Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.

A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.

Cholinergic white matter pathways along the Alzheimer's disease continuum.

Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.

Vessel distance mapping: A novel methodology for assessing vascular-induced cognitive resilience.

The association between cerebral blood supply and cognition has been widely discussed in the recent literature. One focus of this discussion has been the anatomical variability of the circle of Willis, with morphological differences being present in more than half of the general population. While previous studies have attempted to classify these differences and explore their contribution to hippocampal blood supply and cognition, results have been controversial. To disentangle these previously inconsistent findings, we introduce Vessel Distance Mapping (VDM) as a novel methodology for evaluating blood supply, which allows for obtaining vessel pattern metrics with respect to the surrounding structures, extending the previously established binary classification into a continuous spectrum. To accomplish this, we manually segmented hippocampal vessels obtained from high-resolution 7T time-of-flight MR angiographic imaging in older adults with and without cerebral small vessel disease, generating vessel distance maps by computing the distances of each voxel to its nearest vessel. Greater values of VDM-metrics, which reflected higher vessel distances, were associated with poorer cognitive outcomes in subjects affected by vascular pathology, while this relation was not observed in healthy controls. Therefore, a mixed contribution of vessel pattern and vessel density is proposed to confer cognitive resilience, consistent with previous research findings. In conclusion, VDM provides a novel platform, based on a statistically robust and quantitative method of vascular mapping, for addressing a variety of clinical research questions.

The relationship between resting-state amplitude fluctuations and memory-related deactivations of the default mode network in young and older adults.

The default mode network (DMN) typically exhibits deactivations during demanding tasks compared to periods of relative rest. In functional magnetic resonance imaging (fMRI) studies of episodic memory encoding, increased activity in DMN regions even predicts later forgetting in young healthy adults. This association is attenuated in older adults and, in some instances, increased DMN activity even predicts remembering rather than forgetting. It is yet unclear whether this phenomenon is due to a compensatory mechanism, such as self-referential or schema-dependent encoding, or whether it reflects overall reduced DMN activity modulation in older age. We approached this question by systematically comparing DMN activity during successful encoding and tonic, task-independent, DMN activity at rest in a sample of 106 young (18-35 years) and 111 older (60-80 years) healthy participants. Using voxel-wise multimodal analyses, we assessed the age-dependent relationship between DMN resting-state amplitude (mean percent amplitude of fluctuation, mPerAF) and DMN fMRI signals related to successful memory encoding, as well as their modulation by age-related hippocampal volume loss, while controlling for regional grey matter volume. Older adults showed lower resting-state DMN amplitudes and lower task-related deactivations. However, a negative relationship between resting-state mPerAF and subsequent memory effect within the precuneus was observed only in young, but not older adults. Hippocampal volumes showed no relationship with the DMN subsequent memory effect or mPerAF. Lastly, older adults with higher mPerAF in the DMN at rest tend to show higher memory performance, pointing towards the importance of a maintained ability to modulate DMN activity in old age.

Single-value scores of memory-related brain activity reflect dissociable neuropsychological and anatomical signatures of neurocognitive aging.

Memory-related functional magnetic resonance imaging (fMRI) activations show age-related differences across multiple brain regions that can be captured in summary statistics like single-value scores. Recently, we described two single-value scores reflecting deviations from prototypical whole-brain fMRI activity of young adults during novelty processing and successful encoding. Here, we investigate the brain-behavior associations of these scores with age-related neurocognitive changes in 153 healthy middle-aged and older adults. All scores were associated with episodic recall performance. The memory network scores, but not the novelty network scores, additionally correlated with medial temporal gray matter and other neuropsychological measures including flexibility. Our results thus suggest that novelty-network-based fMRI scores show high brain-behavior associations with episodic memory and that encoding-network-based fMRI scores additionally capture individual differences in other aging-related functions. More generally, our results suggest that single-value scores of memory-related fMRI provide a comprehensive measure of individual differences in network dysfunction that may contribute to age-related cognitive decline.

Plasma concentrations of anti-inflammatory cytokine TGF-ß are associated with hippocampal structure related to explicit memory performance in older adults.

Human cognitive abilities, and particularly hippocampus-dependent memory performance typically decline with increasing age. Immunosenescence, the age-related disintegration of the immune system, is increasingly coming into the focus of research as a considerable factor contributing to cognitive decline. In the present study, we investigated potential associations between plasma levels of pro- and anti-inflammatory cytokines and learning and memory performance as well as hippocampal anatomy in young and older adults. Plasma concentrations of the inflammation marker CRP as well as the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine TGF-ß1 were measured in 142 healthy adults (57 young, 24.47 ± 4.48 years; 85 older, 63.66 ± 7.32 years) who performed tests of explicit memory (Verbal Learning and Memory Test, VLMT; Wechsler Memory Scale, Logical Memory, WMS) with an additional delayed recall test after 24 h. Hippocampal volumetry and hippocampal subfield segmentation were performed using FreeSurfer, based on T1-weighted and high-resolution T2-weighted MR images. When investigating the relationship between memory performance, hippocampal structure, and plasma cytokine levels, we found that TGF-ß1 concentrations were positively correlated with the volumes of the hippocampal CA4-dentate gyrus region in older adults. These volumes were in turn positively associated with better performance in the WMS, particularly in the delayed memory test. Our results support the notion that endogenous anti-inflammatory mechanisms may act as protective factors in neurocognitive aging.

Amyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction.

We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A-) of amyloid pathology was defined by CSF amyloid-ß42 (Aß42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A- individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aß42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aß42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A- groups. After classifying this matched sample for phospho-tau pathology (T-/T+), individuals with A+/T+ were significantly more memory-impaired than A-/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer's disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer's disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.

Subjective cognitive decline and stage 2 of Alzheimer disease in patients from memory centers.

INTRODUCTION: It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum. METHODS: Cross-sectional and longitudinal data from the multicenter, memory clinic-based DELCODE study. RESULTS: The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD-A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO-A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group. DISCUSSION: Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD-A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression.

Quantitative evaluation of prospective motion correction in healthy subjects at 7T MRI.

PURPOSE: Quantitative assessment of prospective motion correction (PMC) capability at 7T MRI for compliant healthy subjects to improve high-resolution images in the absence of intentional motion. METHODS: Twenty-one healthy subjects were imaged at 7 T. They were asked not to move, to consider only unintentional motion. An in-bore optical tracking system was used to monitor head motion and consequently update the imaging volume. For all subjects, high-resolution T1 (3D-MPRAGE), T2 (2D turbo spin echo), proton density (2D turbo spin echo), and T2∗ (2D gradient echo) weighted images were acquired with and without PMC. The images were evaluated through subjective and objective analysis. RESULTS: Subjective evaluation overall has shown a statistically significant improvement (5.5%) in terms of image quality with PMC ON. In a separate evaluation of every contrast, three of the four contrasts (T1 , T2 , and proton density) have shown a statistically significant improvement (9.62%, 9.85%, and 9.26%), whereas the fourth one ( T2∗ ) has shown improvement, although not statistically significant. In the evaluation with objective metrics, average edge strength has shown an overall improvement of 6% with PMC ON, which was statistically significant; and gradient entropy has shown an overall improvement of 2%, which did not reach statistical significance. CONCLUSION: Based on subjective assessment, PMC improved image quality in high-resolution images of healthy compliant subjects in the absence of intentional motion for all contrasts except T2∗ , in which no significant differences were observed. Quantitative metrics showed an overall trend for an improvement with PMC, but not all differences were significant.

Resting-State Network Alterations Differ between Alzheimer's Disease Atrophy Subtypes.

Several Alzheimer's disease (AD) atrophy subtypes were identified, but their brain network properties are unclear. We analyzed data from two independent datasets, including 166 participants (103 AD/63 controls) from the DZNE-longitudinal cognitive impairment and dementia study and 151 participants (121 AD/30 controls) from the AD neuroimaging initiative cohorts, aiming to identify differences between AD atrophy subtypes in resting-state functional magnetic resonance imaging intra-network connectivity (INC) and global and nodal network properties. Using a data-driven clustering approach, we identified four AD atrophy subtypes with differences in functional connectivity, accompanied by clinical and biomarker alterations, including a medio-temporal-predominant (S-MT), a limbic-predominant (S-L), a diffuse (S-D), and a mild-atrophy (S-MA) subtype. S-MT and S-D showed INC reduction in the default mode, dorsal attention, visual and limbic network, and a pronounced reduction of "global efficiency" and decrease of the "clustering coefficient" in parietal and temporal lobes. Despite severe atrophy in limbic areas, the S-L exhibited only marginal global network but substantial nodal network failure. S-MA, in contrast, showed limited impairment in clinical and cognitive scores but pronounced global network failure. Our results contribute toward a better understanding of heterogeneity in AD with the detection of distinct differences in functional connectivity networks accompanied by CSF biomarker and cognitive differences in AD subtypes.

A comprehensive score reflecting memory-related fMRI activations and deactivations as potential biomarker for neurocognitive aging.

Older adults and particularly those at risk for developing dementia typically show a decline in episodic memory performance, which has been associated with altered memory network activity detectable via functional magnetic resonance imaging (fMRI). To quantify the degree of these alterations, a score has been developed as a putative imaging biomarker for successful aging in memory for older adults (Functional Activity Deviations during Encoding, FADE; Düzel et al., Hippocampus, 2011; 21: 803-814). Here, we introduce and validate a more comprehensive version of the FADE score, termed FADE-SAME (Similarity of Activations during Memory Encoding), which differs from the original FADE score by considering not only activations but also deactivations in fMRI contrasts of stimulus novelty and successful encoding, and by taking into account the variance of young adults' activations. We computed both scores for novelty and subsequent memory contrasts in a cohort of 217 healthy adults, including 106 young and 111 older participants, as well as a replication cohort of 117 young subjects. We further tested the stability and generalizability of both scores by controlling for different MR scanners and gender, as well as by using different data sets of young adults as reference samples. Both scores showed robust age-group-related differences for the subsequent memory contrast, and the FADE-SAME score additionally exhibited age-group-related differences for the novelty contrast. Furthermore, both scores correlate with behavioral measures of cognitive aging, namely memory performance. Taken together, our results suggest that single-value scores of memory-related fMRI responses may constitute promising biomarkers for quantifying neurocognitive aging.

Triple visual hemifield maps in a case of optic chiasm hypoplasia.

In humans, each hemisphere comprises an overlay of two visuotopic maps of the contralateral visual field, one from each eye. Is the capacity of the visual cortex limited to these two maps or are plastic mechanisms available to host more maps? We determined the cortical organization of the visual field maps in a rare individual with chiasma hypoplasia, where visual cortex plasticity is challenged to accommodate three hemifield maps. Using high-resolution fMRI at 7T and diffusion-weighted MRI at 3T, we found three hemiretinal inputs, instead of the normal two, to converge onto the left hemisphere. fMRI-based population receptive field mapping of the left V1-V3 at 3T revealed three superimposed hemifield representations in the left visual cortex, i.e. two representations of opposing visual hemifields from the left eye and one right hemifield representation from the right eye. We conclude that developmental plasticity including the re-wiring of local intra- and cortico-cortical connections is pivotal to support the coexistence and functioning of three hemifield maps within one hemisphere.

Dynamic 2D self-phase-map Nyquist ghost correction for simultaneous multi-slice echo planar imaging.

PURPOSE: To develop a reconstruction pipeline that intrinsically accounts for both simultaneous multislice echo planar imaging (SMS-EPI) reconstruction and dynamic slice-specific Nyquist ghosting correction in time-series data. METHODS: After 1D slice-group average phase correction, the separate polarity (i.e., even and odd echoes) SMS-EPI data were unaliased by slice GeneRalized Autocalibrating Partial Parallel Acquisition. Both the slice-unaliased even and odd echoes were jointly reconstructed using a model-based framework, extended for SMS-EPI reconstruction that estimates a 2D self-phase map, corrects dynamic slice-specific phase errors, and combines data from all coils and echoes to obtain the final images. RESULTS: The percentage ghost-to-signal ratios (%GSRs) and its temporal variations for MB3Ry 2 with a field of view/4 shift in a human brain obtained by the proposed dynamic 2D and standard 1D phase corrections were 1.37 ± 0.11 and 2.66 ± 0.16, respectively. Even with a large regularization parameter λ applied in the proposed reconstruction, the smoothing effect in fMRI activation maps was comparable to a very small Gaussian kernel size 1 × 1 × 1 mm3 . CONCLUSION: The proposed reconstruction pipeline reduced slice-specific phase errors in SMS-EPI, resulting in reduction of GSR. It is applicable for functional MRI studies because the smoothing effect caused by the regularization parameter selection can be minimal in a blood-oxygen-level-dependent activation map.

The effect of acquisition resolution on orientation decoding from V1 BOLD fMRI at 7T.

A decade after it was shown that the orientation of visual grating stimuli can be decoded from human visual cortex activity by means of multivariate pattern classification of BOLD fMRI data, numerous studies have investigated which aspects of neuronal activity are reflected in BOLD response patterns and are accessible for decoding. However, it remains inconclusive what the effect of acquisition resolution on BOLD fMRI decoding analyses is. The present study is the first to provide empirical ultra high-field fMRI data recorded at four spatial resolutions (0.8mm, 1.4mm, 2mm, and 3mm isotropic voxel size) on this topic - in order to test hypotheses on the strength and spatial scale of orientation discriminating signals. We present detailed analysis, in line with predictions from previous simulation studies, about how the performance of orientation decoding varies with different acquisition resolutions. Moreover, we also examine different spatial filtering procedures and its effects on orientation decoding. Here we show that higher-resolution scans with subsequent down-sampling or low-pass filtering yield no benefit over scans natively recorded in the corresponding lower resolution regarding decoding accuracy. The orientation-related signal in the BOLD fMRI data is spatially broadband in nature, includes both high spatial frequency components, as well as large-scale biases previously proposed in the literature. Moreover, we found above chance-level contribution from large draining veins to orientation decoding. Acquired raw data were publicly released to facilitate further investigation.

False fMRI activation after motion correction.

Motion correction of echo-planar imaging (EPI) data used in functional MRI (fMRI) is an essential preprocessing step performed prior to statistical analysis. At ultra-high resolution fMRI, current requirements regarding translational and rotational motion may no longer be acceptable. This prompts the need for a systematic investigation of the effects of motion correction procedures with in vivo fMRI data. Here we systematically evaluated the effect of retrospective motion correction with freely available fMRI analysis software packages (FSL, AFNI, and SPM) on activation maps using fMRI data acquired with prospective motion detection, to identify and quantify confounding effects of retrospective motion correction, and to evaluate its dependence on spatial resolution and motion correction algorithms. Brain activation maps were obtained for two different resolutions, an ultrahigh, that is, 0.653 mm3 , and a more widely used 2.03 mm3 isotropic resolutions at 7 T. The EPI data were acquired using simultaneous non-image-based optical moiré phase tracking (MPT) of physical motion. The results showed that image-based motion detection, performed by SPM8 software package, may be erroneous in high-field fMRI data with partial brain coverage and can introduce spurious motion leading to false-positive and false-negative activation. Further analyses demonstrated that limited acquisition field of view has the dominant influence on the effect. Hum Brain Mapp 38:4497-4510, 2017. © 2017 Wiley Periodicals, Inc.

Functional locus coeruleus imaging to investigate an ageing noradrenergic system.

The locus coeruleus (LC), our main source of norepinephrine (NE) in the brain, declines with age and is a potential epicentre of protein pathologies in neurodegenerative diseases (ND). In vivo measurements of LC integrity and function are potentially important biomarkers for healthy ageing and early ND onset. In the present study, high-resolution functional MRI (fMRI), a reversal reinforcement learning task, and dedicated post-processing approaches were used to visualise age differences in LC function (N = 50). Increased LC responses were observed during emotionally and task-related salient events, with subsequent accelerations and decelerations in reaction times, respectively, indicating context-specific adaptive engagement of the LC. Moreover, older adults exhibited increased LC activation compared to younger adults, indicating possible compensatory overactivation of a structurally declining LC in ageing. Our study shows that assessment of LC function is a promising biomarker of cognitive aging.

Enlarged perivascular spaces in the basal ganglia are associated with arteries not veins.

Enlarged perivascular spaces (EPVS) are common in cerebral small vessel disease (CSVD) and have been identified as a marker of dysfunctional brain clearance. However, it remains unknown if the enlargement occurs predominantly around arteries or veins. We combined in vivo ultra-high-resolution MRI and histopathology to investigate the spatial relationship of veins and arteries with EPVS within the basal ganglia (BG). Furthermore, we assessed the relationship between the EPVS and measures of blood-flow (blood-flow velocity, pulsatility index) in the small arteries of the BG. Twenty-four healthy controls, twelve non-CAA CSVD patients, and five probable CAA patients underwent a 3 tesla [T] and 7T MRI-scan, and EPVS, arteries, and veins within the BG were manually segmented. Furthermore, the scans were co-registered. Six autopsy-cases were also assessed. In the BG, EPVS were significantly closer to and overlapped more frequently with arteries than with veins. Histological analysis showed a higher proportion of BG EPVS surrounding arteries than veins. Finally, the pulsatility index of BG arteries correlated with EPVS volume. Our results are in line with previous works and establish a pathophysiological relationship between arteries and EPVS, contributing to elucidating perivascular clearance routes in the human brain.

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.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. MATERIALS AND METHODS: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. RESULTS: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD (P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI (P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups (P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. CONCLUSIONS: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.