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Biomarkers in Patients with Idiopathic Normal Pressure Hydrocephalus

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Biomarkers in Patients with Idiopathic Normal Pressure Hydrocephalus Biomarkers in patients with idiopathic normal pressure hydrocephalus Dr Andrew Tarnaris Ptychion Iatrikes, M.R.C.S (Ed) Victor Horsley Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery, and Department of Neuroinflammation, Institute of Neurology, Queen Square, University College London, London, WC1N 3BG. Supervisors: Mr. Laurence Watkins Mr. Neil Kitchen Thesis submitted for the degree of Doctor of Medicine (MD Res) at the University of London 1 Declaration I hereby declare that the work presented in this thesis is my own. Andrew Tarnaris 2 Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a condition affecting a small percentage of the elderly population; however it is the only known treatable cause of dementia. Surgical cerebrospinal fluid (CSF) diversion is the only known treatment for the condition today. However, such a procedure is not to be offered lightly and any expected benefit has to balance the associated surgical risks. The prognosis of a favourable surgical outcome has been problematic since the conception of the syndrome. None of current prognostic tests reaches 100% sensitivity or specificity and it is felt that there might be a need for a combination of tests, rather than a single one to maximize the chances of selecting the right patients to offer a surgical CSF diversion procedure. Biomarkers are biological substances that may act as surrogate markers of response to a treatment or to characterise a disease’s progression over time. The aim of this study was to identify CSF markers of favourable surgical outcome in patients with iNPH undergoing the insertion of a ventriculoperitoneal shunt (VPS). We first describe the effects of external lumbar drainage (ELD) on the CSF biochemistry of these patients. Correlations are made with imaging data obtained from volumetric analysis and neuropsychological tests in order to obtain a complete profile of these patients. The rostrocaudal gradients of the CSF markers examined are reported showcasing the need to understand that commonly reported values from lumbar CSF do not necessarily reflect pathological changes occurring at cerebral level. Finally, we report on the individual as well as combined prognostic value of 7 CSF markers on 3 surgical outcomes at 6 months. The pathophysiological significance of these markers is discussed individually. It is concluded that the combined power of total tau and Aβ 1-42 may be useful in predicting favourable surgical outcomes at 6 months; further studies applying the findings in a larger cohort and correlating findings with longer outcomes are warranted to enhance the clinical application. The biochemical profile of patients with iNPH appears unique and different than patients with Alzheimer’s dementia or control subjects. 4 Acknowledgements I would like to thank primarily Mr Neil D. Kitchen for giving me the opportunity to work in the Victor Horsley Department of Neurosurgery and considering me for my position as a Research Fellow. Equally, I would like to thank Mr Laurence D. Watkins for accepting me as his student, acting as my primary supervisor, and being supportive through a long period not just with regards to the thesis, but also acting as a mentor in my professional career. The guidance, mentorship and understanding of both my supervisors have been most invaluable, and the skills (both surgical and research) I learnt during my position will help me in the years to come. Thirdly, I would like to thank Mr Ahmed Toma, my successor to the department who assisted tremendously in every possible way, but has also become a friend along the way. He has helped in making the process to submission tolerable. I wish him good luck with his own important research on NPH. This work would not have been possible without the tremendous assistance of Dr. Miles Chapman for assisting with the experiments, and Dr. Andrew Church for ensuring the samples were collected appropriately. The hours I spent pipetting were fun, even though I made many times a mess of the lab bench! Equally, Dr. Geoff Keir and Dr. Axel Petzold provided a great insight into experimental design, as well as assistance in understanding all the weird staff about CSF biochemistry. Dr. Louis Lemieux has been invaluable in providing his machines and software for the volumetric analysis performed. The staff at the department of Neuropsychology and in particular Emily Pullen and Lisa Cipolotti, were extremely helpful for carrying out all the required tests mostly in very short notice. I would like to thank Janet Bousquet, Bina Shah, Ida White, and Corinne Docher for all their administrative help while in the department. Also, many thanks to Ms. Joan Grieve and Mr. Michael Powell for assisting in patient recruitment. Finally, I would like to acknowledge Dr Kostas Kallis on statistical advice, and the nursing staff in the 5 Victor Horsley department of Neurosurgery for being patient with all our lumbar drains! This work was made possible with the kind fellowship of B Braun/ Aesculap Academia who I wholeheartedly thank for supporting research. I will not forget the patients and their families who placed their trust in the team hoping for an improvement in their quality of life; hopefully our interventions have fulfilled their expectations in most cases and we have helped a little in making their lives better. This work was done with a sincere hope that any findings will add a small stone to the pyramid of knowledge. We should all be Architects ! Lastly, a big thank you to Angharad for all the insight, help and support throughout all these difficult years. This work is dedicated to my father Vasileios Tarnaris (1940-2012) who passed away suddenly awaiting the award of the degree. Thank you for believing in me. Ζ ϶϶ Α 6 Financial disclosure My salary supporting my research has been provided by a grant from B Braun/ Aesculap. 7 Publications arising from this work Tarnaris, A., L. D. Watkins, et al. (2006). "Biomarkers in chronic adult hydrocephalus." UCerebrospinal Fluid ResU 3(1): 11. Tarnaris, A., R. F. Stephenson, et al. (2007). "Diagnosis, Treatment, and Analysis of Long-term Outcomes in Idiopathic Normal-Pressure Hydrocephalus." UNeurosurgeryU 60(1): E208. Tarnaris, A., N. D. Kitchen, et al. (2008). "Noninvasive biomarkers in normal pressure hydrocephalus: evidence for the role of neuroimaging." UJournal of NeurosurgeryU: 1-15. Tarnaris, A., A. K. Toma, et al. (2009). "The longitudinal profile of CSF markers during external lumbar drainage." UJournal of Neurology, Neurosurgery & PsychiatryU 80(10): 1130-1133. Tarnaris, A., A. K. Toma, et al. (2009). "Ongoing search for diagnostic biomarkers in idiopathic normal pressure hydrocephalus." UBiomarkersU 3(6): 787- 805. Papers submitted for publication Cerebrospinal fluid amyloid-beta and total tau may be able to predict favourable surgical outcomes in patients with idiopathic normal pressure hydrocephalus Rostrocaudal dynamics of cerebrospinal fluid markers in idiopathic normal pressure hydrocephalus Cognitive and biochemical profile of patients suffering from idiopathic normal pressure hydrocephalus 8 Conference Presentations 1. Rostrocaudal dynamics of cerebrospinal fluid markers in idiopathic normal pressure hydrocephalus. UA. TarnarisU, A. Toma, MD Chapman, A. Petzold, ND Kitchen, G. Keir, LD Watkins. Oral presentation. Hydrocephalus 2009, Baltimore, USA- September 2009. 2. Prognostic biomarkers in idiopathic normal pressure hydrocephalus, UA. TarnarisU, A. Toma, MD Chapman, A. Petzold, ND Kitchen, G. Keir, LD Watkins. Oral presentation. Hydrocephalus 2009, Baltimore, USA- September 2009. 3. Prevalence of ventriculomegaly in “falls” clinics. Initial results. A. Toma, UA. Tarnaris, US. Das, B. Glickstein, M. Cohen, R. Gray, C. Pulford, L. Watkins. Oral presentation. Hydrocephalus 2009, Baltimore, USA- September 2009. 4. Outcome assessment in normal pressure hydrocephalus: what is the most important? Patient and carers perspective. A. Toma, UA. Tarnaris, U ND Kitchen, LD Watkins. Oral presentation. Hydrocephalus 2009, Baltimore, USA- September 2009. 5. Investigating shunt function using Continuous Intracranial Pressure Monitoring in adults: single centre experience. Ahmed Toma, UAndrew TarnarisU, Neil Kitchen, Laurence Watkins. Poster presentation Society of British Neurological Surgeons, Birmingham, UK- April 2009. Poster presentation WFNS- Boston, USA- September 2009. 6. Cognitive and biochemical profile of patients suffering from idiopathic normal pressure hydrocephalus. UA. TarnarisU, A. Toma, E. Pullen, MD Chapman, A. Petzold, ND Kitchen, L. Cipolotti, L. Lemieux, G. Keir, LD Watkins Oral Presentation Hydrocephalus 2008, Hannover, Germany- September 2008. 7. Adjustable shunt valve induced MRI artefact: A comparative study. Toma A, UTarnaris A,U Grieve J, Watkins L, Kitchen ND. Oral Presentation Hydrocephalus 2008, Hannover, Germany- September 2008. Poster Presentation Society of British Neurological Surgeons, Notthingham, UK- September 2008. 8. Temporal changes of CSF markers during external lumbar drainage in patients with idiopathic normal pressure hydrocephalus UA. TarnarisU, A. Toma, MD Chapman, A. Petzold, ND Kitchen, G. Keir, LD Watkins Oral Presentation Hydrocephalus 2008, Hannover, Germany- September 2008. 9. Induction of angiogenesis in idiopathic normal pressure hydrocephalus. th A. UTarnarisU, M. Chapman, N. Kitchen, G. Keir, L. Watkins. Oral Presentation 4 International Workshop in Hydrocephalus, Rhodes, Greece- May 2007. 9 Contents Chapter 1 Introduction page 25
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