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Autism and the brain

Except for genetics, no other area has received as much attention in research as the brain and autism. The pathological findings are extensive, and too numerous to adequately cover here.

However, here are a small sampling of the findings scientific investigations have elicudated:

Cortical structural and functional abnormalities

Altered brain connectivity 

Atypical grey and white matter

Abnormalities of neurotransmitters, amino acid and proteins (GABA, glutamate, Reelin, acetylcholine, dopamine, serotonin)


Chronically activated microglia

Loss of Purkinje and granular cells

Impaired mitochondria dynamic

Reduced melatonin synthesis

Seizures and autism
Selected studies

"In this review, we compiled a database of genes associated with both epileptic encephalopathy and ASD, limiting our purview to Mendelian disorders not including inborn errors of metabolism, and we focused on the connection between ASD and epileptic encephalopathy rather than epilepsy broadly. Our review has four goals: to (1) discuss the overlapping presentations of ASD and monogenic epileptic encephalopathies; (2) examine the impact of the epilepsy itself on neurocognitive features, including ASD, in monogenic epileptic encephalopathies; (3) outline many of the genetic causes responsible for both ASD and epileptic encephalopathy; (4) provide an illustrative example of a final common pathway that may be implicated in both ASD and epileptic encephalopathy."

Srivastava, Siddharth, and Mustafa Sahin. “Autism Spectrum Disorder and Epileptic Encephalopathy: Common Causes, Many Questions.” Journal of Neurodevelopmental Disorders 9 (2017): 23. PMC.

"Studies using VNS in children with both epilepsy and an autism spectrum disorder have also yielded positive results. VNS reduces seizure frequency and improves quality of life in individuals with ASD [384651]. In the largest study to date of VNS therapy in individuals with ASD, seizure reduction was similar between individuals with and without autism [46]. After 12 months of VNS therapy, 56% of individuals without autism experienced a ≥50% reduction in seizures, while 62% of individuals with autism experienced a ≥50% reduction in seizures. Individuals with and without autism exhibited similar improvements in alertness, verbal communication, memory, and school/professional achievements.

Engineer, Crystal T., Seth A. Hays, and Michael P. Kilgard. “Vagus Nerve Stimulation as a Potential Adjuvant to Behavioral Therapy for Autism and Other Neurodevelopmental Disorders.” Journal of Neurodevelopmental Disorders 9 (2017): 20. PMC.

"However, some biochemical impairments, including decreased melatonin (crucial for circadian regulation) and elevated platelet N-acetylserotonin (the precursor of melatonin) have been reported as very frequent features in individuals with ASD. To address the mechanisms of these dysfunctions, we investigated melatonin synthesis in post-mortem pineal glands - the main source of melatonin (9 patients and 22 controls) - and gut samples - the main source of serotonin (11 patients and 13 controls), and in blood platelets from 239 individuals with ASD, their first-degree relatives and 278 controls. Our results elucidate the enzymatic mechanism for melatonin deficit in ASD, involving a reduction of both enzyme activities contributing to melatonin synthesis (AANAT and ASMT), observed in the pineal gland as well as in gut and platelets of patients. Further investigations suggest new, post-translational (reduced levels of 14-3-3 proteins which regulate AANAT and ASMT activities) and post-transcriptional (increased levels of miR-451, targeting 14-3-3ζ) mechanisms to these impairments. This study thus gives insights into the pathophysiological pathways involved in ASD."

Pagan, Cécile et al. “Disruption of Melatonin Synthesis Is Associated with Impaired 14-3-3 and miR-451 Levels in Patients with Autism Spectrum Disorders.” Scientific Reports 7 (2017): 2096. PMC.

"Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders."

Zhang, Yiting et al. “Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.” Ed. Joseph Alan Bauer. PLoS ONE 11.1 (2016): e0146797. PMC. 

"A number of studies have reported evidence of oxidative stress in post-mortem brain samples obtained from individuals with ASD compared to controls (Table ​(Table1).1). These studies have demonstrated a decrease in GSH, the major cellular antioxidant, oxidative damage to proteins, lipids and deoxyribonucleic acid (DNA) as well as alternations in the activity of enzymes important in redox metabolism.Several studies have reported GSH abnormalities in the brain tissue of individuals with ASD. In one study of 10 individuals with autism and 10 age-matched controls, GSH/GSSG and reduced GSH levels were both significantly lower in the cerebellum and temporal cortex in the autism group compared to controls (Chauhan et al., 2012a)...Overall, the studies reviewed above provide support for the idea that oxidative stress, mitochondrial dysfunction and inflammation/immune dysfunction, which are physiological abnormalities identified in non-CNS tissue in children with ASD, are also found to affect the CNS."

Rossignol, Daniel A., and Richard E. Frye. “Evidence Linking Oxidative Stress, Mitochondrial Dysfunction, and Inflammation in the Brain of Individuals with Autism.” Frontiers in Physiology 5 (2014): 150. PMC.

"We confirmed the previously reported hyperserotonemia in ASD (40% (35–46%) of patients), as well as the deficit in melatonin (51% (45–57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41–54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS–melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS–melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD."

Pagan, C et al. “The Serotonin-N-Acetylserotonin–melatonin Pathway as a Biomarker for Autism Spectrum Disorders.” Translational Psychiatry 4.11 (2014): e479–. PMC.

"Multiple lines of evidence implicate mitochondrial dysfunction in ASD. In postmortem BA21 temporal cortex, a region that exhibits synaptic pathology in ASD, we found that compared to controls, ASD patients exhibited altered protein levels of mitochondria respiratory chain protein complexes, decreased Complex I and IV activities, decreased mitochondrial antioxidant enzyme SOD2, and greater oxidative DNA damage. Mitochondrial membrane mass was higher in ASD brain, as indicated by higher protein levels of mitochondrial membrane proteins Tom20, Tim23 and porin. No differences were observed in either mitochondrial DNA or levels of the mitochondrial gene transcription factor TFAM or cofactor PGC1α, indicating that a mechanism other than alterations in mitochondrial genome or mitochondrial biogenesis underlies these mitochondrial abnormalities. We further identified higher levels of the mitochondrial fission proteins (Fis1 and Drp1) and decreased levels of the fusion proteins (Mfn1, Mfn2 and Opa1) in ASD patients, indicating altered mitochondrial dynamics in ASD brain. Many of these changes were evident in cortical pyramidal neurons, and were observed in ASD children but were less pronounced or absent in adult patients. Together, these findings provide evidence that mitochondrial function and intracellular redox status are compromised in pyramidal neurons in ASD brain and that mitochondrial dysfunction occurs during early childhood when ASD symptoms appear."

Tang, Guomei et al. “Mitochondrial Abnormalities in Temporal Lobe of Autistic Brain.” Neurobiology of disease 54 (2013): 349–361. PMC.

"The [11C](R)-PK11195 binding potential values were significantly higher in multiple brain regions in young adults with ASD compared with those of controls (P < .05, corrected). Brain regions with increased binding potentials included the cerebellum, midbrain, pons, fusiform gyri, and the anterior cingulate and orbitofrontal cortices. The most prominent increase was observed in the cerebellum. The pattern of distribution of [11C](R)-PK11195 binding potential values in these brain regions of ASD and control subjects was similar, whereas the magnitude of the [11C](R)-PK11195 binding potential in the ASD group was greater than that of controls in all regions.

Conclusions Our results indicate excessive microglial activation in multiple brain regions in young adult subjects with ASD...In conclusion, the present PET measurements revealed marked activation of microglia in multiple brain regions of young adults with ASD. The results strongly support the contention that immune abnormalities contribute to the etiology of ASD."

Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, Yoshihara Y, Omata K, Matsumoto K, Tsuchiya KJ, Iwata Y, Tsujii M, Sugiyama T, Mori N. Microglial Activation in Young Adults With Autism Spectrum Disorder. JAMA Psychiatry. 2013;70(1):49–58. doi:10.1001/jamapsychiatry.2013.272

"In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg−1 per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment."

Frye, R E et al. “Cerebral Folate Receptor Autoantibodies in Autism Spectrum Disorder.” Molecular Psychiatry 18.3 (2013): 369–381. PMC.

   "Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation...One striking feature is the presence of on-going neuroinflammation in postmortem brain tissue from individuals with AD, a finding that is consistent over a broad age range (5–44 years of age) [73]. Compared with controls, brain tissue specimens from cerebellum, midfrontal and cingulate gyrus in AD show marked activation of microglia and astrocytes with the up-regulation of the cell surface major histocompatibility complex (MHC) molecule HLA-DR and, glial fibrillary acidic protein, respectively. Prominent monocyte and macrophage accumulation in the cerebellum is also detected...Our studies of different brain regions showed that oxidative stress differentially affects selective brain regions, i.e., cerebellum, temporal and frontal cortices, in autism [103105107]...Aberrant brain structure has been reported particularly in the cerebellum of children with autism. Loss of Purkinje and granule cells has been reported throughout the cerebellar hemispheres in autism [99118119]. Alterations in neuronal size, density and dendritic branching in the cerebellum and limbic structures (hippocampus and amygdala) have also been reported in autism. In addition, neuropathological abnormalities in autism have also been suggested in the frontal and temporal cortices, cortical white matter, amygdala and brainstem [117121]."

Fatemi, S. Hossein et al. “Consensus Paper: Pathological Role of the Cerebellum in Autism.” Cerebellum (London, England) 11.3 (2012): 777–807. PMC. 

"The obtained data recorded that Saudi autistic patients have remarkably higher plasma HSP70, TGF-β2,Caspase 7 and INF-γ compared to age and gender-matched controls. INF-γ recorded the highest (67.8%) while TGF-β recorded the lowest increase (49.04%). Receiver Operating Characteristics (ROC) analysis together with predictiveness diagrams proved that the measured parameters recorded satisfactory levels of specificity and sensitivity and all could be used as predictive biomarkers..Alteration of the selected parameters confirm the role of neuroinflammation and apoptosis mechanisms in the etiology of autism together with the possibility of the use of HSP70, TGF-β2, Caspase 7 and INF-γ as predictive biomarkers that could be used to predict safety, efficacy of a specific suggested therapy or natural supplements, thereby providing guidance in selecting it for patients or tailoring its dose...Immune factors, such as autoimmunity, have been implicated in the genesis of autism [3].The increase of IFN-γ reported in the present study may indicate antigenic stimulation of Th-1 cells pathogenetically linked to autoimmunity in autism. The reported elevation of IFN-γ could support the previous work of Molloy et al.[5] showing that PBMNC of autistic children produce remarkably high levels of Il-12 and IFN-γ, or express higher than normal levels of mRNA for IFN-γ [39] and the most recent work of Tostes et al.[40] that plasma levels of vasoactive intestinal peptide (VIP), IFN-γ and NO were significantly higher in children with autism, compared to the healthy subjects and that a positive correlation between plasma levels of NO and IFN-γ exists. Moreover, they suggested additional evidence that higher levels of IFN-γ may be associated with increased oxidative stress, a phenomenon greatly involved in the etiology of autism [19]. Collectively, the present study together with the previously mentioned studies confirm the existence of Th-1 type of immune response in autistic children and that would also be consistent with an autoimmune pathology, simply because IFN-γ is among the cytokines well known for inducing autoimmune diseases." 

Afaf El-Ansary and Laila Al-Ayadhi "Neuroinflammation in autism spectrum disorders" Journal of Neuroinflammation 2012 9:265

"In summary, multiple imaging techniques based on the BOLD signal have provided evidence for decreased cortical-cortical connectivity, with possibly increased connectivity between subcortical regions and cortex, and within primary sensory areas such as the visual cortex. These results, in combination with findings of decreased cortical specialization, and supported by structural imaging studies that indicate abnormal growth and organization of both grey and white matter, reinforce the model of atypical connectivity in ASD, possibly resulting in an inefficient system with altered signal-to-noise ratio [73], that is, decreased signal with under-connectivity or increased noise with over-connectivity when defined as increased numbers of connections."

Evdokia Anagnostou and Margot J Taylor "Review of neuroimaging in autism spectrum disorders: what have we learned and where we go from here" Molecular Autism 2011 2:4

"This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-α, IL-6 and GM-CSF), Th1 cytokine (IFN-γ) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. Conclusion: ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD."

Li, Xiaohong et al. “Elevated Immune Response in the Brain of Autistic Patients.” Journal of neuroimmunology 207.1-2 (2009): 111–116. PMC.

"To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)–1 and tumor growth factor–β1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain."

Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W. and Pardo, C. A. (2005), Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol., 57: 67–81. doi:10.1002/ana.20315

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