Loma Linda University

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Wolff Kirsch, MD
Professor, Neurosurgery
School of Medicine
Professor, Basic Sciences
School of Medicine
Member, Biochemistry, SM, Faculty of Graduate Studies
Publications    Scholarly Journals--Published
  • Zabel M, Schrag M, Crofton A, Tung S, Beaufond P, Van Ornam J, DiNinni A, Vinters HV, Coppola G, Kirsch WM. A shift in microglial beta-amyloid binding in Alzheimer''''s disease is associated with cerebral amyloid angiopathy.  Brain Pathology, 23(4)/390-401/2013 Jul. Code 1. PMID 23134465. ( 7/2013 - 6/2014 )
  • Zabel M, Schrag M, Mueller C, Zhou W, Crofton A, Dickson A, Kirsch WM. Assessing candidate serum biomarkers for Alzheimer''''s disease. J Alz Dis. 30(1)/311-321/2012. Code 1.  PMID 22426016. ( 4/2012 - 4/2014 )
  • Zabel MK, Kirsch WM. From development to dysfunction: Microglia and the complement cascade in CNS hemostasis. Ageing Research Reviews, 12(3)/749-756/2013. https://dx.doi.org/10.1016/j.arr.2013.02.00 [Epub date 2/202/2013]. Code 1. PMID 23419464. ( 3/2013 - 3/2014 )
  • Raiszadeh MM, Ross MM, Russo PS, Schaepper MA, Zhou W, Deng J, Ng D, Dickson A, Dickson C, Strom M, Osorio C, Soeprono T, Wulfkuhle JD, Petricoin EF, Liotta LA, Kirsch WM. Proteomic analysis of eccrine sweat: Implications for the discovery of schizophrenia biomarker proteins. J Proteome Res, 11/2127-2139/2012. Code 1. PMID 22256890. ( 3/2012 - 12/2013 )
  • Filippov V, Song MA, Zhang K, Vinters HV, Tung S, Kirsch WM, Yang J, Duerksen-Hughes PJ. Increased ceramide in brains with Alzheimers and other neurodegenerative diseases. J Alz Dis, 29/537-547/2012. PMID 22258513. ( 1/2012 - 12/2013 )
  • Zhang K, Schrag M, Vinters H, Kirsch W. Targeted proteomics for quantification of histone acetylation in Alzheimer''''s disease. Proteomics. Jan 2012;12:1261-68. PMID 22577027. ( 1/2012 - 12/2012 )
  • Mueller C, Schrag M, Crofton A, Stolte J, Muckenthaler M, Magaki S, Kirsch WM. Altered serum iron and copper homeostasis predicts cognitive decline in mild cognitive impairment. J Alz Dis, 2012 Jan;29(2):341-350. PMID 22232013.  ( 1/2012 - 12/2012 )
  • McAuley G, Schrag M, Barnes S, Obenaus A, Dickson A, Kirsch W. In vivo iron quantification in collagenase-induced microbleeds in rat brain, Magnetic Resonance in Medicine, 67(3)/711-717/Mar 2012. PMID 21721041. ( 1/2012 - 12/2012 )
  • McAuley G, Schrag M, Barnes S, Obenaus A, Dickson A, Holshouser B, Kirsch W.  Iron quantification of microbleeds in post-mortem brain.  Magnetic Resonance in Medicine, 65(6)/1592-1601/2011 June. Code 1.  PMID 21590801 ( 6/2011 - 7/2012 )
  • Britt III WB, Hansen AM, Bhaskerrao S, Larsen JP, Petersen F, Dickson A, Dickson, C, Kirsch WM. Mild Cognitive Impairment: Prodromal Alzheimers or Something Else?  J Alz Dis, 27/543-551/2011. PMID 21841247. ( 9/2011 - 6/2012 )
  • Schrag M, Mueller C, Oyoyo U, Kirsch W.  Iron, zinc and copper in the Alzheimers disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Progress in Neurobiology, 94/296-306/2011. Code 1. PMID 21600264 ( 7/2011 - 6/2012 )
  • Barnes SR, Haacke EM, Ayaz M, Boikov AS, Kirsch W, Kido D.  Semi-automated detection of cerebral microbleeds in magnetic resonance images.  2011, Magn Reson Imaging, 29(6)/844-852/Jul 2011. PMIC 21571479. ( 7/2011 - 6/2012 )
  • Schrag M, Dickson A, Jiffry A, Kirsch D, Vinters HVV, Kirsch W.  The effect of formalin fixation on the levels of brain transition metals in archived samples.  Biometals, 23(6)/1123-1127/Dec 2010. PMID:  20582563. ( 6/2010 - 6/2011 )
  • Darwanto A, Curtis M, Schrag M, Kirsch W, Xu G, Neidigh JW, Zhang K.  A modified "cross talk" between histone H2B K123 ubiquitination and H3 K79 methylation.  J Biol Chem, 285(28)/1868-76/2010. 1.  PMID: 20442396. ( 6/2010 - 6/2011 )
  • Ayaz M, Boikov AS, Haacke EM, Kido DK, Kirsch WM, Imaging Cerebral Microbleeds Using Susceptibility Weighted Imaging:  One Step Toward Detecting Vascular Dementia, J Magn Reson Imaging, 31(1)/142-148/2010, 1.  PMID:  20027582. ( 1/2010 - 6/2011 )
  • McAuley G, Schrag M, Sipos P, Sun S-W, Obenaus A, Neelavalli J, Haacke EM, Holshouser B, Madacsi R, Kirsch W.  Quantification of punctate iron sources using magnetic resonance phase.  Magnetic Resonance in Medicine, 63(1)/106-115/2010, 1.  PMID: 19433895. ( 12/2009 - 6/2011 ) Link...
  • Mueller C, Zhou W, VanMeter A, Heiby M, Magaki S, Ross MM, Espina V, Schrag M, Dickson C, Liotta L, Kirsch WM.  The heme degradation pathway as a promising serum biomarker source for the early detection of Alzheimers disease.  J Alz Dis, 19(3)/1081-1091/2010. 1.  PMID: 20157261. ( 12/2009 - 6/2011 )
  • Schrag M, McAuley G, Pomakian J, Jiffry A, Tung S, Mueller C, Vinters HV, Haacke EM, Holshouser B, Kido D, Kirsch WM.  Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy:  a postmortem MRI study.  Acta Neuropathol, 119/291-302/2010. 1.  PMID: 19937043. ( 12/2009 - 6/2011 ) Link...
  • Schrag M, Crofton A, Zabel M, Jiffry A, Kirsch  D, Dickson A, Mao XW, Vinters HV, Domaille DW, Chang CJ, Kirsch W.  Effect of cerebral amyloid angiopathy on brain iron, copper, and zinc in Alzheimers disease.  J Alz Dis, 24(1)/137-149/2011. Code 1.  PMID 21187585. ( 8/2010 - 3/2011 )
  • Mueller C, Magaki S, Schrag M, Ghosh MC, Kirsch WM.  Iron regulatory protein 2 is involved in brain copper homeostasis.  J of Alz Dis, 18/201-208/2009.  1. PMID 19584448. ( 6/2009 - 6/2010 )
    Trace metal homeostasis is tightly controlled in the brain, as even a slight dysregulation may severely impact normal brain function. This is especially apparent in Alzheimers disease, where brain homeostasis of trace metals such as copper and iron is dysregulated. As it is known that iron and copper metabolism are linked, we wanted to investigate if a common mechanism could explain the increase in iron and decrease in copper seen in Alzheimers disease brain. Amyloid-beta protein precursor (AbetaPP) has been implicated in copper efflux from the brain. Furthermore, it was shown that iron regulatory proteins (IRP), which regulate iron homeostasis, can block AbetaPP mRNA translation. In a correlative study we have therefore compared brain regional copper levels and AbetaPP expression in mice with a targeted deletion of IRP2-/-. Compared with controls, six week old IRP2-/- mice had significantly less brain copper in the parietal cortex, hippocampus, ventral striatum, thalamus, hypothalamus, and whole brain, while AbetaPP was significantly upregulated in the hippocampus (p < 0.05) and showed a trend toward upregulation in the thalamus (p < 0.1). This is the first study to demonstrate that iron regulatory proteins affect brain copper levels, which has significant implications for neurodegenerative diseases.
  • Manova ES, Habib CA, Boikov AS, Ayaz M, Khan A, Kirsch WM, Kido DK, Haacke EM.  Characterizing the mesencephalon using susceptibility weighted imaging.  Am J Neuroradiol, 30/569-574/2009, and 1. ( 3/2009 - 6/2010 ) Link...
  • Kirsch WM, McAuley G, Petersen F, Chen LH, Kim I, Baqai W, Schrag M, Haacke EM, Ayaz M, Khan A, Britt III W, Larsen J, Peterson S, Dickson C, Oyoyo U, Holshouser B, Mueller C, Vinters HA, Kido D. Serial Susceptibility Weighted MRI measures brain iron and microbleeds in dementia.  J Alz Dis, 17/599-609/2009.  1. ( 1/2009 - 6/2010 )
  • Bartnik Olson B, Holshouser BA, Britt W, Mueller C, Baqai W, Patra S., Petersen F, Kirsch WM. "Longitudinal metabolic and cognitive changes in mild cognitive impairment patients." Alzheimer Disease & Associated Disorders - an International Journal. 2008;22(3):269-277. ( 9/2008 ) Link...
  • Magaki S, Yellon SM, Mueller C, Kirsch WM. "Immunophenotypes in the circulation of patients with mild cognitive impairment." J Psychiatric Res 42.3 (2008): 240-246. ( 1/2008 ) Link...
  • Magaki S, Mueller C, Yellon SM, Fox J, Kim J, Snissarenko E, Chin V, Ghosh MC, Kirsch WM. "Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain." Brain Research 1158. (2007): 144-150.  1. ( 7/2007 ) Link...
    Iron is a trace metal essential for normal brain development but toxic in excess as it is capable of generating highly reactive radicals that damage cells and tissue. Iron is stringently regulated by the iron regulatory proteins, IRP1 and IRP2, which regulate proteins involved in iron homeostasis at the posttranscriptional level. In this study, 12 distinct regions were microdissected from the mouse brain and regional changes in the levels of loosely bound and non-heme iron that occur with development were measured. We examined 6, 12, and 24 week old wildtype C57BL/6 mice and mice with a targeted deletion of iron regulatory protein 2 (IRP2-/-) that have been reported to develop neurodegenerative symptoms in adulthood. In wildtype mice, levels of loosely bound iron decreased while non-heme iron increased with development. In contrast, an increase in loosely bound and a more pronounced increase in non-heme iron was seen in IRP2-/- mice between 6 and 12 weeks of age, stemming from lower levels at 6 weeks (the youngest age examined) compared to wildtype. These results have implications for understanding the increase in regional brain iron that is associated with normal aging and is postulated to be exacerbated in neurodegenerative disorders.
  • Magaki S, Mueller C, Dickson C, Kirsch W. "Increased production of inflammatory cytokines in mild cognitive impairment." Experimental Gerontology 42.3 (2007): 233-240. ( 3/2007 ) Link...
    Recent studies indicate that chronic inflammation plays a pathogenic role in both the central nervous system (CNS) and periphery in Alzheimer's disease (AD). We have screened for cytokines differentially produced by peripheral blood mononuclear cells (PBMCs) isolated from subjects with mild cognitive impairment (MCI) and mild AD subjects who had progressed from MCI using a commercially available cytokine array. Following determination of expressed cytokines, we quantified levels of the proinflammatory cytokines TNF-alpha, IL-6, and IL-8, and the anti-inflammatory cytokine IL-10 using flow cytometry. We have found a significant increase in the levels of IL-6, IL-8, and IL-10 produced by PBMCs stimulated for 24 h with phytohemagglutinin (PHA) in MCI subjects compared to healthy elderly controls. However, in PBMCs stimulated for 48 h with lipopolysaccharide (LPS), lower TNF-alpha/IL-10, IL-6/IL-10, and IL-8/IL-10 ratios were seen in MCI subjects. There were no differences in plasma levels of IL-8 between aged controls, MCI, and mild AD, and the levels of circulating IL-6 and IL-10 were below detection limits. Our data indicate that changes in cytokine production by PBMCs may be detected early in MCI, and an alteration of the immune response may precede clinical AD.
  • Larsen JP, Britt W, Kido D, Bartnik Olson BL, Holshouser BA, Kirsch WM. "Susceptibility Weighted Imaging in the Evaluation of Dementia." Radiology Case Reports 2.4 (2007): 1-4. ( 1/2007 ) Link...
  • Haacke EM, Ayaz M, Khan A, Manova ES, Krishnamurthy B, Gollapailli L, Ciulla C, Kim I, Petersen F, Kirsch W. "Establishing a baseline phase behavior in magnetic resonance imaging for determining normal versus abnormal iron content in the brain." J Magnetic Resonance Imaging 26.2 (2007): 256-264. ( 1/2007 ) Link...
    PURPOSE: To establish a baseline of phase differences between tissues in a number of regions of the human brain as a means of detecting iron abnormalities using magnetic resonance imaging (MRI). MATERIALS AND METHODS: A fully flow-compensated, three-dimensional (3D), high-resolution, gradient-echo (GRE) susceptibility-weighted imaging (SWI) sequence was used to collect magnitude and phase data at 1.5T. The phase images were high-pass-filtered and processed region by region with hand-drawn areas. The regions evaluated included the motor cortex (MC), putamen (PUT), globus pallidus (GP), caudate nucleus (CN), substantia nigra (SN), and red nucleus (RN). A total of 75 subjects, ranging in age from 55 to 89 years, were analyzed. RESULTS: The phase was found to have a Gaussian-like distribution with a standard deviation (SD) of 0.046 radians on a pixel-by-pixel basis. Most regions of interest (ROIs) contained at least 100 pixels, giving a standard error of the mean (SEM) of 0.0046 radians or less. In the MC, phase differences were found to be roughly 0.273 radians between CSF and gray matter (GM), and 0.083 radians between CSF and white matter (WM). The difference between CSF and the GP was 0.201 radians, and between CSF and the CN (head) it was 0.213 radians. For CSF and the PUT (the lower outer part) the difference was 0.449 radians, and between CSF and the RN (third slice vascularized region) it was 0.353 radians. Finally, the phase difference between CSF and SN was 0.345 radians. CONCLUSION: The Gaussian-like distributions in phase make it possible to predict deviations from normal phase behavior for tissues in the brain. Using phase as an iron marker may be useful for studying absorption of iron in diseases such as Parkinson's, Huntington's, neurodegeneration with brain iron accumulation (NBIA), Alzheimer's, and multiple sclerosis (MS), and other iron-related diseases. The phases quoted here will serve as a baseline for future studies that look for changes in iron content. J. Magn. Reson. Imaging 2007;26:256-264. (c) 2007 Wiley-Liss, Inc.
  • Kirsch W. "Book Review of Bioimaging in Neurodegeneration by Patricia A. Broderick, David N. Rahni, and Edwin H. Kolodny." J Neurosurg 104. (2006): 460-461. ( 3/2006 )
  • Zeebregts CJ, Kirsch WM, Reijnen MMPJ, Zhu Y, van den Dungen JJAM. "Expanding use of non-penetrating clips in various surgical specialties." Surgical Technology International XIV. (2006): 85-95. ( 1/2006 )
  • Miller A, Kirsch WM. "The role of vascular clips in vascular access surgery." Endovascular Today . (2005): 2-6. ( 6/2005 )
  • Whang HS, Zhu YH, Kirsch WM, Yang C-Z, Hudson SM. "Hemostatic agents derived from chitian and chitosan." Journal of Macromolecular Science 45. (2005): 309-323. ( 1/2005 )
  • Haacke EM, Cheng NYC, House MJ, Liu Q, Neelavalli J, Ogg R, Khan A, Ayaz M, Kirsch W, Obenaus A.. "Imaging Iron Stores in the Brain using Magnetic Resonance Imaging." Magnetic Resonance Imaging 23.1 (2005): 1-25. ( 1/2005 )
  • Zeebregts CJ, Kirsch WM, van den Dungen JJ, van Schilfgaarde R, Zhu YH.. "Evolution of staples and clips for vascular anastomosis.." International Surgery 89. (2004): 152-160. ( 1/2004 )
  Scholarly Journals--Accepted
  • Hansen AM, Jeske D, Kirsch W. A chi-square goodness-of-fit test for autregressive logistic regression models with applications to patient screening. J Biopharmaceutical Statistics, accepted July 2013. ( 7/2013 - 6/2014 )
  • Prasanthia JRP, Schrag M, Dasaria B, Marwarha G, Dickson A, Kirsch W, Ghribi O. Deferiprone reduces amyloid-beta and tau phosphorylation levels but not reactive oxygen species generation in hippocampus of rabbits fed a cholesterol-enriched diet. J Alz Dis. 2012;30(1):167-182. PMID 22406440. ( 2/2012 - 6/2014 )
  Books and Chapters
  • Kirsch W. Chapter 13. Microvascular reconstructions with non-penetrating clips: Practical considerations. In: Experimental microsurgery. Practical manual. Eds. M Ionac, WC Lineaweaver and Zhang F. City: Timisoara Romania. Publishers: Orizonturi Universitare. 2012. Pages 5-13. ( 4/2012 - 4/2013 )
  • Ayaz M, Boikov A, McAuley G, Schrag G, Kido DK, Haacke EM, Kirsch W.  Chapter 12.  Imaging cerebral microbleeds with SWI.  In:  Susceptibility Weighted Imaging in MRI:  Basic Concepts and Clinical Applications.  Eds EM Haacke and JR Reichenbach.  Wiley-Blackwell Publisher, 2011. Pages 185-209.  ( 7/2011 - 6/2012 )
  • Wolff M. Kirsch and Lloyd Dayes. Complications of Neurosurgery. United Kingdom: World Scientific Publishing, 2006. Chap 20; 663 - 687 ( 1/2006 )