Dement Neurocogn Disord.  2017 Dec;16(4):104-109. 10.12779/dnd.2017.16.4.104.

Changes in Regional Cerebral Perfusion after Nicergoline Treatment in Early Alzheimer's Disease: A Pilot Study

• Im JJ
• Jeong HS
• Park JS
• Yang Y
• Na SH
• Oh JK
• Chung YA
• Song IU

• KMID: 2442726
• DOI: http://doi.org/10.12779/dnd.2017.16.4.104

Abstract

BACKGROUND AND PURPOSE
Nicergoline is an ergoline derivative that is used to treat cognitive deficits in cerebrovascular disease and various forms of dementia. Although therapeutic effects of nicergoline have been established, little is known about its effects on cerebral perfusion in Alzheimer's disease (AD). The aim of this study was to examine the role of nicergoline in regional cerebral blood flow (rCBF) of AD patients using technetium-99m hexa-methyl-propylene-amine-oxime single photon emission computed tomography (SPECT).
METHODS
Sixteen patients with early AD underwent a comprehensive clinical assessment including cognitive testing and SPECT scans before and after nicergoline treatment. Nicergoline (30 mg twice daily) was administered for an average duration of 1.5 years. Clinical and cognitive functioning was assessed using the Mini-Mental State Examination, Clinical Dementia Rating (CDR), CDR-Sum of Boxes, Global Deterioration Scale, Barthel Activities of Daily Living Index, Instrumental Activities of Daily Living, and Geriatric Depression Scale.
RESULTS
Nicergoline treatment induced changes in the severity of dementia, cognitive function, activities of daily living, and depressive symptoms, which were not statistically significant. During the follow-up, the patients showed significant increases in their relative rCBF in the superior frontal gyrus, precentral gyrus, and postcentral gyrus.
CONCLUSIONS
Nicergoline treatment improves perfusion of the frontal and parietal regions in early AD patients. It is possible that the increased perfusion in the superior frontal gyrus may be related to the mechanisms that delay or prevent progressive deterioration of cognitive functions in AD.

Keyword

Alzheimer disease; nicergoline; regional cerebral blood flow; single photon emission computed tomography; cognition

MeSH Terms

Activities of Daily Living
Alzheimer Disease*
Cerebrovascular Circulation
Cerebrovascular Disorders
Cognition
Cognition Disorders
Dementia
Depression
Ergolines
Follow-Up Studies
Frontal Lobe
Humans
Nicergoline*
Parietal Lobe
Perfusion*
Pilot Projects*
Prefrontal Cortex
Somatosensory Cortex
Therapeutic Uses
Tomography, Emission-Computed, Single-Photon
Ergolines
Nicergoline
Therapeutic Uses

Figure

• 

  Fig. 1 Brain areas showing significantly increased regional cerebral blood flow in nicergoline-treated Alzheimer's disease patients compared with baseline. Images are shown in neurological convention. Color bar represents the voxel-level t-values.

Reference

1. Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer's disease: current status and new perspectives. Lancet Neurol. 2003; 2:539–547.

2. Gorelick PB. Risk factors for vascular dementia and Alzheimer disease. Stroke. 2004; 35:11 Suppl 1. 2620–2622.

3. Skoog I, Kalaria RN, Breteler MM. Vascular factors and Alzheimer disease. Alzheimer Dis Assoc Disord. 1999; 13:Suppl 3. S106–S114.

4. Winblad B, Carfagna N, Bonura L, Rossini BM, Wong EH, Battaglia A. Nicergoline in dementia: a review of its pharmacological properties and therapeutic potential. CNS Drugs. 2000; 14:267–287.

5. Bracco L, Bonura ML, Battaglia A. Six-month, multicentre, double-blind trial of nicergoline in the treatment of mild to moderate AD and its 12-month follow-up [abstract]. Neurosci Lett. 1999; 552:18.

6. Crook TH. Nicergoline in the treatment of probable Alzheimer's disease. Preliminary results of a double-blind, randomized, placebo-controlled study [abstract]. J Neurol Sci. 1997; 150:S18.

7. Winblad B, Bonura ML, Rossini BM, Battaglia A. Nicergoline in the treatment of mild- to- moderate Alzheimer's disease. Clin Drug Investig. 2001; 21:621–632.

8. Arrigo A, Moglia A, Borsotti L. A double-blind, placebo-controlled, crossover trial with nicergoline in patients with senile dementia [abstract]. Int J Clin Pharmacol Res. 1982; 2:4 Suppl 1. 33–41.

9. Battaglia A, Bruni G, Ardia A, Sacchetti G. Nicergoline in mild to moderate dementia. A multicenter, double-blind, placebo-controlled study. J Am Geriatr Soc. 1989; 37:295–302.

10. Nappi G, Bono G, Merlo P, Borromei A, Caltagirone C, Lomeo C, et al. Long-term nicergoline treatment of mild to moderate senile dementia: results of a multicentre, double-blind, placebo-controlled study. Clin Drug Investig. 1997; 13:308–316.

11. Saletu B, Paulus E, Linzmayer L, Anderer P, Semlitsch HV, Grünberger J, et al. Nicergoline in senile dementia of Alzheimer type and multi-infarct dementia: a double-blind, placebo-controlled, clinical and EEG/ERP mapping study. Psychopharmacology (Berl). 1995; 117:385–395.

12. Winblad B, Fioravanti M, Dolezal T, Logina I, Milanov IG, Popescu DC, et al. Therapeutic use of nicergoline. Clin Drug Investig. 2008; 28:533–552.

13. Carfagna N, Di Clemente A, Cavanus S, Damiani D, Gerna M, Salmoiraghi P, et al. Modulation of hippocampal ACh release by chronic nicergoline treatment in freely moving young and aged rats. Neurosci Lett. 1995; 197:195–198.

14. McArthur RA, Carfagna N, Banfi L, Cavanus S, Cervini MA, Fariello R, et al. Effects of nicergoline on age-related decrements in radial maze performance and acetylcholine levels. Brain Res Bull. 1997; 43:305–311.

15. Ogawa N, Asanuma M, Hirata H, Kondo Y, Kawada Y, Mori A. Cholinergic deficits in aged rat brain are corrected with nicergoline. Arch Gerontol Geriatr. 1993; 16:103–110.

16. Moretti A, Carfagna N, Caccia C, Carpentieri M. Effect of ergolines on neurotransmitter systems in the rat brain. Arch Int Pharmacodyn Ther. 1988; 294:33–45.

17. Le Poncin-Lafitte M, Grosdemouge C, Duterte D, Rapin JR. Simultaneous study of haemodynamic, metabolic and behavioural sequelae in a model of cerebral ischaemia in aged rats: effects of nicergoline. Gerontology. 1984; 30:109–119.

18. Miccheli A, Puccetti C, Capuani G, Di Cocco ME, Giardino L, Calzà L, et al. [1-13C]Glucose entry in neuronal and astrocytic intermediary metabolism of aged rats. A study of the effects of nicergoline treatment by 13C NMR spectroscopy. Brain Res. 2003; 966:116–125.

19. Caraci F, Chisari M, Frasca G, Canonico PL, Battaglia A, Calafiore M, et al. Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against beta-amyloid toxicity. Brain Res. 2005; 1047:30–37.

20. Mizuno T, Kuno R, Nitta A, Nabeshima T, Zhang G, Kawanokuchi J, et al. Protective effects of nicergoline against neuronal cell death induced by activated microglia and astrocytes. Brain Res. 2005; 1066:78–85.

21. Sortino MA, Battaglia A, Pamparana F, Carfagna N, Post C, Canonico PL. Neuroprotective effects of nicergoline in immortalized neurons. Eur J Pharmacol. 1999; 368:285–290.

22. Caputi A, Di Luca M, Pastorino L, Colciaghi F, Carfagna N, Wong E, et al. Nicergoline and its metabolite induce translocation of PKC isoforms in selective rat brain areas. Neurosci Res Commun. 1998; 23:159–167.

23. Carfagna N, Cavanus S, Damiani D, Salmoiraghi P, Fariello R, Post C. Modulation of phosphoinositide turnover by chronic nicergoline in rat brain. Neurosci Lett. 1996; 209:189–192.

24. Cedazo-Minguez A, Bonecchi L, Winblad B, Post C, Wong EH, Cowburn RF, et al. Nicergoline stimulates protein kinase C mediated alpha-secretase processing of the amyloid precursor protein in cultured human neuroblastoma SH-SY5Y cells. Neurochem Int. 1999; 35:307–315.

25. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). Washington, DC: American Psychiatric Association;2000.

26. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984; 34:939–944.

27. Kang Y, Na DL, Hahn S. A validity study on the Korean Mini-Mental State Examination (K-MMSE) in dementia patients. J Korean Neurol Assoc. 1997; 15:300–308.

28. Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease. Neurology. 1989; 39:1159–1165.

29. Choi SH, Na DL, Lee BH, Hahm DS, Jeong JH, Jeong Y, et al. The validity of the Korean version of Global Deterioration Scale. J Korean Neurol Assoc. 2002; 20:612–617.

30. Wade DT, Collin C. The Barthel ADL Index: a standard measure of physical disability? Int Disabil Stud. 1988; 10:64–67.

31. Kang SJ, Choi SH, Lee BH, Kwon JC, Na DL, Han SH, et al. The reliability and validity of the Korean Instrumental Activities of Daily Living (K-IADL). J Korean Neurol Assoc. 2002; 20:8–14.

32. Jung IK, Kwak DI, Shin DK, Lee MS, Lee HS, Kim JY. A reliability and validity study of geriatric depression scale. J Korean Neuropsychiatr Assoc. 1997; 36:103–112.

33. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002; 15:273–289.

34. Pickut BA, Dierckx RA, Dobbeleir A, Audenaert K, Van Laere K, Vervaet A, et al. Validation of the cerebellum as a reference region for SPECT quantification in patients suffering from dementia of the Alzheimer type. Psychiatry Res. 1999; 90:103–112.

35. Soonawala D, Amin T, Ebmeier KP, Steele JD, Dougall NJ, Best J, et al. Statistical parametric mapping of (99m)Tc-HMPAO-SPECT images for the diagnosis of Alzheimer's disease: normalizing to cerebellar tracer uptake. Neuroimage. 2002; 17:1193–1202.

36. Kogure D, Matsuda H, Ohnishi T, Asada T, Uno M, Kunihiro T, et al. Longitudinal evaluation of early Alzheimer's disease using brain perfusion SPECT. J Nucl Med. 2000; 41:1155–1162.

37. Benoit M, Robert PH, Staccini P, Brocker P, Guerin O, Lechowski L, et al. One-year longitudinal evaluation of neuropsychiatric symptoms in Alzheimer's disease. The REAL.FR Study. J Nutr Health Aging. 2005; 9:95–99.

38. Burns A, Jacoby R, Levy R. Progression of cognitive impairment in Alzheimer's disease. J Am Geriatr Soc. 1991; 39:39–45.

39. Masdeu JC, Zubieta JL, Arbizu J. Neuroimaging as a marker of the onset and progression of Alzheimer's disease. J Neurol Sci. 2005; 236:55–64.

40. Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC. Mapping the evolution of regional atrophy in Alzheimer's disease: unbiased analysis of fluid-registered serial MRI. Proc Natl Acad Sci U S A. 2002; 99:4703–4707.

41. Coffey CE, Wilkinson WE, Parashos IA, Soady SA, Sullivan RJ, Patterson LJ, et al. Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging. Neurology. 1992; 42(3 Pt 1):527–536.

42. Fox NC, Schott JM. Imaging cerebral atrophy: normal ageing to Alzheimer's disease. Lancet. 2004; 363:392–394.

43. Raz N, Gunning FM, Head D, Dupuis JH, McQuain J, Briggs SD, et al. Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cereb Cortex. 1997; 7:268–282.

44. Resnick SM, Pham DL, Kraut MA, Zonderman AB, Davatzikos C. Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. J Neurosci. 2003; 23:3295–3301.

45. Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study. Eur J Nucl Med Mol Imaging. 2003; 30:1104–1113.

46. Encinas M, De Juan R, Marcos A, Gil P, Barabash A, Fernández C, et al. Regional cerebral blood flow assessed with 99mTc-ECD SPET as a marker of progression of mild cognitive impairment to Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2003; 30:1473–1480.

47. Chase TN, Foster NL, Fedio P, Brooks R, Mansi L, Di Chiro G. Regional cortical dysfunction in Alzheimer's disease as determined by positron emission tomography. Ann Neurol. 1984; 15:Suppl. S170–S174.

48. Friedland RP, Budinger TF, Koss E, Ober BA. Alzheimer's disease: anterior-posterior and lateral hemispheric alterations in cortical glucose utilization. Neurosci Lett. 1985; 53:235–240.

49. Metter EJ, Riege WH, Kameyama M, Kuhl DE, Phelps ME. Cerebral metabolic relationships for selected brain regions in Alzheimer's, Huntington's, and Parkinson's diseases. J Cereb Blood Flow Metab. 1984; 4:500–506.

50. Perani D, Di Piero V, Vallar G, Cappa S, Messa C, Bottini G, et al. Technetium-99m HM-PAO-SPECT study of regional cerebral perfusion in early Alzheimer's disease. J Nucl Med. 1988; 29:1507–1514.

51. du Boisgueheneuc F, Levy R, Volle E, Seassau M, Duffau H, Kinkingnehun S, et al. Functions of the left superior frontal gyrus in humans: a lesion study. Brain. 2006; 129(Pt 12):3315–3328.

52. Albers MW, Gilmore GC, Kaye J, Murphy C, Wingfield A, Bennett DA, et al. At the interface of sensory and motor dysfunctions and Alzheimer's disease. Alzheimers Dement. 2015; 11:70–98.

53. Kimura N, Kumamoto T, Masuda T, Hanaoka T, Okazaki T, Arakawa R. Evaluation of the regional cerebral blood flow changes during long-term donepezil therapy in patients with Alzheimer's disease using 3DSRT. J Neuroimaging. 2012; 22:299–304.

54. Nobili F, Koulibaly M, Vitali P, Migneco O, Mariani G, Ebmeier K, et al. Brain perfusion follow-up in Alzheimer's patients during treatment with acetylcholinesterase inhibitors. J Nucl Med. 2002; 43:983–990.

55. Ushuijima Y, Okuyama C, Mori S, Kubota T, Nakai T, Nishimura T. Regional cerebral blood flow in Alzheimer's disease: comparison between short and long-term donepezil therapy. Ann Nucl Med. 2006; 20:425–429.

56. Shimizu S, Hanyu H, Iwamoto T, Koizumi K, Abe K. SPECT follow-up study of cerebral blood flow changes during Donepezil therapy in patients with Alzheimer's disease. J Neuroimaging. 2006; 16:16–23.

57. Shimizu S, Kanetaka H, Hirose D, Sakurai H, Hanyu H. Differential effects of acetylcholinesterase inhibitors on clinical responses and cerebral blood flow changes in patients with Alzheimer's disease: a 12-month, randomized, and open-label trial. Dement Geriatr Cogn Dis Extra. 2015; 5:135–146.