Longitudinal Neuroimaging Research Articles

Maternal Immune Activation and Child Brain Development: A Longitudinal Population-based Multimodal Neuroimaging study

Maternal Immune Activation (MIA) has been hypothesized to have an adverse effect on child neurodevelopment, but only a few neuroimaging studies have been performed to date, mostly in neonates. In this population-based cohort study, we investigated the association between MIA and multiple neuroimaging modalities depicting brain development from childhood to adolescence. We used data of mother-child pairs from the Generation R Study. To define our exposure, we measured IL-1β, IL-6, IL-17a, IL-23 and IFN-γ, and CRP at two time points during pregnancy. Given that levels of these 5 cytokines were highly correlated, we were able to compute a Cytokine index. We used multiple brain imaging modalities as outcomes, encompassing global and regional measures of brain morphology (structural MRI, volume, n=3,295), white matter microstructure (diffusion MRI, FA and MD, n=3,267), and functional connectivity (functional MRI, graph theory measures and network-level connectivity, n=2,914) at child mean ages 10 and 14 years. We performed mixed-effects models using the child's age as continuous time variable. We found no significant association or time interaction between MIA and any neuroimaging outcomes in children over time. These associations were similar for the Cytokine index, CRP, and individual cytokines. We observed no evidence for differential effects of timing of prenatal MIA or child sex after multiple testing correction. This longitudinal population-based study reports no evidence for an association between MIA and child brain development in the general population. Our findings differ from prior research in neonates showing structural and functional brain abnormalities after MIA.

Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study.

Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease. A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between amyloid and α-syn and their association with disease progression. Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

Neural effects of multisensory dance training in Parkinson's disease: evidence from a longitudinal neuroimaging single case study.

Dance is associated with beneficial outcomes in motor and non-motor domains in Parkinson's disease (PD) and regular participation may help delay symptom progression in mild PD. However, little is known about the neurobiological mechanisms of dance interventions for PD. The present case study explored potential neuroplastic changes in a 69-year-old male with mild PD participating in regular dance classes over 29 weeks. Functional MRI was performed at four timepoints (pre-training, 11 weeks, 18 weeks, 29 weeks), where the individual imagined a dance choreography while listening to the corresponding music. Neural activity was compared between dance-imagery and fixation blocks at each timepoint. Analysis of functionally defined regions revealed significant blood-oxygen-level-dependent (BOLD) signal activation in the supplementary motor area, right and left superior temporal gyri and left and right insula, with modulation of these regions observed over the training period except for the left insula. The results suggest the potential for dance to induce neuroplastic changes in people with PD in regions associated with motor planning and learning, auditory processing, rhythm, emotion, and multisensory integration. The findings are consistent with dance being a multimodal therapeutic activity that could provide long-term benefits for people with PD.

A longitudinal MRI analysis reveals altered brain connectivity and microstructural changes in a transgenic mouse model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuropathological changes, yet the underlying neurobiological mechanisms remain elusive. Here, we employed a multimodal longitudinal neuroimaging approach, using anatomical and functional sequences on a high field magnetic resonance imaging (MRI) preclinical scanner, to investigate alterations in brain connectivity and white matter microstructure in a transgenic mouse model of AD (J20) when compared to wild-type (WT) littermates. Functional connectivity analysis revealed distinct network disruptions in J20 mice, primarily involving connections between posterior and anterior brain regions; importantly, a significant interaction between group and age highlighted an exacerbation of these connectivity changes with advancing age in J20 mice. In addition, significant reductions in fractional anisotropy (FA) were observed in the corpus callosum of J20 mice compared to WT, indicative of microstructural alterations consistent with white matter pathology. The observed alterations in brain connectivity and microstructure provide valuable insights into the spatiotemporal processes underlying AD-related decline and underscore the utility of multimodal neuroimaging in elucidating the neurobiological substrates of AD pathology in animal models.

Creating anatomically-derived, standardized, customizable, and three-dimensional printable head caps for functional neuroimaging.

Consistent and accurate probe placement is a crucial step towards enhancing the reproducibility of longitudinal and group-based functional neuroimaging studies. While the selection of headgear is central to these efforts, there does not currently exist a standardized design that can accommodate diverse probe configurations and experimental procedures. We aim to provide the community with an open-source software pipeline for conveniently creating low-cost, 3-D printable neuroimaging head caps with anatomically significant landmarks integrated into the structure of the cap. We utilize our advanced 3-D head mesh generation toolbox and 10-20 head landmark calculations to quickly convert a subject's anatomical scan or an atlas into a 3-D printable head cap model. The 3-D modeling environment of the open-source Blender platform permits advanced mesh processing features to customize the cap. The design process is streamlined into a Blender add-on named "NeuroCaptain". Using the intuitive user interface, we create various head cap models using brain atlases, and share those with the community. The resulting mesh-based head cap designs are readily 3-D printable using off-the-shelf printers and filaments while accurately preserving the head topology and landmarks. The methods developed in this work result in a widely accessible tool for community members to design, customize and fabricate caps that incorporate anatomically derived landmarks. This not only permits personalized head cap designs to achieve improved accuracy, but also offers an open platform for the community to propose standardizable head caps to facilitate multi-centered data collection and sharing.

Effects of chronic treatment with metformin on brain glucose hypometabolism and central insulin actions in transgenic mice with tauopathy

Brain glucose hypometabolism and insulin alterations are common features of many neurological diseases. Herein we sought to corroborate the brain glucose hypometabolism that develops with ageing in 12-months old Tau-VLW transgenic mice, a model of tauopathy, as well as to determine whether this model showed signs of altered peripheral glucose metabolism. Our results demonstrated that 12-old months Tau mice exhibited brain glucose hypometabolism as well as basal hyperglycemia, impaired glucose tolerance, hyperinsulinemia, and signs of insulin resistance. Then, we further studied the effect of chronic metformin treatment (9 months) in Tau-VLW mice from 9 to 18 months of age. Longitudinal PET neuroimaging studies revealed that chronic metformin altered the temporal profile in the progression of brain glucose hypometabolism associated with ageing. Besides, metformin altered the content and/or phosphorylation of key components of the insulin signal transduction pathway in the frontal cortex leading to significant changes in the content of the active forms. Thus, metformin increased the expression of pAKT-Y474 while reducing pmTOR-S2448 and pGSK3β. These changes might be related, at least partially, to a slow progression of ageing, neurological damage, and cognitive decline. Metformin also improved the peripheral glucose tolerance and the ability of the Tau-VLW mice to maintain their body weight through ageing. Altogether our study shows that the tau-VLW mice could be a useful model to study the potential interrelationship between tauopathy and central and peripheral glucose metabolism alterations. More importantly our results suggest that chronic metformin treatment may have direct beneficial central effects by post-transcriptional modulation of key components of the insulin signal transduction pathway.

Spatiotemporal patterns in cortical development: Age, puberty, and individual variability from 9 to 13 years of age.

Understanding normative patterns of adolescent brain change, and individual variability therein, is crucial for disentangling healthy and abnormal development. We used longitudinal human neuroimaging data to study several aspects of neurodevelopment during early adolescence and assessed their organization along a sensorimotor-to-association (S-A) axis across the cerebral cortex. Age differences in brain changes were linear and curvilinear along this S-A axis. However, individual-level sensorimotor-association alignment varied considerably, driven in part by differences in age, sex, and pubertal development.

IMG-30. DIFFUSE MIDLINE GLIOMA MAP TO A COMMON FUNCTIONAL NETWORK ASSOCIATED WITH TUMOUR PROGRESSION AND OVERALL SURVIVAL

Abstract BACKGROUND Gliomas form bidirectional, functional synapses with otherwise healthy neurons: increasing neuronal excitability and driving tumour growth. The prognostic significance of this phenomenon does, however, remain unknown. METHODS This study used tumour location and tumour network mapping to identify brain networks associated with tumour progression and overall survival (OS) in 90 children with diffuse midline glioma, H3K27-altered (DMG). Tumours were segmented on volumetric magnetic resonance imaging and mapped to a standard template. Brain networks functionally connected to each tumour were computed using normative paediatric resting-state functional magnetic resonance imaging (n=525). RESULTS Median OS in the discovery cohort was 9.5 months (interquartile range 7.0-14.5 months). Comparison of tumour location in short-term (<18 months; n=75) and long-term (≥18 months; n=15) survivors of DMG identified an area of maximal anatomic overlap associated with short-term survival in the mid-pontine tegmentum and corticospinal tracts (89%; P<0.05). Tumour location was, however, not associated with OS (P=0.347). We, therefore, seeded tumour-to-brain resting-state functional connectivity maps from this a priori tegmental region-of-interest, identifying a specific brain network associated with short-term survival defined by functional connectivity to the medial prefrontal cortex, thalami, and cerebellum (P<0.0005). High and low tumour connectivity to this network was associated with short-term and long-term OS, respectively, using both univariate (P=0.013) and multivariate models controlling for treatment and tumour volume (P=0.016). Final, subset analysis of longitudinal neuroimaging in children within one month of death (n=21) showed tumour progression mapped to this same functional network and exhibited a dominant (left) hemispheric predominance (P<0.05), underpinned by increased tumour connectivity to the right (P=0.0270) rather than left (P=0.1802) corticospinal tract, and associated with OS (P=0.02). DISCUSSION We map DMG to a unified and prognostically important functional network, further establishing DMG as a circuit disorder. Interventions aiming to modulate this network may inform future treatment strategies for affected children.

Distinct biological property of tau in tau-first cognitive proteinopathy: Evidence by longitudinal clinical neuroimaging profiles and compared with late-onset Alzheimer disease.

Tau-first cognitive proteinopathy (TCP) denotes a clinical phenotype of Alzheimer disease (AD) showing Florzolotau(18F) positron emission tomography (PET) positivity but a negative amyloid status. We explored the biological property of tau using longitudinal cognitive and neuroimaging data in TCP and compared with late-onset AD (LOAD). We enrolled 56 patients with LOAD, 34 patients with TCP, and 26 cognitive unimpaired controls. All of the participants had historical data of 2 to 4 three-dimensional T1 images and 2 to 6 annual cognitive evaluations over a follow-up period of 7 years. Tau topography was measured using Florzolotau(18F) PET. In the LOAD and TCP groups, we constructed tau or gray matter clusters covarying with the cognitive measurements. We used mediator analysis to explore the regional tau load as predictor, gray matter partitions as mediators, and significant cognitive test scores as outcomes. Longitudinal cognitive decline and cortical thickness degeneration pattern were analyzed using a linear mixed-effects model. The TCP group had longitudinal declines in nonexecutive domains. The deterministic factor predicting the short-term memory score in TCP was the hippocampal volume and not directly via the medial and lateral temporal tau load. These features formed the conceptual differences with LOAD. The biological properties of tau and the longitudinal cognitive-imaging trajectory support the conceptual distinction between TCP and LOAD. TCP represents one specific entity featuring salient short-term memory impairment, declines in nonexecutive domains, a slower gray matter degenerative pattern, and a restricted impact of tau.

Effects of Ambient Air Pollution on Brain Cortical Thickness and Subcortical Volume: A Longitudinal Neuroimaging Study.

Several cross-sectional studies have shown that long-term exposures to air pollutants are associated with smaller brain cortical volume or thickness. Here, we investigated longitudinal associations of long-term air pollution exposures with cortical thickness and subcortical volume. In this longitudinal study, we included a prospective cohort of 361 adults residing in four cities in the Republic of Korea. Long-term concentrations of particulate matter with aerodynamic diameters of ≤10 μm (PM10) and ≤2.5 μm (PM2.5) and nitrogen dioxide (NO2) at residential addresses were estimated. Neuroimaging markers (cortical thickness and subcortical volume) were obtained from brain magnetic resonance images at baseline (August 2014 to March 2017) and at the 3-year follow-up (until September 2020). Linear mixed-effects models were used, adjusting for covariates. A 10-μg/m3 increase in PM10 was associated with reduced whole-brain mean (β = -0.45, standard error [SE] = 0.10; p < 0.001), frontal (β = -0.53, SE = 0.11; p < 0.001) and temporal thicknesses (β = -0.37, SE = 0.12; p = 0.002). A 10-ppb increase in NO2 was associated with a decline in the whole-brain mean cortical thickness (β = -0.23, SE = 0.05; p < 0.001), frontal (β = -0.25, SE = 0.05; p < 0.001), parietal (β = -0.12, SE = 0.05; p = 0.025), and temporal thicknesses (β = -0.19, SE = 0.06; p = 0.001). Subcortical structures associated with air pollutants included the thalamus. Long-term exposures to PM10 and NO2 may lead to cortical thinning in adults.

All Three Supersystems-Nervous, Vascular, and Immune-Contribute to the Cortical Infarcts After Subarachnoid Hemorrhage.

The recently published DISCHARGE-1 trial supports the observations of earlier autopsy and neuroimaging studies that almost 70% of all focal brain damage after aneurysmal subarachnoid hemorrhage are anemic infarcts of the cortex, often also affecting the white matter immediately below. The infarcts are not limited by the usual vascular territories. About two-fifths of the ischemic damage occurs within ~ 48h; the remaining three-fifths are delayed (within ~ 3weeks). Using neuromonitoring technology in combination with longitudinal neuroimaging, the entire sequence of both early and delayed cortical infarct development after subarachnoid hemorrhage has recently been recorded in patients. Characteristically, cortical infarcts are caused by acute severe vasospastic events, so-called spreading ischemia, triggered by spontaneously occurring spreading depolarization. In locations where a spreading depolarization passes through, cerebral blood flow can drastically drop within a few seconds and remain suppressed for minutes or even hours, often followed by high-amplitude, sustained hyperemia. In spreading depolarization, neurons lead the event, and the other cells of the neurovascular unit (endothelium, vascular smooth muscle, pericytes, astrocytes, microglia, oligodendrocytes) follow. However, dysregulation in cells of all three supersystems-nervous, vascular, and immune-is very likely involved in the dysfunction of the neurovascular unit underlying spreading ischemia. It is assumed that subarachnoid blood, which lies directly on the cortex and enters the parenchyma via glymphatic channels, triggers these dysregulations. This review discusses the neuroglial, neurovascular, and neuroimmunological dysregulations in the context of spreading depolarization and spreading ischemia as critical elements in the pathogenesis of cortical infarcts after subarachnoid hemorrhage.

Genetic variation in endocannabinoid signaling: Anxiety, depression, and threat- and reward-related brain functioning during the transition into adolescence

BackgroundThe endocannabinoid system modulates neural activity throughout the lifespan. In adults, neuroimaging studies link a common genetic variant in fatty acid amide hydrolase (FAAH C385A)—an enzyme that regulates endocannabinoid signaling—to reduced risk of anxiety and depression, and altered threat- and reward-related neural activity. However, limited research has investigated these associations during the transition into adolescence, a period of substantial neurodevelopment and increased psychopathology risk. MethodsThis study included FAAH genotype and longitudinal neuroimaging and neurobehavioral data from 4811 youth (46% female; 9–11 years at Baseline, 11–13 years at Year 2) from the Adolescent Brain Cognitive DevelopmentSM Study. Linear mixed models examined the effects of FAAH and the FAAH x time interaction on anxiety and depressive symptoms, amygdala reactivity to threatening faces, and nucleus accumbens (NAcc) response to happy faces during the emotional n-back task. ResultsA significant main effect of FAAH on depressive symptoms was observed, such that depressive symptoms were lower across both timepoints in those with the AA genotype compared to both AC and CC genotypes (p’s<0.05). There were no significant FAAH x time interactions for anxiety, depression, or neural responses (p’s>0.05). Additionally, there were no main effects of FAAH on anxiety or neural responses (p’s>0.05). ConclusionsOur findings add to emerging evidence linking the FAAH C385A variant to lower risk of psychopathology, and extend these findings to a developmental sample. In particular, we found lower depressive symptoms in FAAH AA genotypes compared to AC and CC genotypes. Future research is needed to characterize the role of the FAAH variant and the eCB system more broadly in neurodevelopment and psychiatric risk.

Signatures of abnormal deviations in excitation‐inhibition balance for amyloid positive individuals

AbstractBackgroundDysfunctional excitation‐inhibition balance (EIB) is hypothesized to precede cognitive impairment in Alzheimer’s disease (AD); however, overlapping neuropathology (like amyloid plaques) can develop in cognitively normal (CN) and impaired (CI) individuals. We investigate EIB trajectories for individuals with significant amyloid (Aβ+).MethodMultimodal imaging was used to construct hybrid resting‐state structural connectomes (Fortel, Igor, et al. Network Neuroscience 6.2 (2022): 420‐444.), computing whole‐brain EIB based on 105 ROIs. This cohort (N = 185, 94 Female) aged 55‐90 (μ FEMALES = 74.9, and μ MALES 73) was limited to Aβ+ individuals with APOE genotyping (ε3/ε3, ε3/ε4, ε4/ε4); grouped further by clinical dementia rating (CDR), with CDR &gt; 0 indicating CI. Imaging, Aβ+ classifications, CDR, and APOE were obtained from OASIS‐3: Longitudinal Multimodal Neuroimaging: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P30 AG066444, P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, R01 EB009352. AV‐45 doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly.ResultResults presented in Figure 1 suggest whole‐brain EIB in both CN sexes with Aβ+ decreases with increasing age (APOE‐ε4 agnostic). However, sex differences are highlighted with CI; regression analyses produce a marginally significant 4‐way interaction of age, sex, cognitive status, and APOE (P = 0.085, β = ‐0.013). Partial correlation of EIB with age, controlling for sex, APOE and cognitive status is also significant (P = 0.016, r = ‐0.18). Results indicate sex‐mediated EIB differences in individuals with CI, dominated by APOE‐ε4 in women rather than amyloid.ConclusionWe’ve demonstrated EIB deviations in cognitively impaired men and women that may be associated with AD neuropathology. Our findings are consistent with known AD sex differences and suggest novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not. Figure. 1. Whole‐brain excitation‐Inhibition balance (EIB) trajectories for amyloid positive (Aβ+) men and women. The cognitively normal (CN) group (rows A‐B) suggests no sex differences in EIB trajectories with age, while the cognitively impaired (CI) group (rows C‐D) begins to reveal distinct patterns of dysfunction (more significantly in women with APOE‐ε4). Note a value of 0.5 indicates perfect balance.

Containerizing neuroimaging workflows for scalable and reproducible analyses

AbstractBackgroundLarge multi‐center, longitudinal neuroimaging projects aiming to understand neurodegenerative disorders, such as Alzheimer disease (AD), frequently generate large datasets for use by external researchers. However, maintaining a replicable data processing workflow in an on‐going study can be difficult due to changes in personnel, computer or software upgrades, and disparate computing resources across collaborating institutions. Replicating workflows from prior studies is also important for validating and building scientific knowledge but can present similar challenges. Containerization is an increasingly popular solution to these issues. This process allows users to package their code, software, and any dependencies together, ensuring stable and consistent output across computing platforms. The main goal of this project is to guide researchers through the steps of custom container development for their own needs.MethodWe demonstrate the process of containerization using a neuroimaging workflow that quantifies edge density (ED), an emerging metric of white matter integrity. To calculate ED, structural and diffusion magnetic resonance images were processed using standard FreeSurfer (5.3) and FSL (6.0) procedures. Whole‐brain probabilistic tractography, ED metrics, and diffusion tensor indices were computed. A template for building a container image for neuroimaging use was developed. Scripts used for analyses were incorporated into the template and compiled as reusable container images using Docker and Apptainer. Additional scripts and documentation were released to facilitate custom implementation.ResultContainerized tractography, ED metrics, and tensor indices were identical across multiple computing systems and in‐line with prior research showing white matter integrity begins to decline prior to outward cognitive symptoms. The provided code and documentation outlines the containerization process for our workflow (Figure 1) and describes how to run the resulting container image using data from the recently updated Open Access Series of Imaging Studies 3 dataset (OASIS‐3) as an example.ConclusionContainerizing a neuroimaging processing workflow ensures stable results across the lifespan of a study and facilitates replication of prior workflows in new datasets. The containerized ED pipeline provided enables other researchers to replicate or extend upon our analyses in this cohort. The provided documentation and templates can also be adapted for use with other datasets that use common neuroimaging file formats.

Containerizing neuroimaging workflows for scalable and reproducible analyses

AbstractBackgroundLarge multi‐center, longitudinal neuroimaging projects aiming to understand neurodegenerative disorders, such as Alzheimer disease (AD), frequently generate large datasets for use by external researchers. However, maintaining a replicable data processing workflow in an on‐going study can be difficult due to changes in personnel, computer or software upgrades, and disparate computing resources across collaborating institutions. Replicating workflows from prior studies is also important for validating and building scientific knowledge but can present similar challenges. Containerization is an increasingly popular solution to these issues. This process allows users to package their code, software, and any dependencies together, ensuring stable and consistent output across computing platforms. The main goal of this project is to guide researchers through the steps of custom container development for their own needs.MethodWe demonstrate the process of containerization using a neuroimaging workflow that quantifies edge density (ED), an emerging metric of white matter integrity. To calculate ED, structural and diffusion magnetic resonance images were processed using standard FreeSurfer (5.3) and FSL (6.0) procedures. Whole‐brain probabilistic tractography, ED metrics, and diffusion tensor indices were computed. A template for building a container image for neuroimaging use was developed. Scripts used for analyses were incorporated into the template and compiled as reusable container images using Docker and Apptainer. Additional scripts and documentation were released to facilitate custom implementation.ResultContainerized tractography, ED metrics, and tensor indices were identical across multiple computing systems and in‐line with prior research showing white matter integrity begins to decline prior to outward cognitive symptoms. The provided code and documentation outlines the containerization process for our workflow (Figure 1) and describes how to run the resulting container image using data from the recently updated Open Access Series of Imaging Studies 3 dataset (OASIS‐3) as an example.ConclusionContainerizing a neuroimaging processing workflow ensures stable results across the lifespan of a study and facilitates replication of prior workflows in new datasets. The containerized ED pipeline provided enables other researchers to replicate or extend upon our analyses in this cohort. The provided documentation and templates can also be adapted for use with other datasets that use common neuroimaging file formats.

A - 18 Predicting Incident Amnestic Mild Cognitive Impairment and Alzheimer's Disease with a Computerized Neuropsychological Assessment Device: Comparative Clinical Utility.

Computerized neuropsychological assessment devices (CNADs) offer improved accessibility to screen for neurodegeneration, although their clinical utility is yet to be established. We evaluated the efficacy of a CNAD to predict incident amnestic mild cognitive impairment and Alzheimer's disease (aMCI/ad) compared to a conventional paper-and-pencil screening tool and PET amyloid beta (AB). Data were collected from the longitudinal observational Alzheimer's Disease Neuroimaging Initiative 3. Participants were cognitively normal at baseline (N = 315, mean age = 72.9 +/- 7.1, 59.4% female, 16.8 +/- 2.3years of education, 91.4% White, 33.7% APOE4+). Over four years, 26 (8.3%) participants converted to aMCI and 3 (1.0%) individuals developed ad. Prognostic validity was compared between three measures assessed at baseline. Computerized visual episodic memory scores were evaluated using the One Card Learning (OCL) test. Conventional screening was conducted using the Montreal Cognitive Assessment (MoCA). PET AB+ was quantified as ≥2 SD whole cerebellum referenced region standardized uptake value ratios. Area under the curve (AUC) analyses using logistic regression were adjusted for age, sex, education, race, and APOE4+ status. OCL accuracy yielded AUC = 0.67, p = 0.003, 95% CI [0.58, 0.76]. Total MoCA score demonstrated AUC = 0.75, p < 0.001, 95% CI [0.67, 0.83]. PET AB+ produced AUC = 0.68, p = 0.001, 95% CI [0.58, 0.79]. When assessed at baseline, the MoCA provided the greatest clinical utility to predict incident aMCI/ad. Baseline OCL accuracy and PET AB+ were similarly effective for determining future cognitive decline. Further research is needed to examine the utility of CNADs before they are integrated into clinical practice.

Brain network integration underpins differential susceptibility of adolescent anxiety.

Parenting is a common and potent environmental factor influencing adolescent anxiety. Yet, the underlying neurobiological susceptibility signatures remain elusive. Here, we used a longitudinal twin neuroimaging study to investigate the brain network integration and its heritable relation to underpin the neural differential susceptibility of adolescent anxiety to parenting environments. 216 twins from the Beijing Twin Study completed the parenting and anxiety assessments and fMRI scanning. We first identified the brain network integration involved in the influences of parenting at age 12 on anxiety symptoms at age 15. We then estimated to what extent heritable sensitive factors are responsible for the susceptibility of brain network integration. Consistent with the differential susceptibility theory, the results showed that hypo-connectivity within the central executive network amplified the impact of maternal hostility on anxiety symptoms. A high anti-correlation between the anterior salience and default mode networks played a similar modulatory role in the susceptibility of adolescent anxiety to paternal hostility. Genetic influences (21.18%) were observed for the connectivity pattern in the central executive network. Brain network integration served as a promising neurobiological signature of the differential susceptibility to adolescent anxiety. Our findings deepen the understanding of the neural sensitivity in the developing brain and can inform early identification and personalized interventions for adolescents at risk of anxiety disorders.

Ultra-high-field 7T MRI reveals changes in human medial temporal lobe volume in female adults during menstrual cycle

Ovarian hormones have substantial effects on the brain, and early menopause has been associated with increased risk of accelerated brain aging and dementia later in life. However, the impact of ovarian hormone fluctuations on brain structure earlier in life is less understood. Here we show that ovarian hormone fluctuations shape structural brain plasticity during the reproductive years. We use longitudinal ultra-high field neuroimaging across the menstrual cycle to map the morphology of medial temporal lobe subregions in 27 participants. Controlling for water content and blood flow, our findings reveal positive associations between estradiol and parahippocampal cortex volume, progesterone and subiculum and perirhinal area 35 volumes, and an estradiol*progesterone interaction with CA1 volume. This research offers a blueprint for future studies on the shared dynamics of the brain and ovarian function and a fundamental stepping stone towards developing sex-specific strategies to improve brain health and mental health.

Prevalence and Clinical Implications of a β-Amyloid–Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease

Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile. To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications. This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023. Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240). Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET. A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile. Results suggest that the CSF A-T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.

Sex Differences in Brain Structure in de novo Parkinson's Disease: A Cross-Sectional and Longitudinal Neuroimaging Study.

Parkinson's disease (PD) varies in occurrence, presentation, and severity between males and females. However, the sex effects on the patterns of brain structure, cross-sectionally and longitudinally, are still unclear. We aimed to compare sex differences in brain features cross-sectionally and longitudinally using grey matter volume (GMV) and cortical thickness in a large sample of newly diagnosed drug-naive PD patients. Cognitive assessments and structural MR images of 262 PD patients (171 males) and 113 healthy controls (68 males) were selected from the Parkinson's Progression Markers Initiative. Of these, 97 PD patients (66 males) completed 12- and 24-month follow-up examinations. After regressing out the expected effects of age and sex, brain maps of GMV and cortical thickness were compared using two-sample t tests cross-sectionally and were compared using repeated measurement analyses of variance longitudinally. At baseline, male PD patients exhibited a greater extent of brain atrophy and cortical thickness reduction than females, which mainly occurred in the cerebellum, frontal lobe, parietal lobe, and temporal lobe. At follow-up, female and male PD patients showed similar dynamics of disease progression, as both groups declined over time while the females maintained the advantage. The cortical thickness of the right precentral gyrus at baseline was negatively associated with the longitudinal changes of motor function in male PD patients. The current findings might demonstrate sex effect in neuroanatomy during the course of PD, provide new insights into the neurodegenerative process, and facilitate the development of more effective sex-specific therapeutic strategies.