The Locus Coeruleus in Aging and Alzheimer’s Disease: A Postmortem and Brain Imaging Review

The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer’s disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

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Microglia in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200212155234 ◽

2020 ◽

Vol 17 (1) ◽

pp. 29-43 ◽

Cited By ~ 3

Author(s):

Patrick Süß ◽

Johannes C.M. Schlachetzki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Imaging Techniques ◽

Amyloid Β ◽

Disease Stage ◽

Disease Modifying Therapy ◽

Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

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Lower MR-indexed locus coeruleus integrity in autosomal-dominant Alzheimer’s disease is related to cortical tau burden and memory deficits

10.1101/2020.11.16.20232561 ◽

2020 ◽

Author(s):

Martin J. Dahl ◽

Mara Mather ◽

Markus Werkle-Bergner ◽

Briana L. Kennedy ◽

Yuchuan Qiao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Resolution ◽

Locus Coeruleus ◽

Autosomal Dominant ◽

Brain Regions ◽

Cognitive Testing ◽

Autosomal Dominant Alzheimer’S Disease

AbstractAbnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

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https://link.springer.com/article/10.14283/jfa.2020.9

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2020.42 ◽

2020 ◽

pp. 1-2

Author(s):

E.A. Meyers ◽

M.C. Carrillo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Process ◽

Neuronal Loss ◽

Alzheimer’S Dementia ◽

Alzheimer's Dementia ◽

Minimal Impact ◽

Research Framework ◽

Clinical Consequences

Early detection is critical in our fight to stop or slow Alzheimer’s dementia, and even more so to prevent Alzheimer’s disease (AD). Current diagnosis of Alzheimer’s dementia relies largely on documenting mental decline, at which point, severe cognitive and functional damage has occurred. According to the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct (1). The “Framework” is based on research that confirms Alzheimer’s disease pathologic changes in the brain begin 15-20 years before the development of symptoms (2). The neuropathologic hallmarks of AD include: amyloid plaques, neurofibrillary tangles (NFTs), Glial responses, and synaptic and neuronal loss. This approach enables a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people. It is hypothesized that during the preclinical period, 10-15 years prior to severe symptoms where fibrillar brain amyloid increases with minimal impact on cognition, that disease-modifying therapy can be most effective (3).

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The connections of Locus Coeruleus with hypothalamus: potential involvement in Alzheimer’s disease

Journal of Neural Transmission ◽

10.1007/s00702-021-02338-8 ◽

2021 ◽

Author(s):

Filippo Sean Giorgi ◽

Alessandro Galgani ◽

Stefano Puglisi-Allegra ◽

Carla Letizia Busceti ◽

Francesco Fornai

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Locus Coeruleus ◽

Sleep Disturbances ◽

Current Knowledge ◽

Experimental Studies ◽

Brain Structures ◽

Point Of View ◽

Functional Connections ◽

Relevant Role

AbstractThe hypothalamus and Locus Coeruleus (LC) share a variety of functions, as both of them take part in the regulation of the sleep/wake cycle and in the modulation of autonomic and homeostatic activities. Such a functional interplay takes place due to the dense and complex anatomical connections linking the two brain structures. In Alzheimer’s disease (AD), the occurrence of endocrine, autonomic and sleep disturbances have been associated with the disruption of the hypothalamic network; at the same time, in this disease, the occurrence of LC degeneration is receiving growing attention for the potential roles it may have both from a pathophysiological and pathogenetic point of view. In this review, we summarize the current knowledge on the anatomical and functional connections between the LC and hypothalamus, to better understand whether the impairment of the former may be responsible for the pathological involvement of the latter, and whether the disruption of their interplay may concur to the pathophysiology of AD. Although only a few papers specifically explored this topic, intriguingly, some pre-clinical and post-mortem human studies showed that aberrant protein spreading and neuroinflammation may cause hypothalamus degeneration and that these pathological features may be linked to LC impairment. Moreover, experimental studies in rodents showed that LC plays a relevant role in modulating the hypothalamic sleep/wake cycle regulation or neuroendocrine and systemic hormones; in line with this, the degeneration of LC itself may partly explain the occurrence of hypothalamic-related symptoms in AD.

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Imaging and Molecular Mechanisms of Alzheimer’s Disease: A Review

International Journal of Molecular Sciences ◽

10.3390/ijms19123702 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3702 ◽

Cited By ~ 12

Author(s):

Grazia Femminella ◽

Tony Thayanandan ◽

Valeria Calsolaro ◽

Klara Komici ◽

Giuseppe Rengo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multimodal Imaging ◽

Molecular Mechanisms ◽

Imaging Techniques ◽

Structural Mri ◽

Imaging Biomarkers ◽

Significant Burden ◽

Made In

Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice.

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Emerging biology of the cholinergic system across the spectrum of Alzheimer's disease

International Psychogeriatrics ◽

10.1017/s1041610206003991 ◽

2006 ◽

Vol 18 (s1) ◽

pp. S3-S16 ◽

Cited By ~ 7

Author(s):

Agneta Nordberg

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nicotinic Acetylcholine Receptors ◽

Cholinergic System ◽

Imaging Techniques ◽

Positron Emission Tomography Imaging ◽

Amyloid Plaques ◽

Hippocampal Volume ◽

Brain Morphology

The pathological processes that lead to Alzheimer's disease (AD) begin decades before the onset of dementia. Brain abnormalities in genetically susceptible individuals have been observed even in young adults. Patients with AD differ from normal elderly patients in brain morphology and neurochemistry. Important observations include increasing appearance of amyloid plaques and neurofibrillary tangles, progressive loss of hippocampal volume, reduced cerebral glucose utilization, inflammatory processes, glial activation, and impairment of cholinergic function with losses of nicotinic acetylcholine receptors. These changes appear to begin in the asymptomatic stages and continue as cognition and then function and behavior are disrupted. Mild cognitive impairment (MCI) may be the first cognitive manifestation of this pathogenic process moderated by ongoing compensatory neurochemical mechanisms in the cholinergic system. Recent advances in positron emission tomography imaging techniques, including the development of the Pittsburgh B compound (PIB), allow in vivo visualization of amyloid plaques. These techniques have the potential to enable brain amyloid load to be monitored over time and to be related to brain function. Emerging evidence suggests that β-amyloid may interact with nicotinic receptors. This interaction may have clinically significant downstream effects and may mediate amyloid neurotoxicity. The cholinesterase inhibitors may have multiple actions, depending on the stage of the disease, from very mild to severe.

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In vivo testing of the role of Alzheimer’s disease coding variants

Alzheimer s & Dementia ◽

10.1002/alz.043896 ◽

2020 ◽

Vol 16 (S3) ◽

Author(s):

Michael Sasner ◽

Adrian L. Oblak ◽

Dylan Garceau ◽

Kevin P. Kotredes ◽

Christoph Preuss ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

In Vivo Testing ◽

Coding Variants

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Relationship of Wine Consumption with Alzheimer’s Disease

Nutrients ◽

10.3390/nu12010206 ◽

2020 ◽

Vol 12 (1) ◽

pp. 206 ◽

Cited By ~ 3

Author(s):

Reale ◽

Costantini ◽

Jagarlapoodi ◽

Khan ◽

Belwal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Alcohol Intake ◽

Senile Plaques ◽

Neuronal Loss ◽

Language Function ◽

Reduce Risk ◽

Relationship Of ◽

The Relationship

Background: Alzheimer’s disease (AD), the most threatening neurodegenerative disease, is characterized by the loss of memory and language function, an unbalanced perception of space, and other cognitive and physical manifestations. The pathology of AD is characterized by neuronal loss and the extensive distribution of senile plaques and neurofibrillary tangles (NFTs). The role of environment and the diet in AD is being actively studied, and nutrition is one of the main factors playing a prominent role in the prevention of neurodegenerative diseases. In this context, the relationship between dementia and wine use/abuse has received increased research interest, with varying and often conflicting results. Scope and Approach: With this review, we aimed to critically summarize the main relevant studies to clarify the relationship between wine drinking and AD, as well as how frequency and/or amount of drinking may influence the effects. Key Findings and Conclusions: Overall, based on the interpretation of various studies, no definitive results highlight if light to moderate alcohol drinking is detrimental to cognition and dementia, or if alcohol intake could reduce risk of developing AD.

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Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21228767 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8767

Author(s):

Nicole Jacqueline Jensen ◽

Helena Zander Wodschow ◽

Malin Nilsson ◽

Jørgen Rungby

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Brain Metabolism ◽

Ketone Bodies ◽

Current Knowledge ◽

Ketogenic Diets ◽

Cognitive Benefits ◽

The Brain

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

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