Skip to main content
Erschienen in: Journal of Medical Case Reports 1/2016

Open Access 01.12.2016 | Case report

Effect of deoxyribonuclease I treatment for dementia in end-stage Alzheimer’s disease: a case report

verfasst von: Victor Tetz, George Tetz

Erschienen in: Journal of Medical Case Reports | Ausgabe 1/2016

download
DOWNLOAD
print
DRUCKEN
insite
SUCHEN

Abstract

Background

Alzheimer's disease is the most common cause of dementia and is characterized by a progressive loss of brain tissue leading to amyloid-β accumulation and severe decline in cognitive function. The cause of Alzheimer’s disease is poorly understood, and available treatments are limited in their efficacy, particularly for patients with more severe symptoms.

Case presentation

We report the case of a 77-year-old Caucasian man with severe dementia and behavioral disturbance secondary to Alzheimer’s disease treated with memantine who began adjunct treatment with deoxyribonuclease I. Prior to initiation of deoxyribonuclease I treatment, our patient appeared to be in a stuporous state, with a Mini-Mental State Examination score of 3 and a Functional Assessment Staging Test score of 7. After obtaining informed consent from family members, we started administration of 120 mg of deoxyribonuclease I per day (1500 KU/mg) for treatment of severe cognitive impairment.

Conclusions

Our patient began to demonstrate rapid, considerable improvement in cognitive function 2 days following initiation of deoxyribonuclease I treatment. After 2 months of continued treatment, Mini-Mental State Examination and Functional Assessment Staging Test scores were 18 and 4, respectively.
Abkürzungen
AD
Alzheimer's disease
cf-DNA
cell-free deoxyribonucleic acid
DNase I
deoxyribonuclease I
FAST
Functional Assessment Staging Test
MMSE
Mini-Mental State Examination

Background

Alzheimer's disease (AD) is an incurable, terminal illness characterized by progressive neurodegeneration and cognitive decline, accounting for roughly 60 to 80 percent of dementia cases [1]. More than 30 million people suffer from AD, and the number of patients is predicted to double every 20 years unless preventive measures are developed [2, 3]. The etiology of AD remains unclear; however, the characteristic accumulation of amyloid-β is likely associated with both genetic and environmental factors [4, 5].
Though several medications have been approved to treat the symptoms of Alzheimer’s (donepezil, rivastigmine, memantine, and galantamine), there is no cure for the underlying condition, and the current therapeutic strategies often provide merely temporary relief from symptoms and exhibit poor efficacy in patients with moderate to severe AD [6].
The present report details the case of a patient with severe end-stage AD who experienced significant symptomatic improvement upon treatment with deoxyribonuclease I (DNase I), an enzyme responsible for the cleavage of both human and microbial DNA, including cell-free DNA (cf-DNA). Therapeutic DNase I is a purified solution of recombinant human deoxyribonuclease I approved by the Food and Drug Administration (FDA) for the treatment of abnormal sputum viscosity in patients with cystic fibrosis [7]. As DNase I is an endonuclease, it has been suggested to have a beneficial role in the treatment of cancer; however the anticancer mechanism of action is not completely understood [8, 9].

Case presentation

A 77-year-old Caucasian man was diagnosed with dementia secondary to late-onset Alzheimer’s disease 30 months prior to his presentation at clinic, exhibiting behavioral disturbances, cognitive decline, and decreased ability to engage in activities of daily living. Approximately 14 months following the initial diagnosis, our patient began treatment with 10 mg of memantine per day [10, 11], though his cognitive condition continued to deteriorate, rapidly progressing to include such behavioral changes as aggressiveness and disinhibition, in addition to progressive amnesic syndrome, aphasia, bradykinesia, shuffling gait, loss of balance, and urinary incontinence. Further, our patient experienced a 20-pound weight loss, which is ordinarily indicative of poor prognosis in patients with AD [12, 13]. Analysis of cranial magnetic resonance imaging (MRI) scans revealed age-appropriate losses in volume and mild changes to the periventricular white matter (Fig. 1).
Thirteen months following initiation of memantine treatment, our patient’s total scores on the Mini-Mental State Examination (MMSE) and Functional Assessment Staging Test (FAST) were 10 and 5 points, respectively. He lost points on orientation to time and place, attention, memory, and visuospatial construction, and our patient was noticeably slower in completing the tasks.
He experienced additional difficulty in navigating turns and corners when walking, resulting in recurrent falls, and exhibited fluctuating levels of consciousness, alternating between periods of frank confusion and lucidity. However, he experienced no visual or auditory hallucinations.
A further 3 months later, and a total of 16 months following initiation of memantine treatment, our patient's experienced further deterioration of cognitive function. Our patient had fluctuating level of consciousness. His cognition fluctuated between periods of frank confusion and lucidity, however he had no visual or audial hallucinations.
He was unable to remember his name, the calendar date, day of the week, year, or place, and could not recognize family members. Additional impairments included slurred speech, expressive aphasia, loss of bowel/bladder control, and lack of coordination marked by an inability to sit, stand, or walk unassisted. Our patient became unresponsive to stimuli, with an MMSE score of 3 and a FAST score of 7. One month later, our patient’s relatives provided informed consent for treatment with 40 mg of human recombinant DNase I (1500 KU/mg) given orally three times a day in conjunction with his continued memantine therapy (10 mg daily). The DNase I was well tolerated, and no averse or unanticipated events were registered.
Our patient demonstrated considerable cognitive improvement beginning on the second day of DNase I treatment, becoming partially oriented to time and place, and once again recognizing and remembering the names of family members. He further became able to dress himself, including tying shoelaces and buttons, as well as walk independently, feed himself, and use an exercise bike. Neurologic abnormalities affecting his gait were significantly reduced. His MMSE score increased dramatically from 3 to 16, and his FAST score was reduced from 7 to 5. However, he continued to score low on the MMSE for measures of orientation to time and place, memory, and visuospatial construction.
Two months following the initiation of DNase I treatment (19 months following initiation of memantine treatment), our patient exhibited an MMSE score 18 and a FAST score of 4. Moderate improvements in memory were observed, although visuospatial construction continued to decline. He was better able to speak and interact with others, recognize relatives, and actively attend to television programs. Our patient further became able to perform calculations, play piano, chess, and walk independently.

Conclusions

Treatment with DNase I in the present case allowed our patient to withdraw from a terminal state and resulted in significant improvements in cognitive and behavioral function, including the ability to walk and perform everyday tasks with near independence. DNase I was used as a repurposed FDA-approved medication [14]. Significant recovery was observed in all areas of cognitive and motor function, indicating the possibility of a DNase-sensitive target involved in generating the symptoms of AD.
Cell-free DNA, including bacteria-derived DNA, may be one such target [15]. Circulating cf-DNA has been observed to play an important role in the progression and maintenance of different disease states, including cancer, stroke, and other [16, 17]. Our previous research revealed its possible role as a therapeutic target in graft-versus-host diseases [18].
Though there are various suggestions regarding the origins of serum and plasma cf-DNA, many researchers have speculated that it results from apoptosis, necrosis, or both, or that this cf-DNA is secreted by cancer cells, microorganisms, hematopoietic cells, and/or neutrophils [19]. However, the physiological role of cf-DNA in the progression of these diseases remains to be discovered. Some have theorized that this role is mechanical in nature, increasing blood viscosity and leading to ischemia, while others suggest that cellular uptake of cf-DNA is involved in the development of metastatic conditions [20]. Little research has focused on the role of cf-DNA in neurodegenerative conditions, particularly AD. Further studies are required in order to evaluate the role of cf-DNA in the incidence and progression of neurodegenerative pathologies.

Acknowledgements

We thank the family of the patient for granting permission for publication of this case.

Authors’ contributions

GT participated in the management of patient. VT was involved in the overall supervision and management of this patient. Both authors have been involved in drafting the manuscript or revising it critically for important intellectual content, read and approved the final manuscript, and have given final approval of the version to be published.

Competing interests

The authors declare that they have no competing interests.
Written informed consent was obtained from the patient and his legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.

© Springer Medizin

Bis 11. April 2024 bestellen und im ersten Jahr 50 % sparen!

e.Med Allgemeinmedizin

Kombi-Abonnement

Mit e.Med Allgemeinmedizin erhalten Sie Zugang zu allen CME-Fortbildungen und Premium-Inhalten der allgemeinmedizinischen Zeitschriften, inklusive einer gedruckten Allgemeinmedizin-Zeitschrift Ihrer Wahl.

© Springer Medizin

Bis 11. April 2024 bestellen und im ersten Jahr 50 % sparen!

Literatur
1.
Zurück zum Zitat Kiel C. Brain region's relative proximity as marker for Alzheimer's disease based on structural MRI. Brain. 2014;14:21. Kiel C. Brain region's relative proximity as marker for Alzheimer's disease based on structural MRI. Brain. 2014;14:21.
3.
Zurück zum Zitat Hebert L, Weuve J, Scherr P, Evans D. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013;80:1778–83.CrossRefPubMedPubMedCentral Hebert L, Weuve J, Scherr P, Evans D. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013;80:1778–83.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Schott J, Revesz T. Inflammation in Alzheimer’s disease: insights from immunotherapy. Brain. 2013;136(9):2654–6.CrossRefPubMed Schott J, Revesz T. Inflammation in Alzheimer’s disease: insights from immunotherapy. Brain. 2013;136(9):2654–6.CrossRefPubMed
5.
Zurück zum Zitat Merikangas K, Risch N. Will the genomics revolution revolutionize psychiatry? Am J Psychiatry. 2014;160:625–35.CrossRef Merikangas K, Risch N. Will the genomics revolution revolutionize psychiatry? Am J Psychiatry. 2014;160:625–35.CrossRef
6.
Zurück zum Zitat Lundkvist J, Halldin M, Sandin J, Nordvall G, Forsell P, Svensson S, et al. The battle of Alzheimer’s Disease–the beginning of the future. Unleashing the potential of academic discoveries. Front Pharmacol. 2014;5:102.CrossRefPubMedPubMedCentral Lundkvist J, Halldin M, Sandin J, Nordvall G, Forsell P, Svensson S, et al. The battle of Alzheimer’s Disease–the beginning of the future. Unleashing the potential of academic discoveries. Front Pharmacol. 2014;5:102.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168:918–51.CrossRefPubMed Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168:918–51.CrossRefPubMed
8.
Zurück zum Zitat Wen F, Shen A, Choi A, Gerner EW, Shi J. Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis. Cancer Res. 2013;73:4256–66.CrossRefPubMedPubMedCentral Wen F, Shen A, Choi A, Gerner EW, Shi J. Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis. Cancer Res. 2013;73:4256–66.CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Hawes MC, Wen F, Elquza E. Extracellular DNA: a bridge to cancer. Cancer Res. 2015;75:4260–4.CrossRefPubMed Hawes MC, Wen F, Elquza E. Extracellular DNA: a bridge to cancer. Cancer Res. 2015;75:4260–4.CrossRefPubMed
10.
Zurück zum Zitat Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius H. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333–41.CrossRefPubMed Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius H. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333–41.CrossRefPubMed
11.
Zurück zum Zitat Danysz W, Parsons C. Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine–searching for the connections. Br J Pharmacol. 2012;167:324–52.CrossRefPubMedPubMedCentral Danysz W, Parsons C. Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine–searching for the connections. Br J Pharmacol. 2012;167:324–52.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Soto M, Andrieu S, Gares V, Cesari M, Gillett K, Guyonnet S, et al. Living alone with Alzheimer's disease and the risk of adverse outcomes: results from the plan de soin et d'aide dans la maladie d'Alzheimer study. J Am Geriatr Soc. 2015;63:651–8.CrossRefPubMed Soto M, Andrieu S, Gares V, Cesari M, Gillett K, Guyonnet S, et al. Living alone with Alzheimer's disease and the risk of adverse outcomes: results from the plan de soin et d'aide dans la maladie d'Alzheimer study. J Am Geriatr Soc. 2015;63:651–8.CrossRefPubMed
13.
Zurück zum Zitat White H, Pieper C, Schmader K. The association of weight change in Alzheimer's disease with severity of disease and mortality: a longitudinal analysis. J Am Geriatr Soc. 1998;46:1223–7.CrossRefPubMed White H, Pieper C, Schmader K. The association of weight change in Alzheimer's disease with severity of disease and mortality: a longitudinal analysis. J Am Geriatr Soc. 1998;46:1223–7.CrossRefPubMed
14.
Zurück zum Zitat Appleby S, Cummings L. Discovering new treatments for Alzheimer's disease by repurposing approved medications. Curr Top Med Chem. 2013;13:2306–27.CrossRefPubMed Appleby S, Cummings L. Discovering new treatments for Alzheimer's disease by repurposing approved medications. Curr Top Med Chem. 2013;13:2306–27.CrossRefPubMed
15.
Zurück zum Zitat Holdenrieder S, Stieber P, Chan L, Geiger S, Kremer A, Nagel D, et al. Cell-free DNA in serum and plasma: comparison of ELISA and quantitative PCR. Clin Chem. 2005;51:1544–6.CrossRefPubMed Holdenrieder S, Stieber P, Chan L, Geiger S, Kremer A, Nagel D, et al. Cell-free DNA in serum and plasma: comparison of ELISA and quantitative PCR. Clin Chem. 2005;51:1544–6.CrossRefPubMed
16.
Zurück zum Zitat Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209.CrossRefPubMed Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209.CrossRefPubMed
17.
Zurück zum Zitat Jing R, Cui M, Wang H, Ju S. Cell-free DNA: characteristics, detection and its applications in myocardial infarction. Currt Pharm Des. 2013;19:5135–45.CrossRef Jing R, Cui M, Wang H, Ju S. Cell-free DNA: characteristics, detection and its applications in myocardial infarction. Currt Pharm Des. 2013;19:5135–45.CrossRef
18.
Zurück zum Zitat Li D, Patenia R, Bassett R, Tetz G, Champlin RE, Ma Q. DNase I treatment reduces GVHD in mice. Biol Blood Marrow Tr. 2015;21:S339.CrossRef Li D, Patenia R, Bassett R, Tetz G, Champlin RE, Ma Q. DNase I treatment reduces GVHD in mice. Biol Blood Marrow Tr. 2015;21:S339.CrossRef
19.
Zurück zum Zitat Delgado PO, Alves B, de Sousa GF, Kuniyoshi RK, Wroclavski ML, Del Giglio A, et al. Characterization of cell-free circulating DNA in plasma in patients with prostate cancer. Tumour Biol. 2013;34:983–6.CrossRefPubMed Delgado PO, Alves B, de Sousa GF, Kuniyoshi RK, Wroclavski ML, Del Giglio A, et al. Characterization of cell-free circulating DNA in plasma in patients with prostate cancer. Tumour Biol. 2013;34:983–6.CrossRefPubMed
20.
Zurück zum Zitat Hidalgo-Miranda A, Pérez-Montiel D, Chávez-Blanco A, Cruz-Velázquez J, Díaz-Chávez J, Gaxiola M, et al. Cancer progression mediated by horizontal gene transfer in an in vivo model. PLoS One. 2012;7, e52754.CrossRefPubMedPubMedCentral Hidalgo-Miranda A, Pérez-Montiel D, Chávez-Blanco A, Cruz-Velázquez J, Díaz-Chávez J, Gaxiola M, et al. Cancer progression mediated by horizontal gene transfer in an in vivo model. PLoS One. 2012;7, e52754.CrossRefPubMedPubMedCentral
Metadaten
Titel
Effect of deoxyribonuclease I treatment for dementia in end-stage Alzheimer’s disease: a case report
verfasst von
Victor Tetz
George Tetz
Publikationsdatum
01.12.2016
Verlag
BioMed Central
Erschienen in
Journal of Medical Case Reports / Ausgabe 1/2016
Elektronische ISSN: 1752-1947
DOI
https://doi.org/10.1186/s13256-016-0931-6

Weitere Artikel der Ausgabe 1/2016

Journal of Medical Case Reports 1/2016 Zur Ausgabe