A case-control study of the locus coeruleus degeneration in Alzheimer's disease

doi:10.1016/j.euroneuro.2020.12.013

European Neuropsychopharmacology

Volume 43, February 2021, Pages 153-159

https://doi.org/10.1016/j.euroneuro.2020.12.013 Get rights and content

Highlights

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The individually-matched case-control study of LC degeneration in AD.
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A neuromelanin-sensitive MRI adopted to visualize LC degeneration.
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A significant 22% LC attenuation detected in AD patients compared with controls.
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No significant association between LC degeneration and peripheral inflammation.
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AD patients may benefit from treatment targeting noradrenergic dysfunction.

Abstract

The locus coeruleus (LC) is the major source of noradrenaline, which plays a key role in cognition. We aimed to detect the extent of the LC signal attenuation in Alzheimer's disease (AD) patients using a neuromelanin (NM)-sensitive MRI and how it may correlate with inflammatory and autonomic measures. An individually matched case-control study design was employed. 24 patients with AD and 24 age and gender matched controls with no cognitive impairment were recruited. The primary outcome measure was the LC signal intensity indicated by the LC contrast ratio (CR) and measured by the NM-sensitive MRI. Secondary outcome measures included neuropsychometric tests of cognitive state, peripheral inflammatory and autonomic measures. Conditional logistic regression analysis revealed a significant 22% LC-CR reduction in the AD group compared with the control group. However, there was no statistical significance from inflammatory or autonomic measures. This is the largest individually-matched case-control study to visualise the LC degeneration in AD patients. The study revealed significant LC degeneration which holds promise to stratify patients who may benefit from treatment targeting noradrenergic dysfunction.

Introduction

The locus coeruleus (LC) is a bilateral nucleus located in the dorsal pontine tegmentum (PT) and is the major source of noradrenaline (NA), a neuromodulator that plays a key role in cognition. While cognitive decline in Alzheimer disease (AD) has primarily been related to dysfunction within the cholinergic system in the nucleus basalis, there is considerable research evidence indicating extensive LC degeneration in AD (Zarow et al., 2003; Lyness et al., 2003), with some suggesting that it is among the earliest pathologies (Braak and Del Tredici 2011, 2012). Therefore, the early vulnerability of the LC to AD is of considerable clinical significance (Betts et al., 2019a), as this raises the possibility that changes of the LC activity may provide early detection markers for diagnosis as well as early intervention targets to delay AD progression. However, the contribution of LC degeneration to cognitive decline in the development of AD has been underappreciated due to methodological difficulties, with most evidence coming from animal and post-mortem studies. The absence of reliable non-invasive direct measures of the LC remains the biggest challenge.

Recent research indicates that LC visibility is driven by neuromelanin content of noradrenergic neurons and the intrinsic neuromelanin (NM)-sensitive MRI technique enables direct visualisation of the LC (Sasaki et al., 2006; Shibata et al., 2006; Keren et al., 2009; Betts et al., 2017; Priovoulos et al., 2018; Trujillo et al., 2019). In addition, experimental lesions of the LC in animal models of AD lead to increased inflammation and Aβ plaque burden (Heneka et al., 2010), but this association has not been examined in AD patients. It is also well recognised that the LC plays an important role in controlling autonomic function and sleep/arousal (Hou et al., 2006; Samuels et al. 2008). Therefore, the primary aim of the study was to detect the extent of the LC signal attenuation in AD using the NM-sensitive MRI technique. The secondary aim was to examine how the LC signal attenuation may be linked to cognitive, peripheral inflammatory and autonomic measures.

Section snippets

Participants

24 patients who met the NINCDS-ADRDA criteria for probable AD were recruited from the Memory Assessment and Research Centre at Southampton Moorgreen Hospital. 24 age (within 1-year difference) and gender matched controls with no cognitive impairment were recruited from the Older Adult Volunteer database and individually matched to AD patients. Participants with any medical condition or taking any medication which might potentially affect the LC-NA pathway were excluded.

Study design and procedure

A cross-sectional and

Demographic, cognitive, and biological characteristics of study participants

24 AD participants (aged between 58 and 82) were recruited, but two were excluded due to poor quality MRI scans. Therefore, data from 11 mild AD (scoring 21–25 on the SMMSE) and 11 moderate AD (scoring 10–20) and 22 age and gender matched controls were entered into final analysis. Among 22 AD patients, 11 patients reported shorter memory problem and 11 patients reported longer memory problem using 3 years as a cut-off point. More descriptive data are shown in Table 1.

Comparison of the lc contrast ratio (LC-CR) between groups

MRI brain imaging scans

Discussion

The current study successfully adopted a NM-sensitive MRI imaging technique to directly visualise the LC degeneration in AD patients which provides strong support for the use of this LC imaging technique in future AD research. The study reveals a significant 22% LC signal attenuation in AD patients compared with matched controls, along with significant associations between LC-CR and cognitive measures. These findings have important implications for future work into the role of the LC as

Conclusions

This study is the first individually-matched case-control study to visualise the LC in AD patients adopting a neuromelanin-sensitive imaging protocol. The study revealed a significant LC signal attenuation in AD measured by the NM-sensitive MRI. Significant efforts were taken to achieve an optimally-matched study population, pairing highly compatible datasets between case and controls. This, alongside the specialised statistical analytical approach, allowed valid comparisons to be made. The

Author contributions

Hou and Beardmore had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Hou, Holmes, Darekar. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Hou. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Hou, Osmond. Obtained funding: Hou. Supervision: Hou, Holmes, Darekar.

Acknowledgement

We would like to thank Laurie Lau from Clinical and Experimental sciences for his help with blood sample analysis, and Chris Everitt, Emma Lewis, James Leighs and Neil O'Brien from the Radiology and Medical Physics departments respectively, for their help with the imaging data collection and processing. Also authors would like to thank all participants for their effort and time for taking part this study.

Declaration of Competing Interest

All authors declare that there is no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence, or be perceived to influence, their work.

Funding/Support

The study was funded by a grant awarded to Dr Ruihua Hou by Alzheimer's Research UK (grant reference: ARUK-PPG2016A-6).

Role of the Funder/Sponsor

The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Lower fractional dimension in Alzheimer's disease correlates with reduced locus coeruleus signal intensity
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This study aimed to determine the pattern of fractional dimension (FD) in Alzheimer's disease (AD) patients, and investigate the relationship between FD and the locus coeruleus (LC) signal intensity.A total of 27 patients with AD and 25 healthy controls (HC) were collected to estimate the pattern of fractional dimension (FD) and cortical thickness (CT) using the Computational Anatomy Toolbox (CAT12), and statistically analyze between groups on a vertex level using statistical parametric mapping 12. In addition, they were examined by neuromelanin sensitive MRI(NM-MRI) technique to calculate the locus coeruleus signal contrast ratios (LC-CRs). Additionally, correlations between the pattern of FD and LC-CRs were further examined.Compared to HC, AD patients showed widespread lower CT and FD Furthermore, significant positive correlation was found between local fractional dimension (LFD) of the left rostral middle frontal cortex and LC-CRs. Results suggest lower cortical LFD is associated with LCCRs that may reflect a reduction due to broader neurodegenerative processes. This finding may highlight the potential utility for advanced measures of cortical complexity in assessing brain health and early identification of neurodegenerative processes.
State-of-the-art imaging of neuromodulatory subcortical systems in aging and Alzheimer's disease: Challenges and opportunities
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Citation Excerpt :
However, several other studies were not able to detect a relationship between age and LC integrity (Betts et al., 2017; Maki-Marttunen and Espeseth, 2021; Ye et al., 2021), which may be due to sample size or selection biases towards very healthy individuals, as a negative age-association in older individuals may be explained by the presence of initial AD pathology (Jacobs et al., 2021a). Initial studies with smaller sample sizes demonstrated that LC integrity is lower in AD patients (Betts et al., 2019a; Hou et al., 2021; Olivieri et al., 2019; Takahashi et al., 2015) and MCI patients (Dordevic et al., 2017) relative to healthy older individuals. In the majority of these studies, AD was based on clinical parameters and not on underlying AD pathologic change biomarkers.
Primary prevention trials have shifted their focus to the earliest stages of Alzheimer’s disease (AD). Autopsy data indicates that the neuromodulatory subcortical systems’ (NSS) nuclei are specifically vulnerable to initial tau pathology, indicating that these nuclei hold great promise for early detection of AD in the context of the aging brain. The increasing availability of new imaging methods, ultra-high field scanners, new radioligands, and routine deep brain stimulation implants has led to a growing number of NSS neuroimaging studies on aging and neurodegeneration. Here, we review findings of current state-of-the-art imaging studies assessing the structure, function, and molecular changes of these nuclei during aging and AD. Furthermore, we identify the challenges associated with these imaging methods, important pathophysiologic gaps to fill for the AD NSS neuroimaging field, and provide future directions to improve our assessment, understanding, and clinical use of in vivo imaging of the NSS.
The Neurodegenerative Elderly Syndrome (NES) hypothesis: Alzheimer and Parkinson are two faces of the same disease
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Measuring pupil dilation could be an effective non-invasive way to monitor LC activity for early diagnosis (Joshi et al., 2016; Kremen et al., 2019). Alternatively, could be used traditional but more expensive magnetic resonance imaging approaches (Betts et al., 2019; Hou et al., 2021; Liu et al., 2017). Another early diagnosis action could be monitoring 5-HT release through, for example, high-resolution PET imaging.
Increasing evidence suggests that Alzheimer’s disease (AD) and Parkinson’s disease (PD) share monoamine and alpha-synuclein (αSyn) dysfunctions, often beginning years before clinical manifestations onset. The triggers for these impairments and the causes leading these early neurodegenerative processes to become AD or PD remain unclear. We address these issues by proposing a radically new perspective to frame AD and PD: they are different manifestations of one only disease we call “Neurodegenerative Elderly Syndrome (NES)”. NES goes through three phases. The seeding stage, which starts years before clinical signs, and where the part of the brain-body affected by the initial αSyn and monoamine dysfunctions, influences the future possible progression of NES towards PD or AD. The compensatory stage, where the clinical symptoms are still silent thanks to compensatory mechanisms keeping monoamine concentrations homeostasis. The bifurcation stage, where NES becomes AD or PD. We present recent literature supporting NES and discuss how this hypothesis could radically change the comprehension of AD and PD comorbidities and the design of novel system-level diagnostic and therapeutic actions.
Carving the senescent phenotype by the chemical reactivity of catecholamines: An integrative review
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In the nervous system, the most chemically active molecules are CA. It is no wonder in this perspective that the long lasting efforts to trace the developmental pathways of AD, PD and LBD to their initial steps down from the most apparent features of their advanced stages, i.e. misfolded protein accumulation and neuron loss in specific brain sites, are eventually converging to the brain structures enriched in NA and DA, that is to LC (Dahl et al., 2021; Elman et al., 2021; Hansen, 2021; Hou et al., 2021; Marien et al., 2004; Matchett et al., 2021; Ohm et al., 2020; Plini et al., 2021; Riphagen et al., 2021; Robertson, 2013) and VTA (Caligiore et al., 2020; Krashia et al., 2019; Patthy et al., 2021; Serra et al., 2021). That is where prodromal changes occur long before their divergence, according to the genetic and environmental risk factors, to either AD, PD or LBD as exacerbations of the common age-associated changes (Caligiore et al., 2020; Gallo et al., 2021; Hansen, 2021; Huynh et al., 2021; van Hooren et al., 2021; Venneri and De Marco, 2020).
Macromolecules damaged by covalent modifications produced by chemically reactive metabolites accumulate in the slowly renewable components of living bodies and compromise their functions. Among such metabolites, catecholamines (CA) are unique, compared with the ubiquitous oxygen, ROS, glucose and methylglyoxal, in that their high chemical reactivity is confined to a limited set of cell types, including the dopaminergic and noradrenergic neurons and their direct targets, which suffer from CA propensities for autoxidation yielding toxic quinones, and for Pictet-Spengler reactions with carbonyl-containing compounds, which yield mitochondrial toxins. The functions progressively compromised because of that include motor performance, cognition, reward-driven behaviors, emotional tuning, and the neuroendocrine control of reproduction. The phenotypic manifestations of the resulting disorders culminate in such conditions as Parkinson’s and Alzheimer’s diseases, hypertension, sarcopenia, and menopause. The reasons to suspect that CA play some special role in aging accumulated since early 1970-ies. Published reviews address the role of CA hazardousness in the development of specific aging-associated diseases. The present integrative review explores how the bizarre discrepancy between CA hazardousness and biological importance could have emerged in evolution, how much does the chemical reactivity of CA contribute to the senescent phenotype in mammals, and what can be done with it.
Noradrenaline in the aging brain: Promoting cognitive reserve or accelerating Alzheimer's disease?
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However, due to the LC’s different magnetic properties than surrounding tissue, specialized magnetic resonance imaging (MRI) sequences show high contrast at the site of the LC compared with surrounding brainstem regions [11]. Consistent with postmortem findings of correlations between LC structure and pre-mortem cognition or disease status, measures of LC contrast are lower in patients with mild cognitive impairment and Alzheimer’s disease than in cognitively healthy adults [12–16] and among cognitively healthy adults, higher LC contrast is associated with better memory and cognition [17–20]. Furthermore, recent findings indicate that even standard T1-weighted structural MRI sequences provide some information about LC decline.
Many believe that engaging in novel and mentally challenging activities promotes brain health and prevents Alzheimer’s disease in later life. However, mental stimulation may also have risks as well as benefits. As neurons release neurotransmitters, they often also release amyloid peptides and tau proteins into the extracellular space. These by-products of neural activity can aggregate into the tau tangle and amyloid plaque signatures of Alzheimer’s disease. Over time, more active brain regions accumulate more pathology. Thus, increasing brain activity can have a cost. But the neuromodulator noradrenaline, released during novel and mentally stimulating events, may have some protective effects—as well as some negative effects. Via its inhibitory and excitatory effects on neurons and microglia, noradrenaline sometimes prevents and sometimes accelerates the production and accumulation of amyloid-β and tau in various brain regions. Both α2A- and β-adrenergic receptors influence amyloid-β production and tau hyperphosphorylation. Adrenergic activity also influences clearance of amyloid-β and tau. Furthermore, some findings suggest that Alzheimer’s disease increases noradrenergic activity, at least in its early phases. Because older brains clear the by-products of synaptic activity less effectively, increased synaptic activity in the older brain risks accelerating the accumulation of Alzheimer’s pathology more than it does in the younger brain.
Higher Cognitive Reserve Is Beneficial for Cognitive Performance Via Various Locus Coeruleus Functional Pathways in the Pre-Dementia Stage of Alzheimer’s Disease
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Short CommunicationA case-control study of the locus coeruleus degeneration in Alzheimer's disease

Highlights

Abstract

Introduction

Section snippets

Participants

Study design and procedure

Demographic, cognitive, and biological characteristics of study participants

Comparison of the lc contrast ratio (LC-CR) between groups

Discussion

Conclusions

Author contributions

Acknowledgement

Declaration of Competing Interest

Funding/Support

Role of the Funder/Sponsor

Neuroimage

Alzheimers Dement.

Neuroimage

Neurobiol. Aging

Neuroimage

Neuroimage

Alzheimer’s pathogenesis: is there neuron-to-neuron propagation?

Acta Neuropathol.

Where, when, and in what form does sporadic Alzheimer’s disease begin?

Curr. Opin. Neurol.

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Brain

Optimal cut-off value for locus coeruleus-to-pons intensity ratio as clinical biomarker for Alzheimer’s disease: a pilot study

J. Alzheimers Dis. Rep.

Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans?

Front. Pharmacol.

Short Communication
A case-control study of the locus coeruleus degeneration in Alzheimer's disease