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Cerebrospinal fluid biomarkers: Exploiting advances in humans to improve veterinary care
The Veterinary Journal 197 (2013) 113–114
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Editorial
Cerebrospinal fluid biomarkers: Exploiting advances in humans to improve veterinary care In the last few decades, significant progress has been made to identify and apply biomarkers to support a clinical diagnosis of Alzheimer’s disease (AD) in humans. AD is a devastating neurodegenerative disorder associated with profound cognitive decline and dementia (i.e. dementia of the Alzheimer’s type or DAT). It is difficult to accurately diagnose clinically using only assessment of cognitive abilities (Genius et al., 2012). In addition, ability to predict the disease or its progression is limited. For these reasons, current treatments are essentially geared toward symptomatic improvements with little impact on disease progression. Furthermore, the low performance of the past and current diagnostic and prognostic tools for AD has frustrated drug developers in their quest to develop preventative or disease modifying therapeutic alternatives. The scientific community is well aware of the current dramatic situation. AD is slowly but steadily becoming more prevalent with epidemic proportions. In 2005, it was estimated that 24.3 million people had dementia worldwide (most cases of dementia are DAT), with 4.6 million new cases every year (Ferri et al., 2005). Even more concerning is the fact that the number of people affected is likely to double every 20 years and reach 81.1 million by 2040 (Ferri et al., 2005). Mostly because of better health care and longer lifespans, the increase will be even more visible in developed countries. With such numbers in mind, it is easy to understand the potential medical and socio-economic challenges that our societies will face in the future unless something is done. What are clearly and urgently needed are novel tools to improve the diagnosis and prediction of AD, but also to better assess disease progression. To address this enormous gap, researchers have increased their efforts to identify biomarkers associated with the development and progression of AD, thanks principally to funding by various national and international agencies. Several fluid and imaging biomarkers have or are being validated through large collaborative efforts (Genius et al., 2012). Cerebrospinal fluid (CSF) biomarkers have become particularly attractive and successful because of the intimate contact between the CSF and neurons, the presumed target cells of AD (Fagan and Perrin, 2012). In particular, three CSF proteins are now well-established biomarkers of AD, namely, (1) b-amyloid 42 peptide (Ab42) with lower CSF levels in AD; (2) total tau protein, and (3) phosphorylated tau181, both with higher CSF levels in AD. This vast quantity of research, frequently initiated in the form of consortia or initiatives, has led to findings with implications beyond AD and also with potential applications to veterinary medicine. The article by Dr. Andrea Roerig of the University of Veterinary Medicine in Hannover and her colleagues, published in this issue of The Veterinary Journal, illustrates how some of the knowledge generated in humans can translate back to veterinary
1090-0233/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2013.04.026
medicine and provide opportunities to improve veterinary care (Roerig et al., 2013). In their article, Roerig et al. (2013) evaluated whether CSF levels of total tau protein could be useful in objectively assessing the severity of spinal cord damage and to see if it could represent a prognostic indicator in dogs with intravertebral disk herniation (IVDH). While CSF sampling seems to be a rather invasive approach in veterinary practice, the severity of the disorder (i.e., clinical signs, progression, etc.), the lack of tools to predict progression, and the frequency of this syndrome in the overall canine population all warrant exploration of CSF biomarkers. The selection of tau as a marker is quite logical, since tau is considered a non-specific indicator of axonal and neuronal damage and CSF levels of total tau have been positively correlated with the amount of tissue damage and poor clinical outcomes in acute brain disorders, such as acute ischemic stroke (Hesse et al., 2000). To evaluate the potential utility of CSF tau levels, Roerig et al. (2013) conducted a retrospective study with 51 dogs with thoracolumbar or cervical IVDH and 12 clinically normal dogs. Cisternal CSF tau values were determined using a commercially available enzyme-linked immunosorbent assay (ELISA). Not unexpectedly, CSF tau concentrations were statistically significantly higher in dogs showing plegia compared to healthy dogs and dogs with paresis. But probably more interesting was the finding that plegic dogs with improvement by one neurological grade within 1 week had significantly lower tau protein levels compared to plegic dogs that needed more time for recovery or did not show an improvement. Overall, a receptor-operating curve (ROC) analysis showed that using a cut-off level of 41.3 pg/mL, CSF tau levels had a sensitivity of 86% and a specificity of 83% to predict an unsuccessful outcome in plegic dogs. These preliminary data strongly support the utility of CSF tau levels as a prognostic indicator in dogs with IVDH, but potentially also with other acute brain or spinal cord injuries. However, these quite exciting findings are still exploratory and will need to be confirmed in additional, preferably prospective studies conducted at other sites by multiple investigators. Those investigators engaged in these confirmatory studies are strongly encouraged to consider the typical challenges associated with advancing promising exploratory biomarkers into standard practice, such as the impact of various covariates (e.g. breed, age, sex, etc.), the need for standardization of assays and protocols, as well as of sample collection techniques and processing procedures (Fagan and Perrin, 2012). The article by Roerig et al. (2013) is a good opportunity to highlight the potential translatability of findings in humans to veterinary species. Most scientists involved in translational science
114
Editorial / The Veterinary Journal 197 (2013) 113–114
typically think in terms of translatability of animal models to humans. Veterinarians, on the other hand, are perfectly positioned to back translate findings in humans to veterinary species, usually in cleverly designed studies that are not prohibitively expensive. There are frequent examples of these types of success stories in the literature. One illustrative example is the use of receptor kinase inhibitors for the treatment of various canine tumors, such as mast cell tumors (London et al., 2009). Interestingly, those studies will probably provide additional value to human patients in the clinic. The work of Roerig et al. (2013) is another excellent example of applying scientific and medical advances found in humans back to veterinary species. Scientific Editor Eric A.G. Blomme The Veterinary Journal and Senior Research Fellow, Investigative Toxicology and Pathology, AbbVie Inc.,1 North Chicago, IL, USA E-mail address: [email protected] Jeffrey F. Waring Associate Director, Pharmacogenetics AbbVie Inc.,1 North Chicago, IL, USA E-mail address: [email protected]
1 AbbVie provided no support outside of Eric Blomme and Jeffrey Waring being employees and this presentation contains no proprietary AbbVie data.
References Fagan, A.M., Perrin, R.J., 2012. Upcoming candidate cerebrospinal fluid biomarkers of Alzheimer’s disease. Biomarkers Medicine 6, 455–476. Ferri, C.P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., Hall, K., Hasegawa, K., Hendrie, H., Huang others, Y., 2005. Alzheimer’s Disease International, Global prevalence of dementia: A Delphi consensus study. Lancet 366, 2112–2117. Genius, J., Klafki, H., Benninghoff, J., Esselmann, H., Wiltfang, J., 2012. Current application of neurochemical biomarkers in the prediction and differential diagnosis of Alzheimer’s disease and other neurodegenerative dementias. European Archives if Psychiatry and Clinical Neuroscience 262, S71–S77. Hesse, C., Rosengren, L., Vanmechelen, E., Vanderstichele, H., Jensen, C., Davidsson, P., Blennow, K., 2000. Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. Journal of Alzheimer’s Disease 2, 199– 206. London, C.A., Malpas, P.B., Wood-Follis, S.L., Boucher, J.F., Rusk, A.W., Rosenberg, M.P., Henry, C.J., Mitchener, K.L., Klein, M.K., Hintermeister others, J.G., 2009. Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clinical Cancer Research 15, 3856–3865. Roerig, A., Carlson, R., Tipold, A., Stein, V.M., 2013. Cerebrospinal fluid tau protein as a biomarker for severity of spinal cord injury in dogs with intervertebral disc herniation. The Veterinary Journal 197, 253–258.
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Editorial
Cerebrospinal fluid biomarkers: Exploiting advances in humans to improve veterinary care In the last few decades, significant progress has been made to identify and apply biomarkers to support a clinical diagnosis of Alzheimer’s disease (AD) in humans. AD is a devastating neurodegenerative disorder associated with profound cognitive decline and dementia (i.e. dementia of the Alzheimer’s type or DAT). It is difficult to accurately diagnose clinically using only assessment of cognitive abilities (Genius et al., 2012). In addition, ability to predict the disease or its progression is limited. For these reasons, current treatments are essentially geared toward symptomatic improvements with little impact on disease progression. Furthermore, the low performance of the past and current diagnostic and prognostic tools for AD has frustrated drug developers in their quest to develop preventative or disease modifying therapeutic alternatives. The scientific community is well aware of the current dramatic situation. AD is slowly but steadily becoming more prevalent with epidemic proportions. In 2005, it was estimated that 24.3 million people had dementia worldwide (most cases of dementia are DAT), with 4.6 million new cases every year (Ferri et al., 2005). Even more concerning is the fact that the number of people affected is likely to double every 20 years and reach 81.1 million by 2040 (Ferri et al., 2005). Mostly because of better health care and longer lifespans, the increase will be even more visible in developed countries. With such numbers in mind, it is easy to understand the potential medical and socio-economic challenges that our societies will face in the future unless something is done. What are clearly and urgently needed are novel tools to improve the diagnosis and prediction of AD, but also to better assess disease progression. To address this enormous gap, researchers have increased their efforts to identify biomarkers associated with the development and progression of AD, thanks principally to funding by various national and international agencies. Several fluid and imaging biomarkers have or are being validated through large collaborative efforts (Genius et al., 2012). Cerebrospinal fluid (CSF) biomarkers have become particularly attractive and successful because of the intimate contact between the CSF and neurons, the presumed target cells of AD (Fagan and Perrin, 2012). In particular, three CSF proteins are now well-established biomarkers of AD, namely, (1) b-amyloid 42 peptide (Ab42) with lower CSF levels in AD; (2) total tau protein, and (3) phosphorylated tau181, both with higher CSF levels in AD. This vast quantity of research, frequently initiated in the form of consortia or initiatives, has led to findings with implications beyond AD and also with potential applications to veterinary medicine. The article by Dr. Andrea Roerig of the University of Veterinary Medicine in Hannover and her colleagues, published in this issue of The Veterinary Journal, illustrates how some of the knowledge generated in humans can translate back to veterinary
1090-0233/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2013.04.026
medicine and provide opportunities to improve veterinary care (Roerig et al., 2013). In their article, Roerig et al. (2013) evaluated whether CSF levels of total tau protein could be useful in objectively assessing the severity of spinal cord damage and to see if it could represent a prognostic indicator in dogs with intravertebral disk herniation (IVDH). While CSF sampling seems to be a rather invasive approach in veterinary practice, the severity of the disorder (i.e., clinical signs, progression, etc.), the lack of tools to predict progression, and the frequency of this syndrome in the overall canine population all warrant exploration of CSF biomarkers. The selection of tau as a marker is quite logical, since tau is considered a non-specific indicator of axonal and neuronal damage and CSF levels of total tau have been positively correlated with the amount of tissue damage and poor clinical outcomes in acute brain disorders, such as acute ischemic stroke (Hesse et al., 2000). To evaluate the potential utility of CSF tau levels, Roerig et al. (2013) conducted a retrospective study with 51 dogs with thoracolumbar or cervical IVDH and 12 clinically normal dogs. Cisternal CSF tau values were determined using a commercially available enzyme-linked immunosorbent assay (ELISA). Not unexpectedly, CSF tau concentrations were statistically significantly higher in dogs showing plegia compared to healthy dogs and dogs with paresis. But probably more interesting was the finding that plegic dogs with improvement by one neurological grade within 1 week had significantly lower tau protein levels compared to plegic dogs that needed more time for recovery or did not show an improvement. Overall, a receptor-operating curve (ROC) analysis showed that using a cut-off level of 41.3 pg/mL, CSF tau levels had a sensitivity of 86% and a specificity of 83% to predict an unsuccessful outcome in plegic dogs. These preliminary data strongly support the utility of CSF tau levels as a prognostic indicator in dogs with IVDH, but potentially also with other acute brain or spinal cord injuries. However, these quite exciting findings are still exploratory and will need to be confirmed in additional, preferably prospective studies conducted at other sites by multiple investigators. Those investigators engaged in these confirmatory studies are strongly encouraged to consider the typical challenges associated with advancing promising exploratory biomarkers into standard practice, such as the impact of various covariates (e.g. breed, age, sex, etc.), the need for standardization of assays and protocols, as well as of sample collection techniques and processing procedures (Fagan and Perrin, 2012). The article by Roerig et al. (2013) is a good opportunity to highlight the potential translatability of findings in humans to veterinary species. Most scientists involved in translational science
114
Editorial / The Veterinary Journal 197 (2013) 113–114
typically think in terms of translatability of animal models to humans. Veterinarians, on the other hand, are perfectly positioned to back translate findings in humans to veterinary species, usually in cleverly designed studies that are not prohibitively expensive. There are frequent examples of these types of success stories in the literature. One illustrative example is the use of receptor kinase inhibitors for the treatment of various canine tumors, such as mast cell tumors (London et al., 2009). Interestingly, those studies will probably provide additional value to human patients in the clinic. The work of Roerig et al. (2013) is another excellent example of applying scientific and medical advances found in humans back to veterinary species. Scientific Editor Eric A.G. Blomme The Veterinary Journal and Senior Research Fellow, Investigative Toxicology and Pathology, AbbVie Inc.,1 North Chicago, IL, USA E-mail address: [email protected] Jeffrey F. Waring Associate Director, Pharmacogenetics AbbVie Inc.,1 North Chicago, IL, USA E-mail address: [email protected]
1 AbbVie provided no support outside of Eric Blomme and Jeffrey Waring being employees and this presentation contains no proprietary AbbVie data.
References Fagan, A.M., Perrin, R.J., 2012. Upcoming candidate cerebrospinal fluid biomarkers of Alzheimer’s disease. Biomarkers Medicine 6, 455–476. Ferri, C.P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., Hall, K., Hasegawa, K., Hendrie, H., Huang others, Y., 2005. Alzheimer’s Disease International, Global prevalence of dementia: A Delphi consensus study. Lancet 366, 2112–2117. Genius, J., Klafki, H., Benninghoff, J., Esselmann, H., Wiltfang, J., 2012. Current application of neurochemical biomarkers in the prediction and differential diagnosis of Alzheimer’s disease and other neurodegenerative dementias. European Archives if Psychiatry and Clinical Neuroscience 262, S71–S77. Hesse, C., Rosengren, L., Vanmechelen, E., Vanderstichele, H., Jensen, C., Davidsson, P., Blennow, K., 2000. Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. Journal of Alzheimer’s Disease 2, 199– 206. London, C.A., Malpas, P.B., Wood-Follis, S.L., Boucher, J.F., Rusk, A.W., Rosenberg, M.P., Henry, C.J., Mitchener, K.L., Klein, M.K., Hintermeister others, J.G., 2009. Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clinical Cancer Research 15, 3856–3865. Roerig, A., Carlson, R., Tipold, A., Stein, V.M., 2013. Cerebrospinal fluid tau protein as a biomarker for severity of spinal cord injury in dogs with intervertebral disc herniation. The Veterinary Journal 197, 253–258.