Misa Hosoi

Serum Anticholinergic Activity: A Possible Peripheral Marker of the Anticholinergic Burden in the Central Nervous System in Alzheimer’s Disease

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 Alzheimers 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.

Beyond the Hypothesis of Serum Anticholinergic Activity in Alzheimer's Disease: Acetylcholine Neuronal Activity Modulates Brain-Derived Neurotrophic Factor Production and Inflammation in the Brain

The brain of Alzheimers disease (AD) patients is characterized by neurodegeneration, especially an acetylcholine (ACh) neuronal deficit with accumulation of β-amyloid protein, which leads to oxygen stress and inflammation. The active oxygen directly damages the neuron by increasing intracellular Ca2+. The inflammation is due to activation of the microglia, thereby producing cytokines which inhibit the production of brain-derived neurotrophic factor (BDNF). As the BDNF acts by neuronal protection, synaptogenesis and neurogenesis, the reduction of BDNF in the brain of AD patients worsens the symptoms of AD. On the other hand, treatment of AD patients with a cholinesterase inhibitor enhances ACh activity and inhibits inflammation. Then the expression of BDNF is restored and neuroprotection reestablished. However, there are several reports which showed controversial results concerning the relationship between BDNF and AD. We speculate that BDNF is related to some neurocognitive process and reflects neuronal activity in other neurodegenerative and neuropsychiatric disorders and that in the mild cognitive impairment stage, BDNF and choline acetyltransferase (ChAT) activities are hyperactivated because of a compensatory mechanism of AD pathology. In contrast, in the mild stage of AD, BDNF and ChAT activity are downregulated.

Hypothesis of Endogenous Anticholinergic Activity in Alzheimer's Disease.

In this article, we review and repropose our hypothesis of the endogenous appearance of anticholinergic activity (AA) in Alzheimers disease (AD). First, we introduce our previous articles and speculate that, because acetylcholine (ACh) regulates both cognitive function and inflammation, downregulation of this neurotransmitter causes upregulation of the inflammatory system. AA then appears endogenously with the production of cytokines and the downregulation of ACh in AD. To support our hypothesis, we present a female AD patient whose AA was considered to occur endogenously through her AD pathology. Her serum anticholinergic activity (SAA) was positive at her first visit to our memory clinic, was negative at the 1-year and 2-year follow-up visits, and had become positive again by 3 years. We speculate that the initial positive SAA was related to her AD pathology plus mental stress, and that her SAA at 3 years was related to her AD pathology only. Consequently, we believe that 2 patterns of SAA positivity (and therefore AA) exist. One occurs when the downregulation of ACh reaches a critical level, and the other occurs with the addition of some other factor such as medication, induced illness or mental stress that causes AA to affect AD pathology. Finally, we consider the pharmacotherapy of AD based on the proposed hypothesis and conclude that cholinesterase inhibitors can be used to prevent rapid disease progression, whereas N-methyl-D-aspartate receptor antagonists should be reserved for the treatment of AD that is already in a stage of rapid progression. We also propose a staging schema for patients with AD.

Escitalopram for Delusion in an Oldest Old Patient with Alzheimer's Disease

Objective: To present a case of Alzheimer’s disease (AD) associated with delusions that were satisfactorily treated with escitalopram. Background: In Japan, there are currently no licensed medicines for the management of the behavioral and psychological symptoms of dementia (BPSD) in AD patients. Patient and Results: We present the case of an 88-year-old woman with AD who developed delusions that were successfully treated with escitalopram. We previously reported that anxiety in elderly AD patients was associated with delusions and hallucinations and was caused by disturbance of the serotonergic system. Therefore, we considered that enhancement of the serotonergic system may be useful for ameliorating delusion in the present AD patient. Escitalopram inhibits the reuptake of serotonin and experts allosteric potentiating actions on serotonin reuptake inhibitors, moreover, it has evidence of efficacy for treating affective symptoms in the old patients. Therefore, this agent may be useful for ameliorating serotonin deficiency and delusion in the oldest old AD patients. Conclusions: Escitalopram may be useful for the management of psychotic symptoms in relatively older patients with AD.

Demonstrating the Role of Anticholinergic Activity in a Mood Disorder

We report a case of a 54-year-old woman presenting with amnesia, apathy, work-related difficulties and mental stress. At presentation, her Mini-Mental State Examination score was 27 and her serum anticholinergic activity (SAA) was positive without medication or recent physical illnesses. In addition, magnetic resonance imaging revealed mild atrophy of the frontal and temporal lobes, with a relatively intact hippocampus. Consequently, we diagnosed mild cognitive impairment due to Alzheimers disease and prescribed a cholinesterase inhibitor (donepezil, 10 mg/day); her SAA fully disappeared and clinical symptoms partially resolved. Addition of duloxetine coupled with environmental adjustments caused her cognitive function to return to a normal level, so we diagnosed pseudodementia due to depression. In this case, we believe that the simultaneous cholinergic burden and mental stress led to positive SAA, which made it reasonable to prescribe a cholinesterase inhibitor to ameliorate the associated acetylcholine hypoactivity. We believe that it is essential to recognize the importance of prescribing a cholinesterase inhibitor for specific patients, even those with pseudodementia, to control their clinical symptoms. Moreover, SAA might be a useful biomarker for identifying this subgroup of patients. We propose that anticholinergic activity appears endogenously in mood disorders (depression and bipolar disorder) and set out our rationalization for this hypothesis.

Rivastigimine for Relatively Younger Alzheimer's Disease Patient

We presented the patient with relative younger Alzheimer’s disease (AD) whose clinical symptoms and cognitive functions were responsive not to donepezil but to rivastigmine. Age of initial visit our memory clinic of this patient was relatively younger. It is considered that in relative older patient both AD pathology and aging cause cognitive dysfunctions. However, in relative younger patient not aging but only AD pathology causes cognitive dysfunctions. Therefore, AD pathology was thought to be more pronounced in our patient than relatively older patients with same cognitive disturbances. In AD, glia cells and amyloids proliferate and nervous cells shrink. Butyrylcholinesterase (BuChE) exists in glia cells and amyloids. Therefore, when AD progresses, acetylcholinesterase (AChE) decreases and BuChE increases. Accordingly the ratio of BuChE/AChE increases. Therefore, when at mild stage such our patient, not donepezil but rivastigmine which has inhibiting actions on both AChE and BuChE was suitable.

Serum Anticholinergic Activity as an Index of Anticholinergic Activity Load in Alzheimer's Disease

We reported a procedure of serum anticholinergic activity (SAA) measurement and the reliability and reproducibility of the receptor binding assay, and we also described the usefulness of SAA measurement reflecting the anticholinergic activity (AA) in the central nervous system (CNS). According to the results of a 10 times repeated measurement of standard atropine binding, the relative error was between -5.5 and +3.7%, and we considered that measurement of SAA in our studies is accurate and validated. Downregulation of acetylcholine activates inflammation in both CNS and peripheral tissue, which causes AA in both sites. Therefore, changes of AA in the CNS link with SAA in the peripheral system even if a substance having AA does not penetrate through the blood-brain barrier. Then we redescribe issues that require attention in the measurement of SAA. It is generally defined that any SAA greater than the detection limit of a quantitative atropine equivalent level (≥1.95 nM in our study) is positive. According to previous studies, SAA is considered to be positive when its atropine equivalent is ≥1.95 nM and undetectable when this is <1.95 nM. Nevertheless, as a low SAA can act as AA in the CNS, we should assume that SAA might also be positive if its marker concentration is between 0 and 1.95 nM. In addition, SAA should be measured around 11 a.m. or somewhat later because of the diurnal rhythm of cortisol in humans.

Plasma Cholinesterase Activity in Alzheimer's Disease

Cholinesterase inhibitors (ChEIs) are not allowed to be prescribed in combination, which means that we need to select 1 of 3 ChEIs for use in a patient with Alzheimers disease (AD). However, there is no quantitative analysis on the differences between these agents. In this article, we propose that plasma cholinesterase activity (pChE) could be used as the standard for differentiating between rivastigmine (Riv) and donepezil (Don) in the management of AD. To date, we have treated 6 patients with Riv 18 mg and 5 patients with Don 5 mg. The pChE is related to low-grade inflammation associated with AD, diabetes mellitus and lipid metabolic dysfunction. Moreover, low pChE is related to liver dysfunction. The pChE must be kept under control. We speculated that Riv is the most appropriate therapy for patients with relatively high pChE, whereas Don is best reserved for those AD patients with relatively low pChE.

Case Report: High-Sensitivity C-Reactive Protein is a Potentially Useful Marker of the Need for Psychotic Treatment for Cognitive Dysfunction Related to Low-Grade Inflammation

We encountered a 79 year old female patient with mild cognitive impairment who showed sustained improvement to an almost normal level of global cognitive function for >1 year when treated with donepezil. Her levels of high-sensitivity C-reactive protein (hs-CRP) also showed a sustained decrease with treatment. Here, we describe the clinical changes in her cognition and discuss the relationship between cognitive function and low-grade inflammation, focusing on three important issues. First, cognitive dysfunction may be related to low-grade inflammation. Second, hs-CRP may be a suitable marker for this low-grade inflammation. Third, treatment with cholinesterase inhibitors was effective, either by suppressing this low-grade inflammation or by upregulating acetylcholine, which suppresses such inflammation. In this patient, inflammation appeared to be related to the cholinergic anti-inflammatory pathway.

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 Alzheimers 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.