Clinical Neuropsychiatry (2014) 11, 2, 61-67
Psychiatric effects of ionizing radiation
Donatella Marazziti, Stefano Baroni, Amedeo Lombardi, Valentina Falaschi, Stefano Silvestri, Armando
Piccinni, Federico Mucci, Liliana Dell’Osso
Abstract
Radiation exposure leads to an increased risk for cancer and also atherosclerotic, cardiovascular, cerebro-vascular
and neurodegenerative effects.
Different data would indicate that radiation-induced neurodegeneration is a multifactorial process involving several
all types with oxidatively-stressed mitochondria being a recurring element.
With the present paper we aim to present a comprehensive review on brain effects of radiation exposure, with a
special focus on their possible role in the pathophysiology of different psychiatric disorders.
Key words: ionizing radiation, neurogenesis, hippocampus, brain areas, psychiatric disorders
Declaration of interest: none
Donatella Marazziti, Stefano Baroni, Amedeo Lombardi, Valentina Falaschi, Stefano Silvestri, Armando Piccinni, Federico
Mucci, Liliana Dell’Osso
Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa
Corresponding author
Donatella Marazziti, MD
Phone: +39 050 2219879; Fax: +39 0502219787
e-mail: [email protected]
Introduction
Ionizing radiation (IR) is a radiation with enough
energy so that during an interaction with an atom, it
can remove tightly bound electrons from the orbit of an
atom, causing the atom to become charged or ionized.
The fact that these radiations are ionizing allows them
to be detected and discriminated from other forms of
radiation (such as infra-red or radiowaves). Ionizing
radiation is present in three varieties: α (alpha) particles,
β (beta) particles, and γ (gamma) rays. All these forms
of radiation are energetic enough to remove electrons
from atoms. Alpha particles are strongly ionizing, but
can be stopped by paper or skin. They have a strong
positive charge (+2) and a mass of 4. One alpha particle
can ionize 10,000 atoms. However, because it puts all
its energy into ionizing others, it very quickly runs
out of energy itself. Hence, alpha particles cannot
penetrate through much. Beta particles are electrons,
but they are called beta particles to identify that they
come from the nucleus of the atom; these particles
are also strongly ionizing (perhaps 1 beta particle will
cause 100 ionizations). Gamma rays are very poor at
ionizing (about 1 to 1), but they are very difficult to stop
and are very penetrating. Therefore, gamma emission
accompanies most emissions of beta or alpha particles.
In eukaryotic cells, ionizing radiation induces damages
to proteins, lipids and DNA, directly or indirectly, as a
result of free radical formation. Cell signaling events
in response to IR depend on environmental conditions
occurring during DNA repair, besides genetic and
physiological features of the biological systems (United
Nations Scientific Committee on the Effects of Atomic
Radiation 2008; Food and Drug Administration 2010).
Submitted February 2014, Accepted March 2014
© 2014 Giovanni Fioriti Editore s.r.l.
Medical radiation from x-rays and nuclear medicine
is the largest manmade source of radiation exposure
in Western countries, accounting for a mean effective
dose of 3.0 mSv per capita per year, similar to the
radiologic risk of 150 chest x-rays (Picano 2004;
President’s Cancer Panel 2010). About 30 million
workers are professionally exposed to radiation, and
of these the interventional fluoroscopists (cardiologists
and radiologists) are amongst the most exposed. In fact,
their annual exposure is equivalent to 5 mSv per year
which would lead to a projected lifetime attributable
excess cancer risk of 1 in 100 (United Nations Scientific
Committee on the Effects of Atomic Radiation 2008;
Venneri et al. 2009). This explains the increasing
interest of scientific community on cancer and noncancer, including brain effects of radiation exposure.
The effects can be clustered in low dose effects (<100
mSv), generally reached with acute medical diagnostic
exposures; moderate dose (100-1000 mSv), reached
with chronic repetitive or cumulative professional
fractionated exposures, for instance in interventional
cardiologists and radiologists; and, finally, high dose
(>1 Sv or 1 Gy) exposures, of particular interest in
radiotherapy (Annals of the Institute for International
Research on Criminal Policy 2012). Currently, the
majority of the data are those regarding radiotherapy
dose range, while just a few information is available
on the moderate-to-low dose range, that probably is
where we need them most (Picano and Vano 2011).
Therefore, there is a great need for exploring what and
if low/moderate doses may provoke any dangerous
effect, especially on the brain which is now recognized
one of the main dose-limiting organs in radiotherapy
(Tofilon and Fike 2000). Given the high number of
61
Donatella Marazziti et al.
occupationally exposed workers and the high and rising
number of interventional radiology and CT procedures,
totalling millions each year, this subject becomes of key
scientific and social relevance (Komasa et al. 2013).
Therefore, the aim of the present paper was to review
the main literature on psychiatric effects of IR, while
highlighting the special needs in the field, especially
in terms of data gathering and possible prevention of
detrimental effects.
Psychiatric effects of high doses of IR
In the studies evaluating the effects of total
cranial irradiation on cognition and emotions, IR
was demonstrated to provoke cognitive deficits in
exposed individuals, especially during childhood and
adolescence. However, the relatively short follow-up
time (<10 years) did not allow to evaluate the possible
association between IR and dementia.
In a retrospective study involving the general
population of Rochester, no association was found
between radiation therapy (RT) and Alzheimer’s disease
(AD) (Peper et al. 2000). Another US study carried
out in subjects exposed to whole brain RT reported
an incidence of dementia ranging between 1.9 and
5.1%, not different from that of the general population
(DeAngelis et al. 1989).
In the few studies exploring the possible occurrence
of depression after cranial irradiation, no relationship
was detected (Roman and Sperduto 1995, Armstrong
et al. 2002). In the early-delayed phase, the cranial
irradiation-related cognitive changes were not
accompanied by depression (Armstrong et al. 1995,
Armstrong et al. 2000, Armstrong et al. 2002).
However, depression seemed to occur between the
4th and 6th year after the treatment, possibly related
to fatigue and cognitive impairment (Armstrong et al.
2002). In any case, convergent data from animal studies
showed that cranial irradiation can provoke relevant
damage of the hippocampal areas which are crucial for
neuronal plasticity and, as such, for memory, learning,
emotions and stress response (Monje et al. 2002,
Hartung et al. 2011).
Interestingly, in the last decade, different psychiatric
disorders, including depression, bipolar disorder and
schizophrenia, have been hypothesized to be related
in some ways to neurogenesis disturbances, especially
at hippocampal level. Even several psychotropic
compounds, specifically antidepressants and mood
stabilizers, would exert part of their effects by
improving the survival of selected neurons and neuronal
plasticity in the hippocampus (Duman et al. 1997,
Popoli et al. 2002, Manji et al. 2003, Schumacher et
al. 2005). Therefore, it is plausible that the reduction of
neurogenesis could predispose vulnerable individuals to
the onset of psychiatric disorders and negatively affect
the course of their symptoms and treatment outcome.
This could be especially true for schizophrenia which
is now considered a multifactorial neurodegenerative
illness, where neurobiological genetic predisposition
can be provoked by environmental stressors (such as
IR), while resulting in the occurrence of the disorder.
There are evidence of an increased incidence of
schizophrenia spectrum disorders following exposure
to atomic bombing radiation, or environment with high
natural IR level (Loganovsky et al. 2005). In fact, a
significant enhanced prevalence of schizophrenia has
been reported in the survivors in Nagasaki (Nakane and
Ohta 1986). The prevalence of schizophrenia was about
62
6% significantly higher than that found in the general
population where it is estimated to be about 1% (Shore
et al. 1986, Fuller Torrey 1995). Unfortunately, this
study has several methodological limitations due to the
fact that the Life Span Study, started by the radiation
effects research foundation (RERF) in Japan did not
include data on severe mental disorders. In addition, the
findings were obtained combining the schizophrenia
register of the Department of Neuropsychiatry,
University School of Medicine of Nagasaki, with the
LSS register. However, the schizophrenia register had
been operative only since 1960 and it was not possible
to calculate annual inception rates back to the bombing
in 1945 (Iwata et al. 2008).
As far as Chernobyl survivors are concerned,
there was a significant increase in the incidence of
schizophrenia in the exclusion zone area starting
from the 1990: 5.4 per 10,000 in the exclusion zone
personnel versus 1.1 per 10,000 in Ukraine in 1990
(Loganovsky et al. 2000). It was, thus, proposed
that the development of schizophrenia spectrum
disorders in Chernobyl survivors was the consequence
of a radiation-induced left fronto-temporal limbic
dysfunction. Further, prenatally irradiated children after
the Chernobyl accident were found to be at higher risk
for schizophrenia (Nyagu et al. 1998).
Further, the incidence of schizophrenia was
found to be higher in people living in the region
of the Semipalatinsk nuclear weapon testing area
in Kazakhstan. In fact, about 29% of patients with
mental disorders living in the area were affected by
schizophrenia and, amongst those, 42.3% were born
before the first nuclear test of India that have high
natural background radiation (Loganovsky et al. 2005).
However, in a recent study evaluating the possible
association between exposure to IR and schizophrenia,
a group of more than 10,000 subjects exposed to head
irradiation during childhood for treatment of tinea
capitis did not show a higher incidence of the disorder,
in comparison with two matched groups that had not
been exposed to IR (Sadetzki et al. 2011).
In any case, data are really few and there is a great
need of further studies to better understand the possible
relation between IR, in particular of low to moderate
doses, and different psychiatric disorders.
Psychiatric effects of low-to-moderate doses
of IR
Occupational exposure to radiation was associated
with death from dementia only in nuclear weapons
workers, but not in radiology technicians (Sibley et al.
2003, Park et al. 2005). Further, the studies evaluating
the incidence of dementia amongst atomic-bomb
survivors did not find any associations (Yamada et al.
1999).
The studies on occupational or accidental exposures
to IR are of great potential interest, but the evidence
is limited and conflicting. The available data come
from Hiroshima and Nagasaki atomic bomb survivors,
Chernobyl blast, nuclear power plant workers and
workers in medical fields (biologists, radiology
technicians, radiologists and imaging practitioners,
veterinarians). There are basically two different models
of exposure: relatively high doses (up to 4 Gy) over a
relatively brief period of time, and relatively low doses
(from 5 mGy up to < .5 Gy) over a much longer period
of time. Yamada et al. 1999 reported no relationship
between radiation exposure (< 4 Gy) and dementia in
2286 ageing atomic bomb survivors, with no difference
Clinical Neuropsychiatry (2014) 11, 2
Psychiatric effects of ionizing radiation
in incidence between the < 5 mGy, 5-499 mGy, and > 500
mGy groups. Another study described that an increased
proportion of white female radiologic technicians
experience death from AD, as compared with workers
in other occupations (Schulte et al. 1996). In a study of
female workers from 12 US nuclear weapon plants, an
unexpected increased mortality from mental disorders
was detected (Wilkinson et al. 2000). The most common
diagnosis was dementia, which accounted for 91, out of
the total of 166 deaths from mental disorders. In a nested
case-control study within a pooled cohort of 67,976
female nuclear workers, the total lifetime radiation
doses (consistently less than 100 mSv, and often in
the 10 mSv range) were associated with an odds ratio
of 2.1 (95% CI=1.02, 4.29) for death from dementia
(Sibley et al. 2003). These results are consistent with
Russian reports of cognitive impairments following
occupational radiation exposures in clean-up workers
following the accident at Chernobyl (Zhavoronkova et
al. 1997, Ponomarenko et al. 1999, Loganovsky and
Loganovskaja 2013). Associations between occupation
and neurodegenerative diseases was also reported,
with the highest mortality odds ratio for presenile
dementia in dentists, for Parkinson’s disease (PD) in
biological scientists, and for motor neuron diseases
in veterinarians – all categories exposed to various
environmental toxicants, including IR (Park et al.
2005). Non significant increased risks were reported
for health diagnostic practitioners, and decreased for
radiological technicians (Park et al. 2005).
Children are a particular target group with
high sensitivity for the correlation of radiation and
neurodegenerative diseases: they have still an immature
brain and a long-life expectancy allowing radiationinduced effects with a prolonged latency to develop.
A further group available to study the long-term
effects of moderate doses of IR and its effects on the
central nervous system is represented by children who
received X radiation to treat ringworm on the scalp
(Tinea capitis) (Schulz and Albert 1968).
Recently, a mortality analysis was published
gathered from amongst 11,311 former US flight
attendants, exposed to cosmic radiation, including IR,
up to 10 mSv per year (Pinkerton et al. 2011). Cosmic
radiation is quantitatively different from terrestrial
IR and consists primarily of charged particles and
neutrons, with neutrons contributing 40-60% of the
dose equivalent at average flight altitude (Goldhagen
2000). The ensuing findings showed an elevated
mortality for alcoholism, drowning and interventional
self-harm among women and an increased, albeit non
significantly, mortality for mental psychoneurotic
and personality disorders (Standardized mortality
ratio=1.39; 95% CI, 0.88-2.08). Amongst female flight
attendants, a non significantly 19% increase in mortality
from suicide was also observed (Zeeb et al. 2010).
Taken together, these data all collected for a
cumulative, documented or estimated, dose exposure
in the low-to-moderate dose range (from 10 to 500
mSv) are not reassuring, especially in view of the
already-mentioned data suggesting that moderate
dose (500 mSv) in adult mice can substantially impair
hippocampal neurogenesis, which is important for
memory, learning, stress response and mood regulation
(Silasi et al. 2004). Neural stem cells are highly
sensitive to radiation even at chronic, moderate doses.
Moreover, repetitive fractionated exposure (more
closely mirroring the model of professional exposure)
seems to provoke several more pronounced effects
on cellular signalling and neurogenesis than acute
exposure.
Clinical Neuropsychiatry (2014) 11, 2
Pathophysiology
The IR-related brain injury does not occur as a
single, immediate event. It is considered a dynamic and
multiphasic process occurring over time, characterized
by pathological changes of vessels and myelin, resulting
in vascular damage, white matter injury and coagulation
necrosis (Calvo et al. 1988, Reinhold et al. 1990, Van
Der Maazen et al. 1993, Hopewell and Van Der Kogel
1999, Tofilon and Fike 2000, Belka et al. 2001, Brown et
al. 2007). In terms of pathophysiology, in vitro findings
showed that IR can lead to neuronal death (Enokido et
al. 1996, Gobbel et al. 1998). Moreover, in vivo studies,
carried out in animals, reported significant brain
damage following IR. Histological changes, as well as
cognitive functions, were investigated in the brain of
20 Fischer 344 rats aged 6 months treated with whole
brain irradiation. In parallel to cognitive functions
impairment, as revealed by the water maze task and the
passive avoidance task, a relevant brain damage was
reported, in particular demyelination, in some cases
accompanied by necrosis in the corpus callosum and
the parietal white matter close to the corpus callosum.
The brain areas without necrosis were, however,
characterized by decreased myelin basic proteins,
alterations of neurofilaments and increased glial
fibrillary acidic proteins with gliosis. These histological
alterations of the brain structures after IR were similar
to those found in neurodegenerative conditions such
as Alzheimer’s disease, Binswanger’s disease and
multiple sclerosis (Akiyama et al. 2001).
The occurrence of neuroinflammation has been
found to be a significant component of the brain
response to IR (Tofilon and Fike 2000, Monje and
Palmer 2003). In fact, an increased number of activated
CD68-expressing microglia has been reported after
IR, so that it has been hypothesized that this might
contribute to the alteration of the neurogenesis and to the
hippocampal damage often described in animal models.
The hippocampal granule cell layer, which are those
capable to regenerate, has been found to be injured by
RT, even at lower doses than those believed to damage
glial cells or neurons (Monje 2002, Monje and Palmer
2003, Hartung et al. 2011). There is now convincing
evidence that inhibition of adult neurogenesis in the
dentate gyrus of the hippocampus affects learning and
memory. In particular, the memory linking past events
to the context seems to be very sensitive to a reduction
of the neurogenesis (Winocur et al. 2006, Wojtowicz
et al. 2008, Hernandez-Rabaza et al. 2009). In some
studies, the negative effect of RT on hippocampal
neurogenesis was irreversible (Wojtowicz 2006), while
in others a recovery was observed, possibly related to
the replication of the neural precursors (Monje et al.
2003, Rola et al. 2004, Ben Abdallah et al. 2007).
Significant increase in the incidence of
cerebrovascular disease have been demonstrated in
a cohort study of nuclear workers employed at the
Mayak Production Association (Mayak PA), among
workers who received cumulative doses higher than
0.2 Gy, compared with those who received <0.2 Gy
(Azizova et al. 2011). This study provides evidence for
the harmful effects of chronic low dose IR on the site of
cerebrovascular system and not directly on cognition.
There is also increasing evidence that cerebrovascular
dysfunctions may be a relevant pathogenic factor
in Alzheimer’s (Kurata et al. 2011, Tong et al. 2012,
Viticchi et al. 2012). There are indications that vascular
dysfunction leads to neurodegeneration and might
be involved in cerebrovascular disease (CVD) such
as cerebral beta-amyloidosis and cerebral amyloid
63
Donatella Marazziti et al.
angiopathy with amyloid-β plaque formation in the
brain and the vessel wall, respectively, which are
characteristics of Alzheimer’s (Zlokovic 2008).
Neurodegeneration in other conditions as PD may
be a consequence of histological alterations due to
chronic local inflammation after IR (Knott et al. 2000,
Mirza et al. 2000, McGeer and McGeer 2004, Mrak
and Griffin 2007). It has been suggested that oxidative
stress is involved in PD progression, as increased levels
of reactive oxygen species (ROS) have been shown to
damage the target neuronal cells (Hirsch 1993, Jenner
1998).
Microglia activation has been shown after local
whole brain irradiation (5 Gy—X-rays) of mice (Rola
et al. 2004). As a result microglias can produce and
release large numbers of superoxide ions into the
surroundings, contributing to increased levels of ROS
(McGeer and McGeer 2004). Young mice exposed to
whole brain irradiation showed that low doses of IR
induced neuroinflammation in the hippocampus which
was associated with a decline in cognitive functions
via reduced hippocampal neurogenesis (Rola et al.
2008). Studies demonstrated that microglia activation
and decreased hippocampal neurogenesis were directly
proportional to the radiation dose.
The dopaminergic neurons are more vulnerable to
oxidative stress compared with other brain structures.
This is attributed to their low intracellular levels of
antioxidants and elevated rate of oxygen consumption
and calcium metabolism leading to higher ROS levels
(Licker et al. 2009). It is postulated that dopamine
metabolism and dysfunctions of mitochondria are
themselves the causal factors for the elevated ROS
levels seen in PD (Greenamyre and Hastings 2004,
Licker et al. 2009).
It seems more plausible that the shift in the
metabolism of surviving neurons to compensate
dopamine loss and, thereby increase dopamine level
(Elsworth and Roth 1997a, b) may contribute to
mitochondrial defects and ROS increase during PD
progression.
It is known that low doses of IR may cause immediate
and persistent impairment of cardiac mitochondria,
Complexes I and III being the main targets (Azimzadeh
et al. 2011, Barjaktarovic et al. 2011). The mechanism of
radiation-induced mitochondrial dysfunction both in the
heart and brain is not completely understood. Ionizing
radiation may directly interact with mitochondrial
DNA (mtDNA) inducing mutations and deletions or
indirectly through the formation of reactive hydroxyl
radicals (Prithivirajsingh et al. 2004).
It is noteworthy that intact mitochondrial dynamics
(fission, fusion, migration) are essential for neurotransmission, synaptic maintenance and neuronal survival
(Bueler 2009). Disturbances of mitochondrial activity
may lead to neurodegeneration in PD (Arduino et al.
2011). Impairment of mitochondrial dynamics happens
early in the development of PD (Bueler 2009).
Taken together, mitochondria may not only play
a key role in PD, but also in AD. This stresses the
multifactorial role of mitochondria in the different
cellular actions within the brain.
A generalised depression of the mitochondrial
electron transport chain activity has been observed in
AD patients (Parker et al. 1994). Increased oxidative
stress found in the AD (Butterfield et al. 2007) may
result from oxidative phosphorylation defects; there is
evidence that Complex I defects in particular may play
an important role in the AD physiology (Eckert et al.
2010).
The model suggests that mitochondria play a
64
central role in the radiation response followed by
neuroinflammation and oxidative stress. Subsequent
cellular effects lie in the reduction in neurogenesis and
cerebrovasculature followed by neurodegeneration.
Conclusions
According to Annals of the Institute for International
Research on Criminal Policy (2012), “the adult brain
shows subtle effects at doses around 10 Gy and clear
volume effects are discernable. Low dose irradiation
(1-2 Gy) to the developing brain of children can cause
long-term cognitive and behavioral deficits that may
predispose to subsequent psychiatric symptoms and/or
disorders, detected in adult life after exposure to doses
>100 mGy before 18 months”.The crucial point is that,
with no doubt, we need more data, especially outside
the RT model, as well as in the low-to-moderate dose
range. This is particularly relevant for both the scientific
and social side due to the high number of patients and
professionals involved, taking into account also that
the downside of IR is magnified by the relative lack of
awareness by doctors and patients of doses and effects
of diagnostic IR (Malone et al. 2011). In particular, a
challenging model is represented by contemporary
interventional cardiologists and radiologists, who may
receive a whole body exposure after a professional
lifetime around 100 to 200 mSv and a head dose in
the range of 1 to 3 Gy, falling well within the range
of possible psychological and psychiatric effects. In
studying this population of catheterization laboratory
professionals, we also need to be aware of the
substantial limitations of the epidemiological approach,
which requires very large populations followed-up
for decades to detect clinically overt risks that can
be even of moderate entity (Land 1980). Rather, as
suggested by United Nations Scientific Committee
on the Effects of Atomic Radiation (2008), we should
focus on subclinical endpoints, as well as biomarkers,
since this information is more likely to lead to insight.
The ideal biomarker is a proximal sign of disease and
a long-term predictor of clinical events. In case of
psychological disease, the brain-derived neurotrophic
factor is directly linked to hippocampal neurogenesis
and is reduced in pre-depressive and degenerative
conditions (Piccinni et al. 2008, 2008b, 2009; Zuccato
and Cattaneo 2009). In Italy, this approach will be
used in the Healthy Cath Lab study, promoted by the
Italian National Research Council with endorsement of
Italian Society of Invasive Cardiologist, and designed
by interventional cardiologists for interventional
cardiologists. Similar studies are being organized in
US and sponsored by National Institute of Health
and National Cancer Society (Food and Drug
Administration 2010, President’s Cancer Panel 2010).
These studies will hopefully produce in the forthcoming
years the necessary evidence-base required to answer
the unresolved issue of the psychiatric effects of lowto-moderate IR exposure.
References
Akiyama K, Tanaka R, Sato M, Takeda N (2001). Cognitive
dysfunction and histological findings in adult rats one
year after whole brain irradiation. Neurologia Medico
Chirurgica (Tokyo) 41, 12, 590-8.
Annals of the Institute for International Research on Criminal
Policy (IRCP) (2012). Early and late effects of radiation
in normal tissues and organs: threshold doses for tissue
Clinical Neuropsychiatry (2014) 11, 2
Psychiatric effects of ionizing radiation
reactions and other non-cancer effects of radiation in a
radiation protection context. (published at ICRP website:
www.icrp.org)
Arduino DM, Esteves AR, Cardoso SM (2011). Mitochondrial
fusion/ fission, transport and autophagy in Parkinson’s
disease: when mitochondria get nasty. Parkinson’s
Disease 767230.
Armstrong C, Ruffer J, Corn B, DeVries K, Mollman J (1995).
Biphasic patterns of memory deficits following moderatedose partial-brain irradiation: neuropsychologic outcome
and proposed mechanisms. Journal of Clinical Oncology
13, 9, 2263-2271.
Armstrong CL, Corn BW, Ruffer JE, Pruit AA, Mollman
JE, Phillips PC (2000). Radiotherapeutic effects on
brain function: double dissociation of memory systems.
Neuropsychiatry Neuropsychology & Behavioral
Neurology 13, 101-111.
Armstrong CL, Hunter JV, Ledakis GE, Cohen B, Tallent EM,
Goldstein BH, Tochner Z, Lustig R, Judy KD, Pruitt A,
Mollman JE, Stanczak EM, Jo MY, Than TL, Phillips P
(2002). Late cognitive and radiographic changes related
to radiotherapy: initial prospective findings. Neurology
59, 40-48.
Azimzadeh O, Scherthan H, Sarioglu H, Barjaktarovic Z,
Conrad M, Vogt A, Calzada-Wack J, Neff F, Aubele M,
Buske C, Atkinson MJ, Tapio S (2011). Rapid proteomic
remodeling of cardiac tissue caused by total body ionizing
radiation. Proteomics 11, 3299-3311.
Azizova TV, Muirhead CR, Moseeva MB, Grigoryeva ES,
Sumina MV, O’Hagan J, Zhang W, Haylock RJ, Hunter N
(2011). Cerebrovascular diseases in nuclear workers first
employed at the Mayak PA in 1948-1972. Radiatiation
and Environmental Biophysics 50, 539-552.
Barjaktarovic Z, Schmaltz D, Shyla A, Azimzadeh O, Schulz
S, Haagen J, Dorr W, Sarioglu H, Schafer A, Atkinson MJ,
Zischka H, Tapio S (2011). Radiation-induced signaling
results in mitochondrial impairment in mouse heart at 4
weeks after exposure to X-rays. PLoS One 6, e27811.
Belka C, Budach W, Kortmann RD, Bamberg M (2001).
Radiation induced CNS toxicity-- molecular and cellular
mechanisms. British Journal of Cancer 85, 1233-1239.
Ben Abdallah NMB, Slomianka L, Lipp HP (2007). A
reversible effect of X-irradiation on proliferation,
neurogenesis and cell death in the dentate gyrus of adult
mice. Hippocampus 17, 1230-1240.
Brown WR, Blair RM, Moody DM, Thore CR, Ahmed S,
Robbins ME, Wheeler KT (2007). Capillary loss precedes
the cognitive impairment induced by fractionated wholebrain irradiation: a potential rat model of vascular
dementia. Journal of the Neurological Sciences 257, 6771.
Bueler H (2009). Impaired mitochondrial dynamics and
function in the pathogenesis of Parkinson’s disease.
Experimental Neurology 218, 235-246.
Butterfield DA, Reed T, Newman SF, Sultana R (2007).
Roles of amyloid beta-peptide-associated oxidative stress
and brain protein modifications in the pathogenesis of
Alzheimer’s disease and mild cognitive impairment. Free
Radical Biology & Medicine 43, 658-677.
Calvo W, Hopewell JW, Reinhold HS, Yeung TK (1988).
Time- and dose-related changes in the white matter of the
rat brain after single doses of X rays. British Journal of
Radiology 61, 1043-1052.
DeAngelis LM, Delattre JY, Posner JB (1989). Radiationinduced dementia in patients cured of brain metastases.
Neurology 39, 6, 789-796.
Duman RS, Heninger GR, Nestler EJ (1997). A molecular
and cellular theory of depression. Archives of General
Psychiatry 54, 7, 597-606.
Eckert A, Schulz KL, Rhein V, Gotz J (2010). Convergence
of amyloid-beta and tau pathologies on mitochondria in
Clinical Neuropsychiatry (2014) 11, 2
vivo. Molecular Neurobiology 41, 107-114.
Elsworth JD, Roth RH (1997a). Dopamine synthesis, uptake,
metabolism, and receptors: relevance to gene therapy of
Parkinson’s disease. Experimental Neurology 144, 4-9.
Elsworth JD, Roth RH (1997b) Dopamine synthesis, uptake,
metabolism, and receptors: relevance to gene therapy of
Parkinson’s disease. Experimental Neurology 144, 4-9.
Enokido Y, Araki T, Tanaka K, Aizawa S, Hatanaka H
(1996). Involvement of p53 in DNA strand break-induced
apoptosis in postmitotic CNS neurons. European Journal
of Neuroscience 8, 1812-1821.
Food and Drug Administration (FDA) (2010). Unveils
initiative to reduce unnecessary radiation exposure from
medical imaging. White paper 9.
Fuller Torrey E (1995). Prevalence of psychosis among
the Hutterites: A reanalysis of the 1950–53 study.
Schizophrenia Research 16, 2, 167-170.
Gobbel GT, Bellinzona M, Vogt AR, Gupta N, Fike JR,
Chan PH (1998). Response of postmitotic neurons to
X-irradiation: implications for the role of DNA damage in
neuronal apoptosis. Journal of Neuroscience 18, 147-155.
Goldhagen P (2000). Overview of aircraft radiation exposure
and recent ER-2 measurements. Health Physics 79, 526544.
Greenamyre JT, Hastings TG (2004). Biomedicine
Parkinson’s-divergent causes, convergent mechanisms.
Science 304, 1120-1122.
Hartung H, Tan SK, Steinbusch HM, Temel Y, Sharp T
(2011). High-frequency stimulation of the subthalamic
nucleus inhibits the firing of juxtacellular labelled 5-HTcontaining neurons. Neuroscience 186, 135-145.
Hernandez-Rabaza V, Llorens-Martin MV, Ferragud A,
Velazquez-Sanches C, Arcusa A, Gomez-Pinedo U,
Perez-Villalba A, Rosello J, Trejo JL Barcia JA, Canales
JJ (2009). Inhibition of adult hippocampal neurogenesis
disrupts contextual learning but spares spatial working
memory, long-term conditional rule retention and spatial
reversal. Neuroscience 159, 59-68
Hirsch EC (1993). Does oxidative stress participate in nerve
cell death in Parkinson’s disease? European Neurolology
33, 52-59.
Hopewell JW, Van Der Kogel AJ (1999). Pathophysiological
mechanisms leading to the development of late radiationinduced damage to the central nervous system. Frontiers
of Radiation Therapy and Oncology 33, 265-275.
Iwata Y, Suzuki K, Wakuda T, Seki N, Thanseem I, Matsuzaki
H, Mamiya T, Ueki T, Mikawa S, Sasaki T, Suda S,
Yamamoto S, Tsuchiya KJ, Sugihara G, Nakamura K,
Sato K, Takei N, Hashimoto K, Mori N (2008). Irradiation
in adulthood as a new model of schizophrenia. PLoS One
e2283.
Jenner P (1998). Oxidative mechanisms in nigral cell death
in Parkinson’s disease. Movement Disorders 13, Suppl 1,
24-34.
Komasa Y, Hasebe AK, Tsuboi M, Jimba M, Kimura S
(2013). Prioritizing mental health issues of community
residents affected by Fukushima Daiichi nuclear power
plant accident. Clinical Neuropsychiatry 10, 6, 241-244.
Knott C, Stern G, Wilkin GP (2000). Inflammatory
regulators in Parkinson’s disease: iNOS, lipocortin-1,
and cyclooxygenases-1 and -2. Molecular and Cellular
Neuroscience 16, 724-739.
Kurata T, Miyazaki K, Kozuki M, Morimoto N, Ohta Y, Ikeda
Y, Abe K (2011). Progressive neurovascular disturbances
in the cerebral cortex of Alzheimer’s disease-model mice:
protection by atorvastatin and pitavastatin. Neuroscience
197, 358–368.
Land CE (1980). Estimating cancer risks from low doses of
ionizing radiation. Science 209, 1197-1203
Licker V, Kovari E, Hochstrasser DF, Burkhard PR (2009).
Proteomics in human Parkinson’s disease research.
65
Donatella Marazziti et al.
Journal of Proteomics 73, 10-29.
Loganovsky KN, Loganovskaja TK (2000). Schizophrenia
spectrum disorders in persons exposed to ionizing
radiation as a result of the Chernobyl accident.
Schizophrenia Bulletin 26, 751-773.
Loganovsky KN, Loganovskaja TK (2013). Cortical-limbic
neurogenesis asymmetry as possible cerebral basis of
brain laterality following exposure to ionizing radiation.
Clinical Neuropsychiatry 10, 3/4, 174.
Loganovsky KN, Volovik SV, Manton KG, Bazyka DA, FlorHenry P (2005). Whether ionizing radiation is a risk factor
for schizophrenia spectrum disorders? The World Journal
of Biological Psychiatry 6, 212–230.
Malone J, Guleria R, Craven C, Horton P, Järvinen H, Mayo
J, O’reilly G, Picano E, Remedios D, Leheron J, Rehani
M, Holmberg O, Czarwinski R (2012). Justification of
diagnostic medical exposures, some practical issues:
report of an International Atomic Energy Agency
Consultation. British Journal of Radiology 85, 523-538.
Manji HK, Quiroz JA, Payne JL, Singh J, Lopes BP, Viegas
JS, Zarate CA (2003). The underlying neurobiology of
bipolar disorder. World Psychiatry 2, 3, 136-146.
McGeer PL, McGeer EG (2004). Inflammation and
neurodegeneration in Parkinson’s disease. Parkinsonism
& Related Disorders 10, Suppl 1, S3-S7.
Mirza B, Hadberg H, Thomsen P, Moos T (2000). The
absence of reactive astrocytosis is indicative of a
unique inflammatory process in Parkinson’s disease.
Neuroscience 95, 425-432.
Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002).
Irradiation induces neural precursor-cell dysfunction.
Nature Medicine 8, 955-962.
Monje ML, Palmer T (2003). Radiation injury and
neurogenesis. Current Opinion in Neurology 16, 129-134.
Monje ML, Toda H, Palmer TD (2003). Inflammatory
blockade restores adult hippocampal neurogenesis.
Science 5, 1760-1765.
Mrak RE, Griffin WS (2007). Common inflammatory
mechanisms in Lewy body disease and Alzheimer disease.
Journal of Neuropathology & Experimental Neurology
66, 683-686.
Nakane Y, Ohta Y (1986). An example from the Japanese
Register: Some long-term consequences of the A-bomb
for its survivors in Nagasaki. In: Giel R, Gulbinat WH,
Henderson JH, editors. Psychiatric case registers in
public health. Amsterdam: Elsevier Science Publishers
B.V. pp 26 -27.
Nyagu AI, Loganovsky KN, Loganovskaja TK (1998).
Psychophysiologic aftereffects of prenatal irradiation.
International Journal of Psychophysiology 30, 303-311.
Park RM, Schulte PA, Bowman JD, Walker JT, Bondy SC,
Yost MG, Mouchstone JA, Dosemeci M (2005). Potential
occupational risks for neurodegenerative diseases.
American Journal of Industrial Medicine 48, 1, 63-77.
Peper M, Steinvorth S, Schraube P, Fruehauf S, Haas R,
Kimmig BN, Lohr F, Wenz F, Wannenmacher M (2000).
Neurobehavioral toxicity of total body irradiation: a
follow-up in long-term survivors. International Journal
of Radiation Oncology Biology Physics 46, 2, 303-311.
Picano E (2004). Sustainability of medical imaging. Education
and debate. British Medical Journal 328, 578-580.
Picano E, Vano E (2011). The radiation issue in cardiology:
the time for action is now. Cardiovascolar Ultrasound 9,
35.
Piccinni A, Marazziti D, Del Debbio A, Bianchi C, Roncaglia
I, Mannari C, Origlia N, Catena Dell’Osso M, Massimetti
G, Domenici L, Dell’Osso L (2008a). Diurnal variation
of plasma brain-derived neurotrophic factor (BDNF) in
humans: an analysis of sex differences. Chronobiology
International 25, 5, 819-826.
Piccinni A, Marazziti D, Catena M, Domenici L, Del Debbio
66
A, Bianchi C, Mannari C, Martini, C, Da Pozzo E, Schiavi
E, Mariotti A, Roncaglia I, Palla A, Consoli G, Giovannini
L, Massimetti G, Dell’Osso L (2008b). Plasma and serum
brain-derived neurotrophic factor (BDNF) in depressed
patients during 1 year of antidepressant treatments.
Journal of Affective Disorders 105 (1-3), 279-283.
Piccinni A, Del Debbio A, Medda P, Bianchi C, Roncaglia I,
Veltri A, Zanello S, Massimetti E, Origlia N, Domenici L,
Marazziti D, Dell’Osso L (2009). Plasma Brain-Derived
Neurotrophic Factor in treatment-resistant depressed
patients receiving electroconvulsive therapy. European
Neuropsychopharmacology 19, 5, 349-355.
Pinkerton LE, Waters MA, Hein MJ, Zivkovich Z, SchubauerBerigan MK, Grajewski B (2012). Cause-specific
mortality among a cohort of U.S. flight attendants.
American Journal of Industrial Medicine 55, 1, 25-36.
Ponomarenko VM, Nahorna AM, Osnach HV, Proklina TL
(1999). An epidemiological analysis of the health status
of the participants in the cleanup of the aftermath of the
accident at the Chernobyl atomic electric power station.
Lik Sprava 8, 39-41.
Popoli M, Gennarelli M, Racagni G (2002). Modulation of
synaptic plasticity by stress and antidepressants. Bipolar
Disorder 4, 3, 166-182.
President’s Cancer Panel (2010). Environmental cancer risk
underestimated. (deainfo.nci.nih.gov/advisory/pcp/pcp.
htm)
Prithivirajsingh S, Story MD, Bergh SA, Geara FB, Ang KK,
Ismail SM, Stevens CW, Buchholz TA, Brock WA (2004).
Accumulation of the common mitochondrial DNA
deletion induced by ionizing radiation. FEBS Letters 571,
227-232.
Reinhold HS, Calvo W, Hopewell JW, Van Der Berg AP
(1990). Development of blood vessel-related radiation
damage in the fimbria of the central nervous system.
International Journal of Radiation Oncology Biology
Physics 18, 37-42.
Rola R, Fishman K, Baure J, Rosi S, Lamborn KR, Obenaus A,
Nelson GA, Fike JR (2008). Hippocampal neurogenesis
and neuroinflammation after cranial irradiation with (56)
Fe particles. Radiation Research 169, 626-632.
Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt
DR, Fike JR (2004). Radiation-induced impairment of
hippocampal neurogenesis is associated with cognitive
deficits in young mice. Experimental Neurology 188,
316-330.
Roman DD, Sperduto PW (1995). Neuropsychological
effects of cranial radiation: current knowledge and future
directions. International Journal of Radiation Oncology
Biology Physics 31, 983–998.
Sadetzki S, Chetrit A, Mandelzweig L, Nahon D, Freedman L,
Susser E, Gross R (2011). Childhood exposure to ionizing
radiation to the head and risk of schizophrenia. Radiation
Research 176, 670-677.
Schmäl C, Höfels S, Zobel A, Illig T, Propping P, Holsboer
F, Rietschel M, Nöthen MM, Cichon S (2005). Evidence
for a relationship between genetic variants at the brainderived neurotrophic factor (BDNF) locus and major
depression. Biological Psychiatry 58, 4, 307-314.
Schulte PA, Burnett CA, Boeniger MF, Johnson J (1996).
Neurodegenerative diseases: occupational occurrence
and potential risk factors, 1982 through 1991. American
Journal of Public Health 86, 1281-1288.
Schulz RJ, Albert RE (1968). Follow-up study of patients
treated by X-ray epilation for tinea capitis. 3. Dose to
organs of the head from the X-ray treatment of tinea
capitis. Archives of Environmental Health 17, 935-950.
Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N,
Binder EB, Schulze TG, Deschner M, Schmäl C, Höfels
S, Zobel A, Illig T, Propping P, Holsboer F, Rietschel M,
Nöthen MM, Cichon S (2005). Evidence for a relationship
Clinical Neuropsychiatry (2014) 11, 2
Psychiatric effects of ionizing radiation
between genetic variants at the brain-derived neurotrophic
factor (BDNF) locus and major depression. Biological
Psychiatry 58, 4, 307-314.
Shore JH, Tatum EL, Vollmer WM (1986). Psychiatric
reactions to disaster: the Mount St. Helens experience.
The American Journal of Psychiatry 143, 5, 590-595.
Sibley RF, Moscato BS, Wilkinson GS, Natarajan N (2003).
Nested case-control study of external ionizing radiation
dose and mortality from dementia within a pooled cohort
of female nuclear weapons workers. American Journal of
Industrial Medicine 44, 351-358.
Silasi G, Diaz-Heijtz R, Besplug J, Rodriguez-Juarez R, Titov
V, Kolb B, Kovalchuk O (2004). Selective brain responses
to acute and chronic low-dose X-ray irradiation in males
and females. Biochemical and Biophysical Research
Communications 325, 1223-1235.
Tofilon PJ, Fike JR (2000). The radioresponse of the central
nervous system: a dynamic process. Radiation Research
153, 357-370.
Tong XK, Lecrux C, Hamel E (2012). Age-dependent rescue
by simvastatin of Alzheimer’s disease cerebrovascular
and memory deficits. Journal of Neuroscience 32, 47054715.
United Nations Scientific Committee on the Effects of Atomic
Radiation (UNSCEAR) (2008). Sources and effects of
ionizing radiation. United Nations Scientific Committee
on the Effects of Atomic Radiation.
Van Der Maazen RW, Kleiboer BJ, Verhagen I, Van Der Kogel
AJ (1993). Repair capacity of adult rat glial progenitor
cells determined by an in vitro clonogenic assay after
in vitro or in vivo fractionated irradiation. International
Journal of Radiation Biology 63, 661-666.
Venneri L, Rossi F, Botto N, Andreassi MG, Salcone N,
Emad A, Lazzeri M, Gori C, Vano E, Picano E (2009).
Cancer risk from professional exposure in staff working
in cardiac catheterization laboratory: insights from the
National Research Council’s Biological Effects of Ionizing
Radiation VII Report. American Heart Journal 157, 118124.
Clinical Neuropsychiatry (2014) 11, 2
Viticchi G, Falsetti L, Vernieri F, Altamura C, Bartolini M, Luzzi
S, Provinciali L, Silvestrini M (2012). Vascular predictors of
cognitive decline in patients with mild cognitive impairment.
Neurobiology of Aging 33, 1127, 1-9.
Wilkinson GS, Trieff N, Graham R, Priore RL (2000). Study
of mortality among female nuclear weapons workers.
Final report: NIOSH Grant Nos. 1RO1 OHO3274, RO1/
CCR214546, RO1/CCR61, 2000, 2934-01.
Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang
S (2006). Inhibition of neurogenesis interferes with
hippocampus-dependent memory function. Hippocampus
16, 3, 296-304.
Wojtowicz JM (2006). Irradiation as an experimental tool in
studies of adult neurogenesis. Hippocampus 16, 261-266.
Wojtowicz JM, Askew ML, Winocur G (2008). The effects
of running and inhibiting adult neurogenesis on learning
and memory in rats. European Journal of Neuroscience
27, 1494-1502.
Yamada M, Sasaki H, Mimori Y, Kasagi F, Sudoh S, Ikeda
J, Hosada Y, Nakamura S, Kodama K (1999). Prevalence
and risks of dementia in the Japanese population: RERF’s
adult health study Hiroshima subjects. Radiation effects
research foundation. Journal of The American Geriatric
Society 47, 189-195.
Zeeb H, Hammer GP, Langner I, Schafft T, Bennack S,
Blettner M (2010). Cancer mortality among German
aircrew: second follow-up. Radiation and Environmental
Biophysics 49, 187-194.
Zhavoronkova LA, Gogitidze NV, Kholodova NB (1997).
The characteristics of the late reaction of the human brain
to radiation exposure: the EEG and neuropsychological
study (the sequelae of the accident at the Chernobyl
atomic electric power station). Zhurnal Vysshei Nervnoi
Deiatelnosti Imeni IP Pavlova 46, 699-711.
Zlokovic BV (2008). The blood–brain barrier in health and
chronic neurodegenerative disorders. Neuron 57, 178-201.
Zuccato C, Cattaneo E (2009). Brain-derived neurotrophic
factor in neurodegenerative diseases. Nature Reviews
Neurology 5, 311-322.
67