Temporal Cortical Thickness Research Articles

Association between blood-based protein biomarkers and brain MRI in the Alzheimer's disease continuum: a systematic review.

Blood-based biomarkers (BBM) are becoming easily detectable tools to reveal pathological changes in Alzheimer's disease (AD). A comprehensive and up-to-date overview of the association between BBM and brain MRI parameters is not available. This systematic review aimed to summarize the literature on the associations between the main BBM and MRI markers across the clinical AD continuum. A systematic literature search was carried out on PubMed and Web of Science and a total of 33 articles were included. Hippocampal volume was positively correlated with Aβ42 and Aβ42/Aβ40 and negatively with Aβ40 plasma levels. P-tau181 and p-tau217 concentrations were negatively correlated with temporal grey matter volume and cortical thickness. NfL levels were negatively correlated with white matter microstructural integrity, whereas GFAP levels were positively correlated with myo-inositol values in the posterior cingulate cortex/precuneus. These findings highlight consistent associations between various BBM and brain MRI markers even in the pre-clinical and prodromal stages of AD. This suggests a possible advantage in combining multiple AD-related markers to improve accuracy of early diagnosis, prognosis, progression monitoring and treatment response.

Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer’s disease continuum

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer’s disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

Cortical atrophy patterns in myelin oligodendrocyte glycoprotein antibody-associated disease.

Global brain volume changes in patients with myelin oligodendrocyte glycoprotein antibody-associated disease compared with healthy controls (HC) could be revealed by magnetic resonance imaging, but specific atrophy patterns of cortical structures and relation to cognitive impairment are not yet comprehensively known. Thus, we aimed to investigate cortical thickness differences in patients with myelin oligodendrocyte glycoprotein antibody-associated disease compared with HC. 3-Tesla brain magnetic resonance imaging was performed in 23 patients with myelin oligodendrocyte glycoprotein antibody-associated disease and 49 HC for voxel-wise group comparisons and neuropsychological testing in patients. Surface-based morphometry with region of interest-based surface analysis and region of interest-based extraction of cortical thickness was performed in patients compared with HC and in patient subgroups with and without cognitive impairment. Comparing patients with myelin oligodendrocyte glycoprotein antibody-associated disease with HC, exploratory surface-based morphometry demonstrated cortical volume reduction in pericalcarine and lingual cortical regions. Region of interest-based surface analysis specified reduced cortical thickness in the adjacent pericalcarine and orbitofrontal regions in myelin oligodendrocyte glycoprotein antibody-associated disease, as well as reduced temporal cortical thickness in patients with cognitive impairment (n = 10). Patients without cognitive impairment (n = 13) showed only circumscribed cortical brain volume loss compared with HC in the pericalcarine region. In conclusion, cortical atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease was characterized by cortical thickness reduction in the adjacent pericalcarine and orbitofrontal regions, with a tendency of temporal thickness reduction in cognitively impaired patients.

Lower in vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology: a cohort study

BackgroundAutopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.MethodsA total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.ResultsAcross the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.ConclusionsOur findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.

Whole brain morphologic features improve the predictive accuracy of IDH status and VEGF expression levels in gliomas.

Glioma is a systemic disease that can induce micro and macro alternations of whole brain. Isocitrate dehydrogenase and vascular endothelial growth factor are proven prognostic markers and antiangiogenic therapy targets in glioma. The aim of this study was to determine the ability of whole brain morphologic features and radiomics to predict isocitrate dehydrogenase status and vascular endothelial growth factor expression levels. This study recruited 80 glioma patients with isocitrate dehydrogenase wildtype and high vascular endothelial growth factor expression levels, and 102 patients with isocitrate dehydrogenase mutation and low vascular endothelial growth factor expression levels. Virtual brain grafting, combined with Freesurfer, was used to compute morphologic features including cortical thickness, LGI, and subcortical volume in glioma patient. Radiomics features were extracted from multiregional tumor. Pycaret was used to construct the machine learning pipeline. Among the radiomics models, the whole tumor model achieved the best performance (accuracy 0.80, Area Under the Curve 0.86), while, after incorporating whole brain morphologic features, the model had a superior predictive performance (accuracy 0.82, Area Under the Curve 0.88). The features contributed most in predicting model including the right caudate volume, left middle temporal cortical thickness, first-order statistics, shape, and gray-level cooccurrence matrix. Pycaret, based on morphologic features, combined with radiomics, yielded highest accuracy in predicting isocitrate dehydrogenase mutation and vascular endothelial growth factor levels, indicating that morphologic abnormalities induced by glioma were associated with tumor biology.

Abstract P327: Examination of Cardiometabolic Health Status, Obesity, and Brain Health in Community-Dwelling Older Adults

Introduction: Mid-life and late-life obesity have been associated with changes in brain structure and function, though the exact nature of this dynamic relationship is not well understood. Purpose: To determine whether associations between measures of obesity and neuroimaging biomarkers are independent of cardiometabolic health status in older adults. Methods: Adults 55 and older were recruited into the Clinical Core of the Wake Forest Alzheimer’s Disease Research Center (ADRC) between 2016 and 2023 and underwent standard evaluation in accordance with the National Alzheimer’s Coordinating Center protocols. Body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) were measured to assess obesity. Cardiometabolic health was determined by the presence of impaired glucose tolerance (IGT) and hypertension (HTN). Brain MRI scans were conducted to assess cerebral blood flow (CBF) in white matter (WM) and gray matter (GM), WM microstructure using neurite orientation dispersion and density imaging (NODDI) of free water (FW), total brain volume (GM+WM), and temporal lobe cortical thickness. Linear regression was used to examine associations between anthropometric and neuroimaging measures, controlling for demographics (age, gender, race, education) in model 1 and demographics plus cardiometabolic health (HTN and IGT) in model 2. Results: A total of 647 Clinical Core participants with anthropometric, MRI, cardiometabolic, and demographic data available were analyzed. Mean age of participants was 70.1±8.2 years, 19% were African American, 48% had adjudicated cognitive impairment (35% mild cognitive impairment, 13% dementia), 76% had HTN, and 69% had IGT. BMI (p<0.001), WC (p<0.001), and WHR (p=0.006) were positively associated with WM CBF in models 1 and 2. BMI (p=0.039) was also positively associated with GM CBF in model 2. All three obesity measures were positively associated with NODDI FW in model 1: BMI (p=0.006), WC (p=0.007), and WHR (p=0.039), and WHR was negatively associated with total brain volume (p=0.043). However, these associations were attenuated after further adjustment. Cortical thickness was not significantly associated with obesity in any model. Conclusion: These results demonstrate that, among community-dwelling older adults, having higher BMI, WHR, and WC is associated with higher WM CBF even after adjusting for demographics, HTN and IGT, suggesting that obesity may be a risk factor for impaired brain perfusion in late life.

Cardiorespiratory fitness is associated with cortical thickness of medial temporal brain areas associated with spatial cognition in young but not older adults.

Cardiorespiratory fitness has a potent effect on neurocognitive health, especially regarding the hippocampal memory system. However, less is known about the impact of cardiorespiratory fitness on medial temporal lobe extrahippocampal neocortical regions. Specifically, it is unclear how cardiorespiratory fitness modulates these brain regions in young adulthood and if these regions are differentially related to cardiorespiratory fitness in young versus older adults. The primary goal of this study was to investigate if cardiorespiratory fitness predicted medial temporal lobe cortical thickness which, with the hippocampus, are critical for spatial learning and memory. Additionally, given the established role of these cortices in spatial navigation, we sought to determine if cardiorespiratory fitness and medial temporal lobe cortical thickness would predict greater subjective sense of direction in both young and older adults. Cross-sectional data from 56 young adults (20-35 years) and 44 older adults (55-85 years) were included. FreeSurfer 6.0 was used to automatically segment participants' 3T T1-weighted images. Using hierarchical multiple regression analyses, we confirmed significant associations between greater cardiorespiratory fitness and greater left entorhinal, left parahippocampal, and left perirhinal cortical thickness in young, but not older, adults. Left parahippocampal cortical thickness interacted with age group to differentially predict subjective sense of direction in young and older adults. Young adults displayed a positive, and older adults a negative, correlation between left parahippocampal cortical thickness and sense of direction. Our findings extend previous work on the association between cardiorespiratory fitness and hippocampal subfield structure in young adults to left medial temporal lobe neocortical regions.

Preliminary results investigating synaptic density across the Alzheimer’s Disease continuum

AbstractBackgroundProgressive loss of synapses occurs throughout the Alzheimer’s Disease (AD) continuum and is closely associated with cognitive impairment. Here, we present pilot data investigating variation in synaptic density across aging and AD using 18F‐SynVesT‐1 molecular imaging, a ligand for the SV2A site.Method26 participants underwent 18F‐SynVesT‐1 imaging to estimate synaptic density in‐vivo. Participants were young adults (Y) (n = 7; Age = 26.1+‐3.8; Sex(F) = 4), cognitively unimpaired older adults (O) (n = 13; Age = 79.7+‐4.27; Sex(F) = 7) or patients (P) (n = 6; Age = 66.3 +‐8.2; Sex (F) = 1; Diagnoses EOAD = 3, MCI = 1, PCA(AD) = 1; lvPPA(AD)). We collected a 90 min dynamic sequence after injection of 5 mCi of tracer. Participant whole brain Distribution Volume Ratio (DVR) images were generated using a cerebellar grey matter reference region. O and P groups also underwent tau and β‐amyloid (Aβ) PET imaging (O: 18F‐flortaucipir,11C‐PiB; P: 18F‐PI‐2620, 18F‐Florbetaben) and a visual assessment of tau and Aβ positivity for AD was determined by an expert reviewer (DSM).ResultWe contrasted 18F‐SynVesT‐1 uptake in four cortical regions for Y, O and P. In each region, we observed a significant effect of group (Hippocampus F(1,23) = 4.35, p = 0.025 (uncorrected); Meta‐Temporal ROI F(1,23) = 4.36, p = 0.025 (uncorrected); Temporal F(1,23) = 9, p<0.01(FWE corrected); F(1,23) = 14.4, p<0.001 (FWE corrected)) Figure 1. Further, we observe non‐significant numerical differences suggesting lower synaptic density in participants with biomarker evidence of Aβ and tau Figure 1. Finally, we observe a positive partial correlation between temporal cortical thickness and temporal 18F‐SynVesT‐1 uptake controlling for age (r(23) = 0.54,p = 0.006) Figure 2. We observe no relationship between age and tracer uptake in the cerebral white matter (r(24) = ‐0.01,p = 0.95), suggesting the reference region selected does not introduce systematic biases in the DVR image.ConclusionThis demonstrates 18F‐SynVesT‐1 PET can capture age and AD related decreases in synaptic density across the cortex. Further, we show an association between cortical thickness and synaptic density in the temporal cortex controlling for biases due to age. Future work will incorporate additional participants and investigate participant level associations between regional 18F‐SynVesT‐1 uptake, cognition, and in‐vivo AD pathologies.

Reduced slow‐wave sleep is associated with greater tau accumulation and reduced cortical thickness in the temporal lobe

AbstractBackgroundSlow wave sleep (SWS) plays an important role in overnight memory consolidation and promotes overnight clearance of amyloid‐β and tau proteins. Reduced SWS has been associated with higher amyloid burden in CSF in preclinical stages of Alzheimer’s disease (AD). However, little is known about the relationship between SWS, tau burden and neurodegeneration in cognitively unimpaired (CU) adults. Thus, we investigated the relationships between slow‐wave sleep, regional tau PET (18F‐flortaucipir; FTP‐PET) and temporal lobe cortical thickness in cognitively unimpaired adults at risk of AD.MethodsThis study included 39 CU adults from the Harvard Aging Brain Study (mean age 74.6 years, 61.5% females) who underwent at‐home polysomnography (PSG; Compumedics Somte), tau PET (FTP‐PET, amyloid PET (PIB‐PET) and MRI (Table 1). We used separate multivariate linear regressions to assess associations between the percentage of slow‐wave sleep (SWS) and tau PET signal in the following ROIs: entorhinal cortex, inferior temporal cortex, and a temporal composite comprised of entorhinal, inferior temporal, middle temporal and fusiform cortices. Primary analyses were adjusted for age and sex. Secondary analyses also adjusted for global amyloid (PiB‐PET) burden. Lastly, we investigated the relationship between SWS and cortical thickness in the same ROIs, assessed using FreeSurfer v6.0.ResultsLower percentage of SWS was associated with greater tau burden in entorhinal (p = 0.036), inferior temporal (p = 0.011), and temporal composite ROIs (p = 0.005). Associations between reduced SWS and greater FTP‐PET signal in the inferior temporal cortex and temporal composite ROI remained after controlling for PiB‐PET (p = 0.028; p = 0.017, respectively; Table 2). Additionally, lower SWS was associated with reduced cortical thickness in the entorhinal (p = 0.031), inferior temporal (p = 0.023) and temporal composite ROIs (p = 0.002) (Table 3).ConclusionsLower SWS in CU adults was associated with higher tau burden in regions of the temporal lobe that are commonly sites of early tau accumulation. These effects were independent of amyloid burden, suggesting disrupted sleep may lead to increased tau accumulation via an amyloid‐independent pathway. Importantly, lower SWS was also associated with reduced cortical thickness in temporal regions, suggesting that disrupted sleep may be tied to early AD‐related neuronal loss in the temporal lobe.

Using neuroimaging biomarkers to define plasma thresholds in a community dwelling cohort

AbstractBackgroundAD Imaging biomarkers (IBM) include measures of amyloid (A) on PET, and neurodegeneration (N) on MRI, with thresholds for classification of imaging A/N positivity commonly used at research centers. Novel AD plasma biomarkers (PBM) can potentially enhance neuropathological characterization; however, knowledge regarding which thresholds to use to characterize PBM abnormalities is limited.MethodWe evaluated a range of PBM thresholds based on (1) plasma data alone (gaussian mixture models [GMM]), and (2) when classifying A/N IBM using both existing and data‐driven cutoffs (ROC analyses). Baseline plasma and imaging data were obtained in a community‐dwelling cohort enrolled in the Wake Forest ADRC, including cognitively normal participants (N = 300) and individuals with consensus diagnosis of mild cognitive impairment (N = 192) or dementia (N = 64; Table 1). We examined PBMs (Quanterix SIMOA HD‐X from NCRAD: Aß42/40, GFAP, NfL, p‐tau181) and IBM measures of A (global PiB PET; A+>1.21 SUVR) and N (FreeSurfer temporal cortical thickness; MAYOTHCK), N+ = 2.68mm; FreeSurfer hippocampal volume, N+ = 0.454% head size; HPC‐VOL).ResultOptimal/low/high GMM‐derived thresholds based on PBM distributions (Figure 1a) are provided in Figure 1b. ROC analysis using existing IBM cutoffs are in Figure 1c, with details (sensitivity/specificity/AUC) in Figure 1d. GMM‐ and ROC‐derived p‐tau181 thresholds were highly aligned (range 3.698‐4.071 pg/ml). For NfL and GFAP, imaging ROC‐derived thresholds were lower than GMM‐derived thresholds. AUCs were highest when PBM classification was used to predict A‐PET using existing PET‐positivity cutoffs, with PBM performing more poorly for MRI‐based cutoffs. A/N IBM histograms and current/optimal/low/high GMM‐derived thresholds for each IBM are in Figure 2a. Figure 2b represents how different data‐driven IBM cutoffs impact PBM thresholds in ROC analyses, with AUC statistics for these ROC analyses in Figures 2c‐e. Notably, GMM‐optimal IBM cutoffs performed similarly to current cutoffs for defining PBM thresholds, especially when using A‐PET (AUCs for current and GMM‐optimal >0.747).ConclusionWhile use of existing and data‐driven IBM cutoffs to define PBM thresholds in a community‐dwelling cohort is feasible, some plasma assays (e.g., p‐tau181) are more consistent than others, and caution is warranted against selecting a single threshold. To facilitate clinical use, future work will focus on establishing confidence intervals for PBM abnormalities.

Using neuroimaging biomarkers to define plasma thresholds in a community dwelling cohort

AbstractBackgroundAD Imaging biomarkers (IBM) include measures of amyloid (A) on PET, and neurodegeneration (N) on MRI, with thresholds for classification of imaging A/N positivity commonly used at research centers. Novel AD plasma biomarkers (PBM) can potentially enhance neuropathological characterization; however, knowledge regarding which thresholds to use to characterize PBM abnormalities is limited.MethodWe evaluated a range of PBM thresholds based on (1) plasma data alone (gaussian mixture models [GMM]), and (2) when classifying A/N IBM using both existing and data‐driven cutoffs (ROC analyses). Baseline plasma and imaging data were obtained in a community‐dwelling cohort enrolled in the Wake Forest ADRC, including cognitively normal participants (N = 300) and individuals with consensus diagnosis of mild cognitive impairment (N = 192) or dementia (N = 64; Table 1). We examined PBMs (Quanterix SIMOA HD‐X from NCRAD: Aβ42/40, GFAP, NfL, p‐tau181) and IBM measures of A (global PiB PET; A+>1.21 SUVR) and N (FreeSurfer temporal cortical thickness; MAYOTHCK), N+≤2.68mm; FreeSurfer hippocampal volume, N+≤0.454% head size; HPC‐VOL).ResultsOptimal/low/high GMM‐derived thresholds based on PBM distributions (Figure 1a) are provided in Figure 1b. ROC analysis using existing IBM cutoffs are in Figure 1c, with details (sensitivity/specificity/AUC) in Figure 1d. GMM‐ and ROC‐derived p‐tau181 thresholds were highly aligned (range 3.698‐4.071 pg/ml). For NfL and GFAP, imaging ROC‐derived thresholds were lower than GMM‐derived thresholds. AUCs were highest when PBM classification was used to predict A‐PET using existing PET‐positivity cutoffs, with PBM performing more poorly for MRI‐based cutoffs. A/N IBM histograms and current/optimal/low/high GMM‐derived thresholds for each IBM are in Figure 2a. Figure 2b represents how different data‐driven IBM cutoffs impact PBM thresholds in ROC analyses, with AUC statistics for these ROC analyses in Figures 2c‐e. Notably, GMM‐optimal IBM cutoffs performed similarly to current cutoffs for defining PBM thresholds, especially when using A‐PET (AUCs for current and GMM‐optimal >0.747).ConclusionWhile use of existing and data‐driven IBM cutoffs to define PBM thresholds in a community‐dwelling cohort is feasible, some plasma assays (e.g., p‐tau181) are more consistent than others, and caution is warranted against selecting a single threshold. To facilitate clinical use, future work will focus on establishing confidence intervals for PBM abnormalities.

Changes in cortical thickness along the Alzheimer disease continuum in people with Down syndrome

AbstractBackgroundTriplication of the APP allele in Down syndrome (DS) leads to excess amyloid production and Alzheimer’s disease (AD) related cognitive decline. Key biomarkers (amyloid, tau, neurodegeneration) can identify pathological processes that occur before clinical symptoms and more precisely stage adults with DS along the AD continuum. Previous research has used changes in cortical thickness (CT) as an indicator of neurodegeneration in autosomal‐dominant AD1, but not DS‐related AD. It is unclear when and where cortical thinning occurs along the AD continuum in DS and if these differences are associated with increasing AD pathology.MethodCross‐sectional analysis compared DS participants from the Alzheimer Biomarkers Consortium‐Down Syndrome (106 amyloid‐/cognitively unimpaired, nonclinical, 20% reserved for receiver‐operating characteristic, ROC, analyses; 45 amyloid+/cognitively unimpaired, preclinical; 27 amyloid+/cognitively impaired, clinical) who had amyloid positron emission tomography and magnetic resonance imaging (MRI). Amyloid positivity was defined using standardized uptake value ratio (partial volume corrected) cortical mean values (1.42/1.19 for PIB/AV452) and impairment was based on consensus diagnosis. CT differences between nonclinical and clinical groups were calculated in FreeSurfer v5.3 for multiple thresholds (p<.05/.01/.005/.001/.0005/.0001) using a cluster‐wise false discovery rate of .001, corrected across hemispheres, after controlling for age and sex. CT values were extracted for each threshold and used in ROC analyses (nonclinical reserved participants compared against preclinical and preclinical compared against clinical) to identify key cortical regions that best discriminated amyloid positivity and between unimpaired and impaired.ResultSignificant decreases in parietal and inferior temporal CT were observed between nonclinical and clinical (Figures 1 and 2). ROC analyses identified regions in the left (threshold .05) and right (threshold .005) hemispheres that best differentiated nonclinical from preclinical. Observed area under the curves (AUCs) of .772 and .830 exceeded those previously reported for autosomal‐dominant AD (.547/.540)1. Analyses differentiating preclinical from clinical observed AUCs of .786 for left (threshold .0005) and .770 for right (threshold .0005) hemispheres.ConclusionCT differences primarily within posterior cortical regions differentiated adults with DS by amyloid status and cognitive impairment. CT differences were more diffuse for amyloid positivity but more focal for impairment.1. Dincer (2020). NeuroImage: Clinical, 28, 102491.2. Su (2019). Alzheimer’s Dement, 11, 180‐190.

3 Are we Up-Front About Switching or are we Side-Stepping the Issue: Localization of Cognitive Switching Measures with Cortical Thickness

Objective:Set-shifting/switching tasks, among other measures of executive functioning, are typically thought to represent frontal lobe functioning. However, the neuroanatomical correlates of these tests are not fully established. The aim of this study was to examine associations between individual measures of set-shifting/switching and cortical thickness. We hypothesized that performance on each switching measure would strongly correlate with aggregated cortical thickness within the frontal lobe.Participants and Methods:Measures of interest included set-shifting subtests of the Delis-Kaplan Executive Function System (DKEFS): Color-Word Inhibition Switching, Category Switching, and Trail Making Test Number-Letter Switching. Archival data from an outpatient memory disorders clinic were reviewed to identify individuals whose neuropsychological evaluations included the measures of interest and had quality-assessed, volumetric MRI data available (n=243; 53.1% male, 81.9% Caucasian, Mage=72.4, SDage=6.7). Cortical thickness values were generated by FreeSurfer and averages were calculated for both frontal and temporal lobes, separately. Using partial correlations, controlling for age, we explored associations between each switching trial separately with right and left, frontal and temporal cortical thickness. The strength of associations within each lobe were then compared using Fisher's r-to-z transformations.Results:Category Switching was significantly correlated with left and right hemisphere temporal thickness (r=0.38 and 0.31, respectively), but was not significantly correlated with left or right frontal lobe cortical thickness (r=.12 and .07, respectively). Fisher's r-to-z transformations revealed significantly stronger relationships between Category Switching and temporal thickness, rather than frontal thicknesses. Trails Switching was also significantly correlated with left and right temporal cortical thickness (r=-0.28, and =-0.23, respectively) and bore weaker associations with frontal cortical thickness (r=-.13 and r = -.14 for left and right hemispheres, respectively). In contrast, Color-Word Inhibition-Switching did not show a significant relationship with frontal or temporal cortical thickness.Conclusions:Contrary to our hypothesis, stronger associations were observed with temporal lobe cortical thickness for Category Switching. Category Switching involves a language production component which could explain the strong association with temporal cortical thickness compared to frontal cortical thickness. Additionally, the pattern of associations between Trails Switching and frontal and temporal thickness was non-specific. Perhaps most striking is the lack of association between each switching measure and frontal cortical thickness, which was unexpected, given that these measures are used to assess executive functioning, broadly localized to the frontal lobe. Future directions involve examining the associations of these measure with subcortical structures and replicating these findings in larger datasets.

53 Are Boys (names) Really Just Like Animals? Comparing Multi-Category Fluency Trials from the D-KEFS in Predicting Temporal Cortical Thickness in an Outpatient Memory Disorders Population

Objective:Semantic fluency measures comprise a differing number of trials depending on the test battery and/or normative data used. Using semantic fluency trials from the Delis Kaplan Executive Function System (D-KEFS; Animals and Boys’ names), we sought to examine whether: 1) there was incremental benefit of multiple trials in associations with aggregated temporal cortical thickness and 2) patterns of neuroanatomical associations with specific temporal lobe structures differed between Animals and Boys’ names trials.Participants and Methods:Archival records of adults who completed a neuropsychological evaluation which included the semantic fluency measures of interest and had undergone structural MRI were identified (n=243, Mage=72.35 years, SDage=6.74, Female=46.9%). Cortical thickness values were obtained using FreeSurfer and averaged across sub-regions, separately for the left and right temporal lobe, per recommendations from the FreeSurfer group. Multiple linear regression models were fit to examine separate and incremental contribution of both Animals and Boys’ names, on temporal lobe thickness, including age, sex, and education in the models. Zero order correlations with each of the temporal cortical thickness areas (inferior, middle, and superior temporal; banks of the superior temporal sulcus, fusiform, transverse temporal, entorhinal, temporal pole, and parahippocampal cortices) were also computed to identify more focal neuroanatomical correlates.Results:Animals and Boys’ names trials individually accounted for a significant proportion of variance when predicting temporal cortical thickness over and above demographics, but Animals was a considerably stronger predictor for left temporal cortical thickness (Left: Animals AR2 =.127*, Boys’ names AR2 = .067*; Right: Animals AR2 =.074*, Boys’ names AR2 = .065*). The variance accounted for by Boys’ names incrementally over Animals was not significant (AR2 = .004 for left and .015 for right hemispheres, respectively). Similarly, though the composite Category fluency index accounted for a significant proportion of the variance independently, it did not add incrementally over and above Animals alone when predicting cortical thickness in either hemisphere. When examining simple correlations with specific temporal cortices, Animals consistently had correlations of a greater magnitude than Boys’ names within the left hemisphere (Animals r>.3 for superior, middle, inferior, and fusiform gyri; Boys’ names r< .3 for all cortical thickness regions). Greater variability was noted for associations with right temporal thickness but Animals continued to show associations of a greater magnitude of associations than Boys’ names for several sub-regions. * denotes significance at p < .01.Conclusions:The additional Boys’ names trial does not confer significant benefit over Animals alone, when predicting cortical thickness in either temporal lobe. Additionally, overall category fluency provided little incremental utility over and above the Animals trial alone in predicting temporal thickness. Psychometrically, it is expected that composites derived from multiple trials are more robust. However, this study demonstrates that it is important to examine whether the administration of additional trials is truly beneficial, particularly in a climate where brevity of neuropsychological assessment is critically desired. Further, psychometric tests have historically been validated against other neuropsychological measures, but it is critical we also validate measures against neuroanatomical correlates.

Correlation of NICU anthropometry in extremely preterm infants with brain development and language scores at early school age

Growth in preterm infants in the neonatal intensive care unit (NICU) is associated with increased global and regional brain volumes at term, and increased postnatal linear growth is associated with higher language scores at age 2. It is unknown whether these relationships persist to school age or if an association between growth and cortical metrics exists. Using regression analyses, we investigated relationships between the growth of 42 children born extremely preterm (< 28 weeks gestation) from their NICU hospitalization, standardized neurodevelopmental/language assessments at 2 and 4–6 years, and multiple neuroimaging biomarkers obtained from T1-weighted images at 4–6 years. We found length at birth and 36 weeks post-menstrual age had positive associations with language scores at 2 years in multivariable linear regression. No growth metric correlated with 4–6 year assessments. Weight and head circumference at 36 weeks post-menstrual age positively correlated with total brain volume and negatively with global cortical thickness at 4–6 years of age. Head circumference relationships remained significant after adjusting for age, sex, and socioeconomic status. Right temporal cortical thickness was related to receptive language at 4–6 years in the multivariable model. Results suggest growth in the NICU may have lasting effects on brain development in extremely preterm children.

Testing the brain maintenance and cognitive reserve hypothesis of cognitive aging: Application to vascular and metabolic risk factors

AbstractBackgroundTwo pathways that help explain cognitive health are 1) brain maintenance – referring to the relative absence of brain changes over time; 2) cognitive reserve – a property of the brain that allows for sustained cognitive ability in the presence of brain pathology. Both pathways influence cognitive aging and are best understood using longitudinal data. Our goal was to assess the effect of modifiable vascular/metabolic and lifestyle enrichment factors on these pathways using longitudinal brain changes measured on structural magnetic resonance imaging (MRI) and longitudinal cognitive decline. Lastly, we combined these pathways and their relationships in the same model.MethodWe identified 1250 participants from a well‐characterized sample of older adults from the Mayo Clinic Study of Aging with both longitudinal MRI and cognitive data. Linear mixed models were performed to assess the impact of modifiable factors on brain maintenance and cognitive reserve. Latent growth curve models (SEM) were used to assess the impact of brain structure and cognitive reserve on longitudinal cognition.ResultThe mean age of our sample was 78.8 years, with 45.4% female, and 27.1% APOE4 carriers. Mean follow‐up time was 4.0 years with a mean of 3.2 MRI scans per participant. Linear mixed models showed that poorer vascular/metabolic health (presence of vascular/metabolic conditions) was associated with lower cross‐sectional temporal region cortical thickness (‐0.014 (0.003), p&lt;0.001) and lower global cognition (‐0.042 (0.018), p = 0.024). Higher estimated cognitive reserve at baseline as assessed by education/occupation composite (0.103 (0.01), p&lt;0.001) was associated with higher global cognition. Unexpectedly, late‐life physical activities were related to lower global cognition (‐0.05 (0.007), p = 0.004). Our final latent growth curve SEM fit the data well showing temporal associations between unmodifiable characteristics, cognitive reserve, and brain structural pathways, as well as the influence of modifiable vascular/metabolic factors.ConclusionWe found that brain maintenance and cognitive reserve pathways were related to better cognition over time. We further showed that vascular/metabolic health impacts long‐term cognitive outcomes (i.e. cognitive aging) primarily through the brain maintenance pathway. These data provide a modeling scheme for future studies and can aid in assessing the pathways by which individual factors may influence cognitive aging.

Age-related and amyloid-beta-independent tau deposition and its downstream effects.

Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.

MicroRNA expression in extracellular vesicles as a novel blood-based biomarker for Alzheimer's disease.

Brain cell-derived small extracellular vesicles (sEVs) in blood offer unique cellular and molecular information related to the onset and progression of Alzheimer's disease (AD). We simultaneously enriched six specific sEV subtypes from the plasma and analyzed a selected panel of microRNAs (miRNAs) in older adults with/without cognitive impairment. Total sEVs were isolated from the plasma of participants with normal cognition (CN; n=11), mild cognitive impairment (MCI; n=11), MCI conversion to AD dementia (MCI-AD; n=6), and AD dementia (n=11). Various brain cell-derived sEVs (from neurons, astrocytes, microglia, oligodendrocytes, pericytes, and endothelial cells) were enriched and analyzed for specific miRNAs. miRNAs in sEV subtypes differentially expressed in MCI, MCI-AD, and AD dementia compared to the CN group clearly distinguished dementia status, with an area under the curve (AUC)>0.90 and correlated with the temporal cortical region thickness on magnetic resonance imaging (MRI). miRNA analyses in specific sEVs could serve as a novel blood-based molecular biomarker for AD. Multiple brain cell-derived small extracellular vesicles (sEVs) could be isolated simultaneously from blood. MicroRNA (miRNA) expression in sEVs could detect Alzheimer's disease (AD) with high specificity and sensitivity. miRNA expression in sEVs correlated with cortical region thickness on magnetic resonance imaging (MRI). Altered expression of miRNAs in sEVCD31 and sEVPDGFRβ suggested vascular dysfunction. miRNA expression in sEVs could predict the activation state of specific brain cell types.

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Microstructural evaluation of the brain with advanced magnetic resonance imaging techniques in cases of electrical status epilepticus during sleep (ESES).

The cause and treatment of electrical status epilepticus during sleep (ESES), one of the epileptic encephalopathies of childhood, is unclear. The aim of this study was to evaluate possible microstructural abnormalities in the brain using advanced magnetic resonance imaging (MRI) techniques in ESES patients with and without genetic mutations. This research comprised 12 ESES patients without structural thalamic lesions (6 with genetic abnormalities and 6 without) and 12 healthy children. Whole-exome sequencing was used for the genetic mutation analysis. Brain MRI data were evaluated using tractus-based spatial statistics, voxel-based morphometry, a local gyrification index, subcortical shape analysis, FreeSurfer volume, and cortical thickness. The data of the groups were compared. The mean age in the control group was 9.05 ± 1.85 years, whereas that in the ESES group was 9.45 ± 2.72 years. Compared to the control group, the ESES patients showed higher mean thalamus diffusivity (p < 0.05). ESES patients with genetic mutations had lower axial diffusivity in the superior longitudinal fasciculus and gray matter volume in the entorhinal region, accumbens area, caudate, putamen, cerebral white matter, and outer cerebellar areas. The superior and middle temporal cortical thickness increased in the ESES patients. This study is important in terms of presenting the microstructural evaluation of the brain in ESES patients with advanced MRI analysis methods as well as comparing patients with and without genetic mutations. These findings may be associated with corticostriatal transmission, ictogenesis, epileptogenesis, neuropsychiatric symptoms, cognitive impairment, and cerebellar involvement in ESES. Expanded case-group studies may help to understand the physiology of the corticothalamic circuitry in its etiopathogenesis and develop secondary therapeutic targets for ESES.