\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[polish,ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Slowing of EEG waves correlates with striatal {[}18F{]}fluorodopa PET/CT
uptake and executive dysfunction in Parkinson's disease}



\author[1]{Karolina Lorek}%
\author[2]{Joanna Mączewska}%
\author[2]{Leszek Królicki}%
\author[3]{Magdalena Siemiatycka}%
\author[4]{Małgorzata  Chalimoniuk}%
\author[3]{Katarzyna Kisiel-Sajewicz}%
\author[3]{Jarosław Marusiak}%
\affil[1]{Wroclaw University of Health and Sport Sciences}%
\affil[2]{Medical University of Warsaw}%
\affil[3]{Wroclaw University of Health and Sport Science}%
\affil[4]{Józef Piłsudski University of Physical Education in Warsaw}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Multimodal studies evaluating associations between specific for
Parkinson's disease (PD) neuroimaging and neurophysiological biomarkers
in revealing executive dysfunction mechanisms are scarce and needed to
be validated. Hence, our study aimed to evaluate associations between
electroencephalographic power spectral density (PSD-EEG), striatal
{[}18F{]}Fluorodopa uptake and neuropsychological testing parameters in
PD. Additional aim was to estimate PD diagnostic accuracy of the PSD-EEG
parameters. We compared resting PSD-EEG, striatal {[}18F{]}Fluorodopa
uptake ratio with positron emission computed tomography ({[}18F{]}FDOPA
PET/CT), and neuropsychological test outcomes between PD patients and
healthy controls, and then calculated correlations among these outcomes.
Additionally we estimated PD diagnostic sensitivity and specificity
(with the receiver operating characteristic curves) of the PSD-EEG
parameters in reference to the gold diagnostic standard of the striatal
{[}18F{]}FDOPA PET/CT uptake ratio.PD patients exhibited (i) increased
power of the EEG theta and lower-alpha bands in the frontal lobe areas,
(ii) decreased putaminal and caudate nuclei {[}18F{]}FDOPA PET/CT uptake
ratios and (iii) longer performance times of part A and B of the Trail
Making Test (TMT-A and TMT-B). Most of the PSD-EEG parameters negatively
correlated with striatal {[}18F{]}FDOPA PET/CT uptake ratios and
positively correlated with TMT-A and TMT-B. Furthermore, {[}18F{]}FDOPA
PET/CT uptake ratios positively correlated with TMT-A and TMT-B. Theta
and lower-alpha bands PSD-EEG were found to have high diagnostic
accuracy. Our findings showed that slowing of EEG waves in the frontal
lobe was correlated with striatal dopaminergic deficiency and executive
dysfunction in mild PD patients, and appears to be a promising biomarker
of PD-related executive dysfunction.%
\end{abstract}%



\sloppy


\textbf{Slowing of EEG waves correlates with striatal
{[}\textsuperscript{18}F{]}fluorodopa PET/CT uptake and executive
dysfunction in Parkinson's disease}

\textbf{Running title:} Neural bases of executive dysfunction in PD

Karolina Lorek, MSc, Eng,\textsuperscript{1*} Joanna M\selectlanguage{polish}ą\selectlanguage{english}czewska, MD,
PhD,\textsuperscript{2} Leszek Kr\selectlanguage{ngerman}ólicki, MD,
PhD,\textsuperscript{2}Magdalena Siemiatycka, MSc,\textsuperscript{1}
Ma\selectlanguage{polish}ł\selectlanguage{english}gorzata Chalimoniuk, PhD,\textsuperscript{3} Katarzyna
Kisiel-Sajewicz, PhD,\textsuperscript{1} Jaros\selectlanguage{polish}ł\selectlanguage{english}aw Marusiak,
PhD\textsuperscript{1*}

1-- Department of Kinesiology, Faculty of Physiotherapy, Wroclaw
University of Health and Sport Science, Wroclaw, Poland.

2 -- Nuclear Medicine Department, Medical University of Warsaw, Warsaw,
Poland.

3 -- Department of Physical Education and Health in Biala Podlaska,
Jozef Pilsudski University of Physical Education in Warsaw, Faculty in
Biala Podlaska, Biala Podlaska, Poland.

\textbf{ORCID numbers of all authors} :

Karolina Lorek, 0000-0003-4823-7042; Joanna M\selectlanguage{polish}ą\selectlanguage{english}czewska,
0000-0002-3522-8633; Leszek Kr\selectlanguage{ngerman}ólicki, 0000-0002-7117-9621; Magdalena
Siemiatycka, 0000-0001-8865-0320; Ma\selectlanguage{polish}ł\selectlanguage{english}gorzata Chalimoniuk,
0000-0003-0361-8626; Katarzyna Kisiel-Sajewicz, 0000-0002-3137-2646;
Jaros\selectlanguage{polish}ł\selectlanguage{english}aw Marusiak. 0000-0001-6412-5943

\textbf{Correspondence:}

Lorek Karolina,

address: Department of Kinesiology, Faculty of Physiotherapy, Wroclaw
University of Health and Sport Science, Wroclaw, Poland; 51-612 Wroclaw,
Al. Paderewskiego 35, building P4 telephone number: (+48) 71 347 3532;
fax number: (+48) 71 347 3431e-mail address: karolina.lorek@awf.wroc.pl

Jaros\selectlanguage{polish}ł\selectlanguage{english}aw Marusiak,

address: Department of Kinesiology, Faculty of Physiotherapy, Wroclaw
University of Health and Sport Science, Wroclaw, Poland; 51-612 Wroclaw,
Al. Paderewskiego 35, building P4 telephone number: (+48) 71 347 3057;
fax number: (+48) 71 347 3431e-mail address:
jaroslaw.marusiak@awf.wroc.pl

\textbf{Word count}Number of used words in the main text: 2497; Number
of used words in abstract: 250

\textbf{Financial Disclosure/Conflict of Interest}

No author has a financial relationship with any company that
manufactures products or equipment discussed in this manuscript, or any
other apparent conflict of interest.

\textbf{Funding Sources for study}

The work was supported by the National Science Centre, Poland, under
research project no 2017/25/B/NZ7/02795, entitled ,,Effect of high
intensity interval training on mechanisms of neuroplasticity and
psychomotor behaviours in Parkinson's disease patients: a randomized
study with 1-year follow up'', awarded to Jaroslaw Marusiak.

\section*{Abstract}

{\label{abstract}}

Multimodal studies evaluating associations of the Parkinson's disease
(PD) specific neuroimaging and neurophysiological biomarkers in
revealing executive dysfunction mechanisms are scarce and needed to be
validated.

Hence, our study aimed to evaluate associations between
electroencephalographic power spectral density (PSD-EEG), striatal
{[}\textsuperscript{18}F{]}Fluorodopa uptake and neuropsychological
cognitive testing parameters in PD. Additional aim was to estimate PD
diagnostic accuracy of the PSD-EEG parameters.

We compared resting PSD-EEG, striatal
{[}\textsuperscript{18}F{]}Fluorodopa uptake ratio with positron
emission computed tomography ({[}\textsuperscript{18}F{]}FDOPA PET/CT),
and neuropsychological test outcomes between PD patients and healthy
controls, and then calculated correlations among these outcomes.
Additionally we estimated PD diagnostic sensitivity and specificity
(with the receiver operating characteristic curves) of the PSD-EEG
parameters in reference to the gold diagnostic standard of the striatal
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio.

PD patients exhibited (i) increased power of the EEG theta and
lower-alpha bands in the frontal lobe areas, (ii) decreased putaminal
and caudate nuclei {[}\textsuperscript{18}F{]}FDOPA PET/CT uptake and
(iii) longer performance times of part A and B of the Trail Making Test
(TMT-A and TMT-B). Most of the PSD-EEG parameters negatively correlated
with striatal {[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratios and
positively correlated with TMT-A and TMT-B. Furthermore, striatal
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratios positively
correlated with TMT-A and TMT-B. Theta and lower-alpha bands PSD-EEG
were found to have high diagnostic accuracy.

Our findings showed that slowing of EEG waves in the frontal lobe was
correlated with striatal dopaminergic deficiency and executive
dysfunction in mild PD patients, and appeared to be a promising
biomarker of PD-related executive dysfunction.

\textbf{Key Words:} Parkinson's disease, executive dysfunction, EEG,
{[}\textsuperscript{18}F{]}FDOPA PET/CT, cognitive impairment

\section*{Introduction}

{\label{introduction}}

Previous studies showed that slowing of electroencephalographic (EEG)
and magnetoencephalographic (MEG) waves assessed by power spectral
density (PSD) may be related to cognitive decline in Parkinson's disease
(PD) patients.\textsuperscript{1--3} Multimodal studies evaluating
associations between PD-specific neuroimaging and neurophysiological
biomarkers in revealing executive dysfunction mechanisms in PD are
scarce, and especially in studying the association of resting state
brain waves (PSD-EEG) with the dopaminergic function imaging methods.
Currently, a gold standard diagnostic tool in PD is positron emission
computed tomography (PET/CT), particularly using the PD-specific
radiotracer, e.g., the {[}\textsuperscript{18}F{]}Fluorodopa
({[}\textsuperscript{18}F{]}FDOPA) uptake ratio in the striatum, which
reflects dopaminergic deficiency in idiopathic PD
patients.\textsuperscript{4--7} Multimodal studies with usage of the
PET/CT, EEG and behavioral testing may have scientific relevance in an
understanding of neural mechanisms in PD-related executive dysfunction,
but also they may be of great practical importance for PD diagnosis.

Hence, our study aimed to (i) compare the values of resting state
PSD-EEG, striatal {[}\textsuperscript{18}F{]}FDOPA PET/CT uptake and
neuropsychological cognitive testing parameters between mild PD patients
and healthy controls, as well as (ii) to evaluate associations between
these outcomes. Additional aim was to estimate PD diagnostic accuracy
(with receiver operating characteristic {[}ROC{]} curves) of the PSD-EEG
parameters in reference to the gold diagnostic standard of the striatal
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio.

According to the ``dual hypothesis'',\textsuperscript{8} assuming the
dopaminergic-mediated striatofrontal executive dysfunction in
early-stage PD, we hypothesized that values of (i) the PSD-EEG, striatal
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio and
neuropsychological parameters would differ between mild PD patients and
healthy controls and (ii) that the PD-specific neuroimaging findings
(increased PSD-EEG alpha- and theta- waves and decreased striatal
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio) would be
correlated to each other and with neuropsychological outcomes reflecting
executive dysfunction.

\section*{Materials and methods}

{\label{materials-and-methods}}

\textbf{Participants}

Eleven PD patients (PD; women n = 5, men n = 6; mean age 65.4 \selectlanguage{ngerman}± 4.5
years, body mass 72.2 ± 12.4 kg, height 168.7 ± 8.9 cm) assessed with
the Hoehn and Yahr scale (H\&Y)\textsuperscript{9} to be mildly
affected, and 11 healthy age-matched controls (HCO; women n = 6, men n =
5; mean age 63.4 ± 4.6 years, body mass 74.1 ±18.9 kg, height 166.4 ±
8.9 cm) participated in our study (Table 1). All PD and HCO subjects
were non-demented (confirmed by a neuropsychologist), right-handed, and
the PD patients had an affected dominant side (Table 1). All subjects
wrote informed consent prior participation in this study which was
approved by the local ethical review board. All study participants
underwent EEG recording, PET/CT neuroimaging and neuropsychological
cognitive assessment, and PD patients underwent additional clinical
neurological evaluation. All PD patients' testing procedures were
conducted during their ``off-medication'' phase, i.e. after an overnight
12-hours withdrawal of anti-parkinsonian drugs (24 hours for extended
release medications).

\textbf{EEG recording and data analysis}

EEG data were recorded in an eyes-open resting condition with the
BioSemi system (Biosemi Inc., Amsterdam, the Netherlands), using 128
Ag/AgCl electrodes set and analyzed with MATLAB software (version R2019)
running EEGLAB\textsuperscript{10} functions and proprietary scripts.
Raw data were bandpass filtred (0.5-50 Hz) and manually examined for
artifacts. Contaminated segments and bad channels were removed from the
analysis and then interpolated. In the next step, EEG data underwent an
Independent Component Analysis (ICA) to exclude remaining artifacts. The
PSD-EEG was calculated using the MATLAB pwelch function, with a Hamming
window of 512 samples and 50\% overlap in six frequency bands: delta
(1-4 Hz), theta (4-8 Hz), lower alpha (8-10 Hz), upper alpha (10-13 Hz),
beta (13-30 Hz) and gamma (30-40 Hz)\textsuperscript{3}. Individual
maximal peaks in the theta-alpha band were detected using the
``findpeaks'' function in the 4-13 Hz frequency range. For all channels
and frequency bands, we constructed topographic maps of significant
inter-group differences. These statistical maps revealed clusters of
significant electrodes over midline frontal and left frontal lobe. Based
on the polar coordination system, and according to literature
data,\textsuperscript{11--13} we matched the electrodes to three Regions
of Interest (ROIs): the supplementary motor area (SMA \selectlanguage{english}- C14, C18, C19,
C20, C27), the prefrontal motor cortex (PFC \selectlanguage{english}- D04, D05, D06, C31, C32),
and the primary motor cortex (M1 \selectlanguage{english}- D10, D11, D12, D19, D20). Finally,
from each crucial region, we selected one representative electrode, i.e.
an electrode with the most significant inter-group difference: C21
(SMA), D05 (PFC) and D10 (M1) (Figure 1A) for further analysis.

\textbf{PET imaging and data analysis}

A standard protocol was used for~all {[}\textsuperscript{18}F{]}FDOPA
PET/CT scans. All patients were instructed to adhere to a low protein
diet for 24 hours, fast at least 4 hours before tracer injection, and
withhold anti-parkinsonian medications (L-dopa and dopamine agonists)
that could interfere with {[}\textsuperscript{18}F{]}FDOPA uptake.
Patients were premedicated orally with 150 mg of carbidopa 1 hour prior
to injection with 250 MBq {[}\textsuperscript{18}F{]}FDOPA, and imaging
started 110 minutes post-injection. {[}\textsuperscript{18}F{]}FDOPA
scanning was performed using a Biograph 64 PET/CT scanner (Siemens
Medical Solutions, Malvern, PA, USA, Inc.) operating with the Somaris/5
SyngoCT 2006 software, having a 3-dimensional acquisition mode. PET
images were fused to magnetic resonance T1-weighted images (MRI scanner
model: 3T Siemens Trio scanner; Siemens, Munich Germany), that were
performed before PET/CT scans. Semi-quantitative striatal dopaminergic
function analysis was performed using the VE30 software (Siemens Medical
Solutions, Malvern, PA, USA, Inc.). Interpretation was based on analysis
of {[}\textsuperscript{18}F{]}FDOPA uptake ratios for the putamen and
caudate nucleus versus the occipital cortex as a reference.

\textbf{Clinical and neuropsychological assessment}

The H\&Y scale, the Unified Parkinson's Disease Rating Scale
(UPDRS)\textsuperscript{9} and Schwab \& England scale
(S\&E)\textsuperscript{14} were used to evaluate the severity of PD.
Cognitive assessments were performed using the Trail Making Test, parts
A and B~(TMT-A, TMT-B),\textsuperscript{15,16} and Stroop test, parts I
and II (ST-I, ST-II)\textsuperscript{17,18} in the PD and HCO groups.

\textbf{Statistical Analysis}

Student's t-test was used to examine the statistical significance of
inter-group (PD vs HCO) differences for values of the PSD-EEG, striatal
{[}18F{]}FDOPA PET/CT uptake ratios and cognitive tests parameters. When
comparing PSD-EEG parameters the inter-group comparisons' p-values were
adjusted according to the Bonferroni correction to avoid the type I
error derived from multiple comparisons. Pearson's correlation
coefficient (r) or Spearman's correlation coefficient (\selectlanguage{greek}ρ - \selectlanguage{english}rho) was
calculated to evaluate the associations of the PSD-EEG parameters
revealing statistically significant inter-group differences with the
striatal {[}18F{]}FDOPA PET/CT uptake ratios and neuropsychological
parameters. Additionally, to assess the diagnostic accuracy (sensitivity
and specificity) of the PSD-EEG and striatal {[}18F{]}FDOPA PET/CT
uptake ratio parameters, the ROC curves were estimated and the area
under the curve (AUC) values were calculated. All statistical analyses
were performed with Statistica version 13.1 software, and the
significance level was set at \selectlanguage{greek}α\selectlanguage{english} \selectlanguage{english}= 0.05.

\section*{Results}

{\label{results}}

\textbf{Inter-group comparisons for anthropometric, PSD-EEG, PET/CT and
neuropsychological parameters}

There was no significant difference between the PD and HCO group in age
65.4 \selectlanguage{ngerman}± 4.5 vs. 63.4 ± 4.6 years (\emph{p} = 0.337, \emph{t} = 0.983),
body mass 72.2 ± 12.4 vs. 74.1 ± 18.9 kg (\emph{p} = 0.792, \emph{t} =
-0.267) and height 168.7 ± 8.9 vs. 166.4 ± 8.9 cm (\emph{p} =
0.558,\emph{t} = 0.595) (Table 1), respectively.

Compared with the HCO group, the PD group exhibited: (i) significantly
higher PSD-EEG theta and lower-alpha band and maximal peaks values for:
C21 (SMA), D05 (PFC), and D10 (M1) (\emph{p} \textless{} 0.05) (Figure
1A and Figure 1B); and (ii) significantly lower values of
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio in the putamen
(\emph{p} \textless{} 0.001, \emph{t} = -10.14; Figure 2A), and caudate
nucleus (\emph{p} \textless{} 0.001, \emph{t} = -6.16; Figure 2B).

Inter-group comparison of cognitive tests parameters in PD vs. HCO
showed (i) significantly worse executive function reflected in longer
performance times of TMT-A (\emph{p} = 0.012, \emph{t} = 2.75; Figure
2C) and TMT-B (\emph{p} = 0.004, \emph{t} = 3.22; Figure 2D), and (ii) a
lack of significant inter-group differences for the ST-I (\emph{p} =
0.864, \emph{t} = 0.173; Figure 2E) and ST-II (\emph{p} = 0.074,\emph{t}
= 1.89; Figure 2F), although there was a clear tendency of longer (19\%
inter-group difference) ST-II performance time in PD group (Figure 2F).

\textbf{Correlations among the PSD-EEG, striatal
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio and
neuropsychological parameters}

Almost all of the PSD-EEG parameters significantly negatively correlated
with the {[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio in the
putamen (\emph{p} \textless{} 0.05; Table 2), excluding only the PSD-EEG
theta band of the C21 (SMA) and D10 (M1) (\emph{p} \textgreater{} 0.05;
Table 2). The significant negative correlations between PSD-EEG and
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio in the caudate
nucleus were found for the PSD-EEG of the: (i) lower-alpha band of the
C21 (SMA) and D05 (PFC), (ii) maximal peak of the C21 (SMA) and D10
(M1), as well as for (iii) theta band of the D05 (PFC)
(\emph{p}\textless{} 0.05; Table 2).

Almost all the PDS-EEG parameters positively significantly correlated
with the TMT-A and TMT-B (\emph{p} \textless{} 0.05; Table 2), excluding
only correlations of the lower-alpha band and maximal peak of the D10
(M1) with TMT-A (\emph{p} \textgreater{} 0.05; Table 2). Furthermore,
the PSD-EEG theta band of the C21 (SMA) and D05 (PFC) was positively
significantly correlated with the ST-II (\emph{p} \textless{} 0.05;
Table 2).

Moreover, the {[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio in
the putamen and caudate nucleus negatively significantly correlated with
the TMT-B, as well as the caudate nuclei
{[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio negatively
significantly correlated with the TMT-A (\emph{p} \textless{} 0.05;
Table 2).

\textbf{Diagnostic accuracy analysis for the PSD-EEG and striatal
{[}18F{]}FDOPA PET/CT uptake parameters}

ROC\selectlanguage{english}-AUC values indicated an excellent diagnostic model of PD based on
the results of the {[}\textsuperscript{18}F{]}FDOPA PET/CT uptake ratio
in the putamen, caudate nucleus, and PSD-EEG theta band for the D05
(PFC) (AUC values: 1.000, 0.979, 0.950; respectively) (Figure 1C). Good
diagnostic model was confirmed based on PSD-EEG lower-alpha band for the
D05 (PFC) and maximal peak of the following: D05 (PFC), C21 (SMA) and
D10 (M1) (AUC values: 0.909, 0.946, 0.835, 851; respectively) (Figure
1C).

Fair diagnostic accuracy was found for the PSD-EEG lower-alpha band of
the C21 (SMA) and D10 (M1) (AUC values: 0.810, 0.810; respectively).
However, poor accuracy of the model was achieved based on the PSD-EEG
theta band for the: C21 (SMA) and D10 (M1) (AUC values: 0.674, 0.678;
respectively) (Figure 1C).

\section*{Discussion}

{\label{discussion}}

Our findings of the EEG waves slowing in frontal lobe areas and the
association of this phenomenon with the executive function decline in PD
patients (revealed with neuropsychological assessment using TMT-A and
TMT-B) is in line with the previous literature data describing the
mechanisms of PD-specific frontal
dysfunction.\textsuperscript{1,7,8}Furthermore, lower values of putamen
and caudate nuclei {[}\textsuperscript{18}F{]}Fluorodopa PET/CT uptake
ratios in our PD patients are consistent with the current state of
knowledge and describe PD-related dopaminergic
deficits.\textsuperscript{4--8,19,20} Thus, taking into account the
concept of the ``dual hypothesis'',\textsuperscript{8} which assumes the
dopaminergic-mediated striatofrontal executive dysfunction in
early-stage PD (and cholinergic-based cognitive impairment, especially
in later demented PD patients), we hypothesized a significant
correlation of the frontal lobe EEG waves slowing with the dopaminergic
deficiency and the executive dysfunction measures in mild non-demented
PD patients tested in the present study. Indeed, our results confirmed
almost completely this hypothesis as for the negative correlation
between the PSD-EEG and striatal {[}\textsuperscript{18}F{]}Fluorodopa
PET/CT uptake ratios. However, with regard to consideration on the
associations of the EEG waves slowing in frontal lobe and striatal
dopaminergic deficiency with neuropsychological outcomes describing the
executive dysfunction (i.e. TMT and and ST), one should point out that
in majority of our results these associations were confirmed only with
the Trail Making Test but not with the Stroop Test. The TMT consists of
two parts (TMT-A and TMT-B). In TMT-A part a subject connects (by
drawing a line) numbers in sequential order, but in the TMT-B the
subject alternates between numbers and letters (1, A, 2, B, etc.). The
former is used to examine cognitive processing speed, while the latter
assesses executive function.\textsuperscript{15,16} The ST also consists
of two parts: ST-I, in which a subject reads a list of 40 words, which
are names of colors printed in the color itself; and ST-II, where color
names are printed in an incongruent color and the subject is required to
ignore the word and correctly name the ink color. The former is used as
a measure of processing speed and the latter to test selective attention
and inhibition.\textsuperscript{17,18} Thus, both of these tests (TMT
and ST) evaluate an executive function, but the TMT is more related to
motor skills (due to line's hand drawing task), and therefore a
disordered performance of this test in PD patients might be partly
related to pathological neural networks causing bradykinesia. According
to the triadic subdivision of the parallel striatal projections in the
dopaminergic system (mesostriatal, mesocortical and mesolimbic pathways)
the mesostriatal component is responsible for the bradykinesia in the
hypodopaminergic conditions \textsuperscript{21} as in our PD patients.
At the same time, it is important to note that the mesocortical system
is responsible for executive function.\textsuperscript{21} It is
necessary take into account that the mesostriatal dopaminergic circuit
is most prominently affected, also on the early stage of PD, whereas the
mesocortical and mesolimbic dopaminergic circuits are relatively
preserved in the early stage of the
disease.\textsuperscript{22,23}Therefore in our mild PD patients (being
on early stage of disease) the mesostriatal component of the triadic
striatal projections in the dopaminergic system might be more affected
by stated in our study dopaminergic deficiency. In consequence, this may
be a reason of stated by us significant correlations of the PD-specific
slowing of brain waves and dopaminergic deficiency with the Trail Making
Test, with simultaneous lack of significant correlations with the Stroop
Test.

Our diagnostic accuracy analyses showed that some of the PSD-EEG
parameters might be potentially a good alternative for expensive PET/CT
diagnostics in PD. Particularly, the PSD-EEG theta-alpha maximal peak
and lower-alpha band for the SMA and PFC regions seemed to be promising
PD-related executive dysfunction biomarkers, since they presented high
diagnostic sensitivity and specificity, significantly differentiated
mild PD patients from healthy controls, as well as they were correlated
with dopaminergic deficiency and executive dysfunction parameters.

\textbf{Limitations of the study and future directions}

An important limitation of this study is the relatively small sample
size. Nevertheless, an appropriate statistical analysis applied by us
(for inter-group comparisons and for correlations calculations) was able
to reveal an effect of dopaminergic system pathophysiology in PD PET/CT
neuroimaging, PSD-EEG and neuropsychological parameters outcomes even in
this relatively small sample size. However, due to this relatively small
sample size, the results of this study cannot be generalized for the
whole PD patients population. Another important limitation of our study
is the choice of only two neuropsychological cognitive tests (TMT and
ST). This choice narrowed down a range of our considerations on
associations of the PD-specific EEG brain waves slowing and dopaminergic
deficiency with disordered executive functions in tested by us PD
patients. Hence, further studies are needed using multimodal scientific
approach, with an application of electroencephalography (using EEG
recordings with resting and cognitive paradigms), PET/CT neuroimaging
methods (using dopaminergic and other PD-specific radiotracers) and
broad PD-specific battery of cognitive tests.

\textbf{Conclusion}

Our findings showed that slowing of EEG waves in the frontal lobe was
correlated with striatal dopaminergic deficiency and executive
dysfunction in mild PD patients, and appears to be a promising biomarker
of PD-related executive dysfunction.

\textbf{Acknowledgements}

We thank the patients with Parkinson's disease and healthy individuals
for participation in our

study. Also, we would like to thank M.Sc. Eng. \selectlanguage{polish}Ł\selectlanguage{english}ukasz Szumowski for his
technical assistance

and the following PhD and Master`s Students (stipendists in this grant)
who helped by the data

collection: Bartosz Kami\selectlanguage{polish}ń\selectlanguage{english}ski, Aleksandra Paw\selectlanguage{polish}ł\selectlanguage{english}owska, Katarzyna \selectlanguage{polish}Ś\selectlanguage{english}pik,
Marcin Zawisza and

Katarzyna Moczulska.

\textbf{Data Sharing}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\section*{REFERENCES}

{\label{references}}

1. Kamei S, Morita A, Serizawa K, Mizutani T, Hirayanagi K. Quantitative
EEG analysis of executive dysfunction in Parkinson disease. J Clin
Neurophysiol Off Publ Am Electroencephalogr Soc 2010; 27(3): 193--7.

2. Caviness JN, Hentz JG, Evidente VG, et al. Both early and late
cognitive dysfunction affects the electroencephalogram in Parkinson's
disease. Parkinsonism Relat Disord 2007; 13(6): 348--54.

3. Stoffers D, Bosboom JLW, Deijen JB, Wolters EC, Berendse HW, Stam CJ.
Slowing of oscillatory brain activity is a stable characteristic of
Parkinson's disease without dementia. Brain 2007; 130(7): 1847--60.

4. Darcourt J, Schiazza A, Sapin N, et al. 18F-FDOPA PET for the
diagnosis of parkinsonian syndromes. Q J Nucl Med Mol Imaging Off Publ
Ital Assoc Nucl Med {[}and{]} Int Assoc Radiopharmacol (IAR), {[}and{]}
Sect Soc of. 2014; 58(4): 355--65.

5. Ibrahim N, Kusmirek J, Struck AF, et al. The sensitivity and
specificity of F-DOPA PET in a movement disorder clinic. Am J Nucl Med
Mol Imaging 2016; 6(1): 102--9.

6. Morrish PK, Sawle G V, Brooks DJ. Clinical and {[}18F{]} dopa PET
findings in early Parkinson's disease. J Neurol Neurosurg Psychiatry
199; 59(6): 597--600.

7. Strafella AP, Bohnen NI, Perlmutter JS, et. al. Molecular imaging to
track Parkinson's disease and atypical parkinsonisms: New imaging
frontiers. Mov Disord. 2017 Feb; 32(2): 181--192.

8. Kehagia AA, Barker RA, Robbins TW. Cognitive Impairment in
Parkinson's Disease: The Dual Syndrome Hypothesis. Neurodegener Dis
2013; 11(2): 79--92.

9. Martinez-Martin P, Rodriguez-Blazquez C, Alvarez-Sanchez M, et al.
Expanded and independent validation of the Movement Disorder
Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). J Neurol.
2013; 260(1): 228--36.

10. Delorme A, Mullen T, Kothe C, et al. EEGLAB, SIFT, NFT, BCILAB, and
ERICA: New tools for advanced EEG processing. Comput Intell Neurosci.
2011.

11. Koessler L, Maillard L, Benhadid A, et al. Automated cortical
projection of EEG sensors: Anatomical correlation via the international
10--10 system. Neuroimage 2009; 46(1): 64--72.

12. Siemionow V, Yue GH, Ranganathan VK, Liu JZ, Sahgal V. Relationship
between motor activity-related cortical potential and voluntary muscle
activation. Exp brain Res. 2000; 133(3): 303--11.

13. Yao WX, Ranganathan VK, Allexandre D, Siemionow V, Yue GH.
Kinesthetic imagery training of forceful muscle contractions increases
brain signal and muscle strength. Front Hum Neurosci. 2013; 7(SEP):
1--6.

14. Siderowf A. Schwab and England Activities of Daily Living Scale. In:
Kompoliti K, Metman LVBT-E of MD, editors. Oxford: Academic Press, 2010,
pp 99--100.

15. Arbuthnott K, Frank J. Trail making test, part B as a measure of
executive control: validation using a set-switching paradigm. J Clin Exp
Neuropsychol. 2000; 22(4): 518--28.

16. S\selectlanguage{ngerman}ánchez-Cubillo I, Periáñez JA, Adrover-Roig D, et al. Construct
validity of the Trail Making Test: role of task-switching, working
memory, inhibition/interference control, and visuomotor abilities. J Int
Neuropsychol Soc. 2009; 15(3): 438--50.

17. Zalonis I, Christidi F, Bonakis A, et al. The stroop effect in Greek
healthy population: normative data for the Stroop Neuropsychological
Screening Test. Arch Clin Neuropsychol Off J Natl Acad Neuropsychol.
2009; 24(1): 81--8.

18. Egner T, Hirsch J. The neural correlates and functional integration
of cognitive control in a Stroop task. Neuroimage. 2005; 24(2): 539--47.

19. Rinne OJ, Nurmi E, Ruottinen HM, Bergman J, Eskola O, Solin O.
{[}(18)F{]}FDOPA and {[}(18)F{]}CFT are both sensitive PET markers to
detect presynaptic dopaminergic hypofunction in early Parkinson's
disease. Synapse. 2001; 40(3): 193--200.

20. Stormezand GN, Chaves LT, Vállez García D, et al. Intrastriatal
gradient analyses of 18F-FDOPA PET scans for differentiation of
Parkinsonian disorders. NeuroImage Clin. 2020; 25: 102161.

21. Hirano S. Clinical implications for dopaminergic and functional
neuroimage research in cognitive symptoms of Parkinson's disease. Mol
Med. 2021 Apr 15;27(1):40. doi: 10.1186/s10020-021-00301-7. PMID:
33858320; PMCID: PMC8048076.

22. Ma Y, Dhawan V, Mentis M, Chaly T, Spetsieris PG, Eidelberg D.
Parametric mapping of {[}18F{]}FPCIT binding in early stage Parkinson's
disease: a PET study. Synapse. 2002 Aug;45(2):125-33. doi:
10.1002/syn.10090. PMID: 12112405.

23. Rinne JO, Portin R, Ruottinen H, Nurmi E, Bergman J, Haaparanta M,
Solin O. Cognitive impairment and the brain dopaminergic system in
Parkinson disease: {[}18F{]}fluorodopa positron emission tomographic
study. Arch Neurol. 2000 Apr;57(4):470-5. doi 10.1001/archneur.57.4.470.
PMID: 10768619.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/2)-Figure-1/2)-Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/3)-Figure-2/3)-Figure-2}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`4) Table_1.docx`  available at \url{https://authorea.com/users/614786/articles/641495-slowing-of-eeg-waves-correlates-with-striatal-18f-fluorodopa-pet-ct-uptake-and-executive-dysfunction-in-parkinson-s-disease}

\textbf{Hosted file}

\verb`5) Table_2.docx`  available at \url{https://authorea.com/users/614786/articles/641495-slowing-of-eeg-waves-correlates-with-striatal-18f-fluorodopa-pet-ct-uptake-and-executive-dysfunction-in-parkinson-s-disease}

\selectlanguage{english}
\FloatBarrier
\end{document}

