http://www.molecularneurodegeneration.com/content/1/1/11
Natural distribution of environmental radon daughters in the different brain areas of an Alzheimer Disease victim
Berislav Momčilović1*,
Glenn I Lykken2 and
Marvin Cooley3
1 Institute for Medical Research and Occupational Health, PO Box 291, 10001 Zagreb, Croatia
2 Department of Physics, University of North Dakota, Grand Forks, ND 58202-7129, USA
3 Department of Pathology, University of North Dakota, Grand Forks, ND 58202-7129, USA
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Molecular Neurodegeneration 2006,
1:11
doi:10.1186/1750-1326-1-11
The electronic version of this article is the complete one and can be found online at:
http://www.molecularneurodegeneration.com/content/1/1/11
| Received: | 30 May 2006 |
| Accepted: | 11 September 2006 |
| Published: | 11 September 2006 |
© 2006 Momčilović et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Radon is a ubiquitous noble gas in the environment and a primary source of harmful
radiation exposure for humans; it decays in a cascade of daughters (RAD) by releasing
the cell damaging high energy alpha particles.
Results
We studied natural distribution of RAD 210Po and 210Bi in the different parts of the postmortem brain of 86-year-old woman who had suffered
from Alzheimer's disease (AD). A distinct brain map emerged, since RAD distribution
was different among the analyzed brain areas. The highest RAD irradiation (mSv·year-1) occurred in the decreasing order of magnitude: amygdale (Amy) >> hippocampus (Hip)
> temporal lobe (Tem) ~ frontal lobe (Fro) > occipital lobe (Occ) ~ parietal lobe
(Par) > substantia nigra (SN) >> locus ceruleus (LC) ~ nucleus basalis (NB); generally
more RAD accumulated in the proteins than lipids of gray and white (gray > white)
brain matter. Amy and Hip are particularly vulnerable brain structure targets to significant
RAD internal radiation damage in AD (5.98 and 1.82 mSv·year-1, respectively). Next, naturally occurring RAD radiation for Tem and Fro, then Occ
and Par, and SN was an order of magnitude higher than that in LC and NB; the later
was within RAD we observed previously in the healthy control brains.
Conclusion
Naturally occurring environmental RAD exposure may dramatically enhance AD deterioration
by selectively targeting brain areas of emotions (Amy) and memory (Hip).
Background
Alzheimer's Disease (AD), the most common cause of dementia in the elderly, is a progressive
neurodegenerative disease of unknown origin that gradually robs the patient of cognitive
function and eventually causes death
[
1]. Recently, we showed that radon daughters
210Po and
210Bi (RAD), accrue selectively in the brain proteins and lipids of men and women who
suffered from AD and Parkinson's Disease, respectively
[
2,
3]. We proposed that AD is a systemic brain-cell disease which selectively involves
the cell membrane protein structures of ion gates, pores, and channels, with consequent
chlorine leaking into the cells, collapse of the cell membrane gradient, and functional
cell death. Other authors proposed calcium and potassium channel impairment, respectively
[
4,
5]; the latter authors proposed AD to be a general systemic disease of the body as somatic
fibroblasts showed the same Ca-channel defect as that of neurons. Thus, the pathological
substrate of AD may well be described as "channelopathy", a condition where the impaired
cell membrane protein structures lead to the deregulation of the ionic influx by the
brain cells
[
6-
9].
Most of the AD studies are limited to the brain cortex and limbic system, notably
the hippocampus, since these are the well recognized brain areas involved in the AD
memory loss
[
10]; the role of other brain structures in AD is poorly understood
[
11-
13]. In this case report, we studied the distribution of naturally occurring environmental
RAD in different brain areas in AD. Radon is a ubiquitous noble gas in the air we
breath
[
14], it is lipid soluble and (in spite of being a noble gas) capable of forming weak
chemical bonds
[
15], and tends to accumulate in high-carbon body fat tissue including the brain
[
16]. Radon and RAD are the source of four cell destructive high energy alpha particles
which may significantly contribute to the internal radiation dose of the brain and
play a role in AD etiology and pathology
[
17,
18].
Subject and methods
We studied the distribution of naturally occurring environmental RAD polonium-210
(
210Po; alpha particle emitter) and bismuth-210 (
210Bi; beta particle emitter) in nine different brain regions of an 86-year-old deceased
woman. She was a resident of North Dakota who suffered from AD at old age and with
otherwise uneventful medical history. Post-mortem samples were obtained from all four
brain lobes, i.e., frontal (Fro). parietal (Par), occipital (Occ), and temporal (Tem),
and from the five well defined inside the brain structures, i.e., the hippocampus
(Hip), amygdale (Amy), substantia nigra (SN), locus ceruleus (LC), and nucleus basalis
(NB). The pathological diagnosis of AD was based on the presence of an age-adjusted
moderate to a severe number of plaques in the neocortex
[
19]. We separated cortical gray and subcortical white matter from each brain lobe and
separate gray and adjacent white matter for every subcortical ganglion. One gram of
each sample was fractionated into protein and lipid content before assessing
210Bi and
210Po activity separately.
Quantitative determination of the proteins and lipids from selected brain regions
and their
210Po and
210Bi radioactivity was performed as described previously
[
2,
3]. In brief, the proteins and lipids were extracted from the gray and white matter
of the brain and ganglia by following the respective methods of Bradford
[
20] and Folch et al.
[
21]. The protein fraction was passed through a polymembrane under a negative pressure
gradient
[
22]. The
210Po from the samples and
208Po from a spiked solution were plated on a silver disc
[
23]. Alpha and beta particle activities were determined in an Alpha Spectrometer System
supplied with a radionuclide library software package (EG&G ORTEC, Oak Ridge, TN)
and a Beckman scintillation spectrometer (Beckman Co., Fullerton, CA), respectively.
Lead-210 (
210Pb) decays to
210Bi, which in turn decays to
210Po; each decays at a different rate. After 600 days (1.64 years) a "secular equilibrium"
is reached; the activities of the
210Bi and
210Po in the sample are then equal to the
210Pb activity. The standard Bateman differential equation of growth and decay of radio-nuclides
in a decay chain was used to correct for
210Po formation from
210Bi directly and from
210Pb indirectly via
210Bi
[
24].
The radioactivity of 210Bi and 210Po was assessed in replicates of every studied brain area and expressed in μBq·g-1 tissue (1 μBq equals 1 disintegration per 106 second, i.e., 31 disintegrations per year). The difference between the two replicates
of the same sample and for the same radionuclide didn't exceed 5%. We consider the
difference in the RAD radionuclide retention between any two brain areas of >20% to
be significant (>>), that of 10–20% to be probably significant (>), and that below
10% as non-significant (~). The normal range of the biological variability is ± 20%,
and the maximal acceptable difference between the 210 Po and 210Bi in the same brain area sample was set at 10%.
The particular brain area cell death radiation risk to the high energy RAD alpha particles
was calculated on the assumption of the brain cell density of 6.4·10
6·g
-1 (90% glia, 10% neurons) and the average weight of the adult female brain of 1250 g
[
25,
26]; the brain weight of our subject was in that category. The absorbed physical energy
was first expressed in micro Grays (μGy) and then transformed to mili Sieverts (mSi)
to provide for the assessment of the biological effective dose of radiation
[
27]. It should be noted that every single
210Po disintegration means an instant death to a minimum of three cells along the path
of its high energy (5.305MeV) decaying alpha particle
[
28]; altogether, there are four such "killing" alpha particles in the radon decay chain
(Fig
1)
[
15].
This research was approved by the University of North Dakota Institutional Review
Board, Grand Forks, ND (IRB-9509-027), and carried out in full compliance with Helsinki
Declaration.
Results
The results showed a highly selective distribution of
210Po and
210Bi in the proteins and lipids from the gray and white matter of the brain and ganglia
in AD; indeed, RAD accumulation differs significantly between the brain areas (Fig
2). We observed a very good congruence of
210Po and
210Bi in all the duplicate samples from the same brain areas, indicating reliability
of the results obtained by the two different analytical methods of alpha and beta
particle counting; values for
210Po tend to be somewhat higher than that of
210Bi but still within the accepted limit of accuracy. As a rule, RAD accumulation was
higher in the proteins than lipids of various brain structures, and higher in the
gray than white brain matter proteins, respectively.
Figure 2. Brain structure distribution of polonium-210 (□) and bismuth-210 (■) in the proteins
and lipids of the gray and white brain matter in an Alzheimer disease victim (μBq
g
-1 tissue).
The retention of RAD in the gray brain matter proteins was, in the decreasing order
of magnitude:
Hip >> Amy >> Tem ~ Fro > Occ ~ Par > SN >> LC ~ NB. (A)
RAD retention was generally lower in the white matter brain and cerebral ganglia proteins
than that of the gray brain matter. The comparable sequence for both RAD (210Po and 210Bi) in the white brain matter proteins was somewhat different from that in the grey
matter:
Tem > Fro>> Occ ~ Par ~ Hip >> SN > Amy >> LC ~ NB (B)
It should be noted that the range of the 210Po activity in the gray matter proteins of the different brain structures (A) may
be as low as 150 μBq for NB and as high as 2906 μBq in the Hip [or 100 vs. 2138 μBq
(per gram) of 210Bi for the same brain structures], a factor of 20 difference! A similar range was
also observed in the proteins from the brain white matter (B), although the actual
sequence was somewhat different (50 vs. 1152 μBq·g-1of 210Po and 50 vs. 1119 μBq·g-1of 210Bi for NB and Tem, respectively).
The notable exception to the uniformly higher RAD accumulation in the gray (A) and
white (B) brain matter proteins than lipids in AD was the accentuated RAD retention
in the amygdale lipids. Indeed, the retention of 210Po and 210Bi in the Amy lipids reached astonishing 9285 and 6162 μBq·g-1, respectively, well above anything we have observed of RAD in any other brain area.
The retention of 468 μBq·g-1 of 210Po and 362 μBq·g-1 of 210Bi in the Hip was the next highest for the RAD retention in the lipids. Although increased
in relation to the other lipid RAD, the Hip lipid RAD retention was at the lower end
of the RAD activities seen in the proteins.
To better assess the radiation risk from
210Po "killer" alpha particles over the last year of the subject's life, we combined
together
210Po activity in the gray brain matter proteins and lipids, since proteins and lipids
from the same anatomical structure are not naturally separated. Apparently, a substantial
brain cell loss should have occurred in the Amy and Hip as a result of the cell killing
potential of the high energy RAD alpha particles (Table
1)
[
29]. The decreasing order of magnitude sequence of RAD
210Po in proteins and lipids from different brain areas showed the radiation risk to
be:
Table 1. Estimated annual regional brain cell loss and cell dose per gram tissue from
210Po high energy alpha particles (5.305 MeV) in the proteins and lipids.*
Amy >> Hip > Tem ~ Fro > Occ ~ Par > SN >> LC ~ NB (C)
We estimated that a minimum of 15% of amygdale cell population per gram tissue (>106 cells) was destroyed over a single year, about 5% of hippocampus cell population was
also destroyed over the same time, and as much as 1–2% of that in the four brain lobe
cell population. Since the brain lobes have a total cell mass considerably greater
than that of Amy and Hip, the actual cell loss from brain lobes would be also substantial.
Evidently, the different areas of the AD brain are exposed to a different radiation
risk and consequent cell loss.
Discussion
The major finding of this case report is that the explored areas of the AD brain are
specifically and selectively targeted by RAD, so that there is a different radiation
risk to the various brain structures at the same environmental radon and RAD exposure.
It has never before been observed that naturally occurring environmental RAD can reach
dangerous levels of radiation exposure in certain brain areas such as Amy and Hip.
These findings also confirmed our previous observations about brain proteins as a
targeted biochemical compartment in the AD brain. Indeed, the RAD deposition in the
gray and white brain matter proteins and lipids from the frontal and temporal brain
lobes of this single subject were within the average values we reported for the same
brain structures in a group of people who suffered from AD (see Table
1)
[
2,
3]. Consequently, if the RAD deposition to the proteins and lipids of the two identical
brain regions in these two separate studies is approximately equal, it is reasonable
to assume that RAD distribution in all the other areas of the AD brain would also
have the same pattern of distribution as found here. North Dakota is known for it's
high RAD
[
31], but the RAD in the frontal and temporal region of this case is very well within
the average RAD from the same brain region samples obtained from the Alzheimer's Foundation
[
2,
3]. Since the Alzheimer's Foundation brains came from the different parts of the USA,
it appears that, according to our instrument limits, the regional environmental exposure
to RAD did not affect the RAD brain distribution.
Our study identified the proteins in the hippocampus and amygdale as a two primary
brain area targets for RAD in AD. Further, we noted that there was two times more
RAD deposited in hippocampus than in the cortex per unit mass of the protein. This
is an indicative ratio since the Hip is assembled of three cellular layers identical
with three out of six cell layers of the brain cortex
[
25]. Thus, if three Hip layers yield two times more RAD than the six layers of the brain
cortex, and three of the cortex layers are identical with those of Hip, it is evident
that the presence of three more (but different) cortical layers did not contributed
to the RAD; therefore we think that our finding supports the concept of laminar specificity
of cortical pathology in AD
[
10] We also noted biochemical similarity of RAD retention in the parietal and occipital
lobe proteins vs. that in respective frontal and temporal lobes; the later was higher
(C).
The lowest RAD retention was observed in the proteins of locus ceruleus and nucleus
basalis, otherwise an area where a great neuronal loss was reported for LC, NB, and
SN in AD subjects
[
13,
31]. Since neurons are also composed of proteins, this observation implies how proteins
from these brain areas may have either different affinity for RAD or, perhaps, the
fact that we analyzed proteins in both neurons and glia cells of the brain; the later
is much more abundant (90%). Events like impaired conformational changes in protein
post-synaptic scaffolding
[
32], the fall in number of neuron synaptic contacts
[
33] the failing support of astrocytes which are especially vulnerable to the ionic radiation
[
34], and cyto-architectonic collapse of functional neurons
[
35], may all precede the neuronal loss in AD brain.
We predicted correctly that, as in the previous AD study, RAD would as well selectively
accrue in the brain cell proteins of Amy and Hip
[
2,
3]; what we didn't know at that time was that different brain areas would had quite
distinct RAD affinity. Essentially, our finding of high protein RAD affinity in AD
credits the importance of
mal variant AD proteins in the neurons
[
6-
8], with a caveat that actual
mal variant protein biochemical structure may be quite different for various brain areas
and their cell population. The reason for the repeatedly observed high RAD protein
affinity and respective brain area specific protein affinity in AD remains obscure.
We only know that the biochemical structure of the AD protein could be changed such
that more carbon bonds would be available to moderate radon movement before radon
decays in RAD; it may be even some variety of a prion protein of a chronic disease
[
9]. It has been shown that metals Al, Cu, Fe, Pb, Si, and Zn acts like a potent "seeding"
factors inducing excessive amyloid Aβ peptide formation
[
36-
39]. Indeed, Aβ is a major protein component of the senile plaque and what is the hallmark
of AD
[
40]; the degradation of these excess proteins in the AD brain is further reduced by the
lack of the proteosomes, a large protein complex responsible for intracellular degradation
of misfolded, oxidized, or aggregated proteins
[
41]. Since radon is a radioactive noble gas it transfers freely across the blood-brain
barrier in and out of the brain; when radon decays to RAD both the high energy of
cell killing potential is released and the heavy metals generated, the later would
act as a potent seeding agents for Aβ generation. Thus, radon can be both a direct
cause of AD via the imunogenic debris of the killed cells of already changed proteins
in the AD brain, and by also enhancing Aβ synthesis.
The only exception to the rule that AD specifically targets the brain matter proteins
was that in this subject the highest RAD deposition was observed in the amygdale gray
matter lipids. Since we already saw selective RAD accumulation to the brain lipids
in Parkinson's disease
[
2,
3], we concluded that an unfortunate event had occurred to this study's subject. i.e.,
the combined protein and lipid cell membrane chanellopathy. This failure of AD brain
cell lipids may be secondary to the failures of protein folding, their conformation
change, appearance of false ionic channels, and consequent failure in the Ca-channel
ionic cell influx
[
3,
42,
43].
We are impressed that the tiny amygdale alone received an equivalent of 2/3 of the
respective total yearly human body physical energy dose from cosmic rays (299 vs.
450 μG·y
-1)
[
29]. The biological quality of different types of radiation is different (alpha being
the most adverse to the biological tissue), and when the results are corrected for
the high biological quality factor of alpha radiation, Amy will receive a fifteen-times
greater biological effective radiation dose than the whole human body over the entire
year (5980 vs. 450 μSi·y
-1, respectively). Approximately one million of Amy cells will be killed in a year,
an equivalent of one gram of that 10 gram heavy brain structure. This estimate is
a very conservative approximation, based on only three direct cell kills per decayed
high energy alpha particle, since as much as fifty cells may be irreparably injured
and die after some delay by a single
210Po alpha particle as a result of the "bystander effect"
[
44]. What we observed in this AD brain is the internal radiation "amygdalectomy" and
how that might explain some of the respective emotional torpidity and insensitivity
associated with AD and old age. This case appears to fit the usual pattern of events
in AD; on average, person spend several years in the mild or minimal stages, between
4 and 5 years in the moderate disease stages, and depending on the quality of care
in the depending stages, a year or more requiring full nursing care
[
45].
Conclusion
In conclusion, AD is a complex and progressive brain disease characterized by the
failing ability to cope with environmental xenobiotic hazards
[
2,
3], excessive free radical injury, inflammation and immunity deficiency
[
46], cell repair impairment
[
47], and the protein synthesis
[
48]. The ubiquitous environmental RAD exposure, and high RAD accumulation in the sensitive
brain structures may either induce or hasten or both the irreversible "shut down"
process of the ailing human brain in AD.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
BM planned and designed the study, did data analysis and interpretation, and drafted
the manuscript. GIL conceived the study, coordinated the radio analytical work, did
dose calculations and helped to draft the manuscript. MC did pathology, pathological
diagnosis, disease classification, brain dissection, and helped towards clinical data
interpretation.
Acknowledgements
This study was supported in part by the U.S. Environmental Protection Agency contract
ND92-257, the Technical Training Foundation, North Andover, MA, U.S.A., the Ministry
of Science, Education and Sport of the Republic of Croatia grant 0022013, and the
generous philanthropic support of RCS Trading Co. Ltd., Isle of Man, UK. We wish to
thank Hassaan A. Alkhatib, PhD and John Duerre, Prof. Emeritus Microbiology and Immunology
for their help.
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Figure 1.