A randomized double-blind study comparing 25 and 50 mg TC-1734 (AZD3480) with placebo,in older subjects with age-associated memory impairment

Abstract

Cognitive decline is a feature of ageing and can be defined as normal (age-associated memory impairment) or pathological (mild cognitive impairment/Alzheimer’s disease). Stimulation of selective brain-specific neuronal nicotinic acetylcholine receptors might offer symptomatic treatment for normal ageing. The objective of this study was to assess the safety, tolerability and efficacy of TC-1734 (AZD3480), a selective α4β2 nicotinic agonist, in the treatment of age-associated memory impairment. A randomized placebo-controlled trial was conducted in 16 community-based centers within the USA. Subjects who met objective criteria for age-associated memory impairment were recruited between November 2004 and December 2005. Subjects were randomly assigned to receive orally 25 mg (n = 59), 50 mg (n = 68) TC-1734 (AZD3480) or placebo (n = 66) in a double-blind fashion for 16 weeks. Main outcome measures included routine clinical safety measures, tolerability, cognitive assessment via the Cognitive Drug Research computerized test battery and a Subject Global Impression Scale of Cognition (SCI-Cog). Two outcomes from the computerized test battery – a factor assessing attention and one assessing episodic memory, along with the SGI-Cog were defined as co-primary outcome variables. Baseline to Week 16 differences from placebo for 50 mg TC-1734 (AZD3480) were considered of primary importance. For 50 mg TC-1734 (AZD3480) attention factor the mean drug–placebo difference was 22.9 (95% confidence interval 4.8 to 41.4) p = 0.01 for episodic memory factor the difference was −7.6 (95% confidence interval −14.4 to −0.8), p = 0.029, and for the SGI-Cog the difference was 0.99 (95% confidence interval 0.2 to 1.8), p = 0.015. As all three co-primary outcomes were positive it can be concluded the compound likely had a beneficial effect on cognition. TC-1734 (AZD3480) appeared safe and well tolerated in this study.

Keywords

α4β2 receptor age-associated memory impairment attention AZD3480 cognition elderly ispronicline memory nicotinic TC-1734

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References

Anderson DJ, Malysz J, Halvard J, et al. (2009) Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices, correlates with the profile of high but not low sensitivity α4β2 subunit combination. Biochem Pharmacol 78: 844–851.

Beck

Ward

Mendelson

Mock

Erbaugh

(1961) An inventory for measuring depression. Arch Gen Psychiatry 4: 561–571.

Beck

Epstein

Brown

Steer

(1988) An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 56: 893–897.

Crook

Bartus

Ferris

Whitehouse

Cohen

Gershon

(1986) Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change – report of a National Institute of Mental Health work group. Dev Neuropsychol 2: 261–276.

Crook

Feher

Larrabee

(1992) Assessment of memory complaint in age-associated memory impairment: the MAC-Q. Int Psychogeriatr 4: 165–176.

Court

Lloyd

Johnson

(1997) Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation during development and ageing. Dev Brain Res 101: 93–105.

DSM4 (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn Washington, DC, USA: American Psychiatric Association.

Dunbar

Boeijinga

Demazieres

(2007a) Effects of TC-1734 (AZD3480) a selective neuronal nicotinic receptor agonist on cognitive performance and the EEG of young healthy male volunteers. Psychopharmacology 191: 919–929.

Dunbar

Inglis

Kuchibhatla

Sharma

Tomlinson

Wamsley

(2007b) Effect of ispronicline a neuronal nicotinic acetylcholine receptor partial agonist in subjects with age-associated memory impairment. J Psychopharmacol 21: 171–178.

10.

Endicott

Nee

Harrison

Blumenthal

(1993) Quality of life, enjoyment and satisfaction questionnaire: a new measure. Psychopharmacol Bull 29: 321–326.

11.

Folstein

McHugh

(1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12: 189–198.

12.

Frolich L (2009) Presented at International Congress Alzheimer’s Disease (ICAD – Vienna).

13.

Gatto

Andrees-Bohme

Caldwell

(2004) TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with anti depressant, neuroprotective and long lasting cognitive effects. CNS Drugs Review 10: 147–166.

14.

Goldman

Morris

(2001) Evidence that age-associated memory impairment is not a normal variant of ageing. Alzheimer Dis Assoc Disord 15: 72–79.

15.

Hanninen

Hallikainen

Koivisto

(1995) A follow-up study of age-associated memory impairment: neuropsychological predictors of dementia. J Amer Geriatr Soc 43: 1007–1015.

16.

Hedges DW, Brown BL, Shwalb DA (2009) A direct comparison of effect sizes from clinical global impression – improvement scale to effect sizes from other rating scales in controlled trials of adult social anxiety disorder. Hum Psychopharmacol Clin Exp 24: 35–40.

17.

Khan A, Khan SR, Shankles EB, et al. (2002) Relative sensitivity of the Montgomery Asberg Depression Rating Scale, the Hamilton Depression Rating Scale and the Clinical Global Impression Scales in antidepressant trials. Inter Clin Psychopharmacol 17: 281–285.

18.

Mangan

(1982) The effect of cigarette smoking on vigilance performance. J Gen Psychol 106: 77–83.

19.

McClelland

(1987) The effects of practice on measures of performance. Hum Psychopharmacol 210: 109–118.

20.

Newhouse P (2009) Presented at nicotinic Satellite Symposium associated with Society for Neuroscience meeting – Chicago.

21.

O’Brien

Levy

(1992) Age-associated memory impairment: too broad an entity to justify drug treatment yet. Br Med J 304: 5–6.

22.

Perry

Gibson

Blessed

Tomlinson

(1977) A cholinergic connection between normal aging and senile dementia in human hippocampus. Neurosci Lett 6: 85–89.

23.

Peterson

Doody

Kurz

(2001) Current concepts of mild cognitive impairment. Arch Neurol 58: 1985–1992.

24.

Peterson

Smith

Waring

Ivnik

Tangalos

Kokmen

(1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56: 303–308.

25.

Reitan

Wolfson

(2004) The trail making test as an initial screening procedure for neuropsychological impairment in older children. Arch Clin Neuropsychol 19: 281–288.

26.

Snowdon

Lane

(1994) A longitudinal study of age-associated memory impairment. Int J Geriatr Psychiatry 9: 779–787.

27.

Stroop

(1935) Studies of interference in serial verbal reaction. J Exp Psychol 12: 643–662.

28.

Tierney

Szalai

Snow

(1996) Prediction of probable Alzheimer’s disease in memory-impaired patients: a prospective longitudinal study. Neurology 46: 661–665.

29.

Wechsler

(1981) (*) Sidcup, UK: The Psychological Corporation, Harcourt Brace and Company.

30.

Wechsler

(1987) (*) Sidcup, UK: The Psychological Corporation, Harcourt Brace and Company.

31.

Wesnes

(2000) The value of assessing cognitive function in drug development. Dialogues Clin Neurosci 2: 183–202.

32.

Wesnes KA, McKeith IG, Ferrara R, et al. (2002) Effects of rivastigmine on cognitive function in dementia with Lewy bodies: a randomized placebo controlled international study using the Cognitive Drug Research computerized assessment system. Dement Geriatr Cogn 13: 183–192.

33.

Wesnes KA, Ward T, McGinty A and Petrini O (2000) The memory enhancing effects of a ginkgo biloba/panax ginseng combination in healthy middle-aged volunteers. Psychopharmacology 52: 353–361.

34.

White

Levin

(1998) Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease. Psychopharmacology 143: 158–165.

35.

White

Levin

(2004) Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment. Psychopharmacology 171: 465–471.