The Cholinergic Model of Dementia, Alzheimer Type: Progression from the Unitary Transmitter Concept

Holttum, John; Gershon, Samuel

doi:10.1159/000107013

Cited by 18 publications

(17 citation statements)

References 58 publications

(73 reference statements)

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“…The hypothesis that stresses the significance of aberrations in the functions of cortical cholinergic inputs for the development of cognitive dysfunctions and the associated focus on the development of pharmacological treatments acting via cholinergic mechanisms have been discussed critically in recent years [152,153]. These criticisms have been primarily based on (1) the limited potency of muscarinic antagonists to produce the symptoms of dementia, (2) the failure of conventional cholinomimetic drugs to enhance cognitive functions or to attenuate age-or dementia-related cognitive impairments and, in this context, (3) the rejection of the idea that attentional abnormalities, which represent the primary consequence of cholinergic dysfunction, are sufficiently potent to account for the emergence of clinical syndromes.…”

Section: Age-related Decline In the Function Of Cortical Cholinergic mentioning

confidence: 99%

Age- and Dementia-Associated Impairments in Divided Attention: Psychological Constructs, Animal Models, and Underlying Neuronal Mechanisms

Sarter

Turchi

2001

Dement Geriatr Cogn Disord

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Following a brief description of the psychological construct ‘divided attention’, impairments in divided attention and related executive functions are discussed as the major variable in the development and manifestation of age- and dementia-associated cognitive impairments. Neuropsychological and functional imaging studies in humans have indicated that dorsolateral and ventrolateral prefrontal, cingulate, parietal and premotor cortical areas are involved in the mediation of dual task performance. Furthermore, reduced activity in these areas has been suggested to mediate age- and dementia-associated impairments in divided attention. Experimental studies in animals have provided strong support for the hypothesis that cholinergic projections terminating in all cortical areas and layers crucially mediate the performance in tasks that tax processing capacity and/or the allocation of processing resources to competing demands. This specification of the ‘cholinergic hypothesis’ is evaluated in light of recent critical accounts of the role of this system in the development of age- and dementia- related cognitive disorders. The converging animal experimental and human neuropathological, as well as neuropsychological, evidence indicates that decreases in the integrity of cortical cholinergic inputs represent a necessary, possibly even sufficient, neuronal process mediating the impairments in divided attention and the resulting, broad decline in cognitive functions.

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Section: Age-related Decline In the Function Of Cortical Cholinergic mentioning

confidence: 99%

Age- and Dementia-Associated Impairments in Divided Attention: Psychological Constructs, Animal Models, and Underlying Neuronal Mechanisms

Sarter

Turchi

2001

Dement Geriatr Cogn Disord

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“…As reviewed previously by Holttum and Gershon [72], the cholinergic model proposed to explain the pathophysi ology of AD explains too little of the neuropathological data available. In that review they concluded that se lective cholinergic agents did not prove to be effective in the treatment of AD.…”

Section: Discussionmentioning

confidence: 99%

THA – Historical Aspects, Review of Pharmacological Properties and Therapeutic Effects

Soares¹,

Gershon²

1995

Dement Geriatr Cogn Disord

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The authors reviewed historical data in the development of THA, as well as recent data on its pharmacological properties and therapeutic effects on cognitive dysfunction. A medline search was conducted to identify the trials conducted with THA in Alzheimer''s disease (AD) patients. The findings seem to lend support to some palliative action of THA, especially at higher doses, but in these doses about 2/3 of the patients experience significant adverse reactions. The significance of these findings is discussed, with emphasis on the their relevance for the management of AD patients.

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“…DuP996, an M 2 -receptor antagonist, is thought to increase the release of ACh, as well as other neuromodulators such as serotonin, by modulation of potassium channels in the synaptic terminals [45]. Improvements in subjects with impaired learning have been demonstrated with a galanin antagonist that disinhibits the release of ACh in experimental studies [46].…”

Section: Presynaptic Acetylcholine Release (Receptor Antagonists)mentioning

confidence: 99%

“…The wellknown neurodegenerative 'sprouting' phenomenon of remaining septohippocampal cholinergic fibres [57] may explain why recognition memory, which is dependent on temporal lobe function, is less amenable to tacrine therapy than the attentional deficit in AD patients, which is thought to be dependent upon frontal lobe function [55] where sprouting has not been demonstrated. Additionally, tacrine is associated with a poor side-effect profile, including hepatotoxicity, which results in a large proportion of patients discontinuing therapy [45,58]. Consequently, more specific, potent and tolerable ChE inhibitors are becoming available [50].…”

Section: Muscarinic and Nicotine Receptor Agonists (Direct Postsynaptmentioning

confidence: 99%

Strategies That Support Declining Cholinergic Neurotransmission in Alzheimer’s Disease Patients

Sirviö¹

1999

Gerontology

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With an increased public awareness of Alzheimer’s disease (AD), the last two decades have witnessed an immense research effort directed towards discovering the cause of AD with the ultimate hope of developing safe and effective pharmacological treatments. Biochemical and histopathological changes of neurotransmitter markers in the brains of AD patients both at postmortem and neurosurgical cerebral biopsy have demonstrated an association between a decline in learning and memory, and a deficit in cholinergic and associated excitatory amino acid neurotransmission. These observations illustrate the selective neurotransmitter pathology of AD. Accordingly, although there is presently no ‘cure’ for AD, a large number of potential therapeutic strategies have emerged that are designed to correct the loss of cholinergic neurotransmission in AD. Such strategies include increasing acetylcholine synthesis, enhancing its presynaptic synthesis and/or release, potentiating its pre- or postsynaptic action, obstructing its metabolism, or by influencing the function of cholinergic neurones themselves by administration of nerve growth factor or by trans-synaptic modulation. Indeed, the cholinesterase (ChE) inhibitors have gained the most attention. Adverse events limited the usage of the first ChE inhibitors, but more recently introduced, well-tolerated compounds, for example donepezil, have confirmed efficacy in delaying the deterioration of symptoms of AD, a valuable treatment target considering the progressive nature of the disease. Other agents which affect the cholinergic system, directly or indirectly, that are in the early stages of development for the treatment of AD are also discussed.

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The Cholinergic Model of Dementia, Alzheimer Type: Progression from the Unitary Transmitter Concept

Cited by 18 publications

References 58 publications

Age- and Dementia-Associated Impairments in Divided Attention: Psychological Constructs, Animal Models, and Underlying Neuronal Mechanisms

Age- and Dementia-Associated Impairments in Divided Attention: Psychological Constructs, Animal Models, and Underlying Neuronal Mechanisms

THA – Historical Aspects, Review of Pharmacological Properties and Therapeutic Effects

Strategies That Support Declining Cholinergic Neurotransmission in Alzheimer’s Disease Patients

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