Learning and vulnerability to phonological and semantic interference in normal aging: an experimental study.

ABSTRACTThis study compares semantic and phonological interference vulnerability across the full range of learning processes. Method: 43 controls aged 61-88 underwent a neuropsychological examination, French adaptation of the LASSI-L, and an experimental phonological test, the TIP-A. Paired sample t-tests, factorial ANOVA and hierarchical regressions were conducted, psychometric properties were calculated. Results: TIP-A efficiently generated phonological interference between concurrent word lists and was associated with short-term memory, unlike LASSI-L. On LASSI-L, proactive interference was higher than retroactive interference; the opposite pattern was found on TIP-A. Memory performance was better explained by age in the semantic than in the phonological task. Age was not associated with interference vulnerability. Intrusions and false recognition were associated with cognitive functioning regardless of age, particularly in the semantic context. Conclusion: To our knowledge, this is the first study to assess phonological and semantic interference using homologous concurrent word list tasks, and not a working memory build-up or DRM paradigm. The pattern obtained illustrates the weak initial memory trace in a phonological context and results are discussed according to depth-of-processing and dual-process theories. Similar paradigms could be studied among various pathologies for a better understanding of generalised interference vulnerability vs. specific semantic or phonological impairment.

A Novel Cognitive Stress Test for the Detection of Preclinical Alzheimer Disease: Discriminative Properties and Relation to Amyloid Load.

OBJECTIVE: To examine the utility of a novel "cognitive stress test" to detect subtle cognitive impairments and amyloid load within the brains of neuropsychologically normal community-dwelling elders. METHODS: Participants diagnosed as cognitively normal (CN), subjective memory impairment (SMI), mild cognitive impairment (MCI), and preclinical mild cognitive impairment (PreMCI) were administered the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), a sensitive test of proactive semantic interference (PSI), retroactive semantic interference, and, uniquely, the ability to recover from the effects of PSI. Ninety-three subjects (31 men and 62 women) were recruited from three academic institutions in a research consortium. A subset of these individuals underwent 18F florbetapir positron emission tomography scanning. Relative percentages of impairment for each diagnostic group on the LASSI-L were calculated by χ(2) and Fisher's exact tests. Spearman's rho was used to examine associations between amyloid load and different cognitive measures. RESULTS: LASSI-L deficits were identified among 89% of those with MCI, 47% with PreMCI, 33% with SMI, and 13% classified as CN. CN subjects had no difficulties with recovery from PSI, whereas SMI, preMCI, and MCI participants evidenced deficits in recovery from PSI effects. Among a subgroup of participants with normal scores on traditional neuropsychological tests, the strong associations were between the failure to recover from the effects of PSI and amyloid load in the brain. CONCLUSION: Failure to recover or compensate for the effects of PSI on the LASSI-L distinguishes the LASSI-L from other widely used neuropsychological tests and appears to be sensitive to subtle cognitive impairments and increasing amyloid load.

Different aspects of failing to recover from proactive semantic interference predicts rate of progression from amnestic mild cognitive impairment to dementia.

Introduction: This study investigated the role of proactive semantic interference (frPSI) in predicting the progression of amnestic Mild Cognitive Impairment (aMCI) to dementia, taking into account various cognitive and biological factors. Methods: The research involved 89 older adults with aMCI who underwent baseline assessments, including amyloid PET and MRI scans, and were followed longitudinally over a period ranging from 12 to 55 months (average 26.05 months). Results: The findings revealed that more than 30% of the participants diagnosed with aMCI progressed to dementia during the observation period. Using Cox Proportional Hazards modeling and adjusting for demographic factors, global cognitive function, hippocampal volume, and amyloid positivity, two distinct aspects of frPSI were identified as significant predictors of a faster decline to dementia. These aspects were fewer correct responses on a frPSI trial and a higher number of semantic intrusion errors on the same trial, with 29.5% and 31.6 % increases in the likelihood of more rapid progression to dementia, respectively. Discussion: These findings after adjustment for demographic and biological markers of Alzheimer's Disease, suggest that assessing frPSI may offer valuable insights into the risk of dementia progression in individuals with aMCI.

A Novel Computerized Cognitive Test for the Detection of Mild Cognitive Impairment and Its Association with Neurodegeneration in Alzheimer's Disease Prone Brain Regions.

During the prodromal stage of Alzheimer's disease (AD), neurodegenerative changes can be identified by measuring volumetric loss in AD-prone brain regions on MRI. Cognitive assessments that are sensitive enough to measure the early brain-behavior manifestations of AD and that correlate with biomarkers of neurodegeneration are needed to identify and monitor individuals at risk for dementia. Weak sensitivity to early cognitive change has been a major limitation of traditional cognitive assessments. In this study, we focused on expanding our previous work by determining whether a digitized cognitive stress test, the Loewenstein-Acevedo Scales for Semantic Interference and Learning, Brief Computerized Version (LASSI-BC) could differentiate between Cognitively Unimpaired (CU) and amnestic Mild Cognitive Impairment (aMCI) groups. A second focus was to correlate LASSI-BC performance to volumetric reductions in AD-prone brain regions. Data was gathered from 111 older adults who were comprehensively evaluated and administered the LASSI-BC. Eighty-seven of these participants (51 CU; 36 aMCI) underwent MR imaging. The volumes of 12 AD-prone brain regions were related to LASSI-BC and other memory tests correcting for False Discovery Rate (FDR). Results indicated that, even after adjusting for initial learning ability, the failure to recover from proactive semantic interference (frPSI) on the LASSI-BC differentiated between CU and aMCI groups. An optimal combination of frPSI and initial learning strength on the LASSI-BC yielded an area under the ROC curve of 0.876 (76.1% sensitivity, 82.7% specificity). Further, frPSI on the LASSI-BC was associated with volumetric reductions in the hippocampus, amygdala, inferior temporal lobes, precuneus, and posterior cingulate.

LASSI-L detects early cognitive changes in pre-motor manifest Huntington's disease: a replication and validation study.

Background and objectives: Cognitive decline is an important early sign in pre-motor manifest Huntington's disease (preHD) and is characterized by deficits across multiple domains including executive function, psychomotor processing speed, and memory retrieval. Prior work suggested that the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L)-a verbal learning task that simultaneously targets these domains - could capture early cognitive changes in preHD. The current study aimed to replicate, validate and further analyze the LASSI-L in preHD using larger datasets. Methods: LASSI-L was administered to 50 participants (25 preHD and 25 Healthy Controls) matched for age, education, and sex in a longitudinal study of disease progression and compared to performance on MMSE, Trail A & B, SCWT, SDMT, Semantic Fluency (Animals), and CVLT-II. Performance was then compared to a separate age-education matched-cohort of 25 preHD participants. Receiver operating curve (ROC) and practice effects (12 month interval) were investigated. Group comparisons were repeated using a preHD subgroup restricted to participants predicted to be far from diagnosis (Far subgroup), based on CAG-Age-Product scaled (CAPs) score. Construct validity was assessed through correlations with previously established measures of subcortical atrophy. Results: PreHD performance on all sections of the LASSI-L was significantly different from controls. The proactive semantic interference section (PSI) was sensitive (p = 0.0001, d = 1.548), similar across preHD datasets (p = 1.0), reliable on test-retest over 12 months (spearman rho = 0.88; p = <0.00001) and associated with an excellent area under ROC (AUROC) of 0.855. In the preHD Far subgroup comparison, PSI was the only cognitive assessment to survive FDR < 0.05 (p = 0.03). The number of intrusions on PSI was negatively correlated with caudate volume. Discussion: The LASSI-L is a sensitive, reliable, efficient tool for detecting cognitive decline in preHD. By using a unique verbal learning test paradigm that simultaneously targets executive function, processing speed and memory retrieval, the LASSI-L outperforms many other established tests and captures early signs of cognitive impairment. With further longitudinal validation, the LASSI-L could prove to be a useful biomarker for clinical research in preHD.

Semantic intrusion errors are associated with plasma Ptau-181 among persons with amnestic mild cognitive impairment who are amyloid positive.

Introduction: Semantic intrusion errors (SI) have distinguished between those with amnestic Mild Cognitive Impairment (aMCI) who are amyloid positive (A+) versus negative (A-) on positron emission tomography (PET). Method: This study examines the association between SI and plasma - based biomarkers. One hundred and twenty-eight participants received SiMoA derived measures of plasma pTau-181, ratio of two amyloid-ß peptide fragments (Aß42/Aß40), Neurofilament Light protein (NfL), Glial Fibrillary Acidic Protein (GFAP), ApoE genotyping, and amyloid PET imaging. Results: The aMCI A+ (n = 42) group had a higher percentage of ApoE ɛ4 carriers, and greater levels of pTau-181 and SI, than Cognitively Unimpaired (CU) A- participants (n = 25). CU controls did not differ from aMCI A- (n = 61) on plasma biomarkers or ApoE genotype. Logistic regression indicated that ApoE ɛ4 positivity, pTau-181, and SI were independent differentiating predictors (Correct classification = 82.0%; Sensitivity = 71.4%; Specificity = 90.2%) in identifying A+ from A- aMCI cases. Discussion: A combination of plasma biomarkers, ApoE positivity and SI had high specificity in identifying A+ from A- aMCI cases.

A novel cognitive assessment paradigm to detect Pre-mild cognitive impairment (PreMCI) and the relationship to biological markers of Alzheimer's disease.

OBJECTIVE: A number of older adults obtain normal scores on formal cognitive tests, but present clinical concerns that raise suspicion of cognitive decline. Despite not meeting full criteria for Mild Cognitive Impairment (MCI), these PreMCI states confer risk for progression to Alzheimer's disease (AD). This investigation addressed a pressing need to identify cognitive measures that are sensitive to PreMCI and are associated with brain biomarkers of neurodegeneration. METHOD: Participants included 49 older adults with a clinical history suggestive of cognitive decline but normal scores on an array of neuropsychological measures, thus not meeting formal criteria for MCI. The performance of these PreMCI participants were compared to 117 cognitively normal (CN) elders on the LASSI-L, a cognitive stress test that uniquely assesses the failure to recover from proactive semantic interference effects (frPSI). Finally, a subset of these individuals had volumetric analyses based on MRI scans. RESULTS: PreMCI participants evidenced greater LASSI- L deficits, particularly with regards to frPSI and delayed recall, relative to the CN group. No differences on MRI measures were observed. Controlling for false discovery rate (FDR), frPSI was uniquely related to increased dilatation of the inferior lateral ventricle and decreased MRI volumes in the hippocampus, precuneus, superior parietal region, and other AD prone areas. In contrast, other LASSI-L indices and standard memory tests were not related to volumetric findings. CONCLUSIONS: Despite equivalent performance on traditional memory measures, the frPSI distinguished between PreMCI and CN elders and was associated with reductions in brain volume in numerous AD-relevant brain regions.

Recovery from Proactive Semantic Interference and MRI Volume: A Replication and Extension Study.

BACKGROUND: The rise in incidence of Alzheimer's disease (AD) has led to efforts to advance early detection of the disease during its preclinical stages. To achieve this, the field needs to develop more sensitive cognitive tests that relate to biological markers of disease pathology. Failure to recover from proactive interference (frPSI) is one such cognitive marker that is associated with volumetric reductions in the hippocampus, precuneus, and other AD-prone regions, and to amyloid load in the brain. OBJECTIVE: The current study attempted to replicate and extend our previous findings that frPSI is a sensitive marker of early AD, and related to a unique pattern of volumetric loss in AD prone areas. METHODS: Three different memory measures were examined relative to volumetric loss and cortical thickness among 45 participants with amnestic mild cognitive impairment. RESULTS: frPSI was uniquely associated with reduced volumes in the hippocampus (r = 0.50) precuneus (r = 0.41), and other AD prone regions, replicating previous findings. Strong associations between frPSI and lower entorhinal cortex volumes and cortical thickness (r≥0.60) and precuneus (r = 0.50) were also observed. CONCLUSION: Unique and strong associations between volumetric reductions and frPSI as observed by Loewenstein and colleagues were replicated. Together with cortical thickness findings, these results indicate that frPSI is worthy of further study as a sensitive and early cognitive marker of AD.

Recovery from Proactive Semantic Interference in Mild Cognitive Impairment and Normal Aging: Relationship to Atrophy in Brain Regions Vulnerable to Alzheimer's Disease.

BACKGROUND: There is growing evidence that proactive semantic interference (PSI) and failure to recover from PSI may represent early features of Alzheimer's disease (AD). OBJECTIVE: This study investigated the association between PSI, recovery from PSI, and reduced MRI volumes in AD signature regions among cognitively impaired and unimpaired older adults. METHODS: Performance on the LASSI-L (a novel test of PSI and recovery from PSI) and regional brain volumetric measures were compared between 38 cognitively normal (CN) elders and 29 older participants with amnestic mild cognitive impairment (MCI). The relationship between MRI measures and performance on the LASSI-L as well as traditional memory and non-memory cognitive measures was also evaluated in both diagnostic groups. RESULTS: Relative to traditional neuropsychological measures, MCI patients' failure to recover from PSI was associated with reduced volumes in the hippocampus (rs = 0.48), precuneus (rs = 0.50); rostral middle frontal lobules (rs = 0.54); inferior temporal lobules (rs = 0.49), superior parietal lobules (rs = 0.47), temporal pole (rs = 0.44), and increased dilatation of the inferior lateral ventricle (rs = -0.49). For CN elders, only increased inferior lateral ventricular size was associated with vulnerability to PSI (rs = -0.49), the failure to recover from PSI (rs = -0.57), and delayed recall on the Hopkins Verbal Learning Test-Revised (rs = -0.48). DISCUSSION: LASSI-L indices eliciting failure to recover from PSI were more highly associated with more MRI regional biomarkers of AD than other traditional cognitive measures. These results as well as recent amyloid imaging studies with otherwise cognitively normal subjects, suggest that recovery from PSI may be a sensitive marker of preclinical AD and deserves further investigation.

Validation of the Spanish Version of the LASSI-L for Diagnosing Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: The Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L) is a novel cognitive test that measures recovery from proactive semantic interference, which may be an early cognitive marker of Alzheimer's disease (AD). OBJECTIVE: To generate normative data for a Spaniard population and to validate the LASSI-L for the diagnosis of amnestic mild cognitive impairment (aMCI) and mild AD. METHODS: We performed a cross-sectional study in which 97 healthy participants, 34 with aMCI, and 33 with mild AD were studied with LASSI-L and a comprehensive neuropsychological protocol. The overlapping strategy analysis was used to maximize the sample size and to provide age- and education-adjusted normative data using a logistic regression analysis. RESULTS: Internal consistency was 0.932. Convergent validity with the Free and Cued Selective Reminding Test was moderate. LASSI-L raw scores were correlated with age and years of education, but not gender. The area under the curve for discriminating between healthy controls and aMCI was 0.909, and between healthy controls and mild AD was 0.986. LASSI-L sub-scores representing maximum storage capacity, recovery from proactive interference, and delayed recall yielded the highest diagnostic accuracy. CONCLUSIONS: The LASSI-L is a reliable and valid test for the diagnosis of aMCI and mild AD. The age and education influences on the performance of the test and normative data are provided. LASSI-L merits further studies to evaluate its ability to detect preclinical AD and predict progression to aMCI and early dementia.