Schizophrenia is a highly debilitating disease of great public health importance. This illness typically begins in adolescence, tends to be lifelong, and is one of the leading causes of disability worldwide. While the pathophysiological basis of this illness is still poorly understood, accumulating evidence suggests structural and functional brain abnormalities in the early course of schizophrenia. The view that these abnormalities are related to abnormal brain development is gaining ground; this model suggests that the observed brain abnormalities may be present before illness onset in individuals genetically predisposed to this disorder. Preliminary and ongoing work by this investigator in this little studied area has shown that child and adolescent relatives of schizophrenia patients have evidence of attentional, neurological and executive function deficits, and impaired structural and molecular integrity of the heteromodal association cortex (HAC) and subcortical brain structures; these impairments appear to progressively evolve during adolescence. These observed deficits also appear to predict schizotypy and other measures of behavioral pathology. The central hypotheses of the proposed study are that progressive neurodevelopmental dysmaturation of the HA C and subcortical brain regions underlies the vulnerability to schizophrenia, and may predict schizophrenia spectrum psychopathology (SSP). In the proposed study the investigator will seek to prospectively characterize the nature and longitudinal course of these observations in high-risk non-psychotic adolescent offspring of schizophrenia patients (HR, n=150) and matched and temporally """"""""yoked"""""""" healthy control (HC, n=100) subjects. All the subjects will be evaluated with neurobehavioral (neuropsychological and eye movement studies) and neuroimaging (magnetic resonance imaging and multi-voxel proton and phosphorus magnetic resonance spectroscopy) studies. Subjects will be followed up annually for three years to seek evidence of progressive brain dysmaturation and its relation to the emergence of SSP. These studies will establish a cohort of high-risk subjects for further follow-up studies of developmental vulnerability to schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH064023-01A2
Application #
6579276
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Rumsey, Judith M
Project Start
2002-12-20
Project End
2007-11-30
Budget Start
2002-12-20
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$545,076
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Padmanabhan, Jaya L; Shah, Jai L; Tandon, Neeraj et al. (2017) The ""polyenviromic risk score"": Aggregating environmental risk factors predicts conversion to psychosis in familial high-risk subjects. Schizophr Res 181:17-22
Lizano, Paulo L; Yao, Jeffrey K; Tandon, Neeraj et al. (2017) Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study. Schizophr Res 183:75-81
Lizano, Paulo L; Keshavan, Matcheri S; Tandon, Neeraj et al. (2016) Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study. Schizophr Res 170:115-22
Savadjiev, Peter; Seidman, Larry J; Thermenos, Heidi et al. (2016) Sexual dimorphic abnormalities in white matter geometry common to schizophrenia and non-psychotic high-risk subjects: Evidence for a neurodevelopmental risk marker? Hum Brain Mapp 37:254-61
Keshavan, Matcheri S; Paus, Tomas (2015) Neurodevelopmental Trajectories, Disconnection, and Schizophrenia Risk. JAMA Psychiatry 72:943-5
Shah, J L; Tandon, N; Howard, E R et al. (2015) Pituitary volume and clinical trajectory in young relatives at risk for schizophrenia. Psychol Med 45:2813-24
Ramanathan, Seethalakshmi; Miewald, Jean; Montrose, Debra et al. (2015) Can age at sexual maturity act as a predictive biomarker for prodromal negative symptoms? Schizophr Res 164:35-9
Domen, Patrick A E; Michielse, Stijn; Gronenschild, Ed et al. (2013) Microstructural white matter alterations in psychotic disorder: a family-based diffusion tensor imaging study. Schizophr Res 146:291-300
Tandon, Neeraj; Bolo, Nicolas R; Sanghavi, Kunal et al. (2013) Brain metabolite alterations in young adults at familial high risk for schizophrenia using proton magnetic resonance spectroscopy. Schizophr Res 148:59-66
Thermenos, H W; Whitfield-Gabrieli, S; Seidman, L J et al. (2013) Altered language network activity in young people at familial high-risk for schizophrenia. Schizophr Res 151:229-37

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