Neuroimaging Findings in US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms. Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group. Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit. Exposure: AHIs. Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling. Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs. Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.

Antibody Profiling in COVID-19 Patients with Different Severities by Using Spike Variant Protein Microarrays.

The disease progression of COVID-19 varies from mild to severe, even death. However, the link between COVID-19 severities and humoral immune specificities is not clear. Here, we developed a multiplexed spike variant protein microarray (SVPM) and utilized it for quantifying neutralizing activity, drug screening, and profiling humoral immunity. First, we demonstrated the competition between antispike antibody and ACE2 on SVPM for measuring the neutralizing activity against multiple spike variants. Next, we collected the serums from healthy subjects and COVID-19 patients with different severities and profile the neutralizing activity as well as antibody isotypes. We identified the inhibition of ACE2 binding was stronger against multiple variants in severe compared to mild/moderate or critical patients. Moreover, the serum IgG against nonstructural protein 3 was elevated in severe but not in mild/moderate and critical cases. Finally, we evaluated two ACE2 inhibitors, Ramipril and Perindopril, and found the dose-dependent inhibition of ACE2 binding to all the spike variants except for B.1.617.3. Together, the SVPM and the assay procedures provide a tool for profiling neutralizing antibodies, antibody isotypes, and reagent specificities.

Development of SARS-CoV-2 variant protein microarray for profiling humoral immunity in vaccinated subjects.

SARS-CoV-2 is quickly evolving from wild-type to many variants and spreading around the globe. Since many people have been vaccinated with various types of vaccines, it is crucial to develop a high throughput platform for measuring the antibody responses and surrogate neutralizing activities against multiple SARS-CoV-2 variants. To meet this need, the present study developed a SARS-CoV-2 variant (CoVariant) array which consists of the extracellular domain of spike variants, e.g., wild-type, D614G, B.1.1.7, B.1.351, P.1, B.1.617, B.1.617.1, B.1.617.2, and B.1.617.3. A surrogate virus neutralization on the CoVariant array was established to quantify the bindings of antibody and host receptor ACE2 simultaneously to spike variants. By using a chimeric anti-spike antibody, we demonstrated a broad binding spectrum of antibodies while inhibiting the bindings of ACE2 to spike variants. To monitor the humoral immunities after vaccination, we collected serums from unvaccinated, partial, or fully vaccinated individuals with either mRNA-1273 or AZD1222 (ChAdOx1). The results showed partial vaccination increased the surrogate neutralization against all the mutants while full vaccination boosted the most. Although IgG, IgA, and IgM isotypes correlated with surrogate neutralizing activities, they behave differently throughout the vaccination processes. Overall, this study developed CoVariant arrays and assays for profiling the humoral responses which are useful for immune assessment, vaccine research, and drug development.

Development and Application of Human Coronavirus Protein Microarray for Specificity Analysis.

Coronavirus is an enveloped RNA virus that causes mild to severe respiratory diseases in humans, including HKU1-CoV, 229E-CoV, NL63-CoV, OC43-CoV, SARS-CoV, MERS-CoV, and SARS-CoV-2. Due to the outbreak of SARS-CoV-2, it is important to identify the patients and investigate their immune responses. Protein microarray is one of the best platforms to profile the antibodies in the blood because of its fast, multiplexed, and sensitive nature. To fully understand the immune responses and biological specificities, this study developed a human coronavirus (HCoV) protein microarray and included all seven human coronaviruses and three influenza viruses. Each protein was printed in triplicate and formed 14 identical blocks per array. The HCoV protein microarray showed high reproducibility and sensitivity to the monoclonal antibodies against spike and nucleocapsid protein with detection limits of 10-200 pg. The HCoV proteins that were immobilized on the array were properly folded and functional by showing interactions with a known human receptor, e.g., ACE2. By profiling the serum IgG and IgA from 32 COVID-19 patients and 36 healthy patients, the HCoV protein microarray demonstrated 97% sensitivity and 97% specificity with two biomarkers. The results also showed the cross-reactivity of IgG and IgA in COVID-19 patients to spike proteins from various coronaviruses, including that from SARS-CoV, HKU1-CoV, and OC43-CoV. Finally, an innate immune protein named surfactant protein D showed broad affinities to spike proteins in all human coronaviruses. Overall, the HCoV protein microarray is multiplexed, sensitive, and specific, which is useful in diagnosis, immune assessment, biological development, and drug screening.

Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI.

OBJECTIVE: To determine whether neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) measured in serum relate to traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) measures of traumatic axonal injury (TAI) in patients with TBI. METHODS: Patients with TBI (n = 162) and controls (n = 68) were prospectively enrolled between 2011 and 2019. Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days, and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury. RESULTS: At enrollment, patients with TBI had increased serum NfL compared to controls (p < 0.0001). Serum NfL decreased over the course of 5 years but remained significantly elevated compared to controls. Serum NfL at 30 days distinguished patients with mild, moderate, and severe TBI from controls with an area under the receiver-operating characteristic curve (AUROC) of 0.84, 0.92, and 0.92, respectively. At enrollment, serum GFAP was elevated in patients with TBI compared to controls (p < 0.001). GFAP showed a biphasic release in serum, with levels decreasing during the first 6 months of injury but increasing over the subsequent study visits. The highest AUROC for GFAP was measured at 30 days, distinguishing patients with moderate and severe TBI from controls (both 0.89). Serum tau and UCH-L1 showed weak associations with TBI severity and neuroimaging measures. Longitudinally, serum NfL was the only biomarker that was associated with the likely rate of MRI brain atrophy and DTI measures of progression of TAI. CONCLUSIONS: Serum NfL shows greater diagnostic and prognostic utility than GFAP, tau, and UCH-L1 for subacute and chronic TBI. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that serum NfL distinguishes patients with mild TBI from healthy controls.

Neurofilament light as a biomarker in traumatic brain injury.

OBJECTIVE: To determine whether serum neurofilament light (NfL) correlates with CSF NfL, traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) estimates of traumatic axonal injury (TAI). METHODS: Participants were prospectively enrolled in Sweden and the United States between 2011 and 2019. The Swedish cohort included 45 hockey players with acute concussion sampled at 6 days, 31 with repetitive concussion with persistent postconcussive symptoms (PCS) assessed with paired CSF and serum (median 1.3 years after concussion), 28 preseason controls, and 14 nonathletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls). Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury. RESULTS: In athletes with paired specimens, CSF NfL and serum NfL were correlated (r = 0.71, p < 0.0001). CSF and serum NfL distinguished players with PCS >1 year from PCS ≤1 year (area under the receiver operating characteristic curve [AUROC] 0.81 and 0.80). The AUROC for PCS >1 year vs preseason controls was 0.97. In the clinic-based cohort, NfL at enrollment distinguished patients with mild from those with moderate and severe TBI (p < 0.001 and p = 0.048). Serum NfL decreased over the course of 5 years (ß = -0.09 log pg/mL, p < 0.0001) but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI. CONCLUSIONS: Serum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that increased concentrations of NfL distinguish patients with TBI from controls.

Vascular Abnormalities within Normal Appearing Tissue in Chronic Traumatic Brain Injury.

Magnetic resonance imaging (MRI) is a powerful tool for visualizing traumatic brain injury(TBI)-related lesions. Trauma-induced encephalomalacia is frequently identified by its hyperintense appearance on fluid-attenuated inversion recovery (FLAIR) sequences. In addition to parenchymal lesions, TBI commonly results in cerebral microvascular injury, but its anatomical relationship to parenchymal encephalomalacia is not well characterized. The current study utilized a multi-modal MRI protocol to assess microstructural tissue integrity (by mean diffusivity [MD] and fractional aniosotropy [FA]) and altered vascular function (by cerebral blood flow [CBF] and cerebral vascular reactivity [CVR]) within regions of visible encephalomalacia and normal appearing tissue in 27 chronic TBI (minimum 6 months post-injury) subjects. Fifteen subjects had visible encephalomalacias whereas 12 did not have evident lesions on MRI. Imaging from 14 age-matched healthy volunteers were used as controls. CBF was assessed by arterial spin labeling (ASL) and CVR by measuring the change in blood-oxygen-level-dependent (BOLD) MRI during a hypercapnia challenge. There was a significant reduction in FA, CBF, and CVR with a complementary increase in MD within regions of FLAIR-visible encephalomalacia (p < 0.05 for all comparisons). In normal-appearing brain regions, only CVR was significantly reduced relative to controls (p < 0.05). These findings indicate that vascular dysfunction represents a TBI endophenotype that is distinct from structural injury detected using conventional MRI, may be present even in the absence of visible structural injury, and persists long after trauma. CVR may serve as a useful diagnostic and pharmacodynamic imaging biomarker of traumatic microvascular injury.

Reduced distortion artifact whole brain CBF mapping using blip-reversed non-segmented 3D echo planar imaging with pseudo-continuous arterial spin labeling.

PURPOSE: To implement and evaluate interleaved blip-up, blip-down, non-segmented 3D echo planar imaging (EPI) with pseudo-continuous arterial spin labeling (pCASL) and post-processing for reduced susceptibility artifact cerebral blood flow (CBF) maps. MATERIALS AND METHODS: 3D EPI non-segmented acquisition with a pCASL labeling sequence was modified to include alternating k-space coverage along phase encoding direction (referred to as "blip-reversed") for alternating dynamic acquisitions of control and label pairs. Eight volunteers were imaged on a 3T scanner. Images were corrected for distortion using spatial shifting transformation of the underlying field map. CBF maps were calculated and compared with maps obtained without blip reversal using matching gray matter (GM) images from a high resolution 3D scan. Additional benefit of using the correction for alternating blip-up and blip-down acquisitions was assessed by comparing to corrected blip-up only and corrected blip-down only CBF maps. Matched Student t-test of overlapping voxels for the eight volunteers was done to ascertain statistical improvement in distortion. RESULTS: Mean CBF value in GM for the eight volunteers from distortion corrected CBF maps was 50.8±9.9ml/min/100 gm tissue. Corrected CBF maps had 6.3% and 4.1% more voxels in GM when compared with uncorrected blip up (BU) and blip down (BD) images, respectively. Student t-test showed significant reduction in distortion when compared with blip-up images and blip-down images (p<0.001). When compared with corrected BU and corrected BD only CBF maps, BU and BD corrected maps had 2.3% and 1% more voxels (p=0.006 and 0.04, respectively). CONCLUSION: Pseudo-continuous arterial spin labeling with non-segmented 3D EPI acquisition using alternating blip-reversed k-space traversal and distortion correction provided significantly better matching GM CBF maps. In addition, employing alternating blip-reversed acquisitions during pCASL acquisition resulted in statistically significant improvement over corrected blip-up and blip-down CBF maps.

Brain Volume, Connectivity, and Neuropsychological Performance in Mild Traumatic Brain Injury: The Impact of Post-Traumatic Stress Disorder Symptoms.

Post-traumatic stress disorder (PTSD) is commonly associated with mild traumatic brain injury (mTBI). To better understand their relationship, we examined neuroanatomical structures and neuropsychological performance in a sample of individuals with mTBI, with and without PTSD symptoms. Thirty-nine subjects with mTBI were dichotomized into those with (n = 12) and without (n = 27) significant PTSD symptoms based on scores on the PTSD Checklist. Using a region-of-interest approach, fronto-temporal volumes, fiber bundles obtained by diffusion tensor imaging, and neuropsychological scores were compared between the two groups. After controlling for total intracranial volume and age, subjects with mTBI and PTSD symptoms exhibited volumetric differences in the entorhinal cortex, an area associated with memory networks, relative to mTBI-only patients (F = 4.28; p = 0.046). Additionally, subjects with PTSD symptoms showed reduced white matter integrity in the right cingulum bundle (axial diffusivity, F = 6.04; p = 0.020). Accompanying these structural alterations, mTBI and PTSD subjects also showed impaired performance in encoding (F = 5.98; p = 0.019) and retrieval (F = 7.32; p = 0.010) phases of list learning and in tests of processing speed (Wechsler Adult Intelligence Scale Processing Speed Index, F = 12.23; p = 0.001; Trail Making Test A, F = 5.56; p = 0.024). Increased volume and white matter disruptions in these areas, commonly associated with memory functions, may be related to functional disturbances during cognitively demanding tasks. Differences in brain volume and white matter integrity between mTBI subjects and those with mTBI and co-morbid PTSD symptoms point to neuroanatomical differences that may underlie poorer recovery of mTBI subjects who experience PTSD symptoms. These findings support theoretical models of PTSD and its relationship to learning deficits.

Patch Based Synthesis of Whole Head MR Images: Application to EPI Distortion Correction.

Different magnetic resonance imaging pulse sequences are used to generate image contrasts based on physical properties of tissues, which provide different and often complementary information about them. Therefore multiple image contrasts are useful for multimodal analysis of medical images. Often, medical image processing algorithms are optimized for particular image contrasts. If a desirable contrast is unavailable, contrast synthesis (or modality synthesis) methods try to "synthesize" the unavailable constrasts from the available ones. Most of the recent image synthesis methods generate synthetic brain images, while whole head magnetic resonance (MR) images can also be useful for many applications. We propose an atlas based patch matching algorithm to synthesize T2-w whole head (including brain, skull, eyes etc) images from T1-w images for the purpose of distortion correction of diffusion weighted MR images. The geometric distortion in diffusion MR images due to in-homogeneous B0 magnetic field are often corrected by non-linearly registering the corresponding b = 0 image with zero diffusion gradient to an undistorted T2-w image. We show that our synthetic T2-w images can be used as a template in absence of a real T2-w image. Our patch based method requires multiple atlases with T1 and T2 to be registeLowRes to a given target T1. Then for every patch on the target, multiple similar looking matching patches are found on the atlas T1 images and corresponding patches on the atlas T2 images are combined to generate a synthetic T2 of the target. We experimented on image data obtained from 44 patients with traumatic brain injury (TBI), and showed that our synthesized T2 images produce more accurate distortion correction than a state-of-the-art registration based image synthesis method.

Connecting combat-related mild traumatic brain injury with posttraumatic stress disorder symptoms through brain imaging.

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) may share common symptom and neuropsychological profiles in military service members (SMs) following deployment; while a connection between the two conditions is plausible, the relationship between them has been difficult to discern. The intent of this report is to enhance our understanding of the relationship between findings on structural and functional brain imaging and symptoms of PTSD. Within a cohort of SMs who did not meet criteria for PTSD but were willing to complete a comprehensive assessment within 2 months of their return from combat deployment, we conducted a nested case-control analysis comparing those with combat-related mTBI to age/gender-matched controls with diffusion tensor imaging, resting state functional magnetic resonance imaging and a range of psychological measures. We report degraded white matter integrity in those with a history of combat mTBI, and a positive correlation between the white matter microstructure and default mode network (DMN) connectivity. Higher clinician-administered and self-reported subthreshold PTSD symptoms were reported in those with combat mTBI. Our findings offer a potential mechanism through which mTBI may alter brain function, and in turn, contribute to PTSD symptoms.

Ventricular enlargement and its clinical correlates in the imaging cohort from the ADCS MCI donepezil/vitamin E study.

We analyzed the baseline and 3-year T1-weighted magnetic resonance imaging data of 110 amnestic mild cognitive impairment (MCI) participants with minimal hippocampal atrophy at baseline from the Alzheimer's Disease Cooperative Study group MCI Donepezil/Vitamin E trial. Forty-six subjects converted to Alzheimer disease (AD) (MCIc), whereas 64 remained stable (MCInc). We used the radial distance technique to examine the differences in lateral ventricle shape and size between MCIc and MCInc and the associations between ventricular enlargement and cognitive decline. MCIc group had significantly larger frontal and right body/occipital horns relative to MCInc at baseline and significantly larger bilateral frontal, body/occipital, and left temporal horns at follow-up. Global cognitive decline measured with AD Assessment scale cognitive subscale and Mini-Mental State Examination and decline in activities of daily living (ADL) were associated with posterior lateral ventricle enlargement. Decline in AD Assessment scale cognitive subscale and ADL were associated with left temporal and decline in Mini-Mental State Examination with right temporal horn enlargement. After correction for baseline hippocampal volume, decline in ADL showed a significant association with right frontal horn enlargement. Executive decline was associated with right frontal and left temporal horn enlargement.

Cerebrospinal fluid Aß levels correlate with structural brain changes in Parkinson's disease.

ParkWest is a large Norwegian multicenter study of newly diagnosed drug-naïve subjects with Parkinson's disease (PD). Cognitively normal PD subjects (PDCN) and PD subjects with mild cognitive impairment (PDMCI) from this cohort have significant hippocampal atrophy and ventricular enlargement, compared to normal controls. Here, we aimed to investigate whether the same structural changes are associated with cerebrospinal fluid (CSF) levels of amyloid beta (Aß)38 , Aß40 , Aß42 , total tau (t-tau), and phosphorylated tau (p-tau). We performed three-dimensional radial distance analyses of the hippocampi and lateral ventricles using the MRI data from ParkWest subjects who provided CSF at baseline. Our sample consisted of 73 PDCN and 18 PDMCI subjects. We found significant associations between levels of all three CSF Aß analytes and t-tau and lateral ventricular enlargement in the pooled sample. In the PDCN sample, all three amyloid analytes showed significant associations with the radial distance of the occipital and frontal horns of the lateral ventricles. CSF Aß38 and Aß42 showed negative associations, with enlargement in occipital and frontal horns of the lateral ventricles in the pooled sample, and a negative association with the occipital horns in PDMCI. CSF Aß levels in early PD correlate with ventricular enlargement, previously associated with PD dementia. Therefore, CSF and MRI markers may help identify PD patients at high risk for developing cognitive decline and dementia in the course of their illness. Contrary to Alzheimer's disease, we found no associations between CSF t-tau and p-tau and hippocampal atrophy.

Maximizing power to track Alzheimer's disease and MCI progression by LDA-based weighting of longitudinal ventricular surface features.

We propose a new method to maximize biomarker efficiency for detecting anatomical change over time in serial MRI. Drug trials using neuroimaging become prohibitively costly if vast numbers of subjects must be assessed, so it is vital to develop efficient measures of brain change. A popular measure of efficiency is the minimal sample size (n80) needed to detect 25% change in a biomarker, with 95% confidence and 80% power. For multivariate measures of brain change, we can directly optimize n80 based on a Linear Discriminant Analysis (LDA). Here we use a supervised learning framework to optimize n80, offering two alternative solutions. With a new medial surface modeling method, we track 3D dynamic changes in the lateral ventricles in 2065 ADNI scans. We apply our LDA-based weighting to the results. Our best average n80-in two-fold nested cross-validation-is 104 MCI subjects (95% CI: [94,139]) for a 1-year drug trial, and 75AD subjects [64,102]. This compares favorably with other MRI analysis methods. The standard "statistical ROI" approach applied to the same ventricular surfaces requires 165 MCI or 94AD subjects. At 2 years, the best LDA measure needs only 67 MCI and 52AD subjects, versus 119 MCI and 80AD subjects for the stat-ROI method. Our surface-based measures are unbiased: they give no artifactual additive atrophy over three time points. Our results suggest that statistical weighting may boost efficiency of drug trials that use brain maps.

Global and regional alterations of hippocampal anatomy in long-term meditation practitioners.

Studies linking meditation and brain structure are still relatively sparse, but the hippocampus is consistently implicated as one of the structures altered in meditation practitioners. To explore hippocampal features in the framework of meditation, we analyzed high-resolution structural magnetic resonance imaging data from 30 long-term meditators and 30 controls, closely matched for sex, age, and handedness. Hippocampal formations were manually traced following established protocols. In addition to calculating left and right hippocampal volumes (global measures), regional variations in surface morphology were determined by measuring radial distances from the hippocampal core to spatially matched surface points (local measures). Left and right hippocampal volumes were larger in meditators than in controls, significantly so for the left hippocampus. The presence and direction of this global effect was confirmed locally by mapping the exact spatial locations of the group differences. Altogether, radial distances were larger in meditators compared to controls, with up to 15% difference. These local effects were observed in several hippocampal regions in the left and right hemisphere though achieved significance primarily in the left hippocampal head. Larger hippocampal dimensions in long-term meditators may constitute part of the underlying neurological substrate for cognitive skills, mental capacities, and/or personal traits associated with the practice of meditation. Alternatively, given that meditation positively affects autonomic regulation and immune activity, altered hippocampal dimensions may be one result of meditation-induced stress reduction. However, given the cross-sectional design, the lack of individual stress measures, and the limited resolution of brain data, the exact underlying neuronal mechanisms remain to be established.

Right, left, and center: how does cerebral asymmetry mix with callosal connectivity?

BACKGROUND: Prior research has shown that cerebral asymmetry is associated with differences in corpus callosum connectivity. Such associations were detected in histological and anatomical studies investigating callosal fiber size and density, in neuroimaging investigations based on structural and diffusion tensor imaging, as well as in neuropsychological experiments. However, little is known about typical associations between these factors, and even less about the relative influences of magnitude and direction of cerebral asymmetries. Here, we investigated relationships between callosal connectivity and cerebral asymmetry using precise measures of callosal thickness and selected cerebral structures. We considered both the direction and magnitude of the asymmetries. METHODS: Associations between cerebral asymmetry and callosal thickness were investigated in 348 cognitively healthy older individuals. RESULTS: The magnitude and direction of cerebral lateralization were significant independent predictors of callosal thickness. However, associations were small. Leftward asymmetry and increased magnitude of asymmetry were generally associated with increased callosal thickness, mostly in the callosal midbody and isthmus. CONCLUSIONS: When a large sample of normal individuals is considered, cerebral asymmetries are only subtly associated with callosal thickness.

Hippocampal atrophy and ventricular enlargement in normal aging, mild cognitive impairment (MCI), and Alzheimer Disease.

Alzheimer disease (AD) is the most common type of dementia worldwide. Hippocampal atrophy and ventricular enlargement have been associated with AD but also with normal aging. We analyzed 1.5-T brain magnetic resonance imaging data from 46 cognitively normal elderly individuals (NC), 33 mild cognitive impairment and 43 AD patients. Hippocampal and ventricular analyses were conducted with 2 novel semiautomated segmentation approaches followed by the radial distance mapping technique. Multiple linear regression was used to assess the effects of age and diagnosis on hippocampal and ventricular volumes and radial distance. In addition, 3-dimensional map correction for multiple comparisons was made with permutation testing. As expected, most significant hippocampal atrophy and ventricular enlargement were seen in the AD versus NC comparison. Mild cognitive impairment patients showed intermediate levels of hippocampal atrophy and ventricular enlargement. Significant effects of age on hippocampal volume and radial distance were seen in the pooled sample and in the NC and AD groups considered separately. Age-associated differences were detected in all hippocampal subfields and in the frontal and body/occipital horn portions of the lateral ventricles. Aging affects both the hippocampus and lateral ventricles independent of AD pathology, and should be included as covariate in all structural, hippocampal, and ventricular analyses when possible.

Hippocampal and ventricular changes in Parkinson's disease mild cognitive impairment.

We analyzed T1-weighted brain magnetic resonance imaging data of 100 cognitively normal elderly controls (NC), 127 cognitively normal Parkinson's disease (PD; PDCN) and 31 PD-associated mild cognitive impairment (PDMCI) subjects from the Norwegian ParkWest study. Using automated segmentation methods, followed by the radial distance technique and multiple linear regression we studied the effect of clinical diagnosis on hippocampal and ventricular radial distance while adjusting for age, education, and scanning site. PDCN subjects had significantly smaller bilateral hippocampal radial distance relative to NC. Nonamnestic PDMCI subjects showed smaller right hippocampal radial distance relative to NC. PDMCI subjects showed significant enlargement of all portions of the lateral ventricles relative to NC and significantly larger bilateral temporal and occipital and left frontal lateral ventricular expansion relative to PDCN subjects. Nonamnestic PDMCI subjects showed significant ventricular enlargement spanning all parts of the lateral ventricle while those with amnestic PDMCI showed changes localized to the left occipital horn. Hippocampal atrophy and lateral ventricular enlargement show promise as structural biomarkers for PD.

Surface-based TBM boosts power to detect disease effects on the brain: an N=804 ADNI study.

Computational anatomy methods are now widely used in clinical neuroimaging to map the profile of disease effects on the brain and its clinical correlates. In Alzheimer's disease (AD), many research groups have modeled localized changes in hippocampal and lateral ventricular surfaces, to provide candidate biomarkers of disease progression for drug trials. We combined the power of parametric surface modeling and tensor-based morphometry to study hippocampal differences associated with AD and mild cognitive impairment (MCI) in 490 subjects (97 AD, 245 MCI, 148 controls) and ventricular differences in 804 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI; 184 AD, 391 MCI, 229 controls). We aimed to show that a new multivariate surface statistic based on multivariate tensor-based morphometry (mTBM) and radial distance provides a more powerful way to detect localized anatomical differences than conventional surface-based analysis. In our experiments, we studied correlations between hippocampal atrophy and ventricular enlargement and clinical measures and cerebrospinal fluid biomarkers. The new multivariate statistics gave better effect sizes for detecting morphometric differences, relative to other statistics including radial distance, analysis of the surface tensor and the Jacobian determinant. In empirical tests using false discovery rate curves, smaller sample sizes were needed to detect associations with diagnosis. The analysis pipeline is generic and automated. It may be applied to analyze other brain subcortical structures including the caudate nucleus and putamen. This publically available software may boost power for morphometric studies of subcortical structures in the brain.