Locus coeruleus in memory formation and Alzheimer's disease

James, Tony D.; Kula, Bartosz; Choi, Seowon; Khan, Shahzad S.; Bekar, Lane K.; Smith, Nathan A.

doi:10.1111/ejn.15045

Cited by 34 publications

(27 citation statements)

References 138 publications

(174 reference statements)

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“…This supports a previously theorized buffering role of the LC, due to its high lifetime noradrenergic turnover and neuronal density, in protecting against the detrimental effects of accumulating AD-related pathology (Clewett et al 2015;Robertson 2013). Although the exact role of brainstem degeneration in cognitive dysfunction is not wellunderstood, degeneration of the LC appears to be related to cognitive function in normal aging (Dahl et al 2019;Langley et al 2020) and correlates with cognitive abilities and pathological protein accumulation in animal models of AD (Chalermpalanupap et al 2017;James et al 2020;Kelberman et al 2020). Of note, we found attenuated brainbehavior relationships in the biomarker-confirmed MCI due to AD group compared to the overall MCI group, likely due to the smaller sample size.…”

Section: Discussionsupporting

confidence: 82%

Brainstem substructures and cognition in prodromal Alzheimer’s disease

Dutt

Mather

et al. 2021

Brain Imaging and Behavior

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Neuropathological research suggests the tau pathology of Alzheimer’s disease may originate in brainstem nuclei, yet it remains unknown whether tau-mediated degeneration of brainstem nuclei influences cognitive impairment in prodromal Alzheimer’s disease. The present study examined cognitive domains impacted in prodromal Alzheimer’s disease and brainstem substructure volume in cognitively normal older adults (n = 814) and those with mild cognitive impairment (n = 542). Subsamples of cognitively normal (n = 112) and mild cognitive impairment (n = 202) also had cerebrospinal fluid Alzheimer’s disease biomarker characterization. Region-of-interest and voxel-level analyses related whole brainstem, midbrain, pons, and locus coeruleus volumes to cognition with multiple linear regression models corrected for age, sex, education, apolipoprotein-ε4 carrier status, and MRI magnet strength. Within mild cognitive impairment participants, smaller midbrain and locus coeruleus volumes were significantly related to poorer performance on tests of attention and executive function, and the relationship between locus coeruleus volume and executive abilities remained significant in the mild cognitive impairment subsample with biomarker-confirmed Alzheimer’s disease. A brainstem-masked voxel-wise regression further demonstrated an association between locus coeruleus volume and executive abilities. Brainstem volumes were not significantly related to memory processes. Study findings implicate midbrain and locus coeruleus volume in attention and executive deficits in mild cognitive impairment. Together with prior neuropathological studies, our data suggest a link between Alzheimer’s disease-related degeneration of brainstem nuclei and cognitive deficits in prodromal Alzheimer’s disease.

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Section: Discussionsupporting

confidence: 82%

Brainstem substructures and cognition in prodromal Alzheimer’s disease

Dutt

Mather

et al. 2021

Brain Imaging and Behavior

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“…There is evidence from neuroimaging studies in AD patients that LC degeneration affects functional connectivity between memoryrelevant structures such as the parahippocampus and the LC (Jacobs et al, 2015) leading to memory dysfunction. It is hypothesized that memory functions are impaired in patients with AD due to LC degeneration entailing consecutive dysfunction of cellular correlates of long-term memory formation (James et al, 2020). Animal models have revealed the LC's relevant role in hippocampal long-term plasticity in different hippocampal subregions such as the dentate gyrus and CA1 region (Lemon et al, 2009;Hansen and Manahan-Vaughan, 2015a,b).…”

Section: Noradrenergic Mechanisms Inducing Psychiatric Symptoms In Prmentioning

confidence: 99%

“…The locus coeruleus (LC) is the small, bilaterally shaped structure in the brainstem located in the pons that contributes to cognitive functions (Berridge and Waterhouse, 2003;Sara and Bouret, 2012;Grueschow et al, 2020;James et al, 2020;Poe et al, 2020). The LC is the main location of a highly flexible, adaptable noradrenergic system projecting in many cortical and subcortical brain regions, thus explaining its highly relevant function in humans in everyday life, and essential for us humans as feeling and thinking beings.…”

Section: Introductionmentioning

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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“…The locus coeruleus, which provides NE input to widespread regions of the brain, has repeatedly been shown to degenerate in AD [48], suggesting a noradrenergic deficit in this disorder. A previous publication has suggested, however, that elevated noradrenergic signaling may in some cases be an etiological factor in AD [11], and more recent papers have also suggested that synaptic NE may be elevated or at least not diminished in spite of degeneration of the locus coeruleus, especially in early stages of the disease [4,5,12].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer’s Disease

Fitzgerald

2021

IJMS

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While much of biomedical research since the middle of the twentieth century has focused on molecular pathways inside the cell, there is increasing evidence that extracellular signaling pathways are also critically important in health and disease. The neuromodulators norepinephrine (NE), serotonin (5-hydroxytryptamine, 5HT), dopamine (DA), acetylcholine (ACH), and melatonin (MT) are extracellular signaling molecules that are distributed throughout the brain and modulate many disease processes. The effects of these five neuromodulators on Alzheimer’s disease (AD) are briefly examined in this paper, and it is hypothesized that each of the five molecules has a u-shaped (or Janus-faced) dose-response curve, wherein too little or too much signaling is pathological in AD and possibly other diseases. In particular it is suggested that NE is largely functionally opposed to 5HT, ACH, MT, and possibly DA in AD. In this scenario, physiological “balance” between the noradrenergic tone and that of the other three or four modulators is most healthy. If NE is largely functionally opposed to other prominent neuromodulators in AD, this may suggest novel combinations of pharmacological agents to counteract this disease. It is also suggested that the majority of cases of AD and possibly other diseases involve an excess of noradrenergic tone and a collective deficit of the other four modulators.

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Locus coeruleus in memory formation and Alzheimer's disease

Cited by 34 publications

References 138 publications

Brainstem substructures and cognition in prodromal Alzheimer’s disease

Brainstem substructures and cognition in prodromal Alzheimer’s disease

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

Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer’s Disease

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