Locus Coeruleus Malfunction Is Linked to Psychopathology in Prodromal Dementia With Lewy Bodies

Abstract

Background: The locus coeruleus (LC) is a nucleus in the human brainstem with a variety of noradrenaline-driven functions involved in cognition, emotions, and perception. Dementia with Lewy bodies (DLB) constitutes a neurodegenerative disease involving deposits of alpha-synuclein, first appearing in the brainstem. The goal of this narrative review is to delineate the relationship between the expression of psychiatric symptoms as an early-onset of DLB and the degeneration of the LC's noradrenaline system.Methods: We searched in PubMed for relevant articles concerning LC degeneration and psychiatric symptoms in prodromal DLB in this narrative review. We rely on the McKeith criteria for prodromal psychiatric DLB.Results: We found four studies that document neuronal loss, deposits of Lewy bodies and other hints for neurodegeneration in the LC in patients with DLB. Furthermore, we reviewed theories and studies on how the degenerated noradrenaline LC system contributes to psychiatric DLB's phenotype. We hypothesized how anxiety, hallucinations, delusions, and depressive symptoms might occur in DLB patients due to degenerated noradrenergic neurons entailing consecutive altered noradrenergic transmission in the LC's projection areas.Conclusions: LC degeneration in prodromal DLB might cause psychiatric symptoms as the first and non-motor manifestation of DLB, as the LC is affected earlier by degeneration than are dopaminergic structures such as the substantia nigra, which are impaired later in the disease course.

Delirium-Onset of Prodromal Dementia With Lewy Bodies—Putative Brainstem-Related Pathomechanism and Clinical Relevance

“…The presence of Lewy bodies pathologically reveals the presence of protein alpha synuclein (Burré et al, 2018). The absence of Lewy bodies in the SN could be attributable to initial Lewy body deposited in another brainstem location prior to SN deposition of Lewy bodies, i.e., in the locus coeruleus (LC), as reported recently in a recent review (Hansen, 2021). However, the Lewy body pathology in the LC and SN is one of the potentially diverse patterns of the various anatomical pathways affected early in Lewy body disease (Spotorno et al, 2020;Borghammer et al, 2021) such as an affected olfactory bulb, amygdala with possible olfactory bulb involvement, brainstem with possible amygdala or olfactory bulb contribution, the limbic system (possible olfactory bulb, amygdala and brainstem contribution) and the neocortical pattern with potential involvement of all other aforementioned predilection sites (Attems et al, 2021).…”

Neural basis of impaired narrative discourse comprehension in prodromal and mild dementia with lewy bodies

“…Another limit of our study is that we did not exclude patients with a psychiatric onset of prodromal DLB, even though all of our prodromal DLB patients had MCI. It is of relevance, as the affection of nigrostriatal pathways in either conditions (cognitive or psychiatric onset) can be different ( Hansen et al, 2021 ), possibly in relation with a malfunction of the locus coeruleus ( Hansen, 2021 ) in psychiatric onset patients. Since the locus coeruleus modulates executive functions through the noradrenergic system, and psychiatric symptoms are frequent at the prodromal stage of DLB ( Blanc et al, 2022 ), future studies should explore potential implications of the type of onset of DLB (that is, cognitive, psychiatric or mixed) in this matter.…”

Current Nosology of Neural Autoantibody-Associated Dementia

“…It is worthwhile investigating whether a psychiatric-onset or MCI-onset of DLB reveals more MOG or MBP autoantibodies than controls to seek novel early biomarkers of DLB. In addition, we are interested to see whether MOG autoantibodies can be detected in those patients suffering from degeneration of the locus coeruleus (LC), as it is the structure that degenerates very early in DLB; some researchers have hypothesized that LC dysfunction might cause the psychiatric phenotype of prodromal DLB ( Hansen, 2021 ). LC degeneration can be detected via neuromelanin-sensitive MR-imaging.…”