Acetylcholine blocking agents are commonly prescribed. The elderlies have higher exposure to anticholinergics, and they are more vulnerable to anticholinergic-related ACIs [5] [6] .

In addition, aging is accompanied by a decline in hepatic and renal drugs

>9: definite adverse drug reaction; 5 - 8: probable adverse drug reaction; 1 - 4: possible adverse drug reaction; 0: doubtful adverse drug reaction.

clearance, decrease in central nervous system (CNS) cholinergic activities, and an increase in the blood brain barrier (BBB) drugs permeability [5] [6] . Although studies in rats have shown that tiotropium bromide/olodaterol does not cross the BBB [2] , this has not been evaluated in humans.

Acetylcholine is an important neurotransmitter in the brain. Muscarinic acetylcholine receptor antagonists induce state-dependent ACIs [7] . Anticholinergics have been suggested to disturb neural networks involved in learning and memory, decrease levels of brain phosphatidycholine, and increase the formation of β-amyloid [8] . Boustani et al. developed the Anticholinergic Cognitive Burden (ACB) scale, one of many other cognitive burden assessment scales, as a tool to identify the severity of anticholinergics-related ACIs [5] [6] . The scale ranks anticholinergic activity of medications into four categories, ranging from no anticholinergic activity (=0) to definite/high anticholinergic activity (=3) [5] [6] . Medications with an ACB rating of 1 have an uncertain impact on cognition [5] [6] [9] , while those with an ACB rating of 2 or 3 have established, clinically relevant cognitive anticholinergic effects [5] [9] . There is no gold standard for defining medications with anticholinergic effects, and the ACB does not correlate with medication doses [6] [9] . A study by Rudolph et al. validated that higher ACB scores were associated with increased risk of peripheral and central anticholinergic adverse effects [10] . Anticholinergic activities may not arise exclusively from an individual agent with strong anticholinergic effects [9] [11] . Co-prescribing multiple medications with low ACB scores may result in ACB scores of 3 [9] [11] .

Tiotropium bromide works by inhibiting the action of acetylcholine through muscarinic M3-receptors in bronchial smooth muscles [1] [2] . Each dose (one dose equals two actuations) delivers 5 mcg of tiotropium bromide and 5 mcg of olodaterol [2] . The medicine has a plasma protein binding of 72%, and pharmacokinetics steady state is usually reached by day seven after ongoing therapy [1] [2] . Although it may lead to anticholinergic signs and symptoms at high doses [2] , none were reported following a single inhaled dose of 282 mcg of tiotropium bromide in six healthy volunteers [2] . Although, studies in rats have shown that tiotropium bromide does not cross the BBB [2] , this has not been evaluated in humans.

BBB has tight junctions (TJs) which prevent paracellular transport of compounds into the brain [12] . TJs can be opened under normal conditions to allow the temporary introduction of compounds into the brain, as well as under pathological conditions, for example, after ischemic stroke [12] . Substances cross the BBB by a variety of mechanisms [13] . One example includes drugs that bind to a protein with the conformation of the protein changes while interacting with capillary walls and a drug molecule is freed from the complex into CNS [14] . Another way is that a drug crosses the BBB through permeable capillaries in which dense fenestrated capillaries permit free communications between the brain and blood [15] , or through a leaky BBB that exhibits increased permeability, such as in the case with people who have cerebral amyloid angiopathy (CAA) [12] [16] [17] [18] , or with new openings in TJs like after suffering an ischemic stroke [12] .

1) Tiotropium bromide/olodaterol (Stiolto Respimat) may have entered the CNS, after binding to a protein which facilitates the crossing of the BBB [13] , direct entry may also occur through areas with fenestrated capillaries [15] , leaky BBB secondary to either age-related CAA [5] , or through new openings in TJs of BBB that developed after suffering an ischemic stroke [12] . Although this patient does not have a confirmed diagnosis of CAA, he has diabetes which may contribute to the development of CAA [19] .

2) Being elderly is associated with a reduction in central cholinergic activities (5), and an increased sensitivity to the development of anticholinergic related ACIs [5] . These associations may explain the development of anticholinergic related ACIs, only after three doses/days of initiating treatment and before reaching a steady state.