Individualized network analysis: A novel approach to investigate tau PET using graph theory in the Alzheimer's disease continuum.

Introduction: Tau PET imaging has emerged as an important tool to detect and monitor tangle burden in vivo in the study of Alzheimer's disease (AD). Previous studies demonstrated the association of tau burden with cognitive decline in probable AD cohorts. This study introduces a novel approach to analyze tau PET data by constructing individualized tau network structure and deriving its graph theory-based measures. We hypothesize that the network- based measures are a measure of the total tau load and the stage through disease. Methods: Using tau PET data from the AD Neuroimaging Initiative from 369 participants, we determine the network measures, global efficiency, global strength, and limbic strength, and compare with two regional measures entorhinal and tau composite SUVR, in the ability to differentiate, cognitively unimpaired (CU), MCI and AD. We also investigate the correlation of these network and regional measures and a measure of memory performance, auditory verbal learning test for long-term recall memory (AVLT-LTM). Finally, we determine the stages based on global efficiency and limbic strength using conditional inference trees and compare with Braak staging. Results: We demonstrate that the derived network measures are able to differentiate three clinical stages of AD, CU, MCI, and AD. We also demonstrate that these network measures are strongly correlated with memory performance overall. Unlike regional tau measurements, the tau network measures were significantly associated with AVLT-LTM even in cognitively unimpaired individuals. Stages determined from global efficiency and limbic strength, visually resembled Braak staging. Discussion: The strong correlations with memory particularly in CU suggest the proposed technique may be used to characterize subtle early tau accumulation. Further investigation is ongoing to examine this technique in a longitudinal setting.

A public resource of baseline data from the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial.

INTRODUCTION: The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Trial evaluated the anti-oligomeric amyloid beta (Aß) antibody therapy crenezumab in cognitively unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data. METHODS: We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer's disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure-tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data. RESULTS: Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers. DISCUSSION: Baseline data are publicly available; treatment data and biological samples, including baseline and treatment-related blood-based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer's Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aß plaque deposition.

Sex differences in cognitive resilience in preclinical autosomal-dominant Alzheimer's disease carriers and non-carriers: Baseline findings from the API ADAD Colombia Trial.

INTRODUCTION: Females may have greater susceptibility to Alzheimer's disease (AD)-pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively-unimpaired Presenilin-1 (PSEN1) E280A mutation carriers and non-carriers. METHODS: We analyzed baseline data from 167 mutation carriers and 75 non-carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir- and fludeoxyglucose-PET, MRI based hippocampal volume and cognitive testing. RESULTS: Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. DISCUSSION: Our findings suggest that, among cognitively-unimpaired individuals at genetic risk for autosomal-dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex-specific differences in autosomal-dominant AD is key to elucidating mechanisms of AD risk and resilience.

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers.

BACKGROUND: In contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aß) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aß burden to characterize the presence and age at onset of cerebellar Aß deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD. METHODS: 18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aß-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score. RESULTS: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort). CONCLUSION: This PET study provides evidence of cerebellar Aß plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

AD-NET: Age-adjust neural network for improved MCI to AD conversion prediction.

The prediction of Mild Cognitive Impairment (MCI) patients who are at higher risk converting to Alzheimer's Disease (AD) is critical for effective intervention and patient selection in clinical trials. Different biomarkers including neuroimaging have been developed to serve the purpose. With extensive methodology development efforts on neuroimaging, an emerging field is deep learning research. One great challenge facing deep learning is the limited medical imaging data available. To address the issue, researchers explore the use of transfer learning to extend the applicability of deep models on neuroimaging research for AD diagnosis and prognosis. Existing transfer learning models mostly focus on transferring the features from the pre-training into the fine-tuning stage. Recognizing the advantages of the knowledge gained during the pre-training, we propose an AD-NET (Age-adjust neural network) with the pre-training model serving two purposes: extracting and transferring features; and obtaining and transferring knowledge. Specifically, the knowledge being transferred in this research is an age-related surrogate biomarker. To evaluate the effectiveness of the proposed approach, AD-NET is compared with 8 classification models from literature using the same public neuroimaging dataset. Experimental results show that the proposed AD-NET outperforms the competing models in predicting the MCI patients at risk for conversion to the AD stage.

Baseline demographic, clinical, and cognitive characteristics of the Alzheimer's Prevention Initiative (API) Autosomal-Dominant Alzheimer's Disease Colombia Trial.

INTRODUCTION: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo-controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60-year-old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non-carriers who receive placebo. METHODS: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non-carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. RESULTS: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non-carriers, 30 to 53 years of age. Carriers were significantly younger than non-carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. DISCUSSION: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non-carriers. Their demographic characteristics are representative of the local population.

Computing Univariate Neurodegenerative Biomarkers with Volumetric Optimal Transportation: A Pilot Study.

Changes in cognitive performance due to neurodegenerative diseases such as Alzheimer's disease (AD) are closely correlated to the brain structure alteration. A univariate and personalized neurodegenerative biomarker with strong statistical power based on magnetic resonance imaging (MRI) will benefit clinical diagnosis and prognosis of neurodegenerative diseases. However, few biomarkers of this type have been developed, especially those that are robust to image noise and applicable to clinical analyses. In this paper, we introduce a variational framework to compute optimal transportation (OT) on brain structural MRI volumes and develop a univariate neuroimaging index based on OT to quantify neurodegenerative alterations. Specifically, we compute the OT from each image to a template and measure the Wasserstein distance between them. The obtained Wasserstein distance, Wasserstein Index (WI) for short to specify the distance to a template, is concise, informative and robust to random noise. Comparing to the popular linear programming-based OT computation method, our framework makes use of Newton's method, which makes it possible to compute WI in large-scale datasets. Experimental results, on 314 subjects (140 Aß + AD and 174 Aß- normal controls) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset, provide preliminary evidence that the proposed WI is correlated with a clinical cognitive measure (the Mini-Mental State Examination (MMSE) score), and it is able to identify group difference and achieve a good classification accuracy, outperforming two other popular univariate indices including hippocampal volume and entorhinal cortex thickness. The current pilot work suggests the application of WI as a potential univariate neurodegenerative biomarker.

Brain imaging measurements of fibrillar amyloid-ß burden, paired helical filament tau burden, and atrophy in cognitively unimpaired persons with two, one, and no copies of the APOE ε4 allele.

INTRODUCTION: We previously characterized associations between brain imaging measurements of amyloid-ß (Aß) plaque burden and apolipoprotein E (APOE) ε4 gene dose in a small number of cognitively unimpaired late-middle-aged APOE ε4 homozygotes (HMs), heterozygotes (HTs), and noncarriers (NCs). We now characterize cross-sectional Aß plaque, tau tangle, and cortical atrophy (neurodegeneration) measurements, classifications, and associations with age in a larger number of unimpaired HMs, HTs, and NCs over a wider age range. METHODS: We analyzed 11 C Pittsburgh compound B (Aß) positron emission tomography (PET), flortaucipir (tau) PET, and volumetric magnetic resonance imaging data from 164 study participants of age 47-86 years, including 26 APOE ε4 HMs, 48 HTs, and 90 NCs matched for age and sex. RESULTS: Aß PET measurements rose, plateaued at the respective ages of 68 and 76, and then declined with age in unimpaired HM and HT groups. Compared with NCs, these two groups began to have significantly higher Aß PET measurements at ages 62 and 70, respectively, and no longer had significantly higher measurements by ages 71 and 78, respectively. They began to have significantly higher entorhinal cortex tau PET measurements at ages 66 and 70, respectively, and no longer had significantly higher measurements by ages 74 and 78, respectively. Brain atrophy measurements tended to decline slowly with age in all three genetic groups. Their elevated tau PET measurements were attributable to those with positive Aß PET scans. 41.0%, 18.0%, and 5.0% of the 47- to 70-year-old HMs, HTs, and NCs and 25.0%, 79.0%, and 38.0% of the 71- to 86-year-old HMs, HTs, and NCs had positive Aß PET scans, and the long-term recall memory scores are significantly higher in the older HMs than in HT and NC groups, suggesting resistance to Aß deposition in those HMs who remained unimpaired at older ages. CONCLUSIONS: This study provides information about Aß plaque burden, tau tangle burden, and neurodegeneration in cognitively unimpaired persons at three levels of genetic risk for AD. Unimpaired APOE ε4 HMs can be studied before their 70s to evaluate the understanding of factors, processes, and interventions involved in the predisposition to and prevention of AD, and after their 70s, to discover factors, processes, and interventions involved in the resilience or resistance to and prevention of AD.

Tau Positron-Emission Tomography in Former National Football League Players.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied. METHODS: We used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group. RESULTS: A total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P = 0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease. CONCLUSIONS: A group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.).

An Optimal Transportation based Univariate Neuroimaging Index.

The alterations of brain structures and functions have been considered closely correlated to the change of cognitive performance due to neurodegenerative diseases such as Alzheimer's disease. In this paper, we introduce a variational framework to compute the optimal transformation (OT) in 3D space and propose a univariate neuroimaging index based on OT to measure such alterations. We compute the OT from each image to a template and measure the Wasserstein distance between them. By comparing the distances from all the images to the common template, we obtain a concise and informative index for each image. Our framework makes use of the Newton's method, which reduces the computational cost and enables itself to be applicable to large-scale datasets. The proposed work is a generic approach and thus may be applicable to various volumetric brain images, including structural magnetic resonance (sMR) and fluorodeoxyglucose positron emission tomography (FDG-PET) images. In the classification between Alzheimer's disease patients and healthy controls, our method achieves an accuracy of 82.30% on the Alzheimers Disease Neuroimaging Initiative (ADNI) baseline sMRI dataset and outperforms several other indices. On FDG-PET dataset, we boost the accuracy to 88.37% by leveraging pairwise Wasserstein distances. In a longitudinal study, we obtain a 5% significance with p-value = 1.13×105 in a t-test on FDG-PET. The results demonstrate a great potential of the proposed index for neuroimage analysis and the precision medicine research.

Deep Learning based Classification of FDG-PET Data for Alzheimers Disease Categories.

Fluorodeoxyglucose (FDG) positron emission tomography (PET) measures the decline in the regional cerebral metabolic rate for glucose, offering a reliable metabolic biomarker even on presymptomatic Alzheimer's disease (AD) patients. PET scans provide functional information that is unique and unavailable using other types of imaging. However, the computational efficacy of FDG-PET data alone, for the classification of various Alzheimers Diagnostic categories, has not been well studied. This motivates us to correctly discriminate various AD Diagnostic categories using FDG-PET data. Deep learning has improved state-of-the-art classification accuracies in the areas of speech, signal, image, video, text mining and recognition. We propose novel methods that involve probabilistic principal component analysis on max-pooled data and mean-pooled data for dimensionality reduction, and multilayer feed forward neural network which performs binary classification. Our experimental dataset consists of baseline data of subjects including 186 cognitively unimpaired (CU) subects, 336 mild cognitive impairment (MCI) subjects with 158 Late MCI and 178 Early MCI, and 146 AD patients from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We measured F1-measure, precision, recall, negative and positive predictive values with a 10-fold cross validation scheme. Our results indicate that our designed classifiers achieve competitive results while max pooling achieves better classification performance compared to mean-pooled features. Our deep model based research may advance FDG-PET analysis by demonstrating their potential as an effective imaging biomarker of AD.

Distinct differences in striatal dysmorphology between attention deficit hyperactivity disorder boys with and without a comorbid reading disability.

There is evidence of greater cognitive deficits in attention deficit hyperactivity disorder with a comorbid reading disability (ADHD/+RD) compared to ADHD alone (ADHD/-RD). Additionally, the striatum has been consistently implicated in ADHD. However, the extent of morphological alterations in the striatum of ADHD/+RD is poorly understood, which is the main purpose of this study. Based on structural MRI images, the surface deformation of the caudate and putamen was assessed in 59 boys matching in age and IQ [19 ADHD/-RD, 15 ADHD/+RD and 25 typically developing controls (TDC)]. A vertex based analysis with multiple comparison correction was conducted to compare ADHD/-RD and ADHD/+RD to TDC. Compared to TDC, ADHD/+RD showed multiple bilateral significant clusters of surface compression. In contrast, ADHD/-RD showed fewer significant clusters of surface compression and restricted to the left side. Regarding the putamen, only ADHD/-RD showed significant clusters of surface compression. Results demonstrate for the first time a greater extent of morphological alterations in the caudate of ADHD/+RD than ADHD/-RD compared to TDC, which may suggest greater implicated cortical areas projecting to the caudate that are associated with the greater neuropsychological impairments observed in ADHD/+RD.

Differences in cortico-striatal-cerebellar activation during working memory in syndromal and nonsyndromal children with prenatal alcohol exposure.

Although children with heavy prenatal alcohol exposure may exhibit the distinctive facial dysmorphology seen in full or partial fetal alcohol syndrome (FAS/PFAS), many lack that dysmorphology. This study examined the functional organization of working memory in the brain in three groups of children-those meeting diagnostic criteria for FAS or PFAS, heavily exposed (HE) nonsyndromal children, and healthy controls. A verbal n-back task (1-back and 0-back) was administered to 47 children (17 with FAS/PFAS, 13 HE, and 17 controls) during fMRI. Intra-group one-sample t-tests were used to identify activity regions of interest central to verbal working memory including the dorsal prefrontal cortex (dPFC), inferior frontal gyrus, caudate/putamen, parietal cortex, and cerebellar Crus I/lobule VI and lobule VIIB-IX. Whereas groups did not differ in task sensitivity, fMRI analyses suggested different patterns of sub-network recruitment across groups. Controls primarily recruited left inferior frontal gyrus (Broca's area). By contrast, HE primarily recruited an extensive set of fronto-striatal regions, including left dPFC and left caudate, and the FAS/PFAS group relied primarily on two cerebellar subregions and parietal cortex. This study is, to our knowledge, the first to demonstrate differential recruitment of critical brain regions that subserve basic function in children with different fetal alcohol spectrum disorders compared to controls. The distinct activation patterns seen in the two exposed groups may be related to substantial differences in alcohol dose/occasion to which these groups were exposed in utero.

Brain activation patterns during visual episodic memory processing among first-degree relatives of schizophrenia subjects.

Episodic memory deficits are proposed as a potential intermediate phenotype of schizophrenia. We examined deficits in visual episodic memory and associated brain activation differences among early course schizophrenia (n=22), first-degree relatives (n=16) and healthy controls without personal or family history of psychotic disorders (n=28). Study participants underwent functional magnetic resonance imaging on a 3T scanner while performing visual episodic memory encoding and retrieval task. We examined in-scanner behavioral performance evaluating response time and accuracy of performance. Whole-brain BOLD response differences were analyzed using SPM5 correcting for multiple comparisons. There was an incremental increase in response time among the study groups (healthy controls

Fronto-parietal hypo-activation during working memory independent of structural abnormalities: conjoint fMRI and sMRI analyses in adolescent offspring of schizophrenia patients.

Adolescent offspring of schizophrenia patients (HR-S) are an important group in whom to study impaired brain function and structure, particularly of the frontal cortices. Studies of working memory have suggested behavioral deficits and fMRI-measured hypoactivity in fronto-parietal regions in these subjects. Independent structural MRI (sMRI) studies have suggested exaggerated frontal gray matter decline. Therefore the emergent view is that fronto-parietal deficits in function and structure characterize HR-S. However, it is unknown if fronto-parietal sub-regions in which fMRI-measured hypo-activity might be observed are precisely those regions of the cortex in which gray matter deficits are also observed. To investigate this question we conducted conjoint analyses of fronto-parietal function and structure in HR-S (n=19) and controls (n=24) with no family history of psychoses using fMRI data during a continuous working memory task (2 back), and sMRI collected in the same session. HR-S demonstrated significantly reduced BOLD activation in left dorso-lateral prefrontal cortex (BA 9/46) and bilateral parietal cortex (BA 7/40). Sub-regions of interest were created from the significant fronto-parietal functional clusters. Analyses of gray matter volume from volume-modulated gray matter segments in these clusters did not reveal significant gray matter differences between groups. The results suggest that functional impairments in adolescent HR-S can be independent of impairments in structure, suggesting that the relationship between impaired function and structure is complex. Further studies will be needed to more closely assess whether impairments in function and structure provide independent or interacting pathways of vulnerability in this population.

Progressive gray matter loss and changes in cognitive functioning associated with exposure to herpes simplex virus 1 in schizophrenia: a longitudinal study.

OBJECTIVE: Longitudinal changes in gray matter volume and cognitive performance were evaluated among individuals exposed to neurotropic herpes simplex virus subtype 1 (HSV1). There is a replicable association of HSV1 exposure with smaller prefrontal volumes and cognitive impairments in schizophrenia. METHOD: The authors concurrently examined the whole-brain longitudinal trajectory over 1 year of gray matter volumes and executive functioning measured with the Wisconsin Card Sorting Test among 26 first-episode antipsychotic-naive subjects with schizophrenia and 38 healthy subjects. Age, gender, socioeconomic status, and exposure to cytomegalovirus (another virus of the herpes family that was previously associated with cognitive impairments) were the covariates. RESULTS: Significant gray matter loss in the posterior cingulate gyrus was noted among the HSV1-seropositive schizophrenia subjects over 1 year but not among other groups. Prefrontal gray matter volumes did not show longitudinal changes. Binomial mixed-effects models indicated that improvement over 1 year in Wisconsin Card Sorting Test categories completed and perseverative errors occurred in significantly fewer HSV1-seropositive schizophrenia subjects than in the HSV1-seronegative schizophrenia subjects or the healthy subjects regardless of serological status. Three-way interactions of diagnosis, HSV1 status, and time were significant for both categories completed and perseverative errors. An increase in perseverative errors over 1 year, but not the change in the number of categories completed, correlated with longitudinal volume loss of the posterior cingulate gyrus. CONCLUSIONS: These observations suggest that HSV1 exposure may be associated with longitudinal gray matter loss in the posterior cingulate gyrus and decline in executive functioning among subjects with schizophrenia.

Reorganization of the right arcuate fasciculus following left arcuate fasciculus resection in children with intractable epilepsy.

The authors evaluated postsurgical reorganization of the arcuate fasciculus longitudinally using diffusion tensor imaging in 10 children with intractable epilepsy, whose resections included the left arcuate fasciculus. Evaluation of fractional anisotropy before and after surgery (mean follow-up: 7.5 months) showed a significant increase (P = .002) in the right arcuate fasciculus during follow-up. There was marked enlargement of the right arcuate fasciculus postsurgically in 8 patients. The change in right arcuate fasciculus fractional anisotropy values showed a positive correlation with interval between resection and postsurgical magnetic resonance imaging (MRI) (P = .044). Comparison of 10 age-matched controls to patients pre- and postsurgery showed significantly reduced presurgery fractional anisotropy in the left (P = .018) and right (P = .036) arcuate fasciculus and no difference in postsurgery fractional anisotropy in the right arcuate fasciculus (P = .399) in patients. These findings suggest a compensatory reorganization in the right arcuate fasciculus in children with intractable epilepsy following left arcuate fasciculus resection.

Working memory and attention deficits in adolescent offspring of schizophrenia or bipolar patients: comparing vulnerability markers.

BACKGROUND: Working memory deficits abound in schizophrenia and attention deficits have been documented in schizophrenia and bipolar disorder. Adolescent offspring of patients may inherit vulnerabilities in brain circuits that subserve these cognitive domains. Here we assess impairments in offspring of schizophrenia (SCZ-Offspring) or bipolar (BP-Offspring) patients compared to controls (HC) with no family history of mood or psychotic disorders to the second degree. METHODS: Three groups (n=100 subjects; range: 10-20 yrs) of HC, SCZ-Offspring and BP-Offspring gave informed consent. Working memory was assessed using a delayed spatial memory paradigm with two levels of delay (2s & 12s); sustained attention processing was assessed using the Continuous Performance Task-Identical Pairs version. RESULTS: SCZ-Offspring (but not BP-Offspring) showed impairments in working memory (relative to HC) at the longer memory delay indicating a unique deficit. Both groups showed reduced sensitivity during attention but only BP-Offspring significantly differed from controls. CONCLUSIONS: These results suggest unique (working memory/dorsal frontal cortex) and potentially overlapping (attention/fronto-striatal cortex) vulnerability pathways in adolescent offspring of patients with schizophrenia and bipolar disorder. Working memory and attention assessments in these offspring may assist in the clinical characterization of the adolescents vulnerable to SCZ or BP.

Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia.

BACKGROUND: We previously reported reduced prefrontal cortex (PFC) grey matter volume among first episode, antipsychotic-naïve schizophrenia subjects (SZ) exposed to HSV1 but not among healthy subjects (HS) (Prasad et al., 2007). Independently, rs1051788, an exonic polymorphism of the MHC Class I polypeptide-related sequence B (MICB) gene was associated with HSV1 seropositivity, as well as SZ risk. In this study, we examined whether PFC grey matter changes associated with HSV1 exposure varied against the background of MICB genotypes. METHODS: We examined Caucasian individuals from the sample we studied in our previous report (Prasad et al., 2007) (SZ, n=21 and HS, n=19). Whole brain voxelwise analysis of structural MRI scans was conducted using Statistical Parametric Mapping, ver 5 (SPM5). The impact of rs1051788 variation and HSV1 seropositivity on grey matter volumes was examined using regression models on the combined sample of cases and controls, and then within each diagnostic group. RESULTS: In the combined sample of cases and controls, we observed the main effects of HSV1 seropositivity and genotypes, and a significant joint effect of HSV1 seropositivity and genotype mainly in the PFC. The joint effect was more prominent among cases than among controls. DISCUSSION: Our observations suggest that rs1051788 and HSV1 seropositivity are associated individually and jointly with reduced PFC grey matter volume. The patterns of these associations differ by diagnostic status, and these factors explain only a "small" portion of the variance in the grey matter volume reductions.

Cortical surface characteristics among offspring of schizophrenia subjects.

BACKGROUND: A systematic study of cortical surface parameters in adolescent offspring of schizophrenia subjects before clinical manifestation could clarify neurodevelopmental antecedents of increased genetic risk. We examined these measures obtained on structural magnetic resonance imaging (MRI) scans at baseline and one year on a series of offspring of schizophrenia parents and healthy subjects. METHODS: We measured cortical surface area, curvature and thickness using BRAINS2 on structural MRI scans acquired using 1.5 T GE whole body scanner on all subjects. We examined the differences between study groups at baseline using mixed-effects models, and longitudinal trajectory of these measures using linear mixed-effects models. RESULTS: At baseline, offspring of schizophrenia parents showed reduced gyral surface area in the fronto-parietal lobes along with increased sulcal curvature and parietal gyral cortical thinning compared to healthy subjects. Prospective follow up of these subjects for one year showed shrinking of the total surface area, especially in the bilateral frontal and occipital regions along with preservation of cortical thickness among offspring of schizophrenia parents whereas healthy subjects showed preserved or increased surface area and cortical thinning. Correlation of these measures with lobar volumes was not observed at baseline cross-sectional comparisons but was observed in longitudinal examinations. DISCUSSION: Our observations suggest that adolescents with genetically elevated risk for schizophrenia show altered cortical surface measures affecting cortical surface area and thickness differentially suggesting a divergent trajectory of neurodevelopment. Cortical surface measures appear to be more sensitive to genetic liability to schizophrenia compared to volumetric measures.