Neurotox Res DOI 10.1007/s12640-014-9473-0

REVIEW

Neurodegenerative Aspects in Vulnerability to Schizophrenia Spectrum Disorders Trevor Archer • Serafino Ricci • Danilo Garcia Max Rapp Ricciardi

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Received: 8 January 2014 / Revised: 21 April 2014 / Accepted: 21 April 2014 Ó Springer Science+Business Media New York 2014

Abstract The neurodegenerative and neurotoxic aspects of schizophrenia and/or psychosis involve genetic, epigenetic, and neurotoxic propensities that impinge upon both the symptom domains and the biomarkers of the disorder, involving cellular apoptosis/excitotoxicity, increased reactive oxygen species formation, viral and bacterial infections, anoxic birth injury, maternal starvation, drugs of abuse, particularly cannabis, metabolic accidents, and other chemical agents that disrupt normal brain development or the integrity of brain tissues. Evidence for premorbid and prodromal psychotic phases, aspects of neuroimaging, dopamine, and psychosis vulnerability, and perinatal aspects provide substance for neurodegenerative influences. Not least, the agencies of antipsychotic contribute to the destructive spiral that disrupts normal structure and function. The etiopathogenesis of psychosis is distinguished also by disruptions of the normal functioning of the neurotrophins, in particular brain-derived neurotrophic factor, dyskinesic aspects, immune system disturbances, and metabolic aspects. Whether detrimental to neurodevelopment or tissue-destructive, or an acceleration of

T. Archer (&)
D. Garcia
M. R. Ricciardi Department of Psychology, University of Gothenburg, Box 500, 40530 Go¨thenburg, Sweden e-mail: [email protected] T. Archer
D. Garcia
M. R. Ricciardi Network for Empowerment and Well-Being, Lund, Sweden S. Ricci Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, Rome, Italy D. Garcia Center for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Go¨thenburg, Sweden

neurotoxic pathways, the notion of neurodegeneration in the pathophysiology of schizophrenia spectrum and psychotic disorders continues to gather momentum. Keywords Apoptosis
Infection
Neurotoxin
Neurogenesis
Dopamine
Cannabis
Neurotrophins
Metabolism
Immune system
Neurodevelopment

Introduction The status of the neurodegenerative influence in the development of schizophrenic psychoses has not been considered straightforward and perhaps may even seem tenuous. Nevertheless, the plausibility of evidence from laboratory animal models studies, neuroimaging studies, and postmortem assays together with a neurodevelopmental viewpoint of disorder etiopathogenesis does imply that neurodegenerative processes may contribute to heightened predisposition and susceptibility to the precipitation of symptom domains through a staging notion (Archer et al. 2010a, b). For example, in a five-day repeated ketamine administration animal model of schizophrenia, Faizi et al. (2014) observed increased reactive oxygen species production, mitochondrial membrane potential collapse, mitochondrial swelling, and cytochrome c release in mitochondria of schizophrenia group. Genetic risk factors may impact upon or disrupt developmental trajectories (Dauvermann et al. 2012, 2013; Sullivan et al. 2003). There is much support for the notion that schizophrenia spectrum disorders have their origin during gestation and/or in early infancy (Graff et al. 2011; Sawa and Snyder 2002). Insults, during the early infancy or perinatal period, or even during the course of early-to-late childhood and adolescence, are implicated in the etiopathogenesis of the marked structural

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and functional abnormalities that distinguish the symptoms of disorder (Cannon et al. 2002a, b; Fontes et al. 2011; Geddes et al. 1999). The eventual contribution of neurodegenerative processes affecting the disorder must take into account the plethora of interactive factors and agents that include inherited and acquired attributes (Elia et al. 2011; Jablonka and Raz 2009). The disorder pathophysiology may involve the influences of several contributory process, including cellular apoptosis/excitotoxicity, viral and bacterial infections, anoxic birth injury, maternal starvation, drug abuse in particular cannabis, trauma, and other conditions exerting detrimental effects on neurogenesis. Both neurogenetic and epigenetic forces arising from gene-environment interactions affecting developmental trajectories impart levels of predisposing vulnerability that may or may not lead to the manifestation of schizophrenic symptoms (Gratacos et al. 2007; Hoenicka et al. 2010), or those of related conditions (Bergman et al. 2011; Jacob et al. 2010). Whether or not the neurodegenerative aspect of the disorder may be neurogenetic or epigenetic, there compelling evidence exists for expressions of the disruptive influences affecting normal development. In the present treatise, the available evidence supporting the notion of neurodegenerative impacts of liability to psychosis is reviewed critically. Recent studies showing that psychosis is usually predated by a prodromal phase characterized by dramatic neurobiological and psychopathological changes are reviewed. Then, the imaging findings supporting neurodegenerative impacts in the development of psychosis with some specific insight into molecular and structural studies are examined. Following this, dopamine and psychosis vulnerability, perinatal agents, cannabis abuse, neurotrophin disruption, dyskinetic movement, brain insulin dysregulation, and cytokine imbalance aspects are discussed. Throughout, it ought to be considered that (i) histopathological features are suggestive of apoptotic rather than necrotic processes, and (ii) loss of structure and function in disorder progression, and (iii) the presence of infections and/or adverse environmental conditions that perturb the course of normal development resulting in unsuitable developmental trajectories.

The Evidence for a Prodromal Psychotic Phases Over the recent two decades, accumulating evidence has showed that psychosis onset is usually preceded by a prodromal phase (Fusar-Poli et al. 2013a). This period is spanning childhood and adolescence and is characterized by profound neurodevelopmental changes. Subjects experiencing putative prodromal signs or symptoms of psychosis have a greater risk of developing the disease (from

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Table 1 Putative neurodegenerative factors influencing vulnerability and altered developmental trajectory Imaging Volumetric loss Loss of connectivity Catecholamine metabolite alterations Tissue loss Thalamic gray matter Glutamate-transmission integrity Temporal lobe and Inferior frontal gyrus Dopamine Presynaptic alterations Synthesis and turnover Perinatal Ventral HPL lesion MAM neurotoxicity Adverse childhood experience Infection Neurotrophin BDNF loss/reduction Insulin Brain insulin dysregulation Immune system disturbance Cytokine imbalance HPF hippocampus, MAM methylazoxymethanol, BDNF brainderived neurotrophic factor

18 % at 6 months up to 36 % after 3 years) over time (Fusar-Poli et al. 2012a). The majority of the subjects who will develop a psychotic disorder later on will transit toward schizophrenic psychoses rather than to affective psychoses (Fusar-Poli et al. 2013b). Furthermore, the presence of putative prodromal symptoms per se is associated with significant psychosocial impairment, decreased quality of life, and subtle cognitive deficits (Borgwardt et al. 2006, 2010, 2011; Bu¨schlen et al. 2011; Fusar-Poli et al. 2011a, b, c, 2012b; Haller et al. 2009; Koutsouleris et al. 2012; Mechelli et al. 2011; Rothlisberger et al. 2012; Shenton et al. 2001; Smieskova et al. 2012a, b). At a neurobiological level, the prodromal psychotic phase is characterized by significant alterations in the structure (Buehlmann et al. 2010; Crossley et al. 2009; Fusar-Poli et al. 2007, 2011a, b, c; Smieskova et al. 2010a, b, 2012c), function (Fusar-Poli et al. 2010, 2011a, b, c; Fusar-Poli and Meyer-Lindenberg 2013a), connectivity (Fusar-Poli and Meyer-Lindenberg 2013b), and neurochemistry (Howes et al. 2007; Lyon et al. 2011; McGuire et al. 2008; MeyerLindenberg et al. 2002; Miyake et al. 2011) of the brain (Laruelle et al. 1996). The presence of a subtle prepsychotic phase is the clinical ground on which neurodegenerative factors can be tested. As evident from genetic risk

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factors and risk factors linked to childhood ill health/ adversity, the developmental trajectories of the afflicted individuals are not optimal (Arango and Fraguas 2013). Some of the stronger pieces of evidence supporting the notion of neurodegenerative aspects in liability to psychosis (cf. Pasternak et al. 2012) are considered below (Table 1).

Imaging Aspects At first sight, the accumulated evidence for progressive volumetric loss, e.g., in cortical volume/thickness (Goldman et al. 2009; Honea et al. 2008) and loss of functional connectivity (Meyer-Lindenberg et al. 2005; Yu et al. 2011), argues for the aspect of neurodegeneration in schizophrenia; yet, the possible impacts of peristaltic and environmental agents must needs to be understood prior to a reliable conclusion (Meyer-Lindenberg 2011). For example, Goto et al. (2010) compared 18 patients (nine males, nine females; age range: 13–52 years) with 18 healthy volunteers (nine males, nine females; age range: 15–49 years) with no current or past psychiatric history, using magnetic resonance spectroscopy (MRS). They found that levels of N-acetylaspartate/Cr in the left basal ganglia and parieto-occipital lobe, but not in the frontal lobe, were significantly lower in patients with first-episode schizophrenia psychosis than in control subjects. No differences were observed between the serum brain-derived neurotrophic factor (BDNF) levels of patients with firstepisode schizophrenia psychosis and the healthy control subjects. The plasma levels of catecholamine metabolites, plasma 3-methoxy-4-hydroxyphenylglycol, but not homovanillic acid, were significantly lower in the patients with first-episode psychosis than in control subjects. In addition, a significantly positive correlation was observed between the levels of N-acetylaspartate/Cr of the left basal ganglia and plasma MHPG in all the subjects. The authors concluded that brain N-acetylaspartate levels in the left basal ganglia and plasma 3-methoxy-4-hydroxyphenylglycol levels were significantly reduced at the first-episode of schizophrenia psychosis, indicating that neurodegeneration via noradrenergic neurons might be associated with the initial progression of the disease. Increased prefrontal gyrification (cortical folding) and increased local short range prefrontal connectivity and reduced long range connectivity have been observed in highgenetic risk subjects (Dauvermann et al. 2012); gyrification and connectivity are disrupted in Schizopsychotic disorders. Dauvermann et al. (2013) have found that Bayesian Model Selection analysis has demonstrated significantly lower connection strength of the thalamocortical connection with nonlinear modulation from the mediodorsal thalamus in

high-risk subjects with psychotic symptoms, and those individuals who subsequently developed schizophrenia.

Aspects of Tissue Loss Regional loss of glutamate and glutamine in schizophrenic patients (Tayoshi et al. 2009) may offer evidence of an excitotoxic process in the disorder pathophysiology. The loss of parvalbumin-containing cells, an observation that has been reported consistently in postmortem analysis of the brains of schizophrenic patients) following NMDA receptor blockade offers support for this notion (Adell et al. 2012; Dean et al. 2011). Aoyama et al. (2011) have demonstrated that the loss of thalamic glutamate in the brain of schizophrenia patients correlated significantly with loss a gray matter in the middle and inferior frontal gyrus and temporal pole. Thalamic gray matter and glutamate losses were observed in individuals at risk for developing schizophrenia (see also Aoyama et al. 2013; Stone et al. 2009). Correlations between glutamate and glutamine ratios in the frontal cortices of adolescents at risk for the disorder and performance scores on the Global Assessment of Functioning Scale have been observed (Tibbo et al. 2004). It has been suggested that the elevated glutamine levels in never-treated patients followed by the decreased level of thalamic glutamine and gray-matter loss in connected regions may be indicative of either neurodegeneration or a plastic response to reduced subcortical activity (The´berge et al. 2007). There appears to be a consensus of sorts for an excitotoxic contribution primarily in earlystage schizophrenia (Bustillo et al. 2010). Glutamatergic alterations and loss of cortical gray matter originating from basal ganglia-corticothalamic circuits may be the expressions of excitotoxicity through these regions. First-episode schizophrenic patients have exhibited increased membrane breakdown in a magnetic resonance spectroscopy by applying labeled phosphorous (Miller et al. 2009). Takei et al. (2013) have demonstrated reduced functional performance activation in both the temporal lobes and the right inferior frontal gyrus during task performance (measured by mean [oxyhemoglobin] changes). Reduced activation in the left temporal lobe was negatively correlated with the Positive and Negative Syndrome Scale disorganization and negative symptoms sub-scores; right inferior frontal gyrus activation was negatively correlated with illness duration, Positive and Negative Syndrome Scale disorganization, and negative symptom sub-scores. Their results imply that brain dysfunction in schizophrenia during a conversation task is related to functional deficits in both the temporal lobes and the right inferior frontal gyrus with manifestation primarily in the form of disorganized thinking and negative symptomatology.

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Dopamine and Psychosis Vulnerability Over the past two decades, new neurochemical imaging techniques have enabled the subcortical dopaminergic system to be carefully investigated in vivo (McGuire et al. 2008). In particular, the development of new radiotracers combined with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) techniques has allowed accurate investigations of striatal presynaptic dopaminergic alterations in schizophrenia (for reviews see Howes et al. 2007; Lyon et al. 2011; Miyake et al. 2011). Different indexes of presynaptic dopamine neurotransmission such as dopamine synthesis capacity studies (Meyer-Lindenberg et al. 2002) and dopamine release (Laruelle et al. 1996), or depletion (Kegeles et al. 2010) studies have suggested significant alterations in the striatal presynaptic dopaminergic function in schizophrenia. For the sake of the present discussions, it ought to be noted, however, that elevated dopamine synthesis and release is also seen in subjects at risk for schizophrenia (Huttunen et al. 2008) and in the prodromal state (Mechelli et al. 2011), suggesting that they are part of the risk architecture of schizophrenia. The original neurodegenerative model of schizophrenia proposed that functional alterations in dopamine neurotransmission are secondary to a change in the number or density of striatal dopamine terminals over the course of the illness (Lieberman et al. 1990, 1997). Two recent meta-analyses have recently tested this hypothesis (Fusar-Poli and Meyer-Lindenberg 2013a, b). The authors found that dopamine synthesis capacity was increased of 14 % in patients with schizophrenia as compared to controls, while there were no differences in structural indexes of neuronal integrity (such as measures of Dopamine Active Transporter). The functional alterations observed during the psychosis onset can be related to a number of environmental factors such as perinatal insults, reviewed below here.

Perinatal Aspects Several perinatal insults have been shown to induce schizophrenia-like symptoms in laboratory setting (Archer 2010; Powell et al. 2012). Bilateral excitotoxin-induced lesions, administering ibotenic acid to the ventral hippocampus typically to 7-day-old rat pups, induce disruptions of prepulse inhibition (PPI) to the acoustic startle response, a model of sensory gating in rodents, hyper-responsiveness to stressful stimuli, supersensitivity to dopamine (DA) agonists, and N-methyl-D-aspartic acid (NMDA) antagonists (Lipska et al. 1992, 1995, 2001); additionally, persistent deficits in working memory and spatial navigational learning (O’Donnell et al. 2002), together with hyper-

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responsiveness to stimulation of the ventral tegmental area (Lillrank et al. 1999; Lipska and Weinberger 1994) have all been observed in neonatal ventral hippocampus-lesioned rats. Prenatal administration of methylazoxymethanol (MAM) disrupted early brain development with structural and functional abnormalities in the cortex and hippocampus, many of which bear similarities to schizophrenia, expressed in the adult rats (Flagstad et al. 2005; Lodge and Grace 2008; Mohammed et al. 1986a, b; Moore et al. 2006). The utility of prenatal MAM as an animal model of the disorder highlights the neurodegenerative aspect (Chen and Hillman 1986), particularly with regard to the neurocognitive deficits (Fiore et al. 2004; Gourevitch et al. 2004; Lee et al. 2011; Leng et al. 2005). Similar to patients presenting cognitive deficit profiles in schizophrenia spectrum disorder (Maat et al. 2012), MAM-treated marked deficits on an attentional-shift task (analogous to the Wisconsin Card Sorting Task), and on a differential reinforcement of low rate of responding (DRL-20 performance, analogous to continuous performance) task (Featherstone et al. 2007). Prenatal MAM administration disrupts early cortical development causing deficits in medial prefrontal functions at adult ages (Goto and Grace 2006). These effects of the neurotoxin interrupt normal neuronal development, stress and immune response systems, and signal transduction mechanisms (Ciani et al. 2003; Ferrer et al. 1997; Lafarga et al. 1997; Rice and Barone 2000). Traumatic/adverse experiences during infancy and early childhood compromise healthy brain development in several domains, including cognitive, emotional, and motor. Traumatic environmental confrontation during early neurodevelopment, such as parental loss (maternal separation), that induces a marked provocation of the hypothalamic– pituitary–adrenal (HPA) axis was found to cause schizophrenia-like, e.g., impairments of sensory-gating, symptoms in the rats as adults (Ellenbroek et al. 1998), as well as other expression of the disorder (Furukawa et al. 1998). Rosenberg et al. (2007) surveyed 569 adults presenting schizophrenia with regard adverse childhood events (including physical abuse, sexual abuse, parental mental illnesses, loss of a parent, parental separation or divorce, witnessing domestic violence, and foster or kinship care), evaluating the relationships between cumulative exposure to these events and psychiatric, physical, and functional outcomes. They found that increased exposure to adverse childhood events was strongly related to psychiatric problems in both cognitive and emotional domains (suicidal thinking, hospitalizations, distress, and posttraumatic stress disorder), substance abuse, physical health problems (HIV infection), medical service utilization (physician visits), and poor social and daily care functioning (homelessness or criminal justice involvement). Ellman et al. (2009) observed genetic and/or environmental factors linked to

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psychosis that caused fetal brains to be particularly vulnerable to the effects of influenza B, leading to poorer cognitive performance even before symptom onset. Similarly but related to sorrow, Morgan et al. (2007) observed that separation from, and/or the death of, one parent prior to the age of 16 were both strongly associated with a twoto three-fold increases in the risk of psychosis. It was shown that the strength of these associations were similar for White British and Black Caribbean (but not for Black African) subjects, although separation from (but not death of) a parent was more common among Black Caribbean controls than White British controls. Finally, a 10-year cohort of high secure hospital patients who had either a personality disorder or schizophrenia found a rate of childparent separation of 178/289 (62 %) in the schizophrenia group compared with a rate of 119/147 (81 %) in the personality disorder group of patients that had been separated from one or both parents before the age of 16 years (Pert et al. 2004). Chew et al. (2013) imply that cellular abnormalities extend to glial cells since oligodendroglial, microglial, and astrocyte activity alternations in SSDs are associated with neonatal brain injury.

Neurotrophin Disruption Brain-derived neurotrophic factor is essential for the maintenance of functional neurons, regulating growth, differentiation, synaptic connectivity, neurorepair, and longevity (Altar et al. 1997; Niu and Yip 2011). BDNF, central for the survival and differentiation of midbrain dopamine neurons (Hyman et al. 1991), and phenotypic differentiation of locus coeruleus noradrenergic neurons (Traver et al. 2006), has emerged as an important biomarker for schizophrenia spectrum disorder (Favalli et al. 2012; Pae et al. 2012; Zhang et al. 2012). In 63 patients presenting schizophrenia compared to 52 age- and sex-matched healthy controls were examined with neuropsychological tests, Niitsu et al. (2011) found that although there were no significant differences in serum BDNF levels between normal controls and schizophrenic patients, serum BDNF levels for normal controls, but not schizophrenic patients, showed negative correlations with verbal working memory. On the other hand, serum BDNF levels of schizophrenic patients indicated positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels were related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia. In 22 acute schizo-

phrenic patients and 22 age-matched healthy volunteers, Lee et al. (2011) observed significantly reduced serum levels in the unmedicated schizophrenic patients (n = 22; 4.38 ± 2.1 ng/mL) compared to the age-matched healthy volunteers. The percentage change of BDNF (increase, 173 % ± 110) correlated negatively with the percentage change of PANSS score with BDNF increase during psychotic treatment, as shown by several others (Pedrini et al. 2011; Yoshimura et al. 2007, 2010). Reduced BDNF concentrations have been reported in chronic antipsychotictreated patients (Grillo et al. 2007; Ikeda et al. 2008; Rizos et al. 2010), neuroleptic-free (Palomino et al. 2006), and neuroleptic-naı¨ve (Chen and Huang 2011; Rizos et al. 2008) patients.

Dyskinesic Aspects Long-term administration of antipsychotic agents induces tardive dyskinesias (TDs), a syndrome composed of involuntary, hyperkinetic, and abnormal movements often expressed through excessive chewing or dancing/foot shuffling behaviors (Jafari et al. 2012; Correll and Schenk 2008). Lower serum concentrations of BDNF, inversely correlated with Abnormal Involuntary Movement Scale (AIMS) scores, have been observed in patients presenting TDs (Tan et al. 2005). Additionally, associations between TD and BDNF polymorphisms have accumulated (Park et al. 2009; Zai et al. 2009). Yang et al. (2011) compared serum BDNF levels in schizophrenic patients with (n = 129) and without (n = 235) TDs with healthy controls (n = 323), with concurrent assessment of AIMS and the Positive and Negative Symptoms Scale (PANSS). Schizophrenic patients presenting TDs showed lower BDNF concentrations than those without and healthy controls. Lower BDNF serum concentrations correlated with higher PANSS negative sub-scores, but not with AIMS scores. The authors concluded that reduced BDNF concentrations may be associated with greater TD pathophysiology and negative symptoms in schizophrenia. Zhang et al. (2010) have indicated that schizophrenic patients with TD presented higher serum levels of S100B, a calciumbinding protein, than normal, healthy controls, and those patients without TD. The serum S100B levels were positively correlated with AIMS scores in patients with TD. The authors concluded from these results that increased S100B levels may be related to the neurodegenerative aspect of disorder, associated with TD pathophysiology. TDs are generally indicative of neurodegenerative pathologies (Miller and Chouinard 1993).

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Cannabis Abuse Growing research evidence suggests that cannabis use leads to more frequent psychotic relapses, impairs cognitive performance and is associated generally with a poor prognosis in vulnerable individuals (Borgwardt et al. 2006). A long-term association between treatment adherence, type of first admission, and long cannabis use by firstepisode patients and high-risk juveniles (Barbeito et al. 2013; Gill et al. 2013). Additionally, there is a great interest in the hypothesis that cannabis use plays a causal role in the development of psychosis (Borgwardt et al. 2007; Haller et al. 2009). Analyses of prospective birth cohort and population studies suggest that cannabis use is indeed associated with an earlier age at onset of psychotic disorders, particularly schizophrenia (Smieskova et al. 2012a, b, c; Borgwardt et al. 2011; Bu¨schlen et al. 2011; Rothlisberger et al. 2012). The potential role as risk factor played by cannabis in the development of psychotic disorders has been recently investigated during the early prepsychotic phases of the illness. Cannabis abuse can impact the neurobiological alterations observed in potentially prodromal individuals (Smieskova et al. 2012a, b, c; Borgwardt et al. 2010; Bossong et al. 2013; Garakani et al. 2013; Morgan et al. 2013), with daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users (Di Forti et al. 2013). Imaging research in the healthy brain has consistently indicated cannabis abuse can modulate the neuroanatomical and neurofunctional areas which are implicated in psychosis onset (Buehlmann et al. 2010; Crossley et al. 2009; Fusar-Poli et al. 2007, 2010, 2011a, b, c; Smieskova et al. 2010a, b, 2012a, b, c). Finally, in a first population-based study mapping the association between lifetime cannabis use, psychosis, and schizotypal personality traits, Davis et al. (2013) have observed marked relationships between these factors. Stefanis et al. (2013) have shown that the use of cannabis may induce some cumulative toxic effects on those individuals abusing the drug, thereby placing them on the road to developing psychosis, the manifestation and debut of this condition are delayed for *7–8 years, independent of the age at which cannabis use was initiated.

Metabolic Aspects The glycogen synthase kinase-3s (GSK, a and b), involved in glycogen metabolism, are expressed ubiquitously over various tissues and are abundant in brain tissue (Jaworski et al. 2011). Kaidanovich-Beilin and Woodgett (2011) have discussed the fundamental roles for these protein kinases in memory, behavior, and neuronal fate determination. It has been argued that disrupted in Schizophrenia-1 (DISC1)

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provides a candidate gene for neuropsychiatric disorders and an influential involvement during brain structural and functional development. Singh et al. (2011) have observed that DISC1 variants are implicated in the loss of function in Wnt/GSK3b signaling, and thereby interrupt the course of brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function. The contribution of the DISC1 gene to neural development and the eventual neurodevelopment of schizophrenia risk has been studied (Wexler and Geschwind 2011). GSK-3, a regulator of a wide range of cellular processes, plays a key dual role in apoptosis with putative contribution to schizophrenia neuropathology (Emamian et al. 2004) and other neurodegenerative disorders (Avila et al. 2004; Berger et al. 2005; Onishi et al. 2011). Its role in the apoptotic signaling underlying excessive cell death may imply a neurodegenerative involvement in schizophrenia spectrum disorders, at least during the early stages of development (Gomez-Sintes et al. 2011). Astrocytic glycogenolysis and glycogen mobilization are implicated in normal brain function (Brown and Ransom 2007; Brown et al. 2003; Swanson 1992), and neuronal energy requirements (Brown et al. 2003; Wender et al. 2000), and not least in the necessities of cognitive function (Gibbs et al. 2006; Hertz et al. 2003; Suzuki et al. Suzuki et al. 2011). The links between glycogen metabolism and the glutathione (GSH) system have been studied: Shinohara et al. (2010) have shown that activation of GSK-3beta is a key mediator of the initial phase of acetaminophen-induced liver injury through modulating glutamate cysteine ligase (GCL) and myeloid cell leukemia sequence-1 degradation. GSH deficits occur both in neurodegenerative conditions and schizophrenia (Ballatori et al. 2009; Do et al. 2009; Dringen and Hirrlinger 2003), and a GCL gene polymorphism, affecting GSH synthesis, is associated with the disorder (Tosic et al. 2006). In this regard, Lavoie et al. (2011) have found that glucose metabolism and glycogen utilization are dysregulated in astrocytes showing chronic deficit in GSH implying dysfunctional brain energy metabolism in schizophrenia. It ought to be noted that Saitohin, an intronless gene nested within the human tau gene, that contains a single nucleotide polymorphism (A/G) may be involved in the pathophysiology of neurodegenerative disorders (Combarros et al. 2003). In a sample of 48 schizophrenic patients and 47 healthy controls, Bosia et al. (2011) tested the role of saitohin polymorphism as a concurring factor of cognitive decline among these patients using the Wisconsin Card Sorting Test for executive functioning. They observed a significantly greater frequency of G allele among patients with frontotemporal dementia and schizophrenic patients presenting impaired Wisconsin Card Sorting Test

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performance. They concluded that Saitohin gene products affected core frontal executive function deterioration likely through mechanisms occurring through neurodevelopment with neurodegenerative outcome (Bosia et al. 2011). Finally, there exists shared susceptibility for type 2 diabetes and schizophrenia (Lin and Shuldiner 2010).

Brain Insulin Dysregulation There are several indications that risk factors for psychosis are associated with cardiometabolic disease risk factors, and vice versa (Galletly et al. 2012). Insulin, a major factor in cardiometabolic disease risk, is involved in several physiological function of the brain such as food intake and weight control, reproduction, learning and memory, neuromodulation and neuroprotection development, and progression of neurodegenerative and neuropsychiatric disorders (Bloemer et al. 2014; de la Monte and Tong 2013). In individuals afflicted by dysregulation of insulin the risk of brain plasticity derailment emerges (Deutsch et al. 2006; Ghasemi et al. 2012; Huang and Lee 2010). Graham et al. (2008) have observed in a group of patients presenting first-episode psychosis, 6-month treatment with second generation antipsychotics was associated with the exacerbation of pre-existing and emergence of new CVD and diabetes risk factors. Foley et al. (2013) have observed cardiometabolic risk factors/indicators distinguished those individuals presenting psychosis from the general population, through a number of factors including age, gender, obesity, etc., in a population of 1,642 psychosis-diagnosed Australians (aged 18–64 years) compared with a national comparator sample of 8,866 controls (aged 25–64 years) from the general population. From age 25, psychotic individuals presented a significantly higher mean BMI, waist circumference, triglycerides, glucose [women only], and diastolic blood pressure, and significantly lower HDL-cholesterol than control individuals. With the exception of triglycerides at age 60? in men, and glucose in women at various ages, these differences were present at every age. Differences in BMI and waist circumference between samples, although dramatic, could not explain all differences in diastolic blood pressure, HDL-cholesterol, or triglycerides, but did explain differences in glucose. They have postulated that psychosis shows the hallmarks of insulin-resistance by at least in the age of 25. Similarly, Chen et al. (2013) have shown that schizophreniarelated psychopathology was associated with insulin-resistance and/or dyslipidemia in Chinese patients with antipsychotic-naı¨ve first-episode schizophrenia patients were more prone to insulin-resistance and dyslipidemia as compared to the healthy population, which was correlated negatively to positive symptoms.

Immune System Imbalance Finally, there exists much evidence implicating cytokine imbalance in schizophrenia spectrum/schizopsychotic disorders. For example, Song et al. (2013) showed that drug naı¨ve, first-episode schizophrenic patients presenting normal weight indicated up-regulated inflammatory status associated with elevated levels of the cytokines, IL-1b, IL6, and TNF-a. Furthermore, inflammatory cytokine markers, such as IL-1Ra and sTNF-R1, are associated with both general disease severity and psychotic features (Hope et al. 2013; Kirkpatrick and Miller 2013). Dimitrov et al. (2013) observed that levels of GRO, MCP-1, MDC, and sCD40L were elevated significantly and that levels of IFN-c, IL-2, IL-12p70, and IL-17 were reduced significantly in schizophrenia patients compared to controls; positive correlations between cytokine levels and disorder severity, assessed with Positive and Negative Symptoms Scale (PANSS) scores in schizophrenic subjects, for G-CSF, IL-1b, IL1ra, IL-3, IL-6, IL-9, IL-10, sCD40L, and TNF-b. Bergink et al. (2013a) observed that postpartum psychosis patients failed to show the postpartum T cell level elevations of healthy women, but rather marked elevations of monocyte levels, and up-regulation of several immune-related monocyte genes. Notably, Di Nichola et al. (2013) found markedly higher serum levels of IL-1a, IL-1b, IL-8, and TNF-a as well as the tendency for higher IL-6 serum levels in comparison with controls; Leukocyte m-RNA levels of IL1a, IL-6, and TNF-a, but not IL-1b and IL-8, were significantly higher in patients also. Childhood trauma was associated with greater TNF-a levels with recent stressful life events linked to greater TNF-a m-RNA levels in leukocytes. Bergink et al. (2013b) have described a scenario through which both infection and environmental stressors interact during gestation/early life period to activate microglia thereby disturbing the fine balance neuronal and/or regional development; this concatenation of adverse events sets the stage for the burgeoning vulnerability for later psychotic disorders. As the adverse scenario unfolds, endocrine changes, stress, or infection, may activate microglia alterations further, leading to functional abnormalities of the neuronal circuitry in the brain and the expressions of psychosis. Borovcanin et al. (2012) have shown reduced levels of pro-inflammatory markers, IL-17 and IL-17/TGFb ratio, in patients presenting psychosis. They indicate that the presence of enhanced anti-inflammatory/immunosuppressive activity in schizophrenic patients express attempts of the patients’ immune system to counteract or limit ongoing pro-inflammatory processes and down-regulating chronic inflammatory processes (see also Borovcanin et al. 2013).

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Conclusions Neurodegenerative aspects contributing to the pathophysiology of psychotic disorders appear, by and large, to exert their influences through interruption of the normal structural–functional trajectories of brain development and/or by neurotoxic destruction of tissue integrity. Not least is structural-functional integrity compromised by the presence of motor deficits (Singh et al. 2014). Observations of neuropathological structural/functional abnormalities in the postmortem brains of schizophrenic patients have been shown to occur over a wide range of brain areas (as shown, for example, by reduction in the volume of cerebral cortex and/or thalamus, and an increase in the volume of the ventricles) and nevertheless there are more reports describing the temporal lobe and frontal lobe compared to those describing other areas of the brain; all these suggesting degeneration of developmental origin. Intrauterine infection and inflammation are known risk factors for brain damage in the neonate irrespective of the gestational age. Infection-induced maternal immune activation leads to a fetal inflammatory response mediated by cytokines that has been implicated in the development of not only periventricular leukomalacia and cerebral palsy but also a spectrum of neurodevelopmental disorders, such as autism and schizophrenia (Burd et al. 2012; Ricci et al. 2013). The specific timing of the immune challenge with respect to the gestational age and neurologic development of the fetus may be crucial in the elicited response, which are the neuropsychiatric disorders associated with intrauterine inflammation appears to be the evidence for immune dysregulation in the developing brain. Laboratory model studies of maternal gestational inflammation provide critical roles for the elucidation of mechanisms involved in fetal brain injury associated with exposure to the maternal milieu. These animal models present different expressions of fetal microglial activation, neurotoxicity in combination with motor deficits and behavioral abnormalities in the offspring. The vulnerability bestowed through genetic and epigenetic (i.e., gene-environment interactions) forces exacerbate the deficits expressed through symptom profiles and biomarkers. In this respect, Kirkbride et al. (2012) have proposed that maternal prenatal nutrition can influence offspring schizophrenia risk via epigenetic effects. It appears that the prenatal nutrition may be linked to epigenetic outcomes in offspring and schizophrenia in offspring, and that schizophrenia is associated with these observed epigenetic changes. Disorder progression in the brains of patients was found to be characterized by progressive gray-matter volume decreases and lateral ventricular volume increases (Fusar-Poli et al. 2013a, b, c), possibly related to treatment. Further, increased levels of dopamine synthesis capacity in the dorsal striatum region

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present a robust feature of individuals at ultra-high risk for psychosis (Egerton et al. 2013). Finally, the prevailing and potential risks for disorder, that influence developmental trajectories, yet, render distinctions within the spectrum vague, provoke activation of the immune system, and acting in parallel with underlying genetic liability, are linked with imperfect regulation of the genome mediating these prenatal or early postnatal environmental events (Jenkins 2013). Acknowledgments The development of this manuscript was supported by the Bliwa Stiftelsen. Conflict of interests peting interests.

The authors declare that they have no com-

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