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Purpose of ReviewThe aim of this review is to summarize current conceptual models of cognitive reserve (CR) and related concepts and to discuss evidence for these concepts within the context of aging and Alzheimer’s disease.Recent FindingsEvidence to date supports the notion that higher levels of CR, as measured by proxy variables reflective of lifetime experiences, are associated with better cognitive performance, and with a reduced risk of incident mild cognitive impairment/dementia. However, the impact of CR on longitudinal cognitive trajectories is unclear and may be influenced by a number of factors. Although there is promising evidence that some proxy measures of CR may influence structural brain measures, more research is needed.SummaryThe protective effects of CR may provide an important mechanism for preserving cognitive function and cognitive well-being with age, in part because it can be enhanced throughout the lifespan. However, more research on the mechanisms by which CR is protective is needed.

Converging electrophysiological evidence suggests that the alpha rhythm plays an important and active role in cognitive processing. Here, we systematically studied variability in posterior alpha peak frequency both between and within subjects. We recorded brain activity using MEG in 51 healthy human subjects under three experimental conditions — rest, passive visual stimulation and an N-back working memory paradigm, using source reconstruction methods to separate alpha activity from parietal and occipital sources. We asked how alpha peak frequency differed within subjects across cognitive conditions and regions of interest, and looked at the distribution of alpha peak frequency between subjects. In both regions we observed an increase of alpha peak frequency from resting state and passive visual stimulation conditions to the N-back paradigm, with a significantly higher alpha peak frequency in the 2-back compared to the 0-back condition. There was a trend for a greater increase in alpha peak frequency during the N-back task in the occipital vs. parietal cortex. The average alpha peak frequency across all subjects, conditions, and regions of interest was 10.3Hz with a within-subject SD of 0.9Hz and a between-subject SD of 2.8Hz. We also measured beta peak frequencies, and except in the parietal cortex during rest, found no indication of a strictly harmonic relationship with alpha peak frequencies. We conclude that alpha peak frequency in posterior regions increases with increasing cognitive demands, and that the alpha rhythm operates across a wider frequency range than the 8–12Hz band many studies tend to include in their analysis. Thus, using a fixed and limited alpha frequency band might bias results against certain subjects and conditions. •Alpha peak frequency increases with cognitive demand.•No strict harmonic relationship between alpha and beta.•Using a limited and fixed band for alpha biases against certain subjects/conditions.

INTRODUCTION This review examines the concept of cognitive reserve (CR) in relation to brain aging, particularly in the context of dementia and its early stages. CR refers to an individual's ability to maintain or regain cognitive function despite brain aging, damage, or disease. Various factors, including education, occupation complexity, leisure activities, and genetics are believed to influence CR. METHODS We revised the literature in the context of CR. A total of 842 articles were identified, then we rigorously assessed the relevance of articles based on titles and s, employing a systematic approach to eliminate studies that did not align with our research objectives. RESULTS We evaluate—also in a critical way—the methods commonly used to define and measure CR, including sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures. The challenges and limitations of these measures are discussed, emphasizing the need for more targeted research to improve the understanding, definition, and measurement of CR. CONCLUSIONS The review underscores the significance of comprehending CR in the context of both normal and pathological brain aging and emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation in both healthy and neurologically impaired older individuals. Highlights This review examines the concept of cognitive reserve in brain aging, in the context of dementia and its early stages. We have evaluated the methods commonly used to define and measure cognitive reserve. Sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures are discussed. The review emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation.

To evaluate the effectiveness of the Mental Training Tech 24.5 (MTT24.5) cognitive stimulation program, designed to enhance cognitive performance and neuroplasticity in healthy adults. Cognitive decline is a significant concern in aging populations, with research suggesting that neuroplasticity and cognitive reserve can be enhanced through targeted cognitive training. The MTT24.5 program aims to stimulate brain function through a combination of new knowledge acquisition (DATA) and learning techniques (TECHS), organized into a systematic algorithm. This approach may offer a novel way to prevent or mitigate age-related cognitive decline. Pilot clinical study, active-controlled, open randomization. Adults from the general population with no clinical cognitive deterioration, recruited from three sites within the Autonomous City of Buenos Aires and its metropolitan area. 120 volunteers were enrolled, of which 76 participants (56 in the intervention group, 20 in the control group) met the study requirements and selected a site closest to their residence. The MTT24.5 program consists of 12 weekly in-person sessions (totaling 24.5 hours), during which participants learned 40 knowledge units (DATA) and 100 learning techniques (TECHS). These were organized into binomials, where each unit of DATA was paired with 3-4 TECHS. Pre- and post-intervention assessments included medical history, lifestyle factors, cognitive reserve scale, Addenbrooke's Cognitive Examination-Revised (ACE-R), and Mini-Mental State Examination (MMSE). The mean age was 59 years for both groups. Baseline ACE-R scores were comparable (91.3). The global cognitive score increased by 4.6 points (5%) in the intervention group compared to a decrease of 0.5 points in the control group (p < 0.001). The most significant improvement was observed in the memory domain (2.4 points, 11.4% increase) versus a 0.3-point increase in the control group (p < 0.007), with secondary improvements in verbal fluency, language, and visuospatial skills. Notably, participants with baseline ACE-R scores below 85 showed greater improvements (p < 0.003). The effects were consistent across various phenotypic factors, such as age, sex, chronic disease distribution, and lifestyle. The MTT24.5 program, based on a systematic algorithm for acquiring new knowledge and skills, significantly enhances cognitive reserve and overall cognitive performance, particularly in individuals with lower baseline cognitive scores. These findings suggest that structured cognitive stimulation could play a critical role in preventing cognitive decline and promoting cognitive health in healthy adults. Given the promising results, future studies involving larger populations and long-term follow-up are essential to validate these effects and explore the potential for mitigating age-related cognitive decline and enhancing quality of life. The study was registered in accordance with local regulations at the National Council for Scientific and Technological Research (CONICET) - Institute of Biomedical Research (BIOMED), and also in the National Ethics Committee, and at clinicaltrials.gov (NCT06549517).

Background and aims: The concept of “reserve” has been used to explain the difference between individuals in their capacity to cope with or compensate for pathology. Brain reserve refers to structural aspects of the brain, such as brain size and synapse count. Cognitive reserve is the ability to optimize and maximize performance through two mechanisms: recruitment of brain networks, and/or compensation by alternative cognitive strategies. The aim of the present research was to devise an instrument for comprehensive assessment and measurement of the quantity of cognitive reserve accumulated by individuals throughout their lifespan. Methods: A new approach using the Cognitive Reserve Index questionnaire (CRIq) was developed and tested in a sample of 588 healthy individuals, from 18 to 102 years old, stratified by age (Young, Adults, Elderly) and gender. The CRIq includes demographic data and items grouped into three sections: education, working activity and leisure time, each of which returns a subscore. The WAIS Vocabulary test and TIB were also administered. Results: The main descriptive features and some inferential results are described. Intelligence was only moderately correlated with cognitive reserve, stressing the distinction between these two concepts. Age and gender significantly affected CRIq scores, whereas no effect emerged from their interaction. Adults showed a higher score than Young and Elderly. Conclusions: This study provides a new instrument for a standardized measure of the cognitive reserve accumulated by individuals through their lifespan. The potential use of the CRIq in both experimental research and clinical practice is discussed.

Cognitive training (CT) programs aim to improve cognitive performance and impede its decline. Thus, defining the characteristics of individuals who can benefit from these interventions is essential. Our objectives were to assess if the cognitive reserve (CR), APOE genotype (e4 carriers/non-carriers) and/or hippocampal volume might predict the effectiveness of a CT program. Participants were older adults without dementia (n = 226), randomized into parallel experimental and control groups. The assessment consisted of a neuropsychological protocol and additional data regarding total intracranial, gray matter, left/right hippocampus volume; APOE genotype; and Cognitive Reserve (CR). The intervention involved multifactorial CT (30 sessions, 90 min each), with an evaluation pre- and post-training (at six months); the control group simply following the center’s routine activities. The primary outcome measures were the change in cognitive performance and the predictors of change. The results show that APOE-e4 non-carriers (79.1%) with a larger left hippocampal volume achieved better gains in semantic verbal fluency (R 2  = .19). Subjects with a larger CR and a greater gray matter volume better improved their processing speed (R 2  = .18). Age was correlated with the improvement in executive functions, such that older age predicts less improvement (R 2  = .07). Subjects with a larger left hippocampal volume achieved more significant gains in general cognitive performance (R 2  = .087). In conclusion, besides the program itself, the effectiveness of CT depends on age, biological factors like genotype and brain volume, and CR. Thus, to achieve better results through a CT, it is essential to consider the different characteristics of the participants, including genetic factors. Trial registration : Trial retrospectively registered on January 29th, 2020—( ClinicalTrials.gov -NCT04245579).

BackgroundAmyotrophic lateral sclerosis (ALS) is often associated with cognitive and/or behavioural impairment. Cognitive reserve (CR) may play a protective role in offsetting cognitive impairment. This study examined the relationship between CR and longitudinal change in cognition in an Irish ALS cohort.MethodsLongitudinal neuropsychological assessment was carried out on 189 patients over 16 months using the Edinburgh cognitive and behavioural ALS screen (ECAS) and an additional battery of neuropsychological tests. CR was measured by combining education, occupation and physical activity data. Joint longitudinal and time-to-event models were fitted to investigate the associations between CR, performance at baseline and decline over time while controlling for non-random drop-out.ResultsCR was a significant predictor of baseline neuropsychological performance, with high CR patients performing better than those with medium or low CR. Better cognitive performance in high CR individuals was maintained longitudinally for ECAS, social cognition, executive functioning and confrontational naming. Patients displayed little cognitive decline over the course of the study, despite controlling for non-random drop-out.ConclusionsThese findings suggest that CR plays a role in the presentation of cognitive impairment at diagnosis but is not protective against cognitive decline. However, further research is needed to examine the interaction between CR and other objective correlates of cognitive impairment in ALS.

The default-mode network (DMN) is affected by advancing age, where particularly long-range connectivity has been consistently reported to be reduced as compared to young individuals. We examined whether there were any differences in the effects of intermittent theta-burst stimulation (iTBS) in DMN connectivity between younger and older adults, its associations with cognition and brain integrity, as well as with long-term cognitive status. Twenty-four younger and 27 cognitively normal older adults were randomly assigned to receive real or sham iTBS over the left inferior parietal lobule between two resting-state functional magnetic resonance imaging (rs-fMRI) acquisitions. Three years later, those older adults who had received real iTBS underwent a cognitive follow-up assessment. Among the younger adults, functional connectivity increased following iTBS in distal DMN areas from the stimulation site. In contrast, older adults exhibited increases in connectivity following iTBS in proximal DMN regions. Moreover, older adults with functional responses to iTBS resembling those of the younger participants exhibited greater brain integrity and higher cognitive performance at baseline and at the 3-year follow-up, along with less cognitive decline. Finally, we observed that ‘young-like’ functional responses to iTBS were also related to the educational background attained amongst older adults. The present study reveals that functional responses of the DMN to iTBS are modulated by age. Furthermore, combining iTBS and rs-fMRI in older adults may allow characterizing distinctive cognitive profiles in aging and its progression, probably reflecting network plasticity systems that may entail a neurobiological substrate of cognitive reserve. •iTBS exerts distinctive effects in DMN connectivity in younger and older adults.•iTBS-fMRI metrics can identify meaningful associations between brain networks functioning and cognition in aging.•The iTBS-fMRI approach can allow to distinguish different cognitive trajectories in aging.•iTBS-fMRI measures could reflect a network plasticity mechanism of cognitive reserve.

ObjectiveAlthough post-stroke cognitive deficit can significantly limit patient independence and social re-integration, clinical routine predictors for this condition are lacking. ‘Cognitive reserve’ limits the detrimental effects of slowly developing neurodegeneration. We aimed to determine whether comparable effects also exist in acute stroke. Using 'years of education' as a proxy, we investigated whether cognitive reserve beneficially influences cognitive performance and disability after stroke, whilst controlling for age and lesion size as measure of stroke pathology.MethodsWithin the first week of ischemic right hemisphere stroke, 36 patients were assessed for alertness, working memory, executive functions, spatial neglect, global cognition and motor deficit at 4.9 ± 2.1 days post-stroke, in addition to routine clinical tests (NIH Stroke Scale, modified Rankin Scale on admission < 24 h post-stroke and at discharge 9.5 ± 4.7 days post-stroke). The impact of education was assessed using partial correlation analysis adjusted for lesion size, age, and the time interval between stroke and assessment. To validate our results, we compared groups with similar age and lesion load, but different education levels.ResultsIn the acute stroke phase, years of education predicted both severity of education independent (alertness) and education dependent (working memory, executive functions, global cognition) cognitive deficits and disability (modified Rankin Scale). Spatial neglect seemed to be independent.InterpretationProxies of cognitive reserve should be considered in stroke research as early as in the acute stroke phase. Cognitive reserve contributes to inter-individual variability in the initial severity of cognitive deficits and disability in acute stroke, and may suggest individualised rehabilitation strategies.

More educated elders are less susceptible to age-related or pathological cognitive changes. We aimed at providing a comprehensive contribution to the neural mechanism underlying this effect thanks to a multimodal approach. Thirty-six healthy elders were selected based on neuropsychological assessments and cerebral amyloid imaging, i.e. as presenting normal cognition and a negative florbetapir-PET scan. All subjects underwent structural MRI, FDG-PET and resting-state functional MRI scans. We assessed the relationships between years of education and i) gray matter volume, ii) gray matter metabolism and iii) functional connectivity in the brain areas showing associations with both volume and metabolism. Higher years of education were related to greater volume in the superior temporal gyrus, insula and anterior cingulate cortex and to greater metabolism in the anterior cingulate cortex. The latter thus showed both volume and metabolism increases with education. Seed connectivity analyses based on this region showed that education was positively related to the functional connectivity between the anterior cingulate cortex and the hippocampus as well as the inferior frontal lobe, posterior cingulate cortex and angular gyrus. Increased connectivity was in turn related with improved cognitive performances. Reinforcement of the connectivity of the anterior cingulate cortex with distant cortical areas of the frontal, temporal and parietal lobes appears as one of the mechanisms underlying education-related reserve in healthy elders. •We relate education to gray matter volume, metabolism and functional connectivity.•Volume and metabolism increases with education predominate in the anterior cingulate.•Anterior cingulate connectivity is also reinforced with education.•This increased connectivity relates to improved cognitive performances.