UNASSIGNED: A latent period of variable length elapses between multiple sclerosis (MS) biological onset and the occurrence of the first clinical episode reflecting a central nervous system (CNS) demyelinating event. Factors affecting the duration of such interval are unknown.
UNASSIGNED: To explore whether brain reserve, which moderates the impact of structural damage along MS course, could also affect the timing of MS clinical onset.
UNASSIGNED: We conducted a time-to-event analysis in 326 relapsing-onset multiple sclerosis patients to ascertain the effect of brain reserve, that is, larger maximal lifetime brain growth (MLBG) estimated as intracranial volume, on the risk of an earlier disease onset. For this purpose, we carried out a Cox proportional hazards regression model stratified by sex and adjusted by site and pre-morbid MS risk factors. All patients reached the event (i.e. the disease onset) with no censored case; the age (years) at disease onset was set as the main time variable.
UNASSIGNED: We identified a protective effect of brain reserve on the time to disease onset (HR = 0.11, 95% CI = 0.02-0.83, p = 0.032), unchanged when accounting for MS risk factors.
UNASSIGNED: Brain reserve might counteract the pathological mechanisms ongoing after biological initiation, thus delaying the disease overt clinical manifestation.

Protective factors, including psychological resilience, cognitive reserve, and brain reserve, may be positively associated with recovery after pediatric mild traumatic brain injury (mTBI) but are yet to be studied concurrently. We sought to examine these factors as moderators of post-concussive symptoms (PCS) in pediatric mTBI compared with mild orthopedic injury (OI). Participants included 967 children (633 mTBI, 334 OI) aged 8-16.99 years, recruited from 5 Canadian pediatric emergency departments as part of a prospective longitudinal cohort study. At 10 days post-injury, psychological resilience was measured using the Connor-Davidson Resilience Scale and brain reserve was measured using total brain volume derived from structural magnetic resonance imaging. Cognitive reserve was measured at 3 months post-injury using IQ scores from the Wechsler Abbreviated Scale of Intelligence-Second Edition. Cognitive and somatic PCS were measured using child and parent ratings on the Health and Behavior Inventory, completed weekly for 3 months and biweekly to 6 months. Analyses involved generalized least-squares regression models using restricted cubic splines. Covariates included age at injury, sex, racialized identity, material and social deprivation, pre-injury migraine and concussion history, and retrospective pre-injury PCS. Psychological resilience moderated group differences in parent-reported PCS. At 30 days post-injury, estimated group differences in parent-reported cognitive and somatic PCS (mTBI > OI) were larger at higher (75th percentile) resilience scores (Est = 2.25 [0.87, 3.64] and Est = 2.38 [1.76, 3.00], respectively) than at lower (25th percentile) resilience scores (Est = 1.44 [0.01, 2.86] and Est = 2.08 [1.45, 2.71], respectively). Resilience did not moderate group differences in child-reported PCS but was negatively associated with child-reported PCS in both groups (ps ≤ 0.001). Brain reserve (i.e., total brain volume [TBV]) also moderated group differences, but only for parent-reported somatic PCS (p = 0.018). Group difference (mTBI > OI) at 30 days was larger at smaller (25th percentile) TBV (Est = 2.78 [2.17, 3.38]) than at larger (75th percentile) TBV (Est = 1.95 [1.31, 2.59]). TBV was not associated with parent-reported cognitive PCS or child-reported PCS. IQ did not moderate PCS in either group but had a significant non-linear association in both groups with child-reported somatic PCS (p = 0.018) and parent-reported PCS (p < 0.001), with higher PCS scores at both lower and higher IQs. These findings suggest that higher resilience predicts fewer PCS, but less strongly after mTBI than OI; greater brain reserve may reduce the effect of mTBI on somatic PCS; and cognitive reserve has an unexpected curvilinear association with PCS across injury types. The results highlight the importance of protective factors as predictors of recovery and potential targets for intervention following pediatric mTBI.

Life-course exposure to risk and protective factors impacts brain macro- and micro-structure, which in turn affects cognition. The concept of brain-age gap assesses brain health by comparing an individual\'s neuroimaging-based predicted age with their calendar age. A higher BAG implies accelerated brain ageing and is expected to be associated with worse cognition. In this study, we comprehensively modelled mutual associations between brain health and lifestyle factors, brain age and cognition in a large, middle-aged population. For this study, cognitive test scores, lifestyle and 3T MRI data for n = 4881 participants [mean age (± SD) = 59.2 (±8.6), 50.1% male] were available from The Maastricht Study, a population-based cohort study with extensive phenotyping. Whole-brain volumes (grey matter, cerebrospinal fluid and white matter hyperintensity), cerebral microbleeds and structural white matter connectivity were calculated. Lifestyle factors were combined into an adapted LIfestyle for BRAin health weighted sum score, with higher score indicating greater dementia risk. Cognition was calculated by averaging z-scores across three cognitive domains (memory, information processing speed and executive function and attention). Brain-age gap was calculated by comparing calendar age to predictions from a neuroimaging-based multivariable regression model. Paths between LIfestyle for BRAin health tertiles, brain-age gap and cognitive function were tested using linear regression and structural equation modelling, adjusting for sociodemographic and clinical confounders. The results show that cerebrospinal fluid, grey matter, white matter hyperintensity and cerebral microbleeds best predicted brain-age gap (R 2 = 0.455, root mean squared error = 6.44). In regression analysis, higher LIfestyle for BRAin health scores (greater dementia risk) were associated with higher brain-age gap (standardized regression coefficient β = 0.126, P < 0.001) and worse cognition (β = -0.046, P = 0.013), while higher brain-age gap was associated with worse cognition (β=-0.163, P < 0.001). In mediation analysis, 24.7% of the total difference in cognition between the highest and lowest LIfestyle for BRAin health tertile was mediated by brain-age gap (β indirect = -0.049, P < 0.001; β total = -0.198, P < 0.001) and an additional 3.8% was mediated via connectivity (β indirect = -0.006, P < 0.001; β total = -0.150, P < 0.001). Findings suggest that associations between health- and lifestyle-based risk/protective factors (LIfestyle for BRAin health) and cognition can be partially explained by structural brain health markers (brain-age gap) and white matter connectivity markers. Lifestyle interventions targeted at high-risk individuals in mid-to-late life may be effective in promoting and preserving cognitive function in the general public.

The concept of brain reserve capacity has emerged in stroke recovery research in recent years. Imaging-based biomarkers of brain health have helped to better understand outcome variability in clinical cohorts. Still, outcome inferences are far from being satisfactory, particularly in patients with severe initial deficits. Neurorehabilitation after stroke is a complex process, comprising adaption and learning processes, which, on their part, are critically influenced by motivational and reward-related cognitive processes. Amongst others, dopaminergic neurotransmission is a key contributor to these mechanisms. The question arises, whether the amount of structural reserve capacity in the dopaminergic system might inform about outcome variability after severe stroke. For this purpose, this study analysed imaging and clinical data of 42 severely impaired acute stroke patients. Brain volumetry was performed within the first 2 weeks after the event using the Computational Anatomy Toolbox CAT12, grey matter volume estimates were collected for seven key areas of the human dopaminergic system along the mesocortical, mesolimbic and nigrostriatal pathways. Ordinal logistic regression models related regional volumes to the functional outcome, operationalized by the modified Rankin Scale, obtained 3-6 months after stroke. Models were adjusted for age, lesion volume and initial impairment. The main finding was that larger volumes of the amygdala and the nucleus accumbens at baseline were positively associated with a more favourable outcome. These data suggest a link between the structural state of mesolimbic key areas contributing to motor learning, motivational and reward-related brain networks and potentially the success of neurorehabilitation. They might also provide novel evidence to reconsider dopaminergic interventions particularly in severely impaired stroke patients to enhance recovery after stroke.

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.
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 abstracts, employing a systematic approach to eliminate studies that did not align with our research objectives.
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.
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.
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.

OBJECTIVE: We aimed to create an efficient and valid predicting model which can estimate individuals\' brain age by quantifying their regional brain volumes.
METHODS: A total of 2,560 structural brain magnetic resonance imaging (MRI) scans, along with demographic and clinical data, were obtained. Pretrained deep-learning models were employed to automatically segment the MRI data, which enabled fast calculation of regional brain volumes. Brain age gaps for each subject were estimated using volumetric values from predefined 12 regions of interest (ROIs): bilateral frontal, parietal, occipital, and temporal lobes, as well as bilateral hippocampus and lateral ventricles. A larger weight was given to the ROIs having a larger mean volumetric difference between the cognitively unimpaired (CU) and cognitively impaired group including mild cognitive impairment (MCI), and dementia groups. The brain age was predicted by adding or subtracting the brain age gap to the chronological age according to the presence or absence of the atrophy region.
RESULTS: The study showed significant differences in brain age gaps among CU, MCI, and dementia groups. Furthermore, the brain age gaps exhibited significant correlations with education level and measures of cognitive function, including the clinical dementia rating sum-of-boxes and the Korean version of the Mini-Mental State Examination.
CONCLUSIONS: The brain age that we developed enabled fast and efficient brain age calculations, and it also reflected individual\'s cognitive function and cognitive reserve. Thus, our study suggested that the brain age might be an important marker of brain health that can be used effectively in real clinical settings.

Cognition is a mental process that provides the ability to think, know, and learn. Though cognitive skills are necessary to do daily tasks and activities, cognitive aging causes changes in various cognitive functions. Cognitive abilities that are preserved and strengthened by experience can be kept as a reserve and utilized when necessary. The concept of reserving cognition was found when people with Alzheimer\'s disease had differences in clinical manifestations and cognitive functions. The cognitive reserve builds resilience against cognitive decline and improves the quality of life. Also, several lines of studies have found that the plasticity between neurons has a significant impact on cognitive reserve and acts against cognitive decline. To extend the findings, the present study provides a comprehensive understanding of cognitive reserve and the variables that are involved in maintaining cognition. The study also considers reading as one of the cognitive proxies that develops and maintains cognitive reserve.

The prediction of stroke outcome is challenging due to the high inter-individual variability in stroke patients. We recently suggested the adaptation of the concept of brain reserve (BR) to improve the prediction of stroke outcome. This concept was initially developed alongside the one for the cognitive reserve for neurodegeneration and forms a valuable theoretical framework to capture high inter-individual variability in stroke patients. In the present work, we suggest and discuss (i) BR-proxies-quantitative brain characteristics at the time stroke occurs (e.g., brain volume, hippocampus volume), and (ii) proxies of brain pathology reducing BR (e.g., brain atrophy, severity of white matter hyperintensities), parameters easily available from a routine MRI examination that might improve the prediction of stroke outcome. Though the influence of these parameters on stroke outcome has been partly reported individually, their independent and combined impact is yet to be determined. Conceptually, BR is a continuous measure determining the amount of brain structure available to mitigate and compensate for stroke damage, thus reflecting individual differences in neural resources and a capacity to maintain performance and recover after stroke. We suggest that stroke outcome might be defined as an interaction between BR at the time stroke occurs and lesion load. BR in stroke can potentially be influenced, e.g., by modifying cardiovascular risk factors. In addition to the potential power of the BR concept in a mechanistic understanding of inter-individual variability in stroke outcome and establishing individualized therapeutic approaches, it might help to strengthen the synergy of preventive measures in stroke, neurodegeneration, and healthy aging.

UNASSIGNED: Little is understood about the dynamic interplay between brain morphology and cognitive ability across the life course. Additionally, most existing research has focused on global morphology measures such as estimated total intracranial volume, mean thickness, and total surface area.
UNASSIGNED: Mendelian randomization was used to estimate the bidirectional effects between cognitive ability, global and regional measures of cortical thickness and surface area, estimated total intracranial volume, total white matter, and the volume of subcortical structures (N=37,864). Analyses were stratified for developmental periods (childhood, early adulthood, mid-to-late adulthood; age range: 8-81 years).
UNASSIGNED: The earliest effects were observed in childhood and early adulthood in the frontoparietal lobes. A bidirectional relationship was identified between higher cognitive ability, larger estimated total intracranial volume (childhood, mid-to-late adulthood) and total surface area (all life stages). A thicker posterior cingulate cortex and a larger surface area in the caudal middle frontal cortex and temporal pole were associated with greater cognitive ability. Contrary, a thicker temporal pole was associated with lower cognitive ability.
UNASSIGNED: Stable effects of cognitive ability on brain morphology across the life course suggests that childhood is potentially an important window for intervention.

Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammatory demyelination and neurodegeneration. Numerous disease-modifying therapies for MS exist but are only partially effective, making it essential to optimize all factors that may influence the course of the disease. This includes conscientious management of both mental and physical comorbidities, as well as a comprehensive strategy for promoting wellness in patients with MS. Thoughtful engagement of those living with MS through shared decision making and involvement of a multidisciplinary team that includes primary care, relevant specialists, psychology, and rehabilitation is likely to lead to better outcomes.