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SHIFTING THE PARADIGM FROM THE ACTUAL CATEGORICAL DIAGNOSTIC APPROACH TO A DIMENSIONAL, GENETIC AND QUANTITATIVE NEUROBIOLOGICAL APPROACH IN CHILD AND ADOLESCENT PSYCHOTIC DISORDERS: A PRELIMINARY STUDY

Autor: Laura Nussbaum Axinia Corcheş Nicoleta Andreescu Maria Puiu
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Studying and analyzing the current literature of speciality there are unmet needs concerning: the stratification of the neuropsychiatric and neurodegenerative disorders, based on a novel dimensional symptoms constellation approach; the neurobiological, genetic, neurocognitive and neuroimagistic markers in these neuropsychiatric disorders and the discovery and development of new drug therapies correlated with the real causes, roots and neurobiological substrates of the disorders.
The proposed work is ambitious and pioneering because no present treatment administered in the targeted neuropsychiatric disorders is based on the neurobiological substrates and on the pathophysiological causes, so that new drug discovery should be a priority in this domain.
We expect advances in the regulatory, clinical and healthcare practice – through the implementation of new diagnostic guidelines and guides in neuropsychiatry and addressing these specific societal challenges and unmet needs in this domain, targeting neuropsychiatric disorders.High impact will be expected in the pediatric population with neuropsychiatric disorders, because finding proper drug therapies can change the life trajectory of this population, because the early intervention in a tailored personalized manner will improve the quality of life, especially for this population, who is in a dynamically developmental phase.
High impact is expected concerning the neuronal resiliency of the neuropsychiatric patients population.

Concept and approach

One of the main challenges to developing next-generation therapeutics for neuropsychiatric disorders – Non-affective and Affective Psychoses (especially Schizophrenia, Depressive Disorders, Bipolar Disorders) and for the neurodegenerative disorders, is the fact, that no common valid neurobiological, genetic, imagistic variants of large effect have been identified [18, 20].
Knowing the fact, that the selection of targets for novel drug therapies requires an in depth understanding of the neurobiology of the disorder, from the etiological, causal factors to pathophysiological mechanisms and longitudinal studies of disease onset, progression and duration we have chosen targeted existing cohorts for this research proposal [3, 6, 8, 9, 20].
We use the power of multimodal models that can be used to identify neuropsychiatric disease signatures and bio-signatures.
Because 2/3 of the genes in the genome participate in the development of the brain, through different mechanisms and pathways, it is obvious why the neurodevelopmental but also the neurodegenerative processes which cause multifactorial disorders are extremely complex, so that the research on the candidate genes for the mentioned neuropsychiatric, neurodegenerative disorders, will bring interesting results.
The present research needs an interdisciplinary, multidisciplinary, integrative approach.
Our project proposes the investigation of these genetic polymorphisms and the identification of correlations between SNP’s-Single Nucleotide Polymorphisms, the relation genotype-phenotype, in connection with the clinical profile and evolution and with the response to medication [1, 2, 4, 5, 11, 12, 14, 16].
In our proposed project, we aim through our applied approaches: to improve the dimensional diagnosing and stratification of the neuropsychiatric patients; to develop clinical diagnostic protocols correlated with the neurobiological, neuroimagistic and genetic markers [1, 7, 15, 17, 19].
Knowing that pharmacotherapy depends on knowledge of shared neurobiological and pathophysiological aspects then it means that the symptoms dimension psychosis of schizophrenia is to be confidently extended to the psychosis neurodegenerative disease, so that we aim to prove the shared neurobiology and pathophysiology, in order to warrant the use of new drugs across syndromes [10, 21, 23, 26].
Then it is reasonable to implement drugs known to be useful for the treatment of a symptom in one condition – psychosis in schizophrenia, psychotic depressive and bipolar disorders for conditions with similar symptoms – psychosis in neurodegenerative disorders [10, 13, 22, 26].
This further justifies the fact that we will analyze the symptoms dimensionally in different conditions [13].
We will facilitate the use of appropriate drugs by practitioners, through defining each symptom that is a proper target for pharmacotherapy individually. So that, we will develop specific definitions for each target symptom (psychosis, agitation, depression, apathy, cognitive disturbances) [10, 13, 20, 24, 25].
The current proposed project will address the unmet medical needs in the area of these neuropsychiatric disorders, some of our aims being at the early discovery stage of the continuum but through our multidisciplinary approach, our team comprising experts in neurobiology, pathophysiology, preclinical and clinical pharmacology, translational psychiatry and neuropsychiatry and clinical neuropsychiatrists and psychiatrists, we will be able to translate our hypotheses into clinical practice and access and also we will replicate the obtained results.
The main steps of our work plan will be (Table 1):

Phase Applied Activities
Documentation and validation of the Protocol and Procedures Elaborating a guiding protocol comprising the neurobiological, genetic, pharmacogenetic, imagistic and clinical parameters that will be investigated
Elaborating the guide of preclinical, neurobiological, genetic, imagistic and clinical investigations
Establishing the project cohorts Preparing the documentation for the ethical approval
Establishing the patient population and study cohorts that will be investigated, in function of clear enrollment and exclusion criteria
Elaborating the Informed Consent respectively the Assent in the case of the neuropsychiatric pediatric population, which will contain all the needed information about the project conduct and the methodology
Clinical and Para-Clinical Evaluation of the patients Clinical and Psychiatric Evaluation–K-SADS- DSM IV – Categorial Diagnostic Confirmation and DSM 5 – Dimensional Symptoms, Syndromal based confirmation of the diagnoses, Mini Mental State for Neuropsychiatric Symptoms
Interdisciplinary/ Multidisciplinary Evaluations: Neurological – finding Neurological Soft Signs and Physical Examination and EEG (evoked potentials, SLI, sleep)
Psychologic Evaluation – determination of the development and intelectual niveau – IQ, cognitive niveau-NEPSY, Wechsler Memory Scale (WMS-III)
Shifting the paradigm from the actual categorical diagnostic approach to a dimensional symptoms cluster approach in neuropsychiatric and neurodegenerative disorders (our cohorts being divided in: Schizophrenia, Depressive Disorders, psychotic Bipolar Disorders and Neurodegenerative Disorders )
Refining the taxonomy and stratification of the targeted neuropsychiatric and neurodegenerative disorders – Schizophrenia, Depressive Disorders (psychotic, unipolar depression, major depressive disorders, treatment resistant depression), psychotic Bipolar Disorders and Dementia, on the basis of molecular, neurobiological, imagistic and genetic markers
Capturing the dimensional diagnostic approach through the following symptoms constellations mirrored through the PANSS (Positive and Negative Syndrome Scale) application evaluating the positive, negative, cognitive symptoms dimensions in the chosen neuropsychiatric cohorts:
PANSS Positive Symptoms Delusions, Conceptual Disorganization, Hallucinatory Behavior,Grandiosity, Suspiciousness/ Persecution
PANSS Negative Symptoms Blunted Affect, Apathy, Emotional Withdrawal, Poor Rapport, Passive Apathetic Withdrawal, Lack of Spontaneity and Flow of Conversation
PANSS Cognitive Symptoms (Disorientation, Poor Attention, Lack of Judgement and Insight, Conceptual Disorganization, Difficulty in Abstract Thinking and Stereotyped Thinking)
PANSS General Psychopathology Symptoms (Depression, Anxiety)
Characterisation of disease clinical severity and prediction of changes in disease state and severity through quantifiable variables and scale scores in correlation with some quantifiable neurobiological and genetic / pharmacogenetic markers –CGI-S (Clinical Global Impression Severity), CGI-I (Clinical Global Impression Improvement), SS-DSM5 (Symptom Severity Scale)
Creating the intermediar report of the study, comprising the clinical and anamnestic evaluation data Multimodal Stratification and Classification of the Neuropsychiatric Disorders of Choice through the Support Vector Machine, that will engage supervised learning algorithms that will recognize and analyse dimensional symptomatic patterns
Further phenotyping of the established patient cohorts using standardized instruments and clinical indicators Application of the neuropsychiatric scales:
CGAS (Clinical Global Assessment of Functioning)
CSSRS (Columbia Suicide Rating Scale)
CDRS-R – Child Depression Rating Scale
BDI – Beck Depression Inventory
CDSS – Calgary Depression Scale for Schizophrenia
NY-AACENT (Cognitive Assessment)
UKU (Present Symptoms and Adverse Events), SAS, AIMS, BARS (Extapyramidal Symptoms Scales)
Evaluation of the
Neurobiological Markers
and Pathways and Finding
Targets for New Drug
Therapies
Investigation of the major neurobiological markers and pathways involved in the mechanisms of these neuropsychiatric disorders (schizophrenia, depressive disorders, psychotic bipolar disorders and Alzheimer disease) – GABAergic, glutamatergic, NMDA type glutamate pathways, Nicotinic Acetylcholine pathways, BDNF (brain derived neurotrophic factor) Investigating the NMDA receptors function and activity, through the Mismatch Negativity Amplitude and the levels of D-serine, which can be detected in blood and cerebrospinal fluid, is a co-agonist of NMDA receptors and is supposed to be in law plasma levels for the patients with psychotic symptoms
Investigating specific biomarkers Dicarbonyls (methylglyoxal) and Advanced Glycation End Products – AGE’s (Pentosidine), because of the supposed toxic stress dicarbonyls/AGE’s accumulation in the neuropsychiatric psychotic disorders
Finding bioactives able to inhibit the dicarbonyl accumulation and the AGE’s formation, this being of great therapeutic value
Exploring the relationship between erythrocyte membrane fatty acid levels (significantly lower omega 3 docosahexanoic acid levels), measured by gas chromatography and the cognitive functioning of the neuropsychiatric patients of our cohorts
Genetic and Pharmacogenetic Testing The DNA and RNA probes extraction from peripherical venous blood probes on EDTA and their storage at -40 Grades Celsius in the freeze
Using model systems to understand the functional biological implications of gene variants for these studied neuropsychiatric disorders (DISC1 candidate gene, the G72/G30 gene complex on chromosome 13q33, GRM3 and GRIN2A – polymorphic variants at 16q11.2)
Analyzing through pharmacogenetic testing, the SNP’s and alleles for some key CYP systems and the enzymes of the cytochrome P450 (CYP2D6, CYP3A4, CYP1A2, CYP2C19, CYP2C9, CYP2A6) implied in the metabolization of all the existent Antipsychotics, Antidepressive medication and Mood Stabilizers
Genetic and Pharmacogenetic Testing The genotyping through RT-PCRSNPSingle Nucleotide Polymorphisms Genotyping, the qPCR for the detection of microduplications and deletions causing CNV at 13q33, 16q11.2, using DNAg from the cases confirmed through arrayCGH
the determination of the CNVs involved in the synaptic activity and neurodevelopmental processes for the prospective cohorts with the chosen neuropsychiatric disorders
Extracting genomicDNA from peripheral blood leukocytes, bisulphite-converted, PCR amplified and pyro-sequenced, in order to investigate the DNA hypermethylation of the reelin gene promoter on the reelin CpG island1, which is involved in the neuronal migration and synaptogenesis Analyzing the utility of using the studied genetic markers in the clinical practice
Neuropsychological and Neurocognitive Testing Applying quantitative Neuropsychological Cognitive Testing (for the Cognitive Symptoms and Dysfunctions) – CANTAB Battery, COG State, CRT – Choice Reaction Time, Social Cognition Test Battery (Emotional and Face Processing), NEPSY, in order to evaluate the cognition (Attention/Processing Speed, Verbal Memory, Verbal and Semantic Fluency, Working Memory) and to make some correlations and find new targets for novel drugs that have action not only on the positive symptoms but also on the cognitive dimension
Neuroimagistics and quantitative
Technologies
Identifying and validating the clinically relevant biological substrates of the neuropsychiatric symptom constellations through the use of quantitative technologies: EEG – analyzing the gamma synchrony changes indexing cortical changes / elevation in psychosis (evoked responses, sleep), MRI, fMRI– (Fronto-thalamic-cerebellar gray matter deficit, Fronto-striato-thalamic gray matter deficit, MRI-derived three-factor phenotype, MRI whole-brain nonlinear pattern classification, Neurodevelopmental and neurodegenerative schizophrenia endophenotypes), Spectroscopy (analyzing glutamate dysfunctions, brain temperature), PET (investigating the Sigma 1 receptors occupancycapacity, the activation of the Microglia);peripheral biomarkers, in order to obtain their biological correlates for novel therapies or targets
Finding new drugs that would inhibit the microglia activation, being supposed that in the targeted neuropsychiatric and neurodegenerative disorders, the microglia were highly activated
Study of the Neurobiological, Genetic Neurocognitive and Neuroimagistic Markers
On Ultra High Risk for Psychosis
Patient cohorts
Investigating the same parameters and markers on ultra high risk for psychosis patient cohorts, being offspring or sibblings of psychotic patients
Replicating and Translating the obtained Results – Translational Psychiatry Model Preclinical studies of the obtained neurobiological, genetic variables and of the major markers; Finding parameters for reverse translation
Data Management& IT Collecting, analyzing and Interpreting the multi-site, multi-factor datasets
Clinical Practical Utility and Dissemination as Gold Standards of Care Implementing the obtained relevant parameters, neurobiological, genetic, neurocognitive and neuroimagistic markers in the routing clinical care and obtaining pertinent targets for new drugs discovery in a tailored personalized medicine frame, after a proper dimensional diagnostic stratification and the results obtained from the electronic matrix platform created

Conclusions and Discussions

Studying and analyzing the current literature of speciality there are unmet needs concerning: the stratification of the neuropsychiatric and neurodegenerative disorders, based on a novel dimensional symptoms constellation approach; the neurobiological, genetic, neurocognitive and neuroimagistic markers in these neuropsychiatric disorders and the discovery and development of new drug therapies correlated with the real causes, roots and neurobiological substrates of the disorders.
The proposed work is ambitious, because the objectives, concepts involved, issues and problems to be addressed, and approaches and methods to be used are innovative – high standard neurobiological biomarker platforms, innovative neuroimagistics and techniques, ambitious genetic and pharmacogenetic complex investigations and most important, the correlation of all these procedures through a Support Vector Machine Algorithm of Multimodal Stratification of the neuropsychiatric diagnoses involved, as well as the matrix platform which will incrementally correlate all these variables and parameters with the best treatment of choice for the neuropsychiatric patients.
The proposed work is ambitious and pioneering because no present treatment administered in the targeted neuropsychiatric disorders is based on the neurobiological substrates and on the pathophysiological causes, so that new drug discovery should be a priority in this domain.
We expect advances in the regulatory, clinical and healthcare practice – through the implementation of new diagnostic guidelines and guides in neuropsychiatry and addressing these specific societal challenges and unmet needs in this domain, targeting neuropsychiatric disorders.
Also significant, will be finding some notable biological, neuroimagistic and genetical markers that run in families in the case of our patient cohort with familial neuropsychiatric disorders and for the ultra high risk for psychosis offspring / siblings.
High impact will be expected in the pediatric population with neuropsychiatric disorders, because finding proper drug therapies can change the life trajectory of this population, because the early intervention in a tailored personalized manner will improve the quality of life, especially for this population, who is in a dynamically developmental phase.
High impact is expected concerning the neuronal resiliency of the neuropsychiatric patients population.

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