Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer disease

doi:10.1016/0140-6736(90)93028-N

The Lancet

Volume 335, Issue 8704, 23 June 1990, Pages 1484-1487

https://doi.org/10.1016/0140-6736(90)93028-N Get rights and content

Abstract

Patients with Alzheimer disease (AD) had reduced regional cerebral blood flow (rCBF) in the posterior parietotemporal region compared with controls, as determined with technetium-99m hexamethyl propyleneamine oxime and single photon emission tomography. Central cholinergic stimulation with physostigmine produced a focal increase in rCBF in the posterior parietotemporal region in the patients with AD but not in controls.

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Cited by (119)

Cognitive impairment and cardiovascular disease: So near, so far
2014, International Journal of Cardiology
Citation Excerpt :
More recently, de la Torre hypothesized that AD can be viewed as a predominantly vascular disorder [18]. The hypothesis was based on several converging lines of evidence, including: 1) epidemiological studies showing that AD shares with cardiovascular disease a number of risk factors (from hypertension to diabetes) and virtually all reported risk factors for AD lower cerebral perfusion [19]; 2) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques is capable to identify AD candidates preclinically; 3) the presence of regional brain microvascular abnormalities appear before hypometabolism, cognitive decline and neurodegenerative changes; 4) clinical overlap between AD and vascular dementia; 5) improvement of cerebral perfusion is obtained from drugs (such as cholinesterase inhibitors) used to reduce the symptoms of AD [20] in patients who respond to treatment [21]. However, the interpretation of the cause–effect relationship between hypoperfusion and cognitive decline remains uncertain, since following the metabolism-flow coupling concept, decreased flow is conventionally interpreted as an epiphenomenon or a consequence of reduced neuronal activity.
In the spectrum of cognitive impairment, ranging from “pure” vascular dementia to Alzheimer's disease (AD), clinical interest has recently expanded from the brain to also include the vessels, shifting the pathophysiological focus from the leaves of synaptic dysfunction to the sap of cerebral microcirculation and the roots of cardiovascular function. From a diagnostic viewpoint, a thorough clinical evaluation of individuals presenting cognitive impairment might systematically include the assessment of the major cardiovascular rings of the chain linking regional perfusion to brain function: 1) lung (with assessment of asthma, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome); 2) heart function (with clinical examination and echocardiography) and cardiovascular risk factors; 3) orthostatic hypotension (with medical history and measurement of heart rate and blood pressure in supine and upright positions); 4) aorta and large artery stiffness (with assessment of pulse wave velocity); 5) large cerebro-vascular vessel status (with neuroimaging techniques); 6) assessment of microcirculation (with cerebrovascular reactivity testing with transcranial Doppler sonography or MRI perfusion imaging); and 7) assessment of venous cerebral circulation. The apparent difference in approaches to “brain” and “vascular” environmental enrichment with physical, cognitive and sensorial training is conceptually identical to that of a constant gardener caring for an unhealthy tree, watering the leaves (“train the brain”) or simply the roots (“mind the vessel”). The therapeutic difference probably consists in the amount and quality of water added to the tree, rather than by where one pours it, with either a top-down (leaves to roots) or bottom-up (roots to leaves) approach.
Cholinergic modulation of cognition: Insights from human pharmacological functional neuroimaging
2011, Progress in Neurobiology
Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing ‘effort’-associated activations in prefrontal regions; and deactivation of a ‘resting-state network’ in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an ‘inverted-U shaped’ pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications.
Novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties as cholinesterases inhibitors
2010, European Journal of Medicinal Chemistry
Citation Excerpt :
However, over the course of AD, AChE activity progressively decreases in certain brain regions, whereas BuChE activity increases and BuChE may then act as a compensatory mechanism for acetylcholine hydrolysis [6]. It has also been proved, that aside from their typical enzymatic function, cholinesterases display several non-classical activities like: regulation of cerebral blood flow and metabolism [7,8], modulatory effects on the amyloid cascade [9–11], glial proliferation, tau protein phosphorylation [12,13], and inflammatory processes [14], which are all important for the AD pathogenesis. Influence on the amyloid cascade is of special interest as it has been observed that in Alzheimer’s disease AChE and BuChE are mostly located within neuritic plaques [15] and both seem to be associated with the formation of cytotoxic β-amyloid (Aβ) fibrills.
The study presents synthesis and biological activity of novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties designed as cholinesterases inhibitors. These fragments turned out to determine compounds’ selectivity between AChE and BuChE. Derivatives of N-benzylpiperazine (16–25) were selective BuChE inhibitors with 3-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-phenyl butylcarbamate (22) being the most potent compound (pIC₅₀ = 5.00) while a series of carbamate derivatives of N-benzylpiperidine (5–14) displayed non-selective BuChE/AChE inhibitory activity. Molecular modelling studies point out significant differences between orientations of these two groups of compounds in the active site of AChE, which can be an explanation of their different biological activity.
The short-term effect of acetylcholinesterase inhibitor on the regional cerebral blood flow of Alzheimer's disease
2010, Archives of Gerontology and Geriatrics
Citation Excerpt :
There were various attempts to study the short-term effect of ChEI on rCBF (Staff et al., 2000; Nakano et al., 2001; Nobili et al., 2002a,b; Mee Young and Ihnho, 2003; Tonini et al., 2003; Annalena, 2007). In the earlier study, Geaney et al. (1990) injected physostigmine intravenously to patients with AD, and found an increase in rCBF in the parietotemporal cortex. They interpreted observed effects as a direct action of physostigmine on the cerebral vessels, rather than influencing neuronal functions.
This study is to investigate changes in regional cerebral blood flow (rCBF) of Alzheimer's disease (AD) in short-term treatment with acetylcholinesterase inhibitor (ChEI). rCBF was measured by single photon emission computed tomography (SPECT). CBF measurements were performed in 13 AD patients before treatment and 4 months later, while the control group with syncope or headache consisted of 17 patients. The clinical diagnosis of AD was based on the NINCDS-ADRDA criteria. Significant increases in rCBF were noted in the left angular, the right superior frontal gyrus, the right occipital, the left temporal lobe and the left orbital gyrus at the end of short-term therapy. Reduction in the rCBF before treatment is more profound in the left superior temporal, the right precentral and the both inferior frontal gyri compared with the control group. It achieved increase of rCBF after ChEI treatment. Also it overall increased in global cognitive functions including Korean Version Mini Mental State Examination (K-MMSE) and Clinical Dementia Rating (CDR). Treatment with ChEI for 4 months could increase rCBF and improve cognitive function of patients with AD.
Abnormal brain response to cholinergic challenge in chronic encephalopathy from the 1991 Gulf War
2009, Psychiatry Research - Neuroimaging
Citation Excerpt :
The intravenous infusion for the first scan contained only saline as a placebo and that for the second scan contained physostigmine in the same volume of saline. Prior physostigmine challenge studies obtained cholinergic brain effects with intravenous doses as low as 0.5 mg (Geaney et al., 1990; Hunter et al., 1991), but more commonly used doses have ranged between 1.0 and 2.0 mg (Gustafson et al., 1987; Risch et al., 1981; Janowsky et al., 1986; Furey et al., 2000b). At these doses, the maximal physostigmine effect is achieved by 40 min into the infusion and persists for at least 40 min more (Furey et al., 2000a).
Several case definitions of chronic illness in veterans of the 1991 Persian Gulf War have been linked epidemiologically with environmental exposure to cholinesterase-inhibiting chemicals, which cause chronic changes in cholinergic receptors in animal models. Twenty-one chronically ill Gulf War veterans (5 with symptom complex 1, 11 with complex 2, and 5 with complex 3) and 17 age-, sex- and education-matched controls, underwent an 99mTc-HMPAO-SPECT brain scan following infusion of saline and > 48 h later a second scan following infusion of physostigmine in saline. From each SPECT image mean normalized regional cerebral blood flow (nrCBF) from 39 small blocks of correlated voxels were extracted with geostatistical spatial modeling from eight deep gray matter structures in each hemisphere. Baseline nrCBF in symptom complex 2 was lower than controls throughout deep structures. The change in nrCBF after physostigmine (challenge minus baseline) was negative in complexes 1 and 3 and controls but positive in complex 2 in some structures. Since effects were opposite in different groups, no finding typified the entire patient sample. A hold-out discriminant model of nrCBF from 17 deep brain blocks predicted membership in the clinical groups with sensitivity of 0.95 and specificity of 0.82. Gulf War-associated chronic encephalopathy in a subset of veterans may be due to neuronal dysfunction, including abnormal cholinergic response, in deep brain structures.
Imaging treatment effects in Alzheimer's disease
2007, Magnetic Resonance Imaging
Alzheimer's disease (AD) is the commonest form of degenerative dementia and is characterised by progressive cognitive decline. Despite extensive research, the cause of AD is unknown and there is no cure at present. Of the deficits found in AD, that affecting the cholinergic neurotransmitter system is the best established and the only one translated into symptomatic treatment. Cholinergic enhancement with cholinesterase inhibitor (ChEI) drugs has been achieved and their efficacy and safety ascertained by conventional clinical trials. The mechanism of action of these drugs, however, is not well understood. Imaging with SPECT, PET, MRI and fMRI after treatment has clarified what happens in the brains of those AD patients treated with ChEI drugs. Studies with these techniques have identified increases in brain blood flow and glucose metabolism, restoration of nicotinic receptor function and re-establishment of task-related regional brain activation in response to cognitive stimulation after treatment. Structural MRI studies have explained, to some degree, why only a proportion of patients benefits from ChEI treatment and there is some evidence that some ChEI drugs might be neuroprotective.
There are, however, many unsolved problems. Timing of treatment intervention to obtain maximum response and the determinants of treatment response are mostly unknown. It is also unclear whether administration of treatment in those patients who have no potential for response accelerates disease progression. These issues cannot be solved by conventional clinical trials. Pharmacoimaging studies could assist the development and refinement of drugs to treat those diseases, such as AD, which affect the central nervous system.

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MEDICAL SCIENCEEffect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer disease

Abstract

J Psychiat Res

Brain Res

Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia

Br Med J

Cholinergic approaches to the treatment of Alzheimer's Disease

Br Med Bull

Biochemical measurements in Alzheimer's disease reveal a necessity for improved neurolmaging techniques to study metabolism

Biochem J

Positron emission tomography in Alzheimer's disease

Neurology

Cortical abnormalities in Alzheimer's disease

Ann Neurol

Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with (18F) fluorodeoxyglucose

J Comput Assist Tomogr

Regional cerebral oxygen supply and utilization in dementia

Brain

MEDICAL SCIENCE
Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer disease

Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with (¹⁸F) fluorodeoxyglucose