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4 Evaluating Plasma GFAP for the Detection of Alzheimer’s Disease Dementia
- Madeline Ally, Henrik Zetterberg, Kaj Blennow, Nicholas J. Ashton, Thomas K. Karikari, Hugo Aparicio, Michael A. Sugarman, Brandon Frank, Yorghos Tripodis, Ann C. McKee, Thor D. Stein, Brett Martin, Joseph N. Palmisano, Eric G. Steinberg, Irene Simkina, Lindsay Farrer, Gyungah Jun, Katherine W. Turk, Andrew E. Budson, Maureen K. O’Connor, Rhoda Au, Wei Qiao Qiu, Lee E. Goldstein, Ronald Killiany, Neil W. Kowall, Robert A. Stern, Jesse Mez, Michael L. Alosco
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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. 408-409
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Objective:
Blood-based biomarkers represent a scalable and accessible approach for the detection and monitoring of Alzheimer’s disease (AD). Plasma phosphorylated tau (p-tau) and neurofilament light (NfL) are validated biomarkers for the detection of tau and neurodegenerative brain changes in AD, respectively. There is now emphasis to expand beyond these markers to detect and provide insight into the pathophysiological processes of AD. To this end, a reactive astrocytic marker, namely plasma glial fibrillary acidic protein (GFAP), has been of interest. Yet, little is known about the relationship between plasma GFAP and AD. Here, we examined the association between plasma GFAP, diagnostic status, and neuropsychological test performance. Diagnostic accuracy of plasma GFAP was compared with plasma measures of p-tau181 and NfL.
Participants and Methods:This sample included 567 participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC) Longitudinal Clinical Core Registry, including individuals with normal cognition (n=234), mild cognitive impairment (MCI) (n=180), and AD dementia (n=153). The sample included all participants who had a blood draw. Participants completed a comprehensive neuropsychological battery (sample sizes across tests varied due to missingness). Diagnoses were adjudicated during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using the Simoa platform. Binary logistic regression analyses tested the association between GFAP levels and diagnostic status (i.e., cognitively impaired due to AD versus unimpaired), controlling for age, sex, race, education, and APOE e4 status. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate diagnostic groups compared with plasma p-tau181 and NfL. Linear regression models tested the association between plasma GFAP and neuropsychological test performance, accounting for the above covariates.
Results:The mean (SD) age of the sample was 74.34 (7.54), 319 (56.3%) were female, 75 (13.2%) were Black, and 223 (39.3%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having cognitive impairment (GFAP z-score transformed: OR=2.233, 95% CI [1.609, 3.099], p<0.001; non-z-transformed: OR=1.004, 95% CI [1.002, 1.006], p<0.001). ROC analyses, comprising of GFAP and the above covariates, showed plasma GFAP discriminated the cognitively impaired from unimpaired (AUC=0.75) and was similar, but slightly superior, to plasma p-tau181 (AUC=0.74) and plasma NfL (AUC=0.74). A joint panel of the plasma markers had greatest discrimination accuracy (AUC=0.76). Linear regression analyses showed that higher GFAP levels were associated with worse performance on neuropsychological tests assessing global cognition, attention, executive functioning, episodic memory, and language abilities (ps<0.001) as well as higher CDR Sum of Boxes (p<0.001).
Conclusions:Higher plasma GFAP levels differentiated participants with cognitive impairment from those with normal cognition and were associated with worse performance on all neuropsychological tests assessed. GFAP had similar accuracy in detecting those with cognitive impairment compared with p-tau181 and NfL, however, a panel of all three biomarkers was optimal. These results support the utility of plasma GFAP in AD detection and suggest the pathological processes it represents might play an integral role in the pathogenesis of AD.
5 Antemortem Plasma GFAP Predicts Alzheimer’s Disease Neuropathological Changes
- Madeline Ally, Henrik Zetterberg, Kaj Blennow, Nicholas J. Ashton, Thomas K. Karikari, Hugo Aparicio, Michael A. Sugarman, Brandon Frank, Yorghos Tripodis, Brett Martin, Joseph N. Palmisano, Eric G. Steinberg, Irene Simkina, Lindsay Farrer, Gyungah Jun, Katherine W. Turk, Andrew E. Budson, Maureen K. O’Connor, Rhoda Au, Wei Qiao Qiu, Lee E. Goldstein, Ronald Killiany, Neil W. Kowall, Robert A. Stern, Jesse Mez, Bertran R. Huber, Ann C. McKee, Thor D. Stein, Michael L. Alosco
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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. 409-410
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Objective:
Blood-based biomarkers offer a more feasible alternative to Alzheimer’s disease (AD) detection, management, and study of disease mechanisms than current in vivo measures. Given their novelty, these plasma biomarkers must be assessed against postmortem neuropathological outcomes for validation. Research has shown utility in plasma markers of the proposed AT(N) framework, however recent studies have stressed the importance of expanding this framework to include other pathways. There is promising data supporting the usefulness of plasma glial fibrillary acidic protein (GFAP) in AD, but GFAP-to-autopsy studies are limited. Here, we tested the association between plasma GFAP and AD-related neuropathological outcomes in participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC).
Participants and Methods:This sample included 45 participants from the BU ADRC who had a plasma sample within 5 years of death and donated their brain for neuropathological examination. Most recent plasma samples were analyzed using the Simoa platform. Neuropathological examinations followed the National Alzheimer’s Coordinating Center procedures and diagnostic criteria. The NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Measures of GFAP were log-transformed. Binary logistic regression analyses tested the association between GFAP and autopsy-confirmed AD status, as well as with semi-quantitative ratings of regional atrophy (none/mild versus moderate/severe) using binary logistic regression. Ordinal logistic regression analyses tested the association between plasma GFAP and Braak stage and CERAD neuritic plaque score. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate autopsy-confirmed AD status. All analyses controlled for sex, age at death, years between last blood draw and death, and APOE e4 status.
Results:Of the 45 brain donors, 29 (64.4%) had autopsy-confirmed AD. The mean (SD) age of the sample at the time of blood draw was 80.76 (8.58) and there were 2.80 (1.16) years between the last blood draw and death. The sample included 20 (44.4%) females, 41 (91.1%) were White, and 20 (44.4%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having autopsy-confirmed AD (OR=14.12, 95% CI [2.00, 99.88], p=0.008). ROC analysis showed plasma GFAP accurately discriminated those with and without autopsy-confirmed AD on its own (AUC=0.75) and strengthened as the above covariates were added to the model (AUC=0.81). Increases in GFAP levels corresponded to increases in Braak stage (OR=2.39, 95% CI [0.71-4.07], p=0.005), but not CERAD ratings (OR=1.24, 95% CI [0.004, 2.49], p=0.051). Higher GFAP levels were associated with greater temporal lobe atrophy (OR=10.27, 95% CI [1.53,69.15], p=0.017), but this was not observed with any other regions.
Conclusions:The current results show that antemortem plasma GFAP is associated with non-specific AD neuropathological changes at autopsy. Plasma GFAP could be a useful and practical biomarker for assisting in the detection of AD-related changes, as well as for study of disease mechanisms.
Is self-guided internet-based cognitive behavioural therapy (iCBT) harmful? An individual participant data meta-analysis
- Eirini Karyotaki, Lise Kemmeren, Heleen Riper, Jos Twisk, Adriaan Hoogendoorn, Annet Kleiboer, Adriana Mira, Andrew Mackinnon, Björn Meyer, Cristina Botella, Elizabeth Littlewood, Gerhard Andersson, Helen Christensen, Jan P. Klein, Johanna Schröder, Juana Bretón-López, Justine Scheider, Kathy Griffiths, Louise Farrer, Marcus J. H. Huibers, Rachel Phillips, Simon Gilbody, Steffen Moritz, Thomas Berger, Victor Pop, Viola Spek, Pim Cuijpers
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- Journal:
- Psychological Medicine / Volume 48 / Issue 15 / November 2018
- Published online by Cambridge University Press:
- 15 March 2018, pp. 2456-2466
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Background
Little is known about potential harmful effects as a consequence of self-guided internet-based cognitive behaviour therapy (iCBT), such as symptom deterioration rates. Thus, safety concerns remain and hamper the implementation of self-guided iCBT into clinical practice. We aimed to conduct an individual participant data (IPD) meta-analysis to determine the prevalence of clinically significant deterioration (symptom worsening) in adults with depressive symptoms who received self-guided iCBT compared with control conditions. Several socio-demographic, clinical and study-level variables were tested as potential moderators of deterioration.
MethodsRandomised controlled trials that reported results of self-guided iCBT compared with control conditions in adults with symptoms of depression were selected. Mixed effects models with participants nested within studies were used to examine possible clinically significant deterioration rates.
ResultsThirteen out of 16 eligible trials were included in the present IPD meta-analysis. Of the 3805 participants analysed, 7.2% showed clinically significant deterioration (5.8% and 9.1% of participants in the intervention and control groups, respectively). Participants in self-guided iCBT were less likely to deteriorate (OR 0.62, p < 0.001) compared with control conditions. None of the examined participant- and study-level moderators were significantly associated with deterioration rates.
ConclusionsSelf-guided iCBT has a lower rate of negative outcomes on symptoms than control conditions and could be a first step treatment approach for adult depression as well as an alternative to watchful waiting in general practice.
Performance Monitoring and Cognitive Control in Individuals with Mild Traumatic Brain Injury
- Michael J. Larson, Peter E. Clayson, Thomas J. Farrer
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- Journal:
- Journal of the International Neuropsychological Society / Volume 18 / Issue 2 / March 2012
- Published online by Cambridge University Press:
- 25 January 2012, pp. 323-333
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Literature suggests that individuals with mild traumatic brain injury (mTBI) show subtle abnormalities in the cognitive control process of performance monitoring. The neural bases of performance monitoring can be measured using the error-related negaitivity (ERN) and post-error positivity (Pe) components of the scalp-recorded event-related potential (ERP). Thirty-six individuals with mTBI and 46 demographically similar controls completed a modified color-naming Stroop task while ERPs were recorded. Separate repeated-measures analyses of variance were used to examine the behavioral (response times [RT] and error rates) and ERP (ERN and Pe amplitudes) indices of performance monitoring. Both groups showed slower RTs and increased error rates on incongruent trials relative to congruent trials. Likewise, both groups showed more negative ERN and more positive Pe amplitude to error trials relative to correct trials. Notably, there were no significant main effects or interactions of group for behavioral and ERP measures. Subgroup and correlational analyses with post-concussive symptoms and indices of injury severity were also not significant. Findings suggest comparable performance to non-injured individuals in some aspects of cognitive control in this sample. Neuropsychological implications and comparison with other cognitive control component processes in individuals with TBI are provided. (JINS, 2012, 18, 323–333)
Association between C-reactive protein and cognitive deficits in elderly men and women: a meta-analysis
- Dawson W. Hedges, Thomas J. Farrer, Bruce L. Brown
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- Journal:
- International Psychogeriatrics / Volume 24 / Issue 9 / September 2012
- Published online by Cambridge University Press:
- 04 January 2012, pp. 1387-1392
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Background: Certain risk factors for cognitive decline appear modifiable. A potentially modifiable marker of inflammation, C-reactive protein may be associated with cognitive deficits, although not all studies have found a relationship between C-reactive protein and cognitive ability. Further, few research papers have examined whether gender may affect any association between C-reactive protein and cognitive deficit.
Methods: To better understand the association between C-reactive protein, cognitive deficit, and gender in elderly people, we meta-analyzed cross-sectional studies that reported cognitive ability assessed by the Mini-Mental State Examination or an equivalent measure, C-reactive protein concentrations, and gender.
Results: While we identified no studies containing only male subjects, the two identified studies containing both female and male subjects (n = 2,525) showed an effect size for cognition of −0.1809 (95% confidence interval, −0.2652 to −0.0967, p = 0.000025) between high and low C-reactive-protein groups. In contrast, the two identified studies containing only female subjects (n = 1,754) showed an effect size for cognition of 0.0345 (95% confidence interval, −0.0594 to 0.1285, not significant).
Conclusions: In the context of a small number of source studies and lack of an all-male group, these results suggest that any association between C-reactive protein and cognitive deficits may be stronger in elderly men than in elderly women.