The influence of aging on the methylation status of brain-derived neurotrophic factor gene in blood.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of psychiatric disorders in adults and elderly individuals, and as a result, the DNA methylation (DNAm) of the BDNF gene in peripheral tissues including blood has been extensively examined to develop a useful biomarker for psychiatric disorders. However, studies to date have not previously investigated the effect of age on DNAm of the BDNF gene in blood. In this context, we measured DNAm of 39 CpG units in the CpG island at the promoter of exon I of the BDNF gene. METHODS: We analyzed genomic DNA from peripheral blood of 105 health Japanese women 20 to 80 years of age to identify aging-associated change in DNAm of the BDNF gene. In addition, we examined the relationship between total MMSE scores, numbers of stressful life events, and serum BDNF levels on DNAm of the BDNF gene. The DNAm rate at each CpG unit was measured using a MassArray® system (Agena Bioscience), and serum BDNF levels were measured by ELISA. RESULTS: There was a significant correlation between DNAm and age in 13 CpGs. However, there was no significant correlation between DNAm and total MMSE scores, numbers of life events, or serum BDNF levels. CONCLUSION: Despite the small number of subjects and the inclusion of only female subjects, our results suggest that DNAm of 13 CpGs of the BDNF gene may be an appropriate biomarker for aging and useful for predicting increased susceptibility to age-related psychiatric disorders.

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.

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 Alzheimer's 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.

Pharmacotherapy for Neurocognitive Disorders Based on the Hypothesis of Endogenous Appearance of Anticholinergic Activity.

We previously proposed the hypothesis of endogenous anticholinergic activity (AA) in Alzheimer's disease (AD). According to this hypothesis, the downregulation of acetylcholine seen in AD is associated with upregulation/hyperactivity of N-methyl-D-aspartate receptor (NMDAR). The hyperactivation of NMDAR then induces inflammation, which, in turn, causes AA to appear endogenously. Based on this hypothesis, we commented that cholinesterase inhibitors (ChEIs) are 'preventative' therapy for AD and NMDAR antagonists are the true 'treatment' for AD. We also noted that ChEIs, such as donepezil, could treat delirium. Moreover, we proposed measuring serum anticholinergic activity in patients, particularly AD patients, in out-of-hospital pharmacies to monitor the anticholinergic burden for targeted treatment.

A Review of the Role of Anticholinergic Activity in Lewy Body Disease and Delirium.

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.

Anticholinergic Activity and Schizophrenia.

In this article, we review the downregulation of acetylcholinergic activity in schizophrenia and discuss the similarity and difference between Alzheimer's 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.

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 Alzheimer's disease (AD) patients is characterized by neurodegeneration, especially an acetylcholine (ACh) neuronal deficit with accumulation of ß-amyloid protein, which leads to oxygen stress and inflammation. The active oxygen directly damages the neuron by increasing intracellular Ca(2+). 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.

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 Alzheimer's 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.

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 Alzheimer's 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.

Assessment of Cognitive Dysfunction Caused by Anticholinergic Burden in Japanese Alzheimer's Disease Patients, Using the Most Commonly Used Scales in Japan.

Anticholinergic activity (AA) is generally thought to cause cognitive dysfunction, especially in Alzheimer's disease (AD), one of the neurocognitive disorders related to memory disturbances. Therefore, it is important to evaluate cognitive functions to determine whether they are associated with anticholinergic burden. In Japan, the most frequently used cognitive scale for evaluating cognitive functions is the revised version of Hasegawa's Dementia Rating Scale (HDS-R). However, the relationship between anticholinergic burden and cognitive functions has not been previously examined using the HDS-R. Therefore, here we used the HDS-R to evaluate the relationship between serum anticholinergic activity (SAA) and cognitive functions in 76 patients with AD, 26 of whom had positive SAA [SAA (+)] with a mean of 4.14 ± 2.70 nM. Total scores for orientations to time and place, registration, and recall were significantly lower in the SAA (+) group than in the SAA (-) group (P < 0.05), suggesting potential relationships between SAA and disorientations to time and place in current surroundings as well as memory disturbances. Thus, the disorientations to time and place might explain the clinical features of confusion in current surroundings caused by anticholinergic burden in AD.

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.

[Proposal of endogenous anticholinergic hypothesis in Alzheimer disease].

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.

Effects of beta-hydroxy beta-methyl butyrate calcium combined with exercise therapy in patients with cardiac disease: a study protocol for clinical trial.

INTRODUCTION: The current treatment for heart disease consists of exercise therapy in addition to pharmacotherapy, nutritional support and lifestyle guidance. In general, nutritional support focuses on protein, salt and energy restrictions, with no active protein or amino acid intake in cases involving moderate or higher renal failure. From this perspective, patients with cardiac disease are at high risk of frailty.Beta-hydroxy beta-methyl butyrate (HMB) is a metabolite of leucine. HMB is widely used for muscle strengthening and can be safely ingested even by patients with renal failure. The proposed study protocol will investigate the effects of HMB-calcium (HMB-Ca) administered in combination with comprehensive cardiac rehabilitation for muscle strength, muscle mass and cardiac function in patients with cardiac disease during the convalescent period. The primary outcome will be knee extensor strength. Secondary outcomes will be gross isometric limb strength and skeletal muscle mass. METHODS AND ANALYSIS: This study will be a single-blinded, randomised, controlled trial with parallel comparisons between two groups. The study period will be 60 days from the start of outpatient cardiac rehabilitation. Participants will be randomly divided into two groups: an HMB group consuming HMB-Ca one time per day for 60 days; and a Placebo group consuming reduced maltose once one time per day for 60 days. Exercise therapy will be performed by both groups. ETHICS AND DISSEMINATION: The study protocol will be published in a peer-reviewed journal. Ethics approval was provided by the Showa University Clinical Research Review Board. TRIAL REGISTRATION NUMBER: jRCTs031220139; Japan Registry of Clinical Trails.

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.

[Serum anticholinergic activity: relationship with clinical symptoms in Alzheimer's disease and proposal of new biological marker].

We reviewed the importance of measuring serum anticholinergic activity (SAA) in patients with Alzheimer's disease (AD). Since Tune and Coyle reported a simple method for assessing SAA using radioreceptor-binding assay, SAA is assumed to be the cumulative activity of parent medications and their metabolites and its relationship with delirium and cognitive functions has been debated. However, we evaluated the SAA in AD patients and SAA was correlated with prescription of antipsychotic medications, cognitive dysfunctions, severity of AD and psychotic symptoms, especially, with delusion and diurnal rhythm disturbance. From these results, we should not only pay attention to avoiding the prescription of medications with anticholinergic activity but also we speculated that AA appeared endogenously in AD and accelerated AD pathology. Moreover, there might be the possibility that SAA has predictive value for assessing the progressiveness of AD and as a biological marker for AD.

Higher Serum Brain-Derived Neurotrophic Factor Levels Are Associated With a Lower Risk of Cognitive Decline: A 2-Year Follow Up Study in Community-Dwelling Older Adults.

OBJECTIVE: To assess the relationship of serum brain-derived neurotrophic factor (BDNF) levels with the subsequent short-term decline in cognitive functioning in community-dwelling older adults. DESIGN: Two-year prospective, observational study. SETTING AND PARTICIPANTS: The study included 405 adults aged 65-84 years, initially free of a dementia diagnosis who were living in Tokyo, Japan. METHODS: Participants underwent health assessments at baseline (2011) and follow-up (2013). Serum BDNF levels and scores from the Montreal Cognitive Assessment-Japanese version (MoCA-J) were systematically measured. Logistic regression was used to estimate the odds of cognitive decline between baseline and follow-up assessments in the full MoCA-J scale (operationally defined as a decrease of two or more points), as well as in MoCA-J subscales (decline of one or more points in a specific subscale), as a function of serum BDNF level, adjusting for baseline demographics, prevalent chronic diseases, and baseline cognitive scores. RESULTS: Among individuals who performed worse on the full MoCA-J at baseline (i.e., scores in the bottom quartile [≤21], which is consistent with a mild cognitive impairment status), but not among those who performed better (top 3 quartiles), those with highest baseline serum BDNF levels (top quartile) had lower odds of subsequent decline in the full MoCA-J scale than those with lowest (bottom quartile); i.e., odds ratio (OR): 0.10 (95% confidence interval [CI]: 0.02-0.62; p = 0.013). Regarding MoCA-J subscales, adjusted odds of decline in the executive function subscale, but not in the other five subscales, were substantially low among those with highest baseline serum BDNF levels (top quartile), as compared to those with the lowest (bottom quartile), i.e., OR: 0.27 (95% CI:0.13-0.60; p < 0.001). CONCLUSION AND IMPLICATIONS: Higher serum BDNF levels were associated with a lower risk of decline in cognitive function in a sample of community-dwelling older Japanese adults. Risk varied across cognitive subdomains and according to baseline cognition. This warrants further research to evaluate the added-value of serum BDNF in health promotion initiatives directed toward cognitive decline prevention in community-dwelling older adults.

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

BACKGROUND: Elderly patients with Alzheimer's 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. METHODS: We measured serum anticholinergic activity (SAA) in 76 AD patients referred to a Psychogeriatric Unit and separated them into SAA positive group (n= 26, SAA (+) group) and SAA negative group (n= 50, SAA (-) group). The difference in demographic data and cognitive functions were compared between the two groups. RESULTS AND CONCLUSIONS: The total scores of the Mini-Mental State Examination (MMSE), the score of MMSE domain of registration and recall were significantly lower (P < 0.05) and the Functional Assessment Staging (FAST) score, the number of different kinds of prescribed psychotropic medications (the number of prescribed psychotropic medications) were significantly higher (P < 0.05) in the SAA (+) group than in the SAA (-). These results suggest that a higher number of psychotropic medications prescribed leads to a tendency for SAA to be positive and that anticholinergic activity accelerates Alzheimer's pathology and decreases cognitive function, especially memory in AD patients. We should more prudently prescribe psychotropic medications to AD patients, because the prescribed psychotropic medications are one of the important causes of decline in cognitive function of AD patients by way of anticholinergic activity.

Relationships between serum brain-derived neurotrophic factor concentration and parameters for health scores in community-dwelling older adults.

AIM: Brain-derived neurotrophic factor (BDNF) have been implicated in the progression of neuronal survival, phenotyping differentiation and maintenance of various neurons, as well as neurogenesis. We studied how BDNF affects health parameters of older adults by carrying out a health examination of community-dwelling older adults. METHODS: We measured the serum BDNF concentration of 898 older adults aged 65-84 years who participated in regional health examinations in the Tokyo area and also measured various parameters, such as the thickness of the quadriceps femoris, percentage of body fat, body mass index, grip strength, frequency of walking, and use of sleeping drugs and steroidal anti-inflammatory drugs. RESULTS: We obtained significant relationships between serum BDNF values and thickness of the quadriceps muscle, body mass index or percentage of body fat. Individuals holding onto something when they stood up had lower serum BDNF values than individuals not holding onto something when they stood up. Smokers had higher serum BDNF values than non-smokers. CONCLUSIONS: Older adults who had higher serum BDNF had bigger quadriceps muscles, higher body mass index and higher body fat rate, and were also able to stand up without holding onto something from a sitting position. Geriatr Gerontol Int 2018; 18: 456-461.