Free And Cued Selective Reminding Test Research Articles

Associations Between Blood-Based Biomarkers and Cognitive and Functional Trajectories Among Participants of the MEMENTO Cohort.

Elevated levels of Alzheimer disease (AD) blood-based biomarkers are associated with accelerated cognitive decline. However, their distinct relationships with specific cognitive and functional domains require further investigation. We aimed at estimating the associations between AD blood-based biomarkers and the trajectories of distinct cognitive and functional domains over a 5-year follow-up period. We conducted a clinic-based prospective study using data from the MEMENTO study, a nationwide French cohort. We selected dementia-free individuals at baseline aged 60 years or older. Baseline measurements of β-amyloid (Aβ) 40 and 42, phosphorylated tau (p-tau181), and neurofilament light chain (NfL) concentrations were obtained using the Simoa HD-X analyzer. Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), animal fluency, Trail Making Tests A and B, Short Physical Performance Battery (SPPB), and Instrumental Activities of Daily Living were administered annually for up to 5 years. We used linear mixed models, adjusted for potential confounders, to model AD biomarkers' relation with cognitive and functional decline. A total of 1,938 participants were included in this study, with a mean (SD) baseline age of 72.8 (6.6) years, and 62% were women. Higher baseline p-tau181 and NfL were associated with significantly faster decline in most cognitive, physical, and functional outcomes (+1 SD p-tau181: βMMSE = -0.055, 95% CI -0.067 to -0.043, βFCSRT = -0.034, 95% CI -0.043 to -0.025, βfluency = -0.029, 95% CI -0.038 to -0.020, βSPPB = -0.040, 95% CI -0.057 to -0.022, and β4IADL = -0.115, 95% CI 0.091-0.140. +1 SD NfL: βMMSE = -0.039, 95% CI -0.053 to -0.025, βFCSRT = -0.022, 95% CI -0.032 to -0.012, βfluency = -0.014, 95% CI -0.024 to -0.004, and β4IADL = 0.077, 95% CI 0.048-0.105). A multiplicative association of p-tau181 and NfL with worsening cognitive and functional trajectories was evidenced. Lower Aβ42/40 ratio was only associated with slightly faster cognitive decline in FCSRT and semantic fluency (+1 SD: β = 0.011, 95% CI 0.002-0.020, and β = 0.011, 95% CI 0.003-0.020, respectively). These associations were not modified by APOE ε4, sex, nor education level. In a memory clinic sample, p-tau181 and NfL, both independently and jointly, are linked to more pronounced cognitive, physical and functional declines. Blood-based biomarker measurement in AD research may provide useful insights regarding biological processes underlying cognitive, physical, and functional declines in at-risk individuals.

The Memory Binding Test Detects Early Subtle Episodic Memory Decline in Preclinical Alzheimer's Disease: A Longitudinal Study.

The asymptomatic at-risk phase might be the optimal time-window to establish clinically meaningful endpoints in Alzheimer's disease (AD). We investigated whether, compared with the Free and Cued Selective Reminding Test (FCSRT), the Memory Binding Test (MBT) can anticipate the diagnosis of emergent subtle episodic memory (EM) deficits to an at-risk phase. Five-year longitudinal FCSRT and MBT scores from 45 individuals matched for age, education, and gender, were divided into 3 groups of 15 subjects: Aβ-/controls, Aβ+/stable, and Aβ+/progressors (preclinical-AD). The MBT adds an associative memory component (binding), particularly sensitive to subtle EM decline. In the MBT, EM decline started in the Aβ+/progressors (preclinical-AD) up to 4 years prior to diagnosis in delayed free recall (FR), followed by decline in binding-associated scores 1 year later. Conversely, in the FCSRT, EM-decline began later, up to 3 years prior to diagnosis, in the same group on both immediate and delayed versions of FR, while on total recall (TR) and intrusions decline started only 1 year prior to diagnosis. The MBT seems more sensitive than the FCSRT for early EM-decline detection, regarding the year of diagnosis and the number of scores showing AD-linked EM deficits (associated with the AD-characteristic amnesic hippocampal syndrome). Considering the MBT as a detection tool of early subtle EM-decline in an asymptomatic at-risk phase, and the FCSRT as a classification tool of stages of EM-decline from a preclinical phase, these tests ought to potentially become complementary diagnostic tools that can foster therapies to delay cognitive decline. Clinical trial registration title: Electrophysiological markers of the progression to clinical Alzheimer disease in asymptomatic at-risk individuals: a longitudinal event-related potential study of episodic memory in the INSIGHT pre-AD cohort (acronym: ePARAD).

The Memory Binding Test: a new tool to assess emerging episodic memory decline in asymptomatic at‐risk individuals to Alzheimer’s disease

AbstractBackgroundEpisodic memory (EM) deficits are a hallmark of Alzheimer’s disease (AD). The Free and Cued Selective Reminding Test (FCSRT) is the most specific official diagnostic tool detecting AD‐linked EM alterations in advanced preclinical stages (Grober et al., 2021). However, new tools that anticipate diagnosis to the at‐risk phase are needed, to reach more meaningful therapies. Based on existing research, we aim to investigate the Memory Binding Test (MBT) promising capacity to detect the appearance of subtle AD‐linked EM alterations and anticipate AD‐diagnosis to an at‐risk phase (Bushcke ey al., 2017; Mowrey et al., 2018).MethodsFCSRT and MBT scores were collected yearly during 5 years from the INSIGHT‐preAD cohort. We selected 3 groups controlled for age, education level, gender, beta‐amyloid burden (AB+), and neurodegeneration status based on 15 individuals who converted to prodromal‐AD during follow‐up, as follows: converters/AB+; non‐converters/AB+; controls/AB‐. Evaluation of both list‐learning tests is mainly based on free recall (FR) and total (cued) recall (TR) scores. The FCSRT uses 1‐list of words to remember while the MBT uses 2‐lists, introducing a binding component sensitive to subtle EM alterations. Data was analysed using mixed effect models including age, gender, and education as covariates.ResultsWhen compared with the FCSRT, the MBT anticipated the detection of AD‐linked EM alterations in the converters/AB+ versus the other groups. In the MBT decline started up to 5 years prior to diagnosis, in delayed FR (mainly associated to executive dysfunction), followed by decline in 4 binding‐associated scores 1 year later (linked to storage deficits associated with the amnesic hippocampal syndrome characteristic of AD). Therefore, at an at‐risk phase, MBT outperformed FCSRT, both in the year of diagnosis and in the number of scores confirming AD‐linked EM deficits.ConclusionWe show the MBT capacity to detect the initial subtle EM alterations and to anticipate diagnosis to the at‐risk phase, while participants remain cognitively normal. We argue that the MBT (at‐risk phase detection) and the FCSRT (preclinical phase classification) could be complementary rather than concurrent tools, fostering meaningful innovative treatments to prolong quality of life in AD, a disease that remains without a cure.

The RESIST Study: Do TNF Inhibitors Protect Against Cognitive Decline in Rheumatoid Arthritis Patients With Mild Cognitive Impairment?

AbstractBackgroundRheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation in the joint synovium. Considering growing research interest into the role that systemic inflammation might play in the pathogenesis of Alzheimer’s disease (AD), studying cognitive decline in RA patients can provide important insights into the potential effects of inflammation on cognitive health. Furthermore, evidence suggests that biological drugs used to treat RA, specifically TNF inhibitors (TNFi), may protect against AD progression by reducing systemic inflammation. The rheumatoid arthritis medication and memory study (RESIST) is a multicentre longitudinal observational study which aims to compare rates of cognitive decline in adults with both RA and mild cognitive impairment who are on either a conventional synthetic disease modifying anti‐rheumatic drug (csDMARD) or a TNFi.Method251 participants were recruited (160 on csDMARDs, 91 on TNFis). Participants completed assessments at six‐month intervals for eighteen months. The primary outcome was performance on the Free and Cued Selective Reminding Test (FCSRT). It was hypothesised that the rate of decline in FCSRT score would be lower among participants taking TNFis.ResultBetween‐groups ANCOVA was conducted to compare mean FCSRT scores at 12/18 months, adjusting for baseline score, age, disease activity, pain, wellbeing, depressive symptoms and physical function. Results showed that neither group declined in FCSRT free recall score on average over the 18 month follow‐up period, and that there was no significant difference between groups at 12 (mean difference = 0.59, 95% CI = ‐1.54, 2.72) or 18 months (mean difference = 1.24, 95% CI = ‐0.99, 3.47).ConclusionThe absence of decline in FCSRT performance in either group was unexpected. These findings raise the possibility that both csDMARDs and TNFis may protect against cognitive decline However, a major limitation of the study was attrition due to the COVID‐19 pandemic, which may have influenced results – those who experienced a greater degree of cognitive decline may have been more likely to withdraw from the study. Additional planned analyses will examine the potential moderating effect of APOE genotype, and the relationship between peripheral serum C reactive protein, cytokine levels and cognitive outcomes.

Pesticides and cognitive impairment in older adults: evidence from southern Colombia

AbstractBackgroundEnvironmental exposure to specific chemical groups of pesticides (Carbamates, Organophosphates, Pyrethroids, and Organochlorines), as well as the non or inadequate use of personal protective equipment during pest management, have been associated to cognitive decline and increased risk of dementia (Hayden et al., 2010). This study investigated cognitive functioning in older adults exposed to pesticides in southern Colombia.MethodsA sample of 353 older adults was recruited. Of these, 279 had not been exposed to pesticides (n‐Exp) and 74 had (Exp). They were matched according to age [n‐Ex: 63.80 (3.25), Ex: 63.30 (6.96), t = 0.618, p = 0.538] and years of education [n‐Ex: 9.29 (6.28), Ex: 8.95(6.35), t = 0.418, p = 0.676]. They were assessed with a battery of cognitive tests including CERAD (Aguirre‐Acevedo et al., 2016), The Addenbrooke’s Cognitive Examination (ACE‐R), the Free and Cued Selective Reminding Test (FCSRT) and questionnaires.ResultsFDR corrected comparisons revealed overall lower cognitive abilities in the Exp group (ACE‐R, q = 0.027). They also displayed Memory (FCSRT, q = 0.020; World List Learning q = 0.014) and Constructional Praxis (q = 0.007) impairments. Of those exposed, 73% reported no use of personal protective equipment, and neither the participants nor their family members reported concerns about cognitive decline [Self‐reported: n‐Exp: 14.27 (7.44), Exp: 14.92 (7.98), t = ‐0.654, p = 0.513; Family‐reported: n‐Exp: 10.43 (7.12), Exp: 10.26 (7.45), t = ‐0.182, p = 0.856].ConclusionOlder adults from southern Colombia who have been exposed to pesticides show significant cognitive impairments, which have gone unnoticed by both the affected individuals and their family. Cognitive abilities found to be affected have been associated with risk of dementia caused by Alzheimer’s Disease or Parkinson’s Disease (FCSRT and Constructional Praxis). These types of dementia have been previously associated with this environmental risk factor (Chin‐Chan et al., 2015). More awareness about environmental factors and actions to mitigate their risk are urgently needed, and should be considered by future recommendations (e.g., Livingston et al., 2020).Aguirre‐Acevedo et al. (2016). Int. Psychogeriatr, 28(3), 503‐510. https://doi.org/S1041610215001660.Chin‐Chan et al. (2015). Frontiers in Cellular Neuroscience, 9. https://www.frontiersin.org/articles/10.3389/fncel.2015.00124Hayden et al. (2010). Neurology, 74(19), 1524‐1530. https://doi.org/10.1212/WNL.0b013e3181dd4423Livingston et al. (2020). Lancet, 396(10248), 413‐446. https://doi.org/10.1016/S0140‐6736(20)30367‐6

Longitudinal decrements in the sensitivity of cueing in the Free and Cued Selective Reminding Test predict A+T+ status in cognitively unimpaired individuals

AbstractBackgroundThe Index of Sensitivity of Cueing (ISC) from the Free and Cued Selective Reminding Test (FCSRT) memory test evaluates the efficacy of the semantic cues to facilitate retrieval from stored information. Although the ISC has been extensively studied in individuals with prodromal Alzheimer’s disease (AD), its association with AD core pathology, amyloid‐β (A) and p‐tau (T), in cognitively unimpaired (CU) individuals remains unknown. The aim of the present study was to explore the cross‐sectional and longitudinal differences in ISC scores among cerebrospinal fluid (CSF)‐defined AT groups in CU individuals.MethodsWe studied 341 CU participants from the ALFA+ study with available baseline CSF and longitudinal data for the word‐FCSRT‐without‐immediate‐recall version after 3 years. The ISC was computed as: (“total recall”‐“free recall”)/(48‐“free recall”). We defined AT groups (A‐T‐, A+T‐, and A+T+) using baseline CSF levels (Table1) using the cut‐offs defined in Milà‐Alomà et al., 2020. We set independent ANCOVAs to explore the associations between AT status and cross‐sectional and longitudinal (delta) ISC and main FCSRT variables (Table 1). All models were adjusted for age, education and sex, and longitudinal analyses were further adjusted for inter‐visit time and baseline scores. Nominal and FDR‐adjusted p‐values are reported.ResultsNo differences among AT groups were found for baseline FCSRT variables (Table 2). At nominal p‐value levels We observed differences in total recall (TR) and ISC both at visit2 and delta in association with AT status at nominal p‐value levels (Table2), but only the ISC change survived FDR corrections (pFDR = 0.03). Associations were driven by the A+T+ group (Figure1). No differences between A‐T‐ and A+T‐ were found (p>0.05). TR delta was still significant after adjusting for free recall (nominal p = 0.011), suggesting ISC as the main driver of TR decrements.ConclusionDecrements in sensitivity of cueing after 3 years, that in turn diminish FCSRT total recall, were related to concurrent CSF Aβ and p‐tau abnormal levels in CU individuals. No differences between AT groups were observed in free recall, in contrast with other studies using other FCSRT versions that include immediate recall during learning. Further research on secondary memory variables may elucidate the subtle changes related to early AD pathology.

Plasma biomarkers as prognostic markers in Alzheimer’s disease: Influence of age at onset

AbstractBackgroundLittle is known about the influence of age at onset (AAO) on plasma biomarkers and their use as prognostic biomarkers in Alzheimer’s disease (AD).MethodWe selected patients with AD diagnosis with available neuropsychological testing (NPS) at time of diagnosis and two years later, and plasma biomarkers at baseline.NPS battery included Free and Cued Selective Reminding Test (FCSRT), Landscape test (visual memory), Boston Naming Test, Semantic Fluency, BDAE auditory comprehension, Constructional and Ideomotor Praxis, Visual Object and Space Perception (VOSP) Incomplete Letters and Number Location subtests, Trail Making Test (TMT) A and B, Phonemic Fluency, and Digit Span Forward and Backward. NPS scores were compared by AAO: early‐onset AD (EOAD; <65 years) vs. late onset AD (LOAD; >65y).We analyzed plasma biomarkers phosphorilated‐tau181 (p‐tau181), total tau (t‐tau), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin C‐terminal hydrolase L1 (UCHL‐1) using the Quanterix Simoa p‐tau181 Advantage V2 and Neurology 4‐Plex A assays. Group comparisons and linear regressions adjusted by years of education (YOE) were performed in Stata/IC 16.1.ResultForty‐two participants were included, 23 LOAD and 19 EOAD. Plasma p‐tau181 and GFAP levels were higher in LOAD (Table 1). We did not find differences between LOAD and EOAD in NPS tests at baseline or +2 years (Table 2).Plasma ptau‐181 was associated with progression in MMSE globally, VOSP‐Incomplete letters globally and in EOAD. Plasma NfL were associated to Boston Naming test globally and in EOAD, Semantic fluency test globally, VOSP‐incomplete letters in EOAD, and Free and Total Learning of FCSRT in LOAD. Plasma GFAP was associated to MMSE globally and in EOAD, Free learning of FCSRT in LOAD and VOSP‐Incomplete letters and number location globally. Plasma UCHL‐1 was associated to Semantic fluency test in LOAD (Table 3). Praxis and attention and executive function tests loss were not associated to plasma biomarkers.ConclusionPlasma p‐tau18, NfL, GFAP and UCHL‐1 were associated to pogression in memory, language and visual tests. They were predominantly associated to memory loss in LOAD and language and visual function loss in EOAD. Results need to be interpreted cautiously due to small sample size.

Statistical innovations in the API ADAD Colombia trial: a randomized, double‐blind, placebo‐controlled, parallel‐group study in cognitively unimpaired PSEN1 E280A mutation carriers evaluating efficacy and safety of crenezumab

AbstractBackgroundA number of extended families in Colombia with early‐onset ADAD have a PSEN1 mutation at codon 280 (E280A), comprise the largest ADAD kindred in the world. Trial participants have been treated with crenezumab (an experimental anti‐amyloid monoclonal antibody) or placebo. Topline results were presented in August, 2022 at AAIC. Although the trial did not demonstrate a statistically significant clinical benefit in either of its co‐primary endpoints, multiple statistical innovations were incorporated into this trial.MethodThe API ADAD Colombia trial is a randomized, double‐blind, placebo‐controlled, parallel‐group phase 2b study evaluating the efficacy, safety, and tolerability of crenezumab in cognitively unimpaired ADAD PSEN1 E280A mutation carriers in Colombia (NCT01998841). Due to under enrollment and concerns with the sensitivity of the primary endpoint, the protocol was amended mid‐trial to change from 260 weeks of treatment to a common‐close design whereby treatment continued in the double‐blind portion until the last enrolled participant received 260 weeks of treatment. Because of the change in trial design and power considerations, the primary analysis was adapted from a traditional mixed model with repeated measures (MMRM) based analysis to a random coefficient regression model (RCRM) based analysis. To quantitatively examine the adequacy of the RCRM assumptions, a robust variance estimator (Huber 1967; White 1982) was prespecified as a sensitivity analysis to calculate the standard errors and p‐values of the co‐primary endpoints. This study used a type‐I‐error‐controlled statistical procedure to identify and elevate the Free and Cued Selective Reminding Test (FCSRT) cueing index to a co‐primary endpoint. To comprehensively assess the crenezumab effect across primary and secondary endpoints, the prespecified relative reduction point estimates along with the bootstrapped 95% confidence intervals were generated.ResultInnovative statistical methods in this trial will be presented.ConclusionAlthough the API Colombia study did not meet its co‐primary endpoints, statistical learnings from this trial can benefit development of future AD trials. To further maximize the value of this unique trial dataset, participant‐level data will be made publicly available, including clinical, imaging, and biomarker data.Funding: NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer’s Foundation. FlorbetapirPET was partly supported by Avid and Lilly.

Neuropsychological and biomarker predictors of conversion to dementia in young‐onset Mild Cognitive Impairment

AbstractBackgroundMild Cognitive Impairment (MCI) is a clinical condition that captures the stage between normal aging and dementia along the continuum of cognitive impairment. While it is usually thought to be precursor of Alzheimer’s Disease, when occurring at young ages (i.e., before 65 years old) it may increase the risk of all forms of neurodegenerative dementing diseases. We studied which neuropsychological and biomarker characteristics are predictors of conversion to dementia in a sample of patients with young‐onset MCI.MethodSubjects with a diagnosis of MCI and early‐onset of cognitive symptoms (< 65 yo) were recruited in a prospective longitudinal study. They underwent extended neuropsychological assessment, Magnetic Resonance Imaging with measurement of hippocampal volume, and lumbar puncture with measurements of cerebrospinal fluid (CSF) light‐chain neurofilaments (NFL), beta‐amyloid 1‐42, total‐ and phosphorylated‐tau. They were followed‐up clinically and repeated the neuropsychological evaluation at 18 months from the baseline. Statistical analyses were performed with Stata15. Each biomarker and neuropsychological variable were added in multivariate Cox regression models with age, sex, and education.Result84 young‐onset MCI patients were recruited. After 18 months, 26 converted to dementia while 58 remained stable (i.e., MCI). Preliminary analyses showed that baseline smaller bilateral hippocampal volumes, lower baseline MMSE scores, baseline worst performances in tests of language, verbal long‐term memory, and executive functions, as well as baseline elevated levels of CSF NFLs increased the risk of conversion to dementia. Among them, the higher risk was given by the Free and Cued Selective Reminding Test (FCSRT), the Corsi Supraspan, the Frontal Assessment Battery, and the CSF NFLs levels, as shown by spline regression analyses (Figure 1). Of note, the FCSRT delayed recall showed a U‐shaped relationship with the risk of conversion (i.e., not only low/bad performance but also high/good performance were both related to a higher risk of conversion) suggesting that the types of predicted conversion may be different.ConclusionOur results suggest that, in young‐onset MCI, a combination of CSF‐NFLs levels and baseline performance at long‐term memory tests may be predictive of conversion to dementia, either AD or FTD.

Tracking the progression of Alzheimer's disease: Insights from metabolic patterns of SOMI stages

BackgroundSOMI (Stages of Objective Memory Impairment) is a novel classification that identifies six stages of memory decline in Alzheimer's Disease (AD) using the Free and Cued Selective Reminding Test (FCSRT). However, the relationship between SOMI stages and brain metabolism remains unexplored. This study aims to investigate the metabolic correlates of SOMI stages using FDG-PET in Mild Cognitive Impairment due to AD (MCI-AD) and early AD patients. MethodsOne hundred twenty-nine-patients (99 aMCI-AD and 30 AD), and 42 healthy controls (HCs) (MMSE = 29.2 ± .8; age:69.1 ± 8.6 years; education:10.7 ± 3.8 years) who underwent an extensive neuropsychological battery including FCSRT and brain FDG-PET were enrolled. According to their clinical relevance and available sample sizes, SOMI-4 (N = 24 subjects; MMSE score:26.6 ± 2.6: age:75.4 ± 3.2; education:9.9 ± 4.5) and SOMI-5 groups (N = 97; MMSE:25.3 ± 2.6; age:73.9 ± 5.8; education:9.4 ± 4.1) were investigated. ResultsCompared to HCs, SOMI-4 showed hypometabolism in the precuneus, medial temporal gyrus bilaterally, right pecuneus and angular gyrus. SOMI-5 exhibited broader hypometabolism, extending to the left posterior cingulate and medial frontal gyrus bilaterally. The conjunction analysis revealed overlapping areas in the precuneus, medial temporal gyrus bilaterally, and in the right angular gyrus and cuneus. The disjunction analysis identified SOMI-5 specific hypometabolism encompassing left inferior temporal gyrus, uncus and parahippocampal gyrus, and medial frontal gyrus bilaterally (p < .001, p-value (FWE) < .05). DiscussionSOMI-4 relates to posterior hypometabolism, while SOMI-5 to more extensive hypometabolism further encompassing frontal cortices, suggesting SOMI as a biologically relevant classification system of memory decline. ConclusionMemory decline staged with SOMI is associated with hypometabolism spreading in amnesic MCI-AD/AD, suggesting its usefulness as a clinical marker of increasing neurodegeneration.

26 Religious Stress Coping, Memory, and Markers of Brain Pathology in Individuals with Autosomal Dominant Alzheimer’s Disease from the Colombia-Boston Biomarker Study

Objective:High levels of stress may increase risk for Alzheimer’s disease (AD) dementia. Religious coping practices to deal with stress (i.e., prayer, having faith, attending religious services) may reduce risk of dementia. Studying religious stress coping in cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia later in life, may inform us about the role of religious coping in modifying the clinical trajectory from preclinical to clinical stages of the disease. We examined religious stress coping in cognitively unimpaired mutation carriers from the world’s largest ADAD kindred and its relation to markers of brain pathology and memory.Participants and Methods:16 cognitively unimpaired Presenilin-1 E280A mutation carriers and 19 age and education-matched noncarrier family members from the Colombia-Boston (COLBOS) Biomarker Study were included. A subsample (n=26; 13 cognitively unimpaired carriers) underwent amyloid and tau PET imaging. Participants completed the Coping Strategies Questionnaire (CAE) that includes a subscale used to assess religious stress coping, where a higher score indicates more coping, and underwent memory testing using the Free and Cued Selective Reminding Test (FCSRT). The Geriatric Depression Scale (GDS) was used to assess depression. Mann-Whitney U tests were used to examine group differences in religious stress coping, brain pathology (i.e., cortical amyloid-beta, entorhinal and precuneus tau), memory, and depression. Nonparametric correlations were used to examine associations among religious stress coping, age, education, depression, memory, and pathology.Results:Carriers had poorer FCSRT immediate free recall than noncarriers (U=84.5, p=.024). There was no difference between groups in CAE religious stress coping, other FCSRT memory scores, nor GDS score (all p&gt;.05). Compared to non-carriers, carriers had more cortical amyloid (U=152.0, p&lt;.001) and more precuneus tau (U=123.0, p=.05). In carriers, religious stress coping was positively associated with education (r=.57, p=.022), FCSRT immediate free recall (a=.75, p&lt;.001), FCSRT cued recall (a=.50, p=.047), and FCSRT delayed recall (r=.52, p=.038). After controlling for education, religious stress coping remained positively associated with FCSRT immediate free recall (r=.65, p=.009), but not other FCSRT memory scores (all p&gt;.05). Religious stress coping was not associated with age or GDS score regardless of controlling for education (all p&gt;.05). In carriers, religious stress coping was negatively associated with entorhinal tau (r=-.73, p=.005) and precuneus tau burden (r=-.58, p=.037). The association between religious stress coping and entorhinal tau remained significant after controlling for education (r=-.67, p=.016), but not precuneus tau (p&gt;.05). Religious stress coping was not associated with cortical amyloid regardless of controlling for education in carriers (all p&gt;.05). None of the associations with brain pathology or memory were significant in the non-carrier group.Conclusions:Religious stress coping was associated with better memory performance and a low AD pathology burden in individuals at genetic risk for developing AD dementia. Future studies with independent and larger samples should further examine religious stress coping strategies and their associations with other AD-related biomarkers, as well as with other risk and protective factors to better understand their role at the preclinical and prodromal stages of Alzheimer’s disease.

52 Memory Learning Curve and in vivo Brain Pathology in Non-Demented Individuals with Autosomal Dominant Alzheimer’s Disease: Findings from the Colombia-Boston Biomarker Study

Objective:Associative memory is impacted early in Alzheimer’s disease (AD). Poorer performance on associative memory tests has been related to greater amyloid and regional tau burden in preclinical AD. Our group previously examined the association of brain pathology and performance on the Free and Cued Selective Reminding Test (FCSRT) in Autosomal Dominant Alzheimer’s Disease (ADAD), finding that associative memory summary scores distinguished non-demented mutation carriers from non-carriers several years before clinical onset of cognitive impairment. In the current study, we examined whether FCSRT learning slopes were associated with brain pathology in a sample of ADAD carriers and non-carriers.Participants and Methods:There were 119 participants including 57 non-demented carriers of the Colombian kindred with the Presenilin1 E280A mutation and 62 non-carrier family members (mean age= 36.3, 60% female). Participants were administered the Mini-Mental State Examination (MMSE), a measure of global cognitive status, and the FCSRT, which consists of three trials in which participants are asked to freely recall the same list of 16 items. It is a well-established measure known to be sensitive to early changes in AD. A subsample of 69 participants (32 carriers and 37 non-carriers) underwent positron emission tomography (PET) to measure in vivo cortical amyloid-beta (Pittsburgh compound B, PiB), and regional tau (Flortaucipir, FTP) burden in entorhinal and precuneus regions, which are among the earliest sites of tau accumulation in this ADAD population. Mann Whitney U tests, Spearman correlations, and chi-square tests were used to examine group differences and relations among variables of interest. Learning slope was calculated by subtracting the number of items freely recalled in FCSRT Trial 1 from the number of items freely recalled in Trial 3.Results:Compared to non-carriers, carriers had greater cortical amyloid-ß and regional tau burden, lower MMSE scores (mean [SD]: carriers= 27.5 [2.7]; non-carriers= 28.8 [1.0]), and lower scores on total immediate/ delayed free/ cued recall scores on the FCSRT (all p&lt;.01). The groups did not differ on age, sex, or education level (all p&gt; 0.05). In the whole sample and in carriers only, we found that higher MMSE scores were associated with higher learning slope, meaning faster learning (whole group p= 0.25, p= 0.006; carriers p= 0.30, p=0.029). In the whole sample, we found that lower learning slope was associated with higher levels of amyloid (p=-.34, p=.006) and tau in the left, right, and bilateral precuneus region (p=-.43, p&lt;.001; p=-.46, p&lt;.001; p=-.45, p&lt;.001). In carriers only, lower learning slope was associated with higher tau burden in the left, right, and bilateral precuneus specifically (p=-.43, p=.017; p=-.48, p=.008; p=-.46, p=.010, respectively). No significant associations were found in non-carriers.Conclusions:These findings suggest that learning curves on an associative memory test may be sensitive to preclinical pathological changes in AD, specifically within the precuneus, a brain region known to be involved in cue reactivity, episodic memory retrieval, and mental imagery strategies. Future studies with larger samples are warranted to further examine associations between the FCSRT learning curves and regional tau accumulation in individuals with ADAD.

36 Regional Amyloid and Memory in Amyloid Positive and Negative Older Adults

Objective:Alzheimer’s disease (AD) pathophysiology, including β-amyloid (Aβ), can be appreciated with molecular PET imaging. Among older adults, the distribution of Aβ standard uptake value ratios (SUVR) is typically bimodal and a diagnostic cut is applied to define those who are amyloid ‘positive’ and ‘negative’. However, it is unclear whether the dynamic range of SUVRs in amyloid positive and negative individuals is meaningful and associated with cognition. Previous work by Insel and colleagues (2020) used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial to demonstrate subtle associations between a cortical summary SUVR and cognition, particularly on the Free and Cued Selective Reminding Test (FCSRT). We followed up this study to determine the extent to which regional SUVR is associated with performance on the FCSRT in amyloid positive and negative participants screened for participation in the A4 study.Participants and Methods:We accessed regional Aβ SUVR, including anterior cingulate, posterior cingulate, parietal, precuneus, temporal, and medial/orbital frontal regions, along with FCSRT15 and demographic data from 4492 A4 participants at screening. Participants were coded as amyloid positive (n=1329; 30%) or amyloid negative (n=3169; 70%) based on a summary SUVR of greater than or equal to 1.15. We used separate general linear models to examine the association of total or regional SUVR, amyloid positivity status, and the interaction of SUVR and amyloid status with FCSRT scores. We compared model fits across regions with the Akaike Information Criterion (AIC). We ran post hoc correlational analyses examining the relationship between SUVR and FCSRT scores stratified by amyloid status in the case of significant interactions. Results were similar with and without demographic adjustment.Results:There was a significant interaction of summary and all regional SUVR with FCSRT scores in addition to main effects of amyloid positivity. In all models, there were small negative associations between SUVR and memory in amyloid positive individuals. For amyloid negative individuals, there was a significant and very small negative association between SUVR and FCSRT scores only in the parietal lobes and precuneus regions. Model fits were generally similar across the different analyses.Conclusions:In this sample of individuals screened for a secondary prevention trial of AD, there were consistent associations between Aβ SUVR in all regions and memory for those considered amyloid positive. However, for individuals considered amyloid negative, there were only very small associations between SUVR and memory in parietal and precuneus regions. We conclude that the dynamic range of amyloid may be relevant among those with diagnostic evidence of amyloidosis, but that subtle Aβ accumulation in posterior regions may relate to declining memory in “subthreshold” states.

Protein Plasma Levels of the IGF Signalling System Are Altered in Major Depressive Disorder.

The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression.

The "when" matters: Evidence from memory markers in the clinical continuum of Alzheimer's disease.

Cognitive assessment able to detect impairments in the early neuropathological stages of Alzheimer's disease (AD) is urgently needed. The visual short-term memory binding task (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) have been recommended by the neurodegenerative disease working group as promising tests to aid in the early detection of AD. In this study, we investigated their complementary value across the clinical stages of the AD continuum. One hundred and seventeen older adults with subjective cognitive complaint (SCC), 79 with mild cognitive impairment (MCI), 31 patients with AD dementia (ADD), and 37 cognitively unimpaired (CU) subjects, underwent assessment with the VSTMBT and the picture version of the Spanish FCSRT. After controlling for multiple comparisons, significant differences were found across groups. The VSTMBT was the only test that "marginally" differentiated between CU and SCC (d = 0.47, p = .052). Moreover, whereas the FCSRT showed a gradient (CU = SCC) > MCI > ADD, the VSTMBT gradient was CU > SCC > (MCI = ADD) suggesting that conjunctive binding deficits assessed by the latter may be sensitive to the very early stages of the disease. Our results suggest that the VSTMBT and the FCSRT are sensitive to the clinical continuum of AD. Whereas the former detects changes in the early prodromal stages, the latter is more sensitive to the advanced prodromal stages of AD. These novel tests can aid in the early detection, monitor disease progression and response to treatment, and thus support drug development programs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Genuine Memory Deficits as Assessed by the Free and Cued Selective Reminding Test (FCSRT) in the Behavioural Variant of Frontotemporal Dementia. A Systematic Review and Meta-analysis Study.

The current diagnostic criteria for the behavioural variant of frontotemporal dementia (bvFTD) foresee a relative sparing of long-term memory. Although bvFTD patients were thought to report secondary memory deficits associated with prefrontal dysfunctions, some studies indicated the presence of a "genuine memory deficit" related to mesial temporal lobe dysfunctions. Among various neuropsychological tests, the Free and Cue Selective Reminding Test (FCSRT) has been recommended to distinguish genuine from apparent amnesia. We conducted a systematic review and a random effect Bayesian meta-analysis to evaluate the nature and severity of memory deficit in bvFTD. Our objective was to determine whether the existing literature offers evidence of genuine or apparent amnesia in patients with bvFTD, as assessed via the FCSRT. On 06/19/2021, we conducted a search across four databases (PMC, Scopus, Web of Science, and PubMed). We included all studies that evaluated memory performance using the FCSRT in patients with bvFTD, as long as they also included either cognitively unimpaired participants or AD groups. We tested publication bias through the Funnel plot and Egger's test. To assess the quality of studies, we used the Newcastle-Ottawa quality assessment scale adapted for cross-sectional studies. We included 16 studies in the meta-analysis. The results showed that bvFTD patients perform better than AD patients (pooled effects between 0.95 and 1.14), as their memory performance stands between AD and control groups (pooled effects between - 2.19 and - 1.25). Moreover, patients with bvFTD present both genuine and secondary memory disorders. As a major limitation of this study, due to our adoption of a rigorous methodology and stringent inclusion criteria, we ended up with just 16 studies. Nonetheless, our robust findings can contribute to the ongoing discussion on international consensus criteria for bvFTD and the selection of appropriate neuropsychological tools to facilitate the differential diagnosis between AD and bvFTD.

Cognitive function and brain structure correlates in individuals with subjective cognitive decline: Voxel‐based morphometry results from a lifestyle intervention to prevent Alzheimer’s disease (PENSA study)

AbstractBackgroundInterventions based on the modification of several lifestyle factors have provided promising results to maintain cognitive function in late/middle‐aged individuals at higher risk of developing Alzheimer’s disease (AD). Framed under the WW‐FINGERS network, the PENSA clinical trial is focused on the prevention of cognitive decline in individuals with subjective cognitive decline who are also APOEε4 carriers. It consists of a 12‐month multimodal lifestyle intervention supplemented with EGCG, a natural flavonoid from green tea. In this study, we looked for the brain structure correlates of cognitive performance for PENSA participants at baseline.MethodsOne hundred thirty‐one (N = 131) participants of the PENSA study at baseline [Table 1] with valid T1w, T2w and FLAIR MRI scans were included. They underwent a neuropsychological assessment battery consisting of the modified Alzheimer Disease Cooperative Study ‐ Preclinical Alzheimer Cognitive Composite (ADCS‐PACC‐Plus‐exe) that includes MMSE, Free and Cued Selective Reminding Test (FCSRT), Delayed Recall Logical Memory (DRLM), Five Digits Test, Digit Symbol Substitution Test, and Stroop. Additional cognitive measurements were obtained from semantic verbal fluency (SVF), Boston Naming Test, digit span subtest, visual puzzle subtest (VPT) and the Montreal Cognitive Assessment. FLAIR images were used to segment white matter hyperintensities and perform a lesion filling procedure in T1w and T2w images. These two later modalities were then entered into a multimodal segmentation in the SPM12 voxel‐based morphometry pipeline. Associations between test scores and grey matter volumes (GMv) were sought (p&lt;0.001) including age, sex, education, and total intracranial volume as confounders.ResultsA positive association was found (p uncorr &lt;0.001; k&gt;200) between GMv and ADCS‐PACC‐Plus‐exe composite [Figure 1] in the bilateral hippocampus, amygdala, entorhinal and parahippocampal gyri. Additionally, positive correlations (p uncorr &lt;0.001; k&gt;200) were found between GMv and FCSRT, DRLM, VPT and SVF tests albeit in less consistent regional patterns. No associations were found between GMv and the remaining tests.ConclusionIn a sample at high risk of developing AD, the ADCS‐PACC‐Plus‐exe composite is associated with GMv in brain areas known to be affected in AD. These results suggest that the ADCS‐PACC‐Plus‐exe composite might be sensitive to detect subtle cognitive changes in cognitively unimpaired at‐risk individuals.

Four‐year cognitive decline in mild cognitive impairment patients with distinct baseline neuroanatomical atrophy profiles: A MEMENTO and QyScore® study

AbstractBackgroundNeuroanatomical atrophy profile is increasingly recognised as a valuable characterisation in mild cognitive impairment (MCI) individuals and may provide prognostic information about cognitive decline.Method1153 MCI participants from the MEMENTO memory clinic study with 48‐month longitudinal follow‐up were included (mean (sd) Age = 70.6 (8.2), 60% female, CDR‐SB = 0.63 (0.72)). QyScore® volumetric quantification was applied to baseline 3DT1 images and four recognized neuroanatomical subtypes defined based on regional atrophy with respect to an internal normative database (z←1.64) [1,2]: no/minimal atrophy [N‐] (n = 1,012), limbic predominant: LP (n = 37), hippocampal sparing: HS (n = 84) and combined hippocampal and cortical atrophy [typical/diffuse: TD] (n = 20). 145 participants were amyloid positive (A+) via CSF or PET (Age = 73.7 (5.9): 47% female: N‐ = 114, LP = 8, HS = 21 and TD = 2). All participants underwent cognitive and functional assessments at baseline and 48 months, including mini‐mental state examination (MMSE), clinical dementia rating (CDR), Free and Cued Selective Reminding Test (FCRST) and Instrumental Activities of Daily Living (IADL) scale. Linear regression analysis (correcting for age, sex and baseline performance) investigated the relationship between baseline neuroanatomical subtype and subsequent 4‐year cognitive decline. Bonferroni correction was applied.ResultAt month 48, all subtypes demonstrated significant decline across memory, orientation, and executive function. Severity of decline varied across subscales and subtype and was particularly marked in A+ LP individuals (Figure 1). IADL remained stable for the N‐ and TD subgroups. 143 participants converted to dementia [102 = N‐, 18 = LP, 15 = HS, and 8 = TD subtypes, representing 10%, 49%, 18% and 40% of the total N‐, LP, HS and TD atrophy subtypes respectively]. HS and N‐ individuals also demonstrated the least decline across all domains and did not significantly differ on any tests. LP atrophy subtype demonstrated the greatest decline across all cognitive domains as well as global CDR and IADL (p&lt;0.001 compared with N‐ and HS subtypes). Similarly, TD phenotypes showed significant decline across multiple cognitive subscales compared with N‐ and HS subtypes (p&lt;0.001) particularly for orientation and global CDR.ConclusionEarly atrophy profiles in MCI populations can provide insights into the domains and severity of future patient progression over 4 years.[1] Planche et al., (2020)[2] Schwarz et al., (AAIC2022)

The reliability and validity of the snellen memory test for point‐of‐care detection of Alzheimer’s risk in cognitively unimpaired older adults

AbstractBackgroundEpisodic memory decline is one of the earliest cognitive indicators in Alzheimer’s disease (AD) with impairment in memory in older adults an important indicator of incipient AD. Optometry has potential for population based, point‐of‐care screening as retinal biomarkers can detect both symptomatic and preclinical AD. Here, we aimed to develop and optimize a test of episodic memory for use in clinical optometry/ophthalmology settings alongside retinal imaging methods to detect both preclinical and early symptomatic AD.Method30 cognitively normal (CN) older adults (55‐81 years; 68.5±7) from the Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS) completed the Snellen Memory Test (SMT). Participants completed a a Snellen Eye Chart for three learning trials of 10 seconds exposures, followed by immediate free recall. After a 20‐minute delay, participants completed delayed free recall in which they were asked to recall as many of the letters as they had been shown. This was followed by a recognition test in which participants viewed a mock chart identifying the correct letters and if they were in the correct location as the original chart.ResultAn intraclass correlation coefficient was calculated to determine the inter‐rater reliability among three raters for 10 randomly selected administrations. Overall results indicated good reliability with a mean coefficient of 0.87 (95% CI: 0.71‐1.03). Convergent and divergent validity for the 30 participants was assessed by comparing SMT performance to RBANS indices and the Free and Cued Selective Reminding Test (FCSRT). The SMT significantly correlated with the RBANS Immediate Memory Index (r = 0.38‐0.52), Language Index (r = 0.39‐0.51), and Attention Index (r = 0.39‐0.46) as well as with selective reminding trial 1 and 2 (r = 0.45‐0.78), and free and cued recall for trial 3 (r = 0.45‐0.47).ConclusionThe SMT has potential as an episodic memory test that could be used for point of care detection of preclinical AD. Future work will continue to validate the SMT against reference standard neuropsychological assessments of episodic memory and against AD retinal imaging biomarkers.

A Pilot Study of Free and Cued Selective Reminding Test in a Lebanese Sample: A study on Normal, MCI and AD patients (P6-6.009)

<h3>Objective:</h3> Our aim was to assess the suitability of the use of a culturally adapted version of the FCSRT in the Lebanese population diagnosed with MCI and AD through comparing between three groups of subjects – normal, MCI and AD. <h3>Background:</h3> The Free and Cued Selective Reminding Test (FCSRT) is a memory test that assesses learning and acquisition, by providing category cues in the learning process. It is a reliable tool for the assessment of episodic memory, used to differentiate between Alzheimer Disease (AD) patients and patients with Mild Cognitive Impairment (MCI). <h3>Design/Methods:</h3> Subjects were recruited based on their visit, for a regular memory consultation in a memory clinic in Beirut. All of them completed the test conducted by a clinician. <h3>Results: Results:</h3> The sample included 3 populations divided as follows: 29 normal, 22 MCI and 24 AD subjects. Our results showed that the adapted Arabic version of the FCSRT is discriminating between the 3 populations with a major significant difference between the healthy and AD population. The overall profile on the FCSRT revealed that normal subjects had the highest scores followed by MCI and then AD subjects. The learning curve of normal controls and MCI patients is ascendant while AD subjects exhibit a depressed learning curve. <h3>Conclusions:</h3> This study represents a novel contribution regarding the adequacy of the Arabic version of the FCSRT in terms of distinguishing between AD and non-AD subjects. Besides, it gives new possibilities concerning the use of the FCSRT in the evaluation of the spectrum of memory disorders. <b>Disclosure:</b> Dr. Abou-Mrad has nothing to disclose.