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Quantification of [¹¹C]MP4A PET studies

Analysis methods used in literature

Sato et al. (2004) have made an excellent comparison of most of the proposed methods for a closely related PET tracer, [¹¹C]MP4P.

Compartment model for [¹¹C]MP4A

For the quantification of AChE activity, a three-compartment (two-tissue compartment) model is applied (Iyo et al., 1997; Nagatsuka et al., 1998; Namba et al., 1999; Herholz et al., 2000; Shiraishi et al., 2005). The rate constant k₃ represents the rate of hydrolysis of [¹¹C]MP4A by AChE. The diffusion of [¹¹C]methylpiperidinol ([¹¹C]MP4OH), the radioactive metabolite of [¹¹C]MP4A, through the blood-brain-barrier is negligible during the PET study, thus k₄=0.

Very close correlation between K₁, k₂ and cerebral blood flow (CBF) have been found (Herholz et al., 2000). Linear regression of K₁ on CBF gave a slope of about one 1.1 and intercept close to zero, suggesting that the first-pass extraction rate for MP4A is very high (Herholz et al., 2000).

Reference tissue -based analysis

In the cerebellum and striatum, hydrolysis is extremely rapid, i.e. k₃ >> k₂, therefore k₃^app = k₂ + k₃. Nagatsuka et al. (2001) suggested using cerebellum as a positive reference region for a linearized calculation model, and validated its results against standard non-linear fitting with plasma input; the method performed better than shape analysis (see below). For software, see fit_trtm and lhtrtm. Herholz et al. (2001) used putamen and caudate nucleus as reference region, but a quite different mathematical method for estimation of k₃. For software, see hm4mpa. This method leads to negative bias and it was later developed further and applied to produce parametric k₃ images by the same group (Zündorf et al., 2002).

Radioactivity ratio of cortical regions to the cerebellum 30 to 40 min after injection was calculated by Ota et al. (2004) to develop a simple analysis method for future SPECT tracer. The [¹¹C]MP4A ratios were correlated better with k₃ (r=0.69) than with K₁ (r=0.33). The diagnostic sensitivity for AD was 92%. Coefficient of variance of the [¹¹C]MP4A ratio was small compared with k₃ (Ota et al., 2004). In this method it is assumed that extraction fraction is similar in all brain regions. Also blood flow in cortical regions and in cerebellum (ratio) affect the [¹¹C]MP4A ratio, but in degenerative diseases this may even increase the sensitivity for detecting abnormal change (Ota et al., 2004).

Any of the reference tissue input methods can not be applied to AChE inhibition studies, because the assumption k₃ >> k₂ does not hold.

Shape analysis

Shape analysis (Koeppe et al., 1999) was first introduced to analyze another AChE tracer, [¹¹C]MP4P, also called [¹¹C]PMP, which has somewhat lower specificity for AChE in the human brain. The shape analysis method was also used to analyze [¹¹C]MP4A studies and found to be sensitive technique to detect cortical AChE changes in patients with dementia (Tanaka et al., 2001) but less sensitive in detecting changes in Alzheimer's disease than the reference region input method (Nagatsuka et al., 2001).

The assumption that all tracer is metabolized in the end of the PET scanning would require relatively long scan times, especially in enzyme inhibition studies.

Software: fitshape and simshape

Effect of age

AChE activity, measured as [¹¹C]MP4A k₃ or ratio in the cerebral cortex does not change significantly or at all with age (Namba et al., 1998 and 1999; Ota et al., 2004).

Suggested analysis method for Turku

Image processing

PET images are summed over frames, coregistered with MRI, and regions of interest are defined.

For regional analysis, TACs are calculated from the dynamic PET image. TACs should be weighted.

Without arterial blood sampling: [¹¹C]MP4A ratio

Ota et al. (2004) suggested the use of regional [¹¹C]MP4A ratio for diagnostics of Alzheimer's disease. Ota et al. also proposed using the ratio for monitoring the effects of AChE inhibitors, but this approach has not yet been validated.

Use programs dftratio and imgratio for computing the regional ratio or ratio image, respectively, from 30 to 40 min after injection.

With arterial blood sampling

Compartmental model fit method (Iyo et al., 1997; Namba et al., 1999) with arterial plasma input is the currently recommended method for analysis of acetylcholinesterase inhibition studies.

Pre-processing plasma input

Make sure that you have all the necessary data files:

Then, follow the instructions in http://www.turkupetcentre.net/analysis/doc/tracer_input.html. Note that for [C-11]MP4A:

Conversion from blood to plasma or from plasma to blood is not necessary, because blood and plasma TACs are similar
Plasma TAC is usually measured until 40 min. Extrapolate it to the end of PET scan using extrapol
Hill-type function can be used to fit the fractions of parent tracer in plasma; use default weighting
In the time delay correction, do not use the whole data that was collected but only the first 20 minutes after injection. Time delay must be fitted between PET count-rate curve and metabolite corrected plasma TAC, but remember to correct simulatenously also the total plasma TAC.

Before proceeding, make sure that both the plasma and tissue data are in the same calibration units (preferably kBq/ml) and that the time unit is min. Image data from HR+ and PET-CT may originally be in units Bq/ml.

Regional AChE activity (k₃)

After all the previous steps have been done succesfully, the enzyme activity k₃ can be calculated using fitk3. Program fitk3 allows constraining K₁/k₂ to a value determined as the mean estimate across cortical regions of all subjects from the unconstrained fits: this has been suggested for related tracer [¹¹C]PMP (Koeppe et al., 1999; Kuhl et al., 1999). If K₁/k₂ is not constrained, you should consider reporting (K₁/k₂)*k₃ as an index of enzyme activity, instead of k₃.

Constraints for model parameters can be set with a text file with the following contents:

K1_lower := 0
K1_upper := 2
K1k2_lower := 1
K1k2_upper := 15
k3_lower := 0
k3_upper := 1.5
Vb_lower := 0
Vb_upper := 0.10

To constrain K₁/k₂ to a predetermined value, set the lower and upper limit to that value. This file is then given to fitk3 with option -i.

For example:

fitk3 -i=constraints.set ua1807ap_pure.delay.kbq ua1807ab.delay.kbq ua1807.dft 999 ua1807k3.res ua1807fit.dat

Acetylcholinesterase activity maps

To be added later.

References:

Herholz K, Bauer B, Wienhard K, Kracht L, Mielke R, Lenz O, Strotmann T, Heiss W-D. In-vivo measurements of regional acetylcholine esterase activity in degenerative dementia: comparison with blood flow and glucose metabolism. J. Neural. Transm. 2000; 107:1457-1468.

Herholz K, Lercher M, Wienhard K, Bauer B, Lenz O, Heiss W-D. PET measurement of cerebral acetylcholine esterase activity without blood sampling. Eur. J. Nucl. Med. 2001; 28:472-477.

Irie T, Fukushi K, Akimoto Y, Tamagami H, Nozaki T. Design and evaluation of acetylcholine analogs for mapping brain acetylcholinesterase (AchE) in vivo. Nucl. Med. Biol. 1994; 21(6): 801-808.

Iyo M, Namba H, Fukushi K, Shinotoh H, Nagatsuka S, Suhara T, Sudo Y, Suzuki K, Irie T. Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease. Lancet 1997; 349: 1805-1809.

Kaasinen V, Någren K, Järvenpää T, Roivainen A, Yu M, Oikonen V, Kurki T, Rinne JO. Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease. J. Clin. Psychopharmacol. 2002; 22(6): 615-620.

Koeppe RA, Frey KA, Snyder SE, Meyer P, Kilbourn MR, Kuhl DE. Kinetic Modeling of N-[¹¹C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain. J. Cereb. Blood Flow Metabol. 1999; 19: 1150-1163.

Kuhl DE, Koeppe RA, Minoshima S, Snyder SE, Ficaro EP, Foster NL, Frey KA, Kilbourn MR. In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease. Neurology 1999; 52(4): 691-699.

Nagatsuka S, Fukushi K, Shinotoh H, Namba H, Iyo M, Tanaka N, Aotsuka A, Ota T, Tanada S, Irie T. Kinetic analysis of [¹¹C]MP4A using a high-radioactivity brain region that represents an integrated input function for measurement of cerebral acetylcholinesterase activity without arterial blood sampling. J. Cereb. Blood Flow Metab. 2001; 21:1354-1366.

Nagatsuka S, Namba H, Iyo M, Fukushi K, Shinotoh H, Suhara T, Sudo Y, Suzuki K, Irie T. Quantitative measurement of acetylcholinesterase activity in living human brain using a radioactive acetylcholine analog and dynamic PET. p.393-399, In: Quantitative Functional Brain Imaging with Positron Emission Tomography, Carson et al. eds., Academic Press, San Diego., 1998.

Namba H, Fukushi K, Nagatsuka S, Iyo M, Shinotoh H, Tanada S, Irie T. Positron emission tomography: quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates. Methods 2002; 27:242-250.

Namba H, Iyo M, Fukushi K, Shinotoh H, Nagatsuka S, Suhara T, Sudo Y, Suzuki K, Irie T. Human cerebral acetylcholinesterase activity measured with positron emission tomography: procedure, normal values and effect of age. Eur. J. Nucl. Med. 1999; 26: 135-143.

Namba H, Iyo M, Shinotoh H, Nagatsuka S, Fukushi K, Irie T. Preserved acetylcholinesterase activity in aged cerebral cortex. Lancet 1998; 351(9106): 881-882.

Ota T, Shinotoh H, Fukushi K, Nagatsuka S, Namba H, Iyo M, Aotsuka A, Tanaka N, Sato K, Shiraishi T, Tanada S, Arai H, Irie T. A simple method for the detection of abnormal brain regions in Alzheimer's disease patients using [¹¹C]MP4A: comparison with [¹²³I]IMP SPECT. Ann. Nucl. Med. 2004; 18: 187-193.

Rinne JO, Kaasinen V, Järvenpää T, Någren K, Roivainen A, Yu M, Oikonen V, Kurki T. Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 2003; 74: 113-115.

Sato K, Fukushi K, Shinotoh H, Nagatsuka S, Tanaka N, Aotsuka A, Ota T, Shiraishi T, Tanada S, Iyo M, Irie T. Evaluation of simplified kinetic analyses for measurement of brain acetylcholinesterase activity using N-[¹¹C]Methylpiperidin-4-yl propionate and positron emission tomography. J. Cereb. Blood Flow Metab. 2004; 24(6): 600-611.

Shiraishi T, Kikuchi T, Fukushi K, Shinotoh H, Nagatsuka SI, Tanaka N, Ota T, Sato K, Hirano S, Tanada S, Iyo M, Irie T. Estimation of plasma IC₅₀ of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[¹¹C]methylpiperidin-4-yl acetate ([¹¹C]MP4A) and PET. Neuropsychopharmacology 2005; 30(12): 2154-2161.

Tanaka N, Fukushi K, Shinotoh H, Nagatsuka S, Namba H, Iyo M, Aotsuka A, Ota T, Tanada S, Irie T. Positron emission tomographic measurement of brain acetylcholinesterase activity using N-[¹¹C]methylpiperidin-4-yl acetate without arterial blood sampling: methodology of shape analysis and its diagnostic power for Alzheimer's disease. J. Cereb. Blood Flow Metab. 2001; 21:295-306.

Zündorf G, Herholz K, Lercher M, Wienhard K, Bauer B, Weisenbach S, Heiss W-D. PET functional parametric images of acetylcholine esterase activity without blood sampling. In: Brain Imaging Using PET, 2002. (Eds. Senda M et al.) Academic Press, San Diego, CA, pp. 41-46.

Quantification of [11C]MP4A PET studies