Central Cholinesterase Inhibition Research Articles

Speech Registration in Symptomatic Memory Impairment.

Background: An inability to recall recent conversations often indicates impaired episodic memory retrieval. It may also reflect a failure of attentive registration of spoken sentences which leads to unsuccessful memory encoding. The hypothesis was that patients complaining of impaired memory would demonstrate impaired function of “multiple demand” (MD) brain regions, whose activation profile generalizes across cognitive domains, during speech registration in naturalistic listening conditions.Methods: Using functional MRI, brain activity was measured in 22 normal participants and 31 patients complaining of memory impairment, 21 of whom had possible or probable Alzheimer’s disease (AD). Participants heard a target speaker, either speaking alone or in the presence of distracting background speech, followed by a question to determine if the target speech had been registered.Results: Patients performed poorly at registering verbal information, which correlated with their scores on a screening test of cognitive impairment. Speech registration was associated with widely distributed activity in both auditory cortex and in MD cortex. Additional regions were most active when the target speech had to be separated from background speech. Activity in midline and lateral frontal MD cortex was reduced in the patients. A central cholinesterase inhibitor to increase brain acetylcholine levels in half the patients was not observed to alter brain activity or improve task performance at a second fMRI scan performed 6–11 weeks later. However, individual performances spontaneously fluctuated between the two scanning sessions, and these performance differences correlated with activity within a right hemisphere fronto-temporal system previously associated with sustained auditory attention.Conclusions: Midline and lateralized frontal regions that are engaged in task-dependent attention to, and registration of, verbal information are potential targets for transcranial brain stimulation to improve speech registration in neurodegenerative conditions.

First in human study with a prodrug of galantamine: Improved benefit-risk ratio?

IntroductionGln-1062 (Memogain) is a pharmacologically inactive prodrug of galantamine. Owing to its lipophilic nature, it preferentially enters the brain, where it is cleaved into active galantamine. Gln-1062 is expected to have fewer peripheral side effects than other cholinesterase inhibitors, with improved effectiveness. MethodsThis was a double-blind, comparator and placebo-controlled, sequential cohort, single ascending dose study in 58 healthy subjects with Gln-1062 in doses of 5.5, 11, 22, 33, and 44 mg, compared with oral galantamine 16 mg and donepezil 10 mg. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed. ResultsGln-1062 doses up to 33 mg were well tolerated and induced a dose-dependent increase in the plasma concentrations of Gln-1062 and galantamine. Gln-1062 had a dose-dependent positive effect on verbal memory and attention, mainly in the first hours after drug administration. DiscussionGln-1062 was better tolerated than galantamine in doses with the same molarity and led to improved effects in cognitive tests. This is most likely caused by the more favorable distribution ratio between peripheral and central cholinesterase inhibition. These results give reason for further exploration of this compound.

Frontoparietal cognitive control of verbal memory recall in Alzheimer's disease.

Episodic memory retrieval is reliant upon cognitive control systems, of which 2 have been identified with functional neuroimaging: a cingulo-opercular salience network (SN) and a frontoparietal executive network (EN). In Alzheimer's disease (AD), pathology is distributed throughout higher-order cortices. The hypotheses were that this frontoparietal pathology would impair activity associated with verbal memory recall; and that central cholinesterase inhibition (ChI) would modulate this, improving memory recall. Functional magnetic resonance imaging was used to study normal participants and 2 patient groups: mild cognitive impairment (MCI) and AD. Activity within the EN and SN was observed during free recall of previously heard sentences, and related to measures of recall accuracy. In normal subjects, trials with reduced recall were associated with greater activity in both the SN and EN. Better recall was associated with greater activity in medial regions of the default mode network. By comparison, AD patients showed attenuated responses in both the SN and EN compared with either controls or MCI patients, even after recall performance was matched between groups. Following ChI, AD patients showed no modulation of activity within the SN, but increased activity within the EN. There was also enhanced activity within regions associated with episodic and semantic memory during less successful recall, requiring greater cognitive control. The results indicate that in AD, impaired responses of cognitive control networks during verbal memory recall are partly responsible for reduced recall performance. One action of symptom-modifying treatment is partially to reverse the abnormal function of frontoparietal cognitive control and temporal lobe memory networks.

Auditory cortical function during verbal episodic memory encoding in Alzheimer's disease

Episodic memory encoding of a verbal message depends upon initial registration, which requires sustained auditory attention followed by deep semantic processing of the message. Motivated by previous data demonstrating modulation of auditory cortical activity during sustained attention to auditory stimuli, we investigated the response of the human auditory cortex during encoding of sentences to episodic memory. Subsequently, we investigated this response in patients with mild cognitive impairment (MCI) and probable Alzheimer's disease (pAD). Using functional magnetic resonance imaging, 31 healthy participants were studied. The response in 18 MCI and 18 pAD patients was then determined, and compared to 18 matched healthy controls. Subjects heard factual sentences, and subsequent retrieval performance indicated successful registration and episodic encoding. The healthy subjects demonstrated that suppression of auditory cortical responses was related to greater success in encoding heard sentences; and that this was also associated with greater activity in the semantic system. In contrast, there was reduced auditory cortical suppression in patients with MCI, and absence of suppression in pAD. Administration of a central cholinesterase inhibitor (ChI) partially restored the suppression in patients with pAD, and this was associated with an improvement in verbal memory. Verbal episodic memory impairment in AD is associated with altered auditory cortical function, reversible with a ChI. Although these results may indicate the direct influence of pathology in auditory cortex, they are also likely to indicate a partially reversible impairment of feedback from neocortical systems responsible for sustained attention and semantic processing.

Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease

To investigate if a central cholinesterase inhibitor will reduce falling frequency in subjects with Parkinson disease (PD) with advanced postural instability. Falling due to postural instability is a significant problem in advancing PD, and is minimally impacted by dopaminergic therapy. Anticholinergic medications increase falling in the elderly. Further, CNS cholinergic neuron loss occurs in PD. We hypothesized that acetylcholine augmentation may reduce frequent falling in subjects with PD. We enrolled 23 subjects with PD who reported falling or nearly falling more than 2 times per week. In a randomized, placebo-controlled, crossover design, subjects were given 6 weeks of donepezil or placebo with a 3-week washout between phases. The primary outcomes were daily falls and near falls reported on postcards. Secondary outcomes included scores on the Activities of Balance Confidence Scale, Berg Balance Scale, Clinical Global Impression of Change, Folstein Mini-Mental State Examination, and the motor section of the Unified Parkinson's Disease Rating Scale. Fall frequency per day on placebo was 0.25 ± 0.08 (SEM) compared with 0.13 ± 0.03 on donepezil (p < 0.05). The frequency of near falls was not significantly different between phases. The secondary outcomes did not differ; however, there was a trend to improvement on the subject-completed Global Impression of Change scale. Subjects with PD fell approximately half as often during the 6 weeks on donepezil than on placebo. Larger trials of cholinergic augmentation are warranted in subjects with PD with frequent falls. This study provides Class II evidence that donepezil (maximum 10 mg per day) significantly reduced the number of falls in patients with PD (0.13 falls/day, SEM = 0.03) than when taking placebo (0.25 falls/day, SEM = 0.08, p = 0.049).

Comment on "Survival Pattern in Patients with Acute Organophosphate Poisoning Receiving Intensive Care"

To the Editor: Munidasa et al. observed that refractory hypotension was strongly associated with a high early mortality from organophosphate poisoning despite adequate respiratory support, inotropes, and intensive care (1). The authors speculated that the most likely mechanism was globally impaired myocardial function as these patients typically also had pulmonary oedema. However other smaller series of similar patients with invasive monitoring suggest other mechanisms may be important. We and others have found extremely low vascular resistance in OP poisoned patients with hypotension refractory to catecholamines (2 – 4). Despite the patients being clinically atropinised the low vascular resistence responded partially to very high doses of atropine but not to other vasopressors. We postulated that this vasodilation was due to stimulation of the vascular endothelial muscarinic receptor resulting in the release of nitric oxide (2). We have observed this repeatedly in subsequent patients, and the hypotension in most patients is usually associated with a high rather than a low cardiac output (similar to septic shock) (2 – 4). There are a number of other mechanisms that may contribute to hypotension in organophosphate poisoning. Despite causing generalized vasodilation, acetylcholine can also induce vasoconstriction at sites where the endothelium is damaged (5), and this might lead to myocardial ischemia. Cardiac oxygen demand may be higher, due to the high cardiac output state and excessive endogenous or exogenous catecholamines. As well as contributing to focal ischemia, this could lead to diffuse myocardial necrosis similar to that seen with phaeochromocytoma (6,7). In addition there may be diffuse endothelial injury or cardiotoxicity from reactive oxygen species (8) or cardiac effects may be secondary to acidosis or electrolyte abnormalities (9), and others have speculated that the hypotension may be centrally mediated (3), although generally central cholinesterase inhibition leads to a pressor response (10). We agree with Munidasa et al.’s implication that refractory hypotension is the leading cause of death in anticholinesterase poisonings that are receiving maximal supportive care. It is plausible that one, many or all of these different mechanisms are important. A rational approach to the management of patients with refractory hypotension depends on the development of a much better understanding of the pathophysiology. Only then will it be clearer what treatment options are appropriate, what investigations are required, and whether treatment needs to be individualized or if clinical trials of antidotes for the hypotension are feasible.

Stress interacts with peripheral cholinesterase inhibitors to cause central nervous system effects

Pyridostigmine bromide (PB), a peripheral cholinesterase inhibitor, has been shown to have central cholinesterase inhibition properties under certain conditions (such as when ingested with other chemical compounds or following a high level of stress). Here we tested if stressing rats, using an intermittent 1 hr tailshock protocol, affected the degree of brain acetylcholinesterase (AChE) inhibition caused by a subsequent single injection of PB (2.0 mg/kg) or neostigmine bromide (NB, 0.32 mg/kg), another peripheral carbamate cholinesterase inhibitor. Stressed rats treated with PB had lower levels of AChE activity in the basal forebrain/striatum, but not in other brain areas. Stressed rats treated with NB did not show basal forebrain/striatum AChE activity changes but did show minor reductions of AChE activity in the cortex and cerebellum. These results confirm that prior stress can change the characteristic actions of certain peripherally acting drugs, thus possibly leading to unexpected central nervous system effects. Possible causes for these effects are discussed.

Cholinesterase inhibition improves blood flow in the ischemic cerebral cortex.

The ability of central cholinesterase inhibition to improve cerebral blood flow in the ischemic brain was tested in Sprague-Dawley rats with tandem occlusion of left middle cerebral and common carotid arteries. Cerebral blood flow was measured with lodo- 14C-antipyrine autoradiography in 170 regions of cerebral cortex. The regional distribution of blood flow was characterized in normal animals by cerebral blood flow maxima in the temporal regions. After 2 h ischemia, minimum cerebral blood flow values were found in the lateral frontal and parietal areas on the left hemisphere, and a new maximum was found in the right hemisphere in an area approximately symmetrical to the ischemic focus. Heptyl-physostigmine (eptastigmine), a carbamate cholinesterase inhibitor with prolonged time of action improved cerebral blood flow in most regions, with the exception of the ischemic core. The drug also enhanced the ischemia-induced rostral shift of cerebral blood flow maxima in the right hemisphere. The effects of eptastigmine were more marked 24 h after ischemia. Discriminant analysis showed that data from only 22 regions was sufficient to achieve 100% accuracy in classifying all cases into the various experimental conditions. The redistribution of cerebral blood flow to the sensorimotor area of the right hemisphere of animals with cerebral ischemia, a phenomenon possibly related to recovery of function, was also enhanced by eptastigmine.