Dementia with Lewy bodies and Alzheimer’s disease: an unfortunate couple?

Background Dementia with Lewy Bodies (DLB) is a devastating neurodegenerative disease that. It is the most common form of dementia next to Alzheimer’s disease (around 30.000-50.000 patients in the Netherlands). Aggregation of alpha-synuclein in the brain is the pathological hallmark of DLB, but up to 50-80% of patients with DLB have coexisting AD-pathology (amyloid and tau depositions). Up till now surprisingly very little research has been performed to study the cause or clinical relevance of AD-copathology in DLB. Aggregated evidence from postmortem studies suggests an added effect of AD-pathology on clinical manifestation and disease progression in DLB. But it is questionable how we can translate postmortem data to our patient in daily clinical practice. With current state-of the art biomarkers techniques it is now feasible to detect AD-pathology during life, most effectively by CSF-analysis of disease-specific proteins, i.e amyloid-beta and tau. With CSf we can detect AD-pathology in early stages of disease. We have already shown in a large series of DLB-patients that a substantial portion of patients have a CSF-profile compatible with AD. My questions are now: do these patients differ from DLB-patients without AD-pathology? Do they have a different clinical manifestation? Is the course of the disease different in these patients? Which factors contribute to this co-pathology? And probably most important – would DLB-patients with coexisting AD-pathology benefit from disease modifying drugs, directly targeting amyloid and tau? Clearly there is a need for a comprehensive study on the role of AD-copathology in DLB, preferably in early stages of the disease. The VUmc Alzheimercenter has a well-established, ongoing prospective clinical dementia cohort (Amsterdam Dementia Cohort, ADC) and offers an excellent opportunity to address these research questions. Currently, the ADC comprises over 200 DLB-patients with clinical and biomarker data ready available. The proposed project ties in closely with ongoing research, both locally and internationally. Aim/objectives The overall aim of this project is to investigate the clinical relevance of AD-pathology in early stages of DLB and to understand the biological factors that contribute to this effect, in order to improve care and offer personalized treatment strategies for DLB-patients. AD-pathology is detected by CSF-biomarkers. The following objectives are specified: 1) To compare cross-sectional data in DLB-AD+ and DLB-AD- clinical symptoms, neuropsychological profile, MRI-characteristics (atrophy, vascular lesions) and EEG 2) To compare disease progression and survival (nursing home admission and death) in DLB-AD+ and DLB-AD- patients. Longitudinal clinical data, neuropsychological data as well as biomarkers will be analysed 3) To compare genetic profiles of DLB-AD+ and DLB-AD- by analysis of NeuroX analyses of DNA of DLB-patients 4) To compare levels of CSF amyloid-beta species (Abeta38/40/42) in DLB-AD+, DLB-AD and AD 5) To compare histopathological features in a subset of autopsy-proven DLB-patients Approach Most studies described in this project use ready available data that have been collected in previous research projects. Patients from the Amsterdam Dementia Cohort will be selected by fulfilling criteria for probable DLB and the availability of CSF (n=120). Patients will be divided in DLB-AD+ and DLB-AD- groups based on tau/Abeta42 ratio in CSF. Clinical characteristics, including neuropsychological profile, cognitive decline and survivaldata will be analysed to investigate differences in disease manifestation between groups. Cross-sectional MRI and EEG-analyses are aimed to discover structural and/or functional brain disturbances that are influenced by concomitant AD-pathology. MRI-scans will be analysed for atrophy patterns, regional differences and cerebrovascular lesions. Visual EEG-ratings are semiquantitated and analysed to look at differences in brain activity. Additional longitudinal CSF and MRI-data will be collected during this project and compared between groups for differences in changes over time. MRI atrophy rates will be analysed and correlated with disease progression. CSF-analysis is repeated for AD-biomarkers in DLB-AD- patients to investigate if AD-pathology can emerge at later stages of the disease. To pinpoint biological underpinnings of the effect of concomitant AD-pathology in DLB respectively genetical profiles based on NeuroX-assay performed in the lab of Dr Bras & Dr Hardy UCL, London. Genetic profiles will be correlated with CSF-biomarkers levels. Levels of Abeta-species (Abeta38/Abeta40/Abeta42) are analysed with commercially available kits (triplex-plates, MSD) and compared between groups. Histopathological characteristics in a subset of DLB-patients from the Netherlands Brain Bank are analysed on macroscopical and microscopical measures.