Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design

Abstract

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

Keywords: Lewy body dementia; MRI neurodegeneration; PET; cerebrospinal fluid; clinical trials; dementia; dementia with Lewy bodies; parkinsonism; α-synuclein.

Figure 1.. Application of diagnostic biomarkers.

A) Biomarker applied to identify a single pathology/diagnosis and exclude other pathologies/diagnoses (differential exclusion diagnosis). B) Application of biomarkers to independently identify the different underlying processes leading to cognitive and movement disorders. The radar chart approach accommodates the inclusion of quantitative biomarker data along each axis, including a threshold into normal (green) and pathological (red) biomarker value ranges and offering a specific biomarker fingerprint for each individual. The purple line and dots represent a hypothetical patient. A: Amyloid β; AD: Alzheimer’s disease; CGI: Cytoplasmatic glia inclusion; CVD: Cerebrovascular disease; DLB: Dementia with Lewy bodies; FTLD: Frontotemporal lobar degeneration; I: Inflammation; LATE: Limbic-predominant age-related TDP-43 encephalopathy; LP: Lewy pathology; N: Neurodegeneration; S: α-Synuclein; T: Tau; S: α-synuclein; V: Cerebrovascular pathology; 3R: 3-repeat tauopathy; 4R: 4-repeat tauopathy.

Figure 2.. DLB clinical trial framework accounting for the presence of co-pathologies.

After the initial selection of participants based on clinical disease severity (step 1), Lewy pathology needs to be confirmed based on α-synuclein disease-specific biomarkers (step 2). Co-pathologies are then screened using additional biomarkers (step 3). The combined biomarker information could be part of exclusion or inclusion criteria or be considered during the clinical trial for stratification (step 4) or as co-variates. The biomarker fingerprint (See figure 1B) will estimate the predicted disease progression rate and identify the combination of treatments for each individual (step 5). Finally, biomarkers can be used to verify target engagement and as clinical trial outcome measures (step 6). In steps 2 and 3, the inner green circle represents the biomarker modalities like skin biopsies, neuroimaging (PET, SPECT, and MRI), blood, and cerebrospinal fluid). The outer circle represents the biomarker measurement, including radiotracer binding, quantification of vascular pathology through MRI, immuno-assays, real-time quaking-induced conversion, or protein misfolding cyclic amplification performed on biofluid samples.