Itzhaki and Lathe provide important commentary regarding population studies by Tsai et al., Chen et al., and Tseng et al. These three studies demonstrate acute peripheral infection with VZV or HSV is associated with increased risk of developing senile dementia (SD). In addition, Chen et al. and Tseng et al. present findings whereby treatment with antiviral medication significantly reduces this risk. These results add to a growing body of evidence which supports HSV-1 in combination with APOE-ε4 allele carriage as a causative factor in sporadic AD (1-5). Numerous studies by Itzhaki and others involving epidemiology, neuropathology, molecular biology, and genetics implicates the involvement of herpes simplex virus type 1 in the development of AD (6-10).
Antiviral medications used in the studies by Chen et al. and Tzeng et al., such as acyclovir and valacyclovir, interfere with VZV and HSV-1 replication and likely inhibit viral spreading. Regarding the reduction in SD from Chen et al., Itzhaki and Lathe hypothesize that suppression of VZV infection with AVT may decrease VZV-related inflammatory reactivation of HSV1 in the brain. Reduction in SD with AVT found by Tseng et al. might relate to reduced peripheral HSV-1 replication, thus preventing viral ascent into the brain. The precise underlying mechanisms for how relatively short courses of antiviral medication used to treat peripheral VZV and HSV infections might reduce dementia remain to be elucidated. However, the reductions in SD in patients treated with antiviral medication lends support to the role of HSV-1 in the development of AD. Hopefully, the remarkable findings from these population studies and the commentary by Itzhaki and Lathe will inspire future research into pathogen induced dementia including much needed antiviral clinical trials in MCI/early AD patients.
References
1. Itzhaki, R. F., Lin, W. R., Shang, D., Wilcock, G. K., Faragher, B., and Jamieson, G. A. (1997). Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241–244. doi: 10.1016/S0140-6736(96) 10149-5.
2. Itzhaki, R. F., Lathe, R., Balin, B. J., Ball, M. J., Bearer, E. L., Braak, H., et al. (2016). Microbes and Alzheimer’s disease. J. Alzheimers Dis. 51, 979–984. doi: 10.3233/JAD-160152.
3. Itzhaki, R. F. (2014). Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Front. Aging Neurosci. 6:202.doi: 10.3389/fnagi.2014.00202.
4. Wozniak, M. A., Itzhaki, R. F., Shipley, S. J., and Dobson, C. B. (2007). Herpes simplex virus infection causes cellular amyloid accumulation and secretase up-regulation. Neurosci. Lett. 429, 95–100. doi: 10.1016/j.neulet.2007.
09.077
5. Harris SA, Harris EA. Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer's Disease. J Alzheimers Dis. 2015;48(2):319-53. doi: 10.3233/JAD-142853.
6. Letenneur, L., Pérès, K., Fleury, H., Garrigue, I., Barberger-Gateau, P., Helmer, C., et al. (2008). Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: a population based cohort study. PLoS One 3:e3637. doi: 10.1371/journal.pone.0003637
7. Wozniak, M. A., Mee, A. P., and Itzhaki, R. F. (2009b). Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J. Pathol. 217, 131–138. doi: 10.1002/path.2449.
8. De Chiara, G., Marcocci, M. E., Civitelli, L., Argnani, R., Piacentini, R., Ripoli, C., et al. (2010). APP processing induced by herpes simplex virus type 1 (HSV-1) yields several APP fragments in human and rat neuronal cells. PLoS One 5:e13989. doi: 10.1371/journal.pone.0013989.
9. Burgos, J., Ramirez, C., Sastre, I., and Valdivieso, F. (2006). Effect of Apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J. Virol. 80, 5383–5387. doi: 10.1128/jvi.00006-06.
10. Harris SA and Harris EA (2018) Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer’s Disease. Front. Aging Neurosci. 10:48. doi: 10.3389/fnagi.2018.00048
Steven A. Harris M.D.
St. Vincent Medical Group
Northside Internal Medicine
Indianapolis, Indiana 46260 Sirrah5555@gmail.com
After dozens (maybe hundreds) of trials aimed specifically at removing amyloid peptide have failed to relieve clinical cognitive disorders, we clearly need novel initiatives to prevent and treat dementing diseases. One intriguing hypothesis is the role of microbes, especially that of herpesviridae, for which there are routine drug treatments available. In their thoughtful commentary, Itzhaki (a pioneer on the topic) and Lathe review recent studies that seem to strengthen the hypothesis at the population level. Importantly, one of the studies raises the potential for antiherpes drug treatment, for which a randomized trial would be needed. We argued for this five years ago in a Neurology editorial (Strandberg and Aiello, 2013), and fortunately patients are currently being recruited for such a trial in Sweden (Lövheim et al., 2016 clinical trial).
References:
Strandberg TE, Aiello AE.
Is the microbe-dementia hypothesis finally ready for a treatment trial?.
Neurology. 2013 Mar 26;80(13):1182-3.
PubMed.
Comments
St. Vincent Medical Group
Itzhaki and Lathe provide important commentary regarding population studies by Tsai et al., Chen et al., and Tseng et al. These three studies demonstrate acute peripheral infection with VZV or HSV is associated with increased risk of developing senile dementia (SD). In addition, Chen et al. and Tseng et al. present findings whereby treatment with antiviral medication significantly reduces this risk. These results add to a growing body of evidence which supports HSV-1 in combination with APOE-ε4 allele carriage as a causative factor in sporadic AD (1-5). Numerous studies by Itzhaki and others involving epidemiology, neuropathology, molecular biology, and genetics implicates the involvement of herpes simplex virus type 1 in the development of AD (6-10).
Antiviral medications used in the studies by Chen et al. and Tzeng et al., such as acyclovir and valacyclovir, interfere with VZV and HSV-1 replication and likely inhibit viral spreading. Regarding the reduction in SD from Chen et al., Itzhaki and Lathe hypothesize that suppression of VZV infection with AVT may decrease VZV-related inflammatory reactivation of HSV1 in the brain. Reduction in SD with AVT found by Tseng et al. might relate to reduced peripheral HSV-1 replication, thus preventing viral ascent into the brain. The precise underlying mechanisms for how relatively short courses of antiviral medication used to treat peripheral VZV and HSV infections might reduce dementia remain to be elucidated. However, the reductions in SD in patients treated with antiviral medication lends support to the role of HSV-1 in the development of AD. Hopefully, the remarkable findings from these population studies and the commentary by Itzhaki and Lathe will inspire future research into pathogen induced dementia including much needed antiviral clinical trials in MCI/early AD patients.
References
1. Itzhaki, R. F., Lin, W. R., Shang, D., Wilcock, G. K., Faragher, B., and Jamieson, G. A. (1997). Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241–244. doi: 10.1016/S0140-6736(96) 10149-5.
2. Itzhaki, R. F., Lathe, R., Balin, B. J., Ball, M. J., Bearer, E. L., Braak, H., et al. (2016). Microbes and Alzheimer’s disease. J. Alzheimers Dis. 51, 979–984. doi: 10.3233/JAD-160152.
3. Itzhaki, R. F. (2014). Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Front. Aging Neurosci. 6:202.doi: 10.3389/fnagi.2014.00202.
4. Wozniak, M. A., Itzhaki, R. F., Shipley, S. J., and Dobson, C. B. (2007). Herpes simplex virus infection causes cellular amyloid accumulation and secretase up-regulation. Neurosci. Lett. 429, 95–100. doi: 10.1016/j.neulet.2007.
09.077
5. Harris SA, Harris EA. Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer's Disease. J Alzheimers Dis. 2015;48(2):319-53. doi: 10.3233/JAD-142853.
6. Letenneur, L., Pérès, K., Fleury, H., Garrigue, I., Barberger-Gateau, P., Helmer, C., et al. (2008). Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: a population based cohort study. PLoS One 3:e3637. doi: 10.1371/journal.pone.0003637
7. Wozniak, M. A., Mee, A. P., and Itzhaki, R. F. (2009b). Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J. Pathol. 217, 131–138. doi: 10.1002/path.2449.
8. De Chiara, G., Marcocci, M. E., Civitelli, L., Argnani, R., Piacentini, R., Ripoli, C., et al. (2010). APP processing induced by herpes simplex virus type 1 (HSV-1) yields several APP fragments in human and rat neuronal cells. PLoS One 5:e13989. doi: 10.1371/journal.pone.0013989.
9. Burgos, J., Ramirez, C., Sastre, I., and Valdivieso, F. (2006). Effect of Apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J. Virol. 80, 5383–5387. doi: 10.1128/jvi.00006-06.
10. Harris SA and Harris EA (2018) Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer’s Disease. Front. Aging Neurosci. 10:48. doi: 10.3389/fnagi.2018.00048
Steven A. Harris M.D.
St. Vincent Medical Group
Northside Internal Medicine
Indianapolis, Indiana 46260
Sirrah5555@gmail.com
University of Helsinki
After dozens (maybe hundreds) of trials aimed specifically at removing amyloid peptide have failed to relieve clinical cognitive disorders, we clearly need novel initiatives to prevent and treat dementing diseases. One intriguing hypothesis is the role of microbes, especially that of herpesviridae, for which there are routine drug treatments available. In their thoughtful commentary, Itzhaki (a pioneer on the topic) and Lathe review recent studies that seem to strengthen the hypothesis at the population level. Importantly, one of the studies raises the potential for antiherpes drug treatment, for which a randomized trial would be needed. We argued for this five years ago in a Neurology editorial (Strandberg and Aiello, 2013), and fortunately patients are currently being recruited for such a trial in Sweden (Lövheim et al., 2016 clinical trial).
References:
Strandberg TE, Aiello AE. Is the microbe-dementia hypothesis finally ready for a treatment trial?. Neurology. 2013 Mar 26;80(13):1182-3. PubMed.
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