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Cross-cultural differences in the association between neuropsychiatric symptoms and Alzheimer's disease (AD) biomarkers are not well understood. This study aimed to (1) compare depressive symptoms and frequency of reported apathy across diagnostic groups of participants with normal cognition (CN), mild cognitive impairment (MCI), and dementia, as well as ethnic groups of Hispanic Americans (HA) and European Americans (EA); (2) evaluate the relationship between depression and apathy with Aβ deposition and brain atrophy. Statistical analyses included ANCOVAs, chi-squared, nonparametric tests, correlations, and logistic regressions. Higher scores on the Geriatric Depression Scale (GDS-15) were reported in the MCI and dementia cohorts, while older age corresponded with lower GDS-15 scores. The frequency of apathy differed across diagnoses within each ethnicity, but not when comparing ethnic groups. Reduced volume in the rostral anterior cingulate cortex (ACC) significantly correlated with and predicted apathy for the total sample after applying false discovery rate corrections (FDR), controlling for covariates. The EA group separately demonstrated a significant negative relationship between apathy and superior frontal volume, while for HA, there was a relationship between rostral ACC volume and apathy. Apathy corresponded with higher Aβ levels for the total sample and for the CN and HA groups. [ABSTRACT FROM AUTHOR]

Objective We aimed to evaluate the psychometric properties and diagnostic accuracy of the 32-item version of the Multilingual Naming Test (MINT) in participants from 2 ethnic groups (European Americans [EA; n  = 106] and Hispanic Americans [HA; n  = 175]) with 3 diagnostic groups (cognitively normal [CN], n  = 94, mild cognitive impairment [MCI], n  = 148, and dementia, n  = 39). Method An Item Response Theory model was used to evaluate items across ethnicity and language groups (Spanish and English), resulting in a 24-item version. We analyzed the MINT discriminant and predictive validity across diagnostic groups. Results A total of 8 items were differentially difficult between languages in the 32-item version of the MINT. EA scored significantly higher than HA, but the difference was not significant when removing those 8 items (controlling for Education). The Receiver Operating Characteristics showed that the MINT had poor accuracy when identifying CN participants and was acceptable in identifying dementia participants but unacceptable in classifying MCI participants. Finally, we tested the association between MINT scores and magnetic resonance imaging volumetric measures of language-related areas in the temporal and frontal lobes. The 32-item MINT in English and Spanish and the 24-item MINT in Spanish were significantly correlated with the bilateral middle temporal gyrus. The left fusiform gyrus correlated with MINT scores regardless of language and MINT version. We also found differential correlations depending on the language of administration. Conclusions Our results highlight the importance of analyzing cross-cultural samples when implementing clinical neuropsychological tests such as the MINT. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between age, education, sex, and ApoE4 (+) status to brain volume among a cohort with amnestic mild cognitive impairment (aMCI). Method: One hundred and twenty-three participants were stratified into Hispanic (n = 75) and White non-Hispanic (WNH, N = 48). Multiple linear regression analyses were conducted with age, education, sex, and ApoE4 status as predictor variables and left and right combined MRI volumes of the hippocampus, parahippocampus, and entorhinal cortex as dependent variables. Variations in head sizes were corrected by normalization with a total intracranial volume measurement. Results: Bonferroni-corrected results indicated that when controlling for ApoE4 status, education, and age, sex was a significant predictor of hippocampal volume among the Hispanic group (β =.000464, R 2 =.196, p <.01) and the WNH group (β =.000455, R 2 =.195, p <.05). Education (β =.000028, R 2 =.168, p <.01) and sex (β =.000261, R 2 =.168, p <.01) were significant predictors of parahippocampal volume among the Hispanic MCI group when controlling for the effects of ApoE4 status and age. One-way ANCOVAs comparing hippocampal and parahippocampal volume between males and females within groups revealed that females had significantly larger hippocampal volumes (p <.05). Hispanic females had significantly larger hippocampal (p <.001) and parahippocampal (p <.05) volume compared to males. No sex differences in parahippocampal volume were noted among WNHs. Conclusions: Biological sex, rather than ApoE4 status, was a greater predictor of hippocampal volume among Hispanic and WNH females. These findings add to the mixed literature on sex differences in dementia research and highlight continued emphasis on ethnic populations to elucidate on neurodegenerative disparities. [ABSTRACT FROM AUTHOR]

Background: Estimates from the Alzheimer's Association indicate that approximately one in ten older adults in the US have Alzheimer's disease (AD) dementia while 15 to 20% have mild cognitive impairment (MCI), projecting that about a third of those will develop dementia within five years. The Cognitive Reserve/ Resilience (CR/R) theory postulates that complex mental activity throughout the lifetime builds resilience to cognitive decline despite the biological risk (a neurodegenerative disease). Emerging evidence shows that bilingualism may be one of these neuroprotective factors in the aging brain, but results in bilingualism and CR/R remain inconsistent. Methods: We studied 238 Latino older adults (age 71.8 ± 8.0 years old, 65% female) from the 1Florida Alzheimer's Disease Research Center who were diagnosed as clinically normal, MCI, or dementia. Of these, 158 were Spanish‐English bilinguals and 80 were Spanish monolinguals. Bilingualism was assessed by a proficiency questionnaire. Six cognitive composites were developed (Figure 1). We investigated cognitive test correlates of plasma P‐tau181 (Quanterix simoa), hippocampal volume, and amyloid PET (Centiloid) biomarkers in both language groups, using 2×3 ANCOVAs (controlling for age and level of education). We analyzed correlations between biomarkers and cognition and performed multiple regression analyses within each language group. Results: The main effect of the diagnostic group was significant for all biomarkers (ps <.001). There was no main effect of the language group and no significant interactions. The correlations between biomarkers were equally significant for both language groups but differences in the association of biomarkers with cognitive tests emerged between language groups. Bilinguals showed a stronger negative association between hippocampal volume and cognitive test scores than monolinguals. In bilinguals, higher PTau181 was associated with lower visuomotor composite scores, while amyloid PET positivity and lower hippocampal volume were associated with cognitive stress and working memory. In monolinguals, higher PTau181 was associated with worse inhibitory control, and amyloid PET positivity and lower hippocampal volume were associated with worse memory. Conclusion: Results demonstrated discrepancies between bilingual and monolingual Latinos in the associations between cognitive composites and AD biomarkers. Further exploring the relationship between bilingualism, cognitive test scores, and biomarker patterns is warranted, especially longitudinally. [ABSTRACT FROM AUTHOR]

Background: Dementia diagnoses are more common among Hispanic (HW) than non‐Hispanic white (NHW) older adults. Alzheimer's disease (AD) is the most common neuropathological finding in patients with dementia. Plasma AD biomarkers have accelerated efforts towards increasing access to timely diagnosis, but existing data often come from cohorts lacking ethnic diversity. Clinical translation of plasma AD biomarkers requires continued evaluation in study cohorts that reflect the growing ethnic diversity of the population. Method: We studied 379 older adults (age 71.9±7.8 years old, 60.2% female) from the 1Florida Alzheimer's Disease Research Center who underwent blood draw and analysis for P‐tau181 (Quanterix). Of these, 240 completed Aβ‐PET (converted to Centiloids). Over half (57%) self‐identified as HW (32% Cuba, 18% South American, 7% other). Analyses included 1) comparing plasma biomarker concentrations between clinically normal (CN), amnestic MCI (amnMCI), amnestic dementia (amnDEM), and nonamnestic MCI/dementia (ANCOVA controlling for age), 2) evaluating P‐tau181 correlations with Aβ burden (Spearman's rho), and 3) determining discriminability (AUC) of Aβ‐PET[+] from Aβ‐PET[‐]. Interactions between independent variables and ethnicity were evaluated to inform whether observed relationships differed between HW and non‐Hispanic white (NHW). Lastly, using a cutoff derived from the PET sub‐cohort, we investigated rates of P‐tau181‐defined "AD positivity" (plasmaAD[+]) between HW and NHW diagnosed with amnMCI. Additional data for plasma GFAP and NfL will also be presented. Results: Plasma P‐tau181 was higher in amnMCI (p =.004, d = 0.53) and amnDEM (p<.001, d = 0.97) than CN. Higher P‐tau181 related to greater Aβ burden (ρ =.59 [.50‐.67], p<.001) and had good discriminability between Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86 [0.81‐0.91], Youden's Index = 2.39 pg/mL). There were no significant interactions with ethnicity. Applying the P‐tau181 cutoff (2.39 pg/mL) to all amnMCI participants, HW diagnosed with amnMCI had lower odds of being plasmaAD[+] than NHW (36.5% vs. 58.5%; OR = 0.41 [0.21‐0.78], p =.006). Conclusion: Plasma P‐tau181 may aid etiological diagnosis of cognitively impaired older adults from Hispanic and non‐Hispanic ethnic origins. Hispanic ethnicity alone does not significantly influence the interpretation of how plasma P‐tau181 relates to Aβ‐PET, but may be linked to greater likelihood of non‐AD causes of memory loss. Blood‐based biomarkers could help reduce barriers to clinical diagnosis and research participation that disproportionately impact underrepresented groups. [ABSTRACT FROM AUTHOR]

With the advances in machine learning for the diagnosis of Alzheimer's disease (AD), most studies have focused on either identifying the subject's status through classification algorithms or on predicting their cognitive scores through regression methods, neglecting the potential association between these two tasks. Motivated by the need to enhance the prospects for early diagnosis along with the ability to predict future disease states, this study proposes a deep neural network based on modality fusion, kernelization, and tensorization that perform multiclass classification and longitudinal regression simultaneously within a unified multitask framework. This relationship between multiclass classification and longitudinal regression is found to boost the efficacy of the final model in dealing with both tasks. Different multimodality scenarios are investigated, and complementary aspects of the multimodal features are exploited to simultaneously delineate the subject's label and predict related cognitive scores at future timepoints using baseline data. The main intent in this multitask framework is to consolidate the highest accuracy possible in terms of precision, sensitivity, F1 score, and area under the curve (AUC) in the multiclass classification task while maintaining the highest similarity in the MMSE score as measured through the correlation coefficient and the RMSE for all time points under the prediction task, with both tasks, run simultaneously under the same set of hyperparameters. The overall accuracy for multiclass classification of the proposed KTMnet method is 66.85 ± 3.77. The prediction results show an average RMSE of 2.32 ± 0.52 and a correlation of 0.71 ± 5.98 for predicting MMSE throughout the time points. These results are compared to state-of-the-art techniques reported in the literature. A discovery from the multitasking of this consolidated machine learning framework is that a set of hyperparameters that optimize the prediction results may not necessarily be the same as those that would optimize the multiclass classification. In other words, there is a breakpoint beyond which enhancing further the results of one process could lead to the downgrading in accuracy for the other. [ABSTRACT FROM AUTHOR]

We examined the association between bilingualism, executive function (EF), and brain volume in older monolinguals and bilinguals who spoke English, Spanish, or both, and were cognitively normal (CN) or diagnosed with Mild Cognitive Impairment (MCI) or dementia. Gray matter volume (GMV) was higher in language and EF brain regions among bilinguals, but no differences were found in memory regions. Neuropsychological performance did not vary across language groups over time; however, bilinguals exhibited reduced Stroop interference and lower scores on Digit Span Backwards and category fluency. Higher scores on Digit Span Backwards were associated with a younger age of English acquisition, and a greater degree of balanced bilingualism was associated with lower scores in category fluency. The initial age of cognitive decline did not differ between language groups. The influence of bilingualism appears to be reflected in increased GMV in language and EF regions, and to a lesser degree, in EF. [ABSTRACT FROM AUTHOR]

Background: Early and accurate diagnosis of Alzheimer's disease (AD) is critical to improve illness management and outcomes, making neuropsychological measures an essential tool for clinicians. Research has demonstrated that proactive semantic interference (PSI) and failure to recover from PSI (frPSI) are sensitive to cognitive changes in early mild cognitive impairment (MCI) and preclinical AD determined by Aβ load using PET (Loewenstein et al., 2018; Matias‐Guiu et al., 2017; Curiel et al., 2019). These novel constructs are assessed by the LASSI‐L (Crocco et al., 2018; Crocco et al., 2020). The aim of the current study was to compare a new computerized version of this measure, the LASSI‐BC, to the standard paper‐and‐pencil version of the test. Method: 110 cognitively unimpaired (CU) older adults and 79 older adults diagnosed with amnestic MCI (aMCI) were administered the paper‐and‐pencil form of the LASSI‐L, whereas 62 CU and 52 aMCI participants were administered the LASSI‐BC. Their performance was compared to assess the validity of the LASSI‐BC to discriminate between different diagnostic groups. Result: To assess the validity of the computerized version, both the aMCI and CU groups were compared using χ2 test for categorical variables and ANOVA for continuous variables, with adjustment for covariates such as degree of initial learning, sex, education, and language of evaluation. The performance of CU and aMCI groups using either form was relatively commensurate. Notably, sensitivity and specificity of measures of PSI and frPSI on both versions were calculated to assess diagnostic validity, yielding the following Results Sensitivity of 86.5%, Specificity of 88.1%, and Overall Classification of 87.4% for the LASSI‐BC relative to a Sensitivity of 65.0%, Specificity of 83.6%, and Overall Classification of 75.8% obtained for the paper‐and‐pencil LASSI‐L. Conclusion: The LASSI‐BC displayed exceptionally high diagnostic validity which was comparable to the well‐established LASSI‐L. Notably, the advantages of the LASSI‐BC include a more standardized administration, suitability for remote assessment, and an automated scoring mechanism that can be verified by a built‐in audio recording of responses. These findings support the LASSI‐BC, a novel computerized assessment, as an exceptional tool for the early identification of individuals at risk of progressing to dementia. [ABSTRACT FROM AUTHOR]

Background: Neuropsychological assessments determine the presence of cognitive impairment in Alzheimer's Disease and Related Dementias (ADRD). These tests are susceptible to the influence of cultural and linguistic variables. Bilingualism is a potential contributor to cognitive reserve in elderly individuals. Positive effects of bilingualism have been observed in executive function tasks, while negative effects have been reported on verbal fluency tests. Maintaining two active languages may modify cognitive and brain reserve among bilinguals, but evidence is inconsistent and contradictory. We investigated the relationship between bilingualism and neuropsychological test performance in aging participants from the 1Florida ADRC using a longitudinal design. Methods: We studied 238 Latino older adults (age 71.79 ± 8.01 years old, 65% female). 158 Latino participants were Spanish‐English bilinguals; 80 were Spanish monolinguals. Bilingualism was assessed by a proficiency questionnaire. Six cognitive composites were developed (Figure 1). We investigated cognitive test change scores between language group, visit (2 visits: M = 14.61 months; SD = 3.52), and diagnosis (normal, MCI, dementia) using 2×2×3 repeated measures ANCOVAs (age and level of education). Cognitive scores were correlated with frontal and temporal brain volumes in bilinguals and monolinguals separately. Results: Main effects of the diagnostic group and visit were significant for all composites (ps <.001), with the dementia group showing the lowest scores. No significant main effect of Bilingualism was observed for any of the composites. An interaction between visit and bilingualism was seen for the Trail Making Test B‐ A. Three‐way interactions were found between diagnostic groups, visit, and bilingualism for the Verbal composite and the Logical Memory delay subtest (part of the Memory composite). A more significant decline in the monolingual groups was observed, more so in the dementia group. Significant correlations were found between most composites in both language groups, being more related to the temporal than frontal lobe areas, using MRI volumetric measures. Conclusion: Bilingualism seems to interact with cognitive decline in aging. It is essential to consider the individual's level of bilingualism to obtain an accurate assessment of cognitive impairment. The interaction of bilingualism with other sociodemographic and cognitive variables will be discussed. [ABSTRACT FROM AUTHOR]

Objective To analyze (1) whether there are ethnic differences in the severity of depressive symptoms between groups of elders classified as cognitively normal (CN) or amnestic mild cognitive impairment (aMCI) and (2) the influence of depressive symptoms on specific cognitive performance by ethnicity across diagnoses, controlling for covariates. Methods 164 Hispanics residing in the United States (HAs) and European Americans (EAs) (100 women; M age = 72.1, SD  = 8.0) were diagnosed as either CN or aMCI. Depressive symptoms were measured with the Geriatric Depression Scale (GDS-15). Cognition was assessed using the Loewenstein-Acevedo Scales for Semantic Interference and Learning (semantic memory), Multilingual Naming Test (confrontation naming), and the Stroop Test (Color–Word condition; executive function). A 2 × 2 univariate ANCOVA as well as linear and logistic regressions explored differences in depressive symptoms among diagnostic and ethnic groups. Results Higher depression was seen in aMCI compared to the CN group for both ethnicities, after controlling for age, education, gender, and Mini-Mental State Examination score. Greater levels of depression also predicted lower scores in confrontation naming and semantic memory for only the EA group and marginally in scores of executive function for HA participants. GDS-15 scores of ≤ 4 also predicted less likelihood of aMCI diagnosis. Conclusions Severity of depressive symptoms was associated with greater cognitive impairment, independent of ethnicity. Significant results suggest detrimental effects of depression on clinical diagnoses most evidently for subjects from the EA group. [ABSTRACT FROM AUTHOR]

Objective To investigate the association between the functional activities questionnaire (FAQ) and brain biomarkers (bilateral hippocampal volume [HV], bilateral entorhinal volume [ERV], and entorhinal cortical thickness [ERT]) in cognitively normal (CN) individuals, mild cognitive impairment (MCI), or dementia. Method In total, 226 participants (137 females; mean age = 71.76, SD  = 7.93; Hispanic Americans = 137; European Americans = 89) were assessed with a comprehensive clinical examination, a neuropsychological battery, a structural magnetic resonance imaging, and were classified as CN or diagnosed with MCI or dementia. Linear regression analyses examined the association between functional activities as measured by the FAQ on brain biomarkers, including HV, ERV, and ERT, controlling for age, education, global cognition, gender, and ethnicity. Results The FAQ significantly predicted HV, ERV, and ERT for the entire sample. However, this association was not significant for ERV and ERT when excluding the dementia group. The FAQ score remained a significant predictor of HV for the non-dementia group. Age, education, gender, ethnicity, Montreal Cognitive Assessment score, and FAQ were also significant predictors of HV for the overall sample, suggesting that younger Hispanic females with fewer years of education, higher global mental status, and better functioning, were more likely to have larger HV. Conclusion FAQ scores were related to HV in older adults across clinical groups (CN, MCI, and dementia), but its association with the entorhinal cortex was driven by individuals with dementia. Demographic variables, including ethnicity, additionally influenced these associations. [ABSTRACT FROM AUTHOR]

Objective: Episodic memory is frequently impaired in Multiple Sclerosis (MS), but the cognitive characteristics and neuropsychological processes involved remain controversial. Our aim was to study episodic memory dysfunction in MS, using the LASSI-L, a novel memory-based cognitive stress test that uses a new paradigm that capitalizes on semantic interference. Methods: Cross-sectional study in which 93 patients with MS (relapsing-remitting) and 124 healthy controls were included. The LASSI-L test was administered to all participants, as well as a comprehensive neuropsychological battery including a selective reminding test. MS patients were divided into two groups, with cognitive impairment (CI-MS) and cognitively preserved (CP-MS). Results: Reliability of the LASSI-L test was high (Cronbach's alpha 0.892) and there were less ceiling effects. MS patients scored lower than controls on all LASSI-L subtests, except for maximum storage of the initial target items (CRA2). Effect sizes were moderate-large. A delay in learning, difficulties in retroactive semantic interference, failure to recover from proactive semantic interference, and delayed recall were the most frequent findings in MS patients. Scores associated with maximum storage capacity, and retroactive semantic interference were the most strongly associated with cognitive impairment and employment status. Conclusion: We found that deficits in maximum learning, difficulties in recovery from the effects of proactive semantic interference and retroactive semantic interference are three important breakdowns in episodic memory deficits among patients with MS. The LASSI-L showed good psychometric and diagnostic properties. Overall, our study supports the utility of the LASSI-L, as a new cognitive test, useful for neuropsychological assessment in MS in clinical and research settings. [ABSTRACT FROM AUTHOR]

Objectives: Maintaining two active languages may increase cognitive and brain reserve among bilingual individuals. We explored whether such a neuroprotective effect was manifested in the performance of memory tests for participants with amnestic mild cognitive impairment (aMCI). Methods: We compared 42 bilinguals to 25 monolingual on verbal and nonverbal memory tests. We used; (a) the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive test that taps into proactive, retroactive, and recovery from proactive semantic interference (verbal memory), and (b) the Benson Figure delayed recall (nonverbal memory). A subsample had volumetric MRI scans. Results: The bilingual group significantly outperformed the monolingual group on two LASSI-L cued recall measures (Cued A2 and Cued B2). A measure of maximum learning (Cued A2) showed a correlation with the volume of the left hippocampus in the bilingual group only. Cued B2 recall (sensitive to recovery from proactive semantic interference) was correlated with the volume of the hippocampus and the entorhinal cortex of both cerebral hemispheres in the bilingual group, as well as with the left and right hippocampus in the monolingual group. The memory advantage in bilinguals on these measures was associated with higher inhibitory control as measured by the Stroop Color-Word test. Conclusions: Our results demonstrated a superior performance of aMCI bilinguals over aMCI monolingual on selected verbal memory tasks. This advantage was not observed in nonverbal memory. Superior memory performance of bilinguals over monolinguals suggests that bilinguals develop a different and perhaps more efficient semantic association system that influences verbal recall. (JINS, 2019, 25, 15-28) [ABSTRACT FROM AUTHOR]

In spite of advances in neuroimaging and other brain biomarkers to assess preclinical Alzheimer’s disease (AD), cognitive assessment has relied on traditional memory paradigms developed well over six decades ago. This has led to a growing concern about their effectiveness in the early diagnosis of AD which is essential to develop preventive and early targeted interventions before the occurrence of multisystem brain degeneration. We describe the development of novel tests that are more cognitively challenging, minimize variability in learning strategies, enhance initial acquisition and retrieval using cues, and exploit vulnerabilities in persons with incipient AD such as the susceptibility to proactive semantic interference, and failure to recover from proactive semantic interference. The advantages of various novel memory assessment paradigms are examined as well as how they compare with traditional neuropsychological assessments of memory. Finally, future directions for the development of more effective assessment paradigms are suggested. [ABSTRACT FROM AUTHOR]

Background: The Free and Cued Selective Reminding Test (FCSRT) is the most accurate test for the diagnosis of prodromal Alzheimer's disease (AD). Recently, a novel cognitive test, the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), has been developed in order to provide an early diagnosis.Objective: To compare the diagnostic accuracy of the FCSRT and the LASSI-L for the diagnosis of AD in its preclinical and prodromal stages using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a reference.Methods: Fifty patients consulting for subjective memory complaints without functional impairment and at risk for AD were enrolled and evaluated using FCSRT, LASSI-L, and FDG-PET. Participants were evaluated using a comprehensive neurological and neuropsychological protocol and were assessed with the FCSRT and LASSI-L. FDG-PET was acquired concomitantly and used for classification of patients as AD or non-AD according to brain metabolism using both visual and semi-quantitative methods.Results: LASSI-L scores allowed a better classification of patients as AD/non-AD in comparison to FCSRT. Logistic regression analysis showed delayed recall and failure to recovery from proactive semantic interference from LASSI-L as independent statistically significant predictors, obtaining an area under the curve of 0.894. This area under the curve provided a better discrimination than the best FCSRT score (total delayed recall, area under the curve 0.708, p = 0.029).Conclusions: The LASSI-L, a cognitive stress test, was superior to FCSRT in the prediction of AD features on FDG-PET. This emphasizes the possibility to advance toward an earlier diagnosis of AD from a clinical perspective. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Recent findings indicate that impairments in functional performance do occur among individuals diagnosed with mild cognitive impairment (MCI). Most assessment strategies for everyday competence are associated with challenges with reliability, are typically in paper and pencil format, or require in-person administration by a trained professional.Objective: This paper reports on a novel technology-based assessment battery of everyday competence that includes ecologically valid simulations of daily activities important to independence.Methods: The sample included 85 non-cognitively impaired older adults aged 65+ and 62 older adults diagnosed with amnestic MCI (aMCI). Participants completed standard measures of cognitive abilities and the computerized battery of everyday tasks, which included simulations of a doctor's visit; and medication and financial management tasks.Results: The older adults with aMCI performed significantly poorer on all three tasks in the everyday task battery. Performance on these measures were also moderately correlated with standard measures of cognitive abilities and showed good test-retest reliability.Conclusions: The results show that it is feasible to use a technology-based assessment battery of everyday tasks with both non-cognitively impaired older adults and older adults with MCI. The use of this type of battery can overcome many of the logistic constraints associated with current functional assessment protocols. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Assessment of the earlier stages of Alzheimer's disease requires different strategies than those previously developed for fully syndromal Alzheimer's disease. This challenge is further magnified in very early stages, where symptomatology may be minimal and functional deficits very subtle to absent. This paper reviews strategies for performance-based assessment of the early stages of Alzheimer's disease, including assessments of cognition, functional capacity, and social cognition. Meetings with an International Society for CNS Clinical Trials and Methodology working group served as the basis for this paper and its companion. The current state of the art of detection and staging-oriented assessments is presented, and information is provided regarding the practicality and validity of these approaches, with a special focus on their usefulness in clinical trials for new medication development. [ABSTRACT FROM AUTHOR]

An evolving paradigm shift in the diagnostic conceptualization of Alzheimer's disease is reflected in its recently updated diagnostic criteria from the National Institute on Aging-Alzheimer's Association and the International Working Group. Additionally, it is reflected in the increased focus in this field on conducting prevention trials in addition to improving cognition and function in people with dementia. These developments are making key contributions towards defining new regulatory thinking around Alzheimer's disease treatment earlier in the disease continuum. As a result, the field as a whole is now concentrated on exploring the next-generation of cognitive and functional outcome measures that will support clinical trials focused on treating the slow slide into cognitive and functional impairment. With this backdrop, the International Society for CNS Clinical Trials and Methodology convened semi-annual working group meetings which began in spring of 2012 to address methodological issues in this area. This report presents the most critical issues around primary outcome assessments in Alzheimer's disease clinical trials, and summarizes the presentations, discussions, and recommendations of those meetings, within the context of the evolving landscape of Alzheimer's disease clinical trials. [ABSTRACT FROM AUTHOR]

Background: Semantic memory interference has been found to be a predictive cognitive marker of incipient AD. This is relevant given that developing assessment paradigms to identify subtle cognitive and functional deficits is a priority in preclinical Alzheimer's disease research.Objective: To examine the utility of a novel computerized paired associate test in distinguishing between mild cognitive impairment (MCI) and cognitively normal (CN) groups of older adults residing in the community.Methods: Participants that were CN (n = 64) or MCI (n = 34) were administered the Miami Test of Semantic Interference and Learning (MITSI-L). This novel instrument is a brief, computerized paired associate test that measured the strength of memory binding of semantically related word pairs and introduced a proactive semantic interference condition which required participants to make different associations between semantically similar targets. A series of ANOVAs explored differences on MITSI-L performance. Logistic regression and receiver operator curves (ROC) analyses were employed to further determine discriminative validity.Results: MCI participants had lower scores on all indices relative to CN elders. A composite of two subscores correctly classified 85.3% of MCI and 84.4% of CN participants. Area under the ROC was higher relative to the MMSE, immediate memory for passages, and several subtests of a sensitive memory measure, the LASSI-L.Conclusions: The MITSI-L is a computerized test that can successfully differentiate MCI from CN participants. Area under the ROC curve exceeded that of global mental status and other memory measures. The effectiveness of the MITSI-L in detecting MCI, and its brief administration and portability render it worthy of further research. [ABSTRACT FROM AUTHOR]

Background: The CST is a novel assessment that was designed to measure cognitive changes during preclinical and prodromal stages of AD, that include aMCI and PreMCI, where deficits do not meet MCI. The CST employs semantically competing word lists to measure the impact of semantic interference, failure to recover from proactive semantic interference (frPSI), and its persistent effects, despite multiple trials. We hypothesized that frPSI deficits on the CST would be persistent in pre‐MCI and aMCI groups when compared to cognitively unimpaired (CU) controls. Method: 50 aMCI, 31 pre‐MCI, and 69 CU elders were administered the CST. Participants were presented with List A (18 semantically related words: occupations, household items, or transportation methods) for three initial learning trials, followed by three learning trials of List B, a categorically similar wordlist, to examine PSI and frPSI. Retroactive Semantic Interference (RSI) was assessed by using category cues to elicit recall of List A targets, followed by an additional learning trial to examine failure to recover from RSI (frRSI). Result: Significant differences were observed between all diagnostic groups across CST Cued Recall trials that measure maximum learning, PSI, frPSI, and persistent frPSI. PreMCI and aMCI participants experienced deficits in learning List B despite two additional opportunities; a deficit that was observed even after adjusting for initial learning strength. Older adults with greater risk (preMCI and aMCI) performed similarly on indices that measures PSI, frPSI, and persistent frPSI as compared to controls. There were differences in RSI among CU and aMCI groups yet measuring frRSI did not differentiate groups. aMCI participants made more semantic intrusion errors on recall trials that cued List B words. Pre‐MCI and CU made a similar number of intrusion errors. Conclusion: The CST extends our work by assessing persistent effects of frPSI, which have been shown to predict neurodegenerative progression and have been associated with multiple biomarkers of AD. The finding that persistent frPSI could differentiate CU from preMCI groups is a promising indicator that semantic interference deficits persist in older adults that present a heightened risk for progression to dementia and is worthy of further research. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationship between susceptibility to proactive semantic interference (PSI) and retroactive semantic interference (RSI) and brain amyloid load in non-demented elders.Methods: 27 participants (11 cognitively normal [CN] with subjective memory complaints, 8 CN without memory complaints, and 8 with mild cognitive impairment [MCI]) underwent complete neurological and neuropsychological evaluations. Participants also received the Semantic Interference Test (SIT) and AV-45 amyloid PET imaging.Results: High levels of association were present between total amyloid load, regional amyloid levels, and the PSI measure (in the entire sample and a subsample excluding MCI subjects). RSI and other memory measures showed much weaker associations or no associations with total and regional amyloid load. No associations between amyloid levels and non-memory performance were observed.Conclusions: In non-demented individuals, vulnerability to PSI was highly associated with total and regional beta-amyloid load and may be an early cognitive marker of brain pathology. [ABSTRACT FROM AUTHOR]

This is a case study of an 88-year-old man who presented with agenesis of the corpus callosum and colpocephaly. Symptomatically, he reported a sudden onset of mild, intermittent left hand apraxia, but denied any previous manifestations consistent with this type of brain malformation. The patient underwent neuroimaging, evaluation by neurology, and comprehensive neuropsychological testing to determine the nature of any other associated impairments. Test results indicated that he was, with a few exceptions, neuropsychologically normal. He performed well on tests that are highly sensitive to acquired brain dysfunction. His most notable deficit was failed performance in the simultaneous and coordinated use of both hands in using tactile and proprioceptive feedback on the Tactual Performance Test. This case is discussed in terms of plasticity of the developing brain, including compensatory mechanisms, highlighting the variability in clinical outcome in the context of congenital brain malformation. This case study illustrates the strong influence of cerebral plasticity as well as a possible circumscribed manifestation of interhemispheric disconnection. [ABSTRACT FROM PUBLISHER]

Prospective memory, the inability to remember an intended action, is a common complaint, but not formally assessed in most clinical and research studies of mild cognitive impairment (MCI). In this study, patients with amnestic mild cognitive impairment (aMCI), non-amnestic cognitive impairment (naMCI), and cognitively normal (CN) elders were assessed using the Miami Prospective Memory Test (MPMT). A unique aspect of the paradigm was that participants were scored for intention to perform, accuracy in recollection for specific elements of the task, and the need for reminder cues. Excellent test-retest stability was obtained for MPMT Event-Related (ER), combined Time-Related (TR) subscales, and total MPMT score for aMCI subjects. MPMT impairments were observed in 48.6% of aMCI, 29.4% of naMCI, and 10.0% of normal elderly participants. Prospective memory deficits were common in participants with aMCI, and occurred in almost a third of naMCI participants. Intention to perform and need for reminder cues were significantly more impaired than retrospective memory for specific details of the task. It is concluded that assessment of different elements of prospective memory is important in MCI research and that inability to remember intended actions is a significant feature in those as risk for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: New research criteria for diagnosing Alzheimer's disease (AD) in the mild cognitive impairment stage (MCI-AD) incorporate biomarkers to assign a level of certainty to the diagnosis. Structural MRI is widely available but greatly under-utilized for assessing atrophy of structures affected in early AD, such as the hippocampus (HP), because the quantification of HP volumes (HP-v) requires special expertise, and normative values have not been established. Methods: Elderly subjects (n = 273) from the Florida ADRC were classified as having no cognitive impairment (cognitively normal, CN), amnestic mild cognitive impairment (aMCI) or AD. Volumes for the hippocampus (HP-v) were measured on structural MRI scans. A validated visual rating system for measuring medial temporal atrophy (VRS-MTA), including hippocampal, entorhinal cortex and perirhinal cortex atrophy was employed. The participants were subdivided into younger (less than or equal to 75 years of age) and older (greater than 75 years of age) subgroups. Results: Volumetric and VRS-MTA measures were equivalent in predicting classification of CN vs. aMCI for older (area under the receiver operator curves [aROC]: 0.652 vs. 0.723) and younger subjects (aROC: 0.764 vs. 0.736). However, for younger AD subjects, aROC values were significantly higher for VRS-MTA measures (0.920) than for volumetric measures (0.847). Relative to HP-v, VRS-MTA score was significantly more correlated to impairment on a range of memory tests and was more associated with progression of aMCI to AD than HP-v. Conclusion: Structural MRI with VRS-MTA assessment can serve as a biomarker for supporting the diagnosis of MCI-AD. Age-adjusted VRS-MTA scores are at least as effective as HP-v for distinguishing aMCI and AD from CN and for predicting progression from aMCI to AD. VRS-MTA is convenient for use in the clinic as well as for clinical trials and can readily be incorporated into a standardized radiological report. [ABSTRACT FROM AUTHOR]

Background: Glucose levels, together with hemoglobin A1c (HA1c), have been associated with reduced cognitive performance, particularly on executive functioning and memory measures. Numerous studies using the Loewenstein‐Acevedo Scales for Semantic Interference and Learning (LASSI‐L) have demonstrated that proactive semantic interference (PSI) and failure to recover from PSI (frPSI) are sensitive to early cognitive changes present in the preclinical stages of Alzheimer's disease (AD). Method: The aim of the present study was to examine the association between PSI, frPSI, blood glucose levels, and hemoglobin A1c (HA1c) among cognitively normal middle‐aged adults. Seventy‐five adults (Age: 50.8 ± 6.67; Education: 16.23 ± 2.93; Sex: 68% female) without psychological disorders, substance use disorders, or previous cognitive diagnoses were recruited as part of a memory and aging study. Sixty‐seven participants identified as White (89%) and eight as African American (11%). They were fluent in English and/or Spanish and were tested in their dominant and preferred language (65% English, 35% Spanish), as assessed by the Language Experience and Proficiency Questionnaire. All participants underwent a neuropsychological evaluation and administration of the Clinical Dementia Rating Scale (CDR); all were diagnosed as cognitively normal by trained neuropsychologists. Participants fasted six to eight hours prior to providing a blood sample. Comparisons were made between participants using t‐tests and Chi‐square tests. An additional Spearman correlation was used to determine the relationship between the variables. Blood glucose and HA1c levels were compared to LASSI‐L scores, including the number of words correctly recalled and the number of intrusion errors (IE) on the PSI (List B Cued Recall 1) and frPSI (List B Cued Recall 2) trials. Result: There was no significant association between glucose and the LASSI‐L Scales. However, higher HA1c levels were correlated with lower intrusion errors sensitive to proactive semantic interference. Conclusion: Our findings are inconsistent with previous research, as an increase of blood glucose and HA1c levels have been formerly found to lead to reduced cognitive performance. Based on these findings, further investigations are warranted to better understand the associations between HA1C levels, proactive semantic interference, and varying cognitive domains. [ABSTRACT FROM AUTHOR]

Abstract Objective Methods Results The interaction of ethnicity, progression of cognitive impairment, and neuroimaging biomarkers of Alzheimer’s Disease remains unclear. We investigated the stability in cognitive status classification (cognitively normal [CN] and mild cognitive impairment [MCI]) of 209 participants (124 Hispanics/Latinos and 85 European Americans).Biomarkers (structural MRI and amyloid PET scans) were compared between Hispanic/Latino and European American individuals who presented a change in cognitive diagnosis during the second or third follow-up and those who remained stable over time.There were no significant differences in biomarkers between ethnic groups in any of the diagnostic categories. The frequency of CN and MCI participants who were progressors (progressed to a more severe cognitive diagnosis at follow-up) and non-progressors (either stable through follow-ups or unstable [progressed but later reverted to a diagnosis of CN]) did not significantly differ across ethnic groups. Progressors had greater atrophy in the hippocampus (HP) and entorhinal cortex (ERC) at baseline compared to unstable non-progressors (reverters) for both ethnic groups, and more significant ERC atrophy was observed among progressors of the Hispanic/Latino group. For European Americans diagnosed with MCI, there were 60% more progressors than reverters (reverted from MCI to CN), while among Hispanics/Latinos with MCI, there were 7% more reverters than progressors. Binomial logistic regressions predicting progression, including brain biomarkers, MMSE, and ethnicity, demonstrated that only MMSE was a predictor for CN participants at baseline. However, for MCI participants at baseline, HP atrophy, ERC atrophy, and MMSE predicted progression. [ABSTRACT FROM AUTHOR]

• Introducing a supervised dimensionality reduction algorithm to characterize the optimal Gaussian discriminative components. • Attaining the best performance of CN vs. EMCI and EMCI vs. LMCI classifications compared with recent state-of-the-art models. • Reducing the dimensionality of data and still achieving more effective classification performance than widely used methods. • Yielding an overall accuracy of 66.29% for CN vs. MCI vs. AD multiclass classification. • More notably, distinguishing diseased subjects (i.e., EMCI, LMCI and AD) from CN group with an accuracy of 75.28%. Using multiple modalities of biomarkers, several machine leaning-based approaches have been proposed to characterize patterns of structural, functional and metabolic differences discernible from multimodal neuroimaging data for Alzheimer's disease (AD). Current investigations report several studies using binary classification often augmented with local feature selection methods, while fewer other studies address the challenging problem of multiclass classification. To assess the merits of each of these research directions, this study introduces a supervised Gaussian discriminative component analysis (GDCA) algorithm, which can effectively delineate subtle changes of early mild cognitive impairment (EMCI) group in relation to the cognitively normal control (CN) group. Using 251 CN, 297 EMCI, 196 late MCI (LMCI), and 162 AD subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and considering both structural and functional (metabolic) information from magnetic resonance imaging (MRI) and positron emission tomography (PET) modalities as input, the proposed method conducts a dimensionality reduction algorithm taking into consideration the interclass information to define an optimal eigenspace that maximizes the discriminability of selected eigenvectors. The proposed algorithm achieves an accuracy of 79.25 % for delineating EMCI from CN using 38.97 % of Gaussian discriminative components (i.e., dimensionality reduction). Moreover, for detecting the different stages of AD, a multiclass classification experiment attained an overall accuracy of 67.69 %, and more notably, discriminates MCI and AD groups from the CN group with an accuracy of 75.28 % using 48.90 % of the Gaussian discriminative components. The classification results of the proposed GDCA method outperform the more recently published state-of-the-art methods in AD-related multiclass classification tasks, and seems to be the most stable and reliable in terms of relating the most relevant features to the optimal classification performance. The proposed GDCA model with its high prospects for multiclass classification has a high potential for deployment as a computer aided clinical diagnosis system for AD. [ABSTRACT FROM AUTHOR]

• Developing a new probabilistic approach for obtaining the most relevant features from MRI and PET data. • Achieving higher accuracy in diagnosis of the EMCI from CN compared with the previous studies. • The proposed algorithm is able to rank the features based on their importance in every state of Alzheimer's disease. • Validating the results considering 896 subjects including 296 EMCI subjects as the first study to consider such a large number of EMCI. Diagnosis of early mild cognitive impairment (EMCI) as a prodromal stage of Alzheimer's disease (AD) with its delineation from the cognitively normal (CN) group remains a challenging but essential step for the planning of early treatment. Although several studies have focused on the MCI diagnosis, this study introduces the early stage of MCI to assess more thoroughly the earliest signs of disease manifestation and progression. We used random forest feature selection model with a Gaussian-based algorithm to perform method evaluation. This integrated method serves to define multivariate normal distributions in order to classify different stages of AD, with the focus placed on detecting EMCI subjects in the most challenging classification of CN vs. EMCI. Using 896 participants classified into the four categories of CN, EMCI, late mild cognitive impairment (LMCI) and AD, the results show that the EMCI group can be delineated from the CN group with a relatively high accuracy of 78.8% and sensitivity of 81.3%. The feature selection model and classifier are compared with some other prominent algorithms. Although higher accuracy has been achieved using the Gaussian process (GP) model (78.8%) over the SVM classifier (75.6%) for CN vs. EMCI classification, with 0.05 being the cutoff for significance, and based on student's t-test, it was determined that the differences for accuracy, sensitivity, specificity between the GP method and support vector machine (SVM) are not statistically significant. Addressing the challenging classification of CN vs. EMCI provides useful information to help clinicians and researchers determine essential measures that can help in the early detection of AD. [ABSTRACT FROM AUTHOR]