Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema.

Acetylcholine (ACh), the neurotransmitter of the cholinergic system, regulates inflammation in several diseases including pulmonary diseases. ACh is also involved in a non-neuronal mechanism that modulates the innate immune response. Because inflammation and release of pro-inflammatory cytokines are involved in pulmonary emphysema, we hypothesized that vesicular acetylcholine transport protein (VAChT) deficiency, which leads to reduction in ACh release, can modulate lung inflammation in an experimental model of emphysema. Mice with genetical reduced expression of VAChT (VAChT KDHOM 70%) and wild-type mice (WT) received nasal instillation of 50 uL of porcine pancreatic elastase (PPE) or saline on day 0. Twenty-eight days after, animals were evaluated. Elastase instilled VAChT KDHOM mice presented an increase in macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid and MAC2-positive macrophages in lung tissue and peribronchovascular area that was comparable to that observed in WT mice. Conversely, elastase instilled VAChT KDHOM mice showed significantly larger number of NF-κB-positive cells and isoprostane staining in the peribronchovascular area when compared to elastase-instilled WT-mice. Moreover, elastase-instilled VAChT-deficient mice showed increased MCP-1 levels in the lungs. Other cytokines, extracellular matrix remodeling, alveolar enlargement, and lung function were not worse in elastase-instilled VAChT deficiency than in elastase-instilled WT-controls. These data suggest that decreased VAChT expression may contribute to the pathogenesis of emphysema, at least in part, through NF-κB activation, MCP-1, and oxidative stress pathways. This study highlights novel pathways involved in lung inflammation that may contribute to the development of chronic obstrutive lung disease (COPD) in cholinergic deficient individuals such as Alzheimer's disease patients.

Therapeutic approaches to cholinergic deficiency in Lewy body diseases.

Introduction: Cortical cholinergic denervation resulting from degeneration of the nucleus basalis of Meynert (NBM) is a primary contributor to cognitive impairment and neuropsychiatric symptoms in the Lewy body diseases Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). Considering the morbidity associated with cognitive impairment and neuropsychiatric symptoms in these diseases, it is important to investigate all potential therapies to improve these symptoms.Areas covered: The authors review the current landscape of pharmacological and surgical therapies for mitigating the cortical cholinergic deficiency in PD, PDD, and DLB.Expert opinion: The cholinesterase inhibitors rivastigmine, donepezil, and galantamine are currently the primary pharmacological treatments available to improve cognition and associated neuropsychiatric symptoms in Lewy body diseases. Other possible pharmacological strategies include increasing acetylcholine release with 5-HT4 agonists or directly stimulating cholinergic receptors with muscarinic and nicotinic agonists. The side effect profile of muscarinic agonists is a deterrent to their future study, but 5-HT4 and nicotinic agonists deserve further investigation. Targeting the basal forebrain with either deep brain stimulation (DBS)- or cell-based therapies is another strategy to mitigate cortical cholinergic deficiency. Before NBM DBS studies continue, it will be important to resolve issues related to targeting, stimulation pattern, and duration.

Tackling neuroinflammation and cholinergic deficit in Alzheimer's disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase.

Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1ß and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 µM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.

[The cholinergic deficiency syndrome in patients with depressed consciousness after severe brain injury]. / Sindrom kholinergicheskoi nedostatochnosti pri dlitel'nom ugnetenii soznaniya posle tyazheloi cherepno-mozgovoi travmy.

AIM: To determine the clinical and electrophysiological (EEG) signs of cholinergic deficiency in the process of recovery of consciousness in patients with severe brain injury. MATERIAL AND METHODS: Thirty-seven people (24 men and 13 women, mean age 32±14 years) were studied. A comprehensive study included assessment of neurological status, mental activity, and EEG. RESULTS AND CONCLUSION: A set of neurological symptoms, including reduced muscle tone, autonomic disorders (dry mucous membranes and skin, tachycardia, hypotension, gastrointestinal tract), eye movement disorders, that were,in accordance with the literature, characteristicof the cholinergic deficiency syndrome was found. This syndrome was detected against the background of a comatose state, akinetic mutism and mutism with understanding of speech, disintegration of speech, disorientation and amnestic decline. EEG revealed stable over time (months) characteristic changes: slowing and asymmetric alpha activity, equivalent dipole sources of hippocampal and stem localization, persistent strengthening of intra-hemispheric coherent connections, especially on the left side. The regression of the cholinergic deficiency syndrome was accompanied by an increase of regularity, capacity and frequency of alpha-activity (from 7-8 to 9-10 Hz), prevalence of equivalent dipole sources in the hippocampus with their appearance in the occipital cortex, normalization of connections with right-brain coherence with the preservation of their pathologically high values on the left side.

[Clinical syndromes of neurotransmitter system dysfunction in severe brain injury].

AIM: To explore neurotransmitter system dysfunctions involved in maintaining of consciousness and motor functions in patients with severe traumatic brain injury (TBI) and to assess their severity and predictive value. MATERIAL AND METHODS: Authors examined 100 patients (34 women and 66 men), aged 32.0 ± 13.0 years, with severe TBI. Eighty-eight patients (31 women and 57 men) were studied in the acute stage (1-15 days, mean 5.8 ± 3.7 days) and 70 patients (24 women and 46 men) in the subacute stage (18-70 days, mean 30.4 ± 12.7 days). Inclusion criteria were: severe TBI with depression of consciousness (≤ 7 scores on the Glasgow Coma Scale), admission to the hospital in acute and subacute stages. Outcome of TBI was evaluated using the Glasgow Outcome Scale. RESULTS AND CONCLUSION: The following clinical syndromes of neurotransmitter system dysfunction were singled out: excess or insufficiency of glutamate, cholinergic deficit, excess or insufficiency of dopamine. Their transformation during disease was identified. Predictive value of neurotransmitter dysfunctions for TBI is emphasized.

[Vitamin D and Alzheimer's disease: from an intriguing idea to a therapeutic option]. / Vitamine D et maladie d'Alzheimer : d'une curieuse idée à une possibilité de traitement.

Beyond the classically described regulation of calcium and bone metabolism, vitamin D is a neurosteroid hormone essential to neurophysiological function (regulation of neurotransmitters and neurotrophins) with anti-inflammatory and antioxidant neuroprotective action. In contrast, hypovitaminosis D, which is extremely frequent in the elderly, may result in neurological dysfunction and may explain part of the cognitive disorders in this population. Epidemiology is consistent with this notion and has repeatedly shown an association between hypovitaminosis D and cognitive decline, either in the general population or in Alzheimer's patients. Preliminary intervention trials confirm the causal relationship and quantify the cognitive effect of vitamin D supplementation in the elderly. This raises prospects for primary/secondary prevention of cognitive decline by exogenous supplies of vitamin D. In particular, although current anti-dementia drugs are only symptomatic, future treatment options could rely on drug combinations preventing several neurodegenerative mechanisms at once. As such, vitamin D enhances the efficacy of memantine in terms of neuronal protection and prevention of cognitive decline in Alzheimer's disease.

Lack of synaptic vesicle protein SV2B protects against amyloid-ß25₋35-induced oxidative stress, cholinergic deficit and cognitive impairment in mice.

SV2B is a synaptic protein widely distributed throughout the brain, which is part of the complex vesicle protein machinery involved in the regulation of synaptic vesicle endocytosis and exocytosis, and therefore in neurotransmitters release. The aims of the present work were twofold: (1) phenotype SV2B knockout mice (SV2B KO) in a battery of cognitive tests; and (2) examine their vulnerability to amyloid-ß25-35 (Aß25-35) peptide-induced toxicity. SV2B KO mice showed normal learning and memory abilities in absence of Aß25-35 injection. SV2B KO mice were protected against the learning deficits induced after icv injection of an oligomeric preparation of amyloid-ß25-35 peptide, as compared to wild-type littermates (SV2B WT). These mice failed to show Aß25-35-induced impairments in a number of cognitive domains: working memory measured by a spontaneous alternation procedure, recognition memory measured by a novel object recognition task, spatial reference memory assessed in a Morris water-maze, and long-term contextual memory assessed in a inhibitory avoidance task. In addition, SV2B KO mice were protected against Aß25-35-induced oxidative stress and decrease in ChAT activity in the hippocampus. These data suggest that SV2B could be a key modulator of amyloid toxicity at the synaptic site.

Molecular interaction of acetylcholinesterase with carnosic acid derivatives: a neuroinformatics study.

Alzheimer's disease is a progressive degenerative disease of the brain marked by gradual and irreversible declines in cognitive functions. Acetylcholinesterase (AChE) plays a biological role in the termination of nerve impulse transmissions at cholinergic synapses by rapid hydrolysis of its substrate, "acetylcholine". The deficit level of acetylcholine leads to deprived nerve impulse transmission. Thus the cholinesterase inhibitors would reverse the deficit in acetylcholine level and consequently may reverse the memory impairments, which is characteristic of the Alzheimer's disease. The molecular interactions between AChE and Carnosic acid, a well known antioxidant substance found in the leaves of the rosemary plant has always been an area of interest. Here in this study we have performed in silico approach to identify carnosic acid derivatives having the potential of being a possible drug candidate against AChE. The best candidates were selected on the basis of the results of different scoring functions.

Cognitive effects of dopamine depletion in the context of diminished acetylcholine signaling capacity in mice.

A subset of patients with Parkinson's disease acquires a debilitating dementia characterized by severe cognitive impairments (i.e. Parkinson's disease dementia; PDD). Brains from PDD patients show extensive cholinergic loss as well as dopamine (DA) depletion. We used a mutant mouse model to directly test whether combined cholinergic and DA depletion leads to a cognitive profile resembling PDD. Mice carrying heterozygous deletion of the high-affinity, hemicholinium-3-sensitive choline transporter (CHT(HET)) show reduced levels of acetylcholine throughout the brain. We achieved bilateral DA depletion in CHT(HET) and wild-type (WT) littermates via intra-striatal infusion of 6-hydroxydopamine (6-OHDA), or used vehicle as control. Executive function and memory were evaluated using rodent versions of cognitive tasks commonly used with human subjects: the set-shifting task and spatial and novel-object recognition paradigms. Our studies revealed impaired acquisition of attentional set in the set-shifting paradigm in WT-6OHDA and CHT(HET)-vehicle mice that was exacerbated in the CHT(HET)-6OHDA mice. The object recognition test following a 24-hour delay was also impaired in CHT(HET)-6OHDA mice compared with all other groups. Treatment with acetylcholinesterase (AChE) inhibitors physostigmine (0.05 or 0.1 mg/kg) and donepezil (0.1 and 0.3 mg/kg) reversed the impaired object recognition of the CHT(HET)-6OHDA mice. Our data demonstrate an exacerbated cognitive phenotype with dual ACh and DA depletion as compared with either insult alone, with traits analogous to those observed in PDD patients. The results suggest that combined loss of DA and ACh could be sufficient for pathogenesis of specific cognitive deficits in PDD.

Acetylcholine facilitates recovery of episodic memory after brain damage.

Episodic memory depends on a network of interconnected brain structures including the inferior temporal cortex, hippocampus, fornix, and mammillary bodies. We have previously shown that a moderate episodic memory impairment in monkeys with transection of the fornix is exacerbated by prior depletion of acetylcholine from inferotemporal cortex, despite the fact that depletion of acetylcholine from inferotemporal cortex on its own has no effect on episodic memory. Here we show that this effect occurs because inferotemporal acetylcholine facilitates recovery of function following structural damage within the neural circuit for episodic memory. Episodic memory impairment caused by lesions of the mammillary bodies, like fornix transection, was exacerbated by prior removal of temporal cortical acetylcholine. However, removing temporal cortical acetylcholine after the lesion of the fornix or mammillary bodies did not increase the severity of the impairment. This lesion order effect suggests that acetylcholine within the inferior temporal cortex ordinarily facilitates functional recovery after structural lesions that impair episodic memory. In the absence of acetylcholine innervation to inferotemporal cortex, this recovery is impaired and the amnesia caused by the structural lesion is more severe. These results suggest that humans with loss of cortical acetylcholine function, for example in Alzheimer's disease, may be less able to adapt to memory impairments caused by structural neuronal damage to areas in the network important for episodic memory.

Cholinergic denervation exacerbates amyloid pathology and induces hippocampal atrophy in Tg2576 mice.

The main pathological hallmarks of Alzheimer's disease (AD) consist of amyloid plaques and neurofibrillary tangles. Hippocampal cell loss, atrophy and cholinergic dysfunction are also features of AD. The present work is aimed at studying the interactions between cholinergic denervation, APP processing and hippocampal integrity. The cholinergic immunotoxin mu p-75-saporin was injected into the 3rd ventricle of 6- to 8-month-old Tg2576 mice to induce a cholinergic denervation. Four weeks after cholinergic immunolesion, a significant 14-fold increase of soluble Aß1-42 was observed. Cholinergically lesioned Tg2576 mice showed hippocampal atrophy together with degenerating FluoroJade-B-stained neurons and reduction of synaptophysin expression in CA1-3 pyramidal layers. We also found that cholinergic denervation led to reduced levels of ADAM17 in hippocampus of Tg2576 mice. Inhibition of ADAM17 with TAPI-2 (5 µM) decreased viability of hippocampal primary neurons from Tg2576 brains and decreased phosphorylation of downstream effectors of trophic signalling (ERK and Akt). The cholinergic agonist carbachol (100 µM) rescued these effects, suggesting that cholinergic deficits might render hippocampus more vulnerable to neurotoxicity upon certain toxic environments. The present work proposes a novel model of AD that worsens the patent amyloid pathology of Tg2576 mice together with hippocampal synaptic pathology and neurodegeneration. Drugs aimed at favoring cholinergic transmission should still be considered as potential treatments of AD.

Rapid eye movement sleep atonia in patients with cognitive impairment.

Acetylcholine (ACh) plays an important role in cognitive function and muscle atonia in rapid eye movement (REM) sleep. This quantitative study used surface electromyography (sEMG) to investigate changes in muscular activity, which may indicate a deficiency of ACh among patients with cognitive impairment. We recruited 9 controls without dementia, 6 patients with mild cognitive impairment (MCI), and 6 patients with mild Alzheimer's disease (AD). None of the participants had sleep complaints, and all AD patients were receiving cholinesterase inhibitors. Subjects underwent polysomnography (PSG), including sEMG of the leg muscles, which was analyzed using root mean square (rms), mean frequency, and peak frequency. The average rms values during REM sleep among the control, MCI, and AD patients were 0.553 ± 0.177, 2.886 ± 2.865, and 0.909 ± 0.822, respectively. The average peak frequencies during REM sleep in control, MCI, and AD patients were 0.402 ± 0.758, 30.524 ± 32.237, and 0.566 ± 1.153, respectively. The average mean frequencies during REM sleep in control, MCI, and AD patients were 8.849 ± 6.071, 34.530 ± 25.564, and 9.553 ± 6.308, respectively. All rms, mean frequencies, and peak frequencies increased significantly (p<0.05) in MCI patients. A deficiency of ACh may result in an increase of sEMG activity in MCI patients. Because cholinesterase inhibitors are capable of suppressing sEMG activity in AD patients, we speculate that an increase in sEMG activity is associated with a deficiency of Ach, which could be an early indicator of dementia.

Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics.

Acetylcholine in the brain has been associated with consciousness and general anesthesia effects. We tested the hypothesis that the integrity of the nucleus basalis magnocellularis (NBM) affects the response to general anesthetics. Cholinergic neurons in NBM were selectively lesioned by bilateral infusion of 192IgG-saporin in adult, male Long-Evans rats, and control rats were infused with saline. Depletion of choline-acetyltransferase (ChAT)-immunoreactive cells in the NBM and decrease in optical density of acetylcholinesterase (AChE) staining in the frontal and visual cortices confirmed a significant decrease in NBM cholinergic neurons in lesioned as compared to control rats. AChE staining in the hippocampus and ChAT-positive neurons in the medial septum-vertical limb of the diagonal band were not different between lesioned and control rats. When a general anesthetic was administered, lesioned compared to control rats showed significantly longer duration of loss of righting reflex (LORR) after propofol (5 or 10mg/kg i.v.), pentobarbital (20 or 40 mg/kg i.p.) but not halothane (2%). However, the behavioral excitation, as indicated by horizontal movements, induced by halothane was reduced in lesioned as compared to control rats. Reversible inactivation of NBM with GABA(A) receptor agonist muscimol increased slow waves in the neocortex during awake immobility, and prolonged the duration of LORR and loss of tail-pinch response after propofol, pentobarbital and halothane. In summary, lesion of NBM cholinergic neurons or inactivation of the NBM prolonged the LORR response to general anesthetic drugs.

Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice.

The cholinotrophic system, which is dependent upon nerve growth factor and its receptors for survival, is selectively vulnerable in Alzheimer's disease (AD). But, virtually nothing is known about how this deficit develops in relation to the hallmark lesions of this disease, amyloid plaques and tau containing neurofibrillary tangles. The vast majority of transgenic models of AD used to evaluate the effect of beta amyloid (Aß) deposition upon the cholinotrophic system over-express the amyloid precursor protein (APP). However, nothing is known about how this system is affected in triple transgenic (3xTg)-AD mice, an AD animal model displaying Aß plaque- and tangle-like pathology in the cortex and hippocampus, which receive extensive cholinergic innervation. We performed a detailed morphological and biochemical characterization of the cholinotrophic system in young (2-4 months), middle-aged (13-15 months) and old (18-20 months) 3xTg-AD mice. Cholinergic neuritic swellings increased in number and size with age, and were more conspicuous in the hippocampal-subicular complex in aged female than in 3xTg-AD male mice. Stereological analysis revealed a reduction in choline acetyltransferase (ChAT) positive cells in the medial septum/vertical limb of the diagonal band of Broca in aged 3xTg-AD mice. ChAT enzyme activity levels decreased significantly in the hippocampus of middle-aged 3xTg-AD mice compared to age-matched non-transgenic (or wild type) mice. ProNGF protein levels increased in the cortex of aged 3xTg-AD mice, whereas TrkA protein levels were reduced in a gender-dependent manner in aged mutant mice. In contrast, p75(NTR) protein cortical levels were stable but increased in the hippocampus of aged 3xTg-AD mice. These data demonstrate that cholinotrophic alterations in 3xTg-AD mice are age- and gender-dependent and more pronounced in the hippocampus, a structure more severely affected by Aß plaque pathology.

[Drug-induced delirium]. / Medikamentenassoziiertes Delirium.

Drugs have been strongly associated with the development of delirium, and they are one of the most easily reversible triggers. In addition to polypharmacy, physiological changes with aging including pharmacokinetic and pharmacodynamic changes as well as medical co-morbidities can increase the susceptibility to a drug induced delirium. Since it is widely accepted that delirium represents reversible impairment of cerebral oxidative metabolism and neurotransmission [37], it is not surprising that any drug interfering with the function, the supply or the use of substrates for neurotransmitter metabolism can cause delirium. Drugs with anticholinergic activity, especially those with muscarine receptor activity, constitute a considerable risk-group. Many different classes of drugs can induce delirium, but several studies have shown that it all comes down to the so-called anticholinergic burden, which becomes greater with each medication someone takes. In the elderly, polypharmacy and anticholinergic toxicity is common. Dementia, e.g. Alzheimer's disease, and, to a lesser extent, other chronic brain pathologies, predispose, through reduced integrity of the blood-brain barrier function, additionally to the development of delirium. Misinterpretation of an adverse drug reaction as another medical condition may lead to the prescription of additional medications with their own potential to cause side effects. To reduce the morbidity and mortality associated with drug induced delirium and also to prevent it, patients' medications should be closely monitored. Wherever possible, drugs with anticholinergic effects should be avoided in elderly patients, particularly in those suffering from dementia.

Does age matter? Behavioral and neuro-anatomical effects of neonatal and adult basal forebrain cholinergic lesions.

The "cholinergic hypothesis" of dementia posits that the progressive loss of basal forebrain cholinergic neurons and the consequent decrease of acetylcholine levels in the deafferented projection sites are correlated with degree of cognitive decline in dementia. It has also been proposed that early dysfunction of the basal forebrain (BF) cholinergic system may be a risk factor for subsequent cognitive decline and possibly dementia. To characterize how age when BF cholinergic system is lesioned affects behavioral performances and morphology of neocortical neurons, seven-day-old rats were bilaterally i.c.v. injected with 192 IgG-saporin. In adulthood, these animals were subjected to spatial and associative tests. Subsequently, the morphology of parietal pyramidal neurons was assessed. The same behavioral and morphological evaluations were made in 80-day-old rats tested three weeks after bilateral i.c.v. injections of 192 IgG-saporin. The behavioral consequences of both cholinergic depletions were markedly similar. While both groups of lesioned animals exhibited very subtle deficits in the Morris water maze, they were significantly impaired in spatial discrimination in the open field and the radial maze. Paralleling behavioral data, the results of the morphological analysis revealed comparable increases in number and density of spines in apical and basal dendrites in layer-III parietal pyramidal neurons following both neonatal and adult cholinergic depletions. The present results demonstrate that the consequences of abnormal maturation of the cholinergic system are not substantially different from those evoked by cholinergic dysfunction in adulthood and provide a developmental psychobiological perspective of the neuronal foundations of the impaired cognitive functions.

Functional cholinergic damage develops with amyloid accumulation in young adult APPswe/PS1dE9 transgenic mice.

We investigated the functional characteristics of pre- and postsynaptic cholinergic transmission in APPswe/PS1dE9 double transgenic mice at a young age (7-10 weeks) before the onset of amyloid plaque formation and at adult age (5-6 months) at its onset. We compared brain slices from cerebral cortex and hippocampus with amyloid deposits to slices from striatum with no amyloid plaques by 6 months of age. In young transgenic mice we found no impairments of preformed and newly synthesized [(3)H]-ACh release, indicating intact releasing machinery and release turnover, respectively. Adult transgenic mice displayed a significant increase in preformed [(3)H]-ACh release in cortex but a decrease in hippocampus and striatum. The extent of presynaptic muscarinic autoregulation was unchanged. Evoked release of newly synthesized [(3)H]-ACh was significantly reduced in the cortex and hippocampus but unchanged in the striatum. Carbachol-induced G-protein activation in cortical membranes displayed decreased potency but normal efficacy in adult animals and no changes in young animals. These results indicate that functional pre- and postsynaptic cholinergic deficits are not present in APPswe/PS1dE9 transgenic mice before 10 weeks of age, but develop along with beta-amyloid accumulation in the brain.

Capturing side-effect of medication to identify persons at risk of delirium.

Delirium, an acute confusional state characterized by decline in attention and cognition, is a common, life-threatening, but potentially preventable clinical syndrome among older persons. Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. In particular, an imbalance between levels of acetylcholine and monoamine (such as dopamine) may cause delirium. We describe two cases of delirium in hospitalized older patients, supporting the "cholinergic deficiency hypothesis". In the first patient, hypo-reactive delirium developed a few hours after a dose of the long-acting opiate tramadol (a drug with anticholinergic effect) as analgesic for pain related to advanced peripheral artery disease. In the second patient, with vascular parkinsonism plus pre-frontal cortex vascular lesions, hyper-reactive delirium developed a few hours after a prescribed administration of L-dopa. These symptoms disappeared completely on the following day. These two "natural" experiments support the hypothesis that both hypo-reactive and hyper-active delirium may be caused by a reduction in cholinergic signaling.

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment.

Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.Acta Pharmacologica Sinica (2009) 30: 879-888; doi: 10.1038/aps.2009.82.

Efficacy of rivastigmine for cognitive symptoms in Parkinson disease with dementia.

BACKGROUND: Impairment of multiple neurotransmitter networks, including acetylcholine, may contribute to the cognitive impairment in patients with Parkinson disease with dementia (PDD). Therefore, cholinesterase inhibitors might improve cognitive function in PDD. On the other hand, enhancing cholinergic function could plausibly worsen features of parkinsonism. OBJECTIVE: To determine if oral cholinesterase inhibitors improve measures of cognitive outcome and are tolerated by people with PDD. METHODS: We addressed the question through the development of a critically appraised topic. Participants included consultant and resident neurologists, clinical epidemiologists, a medical librarian, and behavioral neurology and movement disorder specialists. Participants began with a structured clinical question, devised search strategies, compiled the best evidence, performed a critical appraisal, summarized the evidence, provided commentary, and declared bottom-line conclusions. RESULTS: A randomized controlled trial (n = 541) showed that, compared with placebo, rivastigmine (mean, 8.6 mg/d) significantly improved scores on 2 coprimary cognitive outcome scales in PDD, including the Alzheimer disease Cooperative Study-Clinician's Global Impression of Change. When dichotomized to evaluate clinically significant benefit (moderate or marked improvement), this outcome was not significant (risk difference = 5.3%; 95% confidence interval (CI) = -1.6 to 12.1). The number needed to treat (NNT) to avoid clinically significant worsening of cognition was 10 (95% CI = 6-28). The NNT for the combined outcome of either achieving clinically significant benefit or avoiding significant worsening was 7. The numbers needed to harm for cholinergic side effects were 9 (95% CI = 5-24) for parkinsonian symptoms and 11 (95% CI = 6-32) for rivastigmine discontinuation due to any side effect. CONCLUSION: Rivastigmine therapy for PDD is associated with significant tradeoffs in efficacy and adverse effects. Carefully monitored trials of rivastigmine may provide meaningful benefits for a minority of PDD patients.