What Is the Proposed Neurobiology of Hallucinations and Delusions Across the Dementias?

Hello. Research on the neuroanatomical and neurochemical changes in the brain has been conducted to better understand the neural correlates of psychosis in people with dementia. This presentation is intended to provide insight into the complex, proposed neurobiological basis for the development of psychosis, including hallucinations and delusions, in this population.

I’m Dr. Davangere P. Devanand and I am Professor of Psychiatry and Neurology and Director of Geriatric Psychiatry in the Department of Psychiatry at Columbia University Medical Center, in New York, NY.

Please note that this disease-awareness, non-CME program is intended only for healthcare professionals involved in the management of people with dementia-related hallucinations and delusions. It is sponsored by Acadia Pharmaceuticals Inc., and I’m presenting on behalf of Acadia as a paid consultant. This presentation is not meant to discuss specific treatment options for dementia-related psychosis.

The neurobiology of psychosis—particularly its expression in the context of dementia—is complex and unknown. Three interconnected neurotransmitter systems are thought to be involved: dopamine, glutamate, and serotonin.1,2 Other factors may play a role in psychosis, but for purposes of this presentation, the proposed role of neurotransmitters is the focus.

It is thought that hyperactivity in the dopaminergic mesolimbic pathway leads to hallucinations and delusions.1-15 Glutamate neurons project onto dopaminergic neurons in the ventral tegmental area and, therefore, have the ability to modulate their firing.1-15 However, glutamate neurons have serotonin 2A (5-HT2A) receptors, and it is thought that they are, therefore, themselves modulated by serotonin 5-HT2A receptors.1-15

Brain changes have been associated with symptoms of psychosis in dementia. Neurofibrillary tangles are more dense in people with Alzheimer’s disease who have symptoms of psychosis than those who do not, especially in neocortical areas.16

Hyperphosphorylated tau, another key biomarker of Alzheimer’s disease pathophysiology and progression, has also been found to be elevated in the dorsolateral prefrontal cortex of people with Alzheimer’s disease and psychosis compared to those without psychosis, as measured by mean immunofluorescence intensity.17

Individuals with mild cognitive impairment or early Alzheimer’s disease and psychosis have decreased grey matter in right frontal areas compared with those without psychosis, with the largest cluster of grey matter reduction in the insula.18

Serotonin genetic polymorphisms are related to neurotransmission and neuropsychiatric symptoms in Alzheimer’s disease.19 In one study, the TT 5-HT2A receptor genotype was associated with the Neuropsychiatric Inventory, or NPI, delusions subscore, whereas the CC genotype was associated with protection from delusions.19

The finding of a relationship between delusions and the TT 5-HT2A receptor genotype is particularly relevant, given the established relationship between psychosis in dementia and reduced serotonergic neurotransmission.20 An evaluation of brain tissue from patients with Alzheimer’s disease found that psychosis was associated with a statistically significant reduction in serotonin levels in the prosubiculum, and trends in that direction were observed for all other brain areas examined.20 Psychosis was not associated with significant changes in dopamine levels.20

The serotonin theory of psychosis in dementia, 1 of 3 proposed mechanisms, postulates that as serotonergic projections from the Raphe nucleus to the cortex are lost in dementia, 5-HT2A receptors on cortical glutamate neurons are upregulated as a response.21-24 It is thought that this, and the loss of inhibition from gamma-aminobutyric acid-ergic, or GABA-ergic, interneurons due to N-methyl-D-aspartate, or NMDA, receptor hypofunction, leads to increased glutamatergic neurotransmission in the occipital cortex, which leads to visual hallucinations.25-31 At the same time, it is thought that increased glutamatergic input to the ventral tegmental area increases the activity of dopaminergic neurons originating there, leading to increased dopamine release in the ventral striatum and leading to auditory hallucinations and delusions.32-35

In addition to receptor-level alterations, structural and functional neuroimaging studies have identified changes in brain networks that may contribute to the pathophysiology of hallucinations and delusions in dementia.

In 20 people with Alzheimer’s disease, single-photon emission computed tomography, or SPECT, imaging showed that those with hallucinations and delusions had significantly lower perfusion in left and right prefrontal areas, left striatum, and left parietal cortex.36

In another study using SPECT to evaluate individuals with dementia with Lewy bodies with and without hallucinations, people with hallucinations showed significant hypoperfusion compared to those without hallucinations in the left angular gyrus, left occipital gyrus, right supramarginal gyrus, and right angular gyrus.37

In 26 patients with Parkinson’s disease, those with visual hallucinations had more extensive grey-matter loss, involving limbic, paralimbic, and neocortical areas, compared with those without visual hallucinations who had deterioration only in small clusters of frontal areas and the cerebellum.38

In summary, while the neurobiology of psychosis in dementia is complex and not fully understood, research suggests that dementia-related hallucinations and delusions are not solely triggered by increases in brain dopamine. It is proposed that glutamate and serotonin also play important roles, in particular to decreases in serotonergic neurotransmission. There is also growing evidence that neuroanatomic changes and even genetic polymorphisms, specifically in Alzheimer’s disease dementia, can differentiate between patients who have dementia with and without psychosis.

Thank you for joining me for this presentation.

References

    1. Hirvonen J, Hietala J. Dopamine receptor imaging in schizophrenia: focus on genetic vulnerability. In: Seeman P, Madras B, eds. Imaging of the Human Brain in Health and Disease. San Diego, CA: Elsevier Inc.; 2014:341-360.
    2. Rolland B, Jardri R, Amad A, et al. Pharmacology of hallucinations: several mechanisms for one single symptom? Biomed Res Int. 2014;2014:307106.
    3. Stahl SM. New hope for Alzheimer’s dementia as prospects for disease modification fade: symptomatic treatments for agitation and psychosis. CNS Spectr. 2018;23(5):291-297.
    4. Ballanger B, Strafella AP, van Eimeren T, et al. Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol. 2010;67(4):416-421.
    5. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998;9(17):3897-3902.
    6. Kometer M, Schmidt A, Jancke L, Vollenweider FX. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on alpha oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci. 2013;33(25):10544-10551.
    7. Huot P, Johnston TH, Darr T, et al. Increased 5-HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Mov Disord. 2010;25(10):1399-1408.
    8. Zhou Z, Zhang G, Li X, et al. Loss of phenotype of parvalbumin interneurons in rat prefrontal cortex is involved in antidepressant- and propsychotic-like behaviors following acute and repeated ketamine administration. Mol Neurobiol. 2015;51(2):808-819.
    9. Nakazawa K, Zsiros V, Jiang Z, et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology. 2012;62(3):1574-1583.
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    11. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199-214.
    12. Sesack SR, Pickel VM. Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol. 1992;320(2):145-160.
    13. Karreman M, Moghaddam B. The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem. 1996;66(2):589-598.
    14. Watanabe T, Morimoto K, Nakamura M, Suwaki H. Modification of behavioral responses induced by electrical stimulation of the ventral tegmental area in rats. Behav Brain Res. 1998;93(1-2):119-129.
    15. McKetin R, Baker AL, Dawe S, Voce A, Lubman DI. Differences in the symptom profile of methamphetamine-related psychosis and primary psychotic disorders. Psychiatry Res. 2017;251:349-354.
    16. Farber NB, Rubin EH, Newcomer JW, et al. Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis. Arch Gen Psychiatry. 2000;57(12):1165-1173.
    17. Murray PS, Kirkwood CM, Gray MC, et al. Hyperphosphorylated tau is elevated in Alzheimer’s disease with psychosis. J Alzheimers Dis. 2014;39(4):759-773.
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    22. Huot P, Johnston TH, Darr T, et al. Increased 5HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Movement Disord. 2010;25(10):1399-1408.
    23. Ballanger B, Strafella AP, van Eimeren T, et al. Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol. 2010;67(4):416-421.
    24. Cheng AV, Ferrier IN, Morris CM, et al. Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer’s and Parkinson’s diseases. J Neurol Sci. 1991;106(1):50-55.
    25. Zhou Z, Zhang G, Li X, et al. Loss of phenotype of parvalbumin interneurons in rat prefrontal cortex is involved in antidepressant- and propsychotic-like behaviors following acute and repeated ketamine administration. Mol Neurobiol. 2015;51(2):808-819.
    26. Nakazawa K, Zsiros V, Jiang Z, et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology. 2012;62(3):1574-1583.
    27. Lahti AC, Holcomb HH, Medoff DR, Tamminga CA. Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport. 1995;6(6):869-872.
    28. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199-214.
    29. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998;9(17):3897-3902.
    30. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. New York, NY: Cambridge University Press; 2013.
    31. Kometer M, Schmidt A, Jancke L, Vollenweider FX. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on alpha oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci. 2013;33(25):10544-10551.
    32. Sesack SR, Pickel VM. Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol. 1992;320(2):145-160.
    33. Karreman M, Moghaddam B. The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem. 1996;66(2):589-598.
    34. Watanabe T, Morimoto K, Nakamura M, Suwaki H. Modification of behavioral responses induced by electrical stimulation of the ventral tegmental area in rats. Behav Brain Res. 1998;93(1-2):119-129.
    35. McKetin R, Baker AL, Dawe S, Voce A, Lubman DI. Differences in the symptom profile of methamphetamine-related psychosis and primary psychotic disorders. Psychiatry Res. 2017;251:349-354.
    36. Mega MS, Lee L, Dinov ID, Mishkin F, Toga AW, Cummings JL. Cerebral correlates of psychotic symptoms in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2000;69(2):167-171.
    37. Nagahama Y, Okina T, Suzuki N, Matsuda M. Neural correlates of psychotic symptoms in dementia with Lewy bodies. Brain. 2010;133(pt 2):557-567.
    38. Ibarretxe-Bilbao N, Ramirez-Ruiz B, Junque C, et al. Differential progression of brain atrophy in Parkinson’s disease with and without visual hallucinations. J Neurol Neurosurg Psychiatry. 2010;81(6):650-657.

Faculty

Columbia University Medical Center
New York, NY