Progressive Brain Volume Loss in Schizophrenia Over the Course of the Illness: Evidence of Maturational Abnormalities in Early Adulthood

Haren, Neeltje E.M. van; Pol, Hilleke E. Hulshoff; Schnack, Hugo G.; Cahn, Wiepke; Brans, Rachel G.H.; Carati, Inge; Rais, Monica; Kahn, René S.

doi:10.1016/j.biopsych.2007.01.004

Cited by 244 publications

(213 citation statements)

References 36 publications

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“…In a separate electrophysiological study using ERP, O'Donnell et al (1995) observed a greater increase of P300 latency in older chronic schizophrenic patients. Another longitudinal study (van Haren et al, 2007) observed increased cortical gray matter atrophy in schizophrenic patients before the age of 45 in a 5-year-follow-up. This group also found white matter to increase excessively before the age of 32 as compared to normal healthy controls, which showed a steadier trajectory of white matter volume growth.…”

Section: Discussionmentioning

confidence: 94%

Age-related deficits in fronto-temporal connections in schizophrenia: A diffusion tensor imaging study

Rosenberger

Kubicki

Nestor

et al. 2008

Schizophrenia Research

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Objective-Impairment of white matter connecting frontal and temporal cortices has been reported in schizophrenia. Yet, not much is known about the effects of age on fibers connecting these brain regions. Using diffusion tensor imaging tractography, we investigated the relationship between age and fiber integrity in patients with schizophrenia vs. healthy adults.Methods-DTI tractography was used to create 3D reconstructions of the cingulum, uncinate and inferior occipito-frontal fasciculi in 27 patients with schizophrenia and 34 healthy volunteers (23-56 years of age, group-matched on age). Fractional anisotropy (FA), describing fiber integrity, was then calculated along the entire length of these tracts, and correlated with subjects' age.Results-Patients revealed a significant decline in FA with age in both the cingulum and uncinate, but not in the inferior occipito-frontal fasciculi. No statistically significant correlations were found in these fiber bundles in controls. ContributorsRosenberger G. and Kubicki M. designed the study. Connor E., Bushell G., and Markant D. collected some of the data and did PUBMED searchers. Nestor P.G., Niznikiewicz M., and Saykin A., undertook the statistical analyses. Rosenberger G.wrote the first draft of the manuscript. Shenton M.,Kikinis R.,Westin C-F., and McCarley R.W. had substantial input on aspects of the design of the study and Shenton M. and Saykin A. had substantial input in editing multiple versions of the manuscript. Shenton M. and McCarley R.W. also had input on clinical aspects of the design including the selection of diagnostic and clinical measures. All other authors contributed to and have improved the final manuscript. Conflict of interestThere are no conflicts of interest. Conclusions-These results suggest an age-associated reduction of frontal-temporal connectivity in schizophrenia, but not in healthy controls. NIH Public Access

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Section: Discussionmentioning

confidence: 94%

Age-related deficits in fronto-temporal connections in schizophrenia: A diffusion tensor imaging study

Rosenberger

Kubicki

Nestor

et al. 2008

Schizophrenia Research

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“…Furthermore, several studies have found these structural brain abnormalities to be progressive over time (van Haren et al, 2007;Kempton et al, 2010;Fusar-Poli et al, 2013), with greater rates of progression potentially associated with a poorer clinical outcome (Cahn et al, 2006;van Haren et al, 2008). In addition, widespread cortical thinning of the cerebral cortex involving not just frontotemporal regions but also parietal and occipital regions has been demonstrated in individuals with schizophrenia compared with healthy controls (Nesvåg et al, 2008;Sprooten et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Progressive Brain Atrophy and Cortical Thinning in Schizophrenia after Commencing Clozapine Treatment

Ahmed

Cannon

Scanlon

et al. 2015

Neuropsychopharmacol

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Despite evidence that clozapine may be neuroprotective, there are few longitudinal magnetic resonance imaging (MRI) studies that have specifically explored an association between commencement of clozapine treatment for schizophrenia and changes in regional brain volume or cortical thickness. A total of 33 patients with treatment-resistant schizophrenia and 31 healthy controls matched for age and gender underwent structural MRI brain scans at baseline and 6-9 months after commencing clozapine. MRI images were analyzed using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) and FreeSurfer to investigate changes over time in brain volume and cortical thickness respectively. Significantly greater reductions in volume were detected in the right and left medial prefrontal cortex and in the periventricular area in the patient group regardless of treatment response. Widespread further cortical thinning was observed in patients compared with healthy controls. The majority of patients improved symptomatically and functionally over the study period, and patients who improved were more likely to have less cortical thinning of the left medial frontal cortex and the right middle temporal cortex. These findings demonstrate on-going reductions in brain volume and progressive cortical thinning in patients with schizophrenia who are switched to clozapine treatment. It is possible that this gray matter loss reflects a progressive disease process irrespective of medication use or that it is contributed to by switching to clozapine treatment. The clinical improvement of most patients indicates that antipsychotic-related gray matter volume loss may not necessarily be harmful or reflect neurotoxicity.

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“…For example, structural magnetic resonance imaging (MRI) studies have demonstrated reduced gray matter volume across several cortical regions subserving cognitive functions that are impaired in schizophrenia (Wright et al, 2000). Furthermore, longitudinal structural MRI studies indicate that cortical gray matter loss may be progressive, especially in the early stages of psychosis (Gur et al, 1998;Thompson et al, 2001;Van Haren et al, 2008). Consistent with MRI gray matter volume loss, postmortem studies have found reduced cortical neuropil Selemon et al, 1995Selemon et al, , 1998, reduced dendritic length (Glantz and Lewis, 1997) and reduced dendritic spine density (Black et al, 2004;Garey et al, 1998;Glantz and Lewis, 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of Davunetide on N-acetylaspartate and Choline in Dorsolateral Prefrontal Cortex in Patients with Schizophrenia

Jarskog

Dong

Kangarlu

et al. 2013

Neuropsychopharmacol

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Schizophrenia is associated with extensive neurocognitive and behavioral impairments. Studies indicate that N-acetylaspartate (NAA), a marker of neuronal integrity, and choline, a marker of cell membrane turnover and white matter integrity, may be altered in schizophrenia. Davunetide is a neurotrophic peptide that can enhance cognitive function in animal models of neurodegeneration. Davunetide has recently demonstrated modest functional improvement in a study of people with schizophrenia. In a subset of these subjects, proton magnetic resonance spectroscopy ( 1 H-MRS) was conducted to explore the effects of davunetide on change in NAA/ creatine (NAA/Cr) and choline/creatine (choline/Cr) over 12 weeks of treatment. Of 63 outpatients with schizophrenia who received randomized davunetide (5 and 30 mg/day) or placebo in the parent clinical trial, 18 successfully completed 1 H-MRS in dorsolateral prefrontal cortex (DLPFC) at baseline and at 12 weeks. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB). NAA/Cr was unchanged for combined high-and low-dose davunetide groups (N ¼ 11). NAA/Cr in the high-dose davunetide group (N ¼ 8) suggested a trend increase of 8.0% (P ¼ 0.072) over placebo (N ¼ 7). Choline/Cr for combined high-and low-dose davunetide groups suggested a 6.4% increase (P ¼ 0.069), while the high-dose group showed a 7.9% increase (P ¼ 0.040) over placebo. Baseline NAA/Cr correlated with the composite MCCB score (R ¼ 0.52, P ¼ 0.033), as did individual cognitive domains of attention/ vigilance, verbal learning, and social cognition; however, neither metabolite correlated with functional capacity. In this exploratory study, 12 weeks of adjunctive davunetide appeared to produce modest increases in NAA/Cr and choline/Cr in DLPFC in people with schizophrenia. This is consistent with a potential neuroprotective mechanism for davunetide. The data also support use of MRS as a useful biomarker of baseline cognitive function in schizophrenia. Future clinical and preclinical studies are needed to fully define the mechanism of action and cognitive effects of davunetide in schizophrenia.

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Progressive Brain Volume Loss in Schizophrenia Over the Course of the Illness: Evidence of Maturational Abnormalities in Early Adulthood

Cited by 244 publications

References 36 publications

Age-related deficits in fronto-temporal connections in schizophrenia: A diffusion tensor imaging study

Age-related deficits in fronto-temporal connections in schizophrenia: A diffusion tensor imaging study

Progressive Brain Atrophy and Cortical Thinning in Schizophrenia after Commencing Clozapine Treatment

Effects of Davunetide on N-acetylaspartate and Choline in Dorsolateral Prefrontal Cortex in Patients with Schizophrenia

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