Cholinergic Control of Cognitive Resources

We attempted to identify the characteristic patterns in regional cerebral blood flow (rCBF) of patients with Alzheimer’s disease who responded to donepezil therapy. Sixty-one patients treated with donepezil were divided into two groups (responders and nonresponders) on the basis of changes in their Mini Mental State Examination (MMSE) scores from baseline to study endpoint. We analyzed single-photon emission computed tomography data (SPECT) at baseline using three-dimensional stereotactic surface projections and compared differences in rCBF between the two groups. Statistical maps showed a significantly lower rCBF of the lateral and medial frontal lobes in the nonresponders than in the responders. There was a significant inverse correlation between the relative rCBF reduction in the frontal lobe and the MMSE change. These results suggest that frontal function, as assessed by SPECT, affects the patient’s response to treatment with donepezil. Measuring rCBF may aid in the selection of possible treatment responders.

Section: Discussionmentioning

confidence: 99%

Regional Cerebral Blood Flow Patterns and Response to Donepezil Treatment in Patients with Alzheimer’s Disease

Hanyu¹,

Shimizu²,

Tanaka³

et al. 2003

“…The positive effects of treatment with cholinesterase inhibitors on cognitive functions have been argued in terms of improved attention performance rather than episodic memory or visuospatial ability [27][28][29]. Animals with cholinergic lesions of the basal forebrain showed attention deficits which were ameliorated by cholinergic treatments such as physostigmine and nicotine [27,30].…”

Section: Discussionmentioning

confidence: 99%

Atrophy of the Substantia innominata on Magnetic Resonance Imaging Predicts Response to Donepezil Treatment in Alzheimer’s Disease Patients

Tanaka

Hanyu²,

Sakurai³

et al. 2003

To investigate whether atrophy of the substantia innominata as shown on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, predicts response to donepezil treatment in patients with Alzheimer’s disease (AD), we studied correlations between the thickness of the substantia innominata and clinical efficacy. Eighty-two patients were divided into responders, including transiently and continuously responding groups, and nonresponders, based on the changes in the Mini-Mental State Examination (MMSE) score from baseline at 3 months and at 12 months. Atrophy of the substantia innominata was more pronounced in transiently and continuously responding groups than nonresponders, but no significant change in the thickness between transiently and continuously responding groups was found. The MMSE score changes from baseline at 3 months and at 12 months significantly inversely correlated with the thickness of the substantia innominata. Logistic regression analysis revealed that the overall discrimination rate with the thickness of the substantia innominata was 70% between responders and nonresponders. We conclude that atrophy of the substantia innominata on MRI helps to predict response to donepezil treatment in patients with AD.

“…Administration of the muscarinic antagonist scopolamine or the nicotinic antagonist mecamylamine causes cognitive failure [60,61]. The result has been interpreted as major effects on attention mechanisms rather than memory effects [62,63]. Subcutaneous administration of nicotine to AD patients produced improvement in attentional functions [64].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the effects on memory have been questioned, and it has been argued that primarily attention is affected by improving the activity of the basal forebrain cholinergic system [32][33][34][35]. In this explorative study, we investigated the characteristics of AD patients who responded favorably to a single dose of oral tacrine.…”

Section: Introductionmentioning

confidence: 99%

Responder Characteristics to a Single Oral Dose of Cholinesterase Inhibitor: A Double-Blind Placebo-Controlled Study withTacrine in Alzheimer P atients

Almkvist¹,

Jelić²,

Amberla³

et al. 2000

A proportion of Alzheimer’s disease (AD) patients treated for several months with cholinesterase (ChE) inhibitors have shown some favorable response on cognition, but the characteristics of the responders are still unclear. This study attempts to identify the characteristics of individuals with a positive behavioral response after a double-blind randomized administration of a single oral dose of tacrine (40 mg) and placebo to AD patients. Furthermore, the relationship between single-dose and long-term responders are examined. Twenty-four mildly to very mildly demented AD patients participated in the study. They all fulfilled the diagnosis of probable AD according to NINCDS-ADRDA criteria. Active treatment (tacrine 40 mg) and placebo was administered in random order on 2 consecutive days, and the effects were evaluated within 2 h using neuropsychological tests (assessing visuospatial ability, episodic memory and attention), registration of EEG activity and measurement of red blood cells (RBC) acetylcholinesterase (AChE), ChE activity and concentrations of tacrine and its metabolites in plasma. Results demonstrated significant improvement, tacrine compared to placebo, in measures of attention, but not in episodic memory or visuospatial ability. A single-dose response was therefore defined in terms of improvement in attention. The tacrine plasma concentration (pcTHA) showed a positively skewed distribution (mean ± SD: 10.5 ± 11.8, range: 1.0–51.8 ng/ml). There were no significant differences between single-dose responders compared to nonresponders in pcTHA, metabolites of tacrine, inhibition of AChE in RBC, tau levels in CSF, AChE activity in CSF or plasma and demographic variables. However, single-dose responders showed a higher right frontal alpha/theta ratio on EEG and had lower glucose metabolism in the parietal-temporal association cortex at baseline. In addition, the frequency of apolipoprotein E (APOE) Ε4 alleles was higher in responders. Interestingly, the single-dose response was related to the long-term response, although not significantly, which probably was due to lack of power. To conclude, the present study identified single-dose responders in terms of improved attentional performance associated with a relatively higher alpha/theta activity in the right frontal regions of the brain measured on EEG and predominance of APOE Ε4 allele.