Mini Review: Anticholinergic Activity as a Behavioral Pathology of Lewy Body Disease and Proposal of the Concept of “Anticholinergic Spectrum Disorders”

Given the relationship between anticholinergic activity (AA) and Alzheimer's disease (AD), we rereview our hypothesis of the endogenous appearance of AA in AD. Briefly, because acetylcholine (ACh) regulates not only cognitive function but also the inflammatory system, when ACh downregulation reaches a critical level, inflammation increases, triggering the appearance of cytokines with AA. Moreover, based on a case report of a patient with mild AD and slightly deteriorated ACh, we also speculate that AA can appear endogenously in Lewy body disease due to the dual action of the downregulation of ACh and hyperactivity of the hypothalamic-pituitary-adrenal axis. Based on these hypotheses, we consider AA to be a behavioral pathology of Lewy body disease. We also propose the concept of “anticholinergic spectrum disorders,” which encompass a variety of conditions, including AD, Lewy body disease, and delirium. Finally, we suggest the prescription of cholinesterase inhibitors to patients in this spectrum of disorders to abolish AA by upregulating ACh.

Related papers:

title: Serum levels of anticholinergic drugs in treatment of acute extrapyramidal side effects.
abstract: A simple, sensitive, and specific radioreceptor assay has been developed for the measurement of anticholinergic drugs in human serum. The assay is based on the competitive inhibition by free anticholinergic drugs in a 0.2-mL sample of serum with the specific binding of the potent muscarinic antagonists, tritiated quinuclidinyl benzilate, to solubilized brain muscarinic receptors. Anticholinergic activity could be detected regardless of drug structure and was quantified against atropine standards. Although the serum levels of anticholinergic drugs varied considerably in 35 patients receiving both neuroleptic and anticholinergic drugs, there was a highly significant inverse correlation between the presence of acute extrapyramidal side effects due to neuroleptics and the serum levels of anticholinergics.

title: Anticholinergic sensitivity in patients with dementia of the Alzheimer type and age-matched controls. A dose-response study.
abstract: We compared the cognitive and behavioral responses to three intravenous doses of scopolamine (0.1, 0.25, and 0.5 mg) and placebo of ten patients with dementia of the Alzheimer type (DAT) and ten age- and sex-matched elderly control subjects. The patients with DAT showed significant behavioral and cognitive but not physiologic changes at a lower scopolamine dose (0.25 mg) than did the normal elderly controls. Cognitive tests of new learning and semantic knowledge revealed significant impairments at the 0.25-mg scopolamine dose in the patients with DAT, while the responses of the control population were essentially unchanged. Behaviorally, mild euphoria, motor incoordination, and hostility occurred in the patients with DAT but not the controls at the 0.25-mg dose. These differences were unrelated to peripheral physiologic changes produced by the different scopolamine doses. These results indicate that central nervous system functions such as cognition and certain elements of behavior are more sensitive to temporary cholinergic blockade in patients with DAT than in normal age-matched controls. We review implications concerning the status of central cholinergic function in patients with DAT in light of neuropathologically demonstrated cholinergic system lesions in DAT.

title: Cholinesterase inhibitors: A new class of psychotropic compounds.
abstract: This article reviews evidence indicating that acetylcholinesterase inhibitors have psychotropic properties.



The author reviewed the English-language literature pertinent to the response of neuropsychiatric symptoms in Alzheimer's disease and related conditions to cholinergic agents.



The cholinergic system originates in the basal forebrain and projects diffusely to the cerebral cortex; the limbic and paralimbic regions receive the most abundant cholinergic projections. The basal forebrain nuclei are positioned at the interface of the limbic system and cerebral cortex, where they play a role in mediating emotional responses. The basal forebrain nuclei are atrophic in Alzheimer's disease, leading to a widespread cholinergic deficit. The cholinergic disturbance may contribute to neuropsychiatric manifestations of the disease. The treatment of patients with Alzheimer's disease with acetylcholinesterase inhibitors reduces neuropsychiatric symptoms, particularly apathy and visual hallucinations. In some studies, a variety of other neuropsychiatric symptoms have been reported to respond to treatment with acetylcholinesterase inhibitors. Response profiles vary among acetylcholinesterase inhibitors.



Acetylcholinesterase inhibitors have psychotropic effects and may play an important role in controlling neuropsychiatric and behavioral disturbances in patients with Alzheimer's disease. These agents also may contribute to the management of other disorders with cholinergic system abnormalities and neuropsychiatric symptoms. The beneficial response is most likely mediated through limbic cholinergic structures.

title: The Cholinergic Deficiency Syndrome and Its Therapeutic Implications
abstract: Cholinesterase inhibitors are licensed for treatment of dementia in Alzheimer’s disease. However, the effects of these drugs on the cognitive symptoms of dementia are very small. We suggest that symptoms like impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome (CDS), that may be a much better target for such treatment. Changes in the quantitative electroencephalogram, muscarinic subtype radioimaging and serum anticholinergic activity may potentially help to diagnose the CDS. CDS is suggested to occur in various neurodegenerative diseases like Alzheimer’s disease, Lewy body dementia and Parkinson’s disease and to respond well to cholinesterase inhibitor therapy.

title: Serum anticholinergic activity changes with acute illness in elderly medical patients.
abstract: Elevated serum anticholinergic activity levels have been associated with delirium in cross-sectional studies of ill older persons. This study used serial measures of serum anticholinergic activity levels to determine whether these levels change following illness resolution, and if such changes are specific to those with delirium.



Twenty-two nursing home residents with a febrile illness had serum specimens drawn and were evaluated for the presence of delirium during the acute illness and at 1-month follow-up. Delirium was diagnosed using the Confusion Assessment Method. Serum anticholinergic activity was determined using a previously described radionuclide competitive-binding assay.



Delirium was present during illness in 8 of 22 subjects (36%), and had resolved by 1-month follow-up in all but one resident. Serum anticholinergic activity levels were significantly higher during illness than at 1-month follow-up in both the delirious (0.69 +/- 0.85 nM atropine equivalents/200 microL sample versus 0.10 +/- 0.16; p = .06) and non-delirious (0.65 +/- 0.51 nM atropine equivalents/200 microL sample versus 0.08 +/- 0.12; p < .001) groups. Medication changes did not seem to be related to changes in serum anticholinergic activity.



In older nursing home residents with a fever, serum anticholinergic activity appears to be elevated during illness, and declines following recovery from illness. This effect does not seem to be specific to those residents with delirium, nor does it seem related to medication changes.

title: Increased Cortisol Levels and Anticholinergic Activity in Cognitively Unimpaired Patients
abstract: Increased patients' serum anticholinergic activity (SAA) is described as a marker of cognitive dysfunction and can be influenced by different exogenous and endogenous factors. The role of cortisol in relation to SAA and cognition in perioperative conditions has not been investigated so far. In 30 men scheduled for urological surgery, the authors determined SAA and cortisol levels in blood and CSF and conducted neuropsychological testing in two subgroups with comparable pre- and intraoperative characteristics, one group with low SAA (mean=2.4 [SD=0.9], n=23) and the other with high SAA (mean=5.1 [SD=2.4], n=7) values. Increased SAA was associated with two times the number of anticholinergic medications but not with patients' age, medical history or impaired cognition. A significant linear correlation was detected between anticholinergic activities and cortisol levels. Thus, endogenous factors such as patients' stress levels should be taken into account for interpretation of the role of SAA.

title: [Proposal of endogenous anticholinergic hypothesis in Alzheimer disease].
abstract: We previously speculated that anticholinergic activity (AA) endogenously appeared in Alzheimer's disease (AD) and accelerated AD pathology. In this article we introduce manuscripts supporting the endogenous appearance of AA in AD and the acceleration of AD pathology. We speculate that acethylcholine (ACh) not only is related to cognitive functions but also regulates the inflammatory system. Therefore in AD, in which the ACh system is down-regulated, the hyperactivity of the inflammatory system may be caused and among cyctokines, substances having anticholinergic properties may appear. We also refer to a case in which serum anticholinergic activity (SAA) disappeared with the prescription of memantine (an antidementia agent that has the property of the N-methyl-D-aspartate (NMDA) receptor blocker) and speculate that because the hyperactivity of the inflammatory system occurs by way of the hyperactivity of NMDA receptor, memantine could abolish the AA.

title: Serum Anticholinergic Activity: A Possible Peripheral Marker of the Anticholinergic Burden in the Central Nervous System in Alzheimer's Disease
abstract: We review the utility of serum anticholinergic activity (SAA) as a peripheral marker of anticholinergic activity (AA) in the central nervous system (CAA). We hypothesize that the compensatory mechanisms of the cholinergic system do not contribute to SAA if their system is intact and that if central cholinergic system deteriorates alone in conditions such as Alzheimer's disease or Lewy body dementia, CAA and SAA are caused by way of hyperactivity of inflammatory system and SAA is a marker of the anticholinergic burden in CNS. Taking into account the diurnal variations in the plasma levels of corticosteroids, which are thought to affect SAA, it should be measured at noon or just afterward.

title: A Review of the Role of Anticholinergic Activity in Lewy Body Disease and Delirium
abstract: We have previously proposed a hypothesis in which we argue that anticholinergic activity (AA) appears endogenously in Alzheimer's disease (AD). Acetylcholine (ACh) controls both cognitive function and inflammation. Consequently, when the downregulation of ACh reaches critical levels, the inflammatory system is upregulated and proinflammatory cytokines with AA appear. However, factors other than downregulation of ACh can produce AA; even if ACh downregulation does not reach critical levels, AA can still appear if one of these other AA-producing factors is added. These factors can include neurocognitive disorders other than AD, such as delirium and Lewy body disease (LBD). In delirium, ACh downregulation fails to reach critical levels, but AA appears due to the use of medicines, physical illnesses or mental stress (termed ‘AA inserts'). In LBD, we speculate that AA appears endogenously, even in the absence of severe cognitive dysfunction, for 2 reasons. One reason is that patterns of ACh deterioration are different in LBD from those in AD, with synergistic actions between amyloid and α-synuclein thought to cause additional or severe symptoms that accelerate the disease course. The second reason is that AA occurs through disinhibition by reduced cortisol levels that result from severe autonomic parasympathetic dysfunction in LBD.

title: Influence of Anticholinergic Activity in Serum on Clinical Symptoms of Alzheimer’s Disease
abstract: Alzheimer’s disease (AD) is well known as a disease characterized by degeneration of cholinergic neuronal activity in the brain. It follows that patients with AD would be sensitive to an ‘anticholinergic burden’, and also that medicine with anticholinergic properties would promote various clinical symptoms of AD. Despite the relevance of this important phenomenon to the clinical therapeutics of AD patients, few reports have been seen concerning the relationship between anticholinergic burden and clinical AD symptoms. Therefore, we wished to investigate the relationship between serum anticholinergic activity (SAA) and the severity of clinical symptoms of AD patients. Twenty-six out of 76 AD patients referred by practitioners to our hospital were positive for anticholinergic activity in their serum, and the remaining 50 patients were negative. Cognitive and psychiatric symptoms in AD patients were compared between the positive SAA (SAA+) group and the negative SAA (SAA–) group. The SAA+ group showed a significantly (p < 0.05) lower total score on the Mini-Mental State Examination, and significantly (p < 0.05) higher scores on the Functional Assessment Staging and the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD). In particular, certain subscales of the BEHAVE-AD, i.e. the items of paranoid and delusional ideation, hallucinations and diurnal rhythm disturbances, had higher scores in the SAA+ group. Moreover, it was shown that many more psychotropic medicines were prescribed to the SAA+ group. By means of logistic regression analysis, the items of paranoid and delusional ideation and diurnal rhythm disturbances in the BEHAVE-AD were positively correlated with SAA in patients. We hypothesized that SAA in AD patients would be associated with clinical symptoms, especially delusion and diurnal rhythm disturbances.

title: Prevalence, correlates, and disease patterns of antipsychotic use in Taiwan
abstract: The population‐based National Health Insurance database was used to investigate the prevalence, correlates, and disease patterns of antipsychotic use in Taiwan.

title: Factors influencing the prescribing of medications by old age psychiatrists for behavioural and psychological symptoms of dementia: a qualitative study.
abstract: despite evidence of limited efficacy, psychotropic medications are widely used as a first line treatment for those with behavioural and psychological symptoms of dementia (BPSD). Clearly various factors must be influencing their continued use; these are explored here.



to examine the process by which consultant old age psychiatrists prescribe for BPSD and explore the factors that influence their decisions.



a focus group generated initial questions for interviews with eight consultant old age psychiatrists, using a grounded theory methodology.



differences in how assessment information was utilised resulted in inconsistencies in choice of medication between psychiatrists. Psychiatrists felt pressured to prescribe, largely due to resource issues and lack of viable alternative treatments.



the ways in which psychiatrists prescribe for BPSD varies amongst clinicians. Guidelines do exist, but are difficult to implement in practice. Alternative non-pharmacological strategies are required, but as yet they are difficult to access and have a questionable evidence base.

title: The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases
abstract: Cultured brain cells are capable of generating many molecules associated with inflammatory and immune functions. They constitute the endogenous immune response system of brain. They include complement proteins and their regulators, inflammatory cytokines, acute phase reactants and many proteases and protease inhibitors. Most of the proteins are made by microglia and astrocytes, but even neurons are producers. Many appear in association with Alzheimer disease lesions, indicating a state of chronic inflammation in Alzheimer disease brain. Such a state can apparently exist without stimulation by peripheral inflammatory mediators or the peripheral immune system. A strong inflammatory response may be autotoxic to neurons, exacerbating the fundamental pathology in Alzheimer disease and perhaps other neurological disorders. Autotoxic processes may contribute to cellular death in chronic inflammatory diseases affecting other parts of the body, suggesting the general therapeutic value of anti-inflammatory agents. With respect to Alzheimer disease, multiple epidemiological studies indicate that patients taking anti-inflammatory drugs or suffering from conditions in which such drugs are routinely used, have a decreased risk of developing Alzheimer disease. In one very preliminary clinical trial, the anti-inflammatory drug indomethacin arrested progress of the disease. New agents directed against the inflammatory processes revealed in studies of Alzheimer disease lesions may have broad therapeutic applications.

title: Inhibitor of antagonist binding to the muscarinic receptor is elevated in Alzheimer's brain
abstract: The 100,000 x g supernatant fraction of human brain contains endogenous inhibitors of antagonist binding to the muscarinic receptor. Significantly greater inhibition was observed with Alzheimer's than non-demented control supernatant fractions. Low molecular weight inhibitor was separated from larger inhibitor species by membrane dialysis (3,500 dalton cut-off). The activity of low molecular weight inhibitor was greatly increased by sulfhydryl reducing agents. While the low molecular weight inhibitor was stable to heat, acid and base for short time periods (< 20 min), it was inactivated by acid hydrolysis (50% loss after 16 h, 100% loss after 96 h). The low molecular weight inhibitor activity is elevated approximately three-fold in Alzheimer's brain. The low molecular weight inhibitor from Alzheimer's brain was found to be a non-competitive inhibitor. This is the first report of endogenous inhibitors in human brain of ligand binding to the muscarinic receptor and of increased inhibitor activity in Alzheimer's disease.

title: Pharmacological Stimulation of the Cholinergic Antiinflammatory Pathway
abstract: Efferent activity in the vagus nerve can prevent endotoxin-induced shock by attenuating tumor necrosis factor (TNF) synthesis. Termed the “cholinergic antiinflammatory pathway,” inhibition of TNF synthesis is dependent on nicotinic α-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. Here, we studied the effects of pharmacological and electrical stimulation of the intact vagus nerve in adult male Lewis rats subjected to endotoxin-induced shock to determine whether intact vagus nerve signaling is required for the antiinflammatory action of CNI-1493. CNI-1493 administered via the intracerebroventricular route was 100,000-fold more effective in suppressing endotoxin-induced TNF release and shock as compared with intravenous dosing. Surgical or chemical vagotomy rendered animals sensitive to TNF release and shock, despite treatment with CNI-1493, indicating that an intact cholinergic antiinflammatory pathway is required for antiinflammatory efficacy in vivo. Electrical stimulation of either the right or left intact vagus nerve conferred significant protection against endotoxin-induced shock, and specifically attenuated serum and myocardial TNF, but not pulmonary TNF synthesis, as compared with sham-operated animals. Together, these results indicate that stimulation of the cholinergic antiinflammatory pathway by either pharmacological or electrical methods can attenuate the systemic inflammatory response to endotoxin-induced shock.

title: Activation of the Cholinergic Antiinflammatory Pathway Reduces Ricin-Induced Mortality and Organ Failure in Mice
abstract: Exposure to ricin, either by accident through ingestion of castor oil plant seeds or intentionally through its use as a bioweapon, invariably leads to multiple organ damage and death. Currently there is only a vaccine in advanced development to ricin, but no other antidote. Ricin causes systemic inflammation with increased proinflammatory cytokine release and subsequent multiple organ failure, particularly kidney and liver dysfunction. Activation of the cholinergic antiinflammatory pathway, specifically through the alpha7 nicotinic acetylcholine receptor (either indirectly through vagus nerve stimulation or directly through nicotine treatment) reduces proinflammatory gene expression. This activation also increases release of proinflammatory chemokines and cytokines, and has proven effective in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against ricin toxicity in mice. Male Balb/c mice exposed to ricin had increased serum levels of the inflammatory cytokine tumor necrosis factor-α and markers of both kidney (blood urea nitrogen, creatine) and liver (alanine tranaminase) dysfunction, with a subsequent increase in mortality Nicotine administration 2 h after ricin injection significantly delayed and reduced ricin-induced mortality, an effect coupled with reduced serum levels of tumor necrosis factor-a and markers of kidney and liver dysfunction. Both the kidney and liver had markedly increased cellular oxidative stress following ricin exposure, an effect attenuated by nicotine administration. In conclusion, these data demonstrate that in cases of ricin poisoning, activation of the cholinergic antiinflammatory pathway may prove beneficial by reducing organ damage, delaying mortality, and allowing for a greater chance of survival.

title: C-reactive protein: a pentraxin with anti-acetylcholine activity.
abstract: Purified C-reactive protein (CRP) diminished effects of acetylcholine (ACh) on the vascular tone and the heart rate of rats in vivo. In vitro CRP inhibited breakdown of ACh by acetylcholinesterase (AChE) while did not interact with AChE itself. CRP appears to bind ACh. CRP did not modify the cardiovascular effects of adenosine, another vasorelaxant. The data suggest that there is a new line of cross-talk between the inflammation and cholinergic regulation with CRP acting on endothelium via the ACh-dependent pathway.

title: Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists.
abstract: The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.

title: Novel Selective Allosteric Activator of the M1 Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats
abstract: Recent studies suggest that subtype-selective activators of M1/M4 muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment of psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed muscarinic agonists have provided clinical data in support of this hypothesis, but failed in clinical development because of a lack of true subtype specificity and adverse effects associated with activation of other mAChR subtypes. We now report characterization of a novel highly selective agonist for the M1 receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB [1-(1′-2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]. Mutagenesis and molecular pharmacology studies revealed that TBPB activates M1 through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M1 by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M2 and M4. TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Aβ production in vitro. Together, these data suggest that selective activation of M1 may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease.

title: Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs
abstract: The hypothesis that blockade of muscarinic receptors is associated with increased Alzheimer‐type pathology was investigated in Parkinson's disease. Amyloid plaque densities were more than 2.5‐fold higher in cases treated with antimuscarinic medication in the long term compared with untreated or short‐term treated cases (p = 0.005 and 0.00005, respectively). Neurofibrillary tangle densities were also highest in chronic compared with untreated or acute‐treated groups (p = 0.02 and 0.05, respectively). The findings, if replicated, have potential implications for the use of anticholinergic medication in elderly Parkinson's disease patients.

title: Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease.
abstract: Authors examined the effect of chronic exposure to anticholinergics in a cohort of Alzheimer disease (AD) patients.



All patients were examined annually with standard neuropsychologic tests and received the cholinesterase inhibitor donepezil hydrochloride at a dose of 10 mg/day. The study population (N=69) was divided into two groups: those receiving one or more concomitant medications with significant anticholinergic properties (N=16) and those receiving no concomitant medications with anticholinergic properties (N=53).



At 2 years, MMSE scores were significantly worse for patients receiving anticholinergic medications than for those not on anticholinergics.



Although very preliminary, these data suggest that concomitant therapy with anticholinergics may be associated with significant deleterious effects on acetylcholinesterase therapy, or, more speculatively, that chronic exposure to anticholinergics may have adverse effects on the clinical course of AD.

title: Delirium in older people
abstract: Few ill health situations are more degrading to people of any age than loss of reasoning, faculties, and personhood. These are the unpleasant consequences of delirium—a common condition affecting ill older people, particularly those with some degree of dementia. It is characterised by recent onset of fluctuating inattention and confusion, linked to one or more triggering factors. 

 

Delirium is a major burden to healthcare services and has been largely ignored by health service planners and  Moreover, healthcare systems and services often unintentionally stimulate or substantially aggravate the development of delirium in older people.2 This might be understandable if delirium was unavoidable or untreatable, but the existing evidence base for delirium is sufficiently robust for prevention or attenuation of the condition to be a realistic proposition. There is a pressing need to take this action because the outcomes for delirium are poor: it contributes to substantial morbidity and mortality, causes considerable distress to patients and families, and is expensive—an estimated additional $2500 (£1275; €1875) per patient (a $6.9bn annual expenditure for Medicare in 2004).3

We searched Medline and the Cochrane Library from 1996 to 2006. We drew additional material from our personal libraries of delirium references, focusing particularly on systematic reviews.

Delirium is an important problem for all clinical services providing care for older people, particularly emergency departments; general medical, elderly care, surgical, and …

title: Autonomic and Adrenocortical Interactions Predict Mental Health in Late Adolescence: The TRAILS Study
abstract: The present study is informed by the theory of allostatic load to examine how multiple stress responsive biomarkers are related to mental health outcomes. Data are from the TRAILS study, a large prospective population study of 715 Dutch adolescents (50.9 % girls), assessed at 16.3 and 19.1 years. Reactivity measures of the hypothalamic pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) biomarkers (heart rate, HR; respiratory sinus arrhythmia, RSA; and pre-ejection period, PEP) to a social stress task were used to predict concurrent and longitudinal changes in internalizing and externalizing symptoms. Hierarchical linear modeling revealed relatively few single effects for each biomarker with the exception that high HR reactivity predicted concurrent internalizing problems in boys. More interestingly, interactions were found between HPA-axis reactivity and sympathetic and parasympathetic reactivity. Boys with high HPA reactivity and low RSA reactivity had the largest increases in internalizing problems from 16 to 19 years. Youth with low HPA reactivity along with increased ANS activation characterized by both decreases in RSA and decreases in PEP had the most concurrent externalizing problems, consistent with broad theories of hypo-arousal. Youth with high HPA reactivity along with increases in RSA but decreases in PEP also had elevated concurrent externalizing problems, which increased over time, especially within boys. This profile illustrates the utility of examining the parasympathetic and sympathetic components of the ANS which can act in opposition to one another to achieve, overall, stress responsivity. The framework of allostasis and allostatic load is supported in that examination of multiple biomarkers working together in concert was of value in understanding mental health problems concurrently and longitudinally. Findings argue against an additive panel of risk and instead illustrate the dynamic interplay of stress physiology systems.

title: Toll-Like Receptor 4 Promotes Autonomic Dysfunction, Inflammation and Microglia Activation in the Hypothalamic Paraventricular Nucleus: Role of Endoplasmic Reticulum Stress
abstract: Toll-like receptor 4 (TLR4) signaling induces tissue pro-inflammatory cytokine release and endoplasmic reticulum (ER) stress. We examined the role of TLR4 in autonomic dysfunction and the contribution of ER stress. Experimental approach Our study included animals divided in 6 experimental groups: rats treated with saline (i.v., 0.9%), LPS (i.v., 10mg/kg), VIPER (i.v., 0.1 mg/kg), or 4-PBA (i.p., 10 mg/kg). Two other groups were pretreated either with VIPER (TLR4 viral inhibitory peptide) LPS + VIPER (i.v., 0.1 mg/kg) or 4-Phenyl butyric acid (4-PBA) LPS + PBA (i.p., 10 mg/kg). Arterial pressure (AP) and heart rate (HR) were measured in conscious Sprague-Dawley rats. AP, HR variability, as well as baroreflex sensitivity (BrS), was determined after LPS or saline treatment for 2 hours. Immunofluorescence staining for NeuN, Ib1a, TLR4 and GRP78 in the hypothalamic paraventricular nucleus (PVN) was performed. TNF-α, TLR4 and GRP78 protein expression in the PVN were evaluated by western blot. Plasma norepinephrine levels were determined by ELISA.  LPS treatment increased HR and plasma norepinephrine concentration. It also decreased HR variability and high frequency (HF) components of HR variability, as well BrS. Acute LPS treatment increased TLR4 and TNF-α protein expression in the PVN. These hemodynamic and molecular effects were partially abrogated with TLR4 blocker or ER stress inhibitor pretreatment. In addition, immunofluorescence study showed that TLR4 is co-localized with GRP78in the neurons. Further inhibition of TLR4 or ER stress was able to attenuate the LPS-induced microglia activation.  Implications TLR4 signaling promotes autonomic dysfunction, inflammation and microglia activation, through neuronal ER stress, in the PVN.

title: Dorsal Motor Nucleus of Vagus protein aggregates in Lewy Body Disease with autonomic dysfunction
abstract: The Dorsal Motor Nucleus of Vagus (DMV) is degenerated in many patients with early stage Lewy Body Diseases (LBD). Many patients with LBD also develop symptomatic autonomic dysfunction prior to motor and cognitive symptoms. The DMV, along with the Nucleus Ambiguous (NA) and Raphe Obscurus (RO) regulates a variety of autonomic reflexes, suggesting that there may be an association between the degree of neurodegenerative protein aggregation in the DMV and symptomatic autonomic dysfunction in patients with LBD. Using digital in vivo pathology, we quantified alphasynuclein, tau, ubiquitin and Heat Shock Protein 27 (HSP27) containing neurons in the DMV, NA, RO, in addition to the hypoglossal nucleus in 12 LBD patients. , ubiquitin and tau aggregates most greatly affected the DMV followed by the NA, RO, but never the hypoglossal nucleus. There was a positive correlation between DMV alphasynuclein and tau aggregation (p<0.05) and between DMV alphasynuclein and the patients' UPDRS scores (p<0.05) suggesting incremental DMV degeneration with disease progression. However, there was no correlation between DMV alphasynuclein, tau, ubiquitin or HSP27 density and the patient's autonomic dysfunction scores. The specific incremental nature of degeneration in the DMV, suggests that by characterizing region specific molecular mechanisms underpinning DMV as opposed to NA degeneration in LBD, the pathogenesis of the disorder may be better understood. Whether DMV degeneration is causative of symptomatic autonomic dysfunction in LBD remains to be determined.

title: Diagnosis and management of dementia with Lewy bodies
abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

title: Cumulative Anticholinergic Exposure Is Associated with Poor Memory and Executive Function in Older Men
abstract: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men.

title: Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine.
abstract: This article reviews the literature relevant to improving our understanding of the neural underpinnings of delirium. That the characteristic symptoms of delirium occur as a result of a wide diversity of causes supports the concept of a ""final common pathway. " What constitutes this may involve certain brain regions or circuits and certain neurotransmitters. Neuroanatomical data derived from neuroimaging and lesion reports suggest the importance of pathways in prefrontal cortex, thalamus, fusiform cortex, posterior parietal cortex, and basal ganglia. Neurotransmitters most implicated in delirium that could be candidates to mediate the characteristic symptoms of delirium, as well as the electroencephalogram changes, are acetylcholine and dopamine. Acetylcholine deficiency and dopamine excess---absolute and/or relative to each other---appear to be critical in the final common pathway. These neurotransmitters affect each other, depending on the receptor subtype, and their receptor distribution among layers of cortex in areas such as prefrontal cortex and temporal lobe suggests that cholinergic and dopaminergic neurons could interact with each other during delirium. Electroconvulsive therapy is described as a special situation in which excess dopamine and delirium may have a therapeutic effect on depression recovery, in contrast with the usual association of delirium with negative effects.

title: Serum Anticholinergic Activity in Hospitalized Older Persons with Delirium: A Preliminary Study
abstract: To evaluate the relationship between total serum anticholinergic activity (SAA) and the presence or absence of delirium in older hospitalized persons on general medical wards.

title: Importance of Serum Anticholinergic Activity in the Assessment of Elderly Patients with Delirium
abstract: To evaluate the importance of serum anticholinergic activity (SAA) in elderly patients who developed delirium fol lowing hospital admission, we performed a cross-sectional study with consecutively referred inpatients in a university geriatric medical ward. Sixty-one patients aged 66 to 95 years (mean age: 79.2 ± 11.6; 54% females) were recruited. Delirium was assessed by means of the Confusion Assessment Method, SAA determination, questionnaire for cur rent drug treatment, past medical history and clinical examination, and blood chemistries. Patients were divided into two groups according to the absence (N = 49) or the presence (N = 12) of delirium. Delirious patients showed a significantly higher SAA (23.0 vs 3.9 pmol/mL atropine equivalents, P < .004); they were using antibiotics (P < .05), neuroleptics (P < .002), barbiturates (P < .004), and benzodiazepines (P < .005) more frequently. Subjects with delir ium were more likely to have infections and a lower Body Mass Index; they had higher plasma glucose and creatinine. The multivariate analysis identified SAA and use of neuroleptics, and benzodiazepines as the most important fea tures independently associated with delirium. SAA may be a suitable marker for identifying people at risk of developing delirium. Moreover, neuroleptics and benzodiazepines must be carefully used in the elderly because of their relationship with the onset of delirium.

title: Serum anticholinergic activity levels and delirium in the elderly.
abstract: This article will briefly review the clinical studies focusing on measurement of serum levels of anticholinergic activity in delirious states. Three experimental approaches have been taken. First, to identify medications currently prescribed that have subtle anticholinergic effects. The current "list" includes 48 commonly prescribed medications. Second, to associate serum anticholinergic activity with delirium in various clinical states including postcardiotomy delirium, postelectroconvulsive delirium, delirious elderly medical inpatients, and nursing home patients. Third, to intervene in patients with elevated anticholinergic activity by reducing known anticholinergics and correlating this reduction with clinical measures of cognition and delirium. Our most recent data investigate the impact of anticholinergics on demented patients. Prevalence of delirium was significantly higher in patients receiving larger numbers of anticholinergics.

title: Reversal of central anticholinergic syndrome by galanthamine.
abstract: Ten volunteers were given 2 mg scopolamine intravenously (IV) to produce substantial drowsiness and sleepiness. Galanthamine, 0.5 mg/kg IV, effectively reversed the central anticholinergic syndrome produced by scopolamine. Electroencephalographic monitoring of two subjects matched the observed changes of consciousness: scopolamine replaced the dominant awake alpha rhythm with a disorganized, slow, 4- to 6-Hz activity. Galanthamine promptly returned the EEG pattern to the control, awake state. Galanthamine produces effective, safe, and long-lasting reversal of the central anticholinergic syndrome in man.

title: Donepezil Improves Symptoms of Delirium in Dementia: Implications for Future Research
abstract: Delirium is a common complication of dementia and may produce considerable morbidity. In addition to psychotic symptoms such as hallucinations and delusions, delirium may produce considerable agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. The main approach to delirium is to treat any underlying medical problem that could cause the delirium. However, delirium is not always reversible, and there is no specific treatment for persistent delirium. The authors present a case of delirium complicating a preexisting dementia that resolved rapidly following initiation of the cholinesterase inhibitor donepezil, suggesting that cholinergic dysfunction may have played a role in the etiology of this patient's delirium. Future research needs to be directed at the issue of cholinergic activity in delirium through monitoring of serum anticholinergic activity and its response to procholinergic therapy.

title: Challenges in the management of delirium: a case of augmentation with donepezil following inadequate response and adverse effects with risperidone.
abstract: Delirium is a common complication in the course of hospitalization characterized by disturbances of awareness and attention, cognition and psychomotor behavior. Further characteristics include an abrupt onset, fluctuating course, as well as an underlying etiology causing this syndrome (APA 2000). In particular, in the intensive care (ICU) setting delirium is very common and the occurrence reaches up to 80%. The standard management approach includes the elimination and treatment of underlying etiologies, which in many instances cannot be achieved to completeness, supportive interventions such as providing a safe environment, structure, and reorientation, as well as pharmacological interventions such as the administration of antipsychotics in order to manage the symptoms of delirium (Trzepacz et al. 1999). A few years ago, following the paradigm of a final pathway of dopamine-acetylcholine imbalance (Trzepacz 2000) with the contribution of various other neurotransmitters (Maldonado 2008), cholinesterase inhibitors (ChEI) were studied in the management of hypoactive delirium with limited evidence (Moretti et al. 2004, Overshott et al. 2008, Gamberini et al. 2009). This approach has not been followed since then, in part, due to the superior results in management with antipsychotics. However, ChEI merit consideration as an augmentation strategy as illustrated in the following case.