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Mitochondrial Function Is Related to Alterations at Brain SPECT in Depressed Patients

Published online by Cambridge University Press:  07 November 2014

Ann Gardner ,
Dario Salmaso ,
Davide Nardo ,
Federica Micucci ,
Flavio Nobili ,
Alejandro Sanchez-Crespo ,
Hans Jacobsson ,
Stig A. Larsson  and
Marco Pagani
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Abstract

Introduction: 99mTc-d,I-hexamethylpropylene amine oxime (99m Tc-HMPAO) retention in brain is proportional to cerebral blood flow and related to both the local hemodynamic state and to the cellular content of reduced glutathione. Alterations of the regional distribution of 99mTc-HMPAO retention, with discrepant results, have been reported at functional brain imaging of unipolar depression. Since mitochondrial involvement has been reported in depressed patients, the aim of the study was to explore whether the 99mTc-HMPAO retention at single-photon emission computed tomography in depressed patients may relate to different levels of mitochondrial function.

Methods: All patients had audiological and muscular symptoms, somatic symptoms that are common in depression. Citrate synthase (CS) activity assessed in muscle mitochondria correlated strongly with the activities of three mitochondrial respiratory chain enzymes and was used as a marker of mitochondrial function. K-means clustering performed on CS grouped eight patients with low and 11 patients with normal CS. Voxel-based analysis was performed on the two groups by statistical parametric mapping.

Results: Voxel-based analysis showed significantly higher 99mTc-HMPAO retention in the patients with low CS compared with the patients with normal CS in the posterior and inferior frontal cortex, the superior and posterior temporal cortex, the somato-sensory cortex, and the associative parietal cortex.

Conclusion: Low muscle CS in depressed patients is related to higher regional 99mTc-HMPAO retention that may reflect cerebrovascular adaptation to impaired intracellular metabolism and/or intracellular enzymatic changes, as previously reported in mitochondrial disorder. Mitochondrial dysfunction in varying proportions of the subjects may explain some of the discrepant results for 99mTc-HMPAO retention in depression.

Type
Original Research
Information
CNS Spectrums , Volume 13 , Issue 9 , September 2008 , pp. 805 - 814
Copyright
Copyright © Cambridge University Press 2008

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References

REFERENCES

1.Nikolaus, S, Larisch, R, Beu, M, Vosberg, H, Müller-Gärtner, HW. Diffuse cortical reduction of neuronal activity in unipolar major depression: a retrospective analysis of 337 patients and 321 controls. Nucl Med Commun. 2000;21:1119–1125.Google Scholar
2.Pagani, M, Salmaso, D, Nardo, D, et al.Imaging the neurobiological substrate of atypical depression by SPECT. Eur J Nucl Med Mol Imaging. 2007;34:110–120.Google Scholar
3.Krausz, Y, Freedman, N, Lester, H, et al.Brain SPECT study of common ground between hypothyroidism and depression. Int J Neuropsychopharmacol. 2007;10:99–106.Google Scholar
4.Fountoulakis, KN, Iacovides, A, Gerasimou, G, et al.The relationship of regional cerebral blood flow with subtypes of major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:537–546.Google Scholar
5.Bonne, O, Louzoun, Y, Aharon, I, et al.Cerebral blood flow in depressed patients: a methodological comparison of statistical parametric mapping and region of interest analyses. Psychiatry Res. 2003;122:49–57.Google Scholar
6.Gardner, A, Pagani, M, Jacobsson, H, et al.Differences in resting state regional cerebral blood flow assessed with 99mTc-HMPAO SPECT and brain atlas matching between depressed patients with and without tinnitus. Nucl Med Commun. 2002;23:429–439.CrossRefGoogle ScholarPubMed
7.Milo, TJ, Kaufman, GE, Barnes, WE, et al.Changes in regional cerebral blood flow after electroconvulsive therapy for depression. JECT. 2001;17:15–21.Google Scholar
8.Navarro, V, Gastó, C, Lomeña, F, Mateos, JJ, Marcos, T. Frontal cerebral perfusion dysfunction in elderly late-onset major depression assessed by 99MTC-HMPAO SPECT. Neuroimage. 2001;14(1 pt 1 ):202–205.Google Scholar
9.McGuffin, P, Katz, R, Watkins, S, Rutherford, J. A hospital-based twin register of the heritability of DSM-IV unipolar depression. Arch Gen Psychiatry. 1996;53:129–136.Google Scholar
10.Fattal, O, Link, J, Quinn, K, Cohen, BH, Franco, K. Psychiatric comorbidity in 36 adults with mitochondrial cytopathies. CNS Spectr. 2007;12:429–438.Google Scholar
11.Moore, CM, Christensen, JD, Lafer, B, Fava, M, Renshaw, PF. Lower levels of nucleoside triphosphate in the basal ganglia of depressed subjects: a phosphorous-31 magnetic resonance spectroscopy study. Am J Psychiatry. 1997;154:116–118.Google Scholar
12.Volz, HP, Rzanny, R, Riehemann, S, et al.31P magnetic resonance spectroscopy in the frontal lobe of major depressed patients. Eur Arch Psychiatry Clin Neurosci. 1998;248:289–295.Google Scholar
13.Gardner, A, Johansson, A, Wibom, R, et al.Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J Affect Disord. 2003;76:55–68.Google Scholar
14.Beasley, CL, Pennington, K, Behan, A, Wait, R, Dunn, MJ, Cotter, D. Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: evidence for disease-associated changes. Proteomics. 2006;6:3414–3425.Google Scholar
15.Neirinckx, RD, Burke, JF, Harrison, RC, Forster, AM, Andersen, AR, Lassen, NA. The retention mechanism of technetium-99m-HM-PAO: intracellular reaction with glutathione. J Cereb Blood Flow Metab. 1988;8:S4–S12.Google Scholar
16.Babich, JW. Technetium-99m-HMPAO and the role of glutathione: the debate continues. J Nucl Med. 1991;32:1681–1683.Google Scholar
17.Filosto, M, Tonin, P, Vattemi, G, Spagnolo, M, Rizzuto, N, Tomelleri, G. Antioxidant agents have a different expression pattern in muscle fibers of patients with mitochondrial diseases. Acta Neuropathol (Berl). 2002;103:215–220.Google Scholar
18.Tanabe, K, Masuda, K, Hirayama, A, Nagase, S, Kono, I, Kuno, S. Effect of spontaneous exercise on antioxidant capacity in rat muscles determined by electron spin resonance. Acta Physiol (Oxf). 2006;186:119–125.Google Scholar
19.Benard, G, Faustin, B, Passerieux, E, et al.Physiological diversity of mitochondrial oxidative phosphorylation. Am J Physiol Cell Physiol. 2006;291:C1172–C1182.Google Scholar
20.Miles, L, Wong, BL, Dinopoulos, A, Morehart, PJ, Hofmann, IA, Bove, KE. Investigation of children for mitochondriopathy confirms need for strict patient selection, improved morphological criteria, and better laboratory methods. Hum Pathol. 2006;37:173–184.Google Scholar
21.Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.Google Scholar
22.Birch-Machin, MA, Briggs, HL, Saborido, AA, Bindoff, LA, Turnbull, DM. An evaluation of the measurement of the activities of complexes I-IV in the respiratory chain of human skeletal muscle mitochondria. Biochem Med Metabol Biol. 1994;51:35–42.Google Scholar
23.Sottocasa, GL, Kuylenstierna, B, Ernster, L, Bergstrand, A. An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J Cell Biol. 1967;32:415–438.Google Scholar
24.Cooperstein, SJ, Lazarow, A, Kurfess, NJ. A microspectrophotometric method for the determination of succinic dehydrogenase. J Biol Chem. 1950;186:129–139.Google Scholar
25.Cooperstein, SJ, Lazarow, A. A microspectrophotometric method for the determination of cytochrome oxidase. J Biol Chem. 1951;189:665–670.Google Scholar
26.Alp, P, Newsholme, E, Zammit, V. Activities of citrate synthase and NAD+-linked and NADP+-linked isocitrate dehydrogenase in muscle from vertebrates and inverte-brates. Biochem J. 1976;154:689–700.Google Scholar
27.Chang, L-T. A method for attenuation correction in radionuclide computed tomography. IEEE Trans Nucl Sci. 1978;25:638–643.Google Scholar
28. The MNI brain and the Talairach atlas subroutine. Available at: http://imaging.mrccbu.cam.ac.uk/imaging/MniTalairach. Accessed December 8, 2005.Google Scholar
29. The MNI brain and the Talairach atlas. Available at: http://ric.uthscsa.edu/projects/talairachdaemon.htm. Accessed December 8, 2005.Google Scholar
30.Friston, KJ, Holmes, A, Poline, JB, Price, CJ, Frith, CD. Detecting activations in PET and fMRI: levels of inference and power. Neuroimage. 1996;4:223–235.CrossRefGoogle ScholarPubMed
31.Worsley, KJ, Marret, S, Neelin, P, Evans, AC. Searching scale space for activation in PET images. Hum Brain Map. 1996;4:74–90.Google Scholar
32.Fujibayashi, Y, Taniuchi, H, Waki, A, Yokoyama, A, Ishii, Y, Yonekura, Y. Intracellular metabolism of 99mTc-d,I-HMPA0 in vitro: a basic approach for understanding the hyperfixation mechanism in damaged brain. Nucl Med Biol. 1998;25:375–378.Google Scholar
33.Steele, JD, Currie, J, Lawrie, SM, Reid, I. Prefrontal cortical functional abnormality in major depressive disorder: a stereotactic meta-analysis. J Affect Disord. 2007;101:1–11.Google Scholar
34.Marin-Garcia, J, Ananthakrishnan, R, Goldenthal, MJ. Heart mitochondria response to alcohol is different than brain and liver. Alcohol Clin Exp Res. 1995;19:1463–1466.Google Scholar
35.Cocco, T, Sgobbo, P, Clemente, M, et al.Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine. Free Radic Biol Med. 2005;38:796–805.Google Scholar
36.Kasahara, T, Kubota, M, Miyauchi, T, et al.Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. Mol Psychiatry. 2006;11:577–593, 523.Google Scholar
37.Ross-Stanton, J, Meltzer, HY. Skeletal muscle morphology of depressed patients after medication. Muscle Nerve. 1979;2:239–240.Google Scholar
38.Simon, GE, VonKorff, M, Piccinelli, M, Fullerton, C, Ormel, J. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341:1329–1335.Google Scholar
39.Mathew, RJ, Weinman, ML, Mirabi, M. Physical symptoms of depression. Br J Psychiatry. 1981;139:293–296.Google Scholar
40.Gardner, A, Boles, RG. Mitochondrial energy depletion in depression with somatization. Psychother Psychosom. 2008;77:127–129.Google Scholar
41.Gardner, A, Boles, RG. Symptoms of somatization as a rapid screening tool for mitochondrial dysfunction in depression. Biopsychosoc Med. 2008;2:7.Google Scholar
42.Rodriguez, MC, MacDonald, JR, Mahoney, DJ, Parise, G, Beal, MF, Tarnopolsky, MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007;35:235–242.Google Scholar
43.Roitman, S, Green, T, Osher, Y, Karni, N, Levine, J. Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord. 2007;9:754–758.Google Scholar
44.DiMauro, S, Schon, EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2008;31:91–123.Google Scholar
45.Grünwald, F, Zierz, S, Broich, K, Schumacher, S, Bockisch, A, Biersack, HJ. HMPAO-SPECT imaging resembling Alzheimer-type dementia in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). J Nucl Med. 1990;31:1740–1742.Google Scholar
46.Grünwald, F, Zierz, S, Broich, K, Dewes, W, Böker, T, Biersack, HJ. Brain SPECT imaging with Tc-99m HMPAO in ophthalmoplegia plus. Clin Nucl Med. 1991;1:20–23.Google Scholar
47.Watanabe, Y, Hashikawa, K, Moriwaki, H, et al.SPECT findings in mitochondrial encephalomyopathy. J Nucl Med. 1998;39:961–964.Google Scholar
48.Peng, NJ, Liu, RS, Li, JY, et al.Increased cerebral blood flow in MELAS shown by Tc-99m HMPAO brain SPECT. Neuroradiology. 2000;42:26–29.Google Scholar
49.Amagasaki, K, Shimizu, T, Suzuki, Y, Kakizawa, T. Focal hyperperfusion in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Case report. J Neurosurg. 2001;94:133–136.Google Scholar
50.Lien, LM, Lee, HC, Wang, KL, Chiu, JC, Chiu, HC, Wei, YH. Involvement of nervous system in maternally inherited diabetes and deafness (MIDD) with the A3243G mutation of mitochondrial DNA. Acta Neurol Scand. 2001;103:159–165.Google Scholar
51.Rodriguez, G, Nobili, F, Tanganelli, P, Regesta, G, Ottonello, G. Cerebral hyperperfusion antedates by years strokelike episodes in the MELAS syndrome. Stroke. 1996;27:341–342.Google Scholar
52.Nariai, T, Ohno, K, Ohta, Y, Hirakawa, K, Ishii, K, Senda, M. Discordance between cerebral oxygen and glucose metabolism, and hemodynamics in a mitochondrial encephalomyopathy, lactic acidosis, and strokelike episode patient. J Neuroimaging. 2001;11:325–329.Google Scholar
53.Battino, M, Bertoli, E, Formiggini, G, Sassi, S, Gorini, A, Villa, RF, Lenaz, G. Structural and functional aspects of the respiratory chain of synaptic and nonsynaptic mitochondria derived from selected brain regions. J Bioenerg Biomembr. 1991;23:345–363.CrossRefGoogle ScholarPubMed
54.Iizuka, T, Sakai, F. Pathogenesis of stroke-like episodes in MELAS: analysis of neurovascular cellular mechanisms. Curr Neurovasc Res. 2005;2:29–45.Google Scholar
55.Sparaco, M, Bonilla, E, DiMauro, S, Powers, JM. Neuropathology of mitochondrial enceprialomyopathies due to mitochondrial DNA defects. J Neuropathol Exp Neurol. 1993;52:1–10.Google Scholar
56.Sparaco, M, Simonati, A, Cavallaro, T, et al.MELAS: clinical phenotype and morphological brain abnormalities. Acta Neuropathol (Berl). 2003;106:202–212.Google Scholar
57.Filosto, M, Tomelleri, G, Tonin, P, et al.Neuropathology of mitochondrial diseases. Biosci Rep. 2007;27:23–30.Google Scholar
58.Blass, JP. Mitochondria, neurodegenerative diseases, and selective neuronal vulnerability. Ann N Y Acad Sci. 1999;893:434–439.Google Scholar
59.Hargreaves, IP, Sheena, Y, Land, JM, Heales, SJ. Glutathione deficiency in patients with mitochondrial disease: implications for pathogenesis and treatment. J Inherit Metab Dis. 2005;28:81–88.Google Scholar