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Cognitive impairment is an important symptom of Parkinson’s disease (PD) and predicting future cognitive decline is crucial for clinical practice. Here, we aim to identify latent sub-groups of longitudinal trajectories of cognitive change in PD patients, and explore predictors of differences in cognitive change. Longitudinal cognitive performance data from 349 newly diagnosed PD patients and 145 healthy controls from the Parkinson Progression Marker Initiative were modeled using a multivariate latent class linear mixed model. Resultant latent classes were compared on a number of baseline demographics, and clinical variables, as well as cerebrospinal fluid (CSF) biomarkers and striatal dopamine transporter (DAT) density markers of neuropathology. Trajectories of cognitive change in PD were best described by two latent classes. A large subgroup (90%), which showed a subtle impairment in cognitive performance compared to controls but remained stable over the course of the study, and a small subgroup (10%) which rapidly declined in all cognitive performance measures. Rapid decliners did not differ significantly from the larger group in terms of disease duration, severity or motor symptoms at baseline. However, rapid decliners had lower CSF amyloidß42 levels, a higher prevalence of sleep disorder and pronounced loss of caudate DAT density at baseline. These data suggest the existence of a distinct minority sub-type of PD in which rapid cognitive change in PD can occur uncoupled from motor symptoms or disease severity, likely reflecting early pathological change that extends from motor areas of the striatum into associative compartments and cortex.

Working memory (WM) functioning declines in old age. Due to its impact on many higher-order cognitive functions, investigating whether training can modify WM performance has recently been of great interest. We examined the relationship between behavioral performance and neural activity following five weeks of intensive WM training in 23 healthy older adults (M=63.7 years). 12 participants received adaptive training (i.e. individually adjusted task difficulty to bring individuals to their performance maximum), whereas the others served as active controls (i.e. fixed low-level practice). Brain activity was measured before and after training, using fMRI, while subjects performed a WM task under two difficulty conditions. Although there were no training-related changes in WM during scanning, neocortical brain activity decreased post training and these decreases were larger in the adaptive training group than in the controls under high WM load. This pattern suggests intervention-related increases in neural efficiency. Further, there were disproportionate gains in the adaptive training group in trained as well as in non-trained (i.e. attention, episodic memory) tasks assessed outside the scanner, indicating the efficacy of the training regimen. Critically, the degree of training-related changes in brain activity (i.e. neocortical decreases and subcortical increases) was related to the maximum gain score achieved during the intervention period. This relationship suggests that the decreased activity, but also specific activity increases, observed were functionally relevant.

In an fMRI study, 20 younger and 20 healthy older adults were scanned while performing a spatial working-memory task under two levels of load. On a separate occasion, the same subjects underwent PET measurements using the radioligand [(11)C] SCH23390 to determine dopamine D(1) receptor binding potential (BP) in caudate nucleus and dorsolateral prefrontal cortex (DLPFC). The fMRI study revealed a significant load modulation of brain activity (higher load>lower load) in frontal and parietal regions for younger, but not older, adults. The PET measurements showed marked age-related reductions of D(1) BP in caudate and DLPFC. Statistical control of caudate and DLPFC D(1) binding eliminated the age-related reduction in load-dependent BOLD signal in left frontal cortex, and attenuated greatly the reduction in right frontal and left parietal cortex. These findings suggest that age-related alterations in dopaminergic neurotransmission may contribute to underrecruitment of task-relevant brain regions during working-memory performance in old age.

Age constitutes a salient feature of a face and signals group membership. There is evidence of greater attention to and better memory for own-age than other-age faces. However, little is known about the neural and behavioral mechanisms underlying processing differences for own-age vs. other-age faces. Even less is known about the impact of emotion expressed in faces on such own-age effects. Using fMRI, the present study examined brain activity while young and older adult participants identified expressions of neutral, happy, and angry young and older faces. Across facial expressions, medial prefrontal cortex, insula, and (for older participants) amygdala showed greater activity to own-age than other-age faces. These own-age effects in ventral medial prefrontal cortex and insula held for neutral and happy faces, but not for angry faces. This novel and intriguing finding suggests that processing of negative facial emotions under some conditions overrides age-of-face effects.

BACKGROUND: Previous correlational studies have indirectly linked dysfunctional dopaminergic neurotransmission to age-related cognitive deficits and associated reductions in task-induced functional brain activity.

METHODS: We used an experimental-pharmacological functional magnetic resonance imaging (fMRI) approach to more directly examine the role of dopamine in neurocognitive aging. Twenty younger and 20 healthy older adults were included. During fMRI scanning, a spatial working memory (SWM) task was administered under two conditions, varying in cognitive load. Positron emission tomography measurements with the D1 receptor antagonist [(11)C]SCH23390 confirmed that a given experimental dose of unlabeled solution occupied 50% of D1 receptors in younger adults.

RESULTS: An age-related reduction in SWM performance was observed, and fMRI data revealed that, relative to younger adults under placebo conditions, elderly persons under-recruited load-sensitive fronto-parietal regions during SWM. Critically, in younger adults, the D1 antagonist resulted in a similar reduction in SWM performance and fMRI response.

CONCLUSIONS: These results suggest that depletion of dopamine, whether ontogenetically or pharmacologically, results in decreased SWM performance as well as reduced load-dependent modulation of the blood oxygen level dependent signal in fronto-parietal regions, possibly by decreasing the signal-to-noise ratio in relevant neural networks.

To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D1 and D2 receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [11C]Raclopride and [11C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BP ND ), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BP ND for D2 receptors over time, whereas no significant change was found for D1 receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [11C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D2 receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D1 were found, which may be attributed to altered [11C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

The dopaminergic system is firmly implicated in reversal learning but human measurements of dopamine release as a correlate of reversal learning success are lacking. Dopamine release and hemodynamic brain activity in response to unexpected changes in action-outcome probabilities are here explored using simultaneous dynamic [11C]Raclopride PET-fMRI and computational modelling of behavior. When participants encounter reversed reward probabilities during a card guessing game, dopamine release is observed in associative striatum. Individual differences in absolute reward prediction error and sensitivity to errors are associated with peak dopamine receptor occupancy. The fMRI response to perseverance errors at the onset of a reversal spatially overlap with the site of dopamine release. Trial-by-trial fMRI correlates of absolute prediction errors show a response in striatum and association cortices, closely overlapping with the location of dopamine release, and separable from a valence signal in ventral striatum. The results converge to implicate striatal dopamine release in associative striatum as a central component of reversal learning, possibly signifying the need for increased cognitive control when new stimuli-responses should be learned.

Striatal dopamine is involved in facilitation of motor action as well as various cognitive and emotional functions. Positron emission tomography (PET) is the primary imaging method used to investigate dopamine function in humans. Previous PET studies have shown striatal dopamine release during simple finger tapping in both the putamen and the caudate. It is likely that dopamine release in the putamen is related to motor processes while dopamine release in the caudate could signal sustained cognitive component processes of the task, but the poor temporal resolution of PET has hindered firm conclusions. In this study we simultaneously collected [11C]Raclopride PET and functional Magnetic Resonance Imaging (fMRI) data while participants performed finger tapping, with fMRI being able to isolate activations related to individual tapping events. The results revealed fMRI-PET overlap in the bilateral putamen, which is consistent with a motor component process. Selective PET responses in the caudate, ventral striatum, and right posterior putamen, were also observed but did not overlap with fMRI responses to tapping events, suggesting that these reflect non-motor component processes of finger tapping. Our findings suggest an interplay between motor and non-motor-related dopamine release during simple finger tapping and illustrate the potential of hybrid PET-fMRI in revealing distinct component processes of cognitive functions.

Introduction: Rewarding and punishing stimuli elicit BOLD responses in the affective division of the striatum. The responses typically traverse from the affective to the associative division of the striatum, suggesting an involvement of associative processes during the modulation of stimuli valance. In this study, we hypothesized that fMRI responses to rewards versus punishments in a guessing card game can be disassociated into two functional component processes that reflect the convergence of limbic and associative functional networks in the ventral striatum.

Methods: We used fMRI data of 175 (92 female) subjects from the human connectome project ' s gambling task, working memory task, and resting-state scans. A reward > punish contrast identified a ventral striatum cluster from which voxelwise GLM parameter estimates were entered into a k-means clustering algorithm. The k-means analysis supported separating the cluster into two spatially distinct components. These components were used as seeds to investigate their functional connectivity profile. GLM parameter estimates were extracted and compared from the task contrasts reward > punish and 2-back > 0-back from two ROIs in the ventral striatum and one ROI in hippocampus.

Results: The analyses converged to show that a superior striatal component, coupled with the ventral attention and frontal control networks, was responsive to both a modulation of cognitive control in working memory and to rewards, whereas the most inferior part of the ventral striatum, coupled with the limbic and default mode networks including the hippocampus, was selectively responsive to rewards.

Conclusion: We show that the fMRI response to rewards in the ventral striatum reflects a mixture of component processes of reward. An inferior ventral striatal component and hippocampus are part of an intrinsically coupled network that responds to reward-based processing during gambling. The more superior ventral striatal component is intrinsically coupled to networks involved with executive functioning and responded to both reward and cognitive control demands.

Dopamine (DA) losses are associated with various aging-related cognitive deficits. Typically, higher moment-to-moment brain signal variability in large-scale patterns of voxels in neocortical regions is linked to better cognitive performance and younger adult age, yet the physiological mechanisms regulating brain signal variability are unknown. We explored the relationship among adult age, DA availability, and blood oxygen level-dependent (BOLD) signal variability, while younger and older participants performed a spatial working memory (SWM) task. We quantified striatal and extrastriatal DA D1 receptor density with [(11)C]SCH23390 and positron emission tomography in all participants. We found that BOLD variability in a neocortical region was negatively related to age and positively related to SWM performance. In contrast, BOLD variability in subcortical regions and bilateral hippocampus was positively related to age and slower responses, and negatively related to D1 density in caudate and dorsolateral prefrontal cortex. Furthermore, BOLD variability in neocortical regions was positively associated with task-related disengagement of the default-mode network, a network whose activation needs to be suppressed for efficient SWM processing. Our results show that age-related DA losses contribute to changes in brain signal variability in subcortical regions and suggest a potential mechanism, by which neocortical BOLD variability supports cognitive performance.

Age-related alterations in brain structure and function have been challenging to link to cognition due to potential overlapping influences of multiple neurobiological cascades. We examined multiple brain markers associated with age-related variation in cognition. Clinically normal older humans aged 65-90 from the Harvard Aging Brain Study (N = 186) were characterized on a priori magnetic resonance imaging markers of gray matter thickness and volume, white matter hyperintensities, fractional anisotropy (FA), resting-state functional connectivity, positron emission tomography markers of glucose metabolism and amyloid burden, and cognitive factors of processing speed, executive function, and episodic memory. Partial correlation and mediation analyses estimated age-related variance in cognition shared with individual brain markers and unique to each marker. The largest relationships linked FA and striatum volume to processing speed and executive function, and hippocampal volume to episodic memory. Of the age-related variance in cognition, 70-80% was accounted for by combining all brain markers (but only ∼20% of total variance). Age had significant indirect effects on cognition via brain markers, with significant markers varying across cognitive domains. These results suggest that most age-related variation in cognition is shared among multiple brain markers, but potential specificity between some brain markers and cognitive domains motivates additional study of age-related markers of neural health.

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 pre- and 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.

The finding of reduced functional MRI (fMRI) activity in the default mode network (DMN) during externally focused cognitive control has been highly influential to our understanding of human brain function. However, these negative fMRI responses, measured as relative decreases in the blood-oxygenation-level-dependent (BOLD) response between rest and task, have also prompted major questions of interpretation. Using hybrid functional positron emission tomography (PET)-MRI, this study shows that task-positive and -negative BOLD responses do not reflect antagonistic patterns of synaptic metabolism. Task-positive BOLD responses in attention and control networks were accompanied by concomitant increases in glucose metabolism during cognitive control, but metabolism in widespread DMN remained high during rest and task despite negative BOLD responses. Dissociations between glucose metabolism and the BOLD response specific to the DMN reveal functional heterogeneity in this network and demonstrate that negative BOLD responses during cognitive control should not be interpreted to reflect relative increases in metabolic activity during rest. Rather, neurovascular coupling underlying BOLD response patterns during rest and task in DMN appears fundamentally different from BOLD responses in other association networks during cognitive control.

Some studies have suggested that the memory advantage for negative emotional information over neutral information ("negativity effect") is reduced in aging. Besides the fact that most findings are based on immediate retrieval, the neural underpinnings of long-term emotional memory in aging have so far not been investigated. To address these issues, we assessed recognition of neutral and negative scenes after 1- and 3-week retention intervals in younger and older adults using functional magnetic resonance imaging. We further used an event-related design in order to disentangle successful, false, and true recognition. This study revealed four key findings: (1) increased retention interval induced an increased rate of false recognitions for negative scenes, canceling out the negativity effect (present for hit rates only) on discrimination in both younger and older adults; (2) in younger, but not older, adults, reduced activity of the medial temporal lobe was observed over time for neutral scenes, but not for negative scenes, where stable or increased activity was seen; (3) engagement of amygdala (AMG) was observed in older adults after a 3-week delay during successful recognition of negative scenes (hits vs. misses) in comparison with neutral scenes, which may indicate engagement of automatic processes, but engagement of ventrolateral prefrontal cortex was unrelated to AMG activity and performance; and (4) after 3 weeks, but not after 1 week, true recognition of negative scenes was characterized by more activity in left hippocampus and lateral occipito-temporal regions (hits vs. false alarms). As these regions are known to be related to consolidation mechanisms, the observed pattern may indicate the presence of delayed consolidation of true memories. Nonetheless, older adults' low performance in discrimination of negative scenes could reflect the fact that overall, after long delays of retention, they rely more on general information rather than on perceptual detail in making recognition judgments.

Objective: The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age‐related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive.

Methods: The present work used magnetic resonance imaging and positron emission tomography with 11C‐raclopride to jointly examine vascular parameters (white‐matter lesions and perfusion), DA D2‐receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64–68 years) from the Cognition, Brain, and Aging (COBRA) study.

Results: Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White‐matter lesion burden was negatively correlated with caudate DA D2‐receptor availability and white‐matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2‐receptor availability, white‐matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey‐matter volumes, a larger number of white‐matter lesions, and lower episodic memory performance.

Interpretation: Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age‐sensitive cognitive functions, with emphasis on DA integrity.

There is strong evidence that dopamine (DA) is implicated in higher-order cognitive functioning, but it remains controversial whether D1 receptor binding can be modified by cognitive activity. We examined striatal D1 binding potential (BP) in 20 younger (22-30 years) and 20 older (65-75 years) persons who underwent two [(11)C] SCH 23390 PET measurements, one while resting and one while performing a cognitive task taxing inhibitory functioning. The younger persons showed significant task-related BP reductions in sensorimotor, limbic, and associative striatum during cognitive activity compared to rest. Older persons showed no reliable BP reductions in any striatal subregion. These findings demonstrate that D1 receptor binding can be modified by cognitive activity in younger persons, but also provide novel evidence for the notion that human aging is associated not only with lower DA receptor density but also with altered modifiability of the DA system.

Dopamine (DA) availability in both striatal and extrastriatal brain regions has been implicated in cognitive performance. Given that different brain regions are neuroanatomically and functionally different, DA receptor binding in different brain regions may be selectively important to specific cognitive functions. Using PET and the radioligand SCH23390, we measured D1 receptor binding potential (BP(ND)) in dorsolateral prefrontal cortex (DLPFC), hippocampus (HC), as well as in sensorimotor (SMST), associative (AST), and limbic (LST) striatum in 20 healthy younger persons. Subjects completed tasks assessing executive functioning, episodic memory, speed, and general knowledge. Unlike previous reports, we found no linear or curvilinear relationships between D1 receptor binding in DLPFC and performance in any cognitive task. However, BP(ND) in HC was positively linked to executive performance as well as to speed and knowledge. With regard to the striatal subregions, D1 BP(ND) in SMST was more strongly related to speed compared to the other striatal subregions, whereas D1 BP(ND) in AST was more strongly linked to general knowledge. These findings provide support for the notion that D1 receptors in separate brain regions are differentially related to performance in tasks tapping various cognitive domains.

The efficacy of various transmitter systems declines with advancing age. Of particular interest, various pre-synaptic and post-synaptic components of the dopaminergic system change across the human lifespan; impairments in these components play important roles in cognitive deficits commonly observed in the elderly. Here, we review evidence from recent multimodal neuroimaging, pharmacological and genetic studies that have provided new insights for the associations among dopamine functions, aging, functional brain activations and behavioral performance across key cognitive functions, ranging from working memory and episodic memory to goal-directed learning and decision making. Specifically, we discuss these empirical findings in the context of an established neurocomputational theory of aging neuronal gain control. We also highlight gaps in the current understanding of dopamine neuromodulation and aging brain functions and suggest avenues for future research.

Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional implications of a given level of dopamine may therefore differ from person to person. By applying latent-profile analysis to a large (n = 181) sample of adults aged 64-68 years, we probabilistically identified 3 subgroups that explain the multivariate associations between dopamine D2/3R availability (probed with C-11-raclopride-PET, in cortical, striatal, and hippocampal regions) and cognitive performance (episodic memory, working memory, and perceptual speed). Generally, greater receptor availability was associated with better cognitive performance. However, we discovered a subgroup of individuals for which high availability, particularly in striatum, was associated with poor performance, especially for working memory. Relative to the rest of the sample, this subgroup also had lower education, higher body-mass index, and lower resting-state connectivity between caudate nucleus and dorsolateral prefrontal cortex. We conclude that a smaller subset of individuals induces a multivariate non-linear association between dopamine D2/3R availability and cognitive performance in this group of older adults, and discuss potential reasons for these differences that await further empirical scrutiny.

Between-person differences in white matter microstructure may partly generalize across the brain and partly play out differently for distinct tracts. We used diffusion-tensor imaging and structural equation modeling to investigate this issue in a sample of 260 adults aged 60-87 years. Mean fractional anisotropy and mean diffusivity of seven white matter tracts in each hemisphere were quantified. Results showed good fit of a model positing that individual differences in white matter microstructure are structured according to tracts. A general factor, although accounting for variance in the measures, did not adequately represent the individual differences. This indicates the presence of a substantial amount of tract-specific individual differences in white matter microstructure. In addition, individual differences are to a varying degree shared between tracts, indicating that general factors also affect white matter microstructure. Age-related differences in white matter microstructure were present for all tracts. Correlations among tract factors did not generally increase as a function of age, suggesting that aging is not a process with homogenous effects on white matter microstructure across the brain. These findings highlight the need for future research to examine whether relations between white matter microstructure and diverse outcomes are specific or general.

Intraindividual variability (IIV) reflects within-person changes in performance, such as trial-by-trial fluctuations on a reaction-time (RT) task. The neural underpinnings of IIV remain largely unknown. The neurotransmitter dopamine (DA) is of particular interest here, as human populations that exhibit DA alterations, such as the elderly, attention deficit hyperactivity disorder children, persons with schizophrenia, and Parkinson patients, also show increased behavioral IIV. We examined links between DA D-1 binding potential (BP) in multiple brain regions and IIV for the control and interference conditions of the Multi-Source Interference Task (MSIT), tapping the cingulo-fronto-parietal attention network. Participants were 18 young and 20 healthy old adults. PET and the radioligand [C-11]SCH23390 were used to determine D-1 BP. The intraindividual standard deviation (ISD) was computed across successful latency trials of the MSIT conditions, independent of mean RT differences due to age, trial, and condition. Increasing ISDs were associated with increasing age and diminished D-1 binding in several brain regions (anterior cingulate gyrus, dorsolateral prefrontal cortex, and parietal cortex) for the interference, but not control, condition. Analyses of partial associations indicate that the association between age and IIV in the interference condition was linked to D-1 receptor losses in task-relevant brain regions. These findings suggest that dysfunctional DA modulation may contribute to increased variability in cognitive performance among older adults.

D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [C-11]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.

Objectives: Loneliness is a major public health concern. Duration of loneliness is associated with severity of health outcomes, and further research is needed to direct interventions and social policy. This study aimed to identify predictors of the onset vs. the maintenance of loneliness in older adults before and during the pandemic using longitudinal data from the Survey of Health, Age, and Retirement in Europe (SHARE).

Methods: Groupings of persistent, situational, and no loneliness were based on self-reports from an ordinary pre-pandemic SHARE wave and a peri-pandemic telephone interview. Predictors were identified and compared in three hierarchical binary regression analyses, with independent variables added in blocks of geographic region, demographics, pre-pandemic social network, pre-pandemic health, pandemic-related individual, and country level variables.

Results: Self-reported loneliness levels for the persistent, situational, and no loneliness groups were stable and distinct through 7 years preceding the pre-pandemic baseline measure. Shared predictors were chronic diseases, female sex, depression, and no cohabitant partner. Persistent loneliness was uniquely predicted by low network satisfaction (OR: 2.04), functional limitations (OR: 1.40), and a longer country-level isolation period for older adults (OR: 1.24).

Conclusion: Interventions may target persons with depression, functional limitations, chronic health issues, and no cohabitant partner. The added burden of the length of isolation on those who are already lonely should be taken into account when employing social policies that target older adults. Further research should distinguish between situational and persistent loneliness, and seek to identify predictors of chronic loneliness onset.

Insufficient or excessive dopaminergic tone impairs cognitive performance. We examine whether the balance between transmitter availability and dopamine (DA) D2 receptors (D2DRs) is important for successful memory performance in a large sample of adults (n = 175, 64-68 years). The Catechol-O-Methyltransferase polymorphism served as genetic proxy for endogenous prefrontal DA availability, and D2DRs in dorsolateral prefrontal cortex (dlPFC) were measured with [11C]raclopride-PET. Individuals for whom D2DR status matched DA availability showed higher levels of episodic and working-memory performance than individuals with insufficient or excessive DA availability relative to the number of receptors. A similar pattern restricted to episodic memory was observed for D2DRs in caudate. Functional magnetic resonance imaging data acquired during working-memory performance confirmed the importance of a balanced DA system for load-dependent brain activity in dlPFC. Our data suggest that the inverted-U-shaped function relating DA signaling to cognition is modulated by a dynamic association between DA availability and receptor status.

Healthy aging is accompanied by progressive decline in cognitive performance and concomitant changes in brain structure and functional architecture. Age-accompanied alterations in brain function have been characterized on a network level as weaker functional connections within brain networks along with stronger interactions between networks. This phenomenon has been described as age-related differences in functional network segregation. It has been suggested that functional networks related to associative processes are particularly sensitive to age-related deterioration in segregation, possibly related to cognitive decline in aging. However, there have been only a few longitudinal studies with inconclusive results. Here, we used a large longitudinal sample of 284 participants between 25 to 80 years of age at baseline, with cognitive and neuroimaging data collected at up to three time points over a 10-year period. We investigated age-related changes in functional segregation among two large-scale systems comprising associative and sensorimotor-related resting-state networks. We found that functional segregation of associative systems declines in aging with exacerbated deterioration from the late fifties. Changes in associative segregation were positively associated with changes in global cognitive ability, suggesting that decreased segregation has negative consequences for domain-general cognitive functions. Age-related changes in system segregation were partly accounted for by changes in white matter integrity, but white matter integrity only weakly influenced the association between segregation and cognition. Together, these novel findings suggest a cascade where reduced white-matter integrity leads to less distinctive functional systems which in turn contributes to cognitive decline in aging.

Recent work has recognized a gradient-like organization in cortical function, spanning from primary sensory to transmodal cortices. It has been suggested that this axis is aligned with regional differences in neurotransmitter expression. Given the abundance of dopamine D1-receptors (D1DR), and its importance for modulation and neural gain, we tested the hypothesis that D1DR organization is aligned with functional architecture, and that inter-regional relationships in D1DR co-expression modulate functional cross talk. Using the world's largest dopamine D1DR-PET and MRI database (N = 180%, 50% female), we demonstrate that D1DR organization follows a unimodal–transmodal hierarchy, expressing a high spatial correspondence to the principal gradient of functional connectivity. We also demonstrate that individual differences in D1DR density between unimodal and transmodal regions are associated with functional differentiation of the apices in the cortical hierarchy. Finally, we show that spatial co-expression of D1DR primarily modulates couplings within, but not between, functional networks. Together, our results show that D1DR co-expression provides a biomolecular layer to the functional organization of the brain.

A number of genetic polymorphisms are related to individual differences in cognitive performance. Striatal dopamine (DA) functions, associated with cognitive performance, are linked to the TaqIA polymorphism of the DRD2/ANKK1 gene. In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIA polymorphism is related to reduced density of striatal DA D2 receptors. The resource-modulation hypothesis assumes that aging-related losses of neurochemical and structural brain resources modulate the extent to which genetic variations affect cognitive functioning. Here, we tested this hypothesis using functional MRI during long-term memory (LTM) updating in younger and older carriers and noncarriers of the A1-allele of the TaqIa polymorphism. We demonstrate that older A1-carriers have worse memory performance, specifically during LTM updating, compared to noncarriers. Moreover, A1-carriers exhibited less blood oxygen level-dependent (BOLD) activation in left caudate nucleus, a region critical to updating. This effect was only seen in older adults, suggesting magnification of genetic effects on functional brain activity in aging. Further, a positive relationship between caudate BOLD activation and updating performance among non-A1 carriers indicated that caudate activation was behaviorally relevant. These results demonstrate a link between the DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM updating, and provide novel evidence that this effect is magnified in aging. Hum Brain Mapp 36:1325-1334, 2015.

The functional organization of the frontal cortex is dynamic. Age-related increases in frontal functional responses have been shown during various cognitive tasks, but the cross-sectional nature of most past studies makes it unclear whether these increases reflect reorganization or stable individual differences. Here, we followed 130 older individuals' cognitive trajectories over 20-25 years with repeated neuropsychological assessments every 5th year, and identified individuals with stable or declining episodic memory. Both groups displayed significant gray matter atrophy over 2 successive magnetic resonance imaging sessions 4 years apart, but the decline group also had a smaller volume of the right hippocampus. Only individuals with declining memory demonstrated increased prefrontal functional responses during memory encoding and retrieval over the 4-year interval. Regions with increased functional recruitment were located outside, or on the borders of core task-related networks, indicating an expansion of these over time. These longitudinal findings offer novel insight into the mechanisms behind age-associated memory loss, and are consistent with a theoretical model in which hippocampus atrophy, past a critical threshold, induces episodic-memory decline and altered prefrontal functional organization.

Research suggests that the striatum plays an important role in implicit learning (IL). The striatum exhibits marked age-related morphological and neurochemical losses. Yet, behavioral studies suggest that IL is generally well preserved in old age, and that age-related differences emerge only when highly complex IL tasks are used. In this review, we integrate behavioral and neuroimaging evidence on IL in aging. We suggest that relative stability of IL in old age may reflect neural reorganization that compensates for age-related losses in striatal functions. Specifically, there may be an age-related increase in reliance on extrastriatal regions (e.g., medial-temporal, frontal) during IL. This reorganization of function may be beneficial under less taxing performance conditions, but not when task demands become more challenging.

The striatum and connected cortical areas have been implicated in sequence learning (SL) tasks, in which performance increments are gradual and learning typically occurs in the absence of awareness. It has recently been shown that increasing striatal activation during SL may be accompanied by decreasing activation in the medial temporal lobe (MTL) across time, but the specific contribution of the MTL to SL remains unclear. In the current age-comparative fMRI study, we show that gradual SL in the serial reaction time task is associated with activation increases in the striatum and activation decreases in the MTL across time in younger adults. However, in older adults, SL is positively related to activation increases in both the striatum and the MTL. The results are discussed in terms of the functional role of the MTL in SL, and offer a novel explanation of the fact that SL is little affected in aging.

Prior work has shown that functional connectivity between the midbrain and putamen is altered in patients with impairments in the dopamine system. This study examines whether individual differences in midbrain-striatal connectivity are proportional to the integrity of the dopamine system in patients with nigrostriatal dopamine loss (Parkinson's disease and dementia with Lewy bodies). We assessed functional connectivity of the putamen during resting state fMRI and dopamine transporter (DAT) availability in the striatum using 11C-Altropane PET in twenty patients. In line with the hypothesis that functional connectivity between the midbrain and the putamen reflects the integrity of the dopaminergic neurotransmitter system, putamen-midbrain functional connectivity was significantly correlated with striatal DAT availability even after stringent control for effects of head motion. DAT availability did not relate to functional connectivity between the caudate and thalamus/prefrontal areas. As such, resting state functional connectivity in the midbrain-striatal pathway may provide a useful indicator of underlying pathology in patients with nigrostriatal dopamine loss.

Aging-related differences in white matter integrity, the presence of amyloid plaques, and density of biomarkers indicative of dopamine functions can be detected and quantified with in vivo human imaging. The primary aim of the present study was to investigate whether these imaging-based measures constitute independent imaging biomarkers in older adults, which would speak to the hypothesis that the aging brain is characterized by multiple independent neurobiological cascades. We assessed MRI-based markers of white matter integrity and PET-based marker of dopamine transporter density and amyloid deposition in the same set of 53 clinically normal individuals (age 65-87). A multiple regression analysis demonstrated that dopamine transporter availability is predicted by white matter integrity, which was detectable even after controlling for chronological age. Further post-hoc exploration revealed that dopamine transporter availability was further associated with systolic blood pressure, mirroring the established association between cardiovascular health and white matter integrity. Dopamine transporter availability was not associated with the presence of amyloid burden. Neurobiological correlates of dopamine transporter measures in aging are therefore likely unrelated to Alzheimer's disease but are aligned with white matter integrity and cardiovascular risk. More generally, these results suggest that two common imaging markers of the aging brain that are typically investigated separately do not reflect independent neurobiological processes.

Age-related changes in striatel function are potentially important for predicting declining memory performance over the adult life span. Here, we used fMRI to measure functional connectivity of caudate subfields with large-scale association networks and positron emission tomography to measure striatal dopamine transporter (DAT) density in 51 older adults (age 65-86 years) who received annual cognitive testing for up to 7 years (mean = 5.59, range 2-7 years). Analyses showed that cortical-caudate functional connectivity was less differentiated in older compared with younger adults (n = 63, age 18-32 years). Unlike in younger adults, the central lateral caudate was less strongly coupled with the frontal parietal control network in older adults. Older adults also showed less "decoupling" of the caudate from other networks, including areas of the default network (DN) and the hippocampal complex. Contrary to expectations, less decoupling between caudate and the DN was not associated with an age-related reduction of striatal DAT, suggesting that neurobiological changes in the cortex may drive dedifferentiation of cortical-caudate connectivity. Reduction of specificity in functional coupling between caudate and regions of the DN predicted memory decline over subsequent years at older ages. The age-related reduction in striatal DAT density also predicted memory decline, suggesting that a relation between striatal functions and memory decline in aging is multifaceted. Collectively, the study provides evidence highlighting the association of age-related differences in striatal function to memory decline in normal aging.

We assess the relationship of age-related losses in striatal D1 receptor densities to age-related reductions in functional connectivity between spatially distinct cortical regions in healthy human participants. Previous neuroimaging studies have reported age-related differences in functional connectivity of the frontoparietal working memory network and the default mode network during task performance. We used functional magnetic resonance imaging and seed-based connectivity (right dorsolateral and medial prefrontal cortex) to extend these findings: Anterior-posterior connectivity of both these functional networks was reduced in older (65-75 years, n = 18) compared with younger (20-30 years, n = 19) adults, whereas bilateral connectivity in prefrontal cortex was increased in older adults. Positron emission tomography with the D1 receptor ligand [(11)C]SCH23390 was used to assess caudate D1 receptor density in the same sample. Older adults showed significantly reduced caudate D1 receptor density compared to the younger adults. Of key interest, partial correlations showed that individual differences in caudate D1 receptor density were positively associated with individual differences in dorsolateral prefrontal connectivity to right parietal cortex (BA40) and negatively with medial prefrontal connectivity to right parietal cortex (BA40 and postcentral gyrus), after controlling for age. We found no correlation of caudate D1 receptor density with anterior-posterior coupling within the default mode network or with bilateral frontal connectivity. These results are consistent with animal work that has identified a role for caudate D1 receptors in mediating information transfer between prefrontal areas and parietal cortex.

Increased frontal bilaterality in old compared with young adults during cognitive performance is a common finding in human functional neuroimaging studies. Age-related reductions in laterality are a widely debated topic and their origins and consequences may be manifold. The current study demonstrates that a dopamine (DA) D1 antagonist induces increased frontal bilateral connectivity in healthy young adults revealed by functional magnetic resonance imaging during a spatial working memory task. Moreover, increases in functional connectivity between right and left prefrontal cortex during the pharmacological challenge were associated with maintaining performance on drug. To our knowledge, this is the first study to pharmacologically induce increased frontal bilateral functional connectivity during a cognitive task in young adults and to show that increased bilaterality is associated with less severe cognitive impairment under the influence of a DA receptor antagonist.

Age-related dopamine (DA) losses have been extensively demonstrated for the D2 receptor subtype. Comparatively little is known about adult age changes regarding D1 receptors. In this study, we demonstrate marked age-related D1 receptor losses in striatal, limbic, and cortical areas using positron emission tomography and the radioligand [(11)C]SCH23390 in humans. Interregional correlations of binding potential (BP) values were high for areas within DA pathways in younger and elderly adults alike. Furthermore, interregional correlations in D1 BP between DA pathways were uniformly high in younger adults, indicating that D1 receptor densities in striatal, limbic, and cortical areas are not regulated independently, despite dopaminergic innervation from different midbrain areas. For elderly adults, between-pathway correlations of D1 receptor densities were preserved only between mesolimbic and mesocortical areas, whereas striatal BPs were weakly related to those in limbic and neocortical regions. Importantly, weak between-pathway correlations in elderly adults were found only for the slower half of the sample when BP was estimated during a cognitive interference task. These results suggest that D1 receptor densities in different pathways are not regulated independently in younger adults, but segregate in older age, and that this segregation of D1 receptor systems may be related to age-related cognitive slowing.

Much of the extant work in the cognitive neurosciences of aging has focused on identifying the neural correlates of age-related declines in episodic memory and working memory. This chapter reviews evidence from human studies that speaks to the hypothesis that age-related dysfunctions in specific neurotransmitter systems play a critical role in cognitive decline. Based in large part on results from functional neuroimaging studies including positron emission tomography (PET) and pharmacological functional magnetic resonance imaging (fMRI), we conclude that there is emerging evidence that dysfunctions in the dopamine, noradrenaline, and cholinergic systems play a critical role in age- related cognitive decline of working memory and episodic memory. These conclusions are important and encourage further study in order to tailor interventions that preserve cognitive functions in older age via augmentation of neurotransmitter functions.

Working memory (WM) entails maintenance and manipulation of information in the absence of sensory input. This study investigated the trajectories and neural basis of these component processes of WM functions in aging. Longitudinal human functional magnetic resonance imaging (fMRI) data are presented from 136 older individuals (55–80 years) who were scanned at baseline and again 4 years later. We obtained evidence that age-related changes in parietal and frontal components of the WM core network are dissociable in terms of their role in maintenance of perceptual representations and further manipulation of this information, respectively. Individual difference analyses in performance subgroups showed that only prefrontal changes in fMRI activation were accompanied by changes in performance, but parietal brain activity was related to study dropout. We discuss the results in terms of possible neurobiological causes underlying separable aging-related declines in inferior parietal cortex and lateral prefrontal cortex that differentially affect WM functions.

Prior studies have identified white matter abnormalities in Alzheimer's disease (AD). Yet, cross-sectional studies in normal older individuals show little evidence for an association between markers of AD risk (APOE4 genotype and amyloid deposition), and white matter integrity. Here, 108 normal older adults (age, 66-87) with assessments of apolipoprotein e4 (APOE4) genotype and assessment of amyloid burden by positron emission tomography underwent diffusion tensor imaging scans for measuring white matter integrity at 2 time points, on average 2.6 years apart. Linear mixed-effects models showed that amyloid burden at baseline was associated with steeper decline in fractional anisotropy in the parahippocampal cingulum (p < 0.05). This association was not significant between baseline measures suggesting that longitudinal analyses can provide novel insights that are not detectable in cross-sectional designs. Amyloid-related changes in hippocampus volume did not explain the association between amyloid burden and change in fractional anisotropy. The results suggest that accumulation of cortical amyloid and white matter changes in parahippocampal cingulum are not independent processes in individuals at increased risk for AD.

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D_2/3 PET assessment using [¹¹C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D_2/3 receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.

Functional neuroimaging studies demonstrate age-related differences in recruitment of a large-scale attentional network during interference resolution, especially within dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). These alterations in functional responses have been frequently observed despite equivalent task performance, suggesting age-related reallocation of neural resources, although direct evidence for a facilitating effect in aging is sparse. We used the multi-source interference task and multivariate partial-least-squares to investigate age-related differences in the neuronal signature of conflict resolution, and their behavioral implications in younger and older adults. There were interference-related increases in activity, involving fronto-parietal and basal ganglia networks that generalized across age. In addition an age-by-task interaction was observed within a distributed network, including DLPFC and ACC, with greater activity during interference in the old. Next, we combined brain-behavior and functional connectivity analyses to investigate whether compensatory brain changes were present in older adults, using DLPFC and ACC as regions of interest (i.e. seed regions). This analysis revealed two networks differentially related to performance across age groups. A structural analysis revealed age-related gray-matter losses in regions facilitating performance in the young, suggesting that functional reorganization may partly reflect structural alterations in aging. Collectively, these findings suggest that age-related structural changes contribute to reductions in the efficient recruitment of a youth-like interference network, which cascades into instantiation of a different network facilitating conflict resolution in elderly people.

Individuals differ in how they perceive, remember, and think. There is evidence for the existence of distinct subgroups that differ in cognitive performance within the older population. However, it is less clear how individual differences in cognition in old age are linked to differences in brain-based measures. We used latent-profile analysis on n-back working-memory (WM) performance to identify subgroups in a large sample of older adults (n = 181; age = 64-68 years). Our analysis identified one larger normal subgroup with higher performance (n = 113; 63%), and a second smaller subgroup (n = 55; 31%) with lower performance. The low-performing subgroup showed weaker load-dependent BOLD modulation and lower connectivity within the fronto-parietal network (FPN) as well as between FPN and striatum during n-back, along with lower FPN connectivity at rest. This group also exhibited lower FPN structural integrity, lower frontal dopamine D2 binding potential, inferior performance on offline WM tests, and a trend-level genetic predisposition for lower dopamine-system efficiency. By contrast, this group exhibited relatively intact episodic memory and associated brain measures (i.e., hippocampal volume, structural, and functional connectivity within the default-mode network). Collectively, these data provide converging evidence for the existence of a group of older adults with impaired WM functioning characterized by reduced cortico-striatal coupling and aberrant cortico-cortical integrity within FPN.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

Neuroimaging datasets keep growing in size to address increasingly complex medical questions. However, even the largest datasets today alone are too small for training complex machine learning models. A potential solution is to increase sample size by pooling scans from several datasets. In this work, we combine 12,207 MRI scans from 15 studies and show that simple pooling is often ill-advised due to introducing various types of biases in the training data. First, we systematically define these biases. Second, we detect bias by experimentally showing that scans can be correctly assigned to their respective dataset with 73.3% accuracy. Finally, we propose to tell causal from confounding factors by quantifying the extent of confounding and causality in a single dataset using causal inference. We achieve this by finding the simplest graphical model in terms of Kolmogorov complexity. As Kolmogorov complexity is not directly computable, we employ the minimum description length to approximate it. We empirically show that our approach is able to estimate plausible causal relationships from real neuroimaging data.

BACKGROUND: Contralateral brain structures represent a unique, within-patient reference element for disease, and asymmetries can provide a personalized measure of the accumulation of past disease processes. Neuroanatomical shape asymmetries have recently been associated with the progression of Alzheimer's disease (AD), but the biological basis of asymmetric brain changes in AD remains unknown.

METHODS: We investigated genetic influences on brain asymmetry by identifying associations between magnetic resonance imaging-derived measures of asymmetry and candidate single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for AD diagnosis and for brain subcortical volumes. For analyzing longitudinal neuroimaging data (1241 individuals, 6395 scans), we used a mixed effects model with interaction between genotype and diagnosis.

RESULTS: Significant associations between asymmetry of the amygdala, hippocampus, and putamen and SNPs in the genes BIN1, CD2AP, ZCWPW1, ABCA7, TNKS, and DLG2 were found.

CONCLUSIONS: The associations between SNPs in the genes TNKS and DLG2 and AD-related increases in shape asymmetry are of particular interest; these SNPs have previously been associated with subcortical volumes of amygdala and putamen but have not yet been associated with AD pathology. For AD candidate SNPs, we extend previous work to show that their effects on subcortical brain structures are asymmetric. This provides novel evidence about the biological underpinnings of brain asymmetry as a disease marker.

The desire to train complex machine learning algorithms and to increase the statistical power in association studies drives neuroimaging research to use ever-larger datasets. The most obvious way to increase sample size is by pooling scans from independent studies. However, simple pooling is often ill-advised as selection, measurement, and confounding biases may creep in and yield spurious correlations. In this work, we combine 35,320 magnetic resonance images of the brain from 17 studies to examine bias in neuroimaging. In the first experiment, Name That Dataset, we provide empirical evidence for the presence of bias by showing that scans can be correctly assigned to their respective dataset with 71.5% accuracy. Given such evidence, we take a closer look at confounding bias, which is often viewed as the main shortcoming in observational studies. In practice, we neither know all potential confounders nor do we have data on them. Hence, we model confounders as unknown, latent variables. Kolmogorov complexity is then used to decide whether the confounded or the causal model provides the simplest factorization of the graphical model. Finally, we present methods for dataset harmonization and study their ability to remove bias in imaging features. In particular, we propose an extension of the recently introduced ComBat algorithm to control for global variation across image features, inspired by adjusting for unknown population stratification in genetics. Our results demonstrate that harmonization can reduce dataset-specific information in image features. Further, confounding bias can be reduced and even turned into a causal relationship. However, harmonization also requires caution as it can easily remove relevant subject-specific information. Code is available at https://github.com/aimed/Dataset-Bias. (C) 2020 Elsevier B.V. All rights reserved.

Clinically normal aging and pathological processes cause structural changes in the brain. These changes likely occur in overlapping regions that accommodate neural systems with high susceptibility to deleterious factors. Due to the overlap, the separation between aging and pathological processes is challenging when analyzing brain structures independently. We propose to identify multivariate latent processes that govern cross-sectional and longitudinal neuroanatomical changes across the brain in aging and dementia. A discriminative representation of neuroanatomy is obtained from spectral shape descriptors in the BrainPrint. We identify latent factors by maximizing the covariance between morphological change and response variables of age and a proxy for dementia. Our results reveal cross-sectional and longitudinal patterns of change inneuroanatomy that distinguishes aging processes from disease processes. Finally, latent processes do not only yield a parsimonious model but also a significantly improved prediction accuracy.