Use of Mild Cognitive Impairment due to Lewy Bodies Research Diagnostic Criteria in the IMPRINT Study

Mild Cognitive Impairment (MCI) is a well-established clinical diagnosis that is increasingly diagnosed by its driving pathology. The clinical criteria for MCI due to Alzheimer’s disease (AD) has been well defined and increasingly recognized in Parkinson’s disease (PD), but only in recent years has MCI due to Lewy Bodies (MCI-LB) gained consensus. In 2020, a global panel of experts published the first formal criteria for studying the prodromal stage of dementia with Lewy Bodies (DLB) in research (McKeith et al, 2020).

In order to identify appropriate disease modifying treatments, the identification of changes in prodromal and early stages of disease is imperative. Studies including animal models, brain imaging, collection of markers in blood, and genome wide association studies provide evidence to suggest that neurodegenerative diseases such as DLB, AD and PD may be acutely influenced by changes in the immune system, potentially measurable in prodromal stages.

Dementias Platform UK (DPUK), with researchers from the University of Cambridge and Imperial College London, in collaboration with NHS Trust partners, is conducting the IMPRINT (Immune Profiling in Early Cognitive Disorders) study. This is a study exploring immunological biomarkers in early and prodromal stages of Lewy Body dementia and Alzheimer’s disease. Through utilization of the MCI-LB research criteria, alongside clinically accepted NIA-AA criteria for MCI-AD, this study aims to investigate differential patterns of change between DLB and AD at their earliest identifiable stages and compare immunological differences across stages within each disease.

Participants with a clinical diagnosis of MCI are evaluated by study researchers and assessed as having either a possible or probable diagnosis of MCI due to Lewy Bodies (MCI-LB), or MCI due to AD. The MCI-LB research criteria are comprised of three essential features, four core features, and three proposed biomarkers. Essential features must be present and consists of:

1. Concern about cognitive decline by the patient, someone who knows them well, or a clinician
2. Objective evidence of impairment in at least one cognitive domain, and
3. Preserved or minimally affected ability to carry out daily activities independently.

Core features include:

1. Presence of fluctuating cognition with variations in attention and alertness
2. Recurrent visual hallucinations
3. REM Behavioral Sleep Disorder (RBD)
4. At least one spontaneous feature of parkinsonism such as bradykinesia, tremor or rigidity

The proposed biomarkers are:

1. Decreased dopamine transporter uptake seen on dopamine transporter (DAT) imaging
2. A sleep study (polysomnogram) confirmation of RBD without total relaxation of muscles (atonia)
3. Decreased absorption of MIBG measured by a test of blood flow around the heart (myocardial scintigraphy)

A combination of core clinical features and proposed biomarkers creates the distinction between possible and probably MCI-LB, both of which can be diagnosed under two circumstances. Possible MCI-LB must include the presence of one core clinical feature with no proposed biomarkers, or at least one proposed biomarker without a core clinical feature. Probable MCI-LB must include the presence of at least two core clinical features, with or without a proposed biomarker, or one core clinical feature with at least one proposed biomarker.

After initial screening for diagnostic assessment, participants in the IMPRINT study undergo collection of blood, saliva, urine and optionally cerebrospinal fluid (CSF) for immunophenotyping and exosome analysis, as well as comprehensive neuropsychological assessment. Immunophenotyping involves examining different types of cells to understand how the immune system is functioning. Exosome analysis involves examining tiny particles, called exosomes, that are released by cells. These particles carry important messages between cells and studying them can help us understand how cells communicate and allow us to detect diseases.

Two biological sample collections at baseline and 18 months, along with three cognitive assessment timepoints at baseline, 18 months and three years, will allow for longitudinal assessment and monitoring for transition from MCI stage to early disease stage. Once complete, this study will deepen our understanding of the etiological and longitudinal immune changes unique to AD and DLB and may provide evidence for identifying future targets for clinical trials.

About the author: 

Elena Herrero supports the coordination of the IMPRINT study as part of the DPUK immunology theme. She is a research assistant in the Department of Psychiatry at the University of Cambridge supporting studies in the Cambridge NIHR Biomedical Research Centre involving individuals with Lewy Body dementia. She is also an affiliate of the Centre for Healthy Brain Aging in the IOPPN at King’s College London.