Voxel-wise deviations from healthy aging for the detection of region-specific atrophy.

The identification of pathological atrophy in MRI scans requires specialized training, which is scarce outside dedicated centers. We sought to investigate the clinical usefulness of computer-generated representations of local grey matter (GM) loss or increased volume of cerebral fluids (CSF) as normalized deviations (z-scores) from healthy aging to either aid human visual readings or directly detect pathological atrophy. Two experienced neuroradiologists rated atrophy in 30 patients with Alzheimer's disease (AD), 30 patients with frontotemporal dementia (FTD), 30 with dementia due to Lewy-body disease (LBD) and 30 healthy controls (HC) on a three-point scale in 10 anatomical regions as reference gold standard. Seven raters, varying in their experience with MRI diagnostics rated all cases on the same scale once with and once without computer-generated volume deviation maps that were overlaid on anatomical slices. In addition, we investigated the predictive value of the computer generated deviation maps on their own for the detection of atrophy as identified by the gold standard raters. Inter and intra-rater agreements of the two gold standard raters were substantial (Cohen's kappa κ > 0.62). The intra-rater agreement of the other raters ranged from fair (κ = 0.37) to substantial (κ = 0.72) and improved on average by 0.13 (0.57 < κ < 0.87) when volume deviation maps were displayed. The seven other raters showed good agreement with the gold standard in regions including the hippocampus but agreement was substantially lower in e.g. the parietal cortex and did not improve with the display of atrophy scores. Rating speed increased over the course of the study and irrespective of the presentation of voxel-wise deviations. Automatically detected large deviations of local volume were consistently associated with gold standard atrophy reading as shown by an area under the receiver operator characteristic of up to 0.95 for the hippocampus region. When applying these test characteristics to prevalences typically found in a memory clinic, we observed a positive or negative predictive value close to or above 0.9 in the hippocampus for almost all of the expected cases. The volume deviation maps derived from CSF volume increase were generally better in detecting atrophy. Our study demonstrates an agreement of visual ratings among non-experts not further increased by displaying, region-specific deviations of volume. The high predictive value of computer generated local deviations independent from human interaction and the consistent advantages of CSF-over GM-based estimations should be considered in the development of diagnostic tools and indicate clinical utility well beyond aiding visual assessments.

Adaptive working memory training improved brain function in human immunodeficiency virus-seropositive patients.

OBJECTIVE: We aimed to evaluate the effectiveness of an adaptive working memory (WM) training (WMT) program, the corresponding neural correlates, and LMX1A-rs4657412 polymorphism on the adaptive WMT, in human immunodeficiency virus (HIV) participants compared to seronegative (SN) controls. METHODS: A total of 201 of 206 qualified participants completed baseline assessments before randomization to 25 sessions of adaptive WMT or nonadaptive WMT. A total of 74 of 76 (34 HIV, 42 SN) completed adaptive WMT and all 40 completed nonadaptive WMT (20 HIV, 20 SN) and were assessed after 1 month, and 55 adaptive WMT participants were also assessed after 6 months. Nontrained near-transfer WM tests (Digit-Span, Spatial-Span), self-reported executive functioning, and functional magnetic resonance images during 1-back and 2-back tasks were performed at baseline and each follow-up visit, and LMX1A-rs4657412 was genotyped in all participants. RESULTS: Although HIV participants had slightly lower cognitive performance and start index than SN at baseline, both groups improved on improvement index (>30%; false discovery rate [FDR] corrected p < 0.0008) and nontrained WM tests after adaptive WMT (FDR corrected, p ≤ 0.001), but not after nonadaptive WMT (training by training type corrected, p = 0.01 to p = 0.05) 1 month later. HIV participants (especially LMX1A-G carriers) also had poorer self-reported executive functioning than SN, but both groups reported improvements after adaptive WMT (Global: training FDR corrected, p = 0.004), and only HIV participants improved after nonadaptive WMT. HIV participants also had greater frontal activation than SN at baseline, but brain activation decreased in both groups at 1 and 6 months after adaptive WMT (FDR corrected, p < 0.0001), with normalization of brain activation in HIV participants, especially the LMX1A-AA carriers (LMX1A genotype by HIV status, cluster-corrected-p < 0.0001). INTERPRETATION: Adaptive WMT, but not nonadaptive WMT, improved WM performance in both SN and HIV participants, and the accompanied decreased or normalized brain activation suggest improved neural efficiency, especially in HIV-LMX1A-AA carriers who might have greater dopaminergic reserve. These findings suggest that adaptive WMT may be an effective adjunctive therapy for WM deficits in HIV participants. ANN NEUROL 2017;81:17-34.

Brain Microstructure and Impulsivity Differ between Current and Past Methamphetamine Users.

Methamphetamine (Meth) use disorder continues to be highly prevalent worldwide. Meth users have higher impulsivity and brain abnormalities that may be different between current and past Meth users. The current study assessed impulsivity and depressive symptoms in 94 participants (27 current Meth users, 32 past Meth users and 35 non-drug user controls). Additionally, brain microstructure was assessed using diffusion tensor imaging (DTI); fractional anisotropy (FA) and mean diffusivity (MD) were assessed in the striatum, and FA, MD, radial and axial diffusivity were quantified in five white matter structures using DtiStudio.Across the three subject groups, current users had the highest self-reported impulsivity scores, while both Meth user groups had larger striatal structures than the controls. Past Meth users had the highest FA and lowest MD in the striatum, which is likely due to greater magnetic susceptibility from higher iron content and greater dendritic spine density. In white matter tracts, current Meth users had higher AD than past users, indicating greater water diffusion along the axons, and suggesting inflammation with axonal swelling. In contrast, past users had the lowest AD, indicating more restricted diffusion, which might have resulted from reactive gliosis. Although current Meth users had greater impulsivity than past users, the brain microstructural abnormalities showed differences that may reflect different stages of neuroinflammation or iron-induced neurodegeneration. Combining current and past Meth users may lead to greater variability in studies of Meth users. Longitudinal studies are needed to further evaluate the relationship between recency of Meth use and brain microstructure.

Delayed early developmental trajectories of white matter tracts of functional pathways in preterm-born infants: Longitudinal diffusion tensor imaging data.

Probabilistic maps of white matter pathways related to motor, somatosensory, auditory, visual, and limbic functions, and major white matter tracts (the corpus callosum, the inferior fronto-occipital fasciculus, and the middle cerebellar peduncle) were applied to evaluate the developmental trajectories of these tracts, using longitudinal diffusion tensor imaging (DTI) obtained in term-born and preterm-born healthy infants. Nineteen term-born and 30 preterm-born infants completed MR scans at three time points: Time-point 1, 41.6±2.7 postmenstrual weeks; Time-point 2, 46.0±2.9 postmenstrual weeks; and Time-point 3, 50.8±3.7 postmenstrual weeks. The DTI-derived scalar values (fractional anisotropy, eigenvalues, and radial diffusivity) of the three time points are available in this Data article.

Probabilistic maps of the white matter tracts with known associated functions on the neonatal brain atlas: Application to evaluate longitudinal developmental trajectories in term-born and preterm-born infants.

Diffusion tensor imaging (DTI) has been widely used to investigate the development of the neonatal and infant brain, and deviations related to various diseases or medical conditions like preterm birth. In this study, we created a probabilistic map of fiber pathways with known associated functions, on a published neonatal multimodal atlas. The pathways-of-interest include the superficial white matter (SWM) fibers just beneath the specific cytoarchitectonically defined cortical areas, which were difficult to evaluate with existing DTI analysis methods. The Jülich cytoarchitectonic atlas was applied to define cortical areas related to specific brain functions, and the Dynamic Programming (DP) method was applied to delineate the white matter pathways traversing through the SWM. Probabilistic maps were created for pathways related to motor, somatosensory, auditory, visual, and limbic functions, as well as major white matter tracts, such as the corpus callosum, the inferior fronto-occipital fasciculus, and the middle cerebellar peduncle, by delineating these structures in eleven healthy term-born neonates. In order to characterize maturation-related changes in diffusivity measures of these pathways, the probabilistic maps were then applied to DTIs of 49 healthy infants who were longitudinally scanned at three time-points, approximately five weeks apart. First, we investigated the normal developmental pattern based on 19 term-born infants. Next, we analyzed 30 preterm-born infants to identify developmental patterns related to preterm birth. Last, we investigated the difference in diffusion measures between these groups to evaluate the effects of preterm birth on the development of these functional pathways. Term-born and preterm-born infants both demonstrated a time-dependent decrease in diffusivity, indicating postnatal maturation in these pathways, with laterality seen in the corticospinal tract and the optic radiation. The comparison between term- and preterm-born infants indicated higher diffusivity in the preterm-born infants than in the term-born infants in three of these pathways: the body of the corpus callosum; the left inferior longitudinal fasciculus; and the pathway connecting the left primary/secondary visual cortices and the motion-sensitive area in the occipitotemporal visual cortex (V5/MT+). Probabilistic maps provided an opportunity to investigate developmental changes of each white matter pathway. Whether alterations in white matter pathways can predict functional outcomes will be further investigated in a follow-up study.

An observational study of inflammation in the central nervous system in patients with bipolar disorder.

OBJECTIVES: The potential influence of infections and immunological changes on the aetiology and pathogenesis of bipolar disorder (BD) has been discussed. Our aim was to detect intrathecal specific antibody synthesis against the neurotropic infectious agents that have previously been linked to BD. METHODS: Paired cerebrospinal fluid (CSF) and serum samples from 40 patients with BD were analysed using the enzyme-linked immunosorbent assay to detect the concentration of antibodies against the following neurotropic infectious pathogens: Toxoplasma gondii (T. gondii), herpes simplex virus (HSV) types 1 and 2, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The specific antibody index (AI) was calculated, and an AI > 1.4 was considered to be evidence of intrathecal specific antibody synthesis. Twenty-six patients with pseudotumour cerebri served as controls. RESULTS: Eight out of 40 patients with BD displayed specific intrathecal antibody synthesis against at least one of the tested neurotropic agents compared to only one patient in the control group (p = 0.061, not significant). Of these eight patients with BD, no significant prevalence of any particular neurotropic pathogen was evident. Five out of 40 patients with BD showed oligoclonal bands in the CSF, suggestive of a chronic immune reaction in the central nervous system (CNS). CONCLUSIONS: We found evidence for increased production of antibody in the CSF of individuals with BD. However, the trend for polyspecific intrathecal antibody synthesis, as well as the presence of oligoclonal bands, might indicate activation of the intrathecal humoral immune system in a subgroup of patients with BD, as it is known to be associated with autoimmune disorders of the CNS.