Developmental+Diseases_2024 PDF

Development of the Nervous System HS2024 BIO 344 Neurodevelopmental Diseases Esther Stoeckli The prevalence of mental disorders in the US and Europe (incl. Switzerland) Major depression...

Development of the Nervous System HS2024 BIO 344 Neurodevelopmental Diseases Esther Stoeckli The prevalence of mental disorders in the US and Europe (incl. Switzerland) Major depression 5.3 % 5.7% Posttraumatic stress disorder 3.6 % 2.3% OCD (obsessive, compulsive disorder) 2.4 % 0.7% Panic disorders 1.6% 1.2% Schizophrenia/psychotic disorder 1.3 % 1.2% Bipolar disorder 1.1 % 0.7% Autism Spectrum Disorders 0.1-0.2 % today: 1-2% 1.4% Anorexia nervosa 0.1 % 0.1% Hyman, Neuron 28 (2000) 321-323 Wittchen et al., Eur. Neuropharmacol. 21(2011)655-679 Schizophrenia Emil Kraepelin Dementia Praecox, 1919 Eugen Bleuler Schizophrenia, 1911 Schizophrenia is a brain disorder that is characterized by abnormal mental functions and (resulting) disturbed behavior Positive symptoms asociality = social withdrawal Ibrahim and Tamminga, Annu Rev Pharmacol Toxicol 51(2011)189-209  positive symptoms Psychosis – the hallmark feature of schizophrenia distortion of reality hallucinations delusions important feature: lack of insight negative symptoms depressed mood anhedonia social withdrawal alogia Disturbances in basic cognitive functions attention executive functions specific forms of memory (visual & verbal declarative memory, working memory, processing speed) Vulnerability to schizophrenia is clearly related to genetic factors based on evidence from family, twin, and adoption studies lifetime risk 1% in general population 50% in monozygotic twins ~17% in dizygotic twins from Rosenzweig, Breedlove, Watson, 2005 Genetics alone cannot explain the occurrence of schizophrenia, there must be ‘environmental’ factors! identified ‘environmental’ risk factors: viral infection during fetal development exposure to toxic, traumatic, or autoimmune insults poor maternal nutrition problems during gestation (e.g. problems during labor/birth)  Schizophrenia can be associated with physical changes in the brain enlarged ventricles in schizophrenic sibling indicating shrinkage of brain tissue  Ventricle size varies with gender and age 0.1 0.09 0.08 0.07 ventricle/brain volume 0.06 0.05 0.04 0.03 0.02 0.01 0 from Rosenzweig, Breedlove, Watson, 2005 Schizophrenia can be associated with physical changes in the brain - enlarged ventricles in schizophrenic sibling indicating shrinkage of the brain tissue - reduced size of hippocampus and amygdala - changes in fine structure and function of cortical connections dopamine and glutamate transmission Cell polarity is disturbed in some brains of patients suffering from schizophrenia from Rosenzweig, Breedlove, Watson, 2005 Cell polarity is disturbed in some brains of patients suffering from schizophrenia normal control patient with schizophrenia from Rosenzweig, Breedlove, Watson, 2005 Spine density on apical dendrites of pyramidal cells is reduced in schizophrenic patients SCZ patient normal brain control Garey, J. Anatomy, 2006 Schizophrenia can be associated with physical changes in the brain - enlarged ventricles in schizophrenic sibling indicating shrinkage of the brain tissue - reduced size of hippocampus and amygdala - changes in fine structure and function of cortical connections dopamine and glutamate transmission but obviously they are not useful for diagnosis Dopamine hypothesis Antipsychotic drugs that act on D2 receptors are effective in some patients consistent with the hypothesis that positive symptoms of schizophrenia are due to an excess of DA signaling in the striatal and/or mesolimbic areas of the brain however negative symptoms are thought to be due to deficits in DA signaling in the prefrontal cortex probably mediated by D1 receptors In addition to the dopamine system, there is a lot of evidence for a contribution of the glutamate system NMDAR hypofunction hypothesis evidence that NMDA agonists/antagonists affect symptoms/cause symptoms in healthy subjects  Schizophrenia can be associated with functional changes in the brain reduced activity in the frontal cortex in patients compared to unaffected twin sibling at rest during task from Rosenzweig, Breedlove, Watson, 2005 Neuropsychological characteristics differ between schizophrenics and non- affected twin siblings e.g. eye tracking schizophrenic patients are unable to follow the movements of a pendulum smoothly Manifestions supporting neurodevelopmental background of schizophrenia maturational processes are perturbed, such as apoptosis synaptic pruning myelination Thus, rather late developmental events! Why does schizophrenia manifest itself during adolescence? 7 108 Synapses per mm3 6 5 4 1 3 2 1 Age (years) from Rosenzweig, Breedlove, Watson, 2005 The trajectory to schizophrenia showing the evolution of symptoms Howes & Murray, Lancet 2014 Schizophrenic patients often revealed neurological deficits during childhood and adolescence impaired cognitive skills attention deficits irritability delayed gross motor development similar neurological deficits are evident in the non-schizophrenic relatives of patients  Etiology of schizophrenia involves multiple hits: GENES X ENVIRONMENT nature versus nurture difference to other neurodevelopmental diseases: manifestion not immediate but only during second or third decade of life Model by Mirsky and Duncan Schizophrenia emerges when the combination of environmental stressors and brain abnormalities exceeds a threshold value. Environmental stress ‘environment’ brain anomalies genes from Rosenzweig, Breedlove, Watson, 2005 About 5-10% of all patients recover completely and show no obvious signs of having had the disease. About 75% of those that do improve do so within the first 3 years of diagnosis. More than half of the remainder substantially improve but nevertheless show some residual signs, such as occasional memory or sleep problems, or just not being able to tolerate tension and stress. Suggested reading on Schizophrenia: Lewis, D.A. and Levitt, P. (2002) Schizophrenia as a disorder of neurodevelopment Annu Rev Neurosci 25:409-432 Howes, O.D. and Murray, R.M. (2014) Schizophrenia: an integrated sociodevelopmental-cognitive model Lancet 383:1677-1687 Autism (Autism spectrum disorders) first described by Leo Kanner, 1943 Autism is a neurodevelopmental disorder that is defined by deficits in social interaction, impaired communication, and by unusual restricted, repetitive behaviors. The majority of patients is affected by intellectual disability. https://www.youtube.com/watch?v=YtvP5A5OHpU  Autism begins in infancy, before three years of age Often diagnosis of autism is preceeded by observations of ‚abnormal‘ behavior of a child, e.g. parents are concerned because child does not interact or communicate with them or peers Repetitive behaviors begin to develop in preschool years. Signs of sensory overload, avoidance of novel stimuli Autistic children avoid eye contact with parents when held push away from close contact severely impaired language acquisition automatic acts (incessant rocking) may or may not be affected by intellecutal disability up to a third of individuals with ASD report epilepsy Diagnostic criteria for autistic disorder: Social interaction: Qualitative impairment in social interactions, as manifested by at least two of the following: a) marked impairment in the use of multiple nonverbal behaviors, e.g. eye-to-eye gaze b) failure to develop peer relationships c) lack of spontaneous seeking to share enjoyment with other people d) lack of social or emotional reciprocity DSM-IV: Diagnostic and Statistical Manual of Mental Disorders IV, 1994 Communication: Qualitative impairments of communication, as manifested by at least one of the following a) delay in, or total lack of, the development of spoken language b) marked impairment in initiating or sustaining a conversation with others c) stererotyped and repetitive use of language d) lack of varied, spontaneous make-believe or imitative play DSM-IV: Diagnostic and Statistical Manual of Mental Disorders IV, 1994 Behavior: Restricted, repetitive, and stereotyped patterns of behavior, as manifested by at least one of the following a) preoccupation with one or more stereotyped or restricted patterns of interest b) adherence to nonfunctional routines or rituals c) stereotyped and repetitive motor mannerisms d) persistent preoccupation with parts of objects DSM-IV: Diagnostic and Statistical Manual of Mental Disorders IV, 1994 Autism spectrum disorder one of the rare monogenetic forms of ASD: Rett syndrome https://www.youtube.com/watch?v=H2iKz1Cx-HQ Conceptualization of a spectrum of autism-related disorders: Childhood Disintegrative Disorder Asperger‘s Disorder Pervasive Developmental Disorder-Not otherwise specified (PDD-NOS) common theme: qualitative deficits in social behavior and communication facts on ASD: sibling recurrence risk is approx. 4.5% population incidence 3-6/1000 (for full spectrum of autistic disorders) concordance rate for monozygotic twins: ~60% for classical autism, up to 92% for full spectrum (autism is the most heritable psychiatric disorder) concordance rate for dizygotic twins: ~3-10% autism is 4-5 times more prevalent among males Genome-wide linkage studies with large patient cohorts have provided large data sets one common finding: many genes are linked to synaptogenesis and axon guidance Autism as an ‚under-connectivity‘ syndrome ‘environmental’ stressors thalidomide use certain viral infections (rubella, influenza, cytomegalovirus) maternal anticonvulsants (e.g. valproic acid) problems to be solved: definition of brain regions that are most severely affected types of alterations (structural versus neurochemical) biochemical tools for diagnosis overcome problems with diagnosis due to heterogeneity Most prevalent abnormalities found in autistic brains: reduced corpus callosum & changes in cerebellar structure Complete or partial agenesis of the corpus callosum Paul et al., Nature Rev Neurosci. 2007 Loss of Purkinje cells has been commonly found in several studies. Loss of cells in deep cerebellar nuclei in some studies.  additional anatomical/morphological findings changes in synapse formation and elimination cells more densely packed, smaller cells reduced complexity of dendritic arbors However!! Formal reports of autopsy studies during the last 25 years involved less than 100 brains! Disturbance of the Mirror Neuron System in patients with autism Iacoboni and Dapretto, Nature Reviews Neuroscience 7 (2006), 942–951 The MNS helps to understand intentions Iacoboni and Dapretto, Nature Reviews Neuroscience 7 (2006), 942–951 Common to all autism spectrum disorders: disturbance of normal social behavior ranging from subtle abnormalities in social reciprocity, particularly with peers, to much more obvious difficulties in the use of eye contact, facial expression, and social motivation. Interpretation of facial expressions are markedly impaired in autistic subjects. Iacoboni and Dapretto, Nature Reviews Neuroscience 7 (2006), 942–951 Additional reading: Chen et al., Annu Rev Pathol Mech Dis 10(2015)111-144 Geschwind and Levitt, Curr Opin Neurobiol 17(2007)103-111 Intellectual Disability defined as significantly sub-average intellectual functioning IQ < 70 profound: IQ < 20 severe: IQ 20 -35 moderate: IQ 35-50 mild: IQ 50-70 borderline: IQ 70-85  Intellectual Disability sinificantly sub-average intellectual functioning significant limitations in adaptive functioning in at least two of the following skill areas: communication, self-care, ability to live independently, social and interpersonal skills, work, leisure, health and safety onset before the age of 18 years syndromic and non-syndromic forms Syndromic intellectual disability: Down syndrome Novel GDI1 mutation in a large family with nonsyndromic X‐linked intellectual disability American Journal of Medical Genetics Part A Volume 155, Issue 12, pages 3067-3070, 14 OCT 2011 DOI: 10.1002/ajmg.a.34291 http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.34291/full#fig2 ~0.4% of the general population are affected by ID Male to female ratio for moderate to severe ID (IQ