The potential of blood neurofilament light as a marker of neurodegeneration for Alzheimer's disease.

Over the past several years, there has been a surge in blood biomarker studies examining the value of plasma or serum neurofilament light (NfL) as a biomarker of neurodegeneration for Alzheimer's disease. However, there have been limited efforts to combine existing findings to assess the utility of blood NfL as a biomarker of neurodegeneration for Alzheimer's disease. In addition, we still need better insight into the specific aspects of neurodegeneration that are reflected by the elevated plasma or serum concentration of NfL. In this review, we survey the literature on the cross-sectional and longitudinal relationships between blood-based NfL levels and other, neuroimaging-based, indices of neurodegeneration in individuals on the Alzheimer's continuum. Then, based on the biomarker classification established by the FDA-NIH Biomarker Working group, we determine the utility of blood-based NfL as a marker for monitoring the disease status (i.e. monitoring biomarker) and predicting the severity of neurodegeneration in older adults with and without cognitive decline (i.e. a prognostic or a risk/susceptibility biomarker). The current findings suggest that blood NfL exhibits great promise as a monitoring biomarker because an increased NfL level in plasma or serum appears to reflect the current severity of atrophy, hypometabolism and the decline of white matter integrity, particularly in the brain regions typically affected by Alzheimer's disease. Longitudinal evidence indicates that blood NfL can be useful not only as a prognostic biomarker for predicting the progression of neurodegeneration in patients with Alzheimer's disease but also as a susceptibility/risk biomarker predicting the likelihood of abnormal alterations in brain structure and function in cognitively unimpaired individuals with a higher risk of developing Alzheimer's disease (e.g. those with a higher amyloid-ß). There are still limitations to current research, as discussed in this review. Nevertheless, the extant literature strongly suggests that blood NfL can serve as a valuable prognostic and susceptibility biomarker for Alzheimer's disease-related neurodegeneration in clinical settings, as well as in research settings.

Cognitive and Affective Empathy as Indirect Paths Between Heterogeneous Depression Symptoms on Default Mode and Salience Network Connectivity in Adolescents.

Depression amongst adolescents is a prevalent disorder consisting of heterogeneous emotional and functional symptoms-often involving impairments in social domains such as empathy. Cognitive and affective components of empathy as well as their associated neural networks (default mode network for cognitive empathy and salience network for affective empathy) are affected by depression. Depression commonly onsets during adolescence, a critical period for brain development underlying empathy. However, the available research in this area conceptualizes depression as a homogenous construct, and thereby miss to represent the full spectrum of symptoms. The present study aims to extend previous literature by testing whether cognitive and affective empathy indirectly account for associations between brain network connectivity and heterogeneous depression symptoms in adolescents. Heterogeneous functional and emotional symptoms of depression were measured using the child depression inventory. Our results indicate that cognitive empathy mediates the association between default mode network functional connectivity and emotional symptoms of depression. More specifically, that adolescents with a stronger positive association between the default mode network and cognitive empathy show lower emotional depression symptoms. This finding highlights the importance of cognitive empathy in the relationship between brain function and depression symptoms, which may be an important consideration for existing models of depression in adolescents.

Subjective cognitive decline predicts lower cingulo-opercular network functional connectivity in individuals with lower neurite density in the forceps minor.

Cognitive complaints of attention/concentration problems are highly frequent in older adults with subjective cognitive decline (SCD). Functional connectivity in the cingulo-opercular network (CON-FC) supports cognitive control, tonic alertness, and visual processing speed. Thus, those complaints in SCD may reflect a decrease in CON-FC. Frontal white-matter tracts such as the forceps minor exhibit age- and SCD-related alterations and, therefore, might influence the CON-FC decrease in SCD. Here, we aimed to determine whether SCD predicts an impairment in CON-FC and whether neurite density in the forceps minor modulates that effect. To do so, we integrated cross-sectional and longitudinal analyses of multimodal data in a latent growth curve modeling approach. Sixty-nine healthy older adults (13 males; 68.33 ± 7.95 years old) underwent resting-state functional and diffusion-weighted magnetic resonance imaging, and the degree of SCD was assessed at baseline with the memory functioning questionnaire (greater score indicating more SCD). Forty-nine of the participants were further enrolled in two follow-ups, each about 18 months apart. Baseline SCD did not predict CON-FC after three years or its rate of change (p-values > 0.092). Notably, however, the forceps minor neurite density did modulate the relation between SCD and CON-FC (intercept; b = 0.21, 95% confidence interval, CI, [0.03, 0.39], p = 0.021), so that SCD predicted a greater CON-FC decrease in older adults with relatively lower neurite density in the forceps minor. The neurite density of the forceps minor, in turn, negatively correlated with age. These results suggest that CON-FC alterations in SCD are dependent upon the forceps minor neurite density. Accordingly, these results imply modifiable age-related factors that could help delay or mitigate both age and SCD-related effects on brain connectivity.

What have we really learned from functional connectivity in clinical populations?

Functional connectivity (FC), or the statistical interdependence of blood-oxygen dependent level (BOLD) signals between brain regions using fMRI, has emerged as a widely used tool for probing functional abnormalities in clinical populations due to the promise of the approach across conceptual, technical, and practical levels. With an already vast and steadily accumulating neuroimaging literature on neurodevelopmental, psychiatric, and neurological diseases and disorders in which FC is a primary measure, we aim here to provide a high-level synthesis of major concepts that have arisen from FC findings in a manner that cuts across different clinical conditions and sheds light on overarching principles. We highlight that FC has allowed us to discover the ubiquity of intrinsic functional networks across virtually all brains and clarify typical patterns of neurodevelopment over the lifespan. This understanding of typical FC maturation with age has provided important benchmarks against which to evaluate divergent maturation in early life and degeneration in late life. This in turn has led to the important insight that many clinical conditions are associated with complex, distributed, network-level changes in the brain, as opposed to solely focal abnormalities. We further emphasize the important role that FC studies have played in supporting a dimensional approach to studying transdiagnostic clinical symptoms and in enhancing the multimodal characterization and prediction of the trajectory of symptom progression across conditions. We highlight the unprecedented opportunity offered by FC to probe functional abnormalities in clinical conditions where brain function could not be easily studied otherwise, such as in disorders of consciousness. Lastly, we suggest high priority areas for future research and acknowledge critical barriers associated with the use of FC methods, particularly those related to artifact removal, data denoising and feasibility in clinical contexts.

Aberrant memory system connectivity and working memory performance in subjective cognitive decline.

Subjective cognitive decline, a perceived worsening of cognitive functioning without objective deficit on assessment, could indicate incipient dementia. However, the neural correlates of subjective cognitive decline as assessed by magnetic resonance imaging remain somewhat unclear. Here, we evaluated differences in functional connectivity across memory regions, and cognitive performance, between healthy older adults aged 50 to 85 with (n = 35, Age = 68.5 ±â€¯7.7, 22 female), and without (n = 48, Age = 67.0 ±â€¯8.8, 29 female) subjective cognitive decline. We also evaluated neurite density, fractional anisotropy, and mean diffusivity of the parahippocampal cingulum, cingulate gyrus cingulum, and uncinate fiber bundles in a subsample of participants (n = 37). Participants with subjective cognitive decline displayed lower average functional connectivity across regions of a putative posterior memory system, and lower retrosplenial-precuneus functional connectivity specifically, than those without memory complaints. Furthermore, participants with subjective cognitive decline performed poorer than controls on visual working memory. However, groups did not differ in cingulum or uncinate diffusion measures. Our results show differences in functional connectivity and visual working memory in participants with subjective cognitive decline that could indicate potential incipient dementia.

Response Hand and Motor Set Differentially Modulate the Connectivity of Brain Pathways During Simple Uni-manual Motor Behavior.

We investigated the flexible modulation of undirected functional connectivity (uFC) of brain pathways during simple uni-manual responding. Two questions were central to our interests: (1) does response hand (dominant vs. non-dominant) differentially modulate connectivity and (2) are these effects related to responding under varying motor sets. fMRI data were acquired in twenty right-handed volunteers who responded with their right (dominant) or left (non-dominant) hand (blocked across acquisitions). Within acquisitions, the task oscillated between periodic responses (promoting the emergence of motor sets) or randomly induced responses (disrupting the emergence of motor sets). Conjunction analyses revealed eight shared nodes across response hand and condition, time series from which were analyzed. For right hand responses connectivity of the M1 ←→ Thalamus and SMA ←→ Parietal pathways was more significantly modulated during periodic responding. By comparison, for left hand responses, connectivity between five network pairs (including M1 and SMA, insula, basal ganglia, premotor cortex, parietal cortex, thalamus) was more significantly modulated during random responding. uFC analyses were complemented by directed FC based on multivariate autoregressive models of times series from the nodes. These results were complementary and highlighted significant modulation of dFC for SMA → Thalamus, SMA → M1, basal ganglia → Insula and basal ganglia → Thalamus. The results demonstrate complex effects of motor organization and task demand and response hand on different connectivity classes of fMRI data. The brain's sub-networks are flexibly modulated by factors related to motor organization and/or task demand, and our results have implications for assessment of medical conditions associated with motor dysfunction.

Effects of aging on functional and structural brain connectivity.

Over the past decade there has been an enormous rise in the application of functional and structural connectivity approaches to explore the brain's intrinsic organization in healthy and clinical populations. The notion underlying the application of these approaches to study aging is that subtle age-related disruption of the brain's regional integrity and information flow across the brain, are expressed by age-related differences in functional and structural connectivity. In this review I will discus recent advances in our understanding of how age affects our brain's intrinsic organization, and I will share my perspective on potential challenges and future directions of the field.

Differential effect of age on posterior and anterior hippocampal functional connectivity.

Aging is associated with declines in cognitive performance and multiple changes in the brain, including reduced default mode functional connectivity (FC). However, conflicting results have been reported regarding age differences in FC between hippocampal and default mode regions. This discrepancy may stem from the variation in selection of hippocampal regions. We therefore examined the effect of age on resting state FC of anterior and posterior hippocampal regions in an adult life-span sample. Advanced age was associated with lower FC between the posterior hippocampus and three regions: the posterior cingulate cortex, medial prefrontal cortex, and lateral parietal cortex. In addition, age-related reductions of FC between the left and right posterior hippocampus, and bilaterally along the posterior to anterior hippocampal axis were noted. Age differences in medial prefrontal and inter-hemispheric FC significantly differed between anterior and posterior hippocampus. Older age was associated with lower performance in all cognitive domains, but we observed no associations between FC and cognitive performance after controlling for age. We observed a significant effect of gender and a linear effect of COMT val158met polymorphism on hippocampal FC. Females showed higher FC of anterior and posterior hippocampus and medial prefrontal cortex than males, and the dose of val allele was associated with lower posterior hippocampus - posterior cingulate FC, independent of age. Vascular and metabolic factors showed no significant effects on FC. These results suggest differential age-related reduction in the posterior hippocampal FC compared to the anterior hippocampus, and an age-independent effect of gender and COMT on hippocampal FC.

Salience Network Functional Connectivity Mediates Association Between Social Engagement and Cognition in Non-Demented Older Adults: Exploratory Investigation.

Background: Social engagement has beneficial effects during cognitive aging. Large-scale cognitive brain network functions are implicated in both social behaviors and cognition. Objective: We evaluated associations between functional connectivity (FC) of large-scale brain cognitive networks and social engagement, characterized by self-reported social network size and contact frequency. We subsequently tested large-scale brain network FC as a potential mediator of the beneficial relationship between social engagement and cognitive performance. Methods: 112 older adults (70.7±7.3 years, range 54.6-89.7; 84 women) completed the Lubben Social Network Scale 6 (LSNS-6), National Alzheimer's Coordinating Center (NACC) Uniform Data Set 3 (UDS-3) cognitive battery, and resting state fMRI. We completed seed-based correlational analysis in the default mode and salience networks. Significant associations between social engagement scores and cognitive performance, as well as between social engagement and FC of brain networks, informed the construction of mediation models. Results: Social engagement was significantly associated with executive function and global cognition, with greater social engagement associated with better cognitive performance. Social engagement was significantly associated with salience network FC, with greater social engagement associated with higher connectivity. Salience network FC partially mediated associations between social engagement and both executive function and global cognition. Conclusions: Our results suggest that the salience network is a key mediator of the beneficial relationship between social engagement and cognition in older adults.

Fornix fractional anisotropy mediates the association between Mediterranean diet adherence and memory four years later in older adults without dementia.

Here, we investigated whether fractional anisotropy (FA) of hippocampus-relevant white-matter tracts mediates the association between baseline Mediterranean diet adherence (MeDiAd) and verbal episodic memory over four years. Participants were healthy older adults with and without subjective cognitive decline and patients with amnestic mild cognitive impairment from the DELCODE cohort study (n = 376; age: 71.47 ± 6.09 years; 48.7 % female). MeDiAd and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The associations between baseline MeDiAd and white matter, and verbal episodic memory's mean and rate of change over four years were tested with latent growth curve modeling. Baseline MeDiAd was associated with verbal episodic memory four years later (95 % confidence interval, CI [0.01, 0.32]) but not with its rate of change over this period. Baseline Fornix FA mediated - and, thus, explained - that association (95 % CI [0.002, 0.09]). Fornix FA may be an appropriate response biomarker of Mediterranean diet interventions on verbal memory in older adults.

Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels.

We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared with ε3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared with either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.

Yoga, aerobic and stretching exercise effects on neurocognition: Randomized controlled trial protocol.

As the global population ages, the prevalence of cognitive decline and dementia is expected to rise, creating a significant health and economic burden. The purpose of this trial is to rigorously test, for the first time, the efficacy of yoga training as a physical activity intervention to mitigate age-related cognitive decline and impairment. We are conducting a 6-month randomized controlled trial (RCT) of exercise among 168 middle aged and older adults to compare the efficacy of yoga vs. aerobic exercise on cognitive function, brain structure and function, cardiorespiratory fitness, and circulating inflammatory and molecular markers. Using a single-blind, three arm RCT, 168 older adults ages 55-79 will be assigned to either: a Hatha yoga group, an aerobic exercise group or a stretching-toning active control group. Participants will engage in hour long group exercise 3x/week for 6-months. A comprehensive neurocognitive test battery, brain imaging, cardiovascular fitness test, and a blood draw will take place at baseline; end of the 6-month intervention, and at 12-month follow-up. Our primary outcomes of interest are brain regions, such as hippocampal volume and prefrontal cortex, and cognitive functions, such as episodic memory, working memory and executive functions, that are typically affected by aging and Alzheimer's disease. Not only will this RCT test whether yoga is a means to mitigate age-related cognitive decline, but it may also offer an alternative to aerobic exercise, which could be particularly appealing to older adults with compromised physical functioning. ClinicalTrials.gov Identifier: NCT04323163.

Controversies and progress on standardization of large-scale brain network nomenclature.

Progress in scientific disciplines is accompanied by standardization of terminology. Network neuroscience, at the level of macroscale organization of the brain, is beginning to confront the challenges associated with developing a taxonomy of its fundamental explanatory constructs. The Workgroup for HArmonized Taxonomy of NETworks (WHATNET) was formed in 2020 as an Organization for Human Brain Mapping (OHBM)-endorsed best practices committee to provide recommendations on points of consensus, identify open questions, and highlight areas of ongoing debate in the service of moving the field toward standardized reporting of network neuroscience results. The committee conducted a survey to catalog current practices in large-scale brain network nomenclature. A few well-known network names (e.g., default mode network) dominated responses to the survey, and a number of illuminating points of disagreement emerged. We summarize survey results and provide initial considerations and recommendations from the workgroup. This perspective piece includes a selective review of challenges to this enterprise, including (1) network scale, resolution, and hierarchies; (2) interindividual variability of networks; (3) dynamics and nonstationarity of networks; (4) consideration of network affiliations of subcortical structures; and (5) consideration of multimodal information. We close with minimal reporting guidelines for the cognitive and network neuroscience communities to adopt.

Lifespan differences in background functional connectivity of core cognitive large-scale brain networks.

Large-scale brain networks undergo functional reorganization over the course of the lifespan, with concurrent implications for cognition. Characterizing network connectivity during a task may provide complementary insight into cognitive development and aging, to that provided by resting-state. We assessed network background connectivity, which refers to connectivity that remains after task effects have been regressed out, during a visual memory-encoding task in a lifespan sample. More specifically we assessed the within- and between-network background connectivity of the default mode, salience, and frontoparietal networks. Within-network background connectivity of salience and frontoparietal networks differed between age groups, with late-life adults showing lower connectivity. We did not find an effect of age group in default mode network background connectivity, contrary to previous findings using resting-state. However, default mode between-network background connectivity with salience and frontoparietal networks was greater in mid-life and late-life adults than in younger age groups. Overall, our findings in a lifespan sample are in line with previous observations of age-related network de-differentiation. However, the lack of age effect in default mode network background connectivity suggests that background connectivity indeed represents a complementary measure to resting-state connectivity, providing a differential glance of network connectivity during a particular state.

Lower-Resolution Retrieval of Scenes in Older Adults With Subjective Cognitive Decline.

OBJECTIVE: Scenes with more perceptual detail can help detect subtle memory deficits more than scenes with less detail. Here, we investigated whether older adults with subjective cognitive decline (SCD) show less brain activation and more memory deficits to scenes with more (vs. scenes with less) perceptual detail compared to controls (CON). METHOD: In 37 healthy older adults (SCD: 16), we measured blood oxygenation level-dependent-functional magnetic resonance imaging during encoding and behavioral performance during retrieval. RESULTS: During encoding, higher activation to scenes with more (vs. less) perceptual detail in the parahippocampal place area predicted better memory performance in SCD and CON. During retrieval, superior performance for new scenes with more (vs. less) perceptual detail was significantly more pronounced in CON than inSCD. CONCLUSIONS: Together, these results suggest a present, but attenuated benefit from perceptual detail for memory retrieval in SCD. Memory complaints in SCD might, thus, refer to a decreased availability of perceptual detail of previously encoded stimuli.

Sex-specific effects of prenatal undernutrition on resting-state functional connectivity in the human brain at age 68.

Prenatal nutrition may significantly impact brain aging. Results from the Dutch Famine Birth Cohort indicated that prenatal undernutrition is negatively associated with cognition, brain volumes, perfusion and structural brain aging in late life, predominantly in men. This study investigates the association between prenatal undernutrition and late-life functional brain network connectivity. In an exploratory resting-state functional magnetic resonance imaging study of 112 participants from the Dutch Famine Birth Cohort, we investigated whether the within- and between-network functional connectivity of the default mode network, salience network and central executive network differ at age 68 in men (N = 49) and women (N = 63) either exposed or unexposed to undernutrition in early gestation. Additionally, we explored sex-specific effects. Compared to unexposed participants, exposed participants revealed multiple clusters of different functional connectivity within and between the three networks studied. Sex-specific analyses suggested a pattern of network desegregation fitting with brain aging in men and a more diffuse pattern of group differences in women. This study demonstrates that associations between prenatal undernutrition and brain network functional connectivity extend late into life.

Predicting future cognitive decline from non-brain and multimodal brain imaging data in healthy and pathological aging.

Previous literature has focused on predicting a diagnostic label from structural brain imaging. Since subtle changes in the brain precede a cognitive decline in healthy and pathological aging, our study predicts future decline as a continuous trajectory instead. Here, we tested whether baseline multimodal neuroimaging data improve the prediction of future cognitive decline in healthy and pathological aging. Nonbrain data (demographics, clinical, and neuropsychological scores), structural MRI, and functional connectivity data from OASIS-3 (N = 662; age = 46-96 years) were entered into cross-validated multitarget random forest models to predict future cognitive decline (measured by CDR and MMSE), on average 5.8 years into the future. The analysis was preregistered, and all analysis code is publicly available. Combining non-brain with structural data improved the continuous prediction of future cognitive decline (best test-set performance: R2 = 0.42). Cognitive performance, daily functioning, and subcortical volume drove the performance of our model. Including functional connectivity did not improve predictive accuracy. In the future, the prognosis of age-related cognitive decline may enable earlier and more effective individualized cognitive, pharmacological, and behavioral interventions.

Longitudinal change in hippocampal and dorsal anterior insulae functional connectivity in subjective cognitive decline.

BACKGROUND: Subjective cognitive decline, perceived worsening of cognitive ability without apparent performance issues on clinical assessment, may be an important precursor to dementia. While previous cross-sectional research has demonstrated aberrant brain functional connectivity in subjective cognitive decline, longitudinal evaluation remains limited. METHODS: Here, we examined trajectories of functional connectivity over three measurement occasions ~18 months apart, using voxelwise latent growth models in cognitively unimpaired older adults with varying self-report of subjective cognitive decline (N = 69). RESULTS: We found that individuals who reported a greater degree of subjective cognitive decline showed a larger subsequent decrease in connectivity between components of the default mode network and increase in connectivity between salience and default mode network components. The change in functional connectivity was observed in the absence of change in cognitive performance. CONCLUSION: The results indicate that functional brain changes may underly the experience of cognitive decline before deterioration reaches a level detected by formal cognitive assessment.

Age moderation of the association between negative subsequent memory effects and episodic memory performance.

Negative subsequent memory effects in functional MRI studies of memory formation have been linked to individual differences in memory performance, yet the effect of age on this association is currently unclear. To provide insight into the brain systems related to memory across the lifespan, we examined functional neuroimaging data acquired during episodic memory formation and behavioral performance from a memory recognition task in a sample of 109 participants, including three developmental age groups (8-12, 13-17, 18-25 year-olds) and one additional group of older adults (55-85 year-olds). Young adults showed the highest memory performance and strongest negative subsequent memory effects, while older adults showed reduced negative subsequent memory effects relative to young adults. Across the sample, negative subsequent memory effects were associated with better memory performance, and there was a significant interaction between negative subsequent memory effects and memory performance by age group. Posthoc analyses revealed that this moderation effect was driven by a stronger association between negative subsequent memory effects and memory performance in young adults than children, and that neither children nor older adults showed a significant association. These findings suggest that negative subsequent memory effects may differentially support memory performance across a lifespan trajectory characterized by developmental maturation and support further investigation of this effect in aging.

Network functional connectivity underlying dissociable cognitive and affective components of empathy in adolescence.

Empathy, the capacity to understand and share others' emotions, can occur through cognitive and affective components. These components are different conceptually, behaviorally, and in the brain. Neuroimaging task-based research in adolescents and adults document that cognitive empathy associates with the default mode and frontoparietal networks, whereas regions of the salience network underlie affective empathy. However, cognitive empathy is slower to mature than affective empathy and the extant literature reveals considerable developmental differences between adolescent and adult brains within and between these three networks. We extend previous work by examining empathy's association with functional connectivity within and between these networks in adolescents. Participants (n = 84, aged 13-17; 46.4% female) underwent resting state fMRI and completed self-report measures (Interpersonal Reactivity Index) for empathy as part of a larger Nathan-Kline Institute study. Regression analyses revealed adolescents reporting higher cognitive empathy had higher within DMN connectivity. Post hoc analysis revealed cognitive empathy's association within DMN connectivity is independent of affective empathy or empathy in general; and this association is driven by positive pairwise connections between the bilateral angular gyri and medial prefrontal cortex. These results suggest introspective cognitive processes related to the DMN are specifically important for cognitive empathy in adolescence.