Cohort study ON Neuroimaging, Etiology and Cognitive consequences of Transient neurological attacks (CONNECT): Study rationale and protocol

Background: Transient ischemic attacks (TIA) are characterized by acute onset focal neurological symptoms and complete recovery within 24hours. Attacks of nonfocal symptoms not fulfilling the criteria for TIA but lacking a clear alternative diagnosis are called transient neurological attacks (TNA). Although TIA symptoms are transient in nature, cognitive complaints may persist. In particular, attacks consisting of both focal and nonfocal symptoms (mixed TNA) have been found to be associated with an increased risk of dementia. We aim to study the prevalence, etiology and risk factors of cognitive impairment after TIA or TNA. Methods/Design: CONNECT is a prospective cohort study on cognitive function after TIA and TNA. In total, 150 patients aged ≤45years with a recent (<7days after onset) TIA or TNA and no history of stroke or dementia will be included. We will classify events as: TIA, nonfocal TNA, or mixed TNA. Known short lasting paroxysmal neurological disorders like migraine aura, seizures and Ménière disease are excluded from the diagnosis of TNA. Patients will complete a comprehensive neuropsychological assessment and undergo MRI <7days after the qualifying event and again after six months. The primary clinical outcomes will be cognitive function at baseline and six months after the primary event. Imaging outcomes include the prevalence and evolution of DWI lesions, white matter hyperintensities and lacunes, as well as resting state networks functionality and white matter microstructural integrity. Differences between types of event and DWI, as well as determinants of both clinical and imaging outcomes, will be assessed. Discussion: CONNECT can provide insight in the prevalence, etiology and risk factors of cognitive impairment after TIA and TNA and thereby potentially identify a new group of patients at increased risk of cognitive impairment

Topographic hub maps of the human structural neocortical network

Hubs within the neocortical structural network determined by graph theoretical analysis play a crucial role in brain function. We mapped neocortical hubs topographically, using a sample population of 63 young adults. Subjects were imaged with high resolution structural and diffusion weighted magnetic resonance imaging techniques. Multiple network configurations were then constructed per subject, using random parcellations to define the nodes and using fibre tractography to determine the connectivity between the nodes. The networks were analysed with graph theoretical measures. Our results give reference maps of hub distribution measured with betweenness centrality and node degree. The loci of the hubs correspond with key areas from known overlapping cognitive networks. Several hubs were asymmetrically organized across hemispheres. Furthermore, females have hubs with higher betweenness centrality and males have hubs with higher node degree. Female networks have higher small-world indices

Estimating the apparent transverse relaxation time (R2*) from images with different contrasts (ESTATICS) reduces motion artifacts

Relaxation rates provide important information about tissue microstructure. Multi-parameter mapping (MPM) estimates multiple relaxation parameters from multi-echo FLASH acquisitions with different basic contrasts, i.e., proton density (PD), T1 or magnetization transfer (MT) weighting. Motion can particularly affect maps of the apparent transverse relaxation rate R2*, which are derived from the signal of PD-weighted images acquired at different echo times. To address the motion artifacts, we introduce ESTATICS, which robustly estimates R2* from images even when acquired with different basic contrasts. ESTATICS extends the fitted signal model to account for inherent contrast differences in the PDw, T1w and MTw images. The fit was implemented as a conventional ordinary least squares optimization and as a robust fit with a small or large confidence interval. These three different implementations of ESTATICS were tested on data affected by severe motion artifacts and data with no prominent motion artifacts as determined by visual assessment or fast optical motion tracking. ESTATICS improved the quality of the R2* maps and reduced the coefficient of variation for both types of data—with average reductions of 30% when severe motion artifacts were present. ESTATICS can be applied to any protocol comprised of multiple 2D/3D multi-echo FLASH acquisitions as used in the general research and clinical setting

Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease

Leigh Disease is a progressive neurometabolic disorder for which a clinical effective treatment is currently still lacking. Here, we report on the therapeutic efficacy of KH176, a new chemical entity derivative of Trolox, in Ndufs4 (-/-) mice, a mammalian model for Leigh Disease. Using in vivo brain diffusion tensor imaging, we show a loss of brain microstructural coherence in Ndufs4 (-/-) mice in the cerebral cortex, external capsule and cerebral peduncle. These findings are in line with the white matter diffusivity changes described in mitochondrial disease patients. Long-term KH176 treatment retained brain microstructural coherence in the external capsule in Ndufs4 (-/-) mice and normalized the increased lipid peroxidation in this area and the cerebral cortex. Furthermore, KH176 treatment was able to significantly improve rotarod and gait performance and reduced the degeneration of retinal ganglion cells in Ndufs4 (-/-) mice. These in vivo findings show that further development of KH176 as a potential treatment for mitochondrial disorders is worthwhile to pursue. Clinical trial studies to explore the potency, safety and efficacy of KH176 are ongoing

Lower Ipsilateral Hippocampal Integrity after Ischemic Stroke in Young Adults: A Long-Term Follow-Up Study.

BACKGROUND AND PURPOSE: Memory impairment after stroke is poorly understood as stroke rarely occurs in the hippocampus. Previous studies have observed smaller ipsilateral hippocampal volumes after stroke compared with controls. Possibly, these findings on macroscopic level are not the first occurrence of structural damage and are preceded by microscopic changes that may already be associated with a worse memory function. We therefore examined the relationship between hippocampal integrity, volume, and memory performance long after first-ever ischemic stroke in young adults. METHODS: We included all consecutive first-ever ischemic stroke patients, without hippocampal strokes or recurrent stroke/TIA, aged 18-50 years, admitted to our academic hospital between 1980 and 2010. One hundred and forty-six patients underwent T1 MPRAGE, DTI scanning and completed the Rey Auditory Verbal Learning Test and were compared with 84 stroke-free controls. After manual correction of hippocampal automatic segmentation, we calculated mean hippocampal fractional anisotropy (FA) and diffusivity (MD). RESULTS: On average 10 years after ischemic stroke, lesion volume was associated with lower ipsilateral hippocampal integrity (p0.05). CONCLUSIONS: Patients with average ipsilateral hippocampal volume could already have lower ipsilateral hippocampal integrity, although at present with no attendant worse memory performance compared with patients with high hippocampal integrity. Longitudinal studies are needed to investigate whether a low hippocampal integrity after stroke might lead to exacerbated memory decline with increasing age.This study was funded by the Dutch Epilepsy Fund (grant 10–18)

Objective QC for diffusion MRI data: artefact detection using normative modelling

Diffusion MRI is a neuroimaging modality used to evaluate brain structure at a microscopic level and can be exploited to map white matter fibre bundles and microstructure in the brain. One common issue is the presence of artefacts, such as acquisition artefacts, physiological artefacts, distortions or image processing-related artefacts. These may lead to problems with other downstream processes and can bias subsequent analyses. In this work we use normative modelling to create a semi-automated pipeline for detecting diffusion imaging artefacts and errors by modelling 24 white matter imaging derived phenotypes from the UK Biobank dataset. The considered features comprised 4 microstructural features (from models with different complexity such as fractional anisotropy and mean diffusivity from a diffusion tensor model and parameters from neurite orientation, dispersion and density models), each within six pre-selected white matter tracts of various sizes and geometrical complexity (corpus callosum, bilateral corticospinal tract and uncinate fasciculus and fornix). Our method was compared to two traditional quality control approaches: a visual quality control protocol performed on 500 subjects and quantitative quality control using metrics derived from image pre-processing. The normative modelling framework proves to be comprehensive and efficient in detecting diffusion imaging artefacts arising from various sources (such as susceptibility induced distortions or motion), as well as outliers resulting from inaccurate processing (such as erroneous spatial registrations). This is an important contribution by virtue of this methods’ ability to identify the two problem sources (i) image artefacts and (ii) processing errors, which subsequently allows for a better understanding of our data and informs on inclusion/exclusion criteria of participants

Longitudinal changes of ADHD symptoms in association with white matter microstructure: A tract-specific fixel-based analysis

Background: Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18 – 34 years), and using the more physiologically informative fixel-based analysis (FBA). Methods: Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined ADHD and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. Results: Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax = 1.092, standardized effect[SE] = 0.044, pFWE = 0.016). Improvement in combined ADHD symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax = 3.775, SE = 0.051, pFWE = 0.019). Conclusions: Aberrant white matter development involves both lCST micro- and macrostructural alterations, and its path may be moderated by preceding symptom trajectory