Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance

Bjerkén, Sara af; Persson, Rasmus Stenmark; Barkander, Anna; Karalija, Nina; Pelegrina-Hidalgo, Noelia; Gerhardt, Greg A.; Virel, Ana; Strömberg, Ingrid

doi:10.1016/j.neuint.2019.104551

Cited by 15 publications

(7 citation statements)

References 61 publications

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“…In fact, the magnitude of LC neuron loss in de novo PD (Hoehn and Yahr stage 1-2) correlates to the severity of EF impairment [50]. The loss of LC neurons in early stage PD may even contribute in nigrostriatal neuron loss [53,54]. Thus, deficits in EF or decision-making may arise from the loss of LC neurons themselves or the impact of their loss on nigrostriatal neurons early in the disease process.…”

Section: What Neural Areas and Mechanisms Of Pd Are Probed By The Igt?mentioning

confidence: 99%

Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson’s Disease?

Salvatore

Soto

Alphonso

et al. 2021

JPD

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Up to 23% of newly diagnosed, non-demented, Parkinson’s disease (PD) patients experience deficits in executive functioning (EF). In fact, EF deficits may occur up to 39-months prior to the onset of motor decline. Optimal EF requires working memory, attention, cognitive flexibility, and response inhibition underlying appropriate decision-making. The capacity for making strategic decisions requires inhibiting imprudent decisions and are associated with noradrenergic and dopaminergic signaling in prefrontal and orbitofrontal cortex. Catecholaminergic dysfunction and the loss of noradrenergic and dopaminergic cell bodies early in PD progression in the aforementioned cortical areas likely contribute to EF deficits resulting in non-strategic decision-making. Thus, detecting these deficits early in the disease process could help identify a significant portion of individuals with PD pathology (14–60%) before frank motor impairment. A task to evaluate EF in the domain of non-strategic decision-making might be useful to indicate the moderate loss of catecholamines that occurs early in PD pathology prior to motor decline and cognitive impairment. In this review, we focus on the potential utility of the Iowa Gambling Task (IGT) for this purpose, given significant overlap between in loss of dopaminergic and noradrenergic cells bodies in early PD and the deficits in catecholamine function associated with decreased EF. As such, given the loss of catecholamines already well-underway after PD diagnosis, we evaluate the potential utility of the IGT to identify the risk of therapeutic non-compliance and a potential companion approach to detect PD in premotor stages.

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Section: What Neural Areas and Mechanisms Of Pd Are Probed By The Igt?mentioning

confidence: 99%

Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson’s Disease?

Salvatore

Soto

Alphonso

et al. 2021

JPD

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“…This is why non-motoric features may predominate in DLB's prodromal stage. Furthermore, an animal model (Bjerkén et al, 2019) demonstrated that the early degeneration of LC neurons might exacerbate the dopaminergic neuronal loss in the SN and impair its functionality as depicted by striatal dopamine release. In other words, the LC degeneration in DLB might pave the way for later SN degeneration along with worsening psychopathology related to dopaminergic dysfunction.…”

Section: Degeneration Of the Locus Coeruleus In Dementia With Lewy Bomentioning

confidence: 99%

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

Hansen

2021

Front. Aging Neurosci.

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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.

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“…Peripheral administration of the NET blocker atomoxetine also reduced DA damage in a lipopolysaccharide inflammatory rat model of PD (Yssel et al, 2018). Direct noradrenergic damage by the administration of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (or DSP-4) also produces motor deficits and DA cell loss in control rats (Af Bjerkén et al, 2019). In another recent publication, DSP-4 developed motor and nonmotor symptoms in control mice and exacerbated motor disability in mice rendered parkinsonian by the injection of lipopolysaccharide (Song et al, 2019).…”

Section: Noradrenaline Neuroinflammation and Neuroprotectionmentioning

confidence: 99%

“…By contrast, NA deficit accelerates dopaminergic neurodegeneration by promoting inflammation, diminishing neurotrophic factors and promoting oxidation in the SN (Yao et al, 2015;Af Bjerkén et al, 2019). In this sense, a recent publication observed that additional lesion of the LC in animal models of PD promotes enhanced release of interleukins and cytokines, likely due to an incorrect microglial function, and aggravates DA neuron degeneration (Yao et al, 2015) although some authors fails to confirm this cell loss (Iravani et al, 2014).…”

Section: Noradrenaline Neuroinflammation and Neuroprotectionmentioning

confidence: 99%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacologicalbased treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.

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Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance

Cited by 15 publications

References 61 publications

Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson’s Disease?

Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson’s Disease?

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

The Noradrenergic System in Parkinson’s Disease

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