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title: Analysis of [C-11]L-deprenyl-D2
author: Vesa Oikonen
updated_at: 2017-06-26
updated_at: 2021-04-19
created_at: 2014-05-19
tags:
- MAO B
......@@ -9,21 +9,264 @@ tags:
---
<h1>Quantification of MAO B activity with [<sup>11</sup>C]L-deprenyl-D2</h1>
<h1>Quantification of MAO-B activity with [<sup>11</sup>C]L-deprenyl-D2</h1>
<p>[<sup>11</sup>C]L-deprenyl-D2 (DEP-D) is used to measure the activity of monoamine oxidase B
(MAO-B) in the brain. Literature review on quantitative analysis of [<sup>11</sup>C]L-deprenyl-D2
<abbr title="Positron Emission Tomography">PET</abbr> brain studies is available in
<a href="http://www.turkupetcentre.net/reports/tpcmod0033.pdf">TPCMOD0033</a>.</p>
(MAO-B) in the brain. MAO-B is present in the outer mitochondrial membrane occurring in the brain
predominantly in glial cells and in serotonergic neurons
(<a href="https://doi.org/10.1007/s11307-005-0016-1">Fowler et al., 2005</a>).
It oxidises amines (for example <a href="./target_dopamine.html">dopamine</a>) from both endogenous
and exogenous sources. MAO-B is selectively and irreversibly inhibited by L-deprenyl (selegiline).
When the enzyme-substrate complex is formed, the rate-limiting step of MAO-B catalyzed oxidation
creates a highly reactive intermediate, which forms a covalent bond with the enzyme, thus
irreversibly inactivating it
(<a href="https://doi.org/10.1007/s11307-005-0016-1">Fowler et al., 2005</a>).
When L-deprenyl is labelled with <sup>11</sup>C, the active enzyme MAO-B becomes labelled, and it
can be imaged in vivo with PET.</p>
<h2>Compartmental model</h2>
The brain concentrations of [<sup>11</sup>C]L-deprenyl-D2 peak at about 5 min after injection, and
after a washout phase the concentrations reach a plateau about 30 min after injection
(<a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">Fowler et al., 1995</a>).
An irreversible <a href="./model_compartmental.html#3cm">three-compartment model</a>
(two-tissue compartment model) can be applied to the time-activity curves (TACs) of labelled
L-deprenyl in the brain and plasma to estimate MAO-B activity in the brain.
In the model, K<sub>1</sub> represents the plasma-to-organ transfer constant, k<sub>2</sub> is
the transfer rate of radiotracer from organ back to plasma, and k<sub>3</sub> describes the rate of
binding to MAO B. Under the PET study conditions, k<sub>3</sub> is proportional to the functionally
active free enzyme concentration. Because binding is irreversible, it is assumed that k<sub>4</sub>=0.
From these model constants, K<sub>1</sub> and k<sub>2</sub> are dependent on
<a href="./model_perfusion.html">blood flow</a>, but k<sub>3</sub> is not.
Due to the high extraction of L-deprenyl, K<sub>1</sub> is dominated by blood flow instead of
capillary permeability
(Fowler et al., <a href="https://doi.org/10.1111/j.1471-4159.1988.tb01121.x">1988</a> and
<a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">1995</a>).
Also the <a href="./model_ki.html">net influx rate</a> K<sub>i</sub>
(K<sub>i</sub>=K<sub>1</sub>&times;k<sub>3</sub>/(k<sub>2</sub>+k<sub>3</sub>)) is dependent
on blood flow
(<a href="https://doi.org/10.1038/jcbfm.1991.103">Lammertsma et al., 1991</a>), as well as the more
directly radioligand uptake related parameters, like <a href="./model_suv.html">SUV</a>.</p>
<p>The very high rate of binding of labelled L-deprenyl to MAO-B creates difficulties in applying the
compartmental model. The estimates of k<sub>2</sub> and k<sub>3</sub> tend to be highly correlated,
and the rate of radioligand binding (k<sub>3</sub>) and delivery (K<sub>1</sub>) are hard to separate
(<a href="https://doi.org/10.1007/s11307-005-0016-1">Fowler et al., 2005</a>).
Especially in the brain regions of high MAO-B concentrations (basal ganglia, thalamus and cingulate
gyrus), and in the elderly people who have reduced blood flow, the rate limiting step is
the radioligand delivery instead of binding
(<a href="https://doi.org/10.1212/wnl.43.10.1984">Fowler et al., 1993</a>).
To reduce the problem with correlating k<sub>2</sub> and k<sub>3</sub> estimates, a combination
model parameter &lambda;k<sub>3</sub> has been introduced as an index of MAO-B activity; &lambda; is
the K<sub>1</sub> over k<sub>2</sub> ratio
(Fowler et al., <a href="https://doi.org/10.1212/wnl.43.10.1984">1993</a> and
<a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">1995</a>).
K<sub>1</sub> and k<sub>2</sub> are both dependent on the blood flow, but &lambda; and
&lambda;k<sub>3</sub> are independent of blood flow. Because this index contains the ratio
k<sub>3</sub>/k<sub>2</sub>, the effect of their (positive) correlation is expected to be smaller.
Reproducibility in test-retest studies was improved by using &lambda;k<sub>3</sub> instead of
k<sub>3</sub> (<a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al., 2000</a>).</p>
<p>For instance, Fowler et al <a href="https://doi.org/10.1111/j.1471-4159.1988.tb01121.x">1988</a>
and <a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">1995</a>) and
<a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al (2000)</a> have estimated the
three-compartment model parameters using traditional nonlinear least squares approach.
In a addition, <a href="#GA">graphical analysis</a> methods have been used.</p>
<h2>Deuterium substitution</h2>
<p>The rate-limiting step of MAO-B catalyzed oxidation involves cleavage of a certain carbonhydrogen
bond in L-deprenyl. A carbon-deuterium bond is more difficult to cleave than the carbon-hydrogen bond,
which leads to reduced rate of reaction when this hydrogen is substituted with deuterium
(so called <em>deuterium isotope effect</em> ). Because the very high binding rate of
[<sup>11</sup>C]L-deprenyl has been found to be problematic in quantification of MAO-B activity,
the deuterium-substituted L-deprenyl, [<sup>11</sup>C]L-deprenyl-D2 is therefore preferred as PET
radiopharmaceutical
(Fowler et al., <a href="https://doi.org/10.1111/j.1471-4159.1988.tb01121.x">1988</a>,
<a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">1995</a>, and
<a href="https://doi.org/10.1016/j.nucmedbio.2003.10.003">2004</a>).</p>
<h2>Confounding factors</h2>
<h3>Age</h3>
<p>Unlike most enzymes, MAO-B activity (&lambda;k<sub>3</sub>) increases clearly with normal ageing,
which is accompanied by decreasing blood flow (decreasing K<sub>1</sub>)
(<a href="https://doi.org/10.1016/s0197-4580(97)00037-7">Fowler et al., 1997</a>).
Therefore, the age must be controlled in the PET studies of MAO-B activity.
If the age effect is studied, the measured index of MAO-B activity must not be flow dependent.
The age-related and disease-associated increase of MAO-B has been attributed to neuron loss and
gliosis (increase in glial cells).</p>
<h3>Perfusion</h3>
<p>As described above, the tissue uptake of [<sup>11</sup>C]L-deprenyl-D2 and especially
[<sup>11</sup>C]L-deprenyl is strongly dependent on blood flow. Therefore, to quantification of
MAO-B activity, the compartment model and a perfusion-independent model parameter or index, like
k<sub>3</sub> or &lambda;k<sub>3</sub> must be used.
Otherwise, for example, the increase of MAO-B activity in epileptogenic region might be
underestimated because of subsequently reduced blood flow.</p>
<h3>Smoking</h3>
<p>MAO-B is highly and variably inhibited in smokers
(<a href="https://doi.org/10.1016/s0161-813x(02)00109-2">Fowler et al., 2003</a>).
An overnight abstinence for smokers does not produce any recovery of MAO-B activity.
However, smoking a single cigarette does not produce a measurable decrease in MAO-B activity in
non-smokers
(<a href="https://doi.org/10.1016/s0161-813x(02)00109-2">Fowler et al., 2003</a>).</p>
<h3>Decreased K<sub>1</sub> in later scans</h3>
<p>In the test-retest setting, <a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al
(2000)</a> noticed a decrease of K<sub>1</sub> in the second scan (-7.7 &plusmn; 13.2%), although
the decrease was not statistically significant (n=5). This may be caused by familiarization with
the PET procedure and decreased anxiety
(<a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al., 2000</a>).</p>
<h2>Corrections applied to the PET data</h2>
<h3>Blood volume correction</h3>
<p><a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">Fowler et al (1995)</a> subtracted from
the brain PET data an approximate 4% blood volume before analyzing the data using the
three-compartment model or graphical analysis for irreversible systems.
<a href="https://doi.org/10.1038/jcbfm.1991.103">Lammertsma et al (1991)</a> included the
<a href="./blood_volume.html">vascular volume fraction</a> in the model equations, noting that
whole blood curve must be used instead of (total) plasma curve.</p>
<h3>Plasma protein binding</h3>
<p>Free fraction in plasma was 6.0%
(<a href="https://doi.org/10.1016/j.nucmedbio.2003.10.003">Fowler et al., 2004</a>).
Considering the high K<sub>1</sub> estimates in the brain, dissociation rate of the radiotracer from
plasma protein may be high, so that most of protein bound radiotracer is also available for transport
to the tissue. <a href="./plasma_protein_binding.html">Plasma protein binding</a> will affect
K<sub>1</sub>/k<sub>2</sub>, and thus also &lambda;k<sub>3</sub>.</p>
<h3>Blood-to-plasma transformation</h3>
<p>For [<sup>11</sup>C]L-deprenyl, <a href="https://doi.org/10.1038/jcbfm.1991.103">Lammertsma et al
(1991)</a> measured the <a href="./input_blood-to-plasma.html">blood-to-plasma ratio</a> from
discrete samples between 5 and 90 min. Based on <em>in vitro</em> experiments, they assumed that
the plasma-to-blood ratio is 1.126 at the time of the arrival of the tracer in the blood, taken to
be the time where the blood curve increased above 1% of the peak value
(<a href="https://doi.org/10.1038/jcbfm.1991.103">Lammertsma et al., 1991</a>).
They <a href="./input_blood-to-plasma_fitting.html">fitted</a> a multi-exponential function to the
ratios, determining the number of exponentials based on <a href="./model_aic.html">AIC</a> and SC.
The multi-exponential function was then used to calculate the total plasma curve from arterial blood
curve which had been measured on-line.
Fowler and Logan et al do not give details on this transformation in their publications.</p>
<h3>Plasma metabolite correction</h3>
<p>For [<sup>11</sup>C]L-deprenyl, <a href="https://doi.org/10.1038/jcbfm.1991.103">Lammertsma et al
(1991)</a> measured the fraction of <a href="./input_metabolite_correction.html">plasma metabolites</a>
from four samples at 5, 10, 15 and 20 min, and <a href="./input_parent_fitting.html">fitted</a> a
single exponential function to the fractions, assuming no metabolites at time 0.
The exponential function was used to calculate the concentration of unchanged radiopharmaceutical in
the plasma.
Fowler and Logan et al do not give details on this correction in their publications.</p>
<h3>Time delay correction</h3>
<a href="https://doi.org/10.1038/jcbfm.1991.103">Lammertsma et al (1991)</a> corrected for the
<a href="./delaytime.html">time delay</a> between blood curve and whole brain PET data by including
the delay as one of the fitted model parameters. The TACs of smaller ROIs were then fitted with
the delay fixed to this value.</p>
<h2><a name="GA">Graphical analysis</a></h2>
<p><a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">Fowler et al (1995)</a> have used
<a href="./model_mtga.html#patlak">graphical analysis for irreversible systems</a> to calculate the
<a href="./model_ki.html">net influx rate</a> K<sub>i</sub>, using metabolite corrected plasma
curve as input function. K<sub>i</sub> was taken as an average
of slopes of the Patlak plot between 6 and 45 min and 6 and 55 min
(<a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">Fowler et al., 1995</a>).</p>
<h3>Graphical method without plasma sampling</h3>
<p>Graphical method (<a href="./model_mtga.html#patlak_ref">Patlak plot</a>) can be used to estimate
the net MAO-B uptake using either metabolite corrected plasma or
<a href="./model_reference_tissue.html">reference tissue</a>.
<a href="https://doi.org/10.1111/j.1528-1157.1995.tb01051.x">Kumlien et al (1995)</a>
used cerebellar grey matter as reference region in epilepsy study because if its high perfusion and
relatively low MAO-B activity. Later, to compensate the significant amount of MAO-B in cerebellum,
the cerebellar time-activity curves were multiplied by a mono-exponential function to correct
the deviation of the plot from linearity
(<a href="https://doi.org/10.1111/j.1600-0404.1998.tb07300.x">Bergström et al., 1998</a>;
<a href="https://doi.org/10.1111/j.1528-1157.1995.tb01051.x">Kumlien et al., 2001</a>).
However, cerebellar MAO-B activity is probably not constant between individuals, and even less so in
MAO-B inhibition studies.</p>
<p>Note also that the results of graphical method are not independent from perfusion, although the
blood flow effects may be smaller than with <a href="./model_suv.html">SUV</a> method.</p>
<h3><a name=linear_method">Linear method</a></h3>
<p>Fowler et al (<a href="https://doi.org/10.1016/s0197-4580(97)00037-7">1997</a> and
<a href="https://doi.org/10.1016/s1095-0397(99)00010-2">1999</a>) and
<a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al (2000)</a> estimated the
three-compartment model parameters K<sub>1</sub> and &lambda;k<sub>3</sub> in a procedure which
involves also graphical analysis:</p>
<ol>
<li>K<sub>i</sub> is calculated using the average of Patlak graphical analysis slopes between
6-45 min and 7-55 min</li>
<li>K<sub>1</sub> (and k<sub>2</sub>+k<sub>3</sub>) are estimated with bilinear regression using
a modification of the general method of <a href="https://doi.org/10.1038/jcbfm.1984.89">Blomqvist
(1984)</a>, shown in equation 1.
<a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al (2000)</a> describe this process
in more detail: Several values for K<sub>1</sub> were estimated by successively increasing
the maximum time T from 5 to 18 min, because K<sub>1</sub> is more sensitive to data at earlier time
points; an average K<sub>1</sub> was used in the next step.</li>
<li>The &lambda;k<sub>3</sub> is calculated by solving it from the equation that relates
K<sub>i</sub> to the three-compartment model parameters (Eq. 2).</li>
</ol>
<div class="eqs" style="font-size:90%;">
<script type="math/tex; mode=display">
C_T(T) = K_1 \int_0^{T} C_{P}(t)dt + (k_2 + k_3) \left[ K_i \int_0^{T} \int_0^{t} C_P({t'})d{t'}dt - \int_0^T C_T (t)dt \right]
</script>
<script type="math/tex; mode=display">
\lambda k_3 = \frac{K_1 K_i}{K_1 - K_i}
</script>
</div>
<p>The estimates of K<sub>1</sub> and &lambda;k<sub>3</sub> from this linear method correlated very
well with the estimates from the nonlinear method, and no noise-induced bias was noticed in the
linear method, and the repeatability was also similar
(<a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al, 2000</a>).
Note that the equations in the original articles from years 1997 and 1998 do not contain the
necessary square brackets.</p>
<p>The first-pass extraction of [<sup>11</sup>C]L-deprenyl-D2 is high, and, assuming that it is 1,
then K<sub>1</sub> would equal plasma flow, which is about 40% of blood flow. Therefore, the
K<sub>1</sub> estimates by <a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al (
2000)</a>, ranging from 0.476 to 0.845, are quite high.
The step 2) may lead to an overestimation of K<sub>1</sub>, if the blood volume in tissue is not
considered: blood volume correction was not mentioned by Fowler et al
(<a href="https://doi.org/10.1016/s0197-4580(97)00037-7">1997</a> and
<a href="https://doi.org/10.1016/s1095-0397(99)00010-2">1999</a>) and
<a href="https://doi.org/10.1016/s0969-8051(99)00088-8">Logan et al (2000)</a>.</p>
<br>
<h2>Analysis method in <abbr title="Turku PET Centre">TPC</abbr></h2>
<h3>Preprocessing of the plasma input</h3>
<p>For a detailed description on <a href="./input_process.html">preprocessing of blood data</a>,
read the report <a href="http://petintra/imaging/Modelling/[C-11]L-deprenyl-D2/tpcmod0033_app_a.pdf"
>TPCMOD0033 Appendix A</a>. Below is a short instruction on how to do the processing with existing
software.</p>
>TPCMOD0033 Appendix A</a> in PET intranet.</p>
<p>Make sure that you have all the necessary data files:</p>
......@@ -40,17 +283,8 @@ software.</p>
</ol>
<p>Calculate the DEP-D plasma and total blood TACs, corrected for
<a href="./delaytime.html">time delay</a>, using either the GUI <a href=
"./tpcclib/doc/dep-d_input.html">DEP-D_input</a>
(available only in TPC network with a Windows XP computer), or
<a href="./analysis_shell.html">CLI</a> script from Windows command line with command:</p>
<pre>
cscript P:\bin\windows\DEP-D_input.vbs
</pre>
<p>If you are sure that PET scan and blood sampling were started simultaneously, you do not need to
enter the dynamic image file name; write <code>None</code> in the file name field instead.</p>
<a href="./delaytime.html">time delay</a>. The <a href="./analysis_shell.html">CLI</a> script
<code>P:\bin\windows\DEP-D_input.vbs</code> is unfortunately not functional any more.</p>
<h3><a name="regional"></a>Regional MAO B activity</h3>
......@@ -68,8 +302,9 @@ the population average (n=15) in TPC. With <code>fitk3</code> this can be done w
<p>The most reliable model parameter for describing the activity of MAO B is
<em>&lambda;&times;k<sub>3</sub></em>, where <em>&lambda;</em> =
<em>K<sub>1</sub>/k<sub>2</sub></em> (independent from perfusion), and
<em>k<sub>3</sub></em> is proportional to the association constant
<em>k<sub>on</sub></em> (Fowler et al., 1995; Arakawa et al., 2017).</p>
<em>k<sub>3</sub></em> is proportional to the association constant <em>k<sub>on</sub></em>
(<a href="https://pubmed.ncbi.nlm.nih.gov/7790952/">Fowler et al., 1995</a>;
<a href="https://doi.org/10.1186/s13550-017-0301-4">Arakawa et al., 2017</a>).</p>
<h4>MAO B inhibition percentage</h4>
......@@ -86,7 +321,7 @@ can be computed as described <a href="./enzyme_inhibition.html">here</a>.</p>
<a href="./image_clustering.html">clustering algorithm</a>
which groups voxels with similar kinetics could be applied prior to the voxel analysis.
In estimating the model parameters for each voxel, <em>&lambda;</em> could then be fixed at
the cluster value (Shumay et al., 2012).</p>
the cluster value (<a href="https://doi.org/10.4161/epi.21976">Shumay et al., 2012</a>).</p>
<br>
......@@ -97,6 +332,7 @@ the cluster value (Shumay et al., 2012).</p>
<li><a href="./target_dopamine.html">Dopaminergic system</a></li>
</ul>
<br><hr>
<h2>References:</h2>
......@@ -127,15 +363,12 @@ and [<sup>11</sup>C]-L-deprenyl-D<sub>2</sub>: a dose-finding study with a novel
EVT 301. <em>Clin Pharmacol Ther.</em> 2009; 85(5): 506-512.
doi: <a href="https://doi.org/10.1038/clpt.2008.241">10.1038/clpt.2008.241</a>.</p>
<p>Shumay E, Logan J, Volkow ND, Fowler JS. Evidence that the methylation state of the monoamine
oxidase A (MAO<sub>A</sub>) gene predicts brain activity of MAOA enzyme in healthy men.
<em>Epigenetics</em> 2012; 7(10): 1151-1160.</p>
<p>Sturm S, Forsberg A, Nave S, Stenkrona P, Seneca N, Varrone A, Comley RA, Fazio P, Jamois C,
Nakao R, Ejduk Z, Al-Tawil N, Akenine U, Halldin C, Andreasen N, Ricci B.
Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer's
disease and elderly controls after oral administration of sembragiline.
<em>Eur J Nucl Med Mol Imaging</em> 2017; 44: 382-391.</p>
<em>Eur J Nucl Med Mol Imaging</em> 2017; 44: 382-391.
doi: <a href="https://doi.org/10.1007/s00259-016-3510-6">10.1007/s00259-016-3510-6</a>.</p>
<br>
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