The Cholinergic Hypothesis: A Historical Overview, Current Perspective, and Future Directions

Bartus, Raymond T.; Dean, Reginald L.; Pontecorvo, Michael J.; Flicker, Charles

doi:10.1111/j.1749-6632.1985.tb37600.x

Cited by 344 publications

(131 citation statements)

References 132 publications

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“…Neuropathological evidence suggests a selective involvement of specific subcortical areas, most notably the cholinergic nuclei of the basal forebrain [173,174] and noradrenergic nuclei, in the locus coeruleus in AD. Based on mappings of subcortical nuclei from postmortem analyses, MRI scans in cranio will help to identify early changes in cholinergic and noradrenergic projecting nuclei in predementia and dementia stages of AD [175,176].…”

Section: Future Directions: Novel Methodsmentioning

confidence: 99%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

105

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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Section: Future Directions: Novel Methodsmentioning

confidence: 99%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

105

View full text Add to dashboard Cite

show abstract

“…The correlation between cholinergic system dysfunction and cognitive impairment in Alzheimer's disease (AD) has been very influential in the implication of ACh in learning and memory functions (Perry et al, 1978;Bartus et al, 1985). The most prominent early cognitive symptom in AD is a disruption in the ability to acquire new declarative memories (Morris and Kopelman, 1986).…”

Section: Introductionmentioning

confidence: 99%

Paradoxical Facilitation of Object Recognition Memory after Infusion of Scopolamine into Perirhinal Cortex: Implications for Cholinergic System Function

Winters¹,

Saksida²,

Bussey³

2006

J. Neurosci.

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The cholinergic system has long been implicated in learning and memory, yet its specific function remains unclear. In the present study, we investigated the role of cortical acetylcholine in a rodent model of declarative memory by infusing the cholinergic muscarinic receptor antagonist scopolamine into the rat perirhinal cortex during different stages (encoding, storage/consolidation, and retrieval) of the spontaneous object recognition task. Presample infusions of scopolamine significantly impaired object recognition compared with performance of the same group of rats on saline trials; this result is consistent with previous reports supporting a role for perirhinal acetylcholine in object information acquisition. Scopolamine infusions directly before the retrieval stage had no discernible effect on object recognition. However, postsample infusions of scopolamine with sample-to-infusion delays of up to 20 h significantly facilitated performance relative to postsample saline infusion trials. Additional analysis suggested that the infusion episode could cause retroactive or proactive interference with the sample object trace and that scopolamine blocked the acquisition of this interfering information, thereby facilitating recognition memory. This is, to our knowledge, the first example of improved recognition memory after administration of scopolamine. The overall pattern of results is inconsistent with a direct role for cortical acetylcholine in declarative memory consolidation or retrieval. Rather, the cholinergic input to the perirhinal cortex may facilitate acquisition by enhancing the cortical processing of incoming stimulus information.

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“…Supports for this hypothesis have derived from evidence of a cholinergic deficiency in aged animals and humans, as well as in age-related pathological conditions such as Alzheimer's disease (for a review, see Bartus et al 1985;Gallagher and Colombo 1995). This has led to the development of cholinomimetics as potential therapeutic agents, designed to compensate for the atrophy or loss of basal forebrain cholinergic neurones seen in senescence (Bartus et al 1985) and related pathologies (Davies and Maloney 1976;Coyle et al 1983). Among such cholinergic agents, the cholinesterase inhibitor, tacrine, has generated considerable preclinical (for review, see Mohammed 1993) and clinical interests (Qizilbash et al 1998).…”

mentioning

confidence: 99%

Further Evidence for a Dissociation Between Different Forms of Mnemonic Expressions in a Mouse Model of Age-related Cognitive Decline: Effects of Tacrine and S 17092, a Novel Prolyl Endopeptidase Inhibitor

Marighetto¹,

Touzani²,

Etchamendy³

et al. 2000

Learn. Mem.

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It has been demonstrated previously on the radial maze that the emergence of an age-related mnemonic impairment is critically dependent on the form which the discrimination problems took. Hence, when the arms were presented one by one (i.e., successive go-no-go discrimination), both adult and aged mice learned to distinguish between positive (baited) and negative (unbaited) arms readily, as evidenced by their increased readiness to enter positive relative to negative arms (i.e., by a differential in arm-entry latencies). A selective impairment in the aged mice was seen when these arms were presented subsequently as pairs, such that the mice were confronted with an explicit choice (i.e., simultaneous 2-choice discrimination). When discriminative performance was measured by the differential run speed between positive and negative arms, aged mice were also impaired. This was particularly pronounced in the 2-choice discrimination condition. We examined the effects of tacrine (3mg/kg, subcutaneously) or S 17092 (10mg/kg, orally) in aged mice on the three behavioral indices of this 2-stage spatial discrimination paradigm. The results indicated that: (1) Tacrine, but not S 17092, enhanced the acquisition of go-no-go discrimination as reflected in arm-entry latencies; (2) both drugs improved choice accuracy in simultaneous discrimination, although the effect of tacrine was less striking and, in particular, far from statistical significance in the very first 2-choice responses; and (3) neither drugs significantly affected run-speed performance. We conclude further that the specific patterns of drug effects on the three indices of discriminative performance might suggest that each index is associated with a distinct form of mnemonic expression relying on separate neural systems.In humans, declarative/explicit memory appears to be more vulnerable to deterioration in senescence than procedural/ implicit memory (Poon 1985;Gabrieli 1996;Schugens et al. 1997). One cardinal characteristic of declarative memory is its flexibility as exemplified by its capacity to support inferential use of memories in novel situations (Cohen 1984). Using a two-stage paradigm of discrimination learning, Marighetto et al. (1999) have previously demonstrated that aged mice displayed impaired inferential abilities when they were required to make an explicit choice between two eventualities that were only encountered before separately, but never conjointly. In Stage 1, the mice learned to discriminate between the valence of three baited (positive) and three unbaited (negative) arms in a radial maze with each of the arms presented one at a time, i.e., successive go-no-go discrimination. Successful discrimination was indicated by the animals' increased readiness to enter positive arms relative to negative ones. In Stage 2, the animals were confronted with an explicit choice between one positive arm and one negative arm they had learned to discriminate previously. Aged mice, but not young ones, were unable to translate their preference for the positive ...

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The Cholinergic Hypothesis: A Historical Overview, Current Perspective, and Future Directions

Cited by 344 publications

References 132 publications

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Paradoxical Facilitation of Object Recognition Memory after Infusion of Scopolamine into Perirhinal Cortex: Implications for Cholinergic System Function

Further Evidence for a Dissociation Between Different Forms of Mnemonic Expressions in a Mouse Model of Age-related Cognitive Decline: Effects of Tacrine and S 17092, a Novel Prolyl Endopeptidase Inhibitor

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