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Essentials of Neuroscience > Autism > Flashcards

Autism Flashcards

1
Q

Discuss the history of Autism and how it was eventually described

A

The first description of Autism was in 1943 by Dr. Leo Kanner who distinguished it from schizophrenia. One year later Dr. Hans Asperger described patients with autism with very good vocabularies
(they had normal language development)

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2
Q

What was the list of pervasive Developmental Disorders (PDD) according to DSM-IV text (revised)? Which of these were part of ASD?
What is DSM?

A

Terminology of Pervasive Developmental Disorders (PDD) from DSM-IV Revised:
1) Autism
2) Asperger syndrome
3) PDD-NOS (Not otherwise Specified)
4) Rett syndrome
5) Childhood Disintegrative Disorder
#1-3 referred to as Autistic Spectrum Disorder (ASD)
DSM= diagnostic and Statistical Manual of Mental disorders (reference book for psychology)

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3
Q

Discuss how DSM-V combines disorders into one diagnosis for ASD? How is ASD viewed as?

A

DSM-V (May 2013)
-The DSM-V consolidates autism, Asperger, PDD-NOS and Childhood Disintegrative Disorder into one diagnosis: ASD (Autism Spectrum Disorder)
The DSM-V Workgroup considers ASD as a CONTIUUM of one disorder farther than several disorders ranging in severity from mild to severe.
-Some children who previously would have fulfilled criteria for PDD wil NOT fulfill current criteria

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4
Q

What is Autism? What is the diagnosis based on? What are diagnostic markers for autism?

A

Autism is neurodevelopment disorder whose diagnosis is based on the presence of characteristic behaviors of restricted interests, Repetitive behaviors and deficiency in communication and socialization skills
-Currently, there are NO Objective diagnostic markers for autism (ex; X-ray, blood test)
(autism also considered behavioral disorder)

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5
Q

what are the core behaviors for diagnosing patients with Autism? When should pediatricians screen for autism in a child?

A

Core behaviors for diagnosis:
-Delayed speech or regression in speech (start talking, then stopped)
-poor eye contact
-Diminished socialization (parallel play)
-repetitive behavior (speech; restricted interests; motor) (ex; always plating with one toy)

-Pediatricians should screen for Autism in a Speech Delayed child who demonstrates behaviors of excessive shyness, social awkwardness or are obsessive about interests or behavior

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6
Q

What are other common behaviors seen in children with Autism?

A

Other common behaviors:
cognitive impairment (25-70%)
-Toe walking without spasticity (heels do not touch ground)
-Noise sensitivity (vacuum; hair dryer)
-Roteness; needs for routine; poor transitioning (issue in school)
-Fixed interests (ex; Thomas the train)
-Excessive tantrums
-poor sleep
-Fascination with some parts of objects rather than the objects themselves- spinning wheels on cars; fans; light switches; buttons
-splinter skills; hypermedia (advanced reading skills) (but non comprehension)

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7
Q

What other sensory issues occur in people with Autism?

A

Other sensory issues
-hyposensitivity (pain) and hypersensitivity
-Noise
-Textures; foods; clothing labels
- Touch: Squeeze/hug chair
Problems:
inability to ignore extraneous auditory sensory stimuli
Difficulty integrating multiple stimuli simultaneously

(looks like they’re focused, but not able to phase out external stimuli)

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8
Q

What are furthermore other common behaviors are seen in people with Autism?

A

Other common behaviors:
-Spinning behavior
-Stereotypes- hand flapping; finger twirling; body rocking; hands over the ears
-Fascinated with movement: fans; wheels; doors
-Echolalia (repeating what others say)
-perseveration (repetition of an action; like constantly saying Mr. D, Mr. D!!)
-Unusual behavior with inanimate objects: twirling string; smelling non-edible objects
-Fearless; high pain tolerance; inability to recognized danger
-hyperactive (sometimes misdiagnosed as ADHD)
-Aggressive: ? relationship to poor judgement

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9
Q

What are some things you can observe if you place 100 children with ASD (Autism) in a room

A

If you placed 100 children with ASD in a room:
It is amazing how similar they look
(speech, eye contact, same swallowing problems, same core behaviors)
-it is also amazing how different they look (not have same behavior)

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10
Q

Explain how Autism can be distinguished from author types of social avoidance? What are these other types of social avoidance?

A

To be distinguished from other types of social avoidance
-Social phobias: avoids intimate and social contact with others
-social anxiety
-social avoidance disorder
-Avoidance personality disorder: more sensitive interpersonally; low self esteem

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11
Q

What are co-morbid conditions that can occur?

A

Co-morbid conditions
-Cognitive impairment (25-70%)
-Seizures/epilepsy (5-38%)
-Abnormal EEG without clinical seizures
-Symptoms resembling Attention Deficit Hyperactivity Disorder (ADHD)
-Symptoms resembling Oppositional Defiant disorder (ODD) (children who are disobedient)
-Anxiety; social anxiety disorder
-Depression

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12
Q

what are some GI (Gastrointestinal) symptoms that some children with ASD have?

A

Some children with ASD have signifiant GI symptoms:
*abnormal bacterial population in intestine
* Diarrhea or constipation
* abnormal food craving

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13
Q

Discuss the micorbiome in people with ASD (autism spectrum disorder) . What can be seen in gut flora? How does this affect other parts of the body?
What are confiding variables that may be seen in those with ASD?

A

Microbiome in ASD
-The dysbisois (imbalance in microbiota) in gut flora may be related to the gastrointestinal symptoms in some children with ASD, or may be related to their autistic symptoms.
-There is an association between gut pathology and brain disease (brain-gut relationship)
-In ASD, the dysbiosis may be altering immune function via affects on cytokines and chemokines
-studies can be difficult to interpret due to confounding variables; variability in diet, genetics, life-style, and supplement intake (vitamins, probiotics) all of which can affect immune function

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14
Q

What conclusion was made about Yap et al cell paper regarding ASD and microbiome?

A

Yap et al. Cell 2021;
-Study of 247 children with autism
-Negligible (not significant) direct associations between ASD and gut microbiome
Conclusion:
-Microbiome differences in ASD may reflect dietary preferences that relate to Diagnostic features, and it is unlikely that the microbiome has a driving role in ASD>

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15
Q

What are diagnostic tools used for people with Autism? Which are better tools used?

A

Diagnostic Tools
-Screening;
-Checklist for Autism in Toddlers (CHAT/M-CHAT) - anyone (anyone can do it)
-Autism Behavior Checklist (ABC)- parents (must be done by parents)
-childhood Autism Rating Scale (CARS)- parents and physician
Better tools
**Diagnostic and Statistical manual of Mental disorders DSM-V in 2013
**Autism Diagnostic interview- Revised /Autism diagnostic observation Schedule (ADI-ADOS) **
Good history and physical examination

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16
Q

Discuss how predicting ASD in infancy occurs? What can be seen to suspect ASD in infants?

A

Predicting ASD in infancy
-106 infants (study?) at high familiar risk for ASD studied
-15 diagnosed with ASD at a ge 24 moths
- These infants demonstrated hyperexpansion of cortical surface area at 6-12 months which preceded brain volume overgrowth observed at 12-24 months.
problems: NOT all children with ASD have brain overgrowth
(in infancy, can suspect ASD, if they inconsistently respond to their name being called or do not respond to name at all)
(78 regions of interest were studied

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17
Q

Discuss the Etiology of autism? What can cause Autism?

A

Etiology (cause of disease) of Autism:
-Primary (idiopathic autism; or unknown origin of autism; no underlying problem) vs Secondary (syndrome or global developmental delay)
-Syndromic autism (some genetics; autism caused by mutation in gene):
-Fragile X
-Tuberous sclerosis
-Angelman Syndrome
-Fetal alcohol syndrome
-Autism is Probably multifactorial:
Genetics and environmental

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18
Q

Discuss the epidemiology for Autism. What is prevalence of ASD in U.S, Canada, France, Japan, UK. What is the prevalence in boys vs girls?

A

Center for Disease Control
2009: prevalence of ASD in US- 1:110
(1;70 boys) (Nj: 1:94) HIGH Rate in New Jersey
2012: US: 1:88 (NJ: 1:48)
2014: US: 1:59 (very common)
prevalence of autism in US- 1-2 per 1,000
Canada: 1:147 Japan: 1-116-208
France: 1: 166-333 UK: 1 : 335
Boys: girls= 4: 1 ratio (ASD more present in BOYS)
-Dramatic Increase in cases in 1990s and 2000s.

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19
Q

What are reasons for increased prevalence of Autism?

A

reasons for increased prevalence:
-At low end of bell curve of diagnosis, where significant cognitive impairment– much overlap between cognitive impairment and autism
-At High end of bell curve where NO cognitive impairment and mild behavioral symptoms, autism may be Overdiagnosed
-Despite this, the increase is NOT likely only due to increased rates of diagnosis, but may represent a true epidemic

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20
Q

What is the primary mode of treatment for children with autism? What are other forms of treatment used? What do some children require as part of treatment? How do you get a good outcome? What are challenges

A

The primary modality of treatment is EDUCATIONAL
-Speech, occupational and physical therapy
-Applied behavioral analysis therapy (ABA)/floor time/Lovass method
(try and reach child what rules are, and how to follow them)
Some children require Medication:
*ADHD medications
*Atypical antipsychotics for aggression (dopaminergic and serotoninergic) properties)
*selective serotonin uptake inhibitors : SSRI
*Sleep aides (melatonin; valerian root)
*The Earlier and More Intensive the educational intervention, the Better the chance of attaining a good outcome
-Challenges: Intensive intervention <2 years of age, novel therapies who have plateau’d and adolescents/ Adults (iPad)

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21
Q

What are medications that can ameliorate core symptoms of autism?

A

Medications that ameliorate the core symptoms:
*Baclofen/arbaclofen: reduces the excitatory glutamate and improves social impairment in Fragile X/autism
*Minocyclie: improved language and behavior
*Buspirone: improves restricted and repetitive behavior
*Oxytocin: improved sociability and Less irritability

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22
Q

Describe other drug trials that occured in 2015 and what they were used for.

A

Other drug trials (2015)
-Everolimuus (tuberous sclerosis)
-Fingolimod; glatiramer acetate; dextromethorphan (Rett)
-Acamprosate; Ganaxolone (Fragile X)
-Donepezil; low dose nicotine (DOWN)

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23
Q

Discuss how gene therapy is used in some patients with Autism? When can genetic based etiology have harmful effects. What must occur with exogenous genes?

A

Gene therapy
-Since some children have a genetic-based etiology, they may be amenable to Gene therapy (ex, MECP2; CDLK5)
-Dosage effects are key: many of the genes that result in ASD-related phenotype have Harmful effects when they are expressed at a HIGH dosage
-Any delivery of exogenous genes may need to be Regulated in terms of time and levels of expression

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24
Q

Describe how surgery was involved as treatment for Autism? What was the result ?

A

Treatment: Surgery
-Martinez-Alavarex and Torres-Diaz. prog Brain Res (2022; 272:73)
-Treatment of therapy-resistant aggressiveness, obsessive thoughts and compulsions with radiofrequency and Gamma knife radiosurgery
Results: improvement in behavior and quality of life.

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25
Q

Explain whether or not Dietary intervention has been effective in treatment of autism

A

Dietary intervention (ex; Casein or gluten free diet) has NOT generally been effective in treatment of autism. But this requires further study especially in children with GI symptoms

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26
Q

Why should you be cautious of using restrictive diet for children with autism?

A

Be cautious of children with Highly restrictive diets. Vitamin Deficiencies have been describes which have resulted in permanent deficits
(Ex. Vitamin A/B12 deficiency and visual loss )

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27
Q

Describe the negative effects of some treatments

A

Some treatments have NOT been proven efficacious (effective) but have significant risks associated with them
ex: Chelation to remove “heavy metal” toxins from blood (kid died)

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28
Q

What is needed to assess treatment efficacy for children with autism? What are the problems with this? Describe other benefits of it?

A

We need BIOMARKERS to assess treatment efficacy. The obvious problem with biomarkers relates to the heterogeneity of the disease. Ideally, we need to find a Shared biomarker amongst children with ASD that will allow for measurement of treatment outcomes notwithstanding the etiology. Biomarkers will also help with Earlier diagnosis and assessment of phenotype and disease severity

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29
Q

What are outcomes of children with Autism? Compare the outcomes of children with mild vs severe impairment. What are major limitations? What is associated with poorer outcomes?

A

-Most children still retain the diagnosis at 9 years of age
-But children with Mild impairment typically improve and can “outgrow’ many symptoms of the disorder although, some persist with ADHD-like picture
-Children with SEVERE impairment may show Little improvement (non-verbal, no eye contact)
-Major limitations tend to be eye contact/focusing, cognition and communication issues
-poor attention span/interactive skills by age 4 years and lack of functional speech by age 5 years are associated with poorer outcomes

(children that are not talking by age 5 or 6, most likely won’t talk)

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30
Q

What kind of disorder is Autism?

A

Autism is NOT a single discard, but a MULTI-Factorial disorder associated with genetic and Non-genetic risk-factors

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31
Q

Discuss techniques of neuromaging used for Autism. What is the function of each?

A

Neuroimaging;
MRI and CT assess ANATOMY
functional MRI, PET and SPECT assess function
DTI (diffusion tensor imaging) assess white matter

32
Q

What information has been found in Neuroimaging for children with autism?

A

Neuroimaging:
-NO reproducible neuroimaging findings have yet been identified
-Gray-white volume differences: gray matter overgrowth
-Frontal, limbic, basal ganglia and cerebellar abnormalities
-Functional MRI in high functioning persons with autism: different brain areas used to process information: ex; face-recognition; executive function (ex: intellectual processes needed for control of behavior: attention, inhibitory control, memory, planning, problem solving
-Diffusion tensor imaging (DTI): abnormal white matter tracts in 6 mo nth old infants who later developed autism (American J Psych 2/12)

33
Q

Discuss the neuroimaging seen in paper Nature 2/16/2017? how do siblings come to plane? What were results of the results? What was MRI result>
What occurs with early detection of autism?

A

Nature 2/16/2017:
MRI on 109 high-risk infants with older siblings with autism (N.B. risk of having 2nd child with autism is 2-18%)
MRI done at 6, 12, and 24 months;
MRI wer 80% accurate in predicting autism
Result: Hyperexpansion of the cortex between 6-12 months of age predicted brain overgrowth at 2 years.
Early detection= Early treatment

34
Q

What kind of information does PET and SPECT provide about children with Autism?

A

PET (positron emission tomgotraphy) and SPECT (single photon emission computed tomography):
-Studies suggest Altered Dopaminergic function in frontal cortical regions but Not in striatum
-Altered Serotonin Nuerotransmission:
*persistence of the normal high brain serotonin synthesis into adolescence
*asymmetry of serotonin synthesis in various brain regions
*Decreased serotonin transporter binding
*REDUCED serotonin binding to the serotonin receptor

35
Q

Besides altered serotonin neurotransmission and altered dopamine function, what are other functional effects seen in PET and SPECT in children with autism ? What is NAA and its function? Compare NAA levels seen in normal children vs in Autism

A

PET and SPECT:
-Decreased GABA receptor binding
-MRS (magnetic resonance spectroscopy): evaluates hydrogen, phosphorous and carbon in brain to evaluate concentrations of neurochemicals in the brain: NAA, creatine, choline, myoinositol, glutamate/glutamine and GABA; largest peak in brain is NAA ( ? marker of neuronal integrity)
-Large increase of NAA (N-acetly-Aspartic Acid) in the first 3 years of life in normal children
-NAA the second most contracted molecule in brain (Glutamate)
NAA: source for myelin synthesis and mitochondrial energy production
-Reliable brain marker in neurons; decreased in many brain disorders
MRS: Widespread Decreases of NAA in autism

36
Q

what do imaging studies suggest about brain in children with autism? What kind of intervention should be used in children with autism ?

A

Many imaging studies suggest an UNDERCONNECTIVITY of the brain.
Therefore, because of the tremendous axonal sprouting and subsequent “pruning” that occurs in the first seven years of life, intervention should be aggressive and at a young age.
Studies are needed with fMRI and DTI to demonstrate increases in neural connections based on specific therapies

37
Q

Discuss the Neuropathology of children with autism. What are some findings regarding pathology? How are different brain regions affected?

A

Neuropathology:
-Although the findings have NOT been universal, they suggest pathology that arises in utero and relates to both neurogenesis and neuronal migration; NB; cortical neurons migrate from periventricular areas/subpendymal area between week 2-24 gestation:
*reduced number of Purkinje cells
*abnormal maturation of the forebrain limbic system (reduced neuronal size); increased cell packing density; decreased complexity of the neuropil
*abnormal frontal and temporal cellular columns
*devleopmental changes in cell size and number in Broca’s area, cerebellum, fusiform gyrus of the ventral temporal lobe (facial recognition), amygdala (fear/emotions), hippocampus (memory/learning)
*brainstem abnormalities and neocortical malformations

Studies limited by small sample size (Autism Tissue Program)

38
Q

What is the role of amygdala? How is the amygdala affected in children with ASD? What is the neurochemistry of Amygdala. Discuss pathology relating to amygdala in Autism?

A

Amygdala and ASD
-key emotional and behavioral center of the brain
-Specific function: Eye gaze, and face processing
-basolateral part has neurons which react to faces and actions.
-neurochemistry: high density of benzodiazepine/GABA receptors
-Also serotoninergic, dopaminergic, cholinergic and noradrenergic cell bodies and pathways.
-pathology: Small neuronal size and increased cell density
monkeys with Kluver-Bucy syndrome: Absence of social chattering, poor facial expression, absent emotions, repetitive behavior, increased aggression.

39
Q

what kind of implications were found with Cerebellum and ASD in a a studies? what was found in mouse models with? Which infants have higher incidence of ASD?

A

Cerebellum and ASD;
-implication of cerebellum based on histopathology, neuroimaging and epidemiologic studies
-Loss of Purkinje cells
-Neuroimaging; gray and white matter abnormalities
-PET in TSC (tuberous sclerosis complex) with ASD demonstrate cerebellar hypermetabolism , But not in TSC without ASD
Mouse models of TSC: selective loss of TSC1 or TSC2 genes
-Premature infants with isolated cerebellar hemorrhage have a HIGHER incidence of ASD

40
Q

what abnormalities were found in prefrontal cortex in those with ASD?
How is prefrontal cortex connected to other parts of brain?

A

Prefronatal cortex and ASD
-Lesion associated with cognitive, language, social and emotional Deficits including Loss of impulse control
-PFC (prefrontal cortex) has extensive connections without other cortical, subcortical and brainstem centers
-ASD: INCREASED brain volume in PFC (prefrontal cortex)

41
Q

Discuss whether there is a more focal, regional or generalized pathology in Autism? What ws concluded from scientific study (Gandel et al ) ?

A

Analysis of 725 samples spanning 11 distinct brain regions from post mortem samples from 49 individuals with idiopathic (no underlying cause) ASD and 54 controls
-There are Widespread molecular changes across cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions, especially visual cortex
- Gandel et al. Nature 11/2/2022

42
Q

Discuss the effects that Autism has on multiple brain areas, and what the problem may be with Autism in terms of dysfunction

A

Summary point:
-Multiple brain areas have been identified as ABNORMAL
-Autism may NOT be a problem with brain dysfunction involving specific localized brain lesions, but rather Dysfunction of Connections within brain regions such as connections between excitatory and inhibitory pathways.

43
Q

What part of autism is important to understand and has been ignored in research studies?

A

When trying to understand the underling neurobiology of autism, the HETEROGENEITY of the disorder is Critical.
Thus far, this factor has been Ignored in research studies involving both humans and animal

44
Q

Which animals have been used as models for autism? What have been results of this model?

A

Animal models of Autism
-There are both Rodent and Monkey animal models which can be genetically altered (ex: MECP2 gene) to demonstrate Autistic behavior such as repetitive behavior or avoidance of social contact
-Medication trials have shown Promise with some of these models

45
Q

What are some problems that have occurred with Animal Models in ASD?

A

Problems with Animal Models in ASD:
-Large variety of certain animal models with Little consensus on their Validity (rodents)
-Problems with choosing the best behavioral markers to assess efficacy of treatments
-Limited knowledge of the neurobiological pathogenesis of ASD
The problem is that we are dealing with apples and oranges and NOT apples and apples in both animal models and humans; this population is very heterozygous and effective treatment in one person may be ineffective in another due to differences in neurobiology

46
Q

What theories are associated with Causation in Autism?

A

Theories Associated with Causation:
-Genetics
-Mitochondrial dysfunction
-Environmental toxins
-Oxdiative stress
- neurochemical
-Neuroimmunology
-Endocrinological

47
Q

What is the current leading theory of Autism?

A

Autism is heterogeneous disorder which may have many causative etiologies. Currently, the Leading theory relates to a GENETIC PREDISPOSITION, but the percentage is highly variable

48
Q

Discuss how genetics is involved in causing Autism? How does this affect siblings or parents? What are the concordance rates for twins (monozygotic and dizygotic) ?

A

Genetic: a genetic mutation on every chromosome has been detected in children with autism
-between 400-1000 genes may be identified with susceptibility to autism
-Genetic cause may account for 10-40% of cases. MOST are DE NOVO (new mutations)
-materanlly derived 15.q Duplications common
-Increased Risk with advanced maternal
or paternal age.
-10-15% have a single-gene condition, chromosomal abnormality or other genetic syndrome
-Risk of second child with autism in the same family is 50X or 3-10% of subsequent siblings will have ASD
Concordance rates: monozygotic twins 80-90%; dizygotic twins 1-10%
-Fragile X

49
Q

Describe other genetics that may be involved in Autism, including RNAs, microRNAs, genetic linkages. How do microarrays come into play?

A

-Dozens of nuclear and mitochondrial genetic linkages have been identified proving that Different genes cause cause autism in unrelated affected individuals
-Polygenic influence (multiple interacting genes) with environmental effect
-microRNAs are NOT RNAs encoding for proteins but non coding regulatory RNA involved in activation and repression of coding genes
-microRNAs profoundly influence early brain development and are Very SENSITIVE to environmental effects
-Value of microarray analysis is key- most mutations are de novo
-3-10% of ASD risk due to de novo SNP (single nucleotide polymorphism)
-CNV (copy number variants), which represent deletions or duplications in specific regions of the chromosomes are also common; these can be inherited or de novo

50
Q

What is the function of autism related genes?

A

Function of autism-related genes:
-cell adhesion molecules
-Affecting ion channels
-cell cycle regulators
-mRNA translation

51
Q

What is the purpose of the chromosomal microarray analysis (CMA) Why is it important? what are the two CMA techniques. What is a SNP advantage and limitation ?

A

Chromosomal Microarray Analysis (CMA)
-Most widely used genetic testing with high diagnostic yield
-Results may impact prognosis and identify comorbidities
-2 CMA techniques; comparative genome hybridization (CGH) and single nucleotide polymorphism array (SNP)
SNP advantage; identify homozygous region (uniparental disomy or consanguinity)
-Limitation of SNP: Cannot Identify Low level mosaicism or small insertions/deletions (point mutations)

52
Q

Explain in CMA, when the variant may or may not be causative of the disorder? What is the importance of CNV (copy number variants play a role?

A

-Variant may NOT be the causative of the disorder (family trait or normal population variant )
Usually causative if de novo or large mutation/inherited from affected parent
CNV (inherited or de novo ) in specific region of chromosome associated with Increased risk of ASD

53
Q

Discuss the purpose of sequencing data and array data that is used in genetics What do they involve?

A

Sequencing data:
Deep characterization of the exome or whole genome which captures RARE genetic variants: the sequencing of TRIOS (father, mother, child) is commonly designed to IDENTIFY De Novo variants
Array data:
-The most common form of variation is a change in single DNA base, giving rise to Single nucleotide Polymorphism (SNP)
Genome -wide association studies use data from SNP arrays. Arrays commonly include copy number variant (CNV) probes, which can be used to study regions of DNA that are deleted, duplicated or are present in multiple copies

54
Q

What is suggested for families with more than affected child with Autism?

A

Families with more than one affected child should have a more Extensive Diagnostic workup: ex: chromosomal microarray analysis, metabolic studies (AA (amino acid) /OA (organic acid) lactate and pyruvate)

55
Q

Describe the features of Fragile X Syndrome? What causes it? What are full mutations and pre-mutation of the disease? Why is it important in relation to autism? What are the phenotypes of Fragile X? What is at the average age of diagnosis ?

A

Fragile X Syndrome
-Most Common known genetic cause of intellectual disability (ID) (ID can be mild to severe)
-Due to CGG repeat mutation in FMR1 gene
-Full mutation: 200 repeats
-Full mutation: ALL males with ID; 30% of females with ID (intellectual disability)
pre-mutation (55-199 repeats) transmitted by mothers has the potential to amplify to Full mutation in subsequent generations (Amplification)
Pre-mutation female carriers: Ovarian insufficiency and FXTAS (adults) (tremor ataxias)
-Fragile X syndrome is the MOST COMMOn genetic cause of Autism : yield 0-8% (median 3-4%)
-Phenotype subtle: MR (mental retardation) , Macrocephaly, large pinna, large testicles after puberty, joint hyperextensibility
-Extremely important for genetic counseling reasons
*30-50% of patients with Fragile X will demonstrate characteristics of autism
- average of diagnosis: 35-41 months; 55% of patients had another child before 1st child was diagnosed

56
Q

Discuss how TSC (Tuberous sclerosis) and mTOR (mammalian target of rapamycin) are linked? what can happen if there is a loss of function of TSC gene? What about defective mTOR?

A

Tuberous Sclerosis complex and mTOR (mammalian target of rapamycin)
-TSC gene identified
-mTOR is a key pathway of protein synthesis that contributes to synaptic function
-Defective mTOR has been linked to Neurodevelopmental disorders (ASD) and synaptic dysfunction
-Loss of TSC1/TSC2 function leads to activation of mTOR kinase activity resulting in mTORopathies

57
Q

Explain the roles of mTOR and how patients with idiopathic autism are affected by a down regulation of mTOR

A

mTOR :mammalian target of Rapamycin
-plays a critical role not only in regulation of various cellular functions such as cell growth, lipid/protein synthesis but also plays a critical role in neurodevelopment including nuerogenesis, synaptic genesis, and cellular migration
-some patients with idiopathic autism have shown drastic DECREASES in synaptic activity, dendritic spine growth, cell proliferation, and protein synthesis due to down regulation of mTOR signaling molecules in the brain (BMB reports)

58
Q

Explain how genetics (like DNA mutations ) can be involved in ASD?

A

DNA mutation could result in the loss of expression of functional RNA or protein crucial for CNS development or CNS function
-DNA mutation can affect the timing or circumstances as to when a gene is expressed during CNS development, which could impact that development (ex; affecting synapse development or interconnections)
-Impact of microRNAs
(involved in gene expression)

59
Q

What is the problematic issue with gene mutation that can cause ASD?

A

problematic issue
-some gene mutations that are causative of ASD have completely OPPOSITE manifestation at the synaptic level

60
Q

What are Environmental influences that are involved in Autism? What is seen in the prenatal, perinatal and postnatal stages? What other factors suggest a role of environmental influences?

A

Environmental
Prenatal:
* ?? Environmental teratogens in early gestational life (“second” hit phenomenon)
*fetal testosterone concentrations
*thalidomide and valproic acid
*severe early gestational hypothyroidism- ? preventable treatment
*gestational bleeding/diabetes
Perinatal: Term newborn encephalopathy
-Postnatal: NO association with Vaccines or mercury (thimerosal)
-Oxidative stress, neuroinflammation, more frequent de non copy number variants in sporadic autism and mitochondrial dysfunction all suggest a role for environmental influences

61
Q

What kind of environmental toxins are seen in children with autism?

A

Environmental toxins:
Transmission disequilibrium in transmission of 3 alleles of human glutathione peroxidase repeat noted in families with autism
-Increased frequency of enzymes conferring vulnerability to lead toxicity
-PON1, associated with organophosphate degradation, found in LOW activity in a cohort of US children with autism and organophosphate exposure
-other alleged toxins: mercury, cadmium, nickel, trichloroethylene, and vinyl chloride

62
Q

What can be said about Autism and vaccines ?

A

Autism is NOT associated with either vaccines or the mercury (thimerosal) in vaccines

63
Q

Explain how mitochondrial dysfunction can occur with children who have autism. Discuss the compounds affected with animal model of ASD that is injected with propionic acid

A

Mitochondrial dysfunction
-Unique bacterial population in ASD (Clostridium/Desulfovibrio/Sutterella/Bacteroidetes) cause an increase production of short chain FA (fatty acids, ex: Propionic Acid (PA) )
Propionic acid interferes with Mitochondrial metabolism at the level of TCA (citric acid ) cycle
-Animal model of ASD due to intraventricular injection of PA (propionic acid)
subset of ASD:
*Elevated lactic/pyruvic acid
*increased acyl carnitine (standard marker for mFatty acid defect)
*Increased FA or fatty acid (suggesting unprocessed Fa due to reduction in FA beta oxidation)
-Decrease in free carnitine (can be depleted if it ends to unprocessed FA)

64
Q

Explain how oxidative stress occurs and how it is relevant to children with autism

A

Oxidative stress
-OS, a well known consequence of Environmental insults, is INCREASED in patient with Autism
*abnormal sulfur amino acid metabolism seen in leukocytes
*Reduction in ratio of reduced glutathione/oxidized glutathione measured in both cytosol and mitochondria and endogenous detoxifier )
*post mortem brain with abnormal cytokines
Oxidative stress may be related to Immune activation

65
Q

What are the neurochemical influences that are seen in children with Autism ?

A

Neurochemical:
-Serotinin: 30-50% of individuals with ASD have an ELEVATED level of serotonin in blood
-alterations in serotonin receptors
-Alteration in serotonin synthesis/degradation enzymes
-Different doses of serotonin agonists affect different biological mechanisms; pre-synspatic vs post-synaptic affects result in different clinical effects
-Issue with drug treatment: Drugs typically affect more than one neurotransmitter system (ex: busipirone at high doses has activity at the Dopamine D2 receptor)

(lower activity of D2 receptor)

66
Q

Explain how Nueroimmunology is affected in Autism. What is Autoimmune theory? What abnormalities pertaining to immune system is seen in Autism and how can they occur ?

A

Neuroimmunology
Autoimmune theory: circulating autoantibodies targeting brain protein have been identified in both children with autism and their mothers (ex: maternal in origin)
-Immunological abnormalities involving cytokines, immunoglobulins, B-cell and T-cell, inflammation and cellular activation have been noted in patients with autism
-post mortem brain analysis has noted immune activation
-During postnatal life, the bbb blood brain barrier) limits the entry of immune components into the brain. During fetal development, the bbb is permeable and can be compromised by infection and toxins, allowing access of various immune components into the brain

67
Q

What is the role of Cytokines? how are they affected with those who have Autism? What have studies shown regarding an immune influence to Autism?

A

Neuroimmunology: Cytokines
-Cytokines are proteins that are Not only control the intensity, characters and duration of an immune response, but also interact with neural systems and are involved with neural development
-historically, studies demonstrating an immune component to autism have shown inconsistent results: small sample size, poor controls and heterogeneity
-cytokines involved include transformation growth factor beta (TGF-b), macrophage inhibitory factor (MIF) & monocyte chemotactic protein-1 (MCP-1)
- krakowiak et al I(2017 paper) : Elevated inerleukins 1B (mild- moderate ASD) and interleukin 4 (Severe ASD) at birth suggesting that immune dysregulation precedes symptoms

68
Q

Explain wha that been seen with Immunoglobulins in those with Autism. what may lead to altered neural development an immune function? what evidence has been seen for inflammation in ASD?

A

Neuroimmunology: immunoglobulins
-DECREASED levels of plasma IgG and ig M in individuals with autism; the lowest levels are associated with the most Severe behavior
-higher levels of IgG4 compared with controls
? Defect in a shared signal pathway leads to both altered neural development and immune function
-There is growing Radiologic and pathological evidence for a role of Brian inflammation in ASD

69
Q

What is the role of maternal antibodies (IgG)? How can they affect an infant?

A

Maternal antibodies (IgG) are easily transferred across the placenta to the fetus throughout pregnancy. They provide a protective function until the infant’s immune system matures and produces his own IgG (6 months)
-Maternal antibodies are transferred without Specificity (both protective and autoantibodies transfer equally)
-Maternal Autoantibodies can cause disease in infant (neonatal MG) MG: myasthenia gravis

70
Q

Compare the antibodies that the mother has vs child with autism

A

Unlike their mothers, children wi th autism do NOT have antibodies to the fetal brain. The antibodies found in children with autism react with fully developed brain

71
Q

Explain what occurred when serum IgG from mother of children with autism was injected into rhesus monkeys. Why is this significant? What other animal model has similar result?

A

Serum ig G from mothers of children with autism injected into pregnant rhesus monkey produced stereotypical and hyperactive behavior in their offspring. This was NOT observed with injections of IgG purified from mothers of children without Neurological impairment
-similar finding was observing in murine mouse model ?

72
Q

Explain how autoimmunity is related to Autism. which disorders are associated with autoimmunity. What is found in children with autism compared to controls. and what can you discuss about family members of children with autism ?

A

Neuroimmunology: Clinical autoimmunity
-There are numerous pediatric systemic and primary CNS disorders associated with autoimmunity
-Primary CNS disorders associated with autoimmunity:
SLE-Guillan Barre Syndrome- MS
NMDA encephalitis- myasthenia gravis ? PANDAS/PANS
Elevated ANA (antinuclear antibodies) are found in children with autism compared to controls (Mustafa, end Neural 2009 paper)
–Family members of children with autism have a HIGHER incidence of autoimmune disorders
(studies of treatment with IVIG (intravenous immunoglobulin) have NOT shown consistent benefit

73
Q

Describe the role of microglia in autoimmunity? What can affect microglia?

A

Role of microglia in Autoimmunity
-Microglia probably have two CNS functions;
1) inflammatory as CNS macrophages
2) role in synaptic pruning (eliminate synapses at young age)
-ANY type of maternal immune activation may affect microglia function
-Drug affects on microglia

74
Q

Discuss the different effects of endocrine and other hormones on behavior ? What is secretin and where can it be found in body?What is the ratio of autism for boys and girls?

A

Endocrine
-Neuropeptides, hormones or hormone-like substances facilitate the encoding of behavior modulated by brain
-These substances may affect behavior via their direct or indirect action on the amygdala, hippocampus, and related structures
-Pineal gland and affect on sleep
-Secretin: peptide secreted by small intestine that has digestive functions but also found in brain
-Boys: girls = 4: 1

75
Q

Discuss summary of autism including what kind of condition, what are core causes?

A

Summary
Autism is an extremely common neurological condition
-genetics at the core
apples and oranges
-Diverse genetic mutations, diverse neuroanatomical abnormalities, diverse nuero chemical abnormalities, yet all still leading to same core neurobehavioral syndrome

Essentials of Neuroscience (12 decks)

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