FreeSurfer V6 Research Articles

Revealing complexity: beyond the whole—segmentation of hippocampal subfields in adolescents with depression and its relationships with cognition

IntroductionThe occurrence of depression in adolescence, a critical period of brain development, linked with neuroanatomical and cognitive abnormalities. Neuroimaging studies have identified hippocampal abnormalities in those of adolescent patients. However, few studies have investigated the atypically developmental trends in hippocampal subfields in adolescents with depression and their relationships with cognitive dysfunctions.ObjectivesTo explore the structural abnormalities of hippocampal subfields in patients with youth depression and examine how these abnormalities associated with cognitive deficits.MethodsWe included a sample of 79 first-episode depressive patients (17 males, age = 15.54±1.83) and 71 healthy controls (23 males, age = 16.18±2.85). The severity of these adolescent patients was assessed by depression scale, suicidal risk and self-harm behavior. Nine cognitive tasks were used to evaluate memory, cognitive control and attention abilities for all participants. Bilateral hippocampus were segmented into 12 subfields with T1 and T2 weighted images using Freesurfer v6.0. A mixed analysis of variance was performed to assess the differences in subfields volumes between all patients and controls, and between patients with mild and severe depression. Finally, LASSO regression was conducted to explore the associations between hippocampal subfields and cognitive abnormalities in patients.ResultsWe found significant subfields atrophy in the CA1, CA2/3, CA4, dentate gyrus, hippocampal fissure, hippocampal tail and molecular layer subfields in patients. For those patients with severe depression, hippocampal subfields showed greater extensive atrophy than those in mild, particularly in CA1-4 subfields extending towards the subiculum. These results were similar across various severity assessments. Regression indicated that hippocampal subfields abnormalities had the strongest associations with memory dysfunction, and relatively week associations with cognitive control and attention. Notably, CA4 and dentate gyrus had the highest weights in the regression model.ConclusionsAs depressive severity increases, hippocampal subfield atrophy tends to spread from CA regions to surrounding areas, and primarily affects memory function in patients with youth depression. These results suggest hippocampus might be markers in progression of adolescent depression, offering new directions for early clinical intervention.Disclosure of InterestNone Declared

Amygdala structure and function and its associations with social-emotional outcomes in a low-risk preterm sample

Amygdala atypical volume development and functional connectivity (FC) at small gestational ages (GA) have been found across childhood. This adult-oriented study assesses whether altered amygdala structure and function is present following low-risk preterm birth. T1-weighted and resting-state functional MRI images of 33 low-risk preterm (30–36 weeks’ GA) and 29 full-term (37–42 weeks’ GA) young adults of both sexes, aged between 20 and 32 years old, were analyzed using FreeSurfer (v6.0.0) and Coon Toolbox (v21.a). The social-emotional assessment included Happé’s Strange Stories Test, the Moral Judgment Test, Delay-Discounting Test, Adult Self Report, and Emotion Regulation Questionnaire. No differences were found in social-emotional outcomes or amygdala volumes between the groups. Low-risk preterm young adults showed increased FC between the left amygdala, right amygdala and medial frontal cortex (MedFC) (F = 9.89, p-FWE = 0.009) at cluster level compared to their full-term peers. However, significant results at connection level were not observed between left and right amygdala. Lastly, increased FC at cluster level between the right amygdala and MedFC, and left amygdala and MedFC, was related to better social-emotional outcomes only in low-risk preterm young adults (F = 6.60, p-FWE = 0.036) at cluster level. At connection level, in contrast, only right amygdala–MedFC increased FC was significantly associated with better social-emotional outcomes. This study reveals that low-risk prematurity does not have an effect on social-emotional outcomes or structural amygdala volumes during young adulthood. However, individuals who were considered to be at a lower risk of exhibiting neurodevelopmental alterations following preterm birth demonstrated increased FC between the left and right amygdala and MedFC.

Tau Imaging in Late Traumatic Brain Injury: A [18F]MK-6240 Positron Emission Tomography Study.

Epidemiological studies have identified prior traumatic brain injury (TBI) as a risk factor for developing Alzheimer's disease (AD). Neurofibrillary tangles (NFTs) are common to AD and chronic traumatic encephalopathy following repetitive mild TBI. However, it is unclear if a single TBI is sufficient to cause accumulation of NFTs. We performed a [18F]MK-6240 positron emission tomography (PET) imaging study to assess NFTs in patients who had sustained a single TBI at least 2 years prior to study inclusion. Fourteen TBI patients (49 ± 20 years; 5 M/9 F; 8 moderate-severe, 1 mild-probable, 5 symptomatic-possible TBI) and 40 demographically similar controls (57 ± 19 years; 19 M/21 F) underwent simultaneous [18F]MK-6240 PET and magnetic resonance imaging (MRI) as well as neuropsychological assessment including the Cambridge Neuropsychological Test Automated Battery (CANTAB). A region-based voxelwise partial volume correction was applied, using parcels obtained by FreeSurfer v6.0, and standardized uptake value ratios (SUVR) were calculated relative to the cerebellar gray matter. Group differences were assessed on both a voxel- and a volume-of-interest-based level and correlations of [18F]MK-6240 SUVR with time since injury as well as with clinical outcomes were calculated. Visual assessment of TBI images did not show global or focal increases in tracer uptake in any subject. On a group level, [18F]MK-6240 SUVR was not significantly different in patients versus controls or between subgroups of moderate-severe TBI versus less severe TBI. Within the TBI group, One Touch Stockings problem solving and spatial working memory (executive function), reaction time (attention), and Mini-Mental State Examination (MMSE) (global cognition) were associated with [18F]MK-6240 SUVR. We found no group-based increase of [18F]MK-6240 brain uptake in patients scanned at least 2 years after a single TBI compared with healthy volunteers, which suggests that no NFTs are building up in the first years after a single TBI. Nonetheless, correlations with cognitive outcomes were found that warrant further investigation.

Extreme deviations from the normative model reveal cortical heterogeneity and associations with negative symptom severity in first-episode psychosis from the OPTiMiSE and GAP studies

There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness (n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants (n = 149, mean age = 26, SD = 6.7) and patient data (n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/– 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification.

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.

Longitudinal cortical thinning is associated with cognitive decline in MCI and Alzheimer’s disease in the Korean population

AbstractUndAlzheimer’s disease (AD) is characterized by cognitive dysfunction likely secondary to progressive neurodegeneration in the brain. However, to what extent regional cortical thickness (CT) changes are related to cognitive decline in the Asian population remains unclear.MethodWe measured CT using Freesurfer v6 from T1‐weighted magnetic resonance imaging (MRI) data in 603 Korean participants, including 71 young and 288 old cognitively unimpaired (CU young and CU old), 149 with mild cognitive impairment (MCI), and 92 AD from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). Cognitive function of each participant was quantified by the MMSE. MRI and cognitive data were acquired at baseline (n = 603) and a 2‐year follow‐up visit (n = 380). Linear mixed‐effect models were used to estimate diagnosis group, time, and group‐by‐time interaction effects on CT measurements, with age, sex, and education as covariates. Pearson’s correlations between CT measurements and MMSE total score were computed, corrected for multiple comparisons by false discovery rate (FDR).ResultAt baseline, CU old participants had lower CT values than CU young participants in the inferior parietal cortex and frontal and parietal regions. In comparison with CU old participants, MCI and AD showed widespread lower CT values, more pronounced in the medial temporal lobe (i.e., the entorhinal cortex and parahippocampal gyrus), inferior temporal cortex, medial prefrontal cortex, and medial parietal cortex (i.e., the posterior cingulate cortex and precuneus), with AD lower than MCI in these regions. These regions also showed the most longitudinal atrophy in both AD and MCI over 2 years. AD patients showed faster and more widespread atrophy patterns than MCI and CU old participants. We identified significant (PFDR<0.05) positive linear correlations between cognitive decline and regional CT measurements, particularly in regions showing significant cortical thinning across time.ConclusionIn this study, we replicated the typical cross‐sectional and longitudinal brain atrophy patterns, and relationships with cognitive decline in an Asian cohort. Our findings support the generalizability of atrophy patterns in MCI and AD, suggesting common neurobiological mechanisms underlying AD symptoms across different ethnoracial populations.

Sleep fragmentation is associated with lower cerebral structural integrity in females

AbstractBackgroundSex is a risk factor for Alzheimer’s disease (AD), with females accounting for two‐thirds of all cases. Epidemiological evidence showcases that sleep disturbances also increase AD risk, with females reporting more disrupted sleep in ageing compared to males. However, little is understood about how objective measures of sleep are associated with brain structural integrity, especially regarding the role of sex. We explored associations between actigraphy‐measured sleep and regional cortical thickness in middle‐aged cognitively unimpaired (CU) adults at risk of AD.MethodsWe included 151 CU adults from the ALFASleep project (mean age 64.6 years, 64.2% females) (Table 1). Correlates of sleep quality were measured using actigraphy (Actiwatch2®, Philips Respironics) for two weeks. The cortical thickness (CTh) of the “Alzheimer’s disease (AD) signature” composite region of interest (ROI) was calculated using FreeSurfer v6.0. We performed separate general linear models with CTh as the dependent variable, and actigraphy‐derived sleep parameters [total sleep time (TST), sleep efficiency, sleep latency, wake after sleep onset (WASO) and sleep fragmentation] as the predictors of interest. All models were corrected for age, sex, APOE‐ε4 status, sleep medication use and the time difference between MRI and actigraphy data acquisition. To investigate whether sex modified these associations we performed interactions between each actigraphy measure and sex. Finally, we performed stratified analyses to understand which group was driving any significant effects.ResultsHigher sleep fragmentation was associated with lower CTh (p = 0.006) in the whole group (Figure 1). Results remained significant after correction for sleep medication use. Significant interactions were found between sex and sleep efficiency, WASO and sleep fragmentation (Table 2, Figure 2). Stratified analyses showed that, among females, lower sleep efficiency (p = 0.003), higher WASO and higher fragmentation were significantly associated with lower CTh (p<0.001), without any significant associations among males.ConclusionsIn CU, higher sleep fragmentation is associated with reduced cortical thickness in areas vulnerable to early AD‐related neurodegeneration. Importantly, in females, lower sleep efficiency, as well as higher WASO and sleep fragmentation are associated with lower integrity in AD‐vulnerable regions. These results suggest that females in the preclinical stages of AD are more vulnerable to the effects of sleep fragmentation.

Total and posterior cerebral blood flow is associated with white matter hyperintensity volume and Alzheimer’s‐like patterns of brain atrophy in older adults

AbstractBackgroundSmall vessel cerebrovascular disease, often visualized as white matter hyperintensities (WMH) on T2‐weighted MRI scans, contributes to risk, progression, and, possibly, pathogenesis of Alzheimer’s disease (AD). When considered in the context of previous neuroimaging biomarker work in AD, WMH appear to colocalize with other markers of disease risk and progression, including metabolic changes, atrophy, and tau pathology, in areas perfused by the posterior circulation. In the current study, we used a novel MR‐based method, termed phase contrast, to quantitate total cerebral blood flow in anterior and posterior circulations and test its relationship with WMH volume and an AD‐like pattern of brain atrophy in older, community‐dwelling adults.MethodTwo hundred forty‐five older adult participants (77±5.6 mean±SD age, 66% women, 42% Latinx, 30% Black, and 28% White individuals) in the Washington Heights Inwood Columbia Aging Project (WHICAP) received T1‐weighted, T2‐weighted (FLAIR), and phase contrast MR imaging. 2D phase contrast imaging can be used to quantify absolute blood flow rates with cross‐sectional velocity‐encoding of major vasculature leading into the brain. Blood flow rates in the anterior circulation (carotid arteries) and posterior circulation (vertebral arteries) were derived with Medis QFlow 4.0. WMH volume and cortical thickness in AD‐signature regions were derived with in‐house software and FreeSurfer v6.0, respectively. Separate general linear models tested the association of total, anterior, and posterior blood flow rates with WMH volumes and AD‐signature cortical thickness.ResultLower total cerebral blood flow was associated with increased total WMH volume (β = ‐0.14, p<0.05, 95%CI [‐1.37E‐2, ‐7.32E‐4]), an effect that was stronger for posterior flow (β_posterior = ‐0.17, 95%CI [‐3.7E‐2, 2.5E3], β_anterior = ‐0.11, 95%CI [‐1.9E‐2, 5.4E3]). Lower posterior blood flow specifically was associated with lower AD‐signature cortical thickness, but only in older participants (age interaction term: β = ‐3.14, p<0.01, 95%CI [‐2.0E‐4, ‐3.5E‐5]).ConclusionLower total cerebral blood flow, particularly in the posterior circulation, is associated with increased WMH volume and decreased cortical thickness, two neuroimaging markers that are implicated in risk and progression of AD. Future work that examines whether or how diminished total cerebral blood flow accounts for the colocalization of AD biomarkers across modalities will provide insight into the vascular contributions to AD.

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.

Relationship of structural and functional visual biomarkers with measures of amyloid, tau, and neurodegeneration across the AD continuum

AbstractBackgroundThe eye often reflects changes seen in the brain in neurodegenerative diseases. This study sought to examine the relationship of contrast sensitivity measured using frequency doubling technology (FDT) and retinal thickness measured using optical coherence tomography (OCT) with temporal lobe neurodegeneration, cerebral tau deposition, and mean plasma ptau181 in older adults along the Alzheimer’s disease (AD) continuum.MethodParticipants included 28 individuals with subjective cognitive decline (SCD), 18 mild cognitive impairment (MCI), 4 with AD, and 30 age‐matched cognitive normal (CN) from the Indiana Memory and Aging Study at the Indiana ADRC. Participants were excluded from the study if they had significant eye disease determined to interfere with OCT, FDT, non‐AD dementia, or exclusion for MRI or PET. Mean deviation (MD) and pattern standard deviation (PSD) from FDT were used as measures of contrast sensitivity. OCT scans from each eye to measure retinal thickness in the retinal nerve fiber layer (RNFL) and macula. MRI scans were processed using Freesurfer v6 to measure medial (MTL) and lateral temporal lobe (LTL) volumes. LTL SUVR values were extracted from [18F]flortaucipir PET scans. Plasma ptau 181 was measured using a SIMOA assay. Finally, the association between contrast sensitivity, average RNFL thickness, macular volumes with temporal lobe volumes, LTL tau, and mean plasma ptau181 was assessed using a partial Pearson correlation, covaried for age, sex, and diagnosis. p<0.05 was considered significant.ResultRNFL thickness was decreased in patients with AD. Hippocampal volume correlated with RNFL thickness and macular volume in both eyes and with PSD in the left eye. The inferior temporal volume correlated with MD in both eyes, while mean plasma ptau181 with PSD in both eyes. Finally, lateral temporal lobe tau was correlated with the inner retinal layers of ganglion cell layer plus inner plexiform layer thickness.ConclusionContrast sensitivity correlates with temporal lobe volumes and mean plasma ptau181. RNFL thinning and macular volumes are associated with hippocampal atrophy, and inner retinal nuclear layers correlate with lateral temporal tau. Imaging of the eye may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.

52 Open Access, Normative Morphometric Software Indicate Neurodegeneration Associated with Episodic Memory Dysfunction in Amnestic MCI

Objective:Neurodegeneration in Alzheimer’s disease (AD) is typically assessed through brain MRI, and proprietary software can provide normative quantification of regional atrophy. However, proprietary software can be cost-prohibitive for research settings. Thus, we used the freely available software NOrmative Morphometry Image Statistics (NOMIS) which generates normative z-scores of segmented T1-weighted images from FreeSurfer to determine if these scores replicate established patterns of neurodegeneration in the context of amnestic mild cognitive impairment (aMCI), and whether these measures correlate with episodic memory test performance.Participants and Methods:Patients with aMCI (n = 25) and cognitively normal controls (CN; n = 74) completed brain MRI and two neuropsychological tests of episodic memory (the Rey Auditory Verbal Learning Test and the Wechsler Logical Memory Tests I & II), from which a single composite of normed scores was computed. A subset returned for follow-up (aMCI n = 11, CN n = 52) after ∼15 months and completed the same procedures. T1-weighted images were segmented using FreeSurfer v6.0 and the outputs were submitted to NOMIS to generate normative morphometric estimates for AD-relevant regions (i.e., hippocampus, parahippocampus, entorhinal cortex, amygdala) and control regions (i.e., cuneus, lingual gyrus, pericalcarine gyrus), controlling for age, sex, head size, scanner manufacturer, and field strength. Baseline data were used to test for differences in ROI volumes and memory between groups and to assess the within-group associations between ROI volumes and memory performance. We also evaluated changes in ROI volumes and memory over the follow-up interval by testing the main effects of time, group, and the group X time interactions. Lastly, we tested whether change in volume was associated with declines in memory.Results:At baseline, the aMCI group performed 2 SD below the CN group on episodic memory and exhibited smaller volumes in all AD-relevant regions (volumes 0.4 - 1.2 SD below CN group, ps < .041). There were no group differences in control region volumes. Memory performance was associated with volumes of the AD-relevant regions in the aMCI group (average rho = .51) but not with control regions. ROI volumes were not associated with memory in the CN group. At follow-up, the aMCI group continued to perform 2 SD below the CN group on episodic memory tests; however, change of performance over time did not differ between groups. The aMCI group continued to exhibit smaller volumes in all AD-relevant regions than the CN group, with greater declines in hippocampal volume (17% annual decline vs. 8% annual decline) and entorhinal volume (54% annual decline vs. 5% annual decline). There was a trending Group X Time interaction such that decrease in hippocampal volume was marginally associated with decline in memory for the aMCI group but not the CN group.Conclusions:Normative morphometric values generated from freely available software demonstrated expected patterns of group differences in AD-related volumes and associations with memory. Significant effects were localized to AD-relevant brain regions and only occurred in the aMCI group. These findings support the validity of these free tools as reliable and cost-effective alternatives to proprietary software.

Demystifying the Role of Radiation Dose Bath in Brain Injury Using Machine Learning.

It is well known that high-dose radiation results in brain injury, the long-term effects of low-dose radiation, however, is uncertain. The purpose of this study was to investigate the role of low-dose bath on MRI changes, on both clinical and micro-architectural levels, using machine learning and computational methods. Six hundreds and fifty-six temporal lobe and 45 whole brain DVHs from patients treated for nasopharyngeal cancer (NPC) with IMRT or proton were included in this study. Temporal lobe injury (TLI) was defined as development of new T1 enhancement on MRI with or without surrounding T2 edema. Patients were divided randomly into train (50%) and test (50%) sets. Accuracy and AUC were used to evaluate the model performance. Minimum redundancy maximum relevance (MRMR) or SHAP algorithms was employed for feature selection. Support vector machine or random forest was used for classification. Automated cortical region segmentation using FreeSurfer v6 was performed in 33 patients with a minimum follow-up of 4 years. Architectural and biological MRI changes were determined in 34 different brain regions for each individual patient. The top-ranked temporal lobe features predicting TLI were V66/V38 for IMRT patients and V10 for proton patients with an AUC of 0.95 and 0.74, respectively. For whole brain, the top features were V16 and V13 with an AUC of 0.70. The rates of TLI at 5 years for V10-20(whole brain) ≥ 180cc and V10-20(whole brain) < 180 were 39.5% and 6.2%, respectively (HR = 5.5, 95% CI 1.4-22.0, p = 0.02). There were global changes in gray matter thickness, with most pronounced changes occurred in parietal lobe (-4.79%, p = 0.007) and occipital lobe (-5.68%, p = 0.03). Similarly, there were diffuse changes in white matter and subcortical volume. After radiation, the frontal lobe increased by 17.5% (p = 0.04), lateral ventricle 41% (p = 0.03), and choroid plexus 34.3% (p = 0.03). Low-dose radiation bath is associated with increased risk of temporal lobe injury and global disruption in brain architecture in NPC survivors.

Validating ASHS-T1 automated entorhinal and transentorhinal cortical segmentation in Alzheimer's disease

The current study aimed to validate entorhinal and transentorhinal cortical volumes measured by the automated segmentation tool Automatic Segmentation of Hippocampal Subfields (ASHS-T1). The study sample comprised 34 healthy controls (HCs), 37 individuals with amnestic mild cognitive impairment (aMCI), and 29 individuals with Alzheimer's disease (AD) dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Entorhinal and transentorhinal cortical volumes were assessed using ASHS-T1, manual segmentation, as well as a widely used automated segmentation tool, FreeSurfer v6.0.1. Mean differences, intraclass correlation coefficients, and Bland–Altman plots were computed. ASHS-T1 tended to underestimate entorhinal and transentorhinal cortical volumes relative to manual segmentation and FreeSurfer. There was variable consistency and low agreement between ASHS-T1 and manual segmentation volumes. There was low-to-moderate consistency and low agreement between ASHS-T1 and FreeSurfer volumes. There was a trend toward higher consistency and agreement for the entorhinal cortex in the aMCI and AD groups compared to the HC group. Despite the differences in volume measurements, ASHS-T1 was sensitive to entorhinal and transentorhinal cortical atrophy in both early and late disease stages. Based on the current study, ASHS-T1 appears to be a promising tool for automated entorhinal and transentorhinal cortical volume measurement in individuals with likely underlying AD.

Altered Sex Differences in Hippocampal Subfield Volumes in Schizophrenia.

The hippocampus is a heterogenous brain structure that differs between the sexes and has been implicated in the pathophysiology of psychiatric illnesses. Here, we explored sex and diagnostic group differences in hippocampal subfield volumes, in individuals with schizophrenia spectrum disorder (SZ), bipolar disorders (BD), and healthy controls (CTL). One thousand and five hundred and twenty-one participants underwent T1-weighted magnetic resonance imaging (SZ, n = 452, mean age 30.7 ± 9.2 [SD] years, males 59.1%; BD, n = 316, 33.7 ± 11.4, 41.5%; CTL, n = 753, 34.1 ± 9.1, 55.6%). Total hippocampal, subfield, and intracranial volumes were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple regression models were fitted to examine sex-by-diagnostic (sub)group interactions in volume. In SZ and BD, separately, associations between volumes and clinical as well as cognitive measures were examined between the sexes using regression models. Significant sex-by-group interactions were found for the total hippocampus, dentate gyrus, molecular layer, presubiculum, fimbria, hippocampal-amygdaloid transition area, and CA4, indicating a larger volumetric deficit in male patients relative to female patients when compared with same-sex CTL. Subgroup analyses revealed that this interaction was driven by males with schizophrenia. Effect sizes were overall small (partial η < 0.02). We found no significant sex differences in the associations between hippocampal volumes and clinical or cognitive measures in SZ and BD. Using a well-powered sample, our findings indicate that the pattern of morphological sex differences in hippocampal subfields is altered in individuals with schizophrenia relative to CTL, due to higher volumetric deficits in males.

Physical activity engagement, memory function, and hippocampal volume in adults with down syndrome

AbstractBackgroundHigher engagement in moderate‐to‐vigorous physical activity (PA) is related to better cognitive functioning in neurotypical adults; however, little is known about the impact of PA on cognitive aging in adults with Down syndrome (DS). Individuals with DS have three copies of the chromosome 21, which includes the gene for the amyloid precursor protein, resulting in an increased risk for/earlier onset of Alzheimer’s disease. The goal of this study was to understand the relationship between moderate PA engagement and memory functioning in non‐demented adults with DS.MethodAdults with DS participated in an ancillary Lifestyle study linked to the Alzheimer’s Biomarkers Consortium for Down Syndrome (N = 54). Participants completed the Cued Recall Test (CRT) to measure episodic memory. The total free + cued CRT score was used in analyses. Participants wore a wrist‐worn accelerometer (GT9X) for 7 days to measure PA. Moderate PA was classified using the Freedson cutpoints in ActiLife software and was defined as the daily average minutes. Structural MRI data were acquired within 18 months of actigraphy/cognitive data collection. Hippocampal volume was extracted using Freesurfer v5.3. Associations between moderate PA engagement, memory, and hippocampal volume were evaluated with hierarchical linear regressions controlling for relevant covariates (age, body mass index (BMI), intracranial volume (ICV)).ResultParticipants were 37.81 years old (SD = 8.15 years) and 55.6% female. They spent ∼10.67% of their time engaged in moderate PA (SD = 7.48%). Participants recalled an average of 32.09 items on the CRT (SD = 6.09, range = 7‐36). After controlling for age and BMI, greater moderate PA engagement was associated with higher total recall score (b = 0.279, p = 0.044). After controlling for age and ICV, moderate PA engagement was not significantly associated with hippocampal volume (p = 0.48). Greater hippocampal volume was associated with higher total recall score after controlling for age and ICV (b = 0.496, p = 0.004).ConclusionA higher proportion of time spent engaging in moderate PA was related to better memory function in adults with DS. While greater hippocampal volume was related to better memory performance, it was not associated with moderate PA engagement. Greater moderate PA engagement may be a promising lifestyle behavior to preserve memory in aging adults with DS.

Quantification of Thalamic Volume in Multiple Sclerosis: From the Multicenter INNI Dataset Towards the Clinical Application (P10-3.002)

Quantification of Thalamic Volume in Multiple Sclerosis: From the Multicenter INNI Dataset Towards the Clinical Application (P10-3.002)

Sex differences in brainstem structure volumes in patients with schizophrenia

Patients with schizophrenia (SZ) display moderate reductions in brainstem volumes, including the midbrain, pons, superior cerebellar peduncle, and medulla oblongata. Here, we investigated alterations in brainstem volumes between SZ patients and healthy controls (HCs) stratified by sex. T1-weighted MRI brain scans were processed with FreeSurfer v6.0 in 156 SZ patients (61 males/95 females) and 205 HCs (133/72). Of the brainstem structures, pons volumes were significantly reduced, particularly in male SZ patients. The decreased pons volumes were correlated with lower levels of education but not duration of illness in male patients. These findings suggest that the reduction in pons volume in male patients might be occurred before or around the onset of the disorder.

Cytomegalovirus infection associated with smaller cerebellum in severe mental illness

IntroductionPostnatal cytomegalovirus (CMV) infection of immunocompetent hosts is usually inapparent but typically results in lifelong latency. Congenital CMV infections as well as CMV infections in patients with immunodeficiencies have been linked to major cerebellar pathology. Patients with severe mental illness have been repeatedly found to have smaller cerebellum, and they may be particularly susceptible to CMV infections. Finally, both animal and human studies have shown a differential male and female immune response to CMV.ObjectivesWe evaluated whole cerebellar grey matter volumes (CGMV) in CMV immunoglobulin G (IgG) seropositive (CMV+) and seronegative (CMV-) patients with severe mental illness and healthy controls (HC). We hypothesized that CMV seropositivity, reflecting previous infection and current latency, is associated with smaller CGMV in patients but not in HC, and that such a putative association may be sex-dependent.MethodsWe included 529 adult patients with severe mental illness (CMV+ 57%, women 48%), i.e., 324 patients with schizophrenia spectrum disorders and 205 patients with bipolar spectrum disorders, and 494 HC (CMV+ 56%, women 45%). MRI scans were obtained with a 1.5T Siemens scanner (n=596) and two 3.0T General Electric scanners (n=427), and processed with FreeSurfer v6.0. Circulating CMV IgG concentrations were measured with immunoassays. In age-, scanner- and estimated total intracranial volume-adjusted analyses of covariance (ANCOVAs), we investigated main and interaction effects of CMV status and sex on CGMV in patients and HC.ResultsCMV+ patients had smaller CGMV than CMV- patients (p=0.042). There was no CGMV difference between CMV+ and CMV- HC (p=0.858). The adjusted CGMV means in CMV+ patients and CMV- patients were 115078 mm3 and 116725 mm3, respectively (p=0.042); the adjusted CGMV means in CMV+ and CMV- HC were 117980 mm3 and 117840 mm3, respectively (p=0.858) (Image). Among patients, a trend towards CMV-by-sex interaction (p=0.073) was found. Post-hoc analyses showed a significant CMV-CGMV association in the female patient group (p=0.005), with no association among male patients (p=0.840).Image:ConclusionsCMV IgG seropositivity is associated with smaller cerebellum in severe mental illness, an effect driven by the female patients, but not among HC. This may indicate a CMV-related deleterious impact on cerebellum restricted to patients.Disclosure of InterestNone Declared

Phone-Based Memory Test Predicts In-Clinic Memory, MCI Diagnosis, and Alzheimer’s Neuroimaging &amp; Plasma Biomarkers

Background: Early detection of dementia has become important for interventions that are developed to slow disease progression. Due to technological advancements, healthcare is trending toward using more telehealth screenings due to the convenience it provides patients. In our research, we evaluate the accuracy of a phone-based memory screen at diagnosing mild cognitive impairment.&#x0D; Methods: 181 participants from the Indiana Alzheimer’s Disease Research Center (IADRC)were screened using the Memory and Aging Telephone Screen (MATS) and diagnosed as cognitively normal (CN), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). 177 underwent Rey Auditory Verbal Learning Testing (RAVLT); 103 received Aβ PET scans([18F]florbetapir or [18F]florbetaben); 91 had plasma tau levels measured; and 140 received MRI scans (Freesurfer v6). ANCOVAs were used to evaluate differences between diagnostic groups covarying for age, sex, and education. ROC analysis and logistic regressions were used to predict MCI and Aβ positivity. Partial correlations covarying for sex and age (and education for RAVLT) were conducted to evaluate relationships between MATS scores with RAVLT, brain atrophy, pTau level, and amyloid deposition. &#x0D; Results: MCI patients showed significantly lower MATS scores for immediate (p&lt;0.001) and delayed recall (p&lt;0.001) compared to controls. Scores on the MATS correlated well with clinical based testing (MATS learning vs RAVLT learning: r2= 0.318, p&lt;0.001). MATS scores showed strong associations for Alzheimer biomarkers: amyloid and tau deposition, hippocampus atrophy, and temporal atrophy. The accuracy of MATS to predict MCI was found to be about 75% with cutoffs of ≤16 for learning and ≤4 for delayed recall.&#x0D; Conclusion and Potential Impact: The findings support that the phone memory screen can be used to detect dementia early in disease progression. By establishing cutoffs for this screening tool, physicians can easily and quickly detect signs of early Alzheimer’s disease, thus allowing for early intervention to slow disease progression.

Cortical Iron Accumulation as an Imaging Marker for Neurodegeneration in Clinical Cognitive Impairment Spectrum: A Quantitative Susceptibility Mapping Study.

Cortical iron deposition has recently been shown to occur in Alzheimer's disease (AD). In this study, we aimed to evaluate how cortical gray matter iron, measured using quantitative susceptibility mapping (QSM), differs in the clinical cognitive impairment spectrum. This retrospective study evaluated 73 participants (mean age ± standard deviation, 66.7 ± 7.6 years; 52 females and 21 males) with normal cognition (NC), 158 patients with mild cognitive impairment (MCI), and 48 patients with AD dementia. The participants underwent brain magnetic resonance imaging using a three-dimensional multi-dynamic multi-echo sequence on a 3-T scanner. We employed a deep neural network (QSMnet+) and used automatic segmentation software based on FreeSurfer v6.0 to extract anatomical labels and volumes of interest in the cortex. We used analysis of covariance to investigate the differences in susceptibility among the clinical diagnostic groups in each brain region. Multivariable linear regression analysis was performed to study the association between susceptibility values and cognitive scores including the Mini-Mental State Examination (MMSE). Among the three groups, the frontal (P < 0.001), temporal (P = 0.004), parietal (P = 0.001), occipital (P < 0.001), and cingulate cortices (P < 0.001) showed a higher mean susceptibility in patients with MCI and AD than in NC subjects. In the combined MCI and AD group, the mean susceptibility in the cingulate cortex (β = -216.21, P = 0.019) and insular cortex (β = -276.65, P = 0.001) were significant independent predictors of MMSE scores after correcting for age, sex, education, regional volume, and APOE4 carrier status. Iron deposition in the cortex, as measured by QSMnet+, was higher in patients with AD and MCI than in NC participants. Iron deposition in the cingulate and insular cortices may be an early imaging marker of cognitive impairment related neurodegeneration.