Neurological Diseases and DisordersAutism Spectrum Disorders (ASD)

Before we get into ASD…• Function of Amyloid Beta (beyond Alzheimer’s Disease)

Mattson, M. P. (1997). Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiological reviews, 77(4), 1081-1132.

“…released from neurons in response to electrical activity and may function in modulation of neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, and cell survival. modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. modulation of cell adhesion and regulation of proliferation of nonneuronal cells”.

History

Leo Kanner, 1943• Austrian born Physician,

1896-1981

Hans Asperger, 1944• Austrian Born Physician,

1906-1980

“Autistic Disturbances of Affective Contact”, 1943

“Autistic Psychopathy in Childhood”, 1944

DSM-5SOCIAL COMMUNICATION AND SOCIAL INTERACTION• Social emotional reciprocity‐• Nonverbal communicative behaviors• Developing and maintaining relationships,

appropriate to developmental level

RESTRICTED, REPETITIVE PATTERNS OF BEHAVIOR, INTERESTS, OR ACTIVITIES • Repetitive speech, motor movements, or

use of objects • Routines, rituals, resistance to change • Intense, highly restricted, fixated interests• Sensory disturbances

DSM DOESN’T CAPTURE…

• Onset• Early• Regression• Mixed

• Prevalence• 2012 CDC 1 in 88

children, 1 in 54 boys• 2014 CDC 1 in 68 , 1 in

42 boys, 1 in 189 girls

ASD Symptoms CBS News Videohttps://www.youtube.com/watch?v=zVgPlURSad8

The Search for Genes• Early 90’s – Genetic

basis of Autism• 5HTT, GABA receptor

genes• Linkage studies

• Twin studies revisited

Causes?Gene-Environment InteractionsHeritable and Non-heritable Risk

• Certain Medical Disorders• Siblings• Broad Autism Phenotype (Endophenotype)• Environmental Toxins• (Vaccinations)• Prenatal factors

Some Etiological Theories• Underconnectivity theory• Redox/Methylation theory• Neuroimmune theories• Extreme Male Brain theory/Female Protective Effect (FPE) Theory

The Autistic Brain• Brain development• Early brain overgrowth

• Pathology• Structural• White matter• Neuroinflammation

• MFG, ACC, CB• CNS Immunity

• TNF-α, IL-1β, IL-12• Innate Immunity• Auto-antibodies

• Neurotransmitter Systems• 5-HT, OT

Cerebellar Pathology in AutismA, Normal Pathology in Control Brain; B, Loss of Purkinje and Granule Cell Layer; C, Microglial Activation; D

High Magnification of B; E,F, High Magnification microglia around a purkinje, granuale cells

The Autistic Brain• Some Neural correlates• Face Processing• Emotion Recognition• Theory of Mind• Linguistic Reasoning

Fusiform Face AreaLeft,functional activation map Fusiform Face Area (FFA) located within Fusiform Gyrus in the Temporal LoveRight, FFA in Post Mortem Tissue

The Autistic Brain• Some Neural correlates• Face Processing• Emotion Recognition• Theory of Mind• Linguistic Reasoning

Theory of Mind Task Processing Activation in right superior temporal (yellow ovals) and superior medial frontal (blue ovals) areas in autism and control groups for

the contrast of Theory of Mind processing with Random animation processing. The t-maps are thresholded at p < .005 and an extent threshold of 6 voxels.

The Autistic Brain• Some Neural correlates• Face Processing• Emotion Recognition• Theory of Mind• Linguistic Reasoning

Animal Models• Types of Animal Models• Genetic• Lesion• Infectious• Neurochemical• Toxicity

• Valproic Acid Model (VPA)* • Serotonin*

• Developmental Hyperserotonemia Model (DHS)

Treatment• Behavioral Interventions• Drugs• Alternative Therapies

Perrin et al., 2012Autism Speaks Autism Treatment Network RegistryN=3,173

References• The alan mason chesney medical archives of the johns hopkins medical institutions. (n.d.).

Retrieved from http://www.medicalarchives.jhmi.edu/papers/kanner.html• Kanner, L. (1943). Autistic disturbances of affective contact. Nervous child, 2(3), 217-250.• National institute of neurological disorders and stroke. (2013, December 30). Retrieved from

http://www.ninds.nih.gov/disorders/asperger/detail_asperger.htm• Lyons, V., & Fitzgerald, M. (2007). Asperger (1906–1980) and Kanner (1894–1981), the two

pioneers of autism. Journal of autism and developmental disorders, 37(10), 2022-2023.• Ozonoff, S., Heung, K., Byrd, R., Hansen, R., & Hertz Picciotto, I. (2008). The onset of autism: ‐

patterns of symptom emergence in the first years of life. Autism research, 1(6), 320-328.• Insel, T. (2012). Autism Prevalence: More Affected or More Detected. Autism.• Centers for Disease Control and Prevention. (2014). Autism Spectrum Disorder (ASD).

Retrieved from http://www.cdc.gov/ncbddd/autism/data.html.• Hertz-Picciotto, I., & Delwiche, L. (2009). The rise in autism and the role of age at diagnosis.

Epidemiology, 20(1), 84-90.• The Australian Psychological Society. (n.d.). For health professionals: About asd. Retrieved

from http://autism.ahpa.com.au/ForHealthProfessionals/AboutASD.aspx• Kohane, I. S., McMurry, A., Weber, G., MacFadden, D., Rappaport, L., Kunkel, L., ... &

Churchill, S. (2012). The co-morbidity burden of children and young adults with autism spectrum disorders. PloS one, 7(4), e33224.

References• IAN Research Report #13, From First Concern to Diagnosis and Beyond. (2010, February 24).

Interactive Autism Network. Retrieved April 1, 2014, from http://www.iancommunity.org/cs/ian_research_reports/ian_research_report_13

• Simonoff, E., Pickles, A., Charman, T., Chandler, S., Loucas, T., & Baird, G. (2008). Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. Journal of the American Academy of Child & Adolescent Psychiatry, 47(8), 921-929.

• Rosenberg, R. E., Law, J. K., Yenokyan, G., McGready, J., Kaufmann, W. E., & Law, P. A. (2009). Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Archives of pediatrics & adolescent medicine, 163(10), 907-914.

• Hallmayer, J., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., ... & Risch, N. (2011). Genetic heritability and shared environmental factors among twin pairs with autism. Archives of general psychiatry, 68(11), 1095-1102.

• Miles, J. H. (2011). Autism spectrum disorders—a genetics review. Genetics in Medicine, 13(4), 278-294.

• Newschaffer, C. J., Fallin, D., & Lee, N. L. (2002). Heritable and nonheritable risk factors for autism spectrum disorders. Epidemiologic Reviews, 24(2), 137-153.

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• Gardener, H., Spiegelman, D., & Buka, S. L. (2009). Prenatal risk factors for autism: comprehensive meta-analysis. The British Journal of Psychiatry, 195(1), 7-14.

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systems disorder: a theory of frontal-posterior underconnectivity. Neuroscience & Biobehavioral Reviews, 36(4), 1292-1313.

• Werling, D. M., & Geschwind, D. H. (2013). Understanding sex bias in autism spectrum disorder. Proceedings of the National Academy of Sciences, 110(13), 4868-4869.

• Buehler, M. R. (2011). A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder. Medical hypotheses, 76(6), 863-870.

• Deth, R., Trivedi, M. S., Hodgson, N. W., Muratore, C. R., & Waly, M. I. (2014). Redox/Methylation Theory and Autism. In Comprehensive Guide to Autism (pp. 1389-1410). Springer New York.

• Gerdts, J., & Bernier, R. (2011). The broader autism phenotype and its implications on the etiology and treatment of autism spectrum disorders. Autism research and treatment, 2011.

• Melnyk, S., Fuchs, G. J., Schulz, E., Lopez, M., Kahler, S. G., Fussell, J. J., ... & James, S. J. (2012). Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. Journal of autism and developmental disorders, 42(3), 367-377.

• Manning, J. T., Baron Cohen, S., Wheelwright, S., & Sanders, G. (2001). The 2nd to 4th digit ‐ratio and autism. Developmental Medicine & Child Neurology, 43(3), 160-164.

• Baron-Cohen, S., Knickmeyer, R. C., & Belmonte, M. K. (2005). Sex differences in the brain: implications for explaining autism. Science, 310(5749), 819-823.

References• Dalton, K. M., Nacewicz, B. M., Johnstone, T., Schaefer, H. S., Gernsbacher, M. A., Goldsmith,

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• Kana, R. K., Keller, T. A., Cherkassky, V. L., Minshew, N. J., & Just, M. A. (2009). Atypical frontal-posterior synchronization of Theory of Mind regions in autism during mental state attribution. Social Neuroscience, 4(2), 135-152.

• Sahyoun, C. P., Belliveau, J. W., Soulières, I., Schwartz, S., & Mody, M. (2010). Neuroimaging of the functional and structural networks underlying visuospatial vs. linguistic reasoning in high-functioning autism. Neuropsychologia, 48(1), 86-95.

• Wodka, E. L., Mathy, P., & Kalb, L. (2013). Predictors of phrase and fluent speech in children with autism and severe language delay. Pediatrics, 131(4), e1128-e1134.

• UC San Diego Autism Center of Excellence. (2014). Discovering the causes: Functional magnetic resonance imaging (fmri) . Retrieved from http://www.autism-center.ucsd.edu/what-causes-autism/Pages/fmri.aspx

• Courchesne, E., Yeung-Courchesne, R., Hesselink, J. R., & Jernigan, T. L. (1988). Hypoplasia of cerebellar vermal lobules VI and VII in autism. New England Journal of Medicine, 318(21), 1349-1354.

• Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., & Pardo, C. A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of neurology, 57(1), 67-81.

References• Modahl, C., Green, L. A., Fein, D., Morris, M., Waterhouse, L., Feinstein, C., & Levin, H. (1998). Plasma

oxytocin levels in autistic children. Biological psychiatry, 43(4), 270-277.• Tordjman, S., Drapier, D., Bonnot, O., Graignic, R., Fortes, S., Cohen, D., ... & Roubertoux, P. L. (2007).

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