No 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.

The pharmacokinetics, pharmacodynamics, and safety profile of vornorexant were investigated in healthy Japanese participants in three double‐blind studies: a single ascending dose of 1–30 mg (Study 101; n=6) and multiple ascending doses of 10–30 mg (Study 102; n=6). Study 202 consisted of two steps: an open‐label, 20 mg repeated‐dose in non‐elderly individuals (Step 1; n=12) and a double‐blind, 20 mg repeated‐dose in elderly individuals (Step 2; n=8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500–3.00 h (range) and elimination half‐life of 1.32–3.25 h. The area under the plasma concentration‐time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness‐related pharmacodynamic outcome changes (Karolinska Sleepiness Scale, Digit Symbol Substitution Test, and Psychomotor Vigilance Task) were generally increased with dose increments at 1 and 4 h post‐dose, whereas no consistent dose‐related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC0–inf. Exposure in elderly individuals was generally comparable to that in non‐elderly individuals. Altogether, vornorexant may have a favorable profile for insomnia treatment, including rapid onset of action and minimal next‐day residual effects.

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.

Non-alcoholic fatty liver disease is a growing health problem, and rapid diet assessment is required for personal nutrition education. This pilot study aimed to clarify associations between current food intake patterns identified from the short food frequency questionnaire (FFQ) and metabolic parameters, including liver function. We conducted a cross-sectional study on Japanese non-alcoholic residents of Tokyo and surrounding districts, 20 to 49 years of age. Anthropometric measurements, fasting blood samples, three-day dietary records, and FFQ with 21 items were collected. In all 198 participants, the proportions with obesity were 21% in men and 6% in women. Hypertriglyceridemia was significant only in men, affecting 26%. The traditional Japanese (TJ) pattern (greater intakes of green and yellow vegetables, other vegetables, seaweed/mushrooms/konjac, dairy, fruits, fish, salty, and soybeans/soy products) and the Westernized pattern (greater intakes of saturated-fat-rich foods, oily, egg/fish-eggs/liver, and sweets) were identified. The TJ pattern score showed an inverse relationship with body mass index, triglyceride, alkaline-phosphatase, leucine-aminopeptidase, and fatty liver index. The TJ pattern identified from the short FFQ was suggested to be associated with body fat storage. Further large-scale studies are needed to clarify the associations between this dietary pattern and metabolic parameters, including liver function.