Schizophrenia is a devastating and debilitating disorder that affects about 1% of the population and is characterized by a range of symptoms including delusions, hallucinations, impaired cognitive function, mood disturbances and social withdrawal. Little is known about the neuropathology of schizophrenia, yet imaging studies of its earliest stages have the potential to identify initial pathologic traces preceding psychosis onset. New research approaches now allow clinicians to investigate prodromal schizophrenia subjects (prodromes) who experience attenuated psychotic symptoms, and are at high-risk for developing schizophrenia. Diffusion MRI is a promising imaging technique for prodromes, since it consistently and reliably identifies abnormalities in all stages of schizophrenia. However, current diffusion MRI biomarkers and analysis methods have limited sensitivity and poor specificity to the underlying microstructural pathology, which pose barriers to further understanding the etiology of schizophrenia, and to new developments in pharmacological treatment. The goal of this proposal is to develop tools and apply next generation diffusion MRI biomarkers, such as free- water imaging, neurite density, neurite orientation dispersion, and Kurtosis. These biomarkers improve specificity and sensitivity of currently available measures, and are more suited to identify subtle pathologies. Our previous research suggests that neurodevelopmental, neuroinflammatory and neurodegenerative microstructural pathologies are involved in schizophrenia. We hypothesize that neuroinflammation is the dominant pathology responsible for triggering attenuated psychotic symptoms, and that abnormal neurodevelopment, which changes how the brain appears or grows, may be a predisposition for psychosis. Using next generation diffusion MRI biomarkers can distinguish between these micropathologies, which will help explaining their association with attenuated psychotic symptoms, and reveal their role in psychosis onset. Large-scale studies, such as the North American Prodrome Longitudinal Study (NAPLS), have already collected large datasets of CHR that include dMRI data, and this data will be available to us. Our approach is to leverage from these existing data and utilize it to study the pathological correlates of prodromal symptoms, unlike previous studies that focused on risk for conversion to SZ. The assembled unprecedentedly large data (n>700) provide ample sensitivity to identify subtle prodromal pathologies. A highly trained team of computer scientists and clinical neuroscience researchers will work to develop novel tools for next generation diffusion MRI biomarkers in order to localize and to characterize the neurobiology that underlies prodromal symptomatology. The results of this study will have an important impact on our understanding of biological mechanisms underlying the initial stages of schizophrenia, and will lead to improved diagnosis and possibly new treatments that target such phenomena as neuroinflammation.

Public Health Relevance

We will develop novel analysis approaches for next generation diffusion magnetic resonance imaging that will enable the identification of subtle brain pathologies in prodromal schizophrenia subjects. This study, which leverages existing large-scale datasets, aims to identify new biomarkers that will distinguish between neurodevelopmental, neuroinflammatory and neurodegenerative pathologies, and ultimately reveal their role in the earliest stages of schizophrenia. Understanding the pathophysiology of prodromal schizophrenia will improve diagnosis methods and could potentially introduce new treatment strategies that may mitigate or prevent the progression of attenuated psychotic symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH108574-04
Application #
9693085
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Wijtenburg, Andrea
Project Start
2016-08-10
Project End
2021-04-30
Budget Start
2019-07-09
Budget End
2020-04-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Chad, Jordan A; Pasternak, Ofer; Salat, David H et al. (2018) Re-examining age-related differences in white matter microstructure with free-water corrected diffusion tensor imaging. Neurobiol Aging 71:161-170
Duering, Marco; Finsterwalder, Sofia; Baykara, Ebru et al. (2018) Free water determines diffusion alterations and clinical status in cerebral small vessel disease. Alzheimers Dement 14:764-774
McCarthy-Jones, Simon; Oestreich, Lena K L; Lyall, Amanda E et al. (2018) Childhood adversity associated with white matter alteration in the corpus callosum, corona radiata, and uncinate fasciculus of psychiatrically healthy adults. Brain Imaging Behav 12:449-458
Lyall, A E; Pasternak, O; Robinson, D G et al. (2018) Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning. Mol Psychiatry 23:701-707
Guttuso Jr, T; Bergsland, N; Hagemeier, J et al. (2018) Substantia Nigra Free Water Increases Longitudinally in Parkinson Disease. AJNR Am J Neuroradiol :
Ji, Fang; Pasternak, Ofer; Liu, Siwei et al. (2017) Distinct white matter microstructural abnormalities and extracellular water increases relate to cognitive impairment in Alzheimer's disease with and without cerebrovascular disease. Alzheimers Res Ther 9:63
Rydhög, Anna S; Szczepankiewicz, Filip; Wirestam, Ronnie et al. (2017) Separating blood and water: Perfusion and free water elimination from diffusion MRI in the human brain. Neuroimage 156:423-434
Kaufmann, Lisa-Katrin; Baur, Volker; Hänggi, Jürgen et al. (2017) Fornix Under Water? Ventricular Enlargement Biases Forniceal Diffusion Magnetic Resonance Imaging Indices in Anorexia Nervosa. Biol Psychiatry Cogn Neurosci Neuroimaging 2:430-437
Burciu, Roxana G; Ofori, Edward; Archer, Derek B et al. (2017) Progression marker of Parkinson's disease: a 4-year multi-site imaging study. Brain 140:2183-2192
Ofori, Edward; Krismer, Florian; Burciu, Roxana G et al. (2017) Free water improves detection of changes in the substantia nigra in parkinsonism: A multisite study. Mov Disord 32:1457-1464

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