Clinical Studies of the Cholinergic Deficit in Alzheimer's Disease

Mohs, Richard C.; Davis, Bonnie M.; Greenwald, Blaine S.; Mathé, Aleksander A.; Johns, Celeste A.; Horvath, Thomas; Davis, Kenneth L.

doi:10.1111/j.1532-5415.1985.tb04185.x

Cited by 42 publications

(9 citation statements)

References 54 publications

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“…We did not observe a narrow therapeutic window, as described in studies of intravenous physostigmine with SDAT patients (26,27). It is our impression that age may play an important role in defining response to physostigmine.…”

Section: Discussionsupporting

confidence: 49%

“…Second, intravenous administration is impractical as a meaningful long-term treatment of memory loss in MS. Future trials may wish to evaluate the effectiveness of oral cholinesterase inhibitors. Oral physostigmine has been studied extensively in patients with SDAT (26)(27)(28)(29)(30)(31)(32)(33) and amnesic patients (34,35). Third, it is unclear from this study if the positive effects observed on the SRT can be extrapolated to the memory demands of everyday living.…”

Section: Discussionmentioning

confidence: 90%

“…This phase consisted of a double-blind, dose-finding procedure to determine: (a) if intravenous physostigmine improves memory functions compared with a placebo, and (b) the optimal dose for improvement. With regard to the latter, previous research with elderly Alzheimer's disease patients suggests that physostigmine has a narrow window of therapeutic efficacy that may vary from patient to patient (26,27). Consequently, determining the optimal dose of physostigmine.…”

Section: Methodsmentioning

confidence: 97%

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Effects of Intravenous Physostigmine and Lecithin on Memory Loss in Multiple Sclerosis: Report of a Pilot Study

Leo

Rao

1988

Neurorehabilitation and Neural Repair

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This paper reports the results of a pilot study designed to assess the efficacy of intravenous physostigmine and dietary lecithin for treating memory loss in patients with multiple sclerosis (MS). Four patients with definite MS participated in a twophase (dose-finding and crossover), double-blind clinical trial. In the dose-finding phase, all patients exhibited an improvement in verbal memory (as assessed by the Selective Reminding Test) at the highest of four doses (1.0 mg). In the double-blind, crossover phase, patients were administered placebo or physostigmine (1.0 mg). A significant improvement in verbal memory was observed in three of four patients during the drug condition. None of the patients reported significant medication side effects. This study provides preliminary evidence that cholinergic pharmacotherapy may be useful in treating memory disturbance in MS. Key Words: Multiple sclerosis—Memory loss—Physostigmine—Lecithin.In his 1877 description of patients with multiple sclerosis (MS), Charcot (1) listed &dquo;enfeeblement of memory&dquo; as a cardinal feature of the disease. This astute clinical observation was virtually ignored until the past decade, when controlled neuropsychological investigations of memory began to appear in the scientific literature. These neuropsychological investigations have consistently shown that learning and memory functions are impaired in at least 50% of patients with MS (for reviews of the literature, see references 2 and 3). In a previous study, we (4) demonstrated a relationship between the degree of ventricular dilatation on computed tomography (CT) and severity of memory loss in patients with chronic progressive MS, suggesting that memory loss appears to be directly related to the degree of cerebral disease involvement. Although memory loss in MS is now well studied, attempts to treat this symptom have not appeared in the literature.Pharmacological studies during the past three decades have increasingly supported the hypothesis that cholinergic neurons are involved in memory and learning processes (5,6). Interference with cholinergic transmission by scopolamine, a cholinergic blocking agent capable of crossing the blood-brain barrier, results in marked impairment in the normal human's ability to acquire information into long-term storage (7-10). This effect is minimized if physostigmine, a cholinesterase inhibitor, is administered simultaneously (5,8). Scopolamine does not appear to affect attention/vigilance (9,10) or short-term memory functions (i.e., span memory) (7, 11), arguing against a more diffuse sedative effect. Furthermore, if scopolamine is administered with amphetamine, a stimulant, no improvement is observed in long-term memory functions (5). These findings suggest that interference with the normal cholinergic system can interfere with long-term memory.Recent attention has focused on the role of neurotransmitter disruption as an explanation for the memory and cognitive deficits of carious brain-damaged

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 97%

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Effects of Intravenous Physostigmine and Lecithin on Memory Loss in Multiple Sclerosis: Report of a Pilot Study

Leo

Rao

1988

Neurorehabilitation and Neural Repair

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“…Anticholinesterase Physostigmine Yes (Bartus 1979c;Bartus and Dean 1988c) Yes (Agnoli et al 1983;Christie et al 1981;Davis et al 1979;Mohs et al 1985) Anticholinesterase…”

Section: Attempts To Extend the Insight To Help Refine Rodent Modelsmentioning

confidence: 96%

Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

Bartus¹,

Dean

2008

Psychopharmacology

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Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.

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“…This concept has been subsequently supported by the findings of severe degeneration of cholinergic neurons, reduced ACh synthesis and levels, decreased choline levels as well as down-regulated activity of choline acetyltransferase (ChAT), and the deregulations of ACh receptors in AD brains [47, 55–61]. Moreover, the concentration of ACh in the cerebrospinal fluid (CSF) extracted from AD patients is significantly reduced, and the levels of CSF ACh are proportionate to the severity of cognitive deficits in AD [62–64]. These observations have confirmed the perturbations of cholinergic system in the development of AD and further implicated the possibility of using CSF ACh as a diagnostic biomarker of AD.…”

Section: Synaptic Transmission Changes In Admentioning

confidence: 99%

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

Guo

Tian

2017

JAD

145

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Alzheimer's disease (AD) is a chronic neurodegenerative disorder, in which multiple risk factors converge. Despite the complexity of the etiology of the disease, synaptic failure is the pathological basis of cognitive impairment, the cardinal sign of AD. Decreased synaptic density, compromised synaptic transmission, and defected synaptic plasticity are hallmark synaptic pathologies accompanying AD. However, the mechanisms by which synapses are injured in AD-related conditions have not been fully elucidated yet. Mitochondria are a critical organelle in neurons. The pivotal role of mitochondria in supporting synaptic function and the concomitant occurrence of mitochondrial dysfunction with synaptic stress in postmortem AD brains as well as AD animal models seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD. This concept is further strengthened by the protective effect of mitochondrial medicine on synaptic function against the toxicity of amyloid-β, a key player in the pathogenesis of AD. In this review, we focus on the association between mitochondrial dysfunction and synaptic transmission deficits in AD. Impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess mitochondrial reactive oxygen species generation, and release play a crucial role in mediating synaptic transmission deregulation in AD. The understanding of the role of mitochondrial dysfunction in synaptic stress may lead to novel therapeutic strategies for the treatment of AD through the protection of synaptic transmission by targeting to mitochondrial deficits.

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Clinical Studies of the Cholinergic Deficit in Alzheimer's Disease

Cited by 42 publications

References 54 publications

Effects of Intravenous Physostigmine and Lecithin on Memory Loss in Multiple Sclerosis: Report of a Pilot Study

Effects of Intravenous Physostigmine and Lecithin on Memory Loss in Multiple Sclerosis: Report of a Pilot Study

Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

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