Design and validation of the 1-week memory battery for assessing episodic memory and accelerated long-term forgetting in cognitively unimpaired subjects.

OBJECTIVE: Subtle decline in memory is thought to arise in the preclinical phase of Alzheimer's disease (AD). However, detecting these initial cognitive difficulties cross-sectionally has been challenging, and the exact nature of the decline is still debated. Accelerated long-term forgetting (ALF) has been recently suggested as one of the earliest and most sensitive indicators of memory dysfunction in subjects at risk of developing AD. The objective of this study was to design and validate the 1-week memory battery (1WMB) for assessing episodic memory and ALF in cognitively unimpaired individuals. METHOD: The 1WMB is unique in that it assesses multimodal memory and measures recall at both short delay (20 min) and at long term (1 week). Forty-five cognitively unimpaired subjects were assessed with 1WMB and standardized neuropsychological tests. Subjective cognitive decline (SCD), levels of anxiety and depression, and cognitive reserve were also measured. RESULTS: The tests of 1WMB showed a high internal consistency, and concurrent validity was observed with standard tests of episodic memory and executive functions. The analysis revealed a greater loss of information at 1 week compared to short-term forgetting (20 min). Performance in the 1WMB was affected by age and educational level, but was not associated with levels of anxiety and depression. Unlike standard tests, performance in the 1WMB correlated with measures of SCD. CONCLUSION: Our findings indicate that the 1WMB has good psychometric properties, and future studies are needed to explore its potential usefulness to assess cognitively unimpaired subjects at increased risk of developing AD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Accelerated long-term forgetting in individuals with subjective cognitive decline and amyloid-ß positivity.

OBJECTIVES: We studied a sample of cognitively unimpaired individuals, with and without subjective cognitive decline (SCD), in order to investigate accelerated long-term forgetting (ALF) and to explore the relationships between objective and subjective cognitive performance and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. METHODS: Fifty-two individuals were included and SCD was quantified through the Subjective Cognitive Decline Questionnaire (SCD-Q), using its validated cutoff to classify participants as Low SCD-Q (n = 21) or High SCD-Q (n = 31). These groups were further subdivided according to the presence or absence of abnormal levels of CSF Aß42 . Objective cognitive performance was assessed with the Ancient Farming Equipment Test (AFE-T), a new highly-demanding test that calls for acquisition and retention of novel object/name pairs and allows measuring ALF over a 6-month period. RESULTS: The High SCD-Q group showed a significantly higher free forgetting rate at 3 months compared to the Low SCD-Q (F [1,44] = 4.72; p < 0.05). When stratifying by amyloid status, High SCD-Q/Aß+ showed a significantly lower performance than High SCD-Q/Aß-on the final free and cued learning scores (F [1,27] = 6.44, p < 0.05 and F [1,27] = 7.51, p < 0.05, respectively), the 1-week free and cued recall (F [1,24] = 4.49; p < 0.05 and F [1,24] = 7.10; p < 0.01, respectively), the 1-week cued forgetting rate (F [1,24] = 5.13; p < 0.05), and the 3-month cued recall (F [1,24] = 4.27; p < 0.05). Linear regression analyses showed that higher SCD-Q scores were associated with higher forgetting rates on the AFE-T (ß = -0.212; p < 0.05). CONCLUSIONS: It is possible to detect ALF in individuals with high SCD ratings, appearing especially in those with abnormal CSF Aß42 levels. Both in research and the clinical field, there is an increasing need of using more demanding cognitive measures, such as the AFE-T, for identifying and tracking the earliest cognitive changes in these populations.

Accelerated long-term forgetting over three months in asymptomatic APOE ɛ4 carriers.

Accelerated long-term forgetting (ALF) refers to a rapid loss of information over days or weeks despite normal acquisition/encoding. Notwithstanding its potential relevance as a presymptomatic marker of cognitive dysfunction, no study has addressed the relationship between ALF and Alzheimer's disease (AD) biomarkers. We examined ALF in APOE ɛ4 carriers versus noncarriers, and its relationships with AD cerebrospinal fluid (CSF) biomarkers. We found ALF over three months in APOE ɛ4 carriers (F(1,19) = 5.60; P < 0.05; Cohen's d = 1.08), and this performance was associated with abnormal levels of the CSF Aß42 /ptau ratio (r = -.614; P < 0.01). Our findings indicate that ALF is detectable in at-risk individuals, and that there is a relationship between ALF and the pathophysiological processes underlying AD.

Physical activity is associated with better global cognition and frontal function in overweight/obese older adults with metabolic syndrome.

BACKGROUND: There is epidemiological evidence of an association between the metabolic syndrome (MetS), a cluster of cardiovascular risk factors related to central adiposity and insulin resistance, and cognitive impairment and dementia. On the other hand, there is evidence for a beneficial effect of physical activity on cognitive outcomes in older adult populations. In a cross-sectional study, we evaluated the relationship between aerobic physical activity and cognition in a cohort of overweight/obese older adults with MetS at risk for dementia. Cognitive function was assessed in a subsample of 82 subjects (men 55-75 y; women 60-75 y), with MetS and a BMI ≥27 to < 40 kg/m2 enrolled in the PREDIMED-PLUS study, a trial of diet and exercise in individuals with MetS with outcomes of cardiovascular prevention. Domain Z scores were calculated for the different cognitive domains. Aerobic physical activity was determined with the Rapid Assessment of Physical Activity questionnaire. RESULTS: Adjusted covariance analyses revealed that, compared to sedentary participants, those physically active obtained higher scores in mean global cognitive scores, with mean adjusted difference 0.254 (95% CI 0.032 to 0.477, p = 0.026) and frontal composites, with mean adjusted difference 0.375 (95% CI 0.110 to 0.639, p = 0.006). CONCLUSIONS: Our findings indicate that aerobic physical activity is associated with better global cognition and frontal function in overweight/obese older individuals with MetS, suggesting that physical activity could be a therapeutic strategy to reduce the risk of developing cognitive impairment or dementia in this population.

Associations Between the Subjective Cognitive Decline-Questionnaire's Scores, Gray Matter Volume, and Amyloid-ß Levels.

BACKGROUND: Exploring the relationship between Alzheimer's disease (AD) biomarkers and subjective cognitive decline (SCD) is needed for better defining its clinical meaning in preclinical AD (preAD). OBJECTIVE: To assess the association between the Subjective Cognitive Decline Questionnaire (SCD-Q), gray matter (GM), and cerebrospinal fluid amyloid-ß (Aß). METHODS: 56 cognitively healthy older adults and their informants answered the SCD-Q. Correlations between GM and SCD-Q scores were explored using structural voxel-based morphometry models including Aß levels. SCD-Q*Aß vectors were calculated with higher scores reflecting higher SCD and cerebral amyloid, simultaneously. Subjects were classified according to their perception of cognitive worsening in the last two years, exploring for GM differences between-groups. RESULTS: Higher self-reported SCD-Q scores correlated with reduced GM in the right frontal lobe and increased volumes in the occipital lobe, calcarine sulcus, fusiform gyrus, and cerebellum, while higher informant's scores correlated with increased GM in the right middle temporal gyrus. Correlations were more significant for SCD-Q language items, self-complaints, and more positive than negative correlations were found. The SCD-Q*Aß vectors were negatively associated with GM both in self and informant's reports. Finally, lower Aß levels related to lower GM in subjects who noticed cognitive worsening, but related to higher GM in subjects who have not noticed this decline. CONCLUSIONS: Our results suggest that SCD-Q scores relate with incipient brain changes that may be due to preAD. Independent studies are needed to confirm our observations.

Early detection of subtle motor dysfunction in cognitively normal subjects with amyloid-ß positivity.

Since the current neuropsychological assessments are not sensitive to subtle deficits that may be present in cognitively normal subjects with amyloid-ß positivity, more accurate and efficient measures are needed. Our aim was to investigate the presence of subtle motor deficits in this population and its relationship with cerebrospinal fluid (CSF) amyloid-ß levels. We adapted the Finger Tapping Task to measure tapping speed and intrasubject variability. Seventy-two right-handed participants completed the study. Subjects were divided into three groups according to their CSF biomarker profile: 37 control participants (negative CSF AD biomarkers, CTR), 20 cognitively normal subjects with amyloid-ß positivity (abnormal levels of CSF Aß42, Aß+) and 15 AD patients. All subjects underwent lumbar puncture for the CSF analysis, apolipoprotein E genotyping and completed the Finger Tapping Task, a neuropsychological battery and cardiovascular risk factor and physical activity assessments. An overall difference between groups was found both in tapping speed [F(2,66) = 19.37, p < .01] and in intrasubject variability [F(2,66) = 11.40, p < .01]. More specifically, the Aß+ group showed lower speed [F(1,52) = 5.33, p < .05] and greater intrasubject variability [F(1,52) = 8.48, p < .01] than the CTR group, and higher speed than the AD group [F(1,30) = 13.61, p < .01]. Speed (ß = .263, p < .05) and intrasubject variability (ß = -.558, p < .01) were significantly associated with CSF amyloid-ß levels. The present findings suggest that subtle motor difficulties can be detected in cognitively healthy subjects with amyloid-ß positivity and be related to CSF Aß42 levels. An accurate assessment of motor functions could help on identifying individuals at the earliest stage of the Alzheimer's continuum.

Tau Protein is Associated with Longitudinal Memory Decline in Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels.

BACKGROUND: We investigated a sample of cognitively healthy subjects with normal Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker levels to identify the earliest variables related to longitudinal memory changes. OBJECTIVE: Employing a new highly demanding learning and memory test (the Ancient Farming Equipment Test; AFE-T), we aimed to investigate whether a biomarker related to neurodegeneration (i.e., CSF tau) was associated with longitudinal memory decline. METHODS: Thirty-two cognitively and biologically normal (CBN) subjects underwent MRI, neuropsychological assessment, and the AFE-T at baseline and 18 months later. To explore the relationship between cognitive performance and relevant factors, a linear model was set up. For a secondary analysis that further explore the effect of tau, the subjects were divided into CBN-Tau↓ (tau < 228.64 pg/ml; n = 16) and CBN-Tau↑ (tau > 228.64 pg/ml; n = 16). We also performed voxel-based morphometry (VBM) to identify regions of grey matter volume that would predict both baseline and longitudinal cognitive performance. RESULTS: Our main finding was an association between CSF tau and longitudinal memory decline measured with AFE-T (B = -0.17, p < 0.05; r = -0.414; p < 0.01), and further analyses showed different evolvement between subgroups, with an accelerated decline in individuals with higher tau (F(1,31) = 8.37; p < 0.01). VBM results suggested that AFE-T performance is related to grey matter volume in a medial temporal, middle frontal, and posterior cerebellar network at baseline, and that there are strategic brain areas driving the longitudinal cognitive changes. CONCLUSIONS: The present findings provide evidence for structural and biological markers linked to cognitive aging by highlighting the role of tau, a marker of neurodegeneration, which can be related with the earliest memory changes in healthy subjects.

Executive and Language Subjective Cognitive Decline Complaints Discriminate Preclinical Alzheimer's Disease from Normal Aging.

BACKGROUND: There is a need to specify the profile of subjective cognitive decline in preclinical Alzheimer's disease (preAD). OBJECTIVES: To explore specific items of the Subjective Cognitive Decline Questionnaire (SCD-Q) that discriminate preAD from normal aging. METHODS: 68 cognitively normal older adults were classified as controls (n = 52) or preAD (n = 16) according to amyloid-ß (Aß) levels. An exploratory factor analysis and item analysis of the SCD-Q were performed. Informant reports of the SCD-Q were used to corroborate the findings of self-reports. One-year neuropsychological follow-up was available. RESULTS: Four SCD-Q factors were extracted: EM-factor (episodic memory), A-factor (attention), O-factor (organization), and L-factor (language). PreAD reported a significantly higher decline in L-factor (F(1) = 6.49; p = 0.014) and A-factor (F(1) = 4.04; p = 0.049) compared to controls, and showed a higher frequency of perceived decline in SCD-Q items related with language and executive tasks (Sig-items.) Significant discriminative powers for Aß-positivity were found for L-factor (AUC = 0.75; p = 0.003) and A-factor (AUC = 0.74; p = 0.004). Informants in the preAD group confirmed significantly higher scores in L-factor and Sig-items. A significant time×group interaction was found in the Semantic Fluency and Stroop tests, with the preAD group showing a decrease in performance at one-year. CONCLUSIONS: Our results suggest that SCD-Q items related with language and executive decline may help in prediction algorithms to detect preAD. Validation in an independent population is needed.

Early Detection of Learning Difficulties when Confronted with Novel Information in Preclinical Alzheimer's Disease Stage 1.

We employed a highly demanding experimental associative learning test (the AFE-T) to explore memory functioning in Preclinical Alzheimer's Disease stage 1 (PreAD-1) and stage 2 (PreAD-2). The task consisted in the learning of unknown object/name pairs and our comprehensive setup allowed the analysis of learning curves, immediate recall, long-term forgetting rates at one week, three months, and six months, and relearning curves. Forty-nine cognitively healthy subjects were included and classified according to the presence or absence of abnormal CSF biomarkers (Control, n = 31; PreAD-1, n = 14; PreAD-2, n = 4). Control and PreAD-1 performances on the experimental test were compared by controlling for age and education. These analyses showed clear learning difficulties in PreAD-1 subjects (F = 6.98; p = 0.01). Between-group differences in long-term forgetting rates were less notable, reaching statistical significance only for the three-month cued forgetting rate (F = 4.83; p = 0.03). Similarly, relearning sessions showed only statistical trends between the groups (F = 3.22; p = 0.08). In the whole sample, significant correlations between CSF Aß42/tau ratio and the AFE-T were found, both in the total learning score (r = 0.52; p < 0.001) and in the three-month cued forgetting rate (r = -0.38; p < 0.01). Descriptive subanalyses involving PreAD-2 suggested greater learning and recall difficulties in these subjects when compared with the PreAD-1 group. The present results suggest that explicit learning difficulties when binding information could be one of the earliest signs of the future emergence of episodic memory difficulties on the Alzheimer's disease continuum. Our findings indicate that the AFE-T is a sensitive test, capable of detecting subtle memory difficulties in PreAD-1.

Subtle visuomotor difficulties in preclinical Alzheimer's disease.

BACKGROUND: Individuals with preclinical Alzheimer's disease (Pre-AD) present nonimpaired cognition, as measured by standard neuropsychological tests. However, detecting subtle difficulties in cognitive functions may be necessary for an early diagnosis and intervention. OBJECTIVES: A new computer-based visuomotor coordination task (VMC) was developed to investigate the possible presence of early visuomotor difficulties in Pre-AD individuals. Associations between VMC task performance and AD biomarkers were studied. The influence of ApoE status on participants' performance was addressed, as well as the relationship between performance and subjective cognitive decline (SCD). METHODS: Sixty-six cognitively normal (CN) elders (19 Pre-AD and 47 control participants [CTR]) and 15 patients with AD performed the VMC task, which consisted in executing visually guided goal-directed movements that required the coordination of the visual and motor systems. All participants underwent ApoE analysis and lumbar puncture. CN participants also completed an extensive standard neuropsychological battery. RESULTS: Despite presenting normal cognition in standard tests, Pre-AD participants exhibited higher response times (RTs) to complete the VMC task than CTR (p < .01). Besides, patients with AD showed higher RTs than CTR (p < .001) and Pre-AD (p < .05), and more errors than CTR (p < .005). RTs in ApoE4 carriers were higher than that observed in ApoE4 noncarriers (p < .01). In CN individuals, RTs were related to amyloid ß-protein 42 (AB42) biomarker (p < .01) and informant-rated SCD (p < .01). CONCLUSIONS: The VMC task is able to discriminate Pre-AD from CTR individuals. Moreover, VMC results are associated with AB42 levels in CN individuals, suggesting that visuomotor dysfunction may be a sensitive marker of Pre-AD.

Informants' Perception of Subjective Cognitive Decline Helps to Discriminate Preclinical Alzheimer's Disease from Normal Aging.

BACKGROUND: Self-reported and informant-reported subjective cognitive decline (SCD) may be useful in the detection of preclinical Alzheimer's disease (Pre-AD) and cognitive impairment related to abnormal amyloid-ß (Aß 42) levels. OBJECTIVES: a) To compare the Subjective Cognitive Decline Questionnaire (SCD-Q) ratings between Pre-AD subjects and cognitively healthy controls, b) to study the association of SCD-Q scores with levels of AD biomarkers in cognitively healthy and cognitively impaired subjects, and c) to compare SCD-Q ratings in cognitively impaired subjects with or without abnormal Aß 42. METHODS: Two hundred and seventeen participants (111 subjects; 106 informants) answered the SCD-Q. All subjects underwent a lumbar puncture to determine levels of Aß 42 and tau, and an extensive neuropsychological battery. Healthy subjects were classified as Controls (CTR) or Pre-AD according to the absence or the presence of abnormal Aß 42, and those with cognitive impairment (CI) into Non-amyloid (NonAB-CI) or Amyloid (AB-CI) impairment. RESULTS: Informants' SCD-Q scores were significantly higher in the Pre-AD group than in the CTR group (F = 6.75; p = 0.01). No significant differences were found in self-ratings. In the cognitively impaired groups, there were no significant differences in the SCD-Q ratings. In the whole sample, informants' ratings of SCD-Q correlated with Aß 42 (r = -0.21; p = 0.02) and tau levels (r = 0.28; p = 0.00). CONCLUSIONS: Higher informants' ratings of SCD-Q differentiated Pre-AD subjects from CTR. Informants' ratings of SCD-Q correlated weakly with cerebrospinal fluid AD biomarkers.