Archive: Letters to the Editor
December 2010
The article by Walton [1] indicated aluminum is instrumental in causing hyperphosphorylation of tau with subsequent development of neurofibrillary tangle formation. Recently tau has been found to mislocalize to dendritic spines causing early synaptic dysfunction [2]. Aluminum mediated hyperphosphorylation of tau may be a trigger for tau dysfunction and abnormal cellular trafficking with mislocalization to dendrites causing synaptic dysfunction, which probably is an early feature of Alzheimer's disease.
Steven R Brenner, MD
St. Louis VA Medical Center and Department of Neurology and Psychiatry at St. Louis University, St. Louis, MO, USA; Email: SBren20979@aol.com
References:
[1] Walton JR (2010) Evidence for participation of aluminum in neurofibrilllary tangle formation and growth in Alzheimer's disease. J Alzheimers Dis 22, 65-72.
[2] Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D (2010) Tau mislocalizatoin of dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68, 1067-1081.
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May 2010
Response to Letter to Editor, Regarding Article: Electromagnetic Field Treatment Protects Against and Reverses Cognitive Impairment in Alzheimer’s Disease Mice by Arendash et al. , J Alzheimers Dis 19:191-210 (2010).
We thank Dr. Kumlin and colleagues for their insightful comments regarding our paper [1]. Inasmuch as we were unaware of their earlier study involving EMF exposure to normal rats [2], we did not include it among the references in our paper and apologize for this oversight. Kumlin et al. [2] did indeed provide initial evidence that long-term EMF exposure (2 hrs/day, 5 days/week, for 5 weeks) can improve cognitive performance in rodents. It is important to note, however, that they provided EMF exposure to very young rats from 3-8 weeks of age. Thus, the authors were actually investigating effects of EMF exposure on immature rats whose brains were still developing—not adult animals. In utilizing the Morris water maze at a single test point, Kumlin et al. found a positive EMF effect only on the first two days of acquisition testing (not on the final two days of testing or overall), so their acquisitional effect was limited to the “rate” of learning. In the retention phase of testing, they found that rats given the higher of two EMF levels utilized (3.0 W/kg SAR) spent more time in the former platform area compared to non-exposed rats (15 sec vs. 10 sec average).
Kumlin and colleagues are incorrect in their assumption that our study utilized a continuous signal without modulation. In fact, our EMF exposure of 918 MHz frequency involved modulation with GMSK signal and was non-continuous with carrier bursts repeated every 4.6 ms, giving a pulse repetition rate of 217 Hz. The electrical field strength varied between 17 and 35 V/m. This resulted in calculated specific absorption rate (SAR) levels that varied between 0.25 W/kg and 1.05 W/kg. SAR was calculated from the below equation, with σ (0.88 s/m) and ρ (1030 kg/m-3) values attained from Nightingale et al. [3]:
SAR = σE2 σ = mean electrical conductivity of mouse brain tissue ρ ρ = mass density of mouse brain E = electrical field strength
In addition, our animals received “near-field” EMF exposure, given that the antenna was one wavelength long and that far-field exposure begins at 2 antenna lengths away from the antenna. Since our antenna length was 12 inches and the distance to mouse cages was 10 inches, mice in our studies received near field EMF exposure, with far-field exposure beginning at 24 inches from the antenna.
We regret that a number of the aforementioned EMF parameters were not mentioned within the methodology of our paper. However, it should now be clear that the EMF parameters used in our mouse whole-body exposure studies closely mimic the EMF exposure provided to the human brain by a typical cell phone, which is why our study is directly relevant to human cell phone use.
In reference to Kumlin et al. observing cognitive benefits after 5 weeks of EMF exposure, while we reported cognitive benefits in our study beginning at 5 months into EMF exposure, this difference in onset of cognitive benefit is most likely due to: 1) their use of immature, adolescent rats wherein EMF effects could be more easily attained in comparison to our use of adult mice, and/or 2) the much higher (above cell phone level) SAR level employed in their study. Regarding the later, there really was no effect of their EMF exposure on Morris maze “overall” or “final” acquisition, with only a modest enhancement of retention in the probe trial observed at a very high SAR level. By contrast, our paper in “adult” mice involved both normal and Alzheimer’s mice (approximately 100 mice total) given cell phone-level SAR exposure in both protection- and treatment-based studies, tested at multiple time points, and in multiple cognitive tasks. Moreover, several of our cognitive tasks (i.e., the radial arm water maze and cognitive interference task) are far more challenging than the Morris water maze used by Kumlin et al. and involve working/short-term memory rather than the spatial long-term learning/memory evaluated in the Morris maze.
Regarding the comment that there was a surprisingly large increase in body temperature with long-term EMF exposure in mice of our study, we wish to make three points. First, the increase in body/brain temperature (of approximately 1ºC) was consistently observed only in the Alzheimer’s mice and only with long-term (not acute) EMF exposure—normal mice did not consistently show an increase in temperature during EMF exposure. Second, our mice were given longer and more consistent EMF exposure (daily for 8-9 months) than any prior study involving cell phone parameters. Third, Alzheimer’s transgenic mice and their brain Aβ burdens had never before been a subject of EMF studies. Thus, Kumlin et al. are questioning a result that had no prior precedent of what to expect from the literature. What is clear is that the 1ºC increase in body/brain temperature during our EMF exposure to AD mice is a minimal increase that is well below the 41ºC level that begins to result in mammalian brain damage. Moreover, fluctuations of 2ºC or higher in mammalian brains occur regularly, depending on behavioral and metabolic state. Thus, our observed 1ºC elevation in temperature during EMF exposure to AD mice would appear to be safe and cognitively beneficial. It is noteworthy that this increase in body/brain temperature of AD mice during EMF exposure periods occurred at SAR levels (0.25 – 1.05 W/kg) that are well within, and indeed typical of, SAR levels during cell phone use.
Kumlin et al. are mistaken in suggesting that the temperature data from our long-term and acute studies are not directly comparable since only the acute studies involved brain temperature measurement. In fact, the group comparisons for both types of studies are comparable in view of the high correlation (r=0.98) between body temperature and brain temperature that we also presented. Thus, an increase in body temperature would certainly mean an identical increase in brain temperature for the long-term studies, despite our not having measured brain temperature in the long-term studies. Kumlin et al. also believe that, because our temperature recording occurred during EMF exposure, that the temperature probes may have been subjected to interference from the EMF signal. If this was an issue, however, all measurements would be expected to have the same interference, not just those from AD mice and not just those from long-term studies.
Kumlin et al. further suggest that the EMF dose used in our studies is not known. However, as we have now provided fuller details of our EMF exposure methodology, the EMF dose utilized in our studies is now abundantly clear. It should also be evident that the EMF parameters utilized were indeed very similar to those emitted by typical cell phones during their use. We agree with Kumlin et al. that it is important to investigate the dose-response relation in future EMF studies. In that context, our ongoing studies are investigating the best set of EMF parameters for achieving cognitive benefits in the shortest amount of time (if previous cognitive impairment is present), and without incurring any undesirable side-effects.
Finally, we would like to indicate our excitement over the inception of a new field of cognitive neuroscience by recent studies such as ours and Kumlin et al.—namely, Cognitive Benefits of EMF Exposure. Explored in a conscientious manner, with well-designed studies and appropriate behavioral endpoints, this new emerging field could provide a surprising array of benefits against diseases of brain aging.
Gary W. Arendash
Dept. of Cell Biology, Microbiology, and Molecular Biology
University of South Florida
Tampa, FL
Chuanhai Cao
USF/Byrd Alzheimer’s Disease Research Institute
University of South Florida
Tampa, FL
[1] Arendash GW, Sanchez-Ramos J, Mori T, Mamcarz M, Lin X, Runfeldt M, Wang L, Zhang G, Sava V, Tan J, Cao C. Electromagnetic field treatment protects against and reverses cognitive impairment in Alzheimer's disease mice. J Alzheimers Dis. 2010 Jan;19(1):191-210.
[2] Kumlin T, Iivonen H, Miettinen P, Juvonen A, van Groen T, Puranen L, Pitkäaho R, Juutilainen J, Tanila H. Mobile phone radiation and the developing brain: behavioral and morphological effects in juvenile rats. Radiat Res. 2007 Oct;168(4):471-9.
[3] Nightingale NR, Goodridge VD, Sheppard RJ, Christie JL. The dielectric properties of the cerebellum, cerebrum and brain stem of mouse brain at radiowave and microwave frequencies. Phys Med Biol. 1983 Aug;28(8):897-903.
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Response to article: Perucho J, Rubio I, Casarejos MJ, Gomez A, Rodriguez-Navarro JA, Solano RM, de Yebenes JG, Mena MA (2010) Anesthesia with isoflurane increases amyloid pathology in mice models of Alzheimer’s disease. J Alzheimers Dis 19, 1245-1259.
We note that Perucho et al. [1] cite (reference number 28) a 2007 publication by Pravat K Mandal [2], and we wish to point out to the authors and your readers that the Biochemistry paper in question was retracted later that same year [3], as was another article by Mandal [4], because “the anesthetic concentration of our paper[s] was misrepresented”. Those papers should therefore not be cited as evidence.
We also note in passing that the reference to Mandal’s retracted paper was incomplete (missing two authors [2]) and another citation of the work of Mandal and Fodale (reference 7 in Perucho et al) is also misreferenced. The citation to the latter should be 2009, not 2006, and the title of both the article and journal are incorrect [5].
Dr John Loadsman, MB, BS, PhD, FANZCA
Conjoint Senior Lecturer and Staff Specialist
Department of Anaesthetics
University of Sydney and Royal Prince Alfred Hospital
Camperdown 2050
Australia
Dr Francois Stapelberg, MBChB, FANZCA
Specialist Anaesthetist
Department of Anaesthesia
Senior Clinical Lecturer
University of Auckland and Middlemore Hospital
Auckland 1640
New Zealand
References:
[1] Perucho J, Rubio I, Casarejos MJ, Gomez A, Rodriguez-Navarro JA, Solano RM, de Yebenes JG, Mena MA (2010) Anesthesia with isoflurane increases amyloid pathology in mice models of Alzheimer’s disease. J Alzheimers Dis 19, 1247-1259.
[2] Mandal PK, Williams JP, Mandal R (2007) Molecular understanding of Abeta peptide interaction with isoflurane, propofol, and thiopental: NMR spectroscopic study. Biochemistry 46, 762-771.
[3] Mandal PK (2007) Molecular understanding of Abeta peptide interaction with isoflurane, propofol, and thiopental: NMR spectroscopic study. [Retraction of Mandal PK, Williams JP, Mandal R. Biochemistry. 2007 Jan 23;46(3):762-71; PMID: 17223697] Biochemistry 46, 12887.
[4] Mandal PK. Pettegrew JW (2008) Alzheimer's disease: halothane induces Abeta peptide to oligomeric form - solution NMR studies. [Retraction of Mandal PK, Pettegrew JW, McKeag DW, Mandal R. Neurochem Res. 2006 Jul;31(7):883-90; PMID: 16807784] Neurochem Res 33, 220.
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April 2010
Response to article: Cholinesterase activity and mRNA level of nicotinic acetylcholine receptors (α4 and β2 Subunits) in blood of elderly Chinese diagnosed as Alzheimer’s disease by Zhang et al., J Alzheimers Dis 19:849-858 (2010).
In a recent issue of Journal of Alzheimer’s Disease, Zhang and colleagues presented interesting data concerning the cholinergic deficit in Alzheimer’s disease (AD) [1]. These results demonstrated decreases in the activity of acetylcholinesterase (AChE) and reduced mRNA levels of α4 and β2 nicotinic acetylcholine receptor (nAChR) subunits in peripheral blood of patients with AD in an elderly Chinese population. Although accumulating evidence indicates that changes in the AD brain may be reflected by alterations in the peripheral blood cells of AD patients, there are not, as yet, universally accepted biological tests for an unequivocal diagnoses of the disease. As such, an important aspect of this study was that these alterations might be used as supplementary markers for the diagnosis of AD. However, there are several points that merit discussion.
First, as stated in the article, the mean score of MMSE tests for AD patients was 10.25±5.77. Therefore, we understand that all of patients were moderate and severe stages. The natural history of AD has a broad spectrum considered as a presymptomatic stage during which a number of pathological events take place over many years, an early symptomatic or prodromal stage [amnestic-mild cognitive impairment (aMCI)] with cognitive and, at times, neuropsychiatric manifestations, and symptomatic mild, moderate, and severe stages. It should be noted that decline is faster in the moderate and severe stage related to the natural progression of AD. While hopes for reversibility of pathological changes target the early stages of AD (aMCI and mild stage) for disease modification, unfortunately, diagnosis of aMCI and mild stage AD is problematic in general practice [2].
Second, anticholinergic drug use increases with advanced age because of frequently emerging disorders such as chronic obstructive lung disease, overactive bladder, and irritable bowel syndrome. Unfortunately, there was no information about anticholinergic drugs taken from patients or control subjects in the published study. This is important due to the fact that it is known that acetylcholine effect is blocked by these drugs [3-5], and we think that increased acetylcoline may cause changes in AChE activity.
In conclusion, we suggestion that future studies assess aMCI and mild stage AD where the early initiation of cholinesterase inhibitors therapy may defer the progression of disease and may prolong survival time. For this reason, all physicians need a marker for the early stages of AD. Also, as indicated, the confounding effects of any anticholinergic drug is important to consider. The aspects would certainly provide insights into the future identification of candidates with diagnostic biomarkers in peripheral blood.
Mehmet Ilkin Naharci, MD
Gulhane School of Medicine, Department of Internal Medicine, Division of Geriatrics, Ankara, Turkey; Tel: +90-312-304 31 22, Fax: +90-312-304 31 03, Email: inaharci@gata.edu.tr
Huseyin Doruk, MD
Gulhane School of Medicine, Department of Internal Medicine, Division of Geriatrics, Ankara, Turkey
Ergun Bozoglu, MD
Gulhane School of Medicine, Department of Internal Medicine, Division of Geriatrics, Ankara, Turkey
References:
[1] Zhang LJ, Xiao Y, Qi XL, Shan KR, Pei JJ, Kuang SX, Liu F, Guan ZZ (2010) Cholinesterase activity and mRNA level of nicotinic acetylcholine receptors (α4 and β2 Subunits) in blood of elderly Chinese diagnosed as Alzheimer’s disease. J Alzheimer’s Dis 19, 849-858.
[2] Spar JE, La Rue A (2006) Dementia and Alzheimer disease. In Clinical Manual of Geriatric Psychiatry, Washington DC, eds. American Psychiatric Publishing, London, pp. 173-229.
[3] Buhling F, Lieder N, Ulrike C, Kühlmann UC, Waldburg N, Welte T (2007) Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro. Respir Med 101, 2386–2394.
[4] Matsui T, Kimura I, Kimura M (1990) Increase in the activities of plasma pseudocholinesterase dependent on the blood glucose level and its relation to the hypersensitivity to acetylcholine in striated muscles of KK-CAy mice with diabetes. Jpn J Pharmacol 54, 97-103.
[5] Pieper MP, Chaudhary NI, Park JE (2007) Acetylcholine-induced proliferation of fibroblasts and myofibroblasts in vitro is inhibited by tiotropium bromide. Life Sci 80, 2270-2773.
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March 2010
Response to Article: Alzheimer’s Disease Research: Scientific Productivity and Impact of the Top 100 Investigators in the Field by: Aaron A. Sorensen, J Alzh Dis v.16, 451-465.
To the Editors
Like many with an interest in the field of Alzheimer’s disease I was intrigued to read the recent paper in JAD which purported to report the ‘scientific productivity and impact of the top 100 investigators in the field’ [1]. As an outsider to the study of ‘scientometrics’ it appeared a thorough piece of work though there were few indications as to its actual aims. If ‘productivity and impact’ are purely numerical indices then the study has succeeded in informing us whom has published the largest number of papers on Alzheimer’s disease and how often this body of papers has been cited. Perhaps of equal importance to the recognition of the ‘top’ 100 investigators in Alzheimer’s disease the study has also informed as to the areas of Alzheimer’s disease research which have received the largest research effort.
While I am sure that these data will now be used in myriad ways to support the significance of both individuals and research areas they should not be allowed to distract us from the stark realities of Alzheimer’s disease itself. By which I mean that in spite of the ‘scientific productivity and impact’ of these ‘top’ 100 invesitigators; (i) we still do not know the cause of Alzheimer’s disease, (ii) there is no cure for Alzheimer’s disease, (iii) there are no truly effective treatments for Alzheimer’s disease. While we can all argue around the ‘edges’ of each of these statements we all know that they are basically correct and that we remain some distance away from offering individuals diagnosed with Alzheimer’s disease the kind of hope that does exist for other common fatal diseases such as cancer and heart disease.
I have a vain hope that we might look at this scientometric exercise and, in particular, what it tells us about the scientific areas where the vast majority of this research has been carried out and conclude that, for a limited amount of research funding, we are putting too much effort into these areas. The very heavy emphasis upon beta amyloid and tau as prime research targets in elucidating the cause of Alzheimer’s disease, while having revealed much of great interest and fascination, has not been successful in combatting or treating the disease. I do not advocate stopping these lines of enquiry only that they should not be followed at the expense of other possibilities. The paper by Sorensen demonstrates that not only is AD research completely dominated by these subjects but that there is little chance that this will change while the most influential researchers in the field continue to support such studies. If you are one of the ‘top’100 identified in Sorensen’s paper then your ‘productivity and impact’ to-date in Alzheimer’s disease is, upon application of Occam’s razor, purely academic. You should be congratulated on this but you must now use your influence to look beyond the research of the past 40 years to the research of the future 40 years such that in time, and hopefully soon, we will be able to offer hope to the burgeoning numbers of individuals diagnosed with AD.
Christopher Exley PhD
Reader in Bioinorganic Chemistry
The Birchall Centre, Lennard-Jones Laboratories,
Keele University, Staffordshire, ST5 5BG, UK
Tel: 44 1782 734080; Email: c.exley@chem.keele.ac.uk
http://www.keele.ac.uk/depts/ch/groups/aluminium/index.html
Honorary Professor, UHI Millennium Institute
References:
[1] Sorensen AA (2009) Alzheimer’s disease research: Scientific productivity and impact of the top 100 investigators in the field. J Alzh Dis 16, 451-465.
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Response to Article: Electromagnetic Field Treatment Protects Against and Reverses Cognitive Impairment in Alzheimer’s Disease Mice by Arendash et al. , J Alzheimers Dis 19:191-210 (2010).
A very interesting article by Arendash et al. (1) was published in the January 2010 issue of Journal of Alzheimer’s Disease. The results suggested that exposure to radiofrequency (RF) radiation similar to that emitted by mobile phones may provide cognitive benefits both in normal mice and in a transgenic mouse model of Alzheimer’s disease (AD).
In the Introduction, the authors state “To date, no controlled long-term studies of high frequency /cell phone EMF effects on cognitive function have been done in humans, mice, or animal models for AD.” Although the sentence is very true as it is (because rats are not specifically mentioned), another sentence in the Abstract – “this report presents the first evidence that long-term EMF exposure directly associated with cell phone use…provides cognitive benefits” – is certainly not true. In a paper published two years earlier (2), we reported improved learning and memory in water maze tests in young male Wistar rats exposed to a mobile phone RF signal for 5 weeks.
The electromagnetic field exposures in the two studies were similar though not identical: Arendash et al. exposed the animals to a 918 MHz electromagnetic field for 2 h/day at a (reported) exposure level of 0.25 W/kg for 2 h/day, whereas we used a 900 MHz field for 2 h/day at 0.3 or 3 W/kg. However, there are also some differences. We used a pulse-modulated signal similar to that emitted by GSM mobile phones, whereas Arendash et al. probably used a continuous signal (no modulation is reported in the paper). The most important difference in the results is that we found improved learning and memory already after 5 weeks of exposure, while Arendash et al. reported no beneficial effects before 5 months of exposure. It remains to be investigated whether this difference is related to differences in exposure level; a shorter exposure time might be sufficient to cause effects at higher exposure level. We found some evidence of a dose-response relationship - improved task acquisition was found in both exposed groups, but improved memory retention was observed only in the higher exposure group. Of course, differences in results may also be related to the fact that animal models and testing methods were not identical in the two studies.
A major weakness in the article of Arendash et al. is insufficient characterization of the electromagnetic field exposure system and dosimetry. The description of the exposure system is very brief and, most importantly, there is no information on how the specific absorption rate (SAR, the “dose” of RF radiation) was determined. The physics of RF electromagnetic fields is very complex, and exposing animals to a well-defined “dose” is much more difficult than giving a dose of a chemical. Adequate reporting of the dosimetry is therefore essential in any study reporting biological effects of RF radiation. The complexity of the issue is well illustrated in the paper (3) that reports the technical details and dosimetry of the exposure system used in our rat study. Arendash et al. reported surprisingly large increase of body temperature (over 1 °C) in the exposed animals during 1-hour exposure periods. The reported SAR level of 0.25 W/kg is so low that it should not result in measurable increase of body temperature, which raises doubts that the true SAR may have been higher than was reported. The authors’ interpretation was that the temperature increase (seen during 1-h exposure of animals that had been exposed for 8 months) was not a result of direct heating, and they presented data showing that single acute exposures did not increase brain temperature. However, the temperature data from the acute and long-term studies are not directly comparable, as the measurement methods were different (rectal vs. temporal muscle probe). That the temperature measurements (both with the rectal probe and the temporal muscle probe) were performed during electromagnetic field exposure introduces additional problems for the interpretation of the temperature data: the electromagnetic field may have coupled directly into the probes (which can act as antennas) and the resulting interference may have biased the readings up or down.
Inadequate dosimetry does not totally invalidate the results of Arendash et al. The “medicine” is promising although the dose used in the trial is not known. Given that positive effects on cognitive function are supported by two independent experimental studies and recent epidemiological findings (4), it is easy to concur with the conclusions of Arendash et al. that these surprising findings justify RF electromagnetic field exposure “as a non-invasive, non-pharmacologic approach worthy of vigorous investigation”. Like in the case of pharmacological agents, it is important to investigate the dose-response relationship, so any further experimental studies should include proper reporting of dosimetry and preferably more than one exposure level.
Timo Kumlin and Jukka Juutilainen
University of Eastern Finland
Department of Environmental Science
P.O.Box 1627, FI-70211 Kuopio
Finland
Heikki Tanila
University of Eastern Finland
A.I.Virtanen Institute for Molecular Sciences
Kuopio, Finland
Lauri Puranen
STUK- Radiation and Nuclear Safety Authority
Helsinki, Finland
References:
1. Arendash GW, Sanchez-Ramos J, Mori T, Mamcarz M, Lin X, Runfeldt M, Wang L, Zhang G, Sava V, Tan J, Cao C. Electromagnetic field treatment protects against and reverses cognitive impairment in Alzheimer's disease mice. J Alzheimers Dis. 2010 Jan;19(1):191-210.
2. Kumlin T, Iivonen H, Miettinen P, Juvonen A, van Groen T, Puranen L, Pitkäaho R, Juutilainen J, Tanila H. Mobile phone radiation and the developing brain: behavioral and morphological effects in juvenile rats. Radiat Res. 2007 Oct;168(4):471-9
3. Puranen L, Toivo T, Toivonen T, Pitkäaho R, Turunen A, Sihvonen AP, Jokela K, Heikkinen P, Kumlin T, Juutilainen J. Space efficient system for whole-body exposure of unrestrained rats to 900 MHz electromagnetic fields. Bioelectromagnetics. 2009 Feb;30(2):120-8.
4. Schüz J, Waldemar G, Olsen JH, Johansen C. Risks for central nervous system diseases among mobile phone subscribers: a Danish retrospective cohort study. PLoS One. 2009;4(2):e4389.
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