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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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- Article
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- You have access Access
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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.
The Effectiveness of Item-Specific Encoding and Conservative Responding to Reduce False Memories in Patients with Mild Cognitive Impairment and Mild Alzheimer’s Disease Dementia
- Christopher Malone, Katherine W. Turk, Rocco Palumbo, Andrew E. Budson
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- Journal:
- Journal of the International Neuropsychological Society / Volume 27 / Issue 3 / March 2021
- Published online by Cambridge University Press:
- 10 August 2020, pp. 227-238
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Objective:
Patients with mild Alzheimer’s disease dementia are more susceptible to false memories than healthy older adults. Evidence that these patients can use cognitive strategies to reduce false memory is inconsistent.
Method:In the present study, we examined the effectiveness of conservative responding and item-specific deep encoding strategies, alone and in combination, to reduce false memory in a categorized word list paradigm among participants with mild Alzheimer’s disease dementia (AD), amnestic single-domain mild cognitive impairment (MCI), and healthy age-matched older controls (OCs). A battery of clinical neuropsychological measures was also administered.
Results:Although use of conservative responding alone tended to reduce performance in the MCI and OC groups, both deep encoding alone and deep encoding combined with conservative strategies led to improved discrimination for both gist memory and item-specific recollection for these two groups. In the AD group, only gist memory benefited from the use of strategies, boosted equally by deep encoding alone and deep encoding combined with conservative strategies; item-specific recollection was not improved. No correlation between the use of these strategies and performance on neuropsychological measures was found.
Conclusions:These results suggest that further evaluation of these strategies is warranted as they have the potential to reduce related and unrelated memory errors and increase both gist memory and item-specific recollection in healthy older adults and individuals with amnestic MCI. Patients with AD were less able to benefit from such strategies, yet were still able to use them to reduce unrelated memory errors and increase gist memory.
False Memories: The Other Side of Forgetting
- Katherine W. Turk, Rocco Palumbo, Rebecca G. Deason, Anna Marin, Ala’a Elshaar, Emma Gosselin, Maureen K. O’Connor, Yorghos Tripodis, Andrew E. Budson
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- Journal:
- Journal of the International Neuropsychological Society / Volume 26 / Issue 6 / July 2020
- Published online by Cambridge University Press:
- 28 February 2020, pp. 545-556
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Objective:
To measure caregivers’ and clinicians’ perception of false memories in the lives of patients with memory loss due to Alzheimer’s disease (AD) and mild cognitive impairment (MCI) using a novel false memories questionnaire. Our hypotheses were that false memories are occurring as often as forgetting according to clinicians and family members.
Method:This prospective, questionnaire-based study consisting of 20 false memory questions paired with 20 forgetting questions had two forms: one for clinicians and the other for family members of older subjects. In total, 226 clinicians and 150 family members of 49 patients with AD, 44 patients with MCI, and 57 healthy older controls (OCs) completed the questionnaire.
Results:False memories occurred nearly as often as forgetting according to clinicians and family members of patients with MCI and AD. Family members of OCs and patients with MCI reported fewer false memories compared to those of the AD group. As Mini-Mental State Examination scores decreased, the mean score increased for both forgetting and false memories. Among clinicians, correlations were observed between the dementia severity of patients seen with both forgetting and false memories questionnaire scores as well as with the impact of forgetting and false memories on daily life.
Conclusion:Patients with AD experience false memories almost as frequently as they do forgetting. Given how common false memories are in AD patients, additional work is needed to understand the clinical implications of these false memories on patients’ daily lives. The novel false memories questionnaire developed may be a valuable tool.