Cognitive reserve (CR) and brain maintenance (BM) reflect better than expected cognition despite brain pathology and minimal age-related brain changes that explain stable cognition, respectively. Despite being commonly used, joint quantification of these concepts has been limited; our aim is to derive longitudinal CR and BM measures and investigate CR’s relationship with education and functional connectivity. We analyzed longitudinal data from 451 participants (241 female, agemean = 68.5 years, follow-upmean = 4.2 years). From a hippocampus change-memory change regression, we modeled BM as memory stability relative to hippocampal stability and CR as better-than-expected memory stability relative to hippocampal atrophy. We examined whether education and resting-state functional connectivity (Default Mode, Executive Control and anterior Salience Network) (1) moderated the hippocampal-memory relationship using linear mixed effects models (LMEs), (2) moderated the hippocampus change-memory change relationship using linear regressions, and (3) were associated with our CR measure using LMEs. Analyses adjusted for demographics and MRI scanner/cohort, using false discovery rate (FDR) for multiple comparisons. From a significant hippocampus change-memory change relationship (β = 0.130, pFDR = 0.016, r2 = 0.282), we derived continuous CR and BM measures, providing subject-level estimates. Salience Network connectivity moderated the hippocampal-memory relationship (β = − 0.070, pFDR = 0.046, marginal r2 = 0.179). No variable moderated the hippocampus change-memory change relationship or correlated with our CR measure, consistent with the measure’s longitudinal definition. Our CR and BM measures refine phenotyping of aging trajectories. CR may be expressed through increased Salience Network connectivity, preserving memory level in the presence of hippocampal atrophy. Future work should delineate longitudinal CR mechanisms that decouple memory change from hippocampal atrophy.

Age-related loss of dopamine (DA) integrity has been linked to cognitive decline. Relatedly, education and leisure activity engagement have been highlighted as neurocognitive protective factors, but their associations with DA integrity remain poorly understood. Using Bayesian structural equation modeling, we analyzed longitudinal data from the Cognition, Brain, and Aging (COBRA) prospective cohort study with 181 older adults at baseline to examine correlations among DA D2-like receptor (DRD2) availability in the caudate and putamen, measured using [11C]raclopride positron emission tomography (PET), cognition (working memory, episodic memory, and perceptual speed), education, and self-reported physical, cognitive, and social leisure activity measures. Our research questions target whether (i) education or leisure activities are associated with baseline levels or 5-year changes in DRD2 availability; (ii) changes in leisure activities covary with DRD2 changes; and (iii) education or leisure activities moderate DRD2-cognition change-change correlations. Results showed declines in DRD2 availability in the caudate and putamen, with weak overall DRD2-cognition change-change correlations. For both baseline levels and changes in DRD2 availability, the associations with education and leisure activities were uniformly negligible or small and not strongly supported. Neither education nor leisure activities moderated DRD2-cognition change-change correlations.

Substantial heterogeneity in cognitive ageing is well documented. Such heterogeneity has been attributed to individual differences in brain maintenance - i.e., the relative preservation of neural resources in ageing. However, large-scale longitudinal evidence is currently lacking. In this study, we pooled data from three longitudinal population-based Swedish cohorts (total N = 1 356, 60-93 years at baseline, maximum follow-up duration: 7 years) to assess whether global brain maintenance is associated with better preserved cognition in ageing, and to identify lifestyle predictors of brain maintenance. In each cohort, global brain integrity was indexed by the volume of the lateral ventricles, and general cognitive function based on a principal component analysis of four age-sensitive cognitive domains. Participants were classified into subgroups of low (i.e., 'aged') versus high (i.e., 'youth-like') brain integrity based on comparison to ventricular volume estimates from a younger reference sample (N = 60, 25-55 years). Across cohorts, 881 individuals (64.97%) were classified into the high brain integrity subgroup at baseline and 409 individuals (49.82%) over the follow-up. Maintenance of more youth-like brain integrity was associated with better baseline cognition and less cognitive decline longitudinally. Moreover, lower cardiovascular disease risk and the absence of diabetes predicted brain maintenance at baseline and over the follow-up. These findings underscore general brain maintenance as a key determinant of cognitive ageing and highlight the importance of managing cardiovascular and metabolic disease risk factors for promotion of brain and cognitive health in later life.

Normal aging is associated with decline in dopamine function. Factors associated with individual differences in dopamine decline rates remain unclear but are important to map to spare dopamine-related functions, such as cognition. Here we focused on manifestations of cerebral small-vessel disease from magnetic resonance imaging (white-matter lesions, lacunes, and perivascular space dilation) and vascular risk factors (e.g., hypertension, body mass index (BMI), and hyperlipidemia). We assessed striatal dopamine D2-like receptor (DRD2) reductions across five years in healthy, older adults (n = 129, ages: 64-68 years at baseline) using 11C-raclopride/positron emission tomography. Manifestations of confluent lesions and lacunes at baseline had additive effects on DRD2 decline. Individuals with both manifestations showed fastest DRD2 decline rates (∼ -4 %), followed by those with one manifestation (∼ -2 %), whereas individuals spared of confluent lesions and lacunes showed stable DRD2 levels over time (∼ 0 % change). Furthermore, individuals with confluent lesions or lacunes showed more marked decline in perceptual speed performance, as compared to individuals spared of these manifestations (p < 0.05). Higher systolic blood pressure and lower BMI at baseline were associated with faster 5-year DRD2 decline in the putamen (r = -0.17, p < 0.05) and caudate (r = 0.23, p < 0.05), respectively. Together, confluent lesions and lacunes explained up to 8 % of striatal DRD2 change, and up to 10 % when adding hypertension and BMI to the model. These findings suggest that hallmarks of SVD and certain vascular risk factors predispose faster DRD2 decline in aging and may thus serve as factors to consider in future interventions.

Long-term exposure to ambient air pollution has recently been highlighted as a modifiable risk factor for dementia. However, the mechanisms underlying these associations still remain unclear. The goal of this study was to investigate the associations between air pollution and neuroimaging correlates in a sample of middle-aged and older adults. This study used data from the Betula Project, which is a longitudinal study on aging, memory and dementia in Umeå, Northen Sweden. Participants were aged 50-81 years old. For air pollution measures, data were available for local and total fine ambient particulate matter (PM 2.5 , PM 10 ) and black carbon (BC) from vehicle exhaust and wood-smoke. Participants were scanned in a 3T Discovery 750 (General Electric) MR-scanner. All T1-images were processed through a longitudinal pipeline in Freesurfer ver 7.11. MRI outcomes included total grey volume, cortex thickness, ventricle volume, and hippocampus volume. After removing participants due to incorrect hippocampus segmentation or missing values in air pollution or nuisance regressors 249 participants were included in the analyses. Partial correlations were performed, adjusting for age, sex and education. Additional analyses were conducted, stratifying by APOE4 status and sex. The analyses showed that smaller hippocampal volume was associated with higher levels of all three air pollution measures (PM 2.5 (r = -0.159, p = 0.012), PM 10 (r = -0.125, p = 0.048), and BC (r = -0.148, p = 0.019)). In the APOE4 non-carrier group, smaller hippocampal volume was associated with higher PM2.5 (r = -159, p = 0.034), whereas this association was not significant among the APOE4 carriers (r = -0.161, p = 0.178). The association between smaller hippocampal volume and PM2.5 was more pronounced among women (r = -0.168, p = 0.052) compared to men (r = -0.150, p = 0.112) This study shows that ambient air pollution is associated with smaller hippocampal volume, and this association appears to be more pronounced among APOE4 non-carriers and women. These results shed light on the mechanism through which air pollution may increase the risk for cognitive decline and dementia, with important implications for risk reduction initiatives.

Although age differences in the dopamine system have been suggested to contribute to age-related cognitive decline based on cross-sectional data, recent large-scale cross-sectional studies reported only weak evidence for a correlation among aging, dopamine receptor availability, and cognition. Regardless, longitudinal data remain essential to make robust statements about dopamine losses as a basis for cognitive aging. We present correlations between changes in D2/3 dopamine receptor availability and changes in working memory measured over 5 yr in healthy, older adults (n = 128, ages 64 to 68 yr at baseline). Greater decline in D2/3 dopamine receptor availability in working memory-relevant regions (caudate, middle frontal cortex, hippocampus) was related to greater decline in working memory performance in individuals who exhibited working memory reductions across time (n = 43; caudate: rs = 0.494; middle frontal cortex: rs = 0.506; hippocampus; rs = 0.423), but not in individuals who maintained performance (n = 41; caudate: rs = 0.052; middle frontal cortex: rs = 0.198; hippocampus; rs = 0.076). The dopamine-working memory link in decliners was not observed in the orbitofrontal cortex, which does not belong to the core working memory network. Our longitudinal analyses support the notion that aging-related changes in the dopamine system contribute to working memory decline in aging.

The hippocampus is a complex structure critically involved in numerous behavior-regulating systems. In young adults, multiple overlapping spatial modes along its longitudinal and transverse axes describe the organization of its functional integration with neocortex, extending the traditional framework emphasizing functional differences between sharply segregated hippocampal subregions. Yet, it remains unknown whether these modes (i.e. gradients) persist across the adult human lifespan, and relate to memory and molecular markers associated with brain function and cognition. In two independent samples, we demonstrate that the principal anteroposterior and second-order, mid-to-anterior/posterior hippocampal modes of neocortical functional connectivity, representing distinct dimensions of macroscale cortical organization, manifest across the adult lifespan. Specifically, individual differences in topography of the second-order gradient predicted episodic memory and mirrored dopamine D1 receptor distribution, capturing shared functional and molecular organization. Older age was associated with less distinct transitions along gradients (i.e. increased functional homogeneity). Importantly, a youth-like gradient profile predicted preserved episodic memory - emphasizing age-related gradient dedifferentiation as a marker of cognitive decline. Our results underscore a critical role of mapping multidimensional hippocampal organization in understanding the neural circuits that support memory across the adult lifespan.

Cognitive reserve (CR) and Brain Maintenance (BR) are constructs defined at a theoretical level (Stern et al., Neurobiol Aging, 2021 Apr, 124:100-103). Our aim was to propose a reproducible procedure to compare CR-like of BR-like mechanisms underlying interindividual differences in memory stability. Leveraging data from the Lifebrain consortia (Walhovd et al. Eur Psychiatry. 2018 Jan;47:76-87) we gathered information regarding 1) episodic memory (EM) stability, defined as those subjects showing no negative memory changes across two time point assessments (i.e., change ≥0), 2) brain structure and 3) brain functionality (resting-state functional magnetic resonance imaging [MRI]) changes). We designed a unified approach where at each step an analysis between EM and multimodal MRI-based measures provides a general metric, referring to either associations between EM and hippocampal (HC) volume changes, or to EM and fMRI connectivity changes (see Figure). This aimed to distinguish a ‘BM – Pathway 1’ identifying those subjects presenting a correspondence between both stability of EM and of HC volumes (i.e x≥0 & y≥0 quadrants of the upper left scatterplot) and a, ‘BM - pathway 2’ reflecting a correspondence between stability of EM and HPC fMRI functionality (i.e x≥0 & y≥0 quadrants of the bottom right scatterplot). Finally, a CR - pathway (‘deviant cases’ in Figure) was defined for subjects where a discrepancy between EM stability and their neural substrates was found (i.e. x>0 and y<0 quadrants in both scatterplots). Findings obtained from N = 532 participants (67.8 years at baseline, 294 women) revealed that N = 275 exhibited memory stability over time. Present analyses show that from those, N = 166 (60%) could be classified as BM -pathway 1 at the first step, whereas N = 109 (40%) cases were classified as CR - pathway. Further results from a subsample, indicate that CR - pathway cases exhibited a positive change in EM and negative in HC volumes, evidencing reductions in functional connectivity between HC and the Medial Prefrontal node from the dorsal Default Mode Network. The present approach combining structural and functional MRI to study CR and BM constructs shall provide new relevant empirical data helping to clarify the conceptual boundaries between these categories.

Aging-related dopamine decline has been suggested as a key factor behind individual differences in cognitive decline at older ages. Thus far, the hypothesized age-dopamine-cognition triad has been extrapolated from cross-sectional studies, which cannot uncover change associations. Using data from the longitudinal Cognition, Brain, and Aging (COBRA) study, we examined whether dopamine D2-receptor availability changes are correlated with cognitive changes across individuals in old age. At the first wave, 181 healthy adults aged 64 to 68 years underwent positron emission tomography with 11C-raclopride, magnetic resonance imaging, multiple cognitive tests assessing episodic memory, working memory, and perceptual speed, and mapping of health-related factors. The returnees (n = 129 after 5 years; n = 93 after 10 years) were representative of the parent sample regarding gender composition, educational attainment, cognitive performance, and dopamine D2-receptor status at baseline. Bayesian structural equation modeling revealed mean decline and individual differences in decline for striatal dopamine D2-receptor availability (approximately -5% per decade) and for all three cognitive abilities. Changes in dopamine D2-receptor and a factor of general cognition were positively correlated (r = 0.31, P(r > 0.00) > 0.95). Taken together, these longitudinal findings support that striatal dopamine decline is associated with cognitive aging, possibly reflecting dopamine influences via striato-thalamo-cortical loops on general cognitive functions.

Structural decline of the hippocampus occurs in heterogeneous patterns across its spatial extent, and is an important determinant of episodic memory dysfunction in aging. However, evidence indicate that the anatomical landmark uncal apex, used to demarcate anterior and posterior hippocampal subregions, changes position as the hippocampus atrophies. This emphasizes a risk of misclassifying gray matter into the incorrect subregion when using standard demarcation methods, contributing to over- and underestimation of age effects on anterior and posterior hippocampal volume. Yet, it remains unexplored whether inter-individual differences in uncal apex position predict episodic memory performance in itself. Here, we manually identified the uncal apex in anatomical MRI data from a healthy adult-lifespan sample (n=180; 20-79 years), assessed age differences in its position, and associations with word recollection performance. Increasing age was linked to a more anteriorly located uncal apex (retracting ∼0.041 mm/year). Importantly, a more anterior uncal apex position was linked to lower memory performance. Whereas anterior hippocampal volume remained stable with increasing age, posterior volume displayed non-linear decline with an infliction point at approximately 45 years. Neither anterior nor posterior hippocampal volumes predicted memory performance, but the ratio of posterior to anterior volume showed a significant association with memory when taking the position of the uncal apex into account. These results indicate that uncal apex position may provide an estimate of hippocampal integrity sensitive to inter-individual differences in memory, independent of limitations associated with different segmentation methods.### Competing Interest StatementThe authors have declared no competing interest.

After resective glioma surgery in the Supplementary Motor Area (SMA), patients often experience a transient disturbance of the ability to initiate speech and voluntary motor actions, known as the SMA syndrome (SMAS). It has been proposed that enhanced interhemispheric functional connectivity (FC) within the sensorimotor system may serve as a potential mechanism for recovery, enabling the non-resected SMA to assume the function of the resected region. The purpose of the present study was to investigate the extent to which changes in FC can be observed in patients after resolution of the SMAS.Eight patients underwent resection of left SMA due to suspected gliomas, resulting in various levels of the SMA syndrome. Resting-state functional MR images were acquired prior to the surgery and after resolution of the syndrome.At the group level we found an increased connectivity between the unaffected (right) SMA and the primary motor cortex on the same side following surgery. However, no significant increase in interhemispheric connectivity was observed.These findings challenge the prevailing notion that increased interhemispheric FC serves as the only mechanism underlying recovery from SMA syndrome and suggest the presence of one or more alternative mechanisms.

Throughout adulthood and ageing our brains undergo structural loss in an average pattern resembling faster atrophy in Alzheimer's disease (AD). Using a longitudinal adult lifespan sample (aged 30-89; 2-7 timepoints) and four polygenic scores for AD, we show that change in AD-sensitive brain features correlates with genetic AD-risk and memory decline in healthy adults. We first show genetic risk links with more brain loss than expected for age in early Braak regions, and find this extends beyond APOE genotype. Next, we run machine learning on AD-control data from the Alzheimer's Disease Neuroimaging Initiative using brain change trajectories conditioned on age, to identify AD-sensitive features and model their change in healthy adults. Genetic AD-risk linked with multivariate change across many AD-sensitive features, and we show most individuals over age ~50 are on an accelerated trajectory of brain loss in AD-sensitive regions. Finally, high genetic risk adults with elevated brain change showed more memory decline through adulthood, compared to high genetic risk adults with less brain change. Our findings suggest quantitative AD risk factors are detectable in healthy individuals, via a shared pattern of ageing- and AD-related neurodegeneration that occurs along a continuum and tracks memory decline through adulthood.

Losses in dopamine (DA) functioning may contribute to aging-related decline in cognition. Hippocampal DA is necessary for successful episodic memory formation. Previously, we reported that higher DA D2 receptor (D2DR) availability in hippocampus is beneficial for episodic memory only in older carriers of more advantageous genotypes of well-established plasticity-related genetic variations, the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. Extending our observations to the longitudinal level, the current data show that individuals with one or no beneficial BDNF and KIBRA genotype (n = 80) decline more in episodic memory across five years, without any contribution of losses in hippocampal D2DR availability to memory decline. Although carriers of two beneficial genotypes (n = 39) did not decline overall in episodic memory, losses of hippocampal D2DR availability were predictive of episodic-memory decline among these individuals. Our findings have implications for interventions targeting DA modulation to enhance episodic memory in aging, which may not benefit all older individuals.

Dopamine decline is suggested to underlie aging -related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5 -year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64-68 years; 5 -year follow-up: n = 129) who underwent positron emission tomography with 11C- raclopride to assess dopamine D2 -like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A datadriven approach (k -means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age -sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide -ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5 -year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging.

Across healthy adult life our brains undergo gradual structural change in a pattern of atrophy that resembles accelerated brain changes in Alzheimer’s disease (AD). Here, using four polygenic risk scores for AD (PRS-AD) in a longitudinal adult lifespan sample aged 30 to 89 years (2-7 timepoints), we show that healthy individuals who lose brain volume faster than expected for their age, have a higher genetic AD risk. We first demonstrate PRS-AD associations with change in early Braak regions, namely hippocampus, entorhinal cortex, and amygdala, and find evidence these extend beyond that predicted by APOE genotype. Next, following the hypothesis that brain changes in ageing and AD are largely shared, we performed machine learning classification on brain change trajectories conditional on age in longitudinal AD patient-control data, to obtain a list of AD-accelerated features and model change in these in adult lifespan data. We found PRS-AD was associated with a multivariate marker of accelerated change in many of these features in healthy adults, and that most individuals above ∼50 years of age are on an accelerated change trajectory in AD-accelerated brain regions. Finally, high PRS-AD individuals also high on a multivariate marker of change showed more adult lifespan memory decline, compared to high PRS-AD individuals with less brain change. Our results support a dimensional account linking normal brain ageing with AD, suggesting AD risk genes speed up the shared pattern of ageing- and AD-related neurodegeneration that starts early, occurs along a continuum, and tracks memory change in healthy adults.

Stress-related exhaustion is associated with cognitive deficits, measured subjectively using questionnaires targeting everyday slips and failures or more objectively as performance on cognitive tests. Yet, only weak associations between subjective and objective cognitive measures in this group has been presented, theorized to reflect recruitment of compensational resources during cognitive testing. This explorative study investigated how subjectively reported symptoms of cognitive functioning and burnout levels relate to performance as well as neural activation during a response inhibition task. To this end, 56 patients diagnosed with stress-related exhaustion disorder (ED; ICD-10 code F43.8A) completed functional magnetic resonance imaging (fMRI) using a Flanker paradigm. In order to investigate associations between neural activity and subjective cognitive complaints (SCCs) and burnout, respectively, scores on the Prospective and Retrospective Memory Questionnaire (PRMQ) and the Shirom-Melamed Burnout Questionnaire (SMBQ) were added as covariates of interest to a general linear model at the whole-brain level. In agreement with previous research, the results showed that SCCs and burnout levels were largely unrelated to task performance. Moreover, we did not see any correlations between these self-report measures and altered neural activity in frontal brain regions. Instead, we observed an association between the PRMQ and increased neural activity in an occipitally situated cluster. We propose that this finding may reflect compensational processes at the level of basic visual attention which could go unnoticed in cognitive testing but still be reflected in the experience of deficits in everyday cognitive functioning.

BACKGROUND:Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS:Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS:For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS:We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing preand post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.

Age-related changes in cortical volumes are well established but relatively few studies probed its constituents, surface area (SA) and thickness (TH). Here we analyzed 10-year, 3-waves longitudinal data from a large sample of healthy individuals (baseline age = 55- 80). The findings showed marked age-related changes of SA in frontal, temporal, and parietal association cortices, and Bivariate Latent Change Score models revealed significant SAassociations with changes in speed of processing in both the 5- and 10-year models. The corresponding results for TH revealed a late onset of thinning and significant associations with reduced cognition in the 10-year model only. Taken together, our findings suggest that cortical surface area shrinks and impacts information-processing capacity gradually in aging, whereas cortical thinning only manifests and impacts fluid cognition in advanced aging. (c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).