Deficits in short-term memory binding are detectable in individuals with brain amyloid deposition in the absence of overt neurodegeneration in the Alzheimer’s disease continuum
Introduction
The short-term memory binding (STMB) test assesses the ability to hold integrations of surface features (e.g. shape and colour) as a unique representation in memory (Luck and Vogel, 1997, Wheeler and Treisman, 2002). In a frequently used format, participants see two coloured shapes on a screen and subsequently they indicate whether there was a change between the combination of shapes and colours on a test screen. STMB has been used to identify cognitive impairment in patients in different stages of the Alzheimer's disease (AD) continuum. The test showed high sensitivity and specificity for sporadic AD (Cecchini et al., 2020, Cecchini et al., 2017, Della Sala et al., 2016, Kozlova et al., 2020, Parra et al., 2010) and familial AD due to the presenilin-1 E280A mutation (Liang et al., 2016, Norton et al., 2020, Parra et al., 2010, Parra et al., 2015). It has also been shown to differentiate amnestic mild cognitive impairment (MCI) from controls (Cecchini et al., 2020, Koppara et al., 2015, Kozlova et al., 2020, Parra et al., 2019, Parra et al., 2017, Pietto et al., 2016, Valdés Hernández et al., 2020).
In a different study evaluating carriers of the presenilin-1 E280A mutation, Parra et al. (Parra et al., 2011) found that the STMB was the only cognitive test (compared to Paired Associates Learning, Rey Figure test, verbal fluencies, Trail Making test and Mini-mental State Examination) that could discriminate controls from asymptomatic carriers of the mutation in analyses using receiver operating characteristic curves (ROC), with an area under de curve (AUC) equal to 0.86. In addition, the binding deficit of asymptomatic carriers of the mutation showed an equivalent deficit when compared with carriers of the same mutation in the dementia stage (controls > asymptomatic carriers = familial AD dementia) (Parra et al., 2011). These results suggest that binding deficits could be a cognitive marker of early AD that is not followed by a significant drop in performance with the progression of the disease (cognitively unimpaired > preclinical = MCI = AD), which is different of what is consistently observed with usual memory tests (cognitively unimpaired = preclinical > MCI > AD). If AD disrupts the ability to hold temporarily bound information from its early stages, the STMB test would be better used for diagnostic purposes, but not to keep track of the disease progression. Other neuropsychological tests could be less sensitive to detect preclinical AD when compared with the STMB test, but they would be better for following-up the patients.
In recent years, it has been demonstrated that the biological processes associated to sporadic AD may also be identified years before clinical diagnosis (Jack et al., 2018, Jack et al., 2016). This has led to the proposition in 2018 of a research framework that establishes AD as a biological construct rather than a clinical syndrome, relying on the presence of the 42-residue β- amyloid isoform (Aβ42) (A) and phospho-tau (T) to define the diagnosis of AD based on cerebrospinal fluid (CSF) analyses or positron emission tomography (PET) imaging (Jack et al., 2018). The presence of neurodegenerative changes (N) along the course of the disease, identified by structural magnetic resonance imaging (MRI), PET with [18F]fluorodeoxyglucose ([18F]FDG-PET) or total tau CSF measurements, characterizes AD with signs of neurodegeneration (Jack et al, 2018). Within such AT(N) framework, neuropsychological evaluations may be added for disease staging (Jack et al., 2018).
The neuropsychological evaluation in the preclinical stages of AD is important to document the risk of progression to dementia. Nation, Ho, Dutt, Han, and Lai (2019), for instance, showed that a decline over 12 months in neuropsychological tests increases in 2.28 times the risk for a diagnosis of dementia, even after correcting for intersubject variations in the presence and severity of AD biomarker changes. Therefore, there has been great interest in the field of neuropsychology in investigations of cognitive deficits which may be associated to Aβ and phospho-tau biomarkers, signalling the presence of preclinical AD (Hedden et al., 2013, Jansen et al., 2018). In spite of the fact that tau pathology and neurodegeneration have shown to be more associated with cognitive measures than Aβ (Aschenbrenner et al., 2018, Bejanin et al., 2017, Brier et al., 2016, Hanseeuw et al., 2019), they probably occur in a later stage of the disease. Following the amyloid cascade hypothesis, the amyloid deposition is the first sign of AD, probably triggering the other manifestations (Jack et al., 2013, Yasuno et al., 2021). Therefore, tests that significantly correlate with the amyloid burden in the brain may contribute to identify AD in its very early stages.
Different cognitive tasks have been investigated in the context of preclinical AD, especially episodic memory tasks. The Free and Cued Selective Reminding Test (FCSRT) and the Rey Auditory Verbal Learning Test (RAVLT), for instance, showed to be significant predictors of disease progression when used in the preclinical stage (Grande et al., 2018, Grober et al., 2018, Mormino et al., 2017, Schindler et al., 2017, Timmers et al., 2019). However, distinct tests may show different associations with Aβ burden in the preclinical stage of AD. The FCSRT, the Logical Memory from Wechsler Memory Scale, the Memory Capacity Test and the Face-name Association Test, for instance, have been associated with Aβ burden in the preclinical stage (Insel et al., 2020, Rentz et al., 2009, Rentz et al., 2011), while indices based on lists of words, such as the delayed score of the RAVLT, have not (Bilgel et al., 2018, Timmers et al., 2019, but see Bos et al., 2018)). These results could occur due to different methodologies across studies, such as sample characteristics or the technique used to measure Aβ burden or memory. For instance, Dupont et al. (2020) showed an association between Aβ burden and episodic memory in preclinical AD, but the authors used a composite score with RAVLT, Logical Memory, DSM-48 and the Rey Complex Figure Test. Therefore, the contribution of each test for this association was unclear. One other possibility relates to the characteristics of the tests, since they assess episodic memory using different methods. Tests such as the RAVLT, which uses the recall of a list of unrelated words, may be less sensitive to detect subtle memory deficits associated with amyloidosis in the preclinical stage of AD. In consistency with the latter possibility, recent metanalyses of studies with preclinical AD patients have shown only a small effect of amyloidosis on episodic memory performance (Baker et al., 2017).
In a recent study using [11C]PIB-PET to measure Aβ aggregation and [18F]FDG-PET to assess neurodegeneration, Squarzoni et al. (2020) compared episodic memory performance in an elderly sample divided in four groups according to the presence of Aβ burden and neurodegeneration (A−N− | A+N− | A-N+ | A+ N+), including cognitively unimpaired (CU) individuals, amnestic MCI subjects and patients with dementia clinically compatible with AD. Neither the RAVLT nor the memory subscore of the Short Cognitive Performance Test (SKT) differentiated participants with and without Aβ burden in the absence of neurodegeneration. Conversely, memory performance deficits became significant in the presence of neurodegeneration, in consistency with the view that conventional episodic memory tests may not capture the earliest manifestations of the disease.
Notwithstanding the evidence suggesting that AD affects the ability to hold bound information temporarily (Cecchini et al., 2020, Cecchini et al., 2017, Parra et al., 2009), even at preclinical or prodromal stages of the disease (Parra et al., 2010, Parra et al., 2011), only two studies have tested whether the STMB test can differentiate individuals who are positive or negative for biomarkers of AD pathology and neurodegeneration (Norton et al., 2020, Parra et al., 2017). Parra, Gazes and Stern (2017) assessed 39 CU participants and divided the sample according to high versus low STMB test performance. They showed that participants with low performance on the STMB task, who were called weak-binders, had higher Aβ burden (as assessed by CSF or [18F]PIB-PET) relative to strong-binders. Norton et al. (2020) correlated the performance on the STMB test with Aβ and tau burden as assessed with [11C]PIB and 18Fflortaucipir PET in a sample of CU participants, asymptomatic carriers of the presenilin-1 E280A mutation and carriers of this mutation in MCI stage. The authors showed a significant correlation in the asymptomatic sample between STMB scores in the bound condition and mean cortical amyloid deposition (r = -0.50, p = 0.03), but a non-significant correlation with tau deposition on the entorhinal cortex (r = -0.26, p = 0.27) or inferior temporal lobe (r = -0.30, p = 0.21). The authors considered this a preliminary finding due to the small sample size in this correlation (n = 19), and it is not clear if these results could be generalized to a sample of sporadic AD. Therefore, the objective of the present study was to verify whether STMB could differentiate patients who were considered positive or negative for the presence of Aβ burden, in the absence of overt neurodegeneration in the AD continuum.
Section snippets
Participants
The sample involved in this study was a sub-sample from Squarzoni et. al (2020) study, comprising 18 CU participants, 30 patients with amnestic MCI and 23 patients with dementia clinically compatible with mild AD (henceforth referred to as AD), who had data for the STMB test. Participants were recruited from the Neurology and Geriatric Psychiatry outpatient services of the Hospital das Clínicas, School of Medicine, University of Sao Paulo (HC-FMUSP). The ethical committee of the institution
Results
The sociodemographic characteristics and cognitive performance across the clinically defined groups are presented in Table 1.
The groups had similar age and were statistically different in educational level, the CU group being more educated than the AD, with a large effect size. The CU and MCI groups outperformed the AD group in the MMSE and SKT (CU = MCI > AD). The three groups significantly differed in the RAVLT (CU > MCI > AD). The CU group had significantly higher performance on the STMB
Discussion
The aim of the present study was to verify whether the STMB score differs between participants with distinct A(N) profiles drawn from principles of the AT(N) framework, in a sample including CU individuals, amnestic MCI and patients with dementia clinically compatible with AD. Results indicated that in the absence of overt signs of neurodegeneration on [18F]FDG-PET, patients who were positive for brain amyloid deposition on [11C]PIB-PET had significantly lower STMB scores. Comparing the A−N−
Conclusions
The present results related the STMB test with AD biomarkers. Differently from conventional episodic memory measurements, the STMB test was able to discriminate participants with and without brain amyloid deposition in the absence of overt neurodegeneration, indicating that the STMB test may be an important cognitive marker of AD.
CRediT authorship contribution statement
M.A. Cecchini: Conceptualization, Methodology, Formal analysis, Writing - original draft. M.S. Yassuda: Conceptualization, Methodology, Writing - original draft, Supervision. P. Squarzoni: Conceptualization, Investigation, Resources, Data curation, Writing - review & editing. A.M. Coutinho: Investigation, Data curation, Writing - review & editing. D. de Paula Faria: Investigation, Data curation, Writing - review & editing. F.L.S. Duran: Formal analysis, Data curation. N.A. Costa: Formal
Declaration of Competing Interest
The authors have no actual or potential conflicts of interest.
Acknowledgements
Funding: This research was funded by the São Paulo Research Foundation (FAPESP) reference numbers 2012/50329-6, 14/50873-3, 16/50197-3 and 16/07967-2; National Council for Scientific and Technologic in Development (CNPq) in Brazil reference numbers 465412/2014-9 and 304548/2018-9. PS and MSY were supported by the National Council for Scientific and Technologic in Development (CNPq) in Brazil (grant numbers 88887.137488/2017-00 and 304548/2018-9, respectively).
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