variant would have the most difficulty across tasks requiring visuospatial and visual memory abilities. Methods: PPA patients (n=156), diagnosed using current criteria, and controls were tested on a battery of tests tapping different aspects of visuospatial cognition. We compared the groups on an overall visuospatial factor; construction, immediate recall, delayed recall, and executive functioning composites; and on individual tests. Cross-sectional and longitudinal comparisons were made, adjusted for disease severity, age, and education. Results: The logopenic variant had significantly lower scores on the visuospatial factor and the most impaired scores on all composites. The nonfluent variant had significant difficulty on all visuospatial composites except the delayed recall, which differentiated them from the logopenic variant. In contrast, the semantic variants performed poorly only on delayed recall of visual information. The logopenic and nonfluent variants showed decline in figure copying performance over time, whereas in the semantic variant, this skill was remarkably preserved. Conclusions: This extensive examination of performance on visuospatial tasks in the PPA variants solidifies some previous findings, for example, delayed recall of visual stimuli adds value in differential diagnosis between logopenic variant PPA and nonfluent variant PPA variants, and illuminates the possibility of common mechanisms that underlie both linguistic and non-linguistic deficits in the variants. Furthermore, this is the first study that has investigated visuospatial functioning over time in the PPA variants. (JINS, 2018, 24, 259–268)
Canadian Consensus Guidelines on Use of Amyloid Imaging in Canada: Update and Future Directions from the Specialized Task Force on Amyloid imaging in Canada
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- Robert Laforce, Jr., Pedro Rosa-Neto, Jean-Paul Soucy, Gil D. Rabinovici, Bruno Dubois, S. Gauthier
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- Journal:
- Canadian Journal of Neurological Sciences / Volume 43 / Issue 4 / July 2016
- Published online by Cambridge University Press:
- 26 February 2016, pp. 503-512
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Positron emission tomography (PET) imaging of brain amyloid beta is now clinically available in several countries including the United States and the United Kingdom, but not Canada. It has become an established technique in the field of neuroimaging of aging and dementia, with data incorporated in the new consensus guidelines for the diagnosis of Alzheimer disease and predementia Alzheimer’s disease–related conditions. At this point, there are three US Food and Drug Administration– and European Union–approved tracers. Guided by appropriate use criteria developed in 2013 by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging, the utility of amyloid imaging in medical practice is now supported by a growing body of research. In this paper, we aimed to provide an update on the 2012 Canadian consensus guidelines to dementia care practitioners on proper use of amyloid imaging. We also wished to generate momentum for the industry to submit a new drug proposal to Health Canada. A group of local, national, and international dementia experts and imaging specialists met to discuss scenarios in which amyloid PET could be used appropriately. Peer-reviewed and published literature between January 2004 and May 2015 was searched. Technical and regulatory considerations pertaining to Canada were considered. The results of a survey of current practices in Canadian dementia centers were considered. A set of specific clinical and research guidelines was agreed on that defines the types of patients and clinical circumstances in which amyloid PET could be used in Canada. Future research directions were also outlined, notably the importance of studies that would assess the pharmaco-economics of amyloid imaging.
Contributors
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- By Dag Aarsland, Adrià Arboix, Carlos Bazán, James T. Becker, Sylvie Belleville, Kevin M. Biglan, Sandra E. Black, Mariana Blanco, Rémi W. Bouchard, Bruce J. Brew, David J. Burn, Leonardo Caixeta, Richard Camicioli, Paulo Caramelli, Neil Cashman, Nicholas W. S. Davies, Yan Deschaintre, Rachel S. Doody, Bruno Dubois, Uwe Ehrt, Stephane Epelbaum, Ryan V. V. Evans, Joseph M. Ferrara, Bruno Franchi, Morris Freedman, Anders Gade, Serge Gauthier, Marta Grau-Olivares, Matthew E. Growdon, Will Guest, Marie Christie Guiot, Shahul Hameed, Mirna Lie Hosogi-Senaha, Ging-Yuek Robin Hsiung, Masamichi Ikawa, Rajive Jassal, Vesna Jelic, Peter Johannsen, Edward S. Johnson, Mary M. Kenan, Bert-Jan Kerklaan, Benjamin Lam, Gabriel C. Léger, Gabriel Leonard, Emilie Lepage, Irene Litvan, Oscar L. Lopez, Ian R. A. Mackenzie, Mario Masellis, Fodi Massoud, Paige Moorhouse, John C. Morris, Taim Muayqil, Yannick Nadeau, Inger Nennesmo, Jørgen E. Nielsen, Ricardo Nitrini, Sven-Eric Pålhagen, Robert Perry, Gerald Pfeffer, Machiel Pleizier, Steffen Plickert, Gil D. Rabinovici, Philippe H. Robert, Lothar Resch, Gustavo C. Román, Maxime Ros, Pedro Rosa-Neto, Aiman Sanosi, Philip Scheltens, Christian Schmidt, Eric Schmidt, Jean-Paul Soucy, Jette Stokholm, David Summers, Rawan Tarawneh, Louis Verret, Huali Wang, Bengt Winblad, Makoto Yoneda, Xin Yu, Inga Zerr
- Edited by Serge Gauthier, McGill University, Montréal, Pedro Rosa-Neto, McGill University, Montréal
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- Case Studies in Dementia
- Published online:
- 16 May 2011
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- 21 April 2011, pp viii-xiv
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Case 10 - Difficulty playing tennis
- Edited by Serge Gauthier, McGill University, Montréal, Pedro Rosa-Neto, McGill University, Montréal
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- Case Studies in Dementia
- Published online:
- 16 May 2011
- Print publication:
- 21 April 2011, pp 64-70
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Summary
This chapter talks about an 85-year-old man who was enrolled in a longitudinal study of healthy aging and Alzheimer disease (AD) at the Washington University Alzheimer Disease Research Center (ADRC). He was diagnosed with dementia of the Alzheimer's type (DAT) and died shortly after his 91st birthday. A psychometric battery was performed within 2 weeks of each annual clinical assessment. The detection of dementia at the ADRC is based on observations from a collateral source of decline from an individual's previously attained level of cognitive function that is sufficient to interfere with that individual's customary activities. This case illustrates that the accurate diagnosis of DAT can be made in individuals who meet criteria for mild cognitive impairment (MCI). The DAT diagnosis was based on informant observations that the individual had declined from previously attained levels of cognitive function, rather than comparing his cognitive performance to normative values.