Vibrational Spectroscopy 53 (2010) 181–188

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Vibrational Spectroscopy
journal homepage: www.elsevier.com/locate/vibspec

Neural network algorithm for the early detection of Parkinson’s disease from
blood plasma by FTIR micro-spectroscopy
Shiek S.S.J. Ahmed a, Winkins Santosh a,*, Suresh Kumar b,*, T. Hema Thanka Christlet c
a
Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur, Tamil Nadu 603203, India
b
Department of Neurology, SRM Medical College Hospital and Research, SRM University, Kattankulathur, Tamil Nadu 603203, India
c
Department of Physics, Arignar Anna Government Arts College, Cheyyar, Thiruvannamalai -604 407, India

A R T I C L E I N F O A B S T R A C T

Article history: Parkinson’s disease (PD) is a progressive bradykinetic disorder. Diagnosis of PD is entirely clinical, no
Received 31 October 2009 biochemical parameters exist to diagnose PD. The diagnostic problem associated with the early detection
Received in revised form 25 January 2010 has led to an interest in the development of spectroscopic based diagnostic techniques. Fourier-
Accepted 25 January 2010
transform infrared micro-spectroscopy analysis (FTIR) was applied to analyze human plasma samples of
Available online 2 February 2010
69 healthy and 61 drug-naive PD patients in order to detect spectral parameters, which serve as
biomarkers for monitoring and identification of PD. The analysis showed the bands at 1078, 1169 and
Keywords:
1244 cm 1 corresponding to carbohydrates, significantly increased in all tested patient samples
Parkinson’s disease
(p  0.01). Several other spectral regions that attribute to amino acids, lipids and proteins indicate the
FTIR
Blood plasma unique detection of disease stages. Cluster analysis of variable regions provided excellent grouping of the
Spectral diagnosis healthy and the patient samples, which correlate completely with the clinical diagnosis. For automatic
Neural network detection, artificial neural network (ANN) was implemented on the variable regions showed 96.29%
accuracy in the detection of disease progression. These parameters could be used, as a basis for
developing a spectral method for detecting PD. Execution of neural network will be useful in clinical
screening and rapid detection of PD.
ß 2010 Elsevier B.V. All rights reserved.

1. Introduction Many fundamental diagnostic decisions in medical practices

Parkinson’s disease (PD) is a chronic neurodegenerative disorder
characterized by progressive loss of substantia nigra pars compacta
(SNc) neurons of unknown etiology [1,2]. The diagnosis of PD is
entirely clinical, no biochemical tests are currently available to
diagnose PD. At present, the diagnosis is done by standard
neuropathological examination and medical history [3]. The severity
of disease is categorized as stages based on the overall motor
function evaluation using Unified Parkinson’s Disease Rating Scale
(UPDRS) or on an equivalent rating scale such as Hoehn and Yahr
scale and Schwab and England Activities of Daily Living Scale. [4].
Major clinical symptoms like tremor, rigidity and motor dysfunction
significantly help in detection of PD. However, the clinical diagnosis
fails to identify PD before any significant loss of dopamine neurons
[5]. There is immense need for early and rapid detection and more
effective drugs for cure or to stop the ongoing nigral degeneration
[6]. The understanding of molecular mechanism and the changes
acquired during disease progression are ultimately important for
developing biomarkers in the early detection of the disease, which
subsequently provides high value therapeutics.
* Corresponding authors.
E-mail address: parkinresearch@gmail.com (S. Kumar).
were made with the help of biomarkers. Biomarkers serve as
diagnostic tools for diseases that are usually performed on readily
accessible body fluids, such as saliva, urine, serum or cerebrospinal
fluid (CSF). Several studies have suggested the diagnosis of PD from
the serum. Fourier-transform infrared (FTIR) micro-spectroscopy is
a powerful technique applied in biochemistry for studying the
secondary structure of protein molecules [7], nucleic acids [8],
carbohydrates [9] and lipids [10]. FTIR micro-spectroscopy has
been used effectively to diagnose and characterize various types of
disorders. Encouraging results were obtained in an attempt to
detect cancer [11], gastric inflammation [12], Alzheimer’s disease
[13], kidney stones [14], leukemia [15], cervical cancer [16],
melanoma [16], urinary crystals [17], changes in the biochemistry
of oral cavity tissues [18] and congenital hypothyroidism [19]. In
microbiology, FTIR is used to classify and differentiate various
strains and species of microorganisms [20], in the detection of
virus infected cells [21] and fungi in wood [22].
In this study, FTIR analysis of plasma samples of 69 normal and
61 drug-naive patients were carried out to investigate the
presence of spectral markers for PD. The aim is to implement
the band intensity values of spectral markers in neural network
for rapid detection of PD. The results presented contribute to
understanding FTIR spectral differentiation patterns in various
stages of PD.

0924-2031/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.vibspec.2010.01.019
182 S.S.S.J. Ahmed et al. / Vibrational Spectroscopy 53 (2010) 181–188
2. Materials and methods
2.1. Clinical sample
Blood samples of 61 drug-naive PD patients of South Indian
origin were obtained from the outpatients of the Department of
Neurology at SRM Hospital, Tamil Nadu, India and compared with
69 healthy controls of similar origin. The control samples were
grouped into three classes, namely ‘‘Stage 1 control’’, ‘‘Stage 2
control’’ and ‘‘Stage 3 control’’ based on age and gender, in order to
compare with PD stages, respectively (Table 1). All individuals
chosen for this study had no history of smoking, alcoholism, drug
abuse and anti-oxidant exposure for a period of three months
before sample collection. A written consent was obtained from
each participant during an in-person interview and blood
donation. For participants with PD, date of the symptom onset,
date of diagnosis and family history of PD were recorded. The
patients were shown to have symptom onset for the average of
three years before the diagnosis and the samples were collected
immediately after diagnosis. Two patients of stage 3 PD and four
patients of stage 2 PD had reported a family history of PD. All the
patients were evaluated by one or more qualified neurologists and
the pathological status was classified by UPDRS. The ethical
committee of SRM Medical College and Hospital, India reviewed
and approved the protocol of this study.
2.2. Preparation of samples
Blood samples (4 ml) were collected in EDTA vacutainer tube
(Becton-Dickinson, Franklin Lakes, NJ) from individuals and
immediately centrifuged for 5 min at 14,000 rpm to separate
plasma from other cellular material. Subsequently, the plasma was
transferred to fresh tube and kept frozen at 20 8C before
processing. Thallium bromide iodide crystal was used as the slide
materials. 1 ml of the plasma sample was placed on the slide, air-
dried at room temperature for 30 min. The size of each dried spots
was 0.5 cm in radius and the examination was further carried out
using FTIR micro-spectroscopy.
2.3. FTIR data analysis
All experimental samples were subjected to FTIR micro-
spectroscopy Bruker IFS 66 V (Bruker Biospin, Inc., Milton, Canada)
operating at 450–4000 cm 1 coupled with panorama (LabCogni-
tion Inc., Germany) software. The FTIR measurements were
performed in transmission mode with a liquid nitrogen-cooled
detector. The spectrum was obtained in the wavenumber range of
450–4000 cm 1. A spectrum was taken as an average of 137 scans
to increase the signal to noise ratio, and the spectral resolution was
at 1.0 cm 1. The baseline correction, smoothing and normalization
were performed prior to peak finding using panorama software.
Table 1
Statistics of research participants involved in the study.
Sample information No. of samples Gender Mean age
Male Female
Stage 1 control 23 14 9 57.60
Stage 2 control 22 10 12 62.80
Stage 3 control 24 14 10 71.46
PD-stage 1 20 12 8 57.84
PD-stage 2 20 11 9 62.68
PD-stage 3 21 12 9 71.00
The samples were divided into four categories. The normal groups of 69 samples
were categorized into three sub-groups as ‘‘stage 1 control’’, ‘‘stage 2 control’’ and
‘‘stage 3 control’’. Each sub-group was compared with corresponding PD stages.
Stage 1 (20 samples) stage 2 (20 samples) and stage 3 (21 samples), respectively.
Baseline correction was done by rubber band method and
normalization to amide II was performed by vector method. Five
biological replicate spots were measured for each sample and there
are no significant differences in the spectra of replicates each
sample were noticed. The multiple spectra of each population were
normalized prior to average of biological and experimental
replicates. The band positions were determined using second
derivate of Savitzky-Golay algorithm by panorama software.
2.4. Statistical analysis
Statistical analyses were performed using GeneSpring GX
software version 7.3 (Agilent Technologies Inc., Santa Clara, CA).
The significance of spectral variation between the PD stages and
their control groups were calculated by analysis of variance
(ANOVA). The cluster analysis was executed to determine the
grouping ability of identified variable regions into stages. The
analysis was performed on the absorption intensities of each peak
using similarity measurement of Pearson correlation and average
linkage algorithm.
2.5. Artificial neural network (ANN) detection
The neural network design consisted of a three-layer network:
an input layer, with 13 units containing the information on the
diagnostic criteria; a hidden layer, with six units; and an output
layer. A NeuNet Pro software (CorMac Technologies Inc., Canada),
back prop algorithm was used for the prediction of disease stages.
Back prop algorithm of NeuNet Pro software accepts the clinical
data as numerical inputs.
The training variables include age, gender, intensities of 10 FTIR
peaks (689, 1078, 1169, 1244, 1542, 2953, 2930, 3060, 3293 and
3296 cm 1) and disease status (normal: coded 0, stage 1: coded 1,
stage 2: coded 2, stage 3: coded 3). The input variables associated
with diagnoses were trained with randomly selected 103
individuals, which include 53 normal and 50 PD patients (16
samples of stage 1, 16 samples of stage 2 and 18 samples of stage
3). The training process continued until the differences between
the network classifications and the clinical diagnoses diminished.
Once the network was trained, the remaining 27 individuals were
‘‘tested,’’ by the trained network. The neural network classifica-
tions were then compared with the known clinical data, to see the
classification ability network.
3. Results and discussion
The present study is focused on identification of the spectral
markers for the detection of PD from blood plasma. Few successful
breakthroughs have shown metabolite variations in serum/plasma
of patients with PD. For instance, glycine, aspartate and glutamate
were found to be increased in parkinsonian plasma in comparison
with control subjects [23]. Increase in valine and reduction in
arginine and methionine concentrations in serum were noticed in
PD [24]. Additionally, a significant increase of 8-OHdG in serum
and urine was also observed in PD [25]. Our previous study also
showed the feasibility of potential diagnosis of PD from the
detection of 22 differentially regulating metabolites in plasma of
PD [26]. The recent study of early PD plasma using near infrared
spectroscopy (NIR) showed significant variations in oxidative
stress sensitivity bands in comparison with control [27]. And, it
was suggested that reactive oxidative species (ROS) modify the
proteins, lipids and other cellular substrates in plasma [27]. From
the inferences of these studies, FTIR micro-spectroscopy analysis
was executed to scan entire plasma metabolites via functional
group between normal and PD. The typical analysis of FTIR spectra
is aimed for early three stages of disease in order to determine the
 S.S.S.J. Ahmed et al. / Vibrational Spectroscopy 53 (2010) 181–188 183

Fig. 1. Variations in stage 1 Parkinson’s disease in comparison with their control group. Spectra representing the region 450–4000 cm 1 of stage 1 control and stage 1 PD. The
presented spectra are an average of 20 patient samples and 23 healthy samples. (A) FTIR spectra of healthy individuals and PD patients in the region 1078–1244 cm 1. (B) Peak
at 3060 cm 1 area of healthy persons and patients with PD.

early markers for PD. Moreover, this study was made with
unmedicated individuals to avoid the confounding effects of
medication including antioxidant that could potentially interfere
with the spectrum [27]. The results show that the FTIR spectra of
both healthy individuals and PD patients were similar although
there were variations in certain regions of patient samples
compared to normal samples. The identified variations confirm
the statistical significance at all stages of PD (p  0.01).
The bands at 1078, 1169, 1244 and 3060 cm 1 (Figs. 1 and 2)
were altered in stage 1 PD in comparison with their control group
and the variations in spectral regions at 689, 1078, 1169 and
1244 cm 1 were identified in stage 2 PD (Figs. 3 and 4). Similarly,
the difference in band intensities were noticed at 1078, 1169, 1244,
1542, 2930, 2953, 3293 and 3296 cm 1 for stage 3 PD in
comparison with their control (Figs. 5 and 6). The presented
Figs. 1, 3 and 5 are the average spectra of stage 1, stage 2 and stage
3 PD with their respective control groups. The results show a
significant and detectable increase of bands at 1078, 1169 and
1244 cm 1 in all tested plasma of PD patients compared to the
control groups. The overlap of Figs. 1, 3 and 5 at 1078, 1169 and

Fig. 2. Band intensities difference between the variable regions of stage 1 controls and stage 1 patients. The band intensities at variable regions of 23 examined stage 1 control
and 20 stage 1 PD samples were shown. Each point represents the average of five measurements of biological replicates of each sample.
184 S.S.S.J. Ahmed et al. / Vibrational Spectroscopy 53 (2010) 181–188

1
Fig. 3. Spectral variations in stage 2 Parkinson’s disease. The average spectra of 22 ‘‘stage 2 control’’ and 20 stage 2 PD samples in the region 450–4000 cm . (A) FTIR spectra of
healthy persons and PD patients in the region 1078–1244 cm 1. (B) Peak at 689 cm 1 area of healthy individuals and patients with PD.

1244 cm 1 shows a systematic increase in absorption intensities as
the disease progress from stage 1 to 3 (Fig. 7). These spectral
regions were attributed to C–O bending mode of carbohydrates
bands, suggesting variations in plasma carbohydrates of PD
samples [16]. This result supports the previous report of cerebral
hypometabolism of glucose [28] and dysfunction of the glycolysis
pathway in PD [29]. Furthermore, a study suggests the role of
carbohydrate metabolisms in the pathogenesis of motor neuron
disease and spinocerebellar degeneration [30]. Also, variation in
serum glucose was previously reported in early PD [31] and the
validation of plasma glucose level in these samples was shown to
be abnormal (unpublished result). With these carbohydrate
abnormalities in FTIR spectra could be used as a basis for the
detection of PD irrespective of stages. And, these common variable
regions can be used to determine the disease progression in PD
(Fig. 7).

Fig. 4. Band intensities difference between the variable regions of stage 2 controls and stage 2 patients. The band intensities at variable regions of 22 examined stage 2 control
and 20 stage 2 patients samples were shown. Each point represents the average of five measurements of biological replicates of each sample.
 S.S.S.J. Ahmed et al. / Vibrational Spectroscopy 53 (2010) 181–188
Fig. 5. Variations in stage 3 Parkinson’s disease in comparison with their control group. FTIR spectra in the region of 450–4000 cm 1 of stage 3 control and stage 3 of PD. The
presented spectra are an average of 21 stage 3 patient samples and 24 healthy person samples. (A) FTIR spectra of healthy individuals and PD patients in the region 1078–
1244 cm 1. (B) Peak at 1542 cm 1 area of healthy individuals and patients with PD. (C) Indicating the variations at 2930 and 2953 cm 1. (D) Spectra representing the variable
regions at 3293 and 3296 cm 1 between normal and stage 3 PD.
3.1. Identification of unique markers
In order to identify the stage specific spectral markers, the
results were compared. In stage 1 PD, absorbance at 3060 cm 1
was reduced when compared with the control and other two stages
of PD samples. This band corresponds to unsaturated fatty acid
[32], which indicates abnormality in unsaturated fatty acid
derivatives in early PD. This unique variation can serve as spectral
marker for early detection of PD.
In stage 2 PD, the spectra show an increased intensity at
689 cm 1 compared to the control and other disease groups. This
region assigned to C–C twist, C–C stretch and C–S stretch mode
of amino acids [32], show their variation in stage 2 PD samples.
Furthermore, unique spectral variations were observed at 1542,
2930, 2953, 3293 and 3296 cm 1 of stage 3 PD samples. The
band at 1542 cm 1 shows a significant increase in intensity in
stage 3 samples compared to the control and other stages of PD.
This region is attributed to stretching C5 5C vibration of lipids
[32]. In addition, the bands at 2930 and 2953 cm 1 were
significantly increased contributing to stretching vibrations of
C–H of saturated lipids [32]. Also, an increase in absorbance is
observed at 3293 and 3296 cm 1 in stage 3 PD samples. These
regions were attributed to amide I band of proteins [32].
Variations in these regions suggest the abnormality of proteins
in stage 3 PD samples. Hence, the cumulative analysis shows
that these regions are relatively important for stage 3 diagnosis
of disease.
The observed changes in these spectral regions indicate the
metabolite abnormalities in plasma of patients with PD.
The majority of unique changes in PD stages contribute to
amino acids, lipids and proteins. The variations in plasma
amino acids were previously reported. The variation of amino
acid region is may be due to the abnormal concentration of
arginine, aspartate, glutamate, glycine and methionine in PD
plasma [23,24]. Also, this study shows alterations in spectral
regions of lipids. Several studies suggest the alterations in
fat metabolism are involved in the pathogenesis of PD
[33,34]. Lower levels of total cholesterol have been previously
185
described in PD patients compared to control [35]. Furthermore,
the result from a recent meta-analysis showed an increased
risk of PD in carriers of the APOE2 allele [36], which is associated
with lower plasma levels of cholesterol. In addition, in vitro
study of alpha-synuclein protein was shown to have close
association with cholesterol-enriched lipid rafts in the
cell membrane [37]. The aggregation of alpha-synuclein
might be regulated by fatty acids [35]. The increase in alpha-
synuclein protein is the pathological structures, termed Lewy
bodies, in the brain of patient with PD. Thus, variation in protein
region occurs at stage 3 PD due to abnormal regulation of
fatty acids.
The present spectral variations correlate with molecular
abnormalities of previous studies of PD [25]. In other words, the
underling molecular variations in plasma have been detected by
FTIR micro-spectroscopy. And, these supporting spectral changes
can be used as spectral marker for detection of PD. This is the first
study using FTIR micro-spectroscopy for the detection of PD stages
from plasma samples. Based on these findings, it seems that
plasma is an easy and rapid target for detection and identification
of PD.
3.2. Cluster analysis
The cluster analysis was carried out in order to determine the
classification ability of variable regions into PD and normal. The
absorption intensities of all samples for the regions at 689, 1078,
1169, 1244, 1542, 2953, 2930, 3060, 3293 and 3296 cm 1 were
used as input for the cluster analysis. Two major clusters are
formed (Fig. 8). Among these, one of the clusters contains the
normal, whereas the second cluster is composed of stage 1, stage 2
and stage 3 of PD. The normal cluster was highly deviated from the
disease stages suggesting an excellent grouping of three stages
from the absorption intensity values of above spectral regions.
This confirms that these regions can be potentially used as
markers for detection of PD by stages. Hence, the intensities of
these regions were considered for neural-network for automatic
detection.
186 S.S.S.J. Ahmed et al. / Vibrational Spectroscopy 53 (2010) 181–188

Fig. 6. Band intensities difference between the variable regions of stage 3 controls and stage 3 patients. The band intensities at variable regions of 24 examined stage 3 control
and 21 stage 3 patients samples were shown. Each point represents the average of five measurements of biological replicates of each sample.

3.3. Artificial neural network (ANN) for rapid detection

Fig. 7. Comparative analysis of control groups with PD stages. FTIR spectra of
control groups and PD stages in the region 1055–1245 cm 1, indicating the
increased spectral intensities as the disease progress.
The network was tested with 27 test samples. The success rate
in classification of the test set is 96.29% (26/27) accuracy, the
sensitivity is 91% (10/11, one case of stage 2 was misdiagnosed as
stage 3 PD), the specificity is 100% (16/16). Moreover, the values
generated by the neural network were ranged from 0 to 3. Based on
these values, individuals were assigned into normal or diseased
group. Individuals whose final predicted values x  0 are assigned
as normal and the values x > 0 are assigned to the PD groups
(Table 2). For instance, the predicted range from x = 0.51–0.99 was
assigned as stage 1, x = 1.51–1.94 as stage 2 and the values
x = 2.10–3 as stage 3 (Table 2). The utility of this prediction
algorithm is questionable since the analysis was made with a
limited number of samples and comparison with other neurode-
generative disorders was not made. However, the spectral
differentiation between PD and other neurodegenerative disorders
is possible with the understanding of early study of NIR in
comparison with Alzheimer’s and Parkinson’s disease [38]. To
confirm this possibility, further work needs to be done to
 S.S.S.J. Ahmed et al. / Vibrational Spectroscopy 53 (2010) 181–188 187

Table 2
Neural network prediction.

S. no. ANN Neural network Clinical

predicted value classification designation

1 0.845 Normal Normal

2 0.7931 Normal Normal
3 0.676 Normal Normal
4 0.951 Normal Normal
5 0.735 Normal Normal
6 0.9837 Normal Normal
7 0.539 Normal Normal
8 0.898 Normal Normal
9 0.497 Normal Normal
10 0.635 Normal Normal
11 0.978 Normal Normal
12 0.559 Normal Normal
13 0.631 Normal Normal
14 0.809 Normal Normal
15 0.997 Normal Normal
16 0.851 Normal Normal
17 0.174 PD-stage 1 PD-stage 1
18 0.5125 PD-stage 1 PD-stage 1
19 0.767 PD-stage 1 PD-stage 1
20 0.974 PD-stage 1 PD-stage 1
21 1.864 PD-stage 2 PD-stage 2
22 1.945 PD-stage 2 PD-stage 2
23 1.51 PD-stage 2 PD-stage 2
24 2.992 PD-stage 2* PD-stage 3
25 2.133 PD-stage 3 PD-stage 3
26 2.576 PD-stage 3 PD-stage 3
27 2.738 PD-stage 3 PD-stage 3

Neural network classification values, neural network designation and disease

designation, for 36 Individuals who have known clinical information. Individuals
denoted by asterisk.
*
Indicate the misclassification of PD-stage 3 as stage 2 by ANN.

differentiate the PD spectral markers from other neurodegenera-

tive disorders.

4. Conclusions

FTIR micro-spectroscopy technique in detection of PD is simple

and more feasible. It requires a small amount of plasma (1 ml),
which can be easily obtained from patients, and the results can be
obtained within a short interval of time (30 min). ANN can be
further implemented as a tool for the rapid detection of PD. The
spectral markers obtained in this study are crucial and may be
considered as a promising basis for future studies by including
other neurodegenerative disorder samples. At present, it is
suggested to execute the FTIR technique along with the clinical
diagnosis, which additionally improves the accuracy of PD
detection.

Acknowledgments

We thank Dr. K. Ramasamy for his intellectual input and Indian

Institute of Technology, Madras for the instrument facility. This
work was supported by SRM University, Tamil Nadu, India. We
specially thank all the patients and healthy volunteers for their
selfless donation of blood. SSSJA thanks to Mahmoud Huleihel,
Faculty of Health Sciences, Ben-Gurion University of the Negev,
Israel for his support throughout the data analysis.

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