Neuroregeneration in neurodegenerative disorders.
ABSTRACT Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration--implantation of viable cells as a therapeutical approach.
Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies.
In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.
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ABSTRACT: Alzheimer's disease (AD) is a progressive and neurodegenerative disorder that induces dementia in older people. It was first reported in 1907 by Alois Alzheimer, who characterized the disease as causing memory loss and cognitive impairment. Pathologic characteristics of AD are β-amyloid plaques, neurofibrillary tangles and neurodegeneration. Current therapies only target the relief of symptoms using various drugs, and do not cure the disease. Recently, stem cell therapy has been shown to be a potential approach to various diseases, including neurodegenerative disorders, and in this review, we focus on stem cell therapies for AD.International Journal of Molecular Sciences 10/2014; 15(10):19226-19238. · 2.34 Impact Factor
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ABSTRACT: The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a peptide that has a neuroprotective action against dopaminergic damage by MPP(+), both in vitro and in vivo. The trophic effects of Hc-TeTx have been related to its ability to activate the pathways of the tropomyosin receptor kinase, which are crucial for survival process. Our group had previously shown neuroprotective effect of intramuscular Hc-TeTx treatment on animals with a dopaminergic lesion; however, there is no evidence indicating its restorative effects on advanced dopaminergic neurodegeneration. The aim of our study was to examine the restorative effects of an intramuscular injection of the Hc-TeTx fragment on the nigrostriatal system of hemiparkinsonian rats. The animals were administered with a vehicle or Hc-TeTx (20μg/kg) in the gastrocnemius muscle for three consecutive days post-dopaminergic lesion, which was made using 6-hydroxydopamine. Post-Hc-TeTx treatment, the hemiparkinsonian rats showed constant motor asymmetry. Moreover, the ipsilateral striatum of the post-Hc-TeTx group had a lower number of argyrophilic structures and a major immunorreactivity to Tyrosine Hydroxylase in the striatum and the Substantia Nigra pars compacta compared to the 6-OHDA group. Our results show the restorative effect of the Hc-TeTx fragment during the dopaminergic neurodegeneration caused by 6-OHDA.Neuroscience Research 05/2014; · 2.15 Impact Factor
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ABSTRACT: One of the common effects of lithium (Li) and valproic acid (VPA) is their ability to protect against excitotoxic insults. Neurodegenerative and neuropsychiatric diseases may be also associated with altered trophic support of brain-derived neurotrophic factor (BDNF), the most widely distributed neurotrophin in the central nervous system. However, despite these evidences, the effect of Li-VPA combination on BDNF after excitoxic insult has been inadequately investigated. We address this issue by exposing a human neuroblastoma cell line (SH-SY5Y) to neurotoxic concentration of L-glutamate and exploring whether the neuroprotective action of Li-VPA on these cells is associated with changes in BDNF protein and mRNA levels. The results showed that pre-incubation of Li-VPA abolished the toxic effect of glutamate on SH-SY5Y cell survival and this neuroprotective effect was associated with increased synthesis and mRNA expression of BDNF after 24 and 48 h of incubation. In conclusion, this study demonstrates that the neuroprotective effects of Li-VPA against glutamate-induced neurotoxicity in SH-SY5Y neuroblastoma cells is associated with increased synthesis and mRNA expression of BDNF. These data further support the idea that these two drugs can be used for prevention and/or treatment of glutamate-related neurodegenerative disorders.Journal of Psychopharmacology 04/2014; · 2.81 Impact Factor
Neuroregeneration in neurodegenerative
Ana M Enciu1, Mihnea I Nicolescu1,2, Catalin G Manole1,2, Dafin F Mureşanu3, Laurenţiu M Popescu1,2and
Bogdan O Popescu2,4*
Background: Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and
neurorestoration - implantation of viable cells as a therapeutical approach.
Discussion: Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer’s Disease
or Parkinson’s Disease and correlate with low endogenous protection, as a result of a diminished growth factors
expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a
“neuroregenerative reserve”, that could be exploited by growth factors or stem cells-neurorestoration therapies.
Summary: In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer’s
Disease and Parkinson’s Disease.
Adult neuroregeneration is a complex concept, beyond
the common knowledge of neurogenesis that also com-
prises endogenous neuroprotection leading to neuro-
plasticity and neurorestoration -a therapeutical approach
of implantation of viable cells (Figure 1). Regeneration
in the central nervous system (CNS) implies that new
neurons, generated either through proliferation of endo-
genous stem/progenitor cells or by administration of
exogenous stem/precursor cells with potential to substi-
tute for lost tissue, will differentiate, survive, and inte-
grate into existing neural networks . Among the three
components of neuroregeneration previously mentioned,
neuroplasticity was the first one put forward, by Ramon
y Cajal, in 1894: “associations already established among
certain groups of cells would be notably reinforced by
means of the multiplication of the small terminal
branches of the dendritic appendages and axonal collat-
erals; but, in addition, completely new intercellular con-
nections could be established thanks to the new
formation of [axonal] collaterals and dendrites.” .
However, Ramon y Cajal discards, in the same paper,
the possibility of cell renewal: “it is known that the
nerve cells after the embryonic period have lost the
property of proliferation”. Adult neurogenesis was pro-
posed by Joseph Altman in the 1960’s, in a series of arti-
cles involving tritiated thymidine retaining cells in the
rat brain [3-5]. The newly emerged concept was a con-
troversy until the early 1990s, when several reports [6-9]
proved beyond doubt the existence of adult neural stem
The concepts of neuroplasticity and neural stem cells
led to the idea of neurorestoration as an alternative
therapy for neurodegenerative disorders such as Alzhei-
mer’s Disease (AD) and Parkinson’s Disease (PD), both
characterized by neuronal loss. Our review will attempt
to answer the question “Is there any neuroregeneration
in neurodegeneration?” taking into account the three
concepts mentioned above.
Neurogenesis in neurodegenerative diseases
The adult mammalian brain retains a limited capacity of
neurogenesis, which manifests in the subventricular
zone (SVZ) and subgranular zone of the hippocampal
dentate gyrus. The neuronal precursors migrate into the
olfactory bulb, the granular cell layer, or, if necessary, to
the striatum, CA1 region of hippocampus or cerebral
* Correspondence: email@example.com
2Laboratory of Molecular Medicine, ‘Victor Babeş’ National Institute of
Pathology, 99-101 Splaiul Independenţei, sector 5, Bucharest 050096,
Full list of author information is available at the end of the article
Enciu et al. BMC Neurology 2011, 11:75
© 2011 Enciu 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.
Alzheimer’s Disease animal models
Neurogenesis in AD transgenic mice is usually impaired,
but the results may differ from one transgenic strain to
another . Haughey et al. reported that proliferation
and survival of neural precursor cells (NPC) was
reduced in the dentate gyrus of APP mutant mice with
already constituted amyloid deposits . Furthermore,
the decrement in NPC number was correlated with
accumulation of Ab, even in oligomeric, diffusible form
. Although Kolecki et al. confirmed the previous
results, they reported that overexpressing APP and Ab
in transgenic mice do not interfere with the mitotic
activity of NPC, as assessed by Ki-67 .
In vitro, Ab effects reported on mouse brain-derived
neurospheres are different with the type of peptide used:
i) Ab 25-35 induces neuronal differentiation and apop-
tosis in neural committed cells ; ii) Ab40 promotes
neurogenesis in NPCs ; iii) Ab42 stimulates neuro-
sphere formation and increases the number of neuronal
precursors ; it also has a reported effect of inducing
astrocytic differentiation .
Evidence of neurogenesis in AD human brain
An overexpression of neurogenesis markers (Doublecor-
tin - DCX, Polysialylated Neural Cell Adhesion Molecule
- PSA-NCAM and TUC-4) in hippocampus of AD
patients, without a correlated increase in mature neuro-
nal markers (NeuN, Calbinding D28k) is reported by Jin
et al. . This expression disjunction sustains the
hypothesis of AD as a failed attempt of precursor cells to
neuronal differentiation , but Boekhoorn et al argue
that DCX is a nonspecific marker, increased due to reac-
tive gliosis . Furthermore, Verwer et al. questioned
whether DCX+ cells are indeed neuroblasts, presenting
arguments for their astrocytic origin . Investigating
Musashi1 immunoreactivity in SVZ of AD patients, Ziab-
reva et al. also reported impaired neurogenesis, as com-
pared to controls . In turn, although Lovell et al.
isolated viable NSC from AD patients’ hippocampi, they
obtained decreased viable NPC yields and altered division
rates, as compared to controls .
In vitro studies using human neurospheres reported,
unlike in vitro models using rodent NPCs, that Ab 1-40
treatment impaired proliferation and differentiation of
precursor cells .
In order to assess neurogenesis in AD brain, adding to
contradictory results in literature, one must further take
into account the neurogenesis-stimulating effect of AD
Neurogenesis in PD animal models
Adult mice substantia nigra contains bromodeoxyuridine
(BrdU) incorporating cells that show dividing and differ-
entiating properties. In vivo, this potential seems to mate-
rialize into glial lineage, whereas in vitro, under
appropriate growth factors stimulation, neuronal pro-
genitors may be identified . Reports regarding neuro-
genesis in 6-hydroxydopamine (6-OHDA) models of PD
showed increased number of BrdU+ cells and a tendency
to migrate towards the lesioned striatal nuclei , but
without further differentiation on neural lineage .
Transgenic mice overexpressing human mutated a
synuclein exhibited reduced BrdU+ cells and decreased
survival of newly generated neurons, as compared to
aged-matched controls. Interestingly, the cessation of a
synuclein overexpression led to recovered neurogenesis
Neurogenesis in PD human brain
The numbers of proliferating cells in the subependymal
zone and neural precursor cells in the subgranular zone
and olfactory bulb are reduced in postmortem brains of
Parkinson’s Disease patients . However, there are
reports of newly generated neuroblasts PSA-NCAM + in
substantia nigra of PD patients, without a solid proof of
further dopaminergic neuronal differentiation or reinte-
gration in neuronal circuitry .
Endogenous neuroprotection and growth factors
Discovery of growth factors and their pro-survival effect
led to a closer investigation of specific nervous system
Figure 1 The large concept of neuroregeneration contains
three landmarks: endogenous protection by growth factors,
neurogenesis and neurorestoration. Rather than perceiving them
as isolated events, they should be viewed interrelated, one creating
the premises for generating the other.
Enciu et al. BMC Neurology 2011, 11:75
Page 2 of 7
cytokines - Nerve Growth Factor (NGF), Brain-Derived
Nerve Factor (BDNF), Glial-Derived Nerve Factor
(GDNF) - involvement in the outcome of neurodegen-
erative diseases. Interestingly, different neuronal subpo-
pulations require different growth factors to thrive, for
example NGF protects cholinergic neurons from various
insults , whereas for dopaminergic neurons, this
effect is better sustained by BDNF .
Neurotrophins (NGF, BDNF, neurotrophin 3 - NT3
and neurotrophin 4 - NT 4) are most studied for their
involvement in normal central nervous system (CNS)
development [33-36] and in normal  or pathological
ageing [38-40]. They exert their effect through tropo-
myosin-related kinase (Trk) receptors and activation of
several signaling cascades: i) IP3-DAG and subsequent
release of calcium, leading to synaptic plasticity; ii)
PI3K/Akt and transcription of prosurvival genes and iii)
MAPK/ERK and activation of differentiation promoting
substrates . With low affinity and also in immature
form (as proneurotrophins) they interact with p75NTR-
a tumor necrosis factor receptor which, in turn, upon
activation, leads to apoptosis in neuronal and non-neu-
ronal cells . Glial -Derived Neurotrophic Factor
(GDNF) is a growth factor from the transforming
growth factor b (TGFb) superfamily, with documented
neuroprotective effects in dopaminergic neurons cell
cultures , in vivo studies on laboratory animals 
and in animal models of PD [45,46]. It exerts its effects
through Ret receptor tyrosine kinase and GDNF family
receptor a1 (GFRa1) complex , although the role of
Ret signaling is controversial [48,49]. Mesencephalic
Astrocyte-Derived Neurotrophic Factor (MANF) and
Conserved Dopamine Neurotrophic Factor (CDNF) are
members of a novel, evolutionarily conserved neuro-
trophic factor family with specific protective properties
on dopaminergic neurons, as shown in 6-hydroxydopa-
mine (6-OHDA) animal models of PD . Further-
more, they seem to act more effectively than GDNF and
use a different protective mechanism .
Neurotrophins and growth factors in neurodegeneration
In both AD and PD human brains, levels of BDNF 
and its mRNA  are low. Furthermore, BDNF serum
levels correlate with AD severity . Correlated altera-
tion in TrkB expression in AD is also reported in corti-
cal neurons, but not in glial cells, which, surprisingly,
upregulate a truncated form of the receptor .
According to Tong et al., BDNF signaling pathway
seems also to be negatively affected in AD, by Ab 1-42
peptide interference with gene transcription. Treatment
of rat cortical neurons cultures with sublethal doses of
Ab peptide, interfered with the CREB activation-induced
transcription of the BDNF gene and suppressed BDNF-
induced activation of selective signaling pathways such
as Ras-MAPK/ERK and PI3-K/Akt .
The reports regarding NGF mRNA and protein levels
in AD brain are contradictory [57-59]. NGF deficiency
has been proposed as ethiopatogenic factor in sporadic
AD, and the AD11 anti-NGF mice recreate the pheno-
type and the functional impairment of early AD stages
. Also, in early stages, a loss of TrkA has been
reported , while Cuello et Bruno proposed the exis-
tence of a failure of the NGF maturation cascade in AD
. Ab load recreates the same NGF “dismetabolism”
in the hippocampus of laboratory rats, as proposed by
Cuello et al. . In vitro models showed Ab peptide as
a potent NGF -secretion stimulator in astrocytic rat cul-
tures and, in turn, NGF was shown to increase neuro-
toxic potency of amyloid peptide in primary rat
hippocampal cultures via p75 induction .
It is well documented that brains of PD patients
express lower GDNF levels  and growth factor deliv-
ery in brain of PD animal models exerts neuroprotective
effects and improves clinical outcome [65,66]. Further-
more, Sun et al. demonstrated in a rat model that
GDNF is more efficient than BDNF in protecting striatal
neurons from 6-hydroxydopamine (6-OHDA), compared
to the control group or BDNF group. Moreover, simul-
taneous administration of both growth factors showed
no benefit over GDNF treatment alone . However,
using vector-induced striatal neuron-restricted expres-
sion of both GDNF and BDNF genes, Cao et al.
reported an improved protein expression as to either
approach alone .
In human AD studies, there are controversial reports
of GDNF protein levels. Straten et al. reported higher
CSF concentration than age-matched controls along
with decreased serum concentration , whereas
Marksteiner’s et al. results showed increased plasma
levels in AD and mild cognitive impairment (MCI)
patients . However, in light of the serious side
effects reported after intracerebroventricular infusion of
GDNF in parkinsonian patients , attention was
drown toward MANF and CDNF, which will hopefully
make good candidates for novel therapies in PD.
Neuroplasticity in neurodegeneration
Neuroplasticity is a comprehensive term that illustrates
the brain’s capacity to adapt, structurally and function-
ally, to environmental enhancement. According to
Thickbroom and Mastaglia, the molecular mechanisms
underlying neuroplasticity are both neuronal and non-
neuronal and, furthermore, neuronal plasticity may be
synaptic or non-synaptic . Neuroplasticity is substrate
for learning and memory formation, cognitive abilities
progressively lost in AD and in late stages of PD.
Synaptic loss is one of the neurobiological hallmarks
of AD, from the first stages of the disease . The
synaptic dysfunction is apparently due to soluble Ab
Enciu et al. BMC Neurology 2011, 11:75
Page 3 of 7
oligomers, as proven by studies on human AD brains
 and AD animal models . Soluble Ab oligomers
have a proven inhibitory effect on NMDA-R - depen-
dent LTP , impairing even further the neuroplasti-
city, besides their roles in morphological and structural
degeneration of the synapse .
Synapse alteration is initially compensated by
“dynamic synaptic reorganization”, emphasized by a
paradoxical initial increase in synaptic markers . The
proof of network reorganization is sustained by studies
on AD brains showing increased polysialylated neural
cell adhesion molecule (PSA-NCAM) in dentate gyrus,
as compared to controls . Also investigating NCAM,
Jørgensen et al hypothesize that AD brain uses neuro-
plasticity as a compensatory measure for neuronal loss
. Furthermore, inflammatory environment - a con-
stant finding in AD brain - impairs neuronal plasticity
by inhibiting both (NMDA-R) - induced and voltage-
dependent calcium channel (VDCC)-induced LTP .
The other neuropathological hallmark of AD, tau hyper-
phosphorylation, correlates with low neuronal plasticity
and synaptic disorganization, as proven by studies on
hibernating animals . Possibly a protective mechanism
against neuronal apoptosis in unfavorable conditions, per-
sistent hyperphosphorylation will eventually lead to forma-
tion of paired helical filaments and cell destruction.
PD animal models also show impaired neuroplasticity.
Studies in mice overexpressing human a-synuclein
report both short-term and long-term altered presynap-
tic plasticity in the corticostriatal pathway . Trans-
genic mice bearing mutated a-synuclein - (A30P) a-
synuclein - also showed impaired short-time synaptic
plasticity  and the (6-OHDA) PD animal models
develop defective synaptic plasticity induction .
Morphological studies of idiopathic PD brains and PD
animal models reported that loss of dopaminergic input
on medium spiny neurons of striatum resulted in lower-
ment of dendritic length, dendritic spine density, and
total number of dendritic spines .
To conclude so far, there is evidence of impaired
neural plasticity in both AD  and PD  brains,
which occurs on various molecular levels, from growth
factors signaling to synaptic malfunction, disorganization
and cytoskeletal rearrangement. However, the brain pos-
sesses a latent recovery capacity and in early stages
some compensatory mechanisms are triggered (see
Table 1). Furthermore, the brain’s capacity to compen-
sate these structural and functional deficits is exploited
by neurorestoration attempts in animal models and
patients, as discussed below.
At the base of initial neurorestoration attempts lies the
idea of enhancing the endogenous neuroprotective effect
of growth factors in the CNS. At first, genetically modi-
fied fibroblasts to produce either BDNF, or NGF have
been transplanted in laboratory rats [88,89] and pri-
mates . The experiments were successful in rescuing
functional and cellular loss. The same type of experi-
ment was conducted, in 2005, on human patients, diag-
nosed with AD . The delivery system consisted of
induced pluripotent stem cells (iPS), generated from the
recipient’s fibroblast population and genetically modified
into secreting NGF. The authors reported significant
progress at 22 months follow-up, quantified by cognitive
scales and PET -Scan.
For PD patients, there are reports since the 1980’s of
fetal midbrain dopamine cells implants . The clinical
Table 1 Evidences of impaired neuroregeneration in AD and PD
Evidence of impairment Evidence of compensatory mechanism
Neurogenesis AD Decreased number of NPCs and altered division rates Increased neuroproliferation markers 
PD Reduced number of NPCs Increased number of PSA-NCAM + cells 
Neuroprotection AD Low BDNF mRNA and protein levels 
Controversed data on NGF levels [40,48,49]
Upregulation of glial truncated TrkB 
Possibly upregulation of NGF with ageing and
Ab stimulates NGF astrocytic secrection 
High GDNF levels in cerebrospinal fluid
PD Low BDNF mRNA and protein levels  BDNF pretreatment protects dopaminergic neurons
Low GDNF protein levels 
NeuroplasticityAD Synaptic loss 
LTP impairment by Abeta oligomers and inflammatory
“Dynamic synaptic reorganization” .
NCAM increase in dentate gyrus 
PD Loss of dendritic spines following loss of dopaminergic input 
Impaired synaptic plasticity in several models of PD [87-89]
Enciu et al. BMC Neurology 2011, 11:75
Page 4 of 7
outcome was improved [93,94] and engraftment of trans-
planted cells was successful [95,96], although some
authors questioned the utility of the procedure in older
patients . However, two double-blinded, randomized,
controlled trials set back the initial positivism, showing
cell transplantation to be less effective than deep brain sti-
mulation , in preventing recurrent dyskinesia. It seems
however, that reported improvement is due to replace-
ment by graft cells of aged brain cells , rather than sti-
mulation of the brain’s own neurorestorative mechanism.
Other restorative models, tested in vitro or in animal
models of AD and PD, use stem cells therapy: i) embryo-
nic stem cells ; ii) embryonic stem cells-derived neu-
rospheres ; iii) transdifferentiated stem cells (stem
cells forced to differentiate outside their lineage by special
growth media and specific stimuli) (e.g. hematopoietic
stem cells), or iv) mesenchimal stem cells induced into
secreting increased quantities of growth factors .
Apel et al. report neuroprotective effects of dental pulp
cells co-cultured with hippocampal and mesencephalic rat
neurons, in in vitro AD and PD models . Murell et al
used human olfactory mucosa-derived neuronal progeni-
tors to obtain dopaminergic neurons and transplant them
in a rat PD model brain. The outcome was favorable and
no difference was noted between transplants received
form healthy donors or from Parkinson patients .
As expected, most reports incline towards progressive
impairment of neuroregeneration resources in AD and
PD brains, as proven on human post-mortem analysis,
animal models and in vitro studies. However, due to
increased amount of evidence that proper stimulation or
supply of growth factors restores some of the cognitive
loss and ameliorates behavioral skills, we hypothesize
that the brain possess, at least in early and medium stages
of disease, a “neuroregenerative reserve”, that may be and
begins to be, targeted as a therapeutical perspective.
List of abbreviations
AD: Alzheimer’s Disease; PD: Parkinson’s Disease; NPCs: neural precursor cells;
PSA-NCAM: Polysialylated Neural Cell Adhesion Molecule; BDNF: Brain
Derived Nerve Factor; TrkB: tropomyosin-related kinase receptor B; NGF:
Nerve Growth Factor; GDNF: Glial Derived Nerve Factor
This paper is supported by the Sectorial Operational Programme Human
Resources Development (SOP HRD), financed from the European Social Fund
and by the Romanian Government under the contract number POSDRU/89/
1.5/S/64109 and by the Executive Unit for Financing Higher Education,
Research, Development and Innovation - Romania (UEFISCDI), Program 4
(Partnerships in Priority Domains), grant nr. 41-013/2007.
1Department of Cellular and Molecular Medicine, ‘Carol Davila’ University of
Medicine and Pharmacy, School of Medicine, 8 Eroilor Sanitari, sector 5,
Bucharest 050474, Romania.2Laboratory of Molecular Medicine, ‘Victor Babeş’
National Institute of Pathology, 99-101 Splaiul Independenţei, sector 5,
Bucharest 050096, Romania.3Department of Neurology, ‘Iuliu Hatieganu’
University of Medicine and Pharmacy, 8, Victor Babeş, Cluj Napoca 400023,
Romania.4Department of Neurology, University Hospital Bucharest, ‘Carol
Davila’ University of Medicine and Pharmacy, 169 Splaiul Independenţei,
sector 5, Bucharest 050098, Romania.
All authors contributed equally to elaboration of the manuscript, read and
approved the final manuscript.
The authors declare that they have no competing interests.
Received: 5 March 2011 Accepted: 23 June 2011
Published: 23 June 2011
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The pre-publication history for this paper can be accessed here:
Cite this article as: Enciu et al.: Neuroregeneration in neurodegenerative
disorders. BMC Neurology 2011 11:75.
Enciu et al. BMC Neurology 2011, 11:75
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