Task Demands and Sentence Reading Comprehension among Healthy Older Adults: The Complementary Roles of Cognitive Reserve and Working Memory.

Ageing entails different functional brain changes. Education, reading experience, and leisure activities, among others, might contribute to the maintenance of cognitive performance among older adults and are conceptualised as proxies for cognitive reserve. However, ageing also conveys a depletion of working memory capacity, which adversely impacts language comprehension. This study investigated how cognitive reserve proxies and working memory jointly predict the performance of healthy older adults in a sentence reading comprehension task, and how their predictive value changes depending on sentence structure and task demands. Cognitively healthy older adults (n = 120) completed a sentence-picture verification task under two conditions: concurrent viewing of the sentence and picture or their sequential presentation, thereby imposing greater demands on working memory. They also completed a questionnaire on cognitive reserve proxies as well as a verbal working memory test. The sentence structure was manipulated by altering the canonical word order and modifying the amount of propositional information. While the cognitive reserve was the main predictor in the concurrent condition, the predictive role of working memory increased under the sequential presentation, particularly for complex sentences. These findings highlight the complementary roles played by cognitive reserve and working memory in the reading comprehension of older adults.

Normative scores for attentional tests used by the Spanish consortium for ageing normative data (SCAND) study: Trail Making Test, Digit Symbol and Letter Cancellation.

Objective: This paper reports normative data for different attentional tests obtained from a sample of middle-aged and older native Spanish adults and considering effects of age, educational level and sex. Method: 2,597 cognitively intact participants, aged from 50 to 98 years old, participated voluntarily in the SCAND consortium studies. The statistical procedure included conversion of percentile ranges into scaled scores. The effects of age, education and sex were taken into account. Linear regressions were used to calculate adjusted scaled scores. Results: Scaled scores and percentiles corresponding to the TMT, Digit Symbol and Letter Cancellation Task are shown. Additional tables show the values to be added to or subtracted from the scaled scores, for age and education in the case of the TMT and Letter Cancellation Task measures, and for education in the case of the Digit Symbol subtest. Conclusions: The current norms provide clinically useful data for evaluating Spanish people aged 50 to 98 years old and contribute to improving detection of initial symptoms of cognitive impairment.

Cognitive Training Modulates Brain Hypersynchrony in a Population at Risk for Alzheimer's Disease.

BACKGROUND: Recent studies demonstrated that brain hypersynchrony is an early sign of dysfunction in Alzheimer's disease (AD) that can represent a proxy for clinical progression. Conversely, non-pharmacological interventions, such as cognitive training (COGTR), are associated with cognitive gains that may be underpinned by a neuroprotective effect on brain synchrony. OBJECTIVE: To study the potential of COGTR to modulate brain synchrony and to eventually revert the hypersynchrony phenomenon that characterizes preclinical AD. METHODS: The effect of COGTR was examined in a sample of healthy controls (HC, n = 41, 22 trained) and individuals with subjective cognitive decline (SCD, n = 49, 24 trained). Magnetoencephalographic activity and neuropsychological scores were acquired before and after a ten-week COGTR intervention aimed at improving cognitive function and daily living performance. Functional connectivity (FC) was analyzed using the phase-locking value. A mixed-effects ANOVA model with factors time (pre-intervention/post-intervention), training (trained/non-trained), and diagnosis (HC/SCD) was used to investigate significant changes in FC. RESULTS: We found an average increase in alpha-band FC over time, but the effect was different in each group (trained and non-trained). In the trained group (HC and SCD), we report a reduction in the increase in FC within temporo-parietal and temporo-occipital connections. In the trained SCD group, this reduction was stronger and showed a tentative correlation with improved performance in different cognitive tests. CONCLUSION: COGTR interventions could mitigate aberrant increases in FC in preclinical AD, promoting brain synchrony normalization in groups at a higher risk of developing dementia.

Spanish Consortium for Ageing Normative Data (SCAND): Semantic Verbal Fluency Tests.

OBJECTIVE: Semantic verbal fluency constitutes a good candidate for identifying cognitive impairment. This paper offers normative data of different semantic verbal fluency tests for middle-aged and older adults natives from Spain considering sociodemographic factors, and different measures for each specific category (number of words produced, errors, and words evoked every 15 s). METHOD: Two thousand and eighty-eight cognitively unimpaired subjects aged between 50 and 89 years old, community dwelling, participated in the study. The statistical procedure includes the conversion of percentile ranges into scalar scores. Secondly, the effects of age, education and gender were verified. Linear regressions are used to calculate the scalar adjusted scores. RESULTS: Scalar scores and percentiles corresponding to all semantic verbal fluency tests across different measures are shown. Additional tables, which show the points that must be added or subtracted from direct scores, are provided for Education regarding the total number of "animals" and "clothes" evoked by participants, as well as for Age and Education in case of the total number of "clothes". Gender affects the number of "clothes" produced by participants in the first two 15-second segments. CONCLUSIONS: The current norms should provide clinically useful data for evaluating Spanish-speaking natives from Spain aged from 50 to 89 years.

A Structural Connectivity Disruption One Decade before the Typical Age for Dementia: A Study in Healthy Subjects with Family History of Alzheimer's Disease.

The concept of the brain has shifted to a complex system where different subnetworks support the human cognitive functions. Neurodegenerative diseases would affect the interactions among these subnetworks and, the evolution of impairment and the subnetworks involved would be unique for each neurodegenerative disease. In this study, we seek for structural connectivity traits associated with the family history of Alzheimer's disease, that is, early signs of subnetworks impairment due to Alzheimer's disease. The sample in this study consisted of 123 first-degree Alzheimer's disease relatives and 61 nonrelatives. For each subject, structural connectomes were obtained using classical diffusion tensor imaging measures and different resolutions of cortical parcellation. For the whole sample, independent structural-connectome-traits were obtained under the framework of connICA. Finally, we tested the association of the structural-connectome-traits with different factors of relevance for Alzheimer's disease by means of a multiple linear regression. The analysis revealed a structural-connectome-trait obtained from fractional anisotropy associated with the family history of Alzheimer's disease. The structural-connectome-trait presents a reduced fractional anisotropy pattern in first-degree relatives in the tracts connecting posterior areas and temporal areas. The family history of Alzheimer's disease structural-connectome-trait presents a posterior-posterior and posterior-temporal pattern, supplying new evidences to the cascading network failure model.

Preserved semantic categorical organization in mild cognitive impairment: A network analysis of verbal fluency.

The decline in semantic verbal fluency as we age may originate from both semantic memory degradation and executive function deficits. We investigated to what extent semantic memory is organized into categories in older adults with mild cognitive impairment (n = 81) and healthy controls (n = 83). We obtained the semantic networks automatically from the probability of co-occurrence of words in a verbal fluency test and characterized them with graph-theory tools. We found that the degree of categorical organization was similar for both diagnostic groups, but there was a higher tendency to transition to other categories during word production in the patient group. These results suggest that the semantic network is preserved in mild cognitive impairment, but also that the existing associations are exploited less efficiently during long-term memory search, possibly because of deficits in executive function.

Spanish Consortium for Ageing Normative Data (SCAND): Screening Tests (MMSE, GDS-15 and MFE).

BACKGROUND: Detecting cognitive impairment is a priority for health systems. The aim of this study is to create normative data on screening tests (MMSE, GDS and MFE) for middle-aged and older Spanish adults, considering the effects of sociodemographic factors. METHOD: A total of 2,030 cognitively intact subjects who lived in the community, aged from 50 to 88 years old, participated voluntarily in SCAND consortium studies. The statistical procedure included the conversion of percentile ranges into scalar scores. Secondly, the effects of age, educational level and gender were verified. Linear regressions were used to calculate the scalar adjusted scores. Cut-off values for each test were also calculated. RESULTS: Scalar scores and percentiles corresponding to MMSE, GDS-15 and MFE are shown. An additional table is provided which shows the points that must be added or subtracted from MMSE score depending on the subject's educational level. CONCLUSIONS: The current norms should provide clinically useful data for evaluating Spanish people aged 50 to 88 years old and should contribute to improving the detection of initial symptoms of cognitive impairment in people living in the community, taking into account the influence of gender, age and educational level.

Animals in multidimensional space: Interpreting coordinates throughout lexical-semantic features in mild cognitive impairment and control subjects.

INTRODUCTION: Semantic verbal fluency is a useful neuropsychological tool since it involves language and executive abilities that can be impaired in patients with neurodegenerative diseases in comparison to healthy controls. The present study explores retrieve and executive control processes using traditional quantitative and qualitative raw scores and examines the utility of multidimensional scaling combined with linear regression to provide new insights about the underlying semantic network in mild cognitive impairment and in healthy older adults. METHOD: A total of 165 Spanish older adults, 81 patients and 84 controls, were assessed in different cognitive domains and evoked animal names in one minute. Group differences on fluency raw scores were first explored. Regressions using tests to predict groups' fluency scores were also performed. The 12 animals that had been produced more frequently were selected to perform a multidimensional scaling analysis for each group. Four features related to animal names were extracted from normative studies and then were used as predictors in linear regression to provide an interpretation of the resulting dimensions' coordinates. RESULTS: Patients performed worse on memory and naming and produced a shorter list of animals than controls. In controls, naming and visual memory explained a small part of variance related to the total of animals produced and to the number of switches. Both groups exhibited similar semantic maps. CONCLUSIONS: Results suggest that patients' map is influenced by words with a dense associative neighborhood that were acquired at an early age, whereas in controls none of the predictors explained dimensions.

Age and APOE genotype affect the relationship between objectively measured physical activity and power in the alpha band, a marker of brain disease.

BACKGROUND: Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer's disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. METHODS: The relationship between PA and alpha band power was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. RESULTS: We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and only younger adults exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. CONCLUSION: PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults.

The relationship between physical activity, apolipoprotein E ε4 carriage, and brain health.

BACKGROUND: Neuronal hyperexcitability and hypersynchrony have been described as key features of neurophysiological dysfunctions in the Alzheimer's disease (AD) continuum. Conversely, physical activity (PA) has been associated with improved brain health and reduced AD risk. However, there is controversy regarding whether AD genetic risk (in terms of APOE ε4 carriage) modulates these relationships. The utilization of multiple outcome measures within one sample may strengthen our understanding of this complex phenomenon. METHOD: The relationship between PA and functional connectivity (FC) was examined in a sample of 107 healthy older adults using magnetoencephalography. Additionally, we explored whether ε4 carriage modulates this association. The correlation between FC and brain structural integrity, cognition, and mood was also investigated. RESULTS: A relationship between higher PA and decreased FC (hyposynchrony) in the left temporal lobe was observed among all individuals (across the whole sample, in ε4 carriers, and in ε4 non-carriers), but its effects manifest differently according to genetic risk. In ε4 carriers, we report an association between this region-specific FC profile and preserved brain structure (greater gray matter volumes and higher integrity of white matter tracts). In this group, decreased FC also correlated with reduced anxiety levels. In ε4 non-carriers, this profile is associated with improved cognition (working and episodic memory). CONCLUSIONS: PA could mitigate the increase in FC (hypersynchronization) that characterizes preclinical AD, being beneficial for all individuals, especially ε4 carriers.

How cognitive reserve influences older adults' cognitive state, executive functions and language comprehension: A structural equation model.

Cognitive reserve has been defined as the individuals' ability to tolerate age-related and neurodegenerative changes in the brain without developing clinical symptoms or signs of disease. Formal education, occupational attainment, and knowledge of other languages have been assessed as the most relevant factors determining cognitive reserve. The main objective of this study was to develop a structural equation model that reflects the direct influence of cognitive reserve on old adults' general cognitive status and executive functioning, and indirectly on sentence comprehension performance through executive functions mediation. One hundred and fifty eight Spanish-speaking older adults, cognitively intact, were assessed to obtain cognitive reserve data, general cognitive status, executive functioning (inhibitory control, working memory and cognitive flexibility), and sentence comprehension measures. High indicators of adjustment of the proposed model were obtained. The most related factors to cognitive reserve were education and occupational attainment. As we hypothesize, cognitive reserve had a higher direct significant relation to cognitive status and, in a lesser extent, to executive functioning. Participants' general cognitive status and executive function were high and directly related. Furthermore, cognitive reserve has an indirect positive relation to sentence comprehension via executive functions' mediation.

Electrophysiological brain signatures for the classification of subjective cognitive decline: towards an individual detection in the preclinical stages of dementia.

BACKGROUND: Alzheimer's disease (AD) prevalence is rapidly growing as worldwide populations grow older. Available treatments have failed to slow down disease progression, thus increasing research focus towards early or preclinical stages of the disease. Subjective cognitive decline (SCD) is known to increase the risk of developing AD and several other negative outcomes. However, it is still very scarcely characterized and there is no neurophysiological study devoted to its individual classification which could improve targeted sample recruitment for clinical trials. METHODS: Two hundred fifty-two older adults (70 healthy controls, 91 SCD, and 91 MCI) underwent a magnetoencephalography scan. Alpha relative power in the source space was employed to train a LASSO classifier and applied to distinguish between healthy controls and SCD. Moreover, MCI participants were used to further validate the previously trained algorithm. RESULTS: The classifier was significantly associated to SCD with an AUC of 0.81 in the whole sample. After randomly splitting the sample in 2/3 for discovery and 1/3 for validation, the newly trained classifier was also able to correctly classify SCD individuals with an AUC of 0.75 in the validation sample. The regions selected by the algorithm included medial frontal, temporal, and occipital areas. The algorithm trained to select SCD individuals was also significantly associated to MCI diagnostic. CONCLUSIONS: According to our results, magnetoencephalography could be a useful tool for distinguishing individuals with SCD and healthy older adults without cognitive concerns. Furthermore, our classifier showed good external validity, being not only successful for an unseen SCD sample, but also in a different population with MCI cases. This supports its utility in the context of preclinical dementia. These findings highlight the potential applications of electrophysiological techniques to improve sample recruitment at the individual level in the context of clinical trials.

BDNF Val66Met Polymorphism and Gamma Band Disruption in Resting State Brain Functional Connectivity: A Magnetoencephalography Study in Cognitively Intact Older Females.

The pathophysiological processes undermining brain functioning decades before the onset of the clinical symptoms associated with dementia are still not well understood. Several heritability studies have reported that the Brain Derived Neurotrophic Factor (BDNF) Val66Met genetic polymorphism could contribute to the acceleration of cognitive decline in aging. This mutation may affect brain functional connectivity (FC), especially in those who are carriers of the BDNF Met allele. The aim of this work was to explore the influence of the BDNF Val66Met polymorphism in whole brain eyes-closed, resting-state magnetoencephalography (MEG) FC in a sample of 36 cognitively intact (CI) older females. All of them were ε3ε3 homozygotes for the apolipoprotein E (APOE) gene and were divided into two subgroups according to the presence of the Met allele: Val/Met group (n = 16) and Val/Val group (n = 20). They did not differ in age, years of education, Mini-Mental State Examination scores, or normalized hippocampal volumes. Our results showed reduced antero-posterior gamma band FC within the Val/Met genetic risk group, which may be caused by a GABAergic network impairment. Despite the lack of cognitive decline, these results might suggest a selective brain network vulnerability due to the carriage of the BDNF Met allele, which is linked to a potential progression to dementia. This neurophysiological signature, as tracked with MEG FC, indicates that age-related brain functioning changes could be mediated by the influence of particular genetic risk factors.

Factors Explaining Language Performance After Training in Elders With and Without Subjective Cognitive Decline.

The present study explores if cognitive reserve, executive functions, and working memory capacity are predictive of performance in the language domain (specifically in sentence comprehension and naming) after a cognitive training intervention. Sixty-six Spanish older adults voluntarily participated in the study, classified either as older adults with subjective cognitive decline according to Jessen et al.'s (2014) criteria (n = 35; 70.94 ± 4.16 years old) or cognitively intact (n = 31; 71.34 ± 4.96 years old). Written sentence comprehension and visual confrontation naming were assessed both immediately after recruitment (at the baseline), and then 6 months later, once each participant had completed his/her cognitive training (a well-known program in Spain, called UMAM; English translation: Madrid City Council Memory Unit Program). Cognitive reserve, executive functions (cognitive flexibility and controlled interference efficiency), and working memory capacity were measured for all participants at the baseline. Results pointed out that the subjective cognitive decline group presented greater benefits in the language domain than cognitively intact participants. We also observed that lower executive functioning and working memory capacity at the baseline predicted larger benefits in language performance after training, but only in the group of cognitively intact older adults. However, selected predictors hardly explained subjective cognitive decline participants' results in language performance after training.

Physical activity effects on the individual alpha peak frequency of older adults with and without genetic risk factors for Alzheimer's Disease: A MEG study.

OBJECTIVE: Since a cure for Alzheimer's Disease (AD) is yet to be discovered, attention has shifted towards prevention. Physical activity (PA) emerged as a notorious lifestyle factor that could influence brain structure and function. The individual alpha peak frequency (IAPF) is a measure that summarizes the spectral content of brain signals and has been proven to be sensitive to both AD pathology and PA interventions. Therefore, our goal was to unravel whether chronic PA modulates IAPF and if APOE ɛ4 carriage moderates this relationship. METHODS: We analyzed 4-minutes of resting-state magnetoencephalographic recordings from 100 healthy elders that provided self-reported measures of PA, and the IAPF was calculated. RESULTS: We found that IAPF was negatively influenced by age and APOE and positively influenced by PA. The effect of PA on IAPF only remained significant for the ɛ4 non-carriers group. CONCLUSIONS: PA is positively associated to higher IAPF in healthy older adults and could potentially act as a protective factor against cognitive decline. Nevertheless, such effect is non-significant among elders who are more vulnerable to developing AD due to their genetic carriage. SIGNIFICANCE: This investigation offers the first neurophysiological evidences on the combined effects of APOE genotype and PA in healthy elders.

Efficacy of Cognitive Training in Older Adults with and without Subjective Cognitive Decline Is Associated with Inhibition Efficiency and Working Memory Span, Not with Cognitive Reserve.

The present study explores the role of cognitive reserve, executive functions, and working memory (WM) span, as factors that might explain training outcomes in cognitive status. Eighty-one older adults voluntarily participated in the study, classified either as older adults with subjective cognitive decline or cognitively intact. Each participant underwent a neuropsychological assessment that was conducted both at baseline (entailing cognitive reserve, executive functions, WM span and depressive symptomatology measures, as well as the Mini-Mental State Exam regarding initial cognitive status), and then 6 months later, once each participant had completed the training program (Mini-Mental State Exam at the endpoint). With respect to cognitive status the training program was most beneficial for subjective cognitive decline participants with low efficiency in inhibition at baseline (explaining a 33% of Mini-Mental State Exam total variance), whereas for cognitively intact participants training gains were observed for those who presented lower WM span.

Development of the CarMen-Q Questionnaire for mental workload assessment.

BACKGROUND: Mental workload has emerged as one of the most important occupational risk factors present in most psychological and physical diseases caused by work. In view of the lack of specific tools to assess mental workload, the objective of this research was to assess the construct validity and reliability of a new questionnaire for mental workload assessment (CarMen-Q). METHOD: The sample was composed of 884 workers from several professional sectors, between 18 and 65 years old, 53.4% men and 46.6% women. To evaluate the validity based on relationships with other measures, the NASA-TLX scale was also administered. RESULTS: Confirmatory factor analysis showed an internal structure made up of four dimensions: cognitive, temporal and emotional demands and performance requirement. The results show satisfactory evidence of validity based on relationships with NASA-TLX and good reliability. CONCLUSIONS: The questionnaire has good psychometric properties and can be an easy, brief, useful tool for mental workload diagnosis and prevention.

Network Disruption in the Preclinical Stages of Alzheimer's Disease: From Subjective Cognitive Decline to Mild Cognitive Impairment.

INTRODUCTION: Subjective Cognitive Decline (SCD) is a largely unknown state thought to represent a preclinical stage of Alzheimer's Disease (AD) previous to mild cognitive impairment (MCI). However, the course of network disruption in these stages is scarcely characterized. METHODS: We employed resting state magnetoencephalography in the source space to calculate network smallworldness, clustering, modularity and transitivity. Nodal measures (clustering and node degree) as well as modular partitions were compared between groups. RESULTS: The MCI group exhibited decreased smallworldness, clustering and transitivity and increased modularity in theta and beta bands. SCD showed similar but smaller changes in clustering and transitivity, while exhibiting alterations in the alpha band in opposite direction to those showed by MCI for modularity and transitivity. At the node level, MCI disrupted both clustering and nodal degree while SCD showed minor changes in the latter. Additionally, we observed an increase in modular partition variability in both SCD and MCI in theta and beta bands. CONCLUSION: SCD elders exhibit a significant network disruption, showing intermediate values between HC and MCI groups in multiple parameters. These results highlight the relevance of cognitive concerns in the clinical setting and suggest that network disorganization in AD could start in the preclinical stages before the onset of cognitive symptoms.

APOE ε4 Modulation of Training Outcomes in Several Cognitive Domains in a Sample of Cognitively Intact Older Adults.

BACKGROUND: Most research points to the ɛ4 allele of the apolipoprotein E (APOE) gene as the most recognizable genetic risk factor associated with Alzheimer's disease pathogenesis. It has been also suggested that the APOEɛ4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOEɛ4 interaction with cognitive intervention programs. OBJECTIVE: The main goal of this study was to explore whether there was a differential APOE genotype modulation effect after cognitive training in different domains, such as language comprehension, executive functions, and memory. Contrary to other studies, hippocampal volume was controlled for. METHODS: Fifty older adults (65+ years; 30 women and 20 men) participated in a multi-domain cognitive training that involved 30 sessions taking place over 12 weeks. Half of the participants were APOEɛ4 carriers. The control group was matched in age, gender, normalized hippocampal volume, cognitive reserve, Mini-Mental State Examination score, and Geriatric Depression Scale-Short Version. RESULTS: The study revealed that there were consistent treatment benefits in complex sentence comprehension (noncanonical sentences and sentences with two propositions), a domain that was not directly trained, but only in the A POEɛ4 noncarrier group. CONCLUSION: Genetic profile modulates training outcomes in sentence comprehension.