The acetylcholine releaser linopirdine increases parietal regional cerebral blood flow in Alzheimer's disease

Abstract

Centrally acting cholinergic drugs have been reported to increase regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) in brain regions affected by Alzheimer's disease (AD). We studied the effects of the acetylcholine releaser linopirdine (LPD) on SPECT rCBF in patients with probable AD. Twenty-four AD patients (12 M, 12 F; mean age +/- SD = 68.9 +/- 8.2 years) and 13 healthy controls (8 M, 5 F; 68.4 +/- 8.0 years) participated. AD patients were scanned with 20 mCi of Tc99m-ECD at baseline and following 4 weeks of treatment with LPD 40 mg TID (n = 15) or placebo TID (n = 9) in a double-blind trial. Healthy subjects were scanned for comparison with baseline AD scans. Cortical/cerebellar rCBF ratios were derived for nine cortical structures. The combined parietal association cortex showed a 20.6% reduction in patients relative to controls. Patients treated with LPD showed an increase in parietal rCBF of 4.1 +/- 5.8%; whereas those treated with placebo showed a decrease of -2.0 +/- 7.4% (F = 5.13; df = 1, 22; P = 0.03). These data support the conclusion that rCBF abnormalities in AD are, in part, truly "functional" and can be selectively altered with pharmacological interventions. The parietal activation seen with LPD and other cholinergic AD drug therapies suggests the importance of measuring parietal lobe neuropsychological function in the course of evaluating these drugs.

Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention

“…ACh acting on endothelial muscarinic receptors may be expected to induce vasodilation and increase blood flow. Although a vasodilatory effect of linopirdine seems contradictory to the vasoconstrictor actions observed with isolated arteries (Joshi et al, 2006;Yeung et al, 2007;Mackie et al, 2008), a partial reversal of AD-associated hypoperfusion was observed in some but not all brain regions examined (van Dyck et al, 1997). This suggests a localized vasodilatory effect that may correspond to sites in which ACh release is enhanced, perhaps overwhelming any direct constrictor actions of linopirdine at these sites.…”

“…The use of linopirdine in AD has largely been based on its ability to enhance cholinergic neurotransmission. Enhanced release of acetylcholine may account for an observed increase in regional cerebral blood flow in patients with AD who were treated with linopirdine (van Dyck et al, 1997). ACh acting on endothelial muscarinic receptors may be expected to induce vasodilation and increase blood flow.…”

Linopirdine (DUP 996): Cholinergic Treatment of Older Adults Using Successive and Non-successive Tests

“…Although we cannot rule out this possibility entirely, there is now evidence to the point that DUP 996, using similar dose regimens as was the case in our experiment, increases the parietal regional cerebral blood flow in Alzheimer's disease [40]. Previous research has shown that constructional praxis tasks engaging the parietal lobe are enhanced by cholinergic therapy in AD [41,42].…”

Neuroimaging in alzheimer’s disease: Relevance for treatment

“…As previously reviewed [19], the drug most widely studied in rCBF or rCMR-Glu imaging paradigms in AD has been intravenous physostigmine. This formulation has been examined using 133 Xe inhalation [20], 99m Tc-HMPAO SPECT [21,22], 123 I-iodoamphetamine SPECT in conjunction with 18 F-fluorodeoxyglucose (FDG)-PET [23], and 15 O-CO 2 or -H 2 O PET [24].…”

“…The response was dose-related and showed greatest increases in parietal association cortex. The effect of the acetylcholine release enhancer linopirdine on 99m Tc-ECD SPECT was examined by van Dyck et al [19] in 24 patients with probable AD. Patients were scanned at baseline and following 4 weeks of treatment with linopirdine (n = 15) or placebo (n = 9) in a double-blind trial.…”