Resources and Questions about Agitation in Alzheimer’s Dementia (AAD)
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Questions about Agitation in Alzheimer's Dementia (AAD)
Agitation in Alzheimer’s Dementia (AAD) is a frequent manifestation of Alzheimer’s dementia. The International Psychiatric Association (IPA) defines AAD as the manifestations of disruptive behaviors, including verbal aggression, physical aggression, and/or excessive motor activity.1 AAD is a distinct, separate condition from Alzheimer's dementia. ICD-10 codes are available for Agitation in Alzheimer’s Dementia.
Alzheimer’s dementia-related neuronal loss may be the initial cause of dysfunction in norepinephrine, serotonin, and dopamine (NSD) neurotransmitter systems. An emerging hypothesis suggests that this can lead to an imbalance between top-down executive function and bottom-up emotional drive and cause agitated behavior.2-5
Three key neurotransmitter systems—norepinephrine, serotonin, and dopamine (NSD)—may be implicated in AAD.5,6
Agitation may result when there is dysfunction in the NSD neurotransmitter systems. Norepinephrine system hyperactivity may cause an increase of emotional inputs, while serotonin system deficits could lead to an increase in aggression and impulsivity. Dopamine system dysregulation may affect agitated and aggressive behaviors.5-16
In a normal state, appropriate behavior results when there is balance of top-down executive function and bottom-up emotional drive. The amygdala sends signals to the prefrontal cortex, conveying emotional information. An elevated bottom-up emotional drive and a loss of top-down executive function may lead to agitated behaviors.6,17,18
Alzheimer’s dementia causes neuronal loss that may result in dysfunction in NSD neurotransmitter systems. The loss of balance between top-down executive function and bottom-up emotional drive can lead to agitated behaviors.2-5
AAD, Agitation in Alzheimer’s Dementia; NSD, norepinephrine, serotonin, and dopamine.
References: 1. Cummings J, Mintzer J, Brodaty H, et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr. 2015;27(1):7-17. 2. Hirono N, Mega MS, Dinov ID, Mishkin F, Cummings JL. Left frontotemporal hypoperfusion is associated with aggression in patients with dementia. Arch Neurol. 2000;57(6):861-866. 3. Banno K, Nakaaki S, Sato J, et al. Neural basis of three dimensions of agitated behaviors in patients with Alzheimer disease. Neuropsychiatr Dis Treat. 2014;10:339-348. 4. Lanctôt KL, Herrmann N, Mazzotta P. Role of serotonin in the behavioral and psychological symptoms of dementia. J Neuropsychiatry Clin Neurosci. 2001;13(1):5-21. 5. Wright CI, Dickerson BC, Feczko E, Negeira A, Williams D. A functional magnetic resonance imaging study of amygdala responses to human faces in aging and mild Alzheimer's disease. Biol Psychiatry. 2007;62(12):1388-1395. 6. Rosenberg PB, Nowrangi MA, Lyketsos CG. Neuropsychiatric symptoms in Alzheimer's disease: What might be associated brain circuits? Mol Aspects Med. 2015;43-44:25-37. 7. Theofilas P, Ehrenberg AJ, Dunlop S, et al. Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 2017;13(3):236-246. 8. Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Raskind MA. Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: Evidence of compensatory changes. Neuroscience. 2007;146(1):471-480. 9. Gulyás B, Brockschnieder D, Nag S, et al. The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: A post-mortem autoradiographic study. Neurochem Int. 2010;56(6-7):789-798. 10. Jacobs HIL, Riphagen JM, Ramakers IHGB, Verhey FRJ. Alzheimer's disease pathology: Pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms. Mol Psychiatry. 2021;26(3):897-906. 11. Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M, et al. Cholinergic–serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease. Neuropsychologia. 2005;43(3):442-449. 12. Vermeiren Y, Van Dam D, Aerts T, Engelborghs S, De Deyn PP. Monoaminergic neurotransmitter alterations in postmortem brain regions of depressed and aggressive patients with Alzheimer's disease. Neurobiol Aging. 2014;35(12):2691-2700. 13. Lindenmayer JP. The pathophysiology of agitation. J Clin Psychiatry. 2000;61 Suppl 14:5-10. 14. Sala A, Caminiti SP, Presotto L, et al. In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer's disease phases. Alzheimers Res Ther. 2021;13(1):187. 15. Cox SML, Benkelfat C, Dagher A, et al. Effects of lowered serotonin transmission on cocaine-induced striatal dopamine response: PET [¹¹C]raclopride study in humans. Br J Psychiatry. 2011;199(5):391-397. 16. Arai H, Kosaka K, Iizuka R. Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimer-type dementia. J Neurochem. 1984;43(2):388-393. 17. Arnsten AFT, Raskind MA, Taylor FB, Connor DF. The effects of stress exposure on prefrontal cortex: Translating basic research into successful treatments for post-traumatic stress disorder. Neurobiol Stress. 2015;1:89-99. 18. Carrarini C, Russo M, Dono F, et al. Agitation and dementia: Prevention and treatment strategies in acute and chronic conditions. Front Neurol. 2021;12:644317.