The Distribution of Cerebral Muscarinic Acetylcholine Receptors In Vivo in Patients With Dementia

Weinberger, Daniel R.

doi:10.1001/archneur.1991.00530140061018

Cited by 125 publications

(47 citation statements)

References 63 publications

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“…The changes were detected by PET in the frontal and temporal cortices of AD patients compared to controls [ 13], which confirm earlier findings in postmortem studies [14. 15], Deficits in nicotinic receptors have been observed in AD brains with "C-nicotine and PET [16][17][18], Imaging of muscarinic receptors in human brain have been per formed by PET and 1 'C-bcnztropinc [ 19] and 1 'C-scopolamine [20], An age-related decrease in muscarinic recep tors in cortical brain regions was observed in healthy vol unteers using 1 'C-benzlropine and PET [21], The finding is in agreement with measurements in autopsy brain tis sue [22], The muscarinic receptors in AD brains have been studied with '--M-QNB and SPECT and reported to be both decreased in number as well as relatively un changed [23][24][25], Among new treatment strategies in AD. the cholines terase inhibitors have so far been most promising.…”

Section: Introductionsupporting

confidence: 67%

Imaging of Nicotinic and Muscarinic Receptors in Alzheimer's Disease: Effect of Tacrine Treatment

Nordberg¹,

Lundqvist

Hartvig

et al. 1997

Dement Geriatr Cogn Disord

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Functional imaging techniques offer new possibilities for further understanding of changes in functional correlates of structural and biological changes in dementia disorders like Alzheimer''s disease (AD). Regional disturbances in glucose metabolism and cerebral blood flow are known to occur in AD brains and probably roughly correlate to changes in neurotransmitter activities. A proper estimate would be to visualize the neuroreceptors themselves. In this study the cholinergic nicotinic and muscarinic receptors were studied in brain by positron emission tomography (PET). The rate constant k₂* (s) (–)¹¹C-nicotine was significantly higher (+43%) in temporal cortex of AD patients compared to controls (p < 0.017) indicating a lower binding of ¹¹C-nicotine in AD brains compared to controls. Treatment with the cholinesterase inhibitor tacrine (80 mg daily) during 3 months to AD patients resulted in a mean plasma concentration of 7.7 ± 0.8 ng/ml and a corresponding inhibition of the cholinesterase activity in plasma by 34 ± 5%. A significantly lower k₂* (increased binding) for ¹¹C-nicotine binding (–15%; p < 0.006) was obtained in the temporal cortex after 3 months of treatment compared to prior treatment. The muscarinic antagonist ¹¹C-benztropine was used to visualize muscarinic receptors and the binding capacity of ¹¹C-benztropine (K_R) was found to be decreased in the temporal cortex after 3 months of tacrine treatment.

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Section: Introductionsupporting

confidence: 67%

Imaging of Nicotinic and Muscarinic Receptors in Alzheimer's Disease: Effect of Tacrine Treatment

Nordberg¹,

Lundqvist

Hartvig

et al. 1997

Dement Geriatr Cogn Disord

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“…Relative to a matched sample of unmedicated patients, we found significant reductions of 45% (striatum) to 79% (thalamus) of muscarinic availability in patients treated with 200-450 mg/day of clozapine. In both samples, the pattern of [I-123]IQNB binding, our measure of muscarinic availability, was similar to that described in earlier reports (Weinberger et al, 1991;Sunderland et al, 1995;Raedler et al, 2000). In a related [I-123]IQNB SPECT study, we found a significant reduction of muscarinic availability in unmedicated schizophrenia patients (Raedler et al, 2003), a finding consistent with several neuropathological studies of muscarinic receptors in schizophrenia subjects (Dean et al, 1996;Crook et al, 1999Crook et al, , 2000Crook et al, , 2001.…”

Section: Discussionsupporting

confidence: 89%

“…[I-123]IQNB, the iodinated form of QNB, has been used in SPECT studies for in vivo measurements of muscarinic receptor availability (Eckelman et al, 1984;Weinberger et al, 1991;Sunderland et al, 1995). Using [I-123]IQNB SPECT, our group has previously reported reduced muscarinic receptor availability in unmedicated schizophrenic patients in vivo (Raedler et al, 2003), a finding similar to that of the post-mortem studies.…”

Section: Introductionmentioning

confidence: 59%

Central Muscarinic Acetylcholine Receptor Availability in Patients Treated with Clozapine

Raedler

Knable

Jones

et al. 2003

Neuropsychopharmacol

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Clozapine is the prototypical atypical antipsychotic. In vitro, clozapine antagonizes a broad range of receptors, including dopamine, serotonin and muscarinic acetylcholine receptors. In vivo, receptor occupancy studies have shown moderate dopamine D 2 receptor blockade as well as high serotonin 5HT 2 receptor blockade for clozapine. Using [I-123]IQNB SPECT, we explored the influence of clozapine on muscarinic receptors in vivo. Eight schizophrenia patients underwent a total of 12 [I-123]IQNB SPECT scans after treatment with low to moderate doses of clozapine (mean 210 mg/day, range 50-450 mg/day). Muscarinic receptor availability was determined for basal ganglia, cortex, thalamus, and pons. A group of 12 age-and sex-matched unmedicated schizophrenia patients was used for comparison. Compared to unmedicated patients, [I-123]IQNB binding was lower in all regions in subjects treated with clozapine and decreased with increasing dose. In patients treated with a daily clozapine dose of at least 200 mg (mean 275 7 88 mg/day), these differences were highly significant (po0.003) with mean reductions of muscarinic receptor availability of 45% for basal ganglia, 58% for cortex, 66% for pons, and 79% for thalamus. These preliminary data indicate that reduction of muscarinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptor availability. These results may explain, at least in part, the lack of extrapyramidal side effects as well as some side effects seen with clozapine.

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“…This evidence includes a preservation or increase in cortical choline acetyltransferase, 14,17,18,[39][40][41][42][43][44] intact acetylcholinesterase levels, 45 intact post-synaptic muscarinic receptor binding, 17 preservation of neurons in the nucleus basalis of Meynert (nbM, the largest collection of presynaptic cholinergic neurons), 41,43,46,47 and lack of response to a scopolamine challenge in one patient. 39 However, some studies have shown decreased muscarinic receptor binding on autopsy 41,[48][49][50] and in living subjects with SPECT, 51 and decreased neuron density in the nbM on autopsy. 52 Norepinephrine-There is little evidence on norepinephrine abnormalities in FTD; one study showed decreased number and increased morphologic alterations of noradrenergic neurons in the locus coeruleus in PiD, 53 while another showed relative preservation of the locus coeruleus in FTD.…”

Section: Mechanism Reviewmentioning

confidence: 99%

A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia

2006

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Objective-To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD).Methods-The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD.Results-Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD.Conclusions-Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner.Frontotemporal dementia (FTD) is increasingly recognized as an important cause of dementia. 1 The symptoms of FTD include behavioral symptoms such as disinhibition, inappropriate social behavior, and apathy. Other symptoms include language and executive dysfunction. 2,3 The behavioral symptoms of FTD can be difficult to manage for caregivers and clinicians.The paucity of pharmacologic trials for FTD is likely due to the only recent clinical definition of the illness, limitations in understanding the biology of FTD, and the difficulty of assembling well-characterized groups of patients.

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The Distribution of Cerebral Muscarinic Acetylcholine Receptors In Vivo in Patients With Dementia

Cited by 125 publications

References 63 publications

Imaging of Nicotinic and Muscarinic Receptors in Alzheimer's Disease: Effect of Tacrine Treatment

Imaging of Nicotinic and Muscarinic Receptors in Alzheimer's Disease: Effect of Tacrine Treatment

Central Muscarinic Acetylcholine Receptor Availability in Patients Treated with Clozapine

A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia

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