Mitsugu Hachisu

Influence of Anticholinergic Activity in Serum on Clinical Symptoms of Alzheimer's Disease

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.

Adverse effects of anticholinergic activity on cognitive functions in Alzheimer's disease

Background:  Elderly patients with Alzheimers disease (AD) take more medicines, other than those for anti‐dementia agents, than healthy people and are sensitive to anticholinergic medications. There are only a few reports, however, on the relationship between cognitive function and anticholinergic activity in AD patients, which is caused by taking prescribed medication.

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.

Donepezil abolishes anticholinergic activity in a patient with amnesia.

We report the case of a 74-year-old woman who presented with amnesia and positive serum anticholinergic activity (SAA), which disappeared after treatment with the cholinesterase inhibitor donepezil for 1 year. Her only other regular medications were topical glaucoma preparations. We suggest that mental stress, mild cognitive impairment and Alzheimer’s disease pathology combined to generate SAA in this patient. We also consider that SAA may have subsequently become negative because of upregulation of acetylcholine production by donepezil, and because the patient’s other medications and physical condition (including glaucoma) remained unchanged during the 1-year period.

Effects of aging on behavioral symptoms in Alzheimer's disease

Aim:  The aim of the present study was to evaluate the relationship between aging and the behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimers disease (AD).

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.

Reviews: Serum Anticholinergic Activity: A Biomarker for Rapid Progression of Alzheimer's Disease

We have previously reported the possibilities that anticholinergic activity (AA) appeared endogenously in Alzheimer’s disease (AD) and accelerated AD pathology. In this article we reviewed the reasons why AA endogenously appeared in AD and accelerated AD pathology and that the serum anticholinergic activity (SAA) was suitable as one of the biological marker of AD. We argued firstly that an acethycholine (Ach) played a role to maintain an endogenous anti-inflammatory pathway in the brain and the peripheral tissue. Secondarily, the deficiency of Ach in the brain might trigger the inflammatory process in AD patients by way of the suppression of cholinergic anti-inflammatory pathway and AA might be generated by inflammatory process. At third, AA disturbed not only memory functions but also accelerated AD pathology (increasing of amyloidgenic), and at fourth, we proposed a possibility that the SAA was useful as a marker of rapid progression of AD pathology in the moderate stage. SAA was considered to appear at moderate stage of AD when the symptoms rapidly were progress and an inflammation was occurred in the brain. The activities of N-methyl-D-aspartate (NMDA) receptors were accelerated and it progressed an inflammation in the brain. Memantine should be prescribed to AD patients with positive SAA in order to suppress inflammation by antagonizing the NMDA receptor. Therefore, when SAA was detected in AD, it should be considered to prescribe memantine. Finally, we speculated that down regulation of Ach and up regulation of NMDA receptor were involved in the pathology (increasing of amyloid) of AD disease and commented that cholinesterase inhibitors in mild stage and NMDA receptor antagonist in moderate stage in AD should be prescribed to prevent appearance of AA as well as to ameliorate symptoms by way of the up-regulation of Ach and the suppression of inflammation process.

Anticholinergic Activity and Schizophrenia.

In this article, we review the downregulation of acetylcholinergic activity in schizophrenia and discuss the similarity and difference between Alzheimers disease (AD) and schizophrenia in terms of acetylcholine (ACh) and anticholinergic activity (AA); then, we propose the use of cognition-enhancing therapy for schizophrenia. As ACh regulates an inflammatory system, when the cholinergic system is downregulated to a critical level, the inflammatory system is activated. We consider the possibility that AA appears endogenously in AD and accelerates AD pathology. This hypothesis can also be applied to schizophrenia. In fact, even before the onset of the disorder, in the prodromal phase of schizophrenia, cognitive dysfunction exists, and antibodies against astrocyte muscarinic-1 and muscarinic-2 receptors are present in the serum of patients with the paranoid type of schizophrenia. Then we noted that the prodromal phase in schizophrenia might correspond to the mild stage in AD and the acute phase to moderate stage concerning AA. We also think that we should enhance cognition in schizophrenia even in the prodromal phase because as mentioned above, downregulation of ACh is prominent in schizophrenia even in the prodromal phase.

Memantine Abolishes Anticholinergic Activity in Patient with Alzheimer's Disease at Moderate Stage

We already reported that anticholinergic activity (AA) can occur endogenously in patients with Alzheimer’s disease (AD) at moderate stage. Since there is a possibility that AA might accelerate the pathologic changes of AD (amyloid plaques and tau protein), it is important to establish treatment for abolishing AA. We report a 76-year-old man with Alzheimer’s disease (AD) at moderate stage, whose serum anticholinergic activity (SAA) was positive when his memory disturbance, disorientation, apathy and aphasia were worsened. His SAA disappeared after 3 months of treatment with memantine, antidementia agent with N-methyl-D-aspartate (NMDA) receptor antagonist. At the same time his apathy and aphasia were ameliorated. We speculated that down-regulation of acetylcholine (ACh) caused the appearance of clinical symptoms and the hyperactivity of NMDA at moderate stage, that the hyperactivity of NMDA caused the up-regulation of inflammation, which caused AA and that the suppressions not only of the clinical symptoms and but also of the inflammation were thought to be caused by the down-regulation of NMDA receptor by memantine, which caused the ameliorations of some kinds of clinical symptoms and the disappearance of AA. We considered our patient supported previous hypothesis that AA is generated endogenously in AD, SAA was a biological marker for rapid progression of AD and memantine abolished AA in AD in moderate stage.