Looking for the Silent Fire: Are there signs of Neuroinflammation in Toddlers with ASD and Regression?
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1 Looking for the Silent Fire: Are there signs of Neuroinflammation in Toddlers with ASD and Regression? Autism Research Parent Conference Jan 15 th, 2011 Alvin Loh, MD Developmental Paediatrician, Surrey Place Centre Assistant Professor, University of Toronto
2 STAR Study of Toddlers with Autism and Regression: Biomarkers of immune activation and oxidative stress Could inflammation in the brain be contributing to ASD? Brain Pathology and fluid (CSF) studies, small sample (Vargas 05) Increase in head circumference in ASD at 6-18 months of life Subtle MRI brain differences:?atypical cells? edema (Dager 08) Uncontrolled epilepsy associated with neuroinflammation (Choi 09) How can we detect this? Brain imaging? Too mild for MRI, SPECT scans with radioisotopes not ethical EEG? not specific for inflammation CSF? Some enthusiasm but challenging to obtain CSF Is there a correlation between inflammation in blood and CNS Funded: pilot study on biomarkers of immune activation (blood)
3 Purpose of STAR protocol To compare immune activation and oxidative stress markers in month toddlers: autism and regression vs autism and no regression 50 cases and 50 controls: Toronto, Baltimore, Arkansas Immune Dysfunction in ASD NIMH: ASD vs Delays, +/- Regression CD 40L, chronic inflammation (Pardo 2009)
4 Oxidative stress in ASD Glutathione (antioxidant) is decreased in ASD (James 2006) Oxygen reacts in our body leading to oxidants Potentially damaging free radicals are made and mopped up an increase in production of oxygen molecules that can damage cells and impair their function Jill James
5 Responding Quickly When Regression Occurs Make MDs and early childhood centres aware Screen with Regression questionnaire parts of Toddler ADI-R Assessment with ASD testing (ADOS), and Developmental testing (Mullen), and Clinical History Clinical Tests (metabolic disorders, inflammatory markers) EEG and MRI if indicated Research Testing (immune overactivation, oxidative stress) Research Co-ordinator at SPC Melanie Fenwick, x 2527 Subspecialists: E. Anagnostou, W. Logan & B. Banwell (Neurology); S. Benseler (rheumatology); A. Schulze & A. Feigenbaum (Metabolics); J. Brian Collaborators: J. James, A. Zimmerman, C. Pardo
6 Outcomes from this Pilot Study Compare levels of immune overactivation (increased cytokines), and oxidative stress, and also relationship of both in ASD (regresssion vs non regression) Future studies more specific to brain: CSF, Imaging Abnormalities in CSF could prompt a trial of therapy (? Antioxidants,?immune modulation)
7 Creatine Deficiency Syndromes in ASD Potentially Treatable metabolic cause of Delays Poor speech ASD mannerisms Seizures (in some cases) 1-2 % prevalence in populations with DD? similar prevalence in ASD
8 Creatine Metabolism Creatine - energy delivery muscle and brain Actively moved into brain by Creatine Transporter pump Brain also makes creatine Three disorders in CDS GAMT, guanidinoacetate methyltransferase (1994) AGAT, arginine:glycine amidinotrasferase (2001) CrT1, creatine transporter defect (2001)
9 GAMT (severe) AGAT (mild) Creatine Transporter Deficiency Prevalence < 2.7% rare % Genetics AR AR X linked Clinical Dev Delay Dev Delay Dev Delay Speech Delay Speech Delay Severe Speech Delay Hypotonia, Dyskinesia (Seizures) Autistic mannerisms Refractory seizures Autistic Mannerisms/SIB (Mild seizures ) Pathophysiology High GAA, Low creatine Low creatine Low creatine Treatment Creatine, restrict arginine Creatine 400mg/kg/d Diet Outcome Some improvement Improvment No clear changes
10 Testing for Creatine Deficiency Clinical Indication in Toronto Global Delays, Poor Speech (+/- abnormal movements, seizures) Research Indication ASD (supported by ADOS) Screening First morning urine, Sick Kids, Dr Andreas Schulze s Lab If abnormal, repeat urine (12-24 hr collection ideal) Diagnostic Confirmation Genetic (blood test): GAMT, AGAT, SLC 6A8 Brain Scan (MRS) shows Absent Creatine Adults Genetic Metabolic Consultation at TGH Dr Hannah Fagfoury taking clinical referrals from your MD
11 Creatine Deficiency Syndrome in ASD Study in Toronto Contact Person: Research co-ordinator, Melanie Fenwick, , ext 2527 Principal Investigators: Andreas Schulze, Alvin Loh Co-Investigators: E. Anagnostou, W. Roberts, S. Scherer
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