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Background: Education influences brain health and dementia. However, its impact across regions, specifically Latin America (LA) and the United States (US), is unknown., Methods: A total of 1412 participants comprising controls, patients with Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) from LA and the US were included. We studied the association of education with brain volume and functional connectivity while controlling for imaging quality and variability, age, sex, total intracranial volume (TIV), and recording type., Results: Education influenced brain measures, explaining 24%-98% of the geographical differences. The educational disparities between LA and the US were associated with gray matter volume and connectivity variations, especially in LA and AD patients. Education emerged as a critical factor in classifying aging and dementia across regions., Discussion: The results underscore the impact of education on brain structure and function in LA, highlighting the importance of incorporating educational factors into diagnosing, care, and prevention, and emphasizing the need for global diversity in research., Highlights: Lower education was linked to reduced brain volume and connectivity in healthy controls (HCs), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Latin American cohorts have lower educational levels compared to the those in the United States. Educational disparities majorly drive brain health differences between regions. Educational differences were significant in both conditions, but more in AD than FTLD. Education stands as a critical factor in classifying aging and dementia across regions., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Dementia can disrupt how people experience and describe events as well as their own role in them. Alzheimer's disease (AD) compromises the processing of entities expressed by nouns, while behavioral variant frontotemporal dementia (bvFTD) entails a depersonalized perspective with increased third-person references. Yet, no study has examined whether these patterns can be captured in connected speech via natural language processing tools. To tackle such gaps, we asked 96 participants (32 AD patients, 32 bvFTD patients, 32 healthy controls) to narrate a typical day of their lives and calculated the proportion of nouns, verbs, and first- or third-person markers (via part-of-speech and morphological tagging). We also extracted objective properties (frequency, phonological neighborhood, length, semantic variability) from each content word. In our main study (with 21 AD patients, 21 bvFTD patients, and 21 healthy controls), we used inferential statistics and machine learning for group-level and subject-level discrimination. The above linguistic features were correlated with patients' scores in tests of general cognitive status and executive functions. We found that, compared with HCs, (i) AD (but not bvFTD) patients produced significantly fewer nouns, (ii) bvFTD (but not AD) patients used significantly more third-person markers, and (iii) both patient groups produced more frequent words. Machine learning analyses showed that these features identified individuals with AD and bvFTD (AUC = 0.71). A generalizability test, with a model trained on the entire main study sample and tested on hold-out samples (11 AD patients, 11 bvFTD patients, 11 healthy controls), showed even better performance, with AUCs of 0.76 and 0.83 for AD and bvFTD, respectively. No linguistic feature was significantly correlated with cognitive test scores in either patient group. These results suggest that specific cognitive traits of each disorder can be captured automatically in connected speech, favoring interpretability for enhanced syndrome characterization, diagnosis, and monitoring., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lopes da Cunha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities., Methods: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population., Results: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10 -23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose., Discussion: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations., Highlights: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Verbal fluency tasks are common in Alzheimer's disease (AD) assessments. Yet, standard valid response counts fail to reveal disease-specific semantic memory patterns. Here, we leveraged automated word-property analysis to capture neurocognitive markers of AD vis-à-vis behavioral variant frontotemporal dementia (bvFTD)., Methods: Patients and healthy controls completed two fluency tasks. We counted valid responses and computed each word's frequency, granularity, neighborhood, length, familiarity, and imageability. These features were used for group-level discrimination, patient-level identification, and correlations with executive and neural (magnetic resonanance imaging [MRI], functional MRI [fMRI], electroencephalography [EEG]) patterns., Results: Valid responses revealed deficits in both disorders. Conversely, frequency, granularity, and neighborhood yielded robust group- and subject-level discrimination only in AD, also predicting executive outcomes. Disease-specific cortical thickness patterns were predicted by frequency in both disorders. Default-mode and salience network hypoconnectivity, and EEG beta hypoconnectivity, were predicted by frequency and granularity only in AD., Discussion: Word-property analysis of fluency can boost AD characterization and diagnosis., Highlights: We report novel word-property analyses of verbal fluency in AD and bvFTD. Standard valid response counts captured deficits and brain patterns in both groups. Specific word properties (e.g., frequency, granularity) were altered only in AD. Such properties predicted cognitive and neural (MRI, fMRI, EEG) patterns in AD. Word-property analysis of fluency can boost AD characterization and diagnosis., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The Latin American Brain Health Institute (BrainLat) has released a unique multimodal neuroimaging dataset of 780 participants from Latin American. The dataset includes 530 patients with neurodegenerative diseases such as Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), multiple sclerosis (MS), Parkinson's disease (PD), and 250 healthy controls (HCs). This dataset (62.7 ± 9.5 years, age range 21-89 years) was collected through a multicentric effort across five Latin American countries to address the need for affordable, scalable, and available biomarkers in regions with larger inequities. The BrainLat is the first regional collection of clinical and cognitive assessments, anatomical magnetic resonance imaging (MRI), resting-state functional MRI (fMRI), diffusion-weighted MRI (DWI), and high density resting-state electroencephalography (EEG) in dementia patients. In addition, it includes demographic information about harmonized recruitment and assessment protocols. The dataset is publicly available to encourage further research and development of tools and health applications for neurodegeneration based on multimodal neuroimaging, promoting the assessment of regional variability and inclusion of underrepresented participants in research., (© 2023. The Author(s).)

Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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

Background: Although social cognition is compromised in patients with neurodegenerative disorders such as behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD), research on moral emotions and their neural correlates in these populations is scarce. No previous study has explored the utility of moral emotions, compared to and in combination with classical general cognitive state tools, to discriminate bvFTD from AD patients., Objective: To examine self-conscious (guilt and embarrassment) and other-oriented (pity and indignation) moral emotions, their subjective experience, and their structural brain underpinnings in bvFTD (n = 31) and AD (n = 30) patients, compared to healthy controls (n = 37). We also explored the potential utility of moral emotions measures to discriminate bvFTD from AD., Methods: We used a modified version of the Moral Sentiment Task measuring the participants' accuracy scores and their emotional subjective experiences., Results: bvFTD patients exhibited greater impairments in self-conscious and other-oriented moral emotions as compared with AD patients and healthy controls. Moral emotions combined with general cognitive state tools emerged as useful measures to discriminate bvFTD from AD patients. In bvFTD patients, lower moral emotions scores were associated with lower gray matter volumes in caudate nucleus and inferior and middle temporal gyri. In AD, these scores were associated with lower gray matter volumes in superior and middle frontal gyri, middle temporal gyrus, inferior parietal lobule and supramarginal gyrus., Conclusion: These findings contribute to a better understanding of moral emotion deficits across neurodegenerative disorders, highlighting the potential benefits of integrating this domain into the clinical assessment.

Background: Processing of linguistic negation has been associated to inhibitory brain mechanisms. However, no study has tapped this link via multimodal measures in patients with core inhibitory alterations, a critical approach to reveal direct neural correlates and potential disease markers., Methods: Here we examined oscillatory, neuroanatomical, and functional connectivity signatures of a recently reported Go/No-go negation task in healthy controls and behavioral variant frontotemporal dementia (bvFTD) patients, typified by primary and generalized inhibitory disruptions. To test for specificity, we also recruited persons with Alzheimer's disease (AD), a disease involving frequent but nonprimary inhibitory deficits., Results: In controls, negative sentences in the No-go condition distinctly involved frontocentral delta (2-3 Hz) suppression, a canonical inhibitory marker. In bvFTD patients, this modulation was selectively abolished and significantly correlated with the volume and functional connectivity of regions supporting inhibition (e.g. precentral gyrus, caudate nucleus, and cerebellum). Such canonical delta suppression was preserved in the AD group and associated with widespread anatomo-functional patterns across non-inhibitory regions., Discussion: These findings suggest that negation hinges on the integrity and interaction of spatiotemporal inhibitory mechanisms. Moreover, our results reveal potential neurocognitive markers of bvFTD, opening a new agenda at the crossing of cognitive neuroscience and behavioral neurology., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective. The differential diagnosis of behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) remains challenging in underrepresented, underdiagnosed groups, including Latinos, as advanced biomarkers are rarely available. Recent guidelines for the study of dementia highlight the critical role of biomarkers. Thus, novel cost-effective complementary approaches are required in clinical settings. Approach . We developed a novel framework based on a gradient boosting machine learning classifier, tuned by Bayesian optimization, on a multi-feature multimodal approach (combining demographic, neuropsychological, magnetic resonance imaging (MRI), and electroencephalography/functional MRI connectivity data) to characterize neurodegeneration using site harmonization and sequential feature selection. We assessed 54 bvFTD and 76 AD patients and 152 healthy controls (HCs) from a Latin American consortium (ReDLat). Main results . The multimodal model yielded high area under the curve classification values (bvFTD patients vs HCs: 0.93 (±0.01); AD patients vs HCs: 0.95 (±0.01); bvFTD vs AD patients: 0.92 (±0.01)). The feature selection approach successfully filtered non-informative multimodal markers (from thousands to dozens). Results . Proved robust against multimodal heterogeneity, sociodemographic variability, and missing data. Significance . The model accurately identified dementia subtypes using measures readily available in underrepresented settings, with a similar performance than advanced biomarkers. This approach, if confirmed and replicated, may potentially complement clinical assessments in developing countries., (Creative Commons Attribution license.)

Neurodegeneration has multiscalar impacts, including behavioral, neuroanatomical, and neurofunctional disruptions. Can disease-differential alterations be captured across such dimensions using naturalistic stimuli? To address this question, we assessed comprehension of four naturalistic stories, highlighting action, nonaction, social, and nonsocial events, in Parkinson's disease (PD) and behavioral variant frontotemporal dementia (bvFTD) relative to Alzheimer's disease patients and healthy controls. Text-specific correlates were evaluated via voxel-based morphometry, spatial (fMRI), and temporal (hd-EEG) functional connectivity. PD patients presented action-text deficits related to the volume of action-observation regions, connectivity across motor-related and multimodal-semantic hubs, and frontal hd-EEG hypoconnectivity. BvFTD patients exhibited social-text deficits, associated with atrophy and spatial connectivity patterns along social-network hubs, alongside right frontotemporal hd-EEG hypoconnectivity. Alzheimer's disease patients showed impairments in all stories, widespread atrophy and spatial connectivity patterns, and heightened occipitotemporal hd-EEG connectivity. Our framework revealed disease-specific signatures across behavioral, neuroanatomical, and neurofunctional dimensions, highlighting the sensitivity and specificity of a single naturalistic task. This investigation opens a translational agenda combining ecological approaches and multimodal cognitive neuroscience for the study of neurodegeneration., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The predictive coding theory of allostatic-interoceptive load states that brain networks mediating autonomic regulation and interoceptive-exteroceptive balance regulate the internal milieu to anticipate future needs and environmental demands. These functions seem to be distinctly compromised in behavioral variant frontotemporal dementia (bvFTD), including alterations of the allostatic-interoceptive network (AIN). Here, we hypothesize that bvFTD is typified by an allostatic-interoceptive overload., Methods: We assessed resting-state heartbeat evoked potential (rsHEP) modulation as well as its behavioral and multimodal neuroimaging correlates in patients with bvFTD relative to healthy control subjects and patients with Alzheimer's disease (N = 94). We measured 1) resting-state electroencephalography (to assess the rsHEP, prompted by visceral inputs and modulated by internal body sensing), 2) associations between rsHEP and its neural generators (source location), 3) cognitive disturbances (cognitive state, executive functions, facial emotion recognition), 4) brain atrophy, and 5) resting-state functional magnetic resonance imaging functional connectivity (AIN vs. control networks)., Results: Relative to healthy control subjects and patients with Alzheimer's disease, patients with bvFTD presented more negative rsHEP amplitudes with sources in critical hubs of the AIN (insula, amygdala, somatosensory cortex, hippocampus, anterior cingulate cortex). This exacerbated rsHEP modulation selectively predicted the patients' cognitive profile (including cognitive decline, executive dysfunction, and emotional impairments). In addition, increased rsHEP modulation in bvFTD was associated with decreased brain volume and connectivity of the AIN. Machine learning results confirmed AIN specificity in predicting the bvFTD group., Conclusions: Altogether, these results suggest that bvFTD may be characterized by an allostatic-interoceptive overload manifested in ongoing electrophysiological markers, brain atrophy, functional networks, and cognition., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Social feedback can selectively enhance learning in diverse domains. Relevant neurocognitive mechanisms have been studied mainly in healthy persons, yielding correlational findings. Neurodegenerative lesion models, coupled with multimodal brain measures, can complement standard approaches by revealing direct multidimensional correlates of the phenomenon. To this end, we assessed socially reinforced and non-socially reinforced learning in 40 healthy participants as well as persons with behavioural variant frontotemporal dementia (n = 21), Parkinson's disease (n = 31) and Alzheimer's disease (n = 20). These conditions are typified by predominant deficits in social cognition, feedback-based learning and associative learning, respectively, although all three domains may be partly compromised in the other conditions. We combined a validated behavioural task with ongoing EEG signatures of implicit learning (medial frontal negativity) and offline MRI measures (voxel-based morphometry). In healthy participants, learning was facilitated by social feedback relative to non-social feedback. In comparison with controls, this effect was specifically impaired in behavioural variant frontotemporal dementia and Parkinson's disease, while unspecific learning deficits (across social and non-social conditions) were observed in Alzheimer's disease. EEG results showed increased medial frontal negativity in healthy controls during social feedback and learning. Such a modulation was selectively disrupted in behavioural variant frontotemporal dementia. Neuroanatomical results revealed extended temporo-parietal and fronto-limbic correlates of socially reinforced learning, with specific temporo-parietal associations in behavioural variant frontotemporal dementia and predominantly fronto-limbic regions in Alzheimer's disease. In contrast, non-socially reinforced learning was consistently linked to medial temporal/hippocampal regions. No associations with cortical volume were found in Parkinson's disease. Results are consistent with core social deficits in behavioural variant frontotemporal dementia, subtle disruptions in ongoing feedback-mechanisms and social processes in Parkinson's disease and generalized learning alterations in Alzheimer's disease. This multimodal approach highlights the impact of different neurodegenerative profiles on learning and social feedback. Our findings inform a promising theoretical and clinical agenda in the fields of social learning, socially reinforced learning and neurodegeneration., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Dementia in Latin America is a crucial public health problem. Identifying brief cognitive screening (BCS) tools for the primary care setting is crucial, particularly for illiterate individuals. We evaluated tool performance characteristics and validated the free and total recall sections of the Free and Cued Selective Reminding Test-Picture version (FCSRT-Picture) to discriminate between 63 patients with early Alzheimer's disease dementia (ADD), 60 amnestic mild cognitive impairment (aMCI) and 64 cognitively healthy Peruvian individuals with illiteracy from an urban area. Clinical, functional, and cognitive assessments were performed. FCSRT-Picture performance was assessed using receiver operating characteristic curve analyses. The mean ± standard deviation scores were 7.7 ± 1.0 in ADD, 11.8 ± 1.6 in aMCI, and 29.5 ± 1.8 in controls. The FCSRT-Picture had better performance characteristics for distinguishing controls from aMCI compared with several other BCS tools, but similar characteristics between controls and early ADD. The FCSRT-Picture is a reliable BCS tool for illiteracy in Peru.

Background: Social cognition is critically compromised across neurodegenerative diseases, including the behavioral variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), and Parkinson's disease (PD). However, no previous study has used social cognition and other cognitive tasks to predict diagnoses of these conditions, let alone reporting the brain correlates of prediction outcomes., Objective: We performed a diagnostic classification analysis using social cognition, cognitive screening (CS), and executive function (EF) measures, and explored which anatomical and functional networks were associated with main predictors., Methods: Multiple group discriminant function analyses (MDAs) and ROC analyses of social cognition (facial emotional recognition, theory of mind), CS, and EF were implemented in 223 participants (bvFTD, AD, PD, controls). Gray matter volume and functional connectivity correlates of top discriminant scores were investigated., Results: Although all patient groups revealed deficits in social cognition, CS, and EF, our classification approach provided robust discriminatory characterizations. Regarding controls, probabilistic social cognition outcomes provided the best characterization for bvFTD (together with CS) and PD, but not AD (for which CS alone was the best predictor). Within patient groups, the best MDA probabilities scores yielded high classification rates for bvFTD versus PD (98.3%, social cognition), AD versus PD (98.6%, social cognition + CS), and bvFTD versus AD (71.7%, social cognition + CS). Top MDA scores were associated with specific patterns of atrophy and functional networks across neurodegenerative conditions., Conclusion: Standardized validated measures of social cognition, in combination with CS, can provide a dimensional classification with specific pathophysiological markers of neurodegeneration diagnoses.

Accurate early diagnosis of neurodegenerative diseases represents a growing challenge for current clinical practice. Promisingly, current tools can be complemented by computational decision-support methods to objectively analyze multidimensional measures and increase diagnostic confidence. Yet, widespread application of these tools cannot be recommended unless they are proven to perform consistently and reproducibly across samples from different countries. We implemented machine-learning algorithms to evaluate the prediction power of neurocognitive biomarkers (behavioral and imaging measures) for classifying two neurodegenerative conditions -Alzheimer Disease (AD) and behavioral variant frontotemporal dementia (bvFTD)- across three different countries (>200 participants). We use machine-learning tools integrating multimodal measures such as cognitive scores (executive functions and cognitive screening) and brain atrophy volume (voxel based morphometry from fronto-temporo-insular regions in bvFTD, and temporo-parietal regions in AD) to identify the most relevant features in predicting the incidence of the diseases. In the Country-1 cohort, predictions of AD and bvFTD became maximally improved upon inclusion of cognitive screenings outcomes combined with atrophy levels. Multimodal training data from this cohort allowed predicting both AD and bvFTD in the other two novel datasets from other countries with high accuracy (>90%), demonstrating the robustness of the approach as well as the differential specificity and reliability of behavioral and neural markers for each condition. In sum, this is the first study, across centers and countries, to validate the predictive power of cognitive signatures combined with atrophy levels for contrastive neurodegenerative conditions, validating a benchmark for future assessments of reliability and reproducibility., Competing Interests: Declarations of competing interest None., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most common neurodegenerative early-onset dementias. Despite the fact that both conditions have a very distinctive clinical pattern, they present with an overlap in their cognitive and behavioral features that may lead to misdiagnosis or delay in diagnosis. The current review intends to summarize briefly the main differences at the clinical, neuropsychological, and behavioral levels, in an attempt to suggest which aspects would facilitate an adequate diagnosis in a clinical setting, especially in Latin American and low- and middle-income countries, where the resources needed for a differential diagnosis (such as MRI or biomarkers) are not always available. A timely diagnosis of AD and FTD have significant implications for the medical management and quality of life of patients and careers.

Background: Impairments in activities of daily living (ADL) are a criterion for Alzheimer's disease (AD) dementia. However, ADL gradually decline in AD, impacting on advanced (a-ADL, complex interpersonal or social functioning), instrumental (IADL, maintaining life in community), and finally basic functions (BADL, activities related to physiological and self-maintenance needs). Information and communication technologies (ICT) have become an increasingly important aspect of daily functioning. Yet, the links of ADL, ICT, and neuropathology of AD dementia are poorly understood. Such knowledge is critical as it can provide biomarker evidence of functional decline in AD., Methods: ADL were evaluated with the Technology-Activities of Daily Living Questionnaire (T-ADLQ) in 33 patients with AD and 30 controls. ADL were divided in BADL, IADL, and a-ADL. The three domain subscores were covaried against gray matter atrophy via voxel-based morphometry., Results: Our results showed that three domain subscores of ADL correlate with several brain structures, with a varying degree of overlap between them. BADL score correlated mostly with frontal atrophy, IADL with more widespread frontal, temporal and occipital atrophy and a-ADL with occipital and temporal atrophy. Finally, ICT subscale was associated with atrophy in the precuneus., Conclusions: The association between ADL domains and neurodegeneration in AD follows a traceable neuropathological pathway which involves different neural networks. This the first evidence of ADL phenotypes in AD characterised by specific patterns of functional decline and well-defined neuropathological changes. The identification of such phenotypes can yield functional biomarkers for dementias such as AD.

Background: Neuropsychiatric symptoms and cognitive impairment are independent contributors of functional impairment in activities of daily living (ADL) in Alzheimer's disease (AD) patients. ADL could be divided according to its complexity in three subdomains: basic (BADL), instrumental (IADL), and advanced (a-ADL)., Objective: Studying the cognitive and neuropsychiatric determinants of BADL, IADL, and a-ADL in normal cognitive elders and AD patients., Methods: 144 subjects were graduated using the clinical dementia rating (CDR) in CDR = 0, n = 52 (control group) and 92 AD patients CDR = 0.5, n = 34 and CDR = 1&2, n = 58. They were assessed with measures of cognitive performance and neuropsychiatric symptoms that were included in regression models to measure the best predictors for each ADL subdomain at every CDR status., Results: AD patients were significantly older, and had significantly more severe functional impairment, neuropsychiatric symptoms, and cognitive decline than controls. The best predictors of functional impairment in controls and CDR = 0.5 AD patients were neuropsychiatric symptoms; in the CDR 0.5 patients, apathy severity was the most important determinant of IADL and a-ADL impairment. While in the CDR 1&2 AD patients, cognitive impairment was the principal determinant of functional impairment, being memory the best determinant of IADL and a-ADL impairment, while global cognition was of BADL impairment., Conclusions: The contribution of cognitive impairment and neuropsychiatric symptoms varied according to the subdomain of ADL, and the CDR. In very mild AD and controls the neuropsychiatric symptoms are the best predictors of more complex ADL impairment, while cognitive impairment is more important at mild to moderate states of AD.

Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34 AD patients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (pFWE<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findings showed the involvement of prefrontal as well as medial/lateral temporal atrophy in memory deficits of bvFTD patients. This contradicts the common view that only frontal deficits explain memory impairment in this disease and plead for an updated view on memory dysfunctions in bvFTD.

Episodic memory tests with cued recall, such as the Free and Cued Selective Reminding Test (FCSRT), allow for the delineation of hippocampal and prefrontal atrophy contributions to memory performance in Alzheimer's disease (AD). Both Word and Picture versions of the test exist but show different profiles, with the Picture version usually scoring higher across different cohorts. One possible explanation for this divergent performance between the different modality versions of the test might be that they rely on different sets of neural correlates. The current study explores this by contrasting the neural correlates of the Word and Picture versions of the FCSRT with voxel-based morphometry (VBM) in AD and healthy subjects. We predicted that the Picture version would be associated with different cortical regions than the Word version, which might be more hippocampal-centric. When comparing 35 AD patients and 34 controls, AD patients exhibited impairments on both versions of the FCSRT and both groups performed higher in the Picture version. A region of interest analysis based on prior work revealed significant correlations between free recall of either version with atrophy of the temporal pole and hippocampal regions. Thus, contrary to expectations, performance on both the Word and the Picture version of the FCSRT is associated with largely overlapping networks. Free recall is associated with hippocampal volume and might be properly considered as an indicator of hippocampal structural integrity.

Background: Intracellular neurofibrillary tangles are part of the core pathology of Alzheimer's disease (AD), which are mainly composed of hyperphosphorylated tau protein., Objectives: The purpose of this study is to determine whether high molecular weight (HMW) or low molecular weight (LMW) tau protein levels, as well as the ratio HMW/LMW, present in platelets correlates with brain magnetic resonance imaging (MRI) structural changes in normal and cognitively impaired subjects., Methods: We examined 53 AD patients and 37 cognitively normal subjects recruited from two Memory Clinics at the Universidad de Chile. Tau levels in platelets were determined by immunoreactivity and the MRI scans were analyzed using voxel-based morphometry in 41 AD patients., Results: The HMW/LMW tau ratio was statistically different between controls and AD patients, and no associations were noted between HMW or LMW tau and MRI structures. In a multivariate analysis controlled for age and education level, the HMW/LMW tau ratio was associated with reduced volume in the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region., Conclusions: This exploratory study showed that HMW/LMW tau ratio is significantly higher in AD patients than control subjects, and that it is associated with specific brain regions atrophy. Determination of peripheral markers of AD pathology can help understanding the pathophysiology of neurodegeneration in AD.

Recursive social decision-making requires the use of flexible, context-sensitive long-term strategies for negotiation. To succeed in social bargaining, participants' own perspectives must be dynamically integrated with those of interactors to maximize self-benefits and adapt to the other's preferences, respectively. This is a prerequisite to develop a successful long-term self-other integration strategy. While such form of strategic interaction is critical to social decision-making, little is known about its neurocognitive correlates. To bridge this gap, we analysed social bargaining behaviour in relation to its structural neural correlates, ongoing brain dynamics (oscillations and related source space), and functional connectivity signatures in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal stroke: behavioural variant frontotemporal dementia, Alzheimer's disease, and frontal lesions. All groups showed preserved basic bargaining indexes. However, impaired self-other integration strategy was found in patients with behavioural variant frontotemporal dementia and frontal lesions, suggesting that social bargaining critically depends on the integrity of prefrontal regions. Also, associations between behavioural performance and data from voxel-based morphometry and voxel-based lesion-symptom mapping revealed a critical role of prefrontal regions in value integration and strategic decisions for self-other integration strategy. Furthermore, as shown by measures of brain dynamics and related sources during the task, the self-other integration strategy was predicted by brain anticipatory activity (alpha/beta oscillations with sources in frontotemporal regions) associated with expectations about others' decisions. This pattern was reduced in all clinical groups, with greater impairments in behavioural variant frontotemporal dementia and frontal lesions than Alzheimer's disease. Finally, connectivity analysis from functional magnetic resonance imaging evidenced a fronto-temporo-parietal network involved in successful self-other integration strategy, with selective compromise of long-distance connections in frontal disorders. In sum, this work provides unprecedented evidence of convergent behavioural and neurocognitive signatures of strategic social bargaining in different lesion models. Our findings offer new insights into the critical roles of prefrontal hubs and associated temporo-parietal networks for strategic social negotiation., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this study was to compare the psychometric properties of the "Word" and "Picture" versions of the Spanish FCSRT across the same sample of mild Alzheimer disease (AD) patients and controls. Mild AD patients (N = 50, 27 CDR = 0.5; 23 CDR = 1) and controls (N = 42, CDR = 0) were assessed with an extensive clinical and neuropsychological evaluation. Psychometric characteristics for both versions of the FCSRT were compared. Free recall (FR) and total recall (TR) across both versions of the FCSRT showed areas under the curve >0.9 and did not significantly differ between them. The scores of both versions were well correlated, although the scores for the Picture version were greater than those for the Word version, particularly for the TR scores of the mild AD group. Both versions of the FCSRT showed an appropriate accuracy to distinguish mild AD patients and controls. Visual cues were easier to recall than verbal cues, especially in the memory impaired patients., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Platelets are major reservoirs of circulating amyloid-β and amyloid-β protein precursor (AβPP) and have been postulated as a reliable source for biological markers of Alzheimer's disease (AD). We have recently demonstrated that tau is also present in platelets, and that there are differences in the electrophoretic patterns of platelet tau forms in AD subjects with respect to controls. Here, we demonstrate that modifications in platelet tau forms occur independently of age in a broad population of 104 neurologically healthy individuals. More interesting, a strong correlation of platelet markers with the degree of cognitive impairment was evidenced in a group of 47 AD patients in comparison with 19 cognitive healthy subjects. In our series, platelet tau forms ratio had a sensitivity of 75.7% and specificity of 73.7%, respectively. We also found that platelet tau displays a significantly higher correlation with the presence of AD than the analyses of platelet AβPP.

Platelets are a major peripheral reservoir of the amyloid-β protein precursor, so they have been considered as a potential biological marker of Alzheimer's disease (AD). Here, it is demonstrated that tau protein is also present in platelets and that the levels of oligomeric species of this protein could serve as a novel and reliable biological marker for AD. Blood samples were obtained from 15 AD patients and 10 paired-age controls and platelets were separated via differential centrifugation. The purity of platelets was determined by flow cytometry and microscopy and the presence of tau was determined by immunofluorescence and immunoblots with tau specific antibodies. Immunofuorescence and immunoblot patterns of platelets were positive for tau. Immunoblots also showed the presence of high molecular weight (HMW) variants of tau that appeared to correspond to oligomeric forms of the protein. The ratio of HMW tau respect to tau monomeric species was significantly higher in AD patients than controls. The present is the first description of the presence of tau in platelets. The analysis of different tau fractions in platelets could serve as a new biological marker for AD.

Dementia in general, especially Alzheimer disease and vascular dementia, are diseases of high prevalence with severe socio-economic consequences in all countries. In recent years, due to the obtention of new pharmaceutical products acting on different brain neurotransmitters, there has been important changes in the therapy of these diseases. Although these drugs do not stop disease progression, there is consistent evidence of their usefulness in cognitive, behavioral and functional domains and of their pharmaco-economical justification. This article reviews the main drugs available for Alzheimer disease and some future therapeutic perspectives.

Background: The different distribution of pathologic features in frontotemporal dementia (FTD) and Alzheimer disease (AD) predicts a predominant dysexecutive syndrome in FTD. The Frontal Assessment Battery (FAB) has previously been validated in diseases associated with a frontal lobe dysfunction., Objective: To evaluate the sensitivity of the FAB to differentiate FTD and AD., Design: Comparison study., Setting: Memory Clinic of the Salpêtrière Hospital, Paris, France., Patients: Twenty-six patients with FTD and 64 patients with AD., Main Outcome Measures: Comparison of FAB and Mini-Mental State Examination (MMSE) scores between patients with FTD and those with AD., Results: The mean +/- SD FAB scores significantly differed between patients with FTD (7.6 +/- 4.2) and those with AD (12.6 +/- 3.7) (P<.001), but not MMSE scores. The FAB correctly identified 78.9% of the patients. These results were maintained in a subgroup of mildly demented patients (MMSE score, > or =24). In these patients, a cutoff score of 12 on the FAB was optimal to differentiate both disorders (sensitivity, 77%; specificity, 87%)., Conclusions: The FAB takes less than 10 minutes to administer and provides an objective measure to distinguish FTD from AD in mildly demented patients.