Executive function and uptake of 99m Tcexametazime shown by single photon emission tomography after oral idazoxan in probable Alzheimer-type dementia

Abstract

Preliminary reports suggest improved executive function in patients with lobar dementia after treatment with single doses of the alpha 2 adrenoceptor antagonist, idazoxan. The potential for use in probable Alzheimer-type dementia prompted the present study. Fifteen patients with probable Alzheimer-type dementia were examined twice with neuropsychological measures and 14 also with single photon emission tomography (SPET) after a single double blind oral administration of 40 mg idazoxan or placebo in a balanced cross-over design. Brain perfusion maps were spatially transformed into standard stereotactic space and compared pixel-by-pixel. A parametric analysis was used to examine the relationship between the drug effect, verbal fluency and brain perfusion. Two to 3 h after idazoxan, measures of reaction time, Stroop test, category fluency and anxiety were unchanged. Verbal fluency (letter) and spatial working memory were impaired and performance on the Tower of London test in a sub-set of patients showed a trend to impairment in the idazoxan condition. Idazoxan produced a modest relative activation in left thalamus and inferior occipital cortex: decreases occurred in inferior anterior cingulate and left insular cortex. There were significant correlations on both days between measures of fluency and brain perfusion in left lateral prefrontal cortex. The reduced performance with idazoxan was directly correlated with reduced perfusion in left lateral prefrontal cortex, supporting an important interaction between drug and task performance. The imaging component of the study therefore suggested that activation of frontal networks is necessary for performing fluency tasks in Alzheimer-type dementia. Brain networks involving prefrontal cortex are the locus for the primary cognitive effects of noradrenergic drugs. The direction of the effect of any dose of agonist or antagonist may depend critically upon the age and pathology of the experimental subjects and the relationship between performance, noradrenergic drive and task difficulty.

THA Improves Word Priming and Clonidine Enhances Fluency and Working Memory in Alzheimer's Disease

“…Moffoot et al 1994). The involvement of ␣2-adrenoceptors in the improvement of fluency and spatial working memory observed in AD (the present study) and Korsakoff's psychosis or in healthy volunteers is supported by a recent report describing the effect of idazoxan, an ␣2-antagonist, on cognition (Goodwin et al 1997). Goodwin et al (1997) found that idazoxan treatment disrupted spatial working memory and word fluency in AD patients, and that the reduction in blood flow in the lateral prefrontal area correlated with impaired fluency performance.…”

Cerebral blood flow patterns underlying the differential impairment in category vs letter fluency in Alzheimer’s disease

“…The one functional imaging study comparing activation during the two types of ¯uency performance in healthy controls, however, revealed a similar pattern of activation and deactivation in a network involving both left frontal cortex and superior temporal regions [11]. Also, a study by Goodwin, et al [12] using Letter Fluency as an activation during SPECT in a sample of AD patients, revealed a circumscribed association between performance and left frontal activity at baseline, but a spreading of this association to incorporate temporopartietal regions on the right side during administration of the adrenergic a-2 receptor antagonist idazoxan, which impaired performance. Letter ¯uency performance appears to be aected, then, by regional brain activity beyond what is suggested by lesion studies.…”

Comparative Cognitive Neuropsychological Studies of Frontal Lobe Function: Implications for Therapeutic Strategies in Frontal Variant Frontotemporal Dementia

“…This may have some relevance to the detrimental effect of IDZ in fvFTD patients on this task, in that IDZ may somehow have an 'overdose' effect upon performance, and highlights further the neural specificity of the deficits in fvFTD. It is notable that IDZ has also recently been found to produce deficits in spatial working memory in patients with pDAT [71].…”