Cognitive Dysfunction and Prefrontal Cortical Circuit Alterations in Schizophrenia: Developmental Trajectories

Dienel, Samuel; Schoonover, Kirsten E.; Lewis, David A.

doi:10.1016/j.biopsych.2022.03.002

Cited by 54 publications

(32 citation statements)

References 153 publications

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“…(3) action at postsynaptic [56] and perisynaptic receptors [57]; (4) modulation of postsynaptic density proteins (PSD) [58] and intracellular signaling cascades [59]; (5) reuptake by glial cells through excitatory amino acid transporters (EAATs) [60]. In this framework, D-amino acids and related enzymes may directly or indirectly influence these processes.…”

Section: The Neurobiology Of Treatment-resistant Schizophrenia and Am...mentioning

confidence: 99%

“…It is noteworthy that glutamate can be affected at multiple molecular levels in refractory schizophrenia [ 53 ]: (1) synthesis, which directly involves astrocytes [ 54 ]; (2) release [ 55 ]; (3) action at postsynaptic [ 56 ] and perisynaptic receptors [ 57 ]; (4) modulation of postsynaptic density proteins (PSD) [ 58 ] and intracellular signaling cascades [ 59 ]; (5) reuptake by glial cells through excitatory amino acid transporters (EAATs) [ 60 ]. In this framework, D-amino acids and related enzymes may directly or indirectly influence these processes.…”

Section: The Neurobiology Of Treatment-resistant Schizophrenia and Am...mentioning

confidence: 99%

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Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

et al. 2022

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Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30–40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics’ effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.

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Section: The Neurobiology Of Treatment-resistant Schizophrenia and Am...mentioning

confidence: 99%

Section: The Neurobiology Of Treatment-resistant Schizophrenia and Am...mentioning

confidence: 99%

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

et al. 2022

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“…Cognitive impairment refers to deficits in the neurocognitive domains, including complex attention, executive function, learning, and memory, language, perceptual-motor, and social cognition (36,41,42). Based on neurodevelopment hypothesis of schizophrenia, cognitive impairment can be viewed as a reflection of the brain's functional and structural abnormalities, especially within the brain circuits involved in information processing (43)(44)(45). Many neuroimaging studies support the notion that brain gray matter volume (GMV) abnormalities and brain functional connectivity density (FCD) disturbances in the whole brain can be the neural basis of cognitive impairments (18,24,25,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(46)(47)(48)(49)(50)(51)(52)(53)(54).…”

Section: Introductionmentioning

confidence: 99%

Baseline global brain structural and functional alterations at the time of symptom onset can predict subsequent cognitive deterioration in drug-naïve first-episode schizophrenia patients: Evidence from a follow-up study

Zhuo

Chen

et al. 2022

Front. Psychiatry

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Alterations in the global brain gray matter volume (gGMV) and global functional connectivity density (gFCD) play a pivotal role in the cognitive impairment and further deterioration in schizophrenia. This study aimed to assess the correlation between alterations in the gGMV and gFCD at baseline (ΔgGMV and ΔgFCD), and the subsequent alterations of cognitive function in schizophrenia patients after 2-year antipsychotic treatment. Global-brain magnetic resonance imaging scans were acquired from 877 drug-naïve, first-episode schizophrenia patients at baseline and after two years of antipsychotic treatment with adequate dosage and duration, and 200 healthy controls. According to ΔgGMV at baseline, schizophrenia patients were divided into mild, moderate, and severe alteration groups. The MATRICS consensus cognitive battery and Global Deficit Score (GDS) were used to assess cognitive impairment. We found that ΔgGMV and ΔgFCD at baseline were significantly correlated with the severity of the cognitive deterioration (ΔGDS). The correlation coefficient indicated a significant positive correlation between baseline ΔgFCD and subsequent cognitive deterioration, with a relatively stronger relation in the mild alteration group (r = 0.31). In addition, there was a significant positive correlation between baseline ΔgGMV and subsequent cognitive deterioration, with a stronger relation in the moderate and severe alteration groups (r = 0.303; r = 0.302, respectively). Our results showed that ΔgGMV and ΔgFCD are correlated with the severity of cognitive deterioration after completion of a 2-year antipsychotic treatment in schizophrenia patients. These findings suggest that baseline alterations in gGMV and gFCD hold potential for predicting subsequent cognitive decline in schizophrenia.

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“…For example, Dixon et al reported that decreased GABA or glutamate concentrations in frontal lobe areas correlated with cognitive performance in patients with SCZ (Miskowiak et al, 2016), Picó-Pérez et al reported that structural aberrations in the neocortex (frontal, parietal, occipital, and temporal lobes) and in subcortical structures (amygdala, nucleus accumbens, caudate, putamen, and pallidum) correlated with cognitive dysfunction in patients with SCZ (Reilly and Sweeney, 2014). Dienel et al (2022) found that genetic changes associated with altered excitatory signaling in layer 3 pyramidal neurons were associated with cognitive impairments in the prodromal phase of SCZ (Ivleva et al, 2010). Importantly, Mahmoudi et al (2021) reported that rs58335419, a variable number tandem repeat variant of MIR137, is associated with cognitive impairment and altered cortical morphology in patients with SCZ (McCleery and Nuechterlein, 2019).…”

Section: Introductionmentioning

confidence: 99%

Associations of cognitive impairment in patients with schizophrenia with genetic features and with schizophrenia-related structural and functional brain changes

Zhuo

Tian²,

Chen³

et al. 2022

Front. Genet.

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Cognitive impairment is highly prevalent in patients with major psychiatric disorders (MPDs), including schizophrenia (SCZ), bipolar disorder, major depressive disorder, in whom it can be highly disruptive to community functioning and worsen prognosis. Previously, genetic factors and cognitive impairments in MPD patients have been examined mostly in isolated circuits rather than in the whole brain. In the present study, genetic, neuroimaging, and psychometric approaches were combined to investigate the relationship among genetic factors, alterations throughout the brain, and cognitive impairments in a large cohort of patients diagnosed with SCZ, with a reference healthy control (HC) group. Single nucleotide polymorphisms (SNPs) in SCZ-risk genes were found to be strongly related to cognitive impairments as well as to gray matter volume (GMV) and functional connectivity (FC) alterations in the SCZ group. Annotating 136 high-ranking SNPs revealed 65 affected genes (including PPP1R16B, GBBR2, PDE4B, CANCNA1C, SLC12AB, SATB2, MAG12, and SATB2). Only one, a PDE4B SNP (rs1006737), correlated with GMV (r = 0:19 p = 0.015) and FC (r = 0.21, p = 0.0074) in SCZ patients. GMV and FC alterations correlated with one another broadly across brain regions. Moreover, the present data demonstrate three-way SNP-FC-GMV associations in patients with SCZ, thus providing clues regarding potential genetic bases of cognition impairments in SCZ. SNP-FC-GMV relationships correlated with visual learning and reasoning dimensions of cognition. These data provide evidence that SCZ-related cognitive impairments may reflect genetically underlain whole-brain structural and functional alterations.

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Cognitive Dysfunction and Prefrontal Cortical Circuit Alterations in Schizophrenia: Developmental Trajectories

Cited by 54 publications

References 153 publications

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

Baseline global brain structural and functional alterations at the time of symptom onset can predict subsequent cognitive deterioration in drug-naïve first-episode schizophrenia patients: Evidence from a follow-up study

Associations of cognitive impairment in patients with schizophrenia with genetic features and with schizophrenia-related structural and functional brain changes

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