Regionally Specific Cortical Thinning and Gray Matter Abnormalities in the Healthy Relatives of Schizophrenia Patients

Goghari, Vina M.; Rehm, Kelly; Carter, Cameron S.; MacDonald, Angus W.

doi:10.1093/cercor/bhj158

Cited by 111 publications

(114 citation statements)

References 64 publications

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“…Increased average head size, childhood brain volume, or cortical thickness in individuals with: (i) idiopathic autism (50-53), (ii) the autism-associated duplications at 1q21.1 (17) and 16p13.1 (32) and the autism-associated deletions at 16p11.2 (31), and (iii) autism due to loss of function (or haploinsufficiency) of FMR1 (54), NF1 (55), PTEN (56) and RNF135 (57). By contrast, reduced average values for brain size and cortical thickness, due to some combination of reduced growth and accelerated gray matter loss, have been demonstrated with notable consistency across studies of schizophrenia (58)(59)(60)(61)(62), and such reduced head or brain size has also been associated with the schizophrenia-linked CNVs at 1q21.1 and 22q11.21 (17,63,64), and with deletions of 16p13.1 (65).…”

Section: Discussionmentioning

confidence: 99%

Comparative genomics of autism and schizophrenia

Crespi

Stead

Elliot

2010

Proc. Natl. Acad. Sci. U.S.A.

236

138

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We used data from studies of copy-number variants (CNVs), singlegene associations, growth-signaling pathways, and intermediate phenotypes associated with brain growth to evaluate four alternative hypotheses for the genomic and developmental relationships between autism and schizophrenia: (i) autism subsumed in schizophrenia, (ii) independence, (iii) diametric, and (iv) partial overlap. Data from CNVs provides statistical support for the hypothesis that autism and schizophrenia are associated with reciprocal variants, such that at four loci, deletions predispose to one disorder, whereas duplications predispose to the other. Data from single-gene studies are inconsistent with a hypothesis based on independence, in that autism and schizophrenia share associated genes more often than expected by chance. However, differentiation between the partial overlap and diametric hypotheses using these data is precluded by limited overlap in the specific genetic markers analyzed in both autism and schizophrenia. Evidence from the effects of risk variants on growth-signaling pathways shows that autism-spectrum conditions tend to be associated with upregulation of pathways due to loss of function mutations in negative regulators, whereas schizophrenia is associated with reduced pathway activation. Finally, data from studies of head and brain size phenotypes indicate that autism is commonly associated with developmentally-enhanced brain growth, whereas schizophrenia is characterized, on average, by reduced brain growth. These convergent lines of evidence appear most compatible with the hypothesis that autism and schizophrenia represent diametric conditions with regard to their genomic underpinnings, neurodevelopmental bases, and phenotypic manifestations as reflecting under-development versus dysregulated over-development of the human social brain.genetics | evolution | psychiatry T he Swiss psychiatrist Eugen Bleuler coined the terms "schizophrenia", for the splitting of psychic functions, and "autism", for withdrawal from external reality in patients with schizophrenia, almost exactly a century ago (1). Ever since 1943, when Leo Kanner (2) coopted autism to refer to a new condition involving "disturbance of affective contact" manifested in children, the relationship between schizophrenia and Kanner's autism has remained unclear (3). Kanner originally conceived autism as an early, distinct subtype of schizophrenia (model 1A) (Fig. 1A), a view he later renounced in favor of a model, which was also supported by Rutter (4) with the conditions as distinct, separate, and unrelated (model 1B) (Fig. 1B). Under each of these two hypotheses, autism and schizophrenia may each grade more or less smoothly, and independently, into so-called normality. Schizophrenia and autism have also been considered as diametric, or opposite sets of conditions (model 1C) (Fig. 1C) along a spectrum of social-brain phenotypes from hypodevelopment in autism, to normality, to hyperdevelopment in schizophrenia (5). By a fourth model, autism overlaps broadly yet...

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Section: Discussionmentioning

confidence: 99%

Comparative genomics of autism and schizophrenia

Crespi

Stead

Elliot

2010

Proc. Natl. Acad. Sci. U.S.A.

236

138

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“…In fact, one of the principal pathological findings in the brains of those affected with schizophrenia involves abnormal cortical thinning (Cannon et al, 2015). Reduced cortical thickness has also been demonstrated in the unaffected siblings of patients with the disorder (Goldman et al, 2009;Goghari, Rehm, Carter, & MacDonald, 2007;Gogtay et al, 2007), suggesting a possible relationship of these cortical changes to the genetic liability for developing the illness. Indeed, schizophrenia's strongest genetic association involves variation in the major histocompatibility complex (MHC) locus, which mediates synapse elimination during postnatal development in mice (Sekar et al, 2016).…”

Section: Structural Abnormalities In Schizophreniamentioning

confidence: 99%

Preserved, deteriorated, and premorbidly impaired patterns of intellectual ability in schizophrenia.

Ammari¹,

Heinrichs²,

Pinnock³

et al. 2014

Neuropsychology

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Objective: Although impaired general intellectual ability is a prevalent feature in schizophrenia, patterns suggesting preserved, deteriorated, and premorbidly impaired intellect have also been identified. The main purpose of this investigation was to examine the clinical, cognitive, and neuroanatomical characteristics of these intellectual subtypes, and to establish the value and validity of this approach for reducing the heterogeneity of schizophrenia. Methods: A total of 71 patients with a diagnosis of schizophrenia or schizoaffective disorder and 66 healthy controls were assessed. A 'preserved' performance pattern (n=29) was defined by average-range estimated premorbid and current IQ with no evidence of decline (premorbid-current IQ difference <10 points). A 'deteriorated' pattern (n=14) was defined by a difference between estimated premorbid and current IQ estimates of 10 points or more. A 'premorbidly impaired' pattern (n=14) was defined by below average estimated premorbid and current IQ and no evidence of decline greater than 10 points. The groups were compared on demographic,

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“…Older Relatives (Keshavan et al 1997) (Suddath et al 1990) (Lawrie et al 1999) (Noga et al 1996) (Schreiber et al 1999) (Seidman et al 1997) (Lawrie et al 2001) (Cannon et al 1998) (Keshavan et al 2002a ) (Staal et al 1998) ) (Seidman et al 1999) (Gogtay et al 2003) (Sharma et al 1999) (Job et al 2003) (Dickerson et al 1999) (Rajarethinam et al 2004) (Chua et al 2000) (Job et al 2005a ) (Staal et al 2000) (Goghari et al 2007) …”

Section: Young Relativesmentioning

confidence: 99%

MRI brain volume abnormalities in young, nonpsychotic relatives of schizophrenia probands are associated with subsequent prodromal symptoms

2007

Schizophrenia Research

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Schizophrenia is characterized by subtle but well-replicated total and regional (frontal and temporal) brain tissue volume deficits. Studies of individuals at-risk for developing schizophrenia suggest that the onset of brain volume decrement may closely pre-date overt manifestations of schizophrenia, making brain volume abnormalities potential predictors for early identification. In an ongoing longitudinal morphometric MRI study of young, nonpsychotic first-or second-degree relatives of schizophrenia probands, we compared brain volumes in 46 relatives who are still within age range for developing schizophrenia against comparison groups of 46 schizophrenia patients and 46 healthy volunteers without family history of schizophrenia. Relatives had similar brain volume abnormalities as schizophrenia patients albeit less severe. Relatives had significantly larger whole brain, frontal, temporal and parietal gray matter (GM) volumes than patients. Relatives also had significantly smaller frontal GM volumes than healthy volunteers. Both relatives and patients had significantly larger whole brain WM (specifically parietal WM) volumes compared to healthy volunteers. Abnormally greater WM volumes in relatives and patients are suggestive of genetically-mediated dysmaturation of the age-expected myelination during adolescence through mid adulthood. On prodromal symptoms assessed in relatives one year after MRI brain scans, initial GM deficits as well as larger WM volumes correlated significantly with greater severity of subsequent prodromal symptoms. Together with previous genetic high-risk studies of adolescent or young adult relatives, these findings indicate that premorbid MRI brain abnormalities may be of predictive value for the early identification of schizophrenia.

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Regionally Specific Cortical Thinning and Gray Matter Abnormalities in the Healthy Relatives of Schizophrenia Patients

Cited by 111 publications

References 64 publications

Comparative genomics of autism and schizophrenia

Comparative genomics of autism and schizophrenia

Preserved, deteriorated, and premorbidly impaired patterns of intellectual ability in schizophrenia.

MRI brain volume abnormalities in young, nonpsychotic relatives of schizophrenia probands are associated with subsequent prodromal symptoms

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