Dataset Information

Ligand autoradiographical quantification of histamine H₃ receptor in human dementia with Lewy bodies.

ABSTRACT: Dementia with Lewy bodies (DLB) is a serious age-dependent human neurodegenerative disease, with multiple debilitating symptoms, including dementia, psychosis and significant motor deficits, but with little or no effective treatments. This comparative ligand autoradiographical study has quantified histamine H₃ receptors (H₃R) in a series of major cortical and basal ganglia structures in human DLB and Alzheimer's (AD) post-mortem cases using the highly selective radioligand, [³H] GSK189254. In the main, the levels of H₃ receptor were largely preserved in DLB cases when compared with aged-matched controls. However, we provide new evidence showing variable levels in the globus pallidus, and, moreover, raised levels of Pallidum H₃ correlated with positive psychotic symptoms, in particular delusions and visual hallucinations, but not symptoms associated with depression. Furthermore, no correlation was detected for H₃ receptor levels to MMSE or IUPRS symptom severity. This study suggests that H₃R antagonists have scope for treating the psychotic symptomologies in DLB and other human brain disorders.

SUBMITTER: Lethbridge NL

PROVIDER: S-EPMC5113906 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Ligand autoradiographical quantification of histamine H3 receptor in human dementia with Lewy bodies.

Lethbridge Natasha L NL Chazot Paul L PL

Pharmacological research 20160831 Pt A

Dementia with Lewy bodies (DLB) is a serious age-dependent human neurodegenerative disease, with multiple debilitating symptoms, including dementia, psychosis and significant motor deficits, but with little or no effective treatments. This comparative ligand autoradiographical study has quantified histamine H3 receptors (H3R) in a series of major cortical and basal ganglia structures in human DLB and Alzheimer's (AD) post-mortem cases using the highly selective radioligand, ...[more]

PMID: 27592250

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Project description:Cholinergic dysfunction is central in dementia with Lewy bodies, possibly contributing to the cognitive and psychiatric phenotypes of this condition. We investigated baseline muscarinic M1/M4 receptor spatial covariance patterns in dementia with Lewy bodies and their association with changes in cognition and neuropsychiatric symptoms after 12 weeks of treatment with the cholinesterase inhibitor donepezil. Thirty-eight participants (14 cholinesterase inhibitor naive patients, 24 healthy older individuals) underwent 123I-iodo-quinuclidinyl-benzilate (M1/M4 receptor assessment) and 99mTc-exametazime (perfusion) single-photon emission computed tomography scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of inter-correlated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns associated with patients. A discreet M1/M4 pattern that distinguished patients from controls (W1,19.7 = 16.7, P = 0.001), showed relative decreased binding in right lateral temporal and insula, as well as relative preserved/increased binding in frontal, precuneus, lingual and cuneal regions, implicating nodes within attention and dorsal visual networks. We then derived from patients an M1/M4 pattern that correlated with a positive change in mini-mental state examination (r = 0.52, P = 0.05), showing relative preserved/increased uptake in prefrontal, temporal pole and anterior cingulate, elements of attention-related networks. We also generated from patients an M1/M4 pattern that correlated with a positive change in neuropsychiatric inventory score (r = 0.77, P = 0.002), revealing relative preserved/increased uptake within a bilateral temporal-precuneal-striatal system. Although in a small sample and therefore tentative, we posit that optimal response of donepezil on cognitive and neuropsychiatric signs in patients with dementia with Lewy bodies were associated with a maintenance of muscarinic M1/M4 receptor expression within attentional/executive and ventral visual network hubs, respectively.

Dataset Information

Ligand autoradiographical quantification of histamine H₃ receptor in human dementia with Lewy bodies.

Publications

Ligand autoradiographical quantification of histamine H<sub>3</sub> receptor in human dementia with Lewy bodies.

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