Bermans J. Iskandar Lab

Research Interests

Basic Research in CNS Regeneration

The role of folic acid supplementation has proven to be extremely effective in preventing the occurrence of neural tube defects and other congenital abnormalities in humans. Because this suggests that folic acid can modulate or enhance key mechanisms for growth and differentiation in the CNS, our laboratory has been instrumental in hypothesizing and proving a significant role for folic acid in regeneration and repair of the adult CNS after injury. As part of an effort to study the mechanism of such a pro-regenerative response, we have shown using NIH funding that folate-mediated CNS regeneration depends on injury-related induction of folate receptor FOLR1 expression, intact intracellular folate activation, and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons is biphasic and dose-dependent, and correlates closely over its dose range with global and gene-specific DNA methylation, and with expression of both the folate receptor FOLR1 as well as the de novo DNA methyltransferases. Accordingly, we hypothesize an epigenetic mechanism in CNS repair, and through our laboratory efforts, we seek to understand the underpinnings of this mechanism and its implications. This work provides possible avenues for new pharmacologic approaches to treating brain and spinal cord injuries. Most recently, using March of Dimes funding, we’ve demonstrated that such methylation-mediated phenotypic changes are transmitted through multiple generations.

Select CNS Axon Regeneration References

1. Iskandar BJ, Nelson A, Resnick DK, Skene JHP, Gao P, Johnson C, & Hariharan N: Folic acid supplementation enhances repair mechanism in the adult CNS. Annals of Neurology 56:221-227,2004.
2. Bomze HM, Bulsara KR, Iskandar BJ, Caroni P, Skene JHP: Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons. Nature Neuroscience 4(1):38-43, 2001. PMID: 11135643 Policy Exempt: Accepted prior to April 7, 2008.
3. Iskandar BJ, Rizk E, Meier B, Hariharan N, Bottiglieri T, Finnell RH, Jarrard DF, Banerjee RV, Skene JH, Nelson A, Patel N, Gherasim C, Simon K, Cook TD, Hogan KJ. Folate regulation of CNS regeneration through DNA methylation. J Clin Invest. 2010 May 3;120(5):1603-16. doi: 10.1172/JCI40000. Epub 2010 Apr 26. PMCID: PMC2860927.
4. Stewart KJ, Iskandar BJ, Meier BM, Rizk EB, Hariharan N, Koueik J, Andrei AC, Hogan KJ. Nitrous Oxide Impairs Axon Regeneration after Nervous System Injury in Male Rats. 2019 Nov;131(5):1063-1076. doi: 10.1097/ALN.0000000000002906.PMID: 31490294.
5. Patel NJ, Hogan KJ, Rizk E, Stewart K, Madrid A, Vadakkadath Meethal S, Alisch R, Borth L, Papale LA, Ondoma S, Gorges LR, Weber K, Lake W, Bauer A, Hariharan N, Kuehn T, Cook T, Keles S, Newton MA, Iskandar BJ. Ancestral Folate Promotes Neuronal Regeneration in Serial Generations of Progeny. Mol Neurobiol. 2020 Apr;57(4):2048-2071. doi: 10.1007/s12035-019-01812-5. Epub 2020 Jan 10. PubMed PMID: 31919777; PubMed Central PMCID: PMC7125003.
6. Madrid A, Borth LE, Hogan KJ, Hariharan N, Papale LA, Alisch RS, Iskandar BJ. DNA methylation and hydroxymethylation have distinct genome-wide profiles related to axonal regeneration. 2020 Jul 7:1-15. doi: 10.1080/15592294.2020.1786320. Online ahead of print. PMID: 32633672.
7. Rizk E, Madrid A, Koueik J, Sun D, Stewart K, Chen D, Luo S, Hong F, Papale LA, Hariharan N, Alisch RS, Iskandar BJ. Purified regenerating retinal neurons reveal regulatory role of DNA methylation-mediated Na+/K+-ATPase in murine axon regeneration. Commun Biol. 2023 Jan 30;6(1):120. doi: 10.1038/s42003-023-04463-4. PMID: 36717618; PMCID: PMC9886953.
8. Madrid A, Alisch RS, Rizk E, Papale LA, Hogan KJ, Iskandar BJ. Transgenerational epigenetic inheritance of axonal regeneration after spinal cord injury. Environ Epigenet. 2023 Jan 17;9(1):dvad002. doi: 10.1093/eep/dvad002. PMID: 36843857; PMCID: PMC9949995.
9. Madrid A, Koueik J, Papale LA, Chebel R, Renteria I, Cannon E, Hogan KJ, Alisch RS, Iskandar BJ. Folate-mediated transgenerational inheritance of sperm DNA methylation patterns correlate with spinal axon regeneration. Epigenetics. 2024 Dec;19(1):2380930. doi:10.1080/15592294.2024.2380930. Epub 2024 Jul 27. PMID: 39066680; PMCID: PMC11285217.

Clinical Research in Chiari I Malformation and Syringomyelia

In close collaboration with the UW Departments of Radiology and Medical Physics we’ve developed/adapted novel MRI-based techniques to study the pathophysiological processes underlying the Chiari/Syringomyelia disorder, and potentially help us understand foramen magnum physiology more thoroughly. This allowed us to develop a focused clinical research program for a systematic analysis of CSF pathophysiology under specific clinical conditions. For that purpose, we developed software to display the velocity of each voxel at each time point in the cardiac cycle using MRI data from normal subjects and patients with the disorder. Our work indicated that the “cine MRI” flow studies used commonly are not sufficiently sensitive. Instead, a thorough analysis of CSF flow in each voxel of the foramen magnum is desirable and feasible.

Select Chiari I References

1. Iskandar BJ, Quigley M, Haughton V: Effect of posterior fossa decompression on CSF flow pattern in the foramen magnum of children with Chiari I malformations. J Neurosurgery-Pediatrics 101:169-178,2004 (Journal Cover Illustration).
2. Haughton V, Korosek F, Medow J, Dolar M, Iskandar BJ: Peak systolic and diastolic CSF velocity in the foramen magnum in adult Chiari I patients and normal subjects AJNR 24:168-176, 2003 (Journal Cover Illustration).
3. Hofkes S, Iskandar BJ, Turski PA, Gentry L, McCue J, Haughton VM. Differentiation of symptomatic Chiari I malformation from asymptomatic tonsilar ectopia by CSF flow imaging–an initial estimate of the accuracy of imaging. Radiology 245(2):532-40, 2007.
4. Markunas CA, Tubbs RS, Moftakhar R, Ashley-Koch AA, Gregory SG, Oakes WJ, Speer MC, and Iskandar BJ. Clinical, radiologic, and genetic similarities between patients with Chiari 1 and 0 Malformations. J Neurosurg:Peds 9(4):372-8, 2012.
5. Koueik J, Sandoval-Garcia C, Kestle JRW, Rocque BG, Frim DM, Grant GA, Keating RF, Muh CR, Oakes WJ, Pollack IF, Selden NR, Tubbs RS, Tuite GF, Warf B, Rajamanickam V, Broman AT, Haughton V, Rebsamen S, George TM, Iskandar BJ. Outcomes in children undergoing posterior fossa decompression and duraplasty with and without tonsillar reduction for Chiari malformation type I and syringomyelia: a pilot prospective multicenter cohort study. J Neurosurg Pediatr. 2019 Oct 18:1-9. doi: 10.3171/2019.8.PEDS19154. Online ahead of print. PMID: 31628281

Clinical Research in Hydrocephalus

The mainstay treatment for children with hydrocephalus is the insertion of a CSF shunt, which carries the pressurized cerebrospinal fluid from the brain ventricles to other body cavities. Children with shunted hydrocephalus require brain imaging at regular intervals as well as under urgent conditions. With standard imaging methods, these children are exposed to unacceptable doses of radiation, which increase the life-long risk of cancer significantly. In an effort to resolve this issue, in collaboration with the UW Department of Radiology, we have adapted a rapid MRI technique that removes the risk of CT radiation in hydrocephalic children without extending the length of the procedure or subjecting them to sedation. The “Quick-Brain” MRI is now widely used throughout North America and adapted by us and others for spinal problems and other cranial applications. As well, we have shown that the high rate of death in hydrocephalic children who have cerebrospinal fluid shunts can, in large part, be prevented; that ventricular dilatation on brain imaging is not essential in determining shunt malfunction, and that overdrainage is a significant cause of shunt obstruction. In our current work, we study the relationship between shunt obstruction and the problems of overdrainage and compliance, as well as the importance of antisiphon device and smart valve technologies in improving shunt obstruction rates.

Select Hydrocephalus References

1. Iskandar BJ, McLaughlin C, Mapstone TB, Grabb PA, Oakes WJ: Pitfalls in the diagnosis of ventricular shunt dysfunction: Radiology reports and ventricular size. Pediatrics 101(6): 1031-1036, 1998.
2. Iskandar BJ, Tubbs S, Mapstone T, Grabb PA, Bartolucci AA, Oakes WJ: Shunt Deaths in the 1990s. Pediatric Neurosurgery 28:173-176, 1998.
3. Acakpo-Satchivi L, Shannon CN, Tubbs RS, Wellons JC 3rd, Blount JP, Iskandar BJ, Oakes WJ. Death in shunted hydrocephalic children: a follow-up study. Childs Nerv Syst. 2008 Feb;24(2):197-201.
4. Kraemer MR, Sandoval-Garcia C, Bragg T, Iskandar BJ: Shunt-dependent hydrocephalus: management style among members of the American Society of Pediatric Neurosurgeons. J Neurosurg Pediatr 20:216-224, 2017. See accompanying editorial J Neurosurg Pediatr 20:213–215, 2017.
5. Wang F, Zhang X, Shokoueinejad M, Iskandar BJ, Medow JE, Webster JG: A Novel Intracranial Pressure Readout Circuit for Passive Wireless LC Sensor. IEEE Trans Biomed Circuits Syst 11:1123-1132, 2017.
6. Kraemer M, Koueik J, Rebsamen S, Hsu D, Salamat S, Luo S, Saleh S, Bragg, T, and Iskandar BJ. Overdrainage-related ependymal bands: A postulated cause of proximal shunt obstruction. J Neurosurg Pediatr. 17:1-11, 2018. doi: 10.3171/2018.5.PEDS18111.
7. Webster JG, Iskandar B, Medow J, Luzzio C, Zhang X, Guan C, Yang Z. Intracranial Pressure Sensor and Valve to Control Hydrocephalus. Conf Proc IEEE Eng Med Biol Soc. 2018 Jul;2018:1-7. Doi: 10.1109/EMBC.2018.8512916. PubMed PMID: 30440275.
8. Koueik J, Kraemer MR, Hsu D, Rizk E, Zea R, Haldeman C, Iskandar BJ. A 12-year single-center retrospective analysis of antisiphon devices to prevent proximal ventricular shunt obstruction for hydrocephalus. J Neurosurg Pediatr. 2019 Sep 6:1-10. doi: 10.3171/2019.6.PEDS1951. PubMed PMID: 31491755.
9. Koueik J, Iskandar BJ, Yang Z, Kraemer MR, Armstrong S, Wakim V, Broman AT, Medow J, Luzzio C, Hsu DA. Ventriculoperitoneal Shunt Drainage Increases With Gravity and Cerebrospinal Fluid Pressure Pulsations: Benchtop Model. Neurosurgery. 2021 Nov 18;89(6):1141-1147. doi: 10.1093/neuros/nyab336. PMID: 34528096; PMCID: PMC8600163.