Locus Coeruleus-to-Pons Intensity Ratio as Clinical Biomarker for AD

Alzheimer’s disease (AD) leads to severe cognitive and behavioral impairments that compromise independent daily activities. Atypical development or degeneration of the Locus Coeruleus (LC) has been implicated in the etiology of a variety of disorders involving cognitive dysfunction, including AD. In fact, it has been proposed that the prodromal phase of AD begins in the LC and not in the temporal cortical regions, as previously believed.

A biomarker of the LC structural integrity would aid in the characterization of the etiology of LC neurodegeneration in these and other disorders, and could guide targeted pharmacotherapies for individuals with LC dysfunction.Human LC neurons contain a melanin pigment known as neuromelanin, which is a byproduct of the monoamine synthesis that gives the LC its blue/black appearance and makes its neurons clearly distinguishable from nearby non-pigmented neurons. A major loss of LC neurons occurs in patients suffering from AD. Recently, a neuromelanin-sensitive MRI imaging technique that can enhance the T1-related contrast between neuromelanin and brain tissue has been developed and histologically validated. In our own earlier pilot-study we could demonstrate good sensitivity and specificity levels of this method (Dordevic et al, 2017). 

In this study it will be investigated if the patients suffering from various stages of dementia can be accurately diagnosed using LC-to-pons intensity ratio on neuromelanin-sensitive MRI scans.

Primary aims:

• Estimate sensitivity and specificity rates for distinguishing individuals with and without AD in a larger cohort
• Assess the capacity of the biomarker to detect AD pathology in the prodromal phase (i.e. predictor of conversion from SCI and MCI to dementia)
• Assess the ability of the method to track disease progression

This study consists of a cross-sectional and longitudinal studies. First a cross sectional study will be carried out on 150 participants, divided into three groups:

1.      healthy elderly (n= 50),
2.      elderly with mild cognitive impairment (n = 50) and
3.      elderly with Alzheimer’s dementia (n = 50).

Each time the patients are invited the following tests will be applied:

• Neuromelanin-sensitive T₁-weighted TSE sequence for LC intensity analysis
• MPRAGE T₁-weighted sequence for volumetric analysis
• Functional MRI in the resting condition (resting-state sequence)
• CERAD plus test battery
• CSF (β-amyloid (1–42) and (1-40), total tau, phospho-tau-181)

The measurements will be repeated once a year for the next 5 years.

Principle Investigator: Prof. Dr. Notger Müller
Start of the study: 2018
Status: mono centric, ongoing, recruiting active

Study Coordination / Project Management
Dr. Milos Dordevic
milos.dordevic(at)dzne.de
+49 391 6724592