1. Dementia with Lewy bodies: diagnostic and predictive biomarkers
Dra. Carla Abdelnour Ruiz

3. Dementia with Lewy bodies
Demencia +
- Fluctuating cognition
- Visual hallucinations
- Parkinsonism

4. Dementia with Lewy bodies
Fluctuation cognition.
Visual hallucinations.
Parkinsonism.
Core features
RBD.
Severe neuroleptic sensitivity.
Positive DaTSCAN.
Suggestive features
Repeated falls.
Orthostatic hypotension.
Transient unexplained loss of consciousness.
Reduced occipital activity and generalized low uptake on SPECT/PET perfusion scan.
Support features
Clinical or radiological features of cerebrovascular disease.
If parkinsonism only appears for the first time at a stage of severe dementia.
In the presence of any other disorder sufficient to account for some or all the clinical picture.
Unlikely features

5. Dementia with Lewy bodies
10-20%
Pure DLB
30 %
DLB + vascular
DLB +
Alzheimer disease

6. Dementia with Lewy bodies: diagnostic and predictive biomarkers
Joint Programme-Neurodegenerative Disease Research
15/05 Answer about full application
30/06 Submission deadline for full application

7. Scheme of the presentation
Structure of the consortium.
Objective of the project.
Overall design.
Overall assessment.
Clinical.
Neuropsychological.
Biomarkers.
Summary of the proposal.
Budget plan.

8. Structure of the consortium
8 partners
Coordinator:
Dag Aarsland
Norway
Sweden UK
Netherlands
Germany
Romania
Lund (Sweden), Malmö (Sweden), Amsterdam (Netherlands), Newcastle (UK), Brno (Czech Republic), Ljubljana (Slovene), Oslo (Norway), Londres (UK), Marburg (Germany), Kassel (Germany), Chieti (Italy), Stockholm(Sweden), Rochester (UK), Penn (UK), Venice(Italy), St. Petersburgo (Russia), Haugesund (Norway), Brasov (Romanie), Thessaloniki (Grece), Rotterdam (Netherlands), Sofia (Bulgary), Barcelona (Spain).
Total: 22 centers
Spain
Italy

9. Structure of the consortium
Spain partnership:
Principal investigator: Dr. Joan Castell.
Girona: Dr. Josep Garré Olmo. Epidemiologist at the Research Unit of the Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta.
Barcelona: Dra. Carla Abdelnour. Neurologist at Fundació ACE.

10. Objectives of the project
Identify novel diagnostic and prognostic biomarkers of Lewy body dementia
Aims
Can structural and functional imaging, EEG, blood, genetic, and CSF markers aid in the diagnosis of DLB?
How are the markers related to the variety of clinical symptoms in DLB?
Can they identify patients at increased risk for early and rapid cognitive decline and poor treatment response?
Research
Questions
By combining novel analyses techniques of imaging, EEG, DNA, blood, CSF and multivariate bioinformatics strategies, the diagnostic accuracy of DLB vs AD and normal control subjects can be increased, and the future rate of cognitive decline can be predicted.
Biomarkers will identify specific associations between regional and/or pathological changes and specific clinical symptoms.
Hypotheses

11. Functional neuroimaging techniques
Overall design
400 mild DLB
200 mild AD
200 mild PD
Functional neuroimaging techniques
Genetics
EEG
CSF
Serum analyses
2-year follow-up

12. Overview assessment Clinical Neuropsycological Neuroimaging EEG
Blood samples
CSF
Genetics

13. Clinical assessment Inclusion criteria Exclusion criteria
Mild dementia.
CDR: 1, MMSE >20.
Fulfilling criteria for possible or probable DLB.
Core features:
Dementia.
Visual hallucinations.
Parkinsonism.
Fluctuating cognition.
Suggestive features:
REM behavior disorder.
Positive DaTSCAN.
Neuroleptic hypersensitivity.
Exclusion criteria
Severe physical or life-threatening conditions.
Post-stroke dementia.
Possible DLB with negative DaTSCAN.
Long-term previous use of antipsychotic drugs.

14. Clinical assessment Level 1 Level 2 Depresion NPI-Q NPI
Psychotic symptoms
NPI items 1 (delusions) and 2 (hallucinations)
North-East visual hallucinations interview
CUSPAD misidentification item
Apathy
NPI apathy item
Apathy evaluation scale-clinical version
Sleep symptoms
NPI and RBD item from Mayo sleep questionnaire
Daytime somnolence: NMSS item 3
Full Mayo sleep questionnaire
ADL
Functional activities questionnaire
Fluctuations
Mayo fluctuation scale
+ Fluctuation Assessment Scale
Falls
Semiquantitative question about falls
NMSS items 1 and 2
Tinetti scale
Falls questionnaire
Motor function
UPDRS motor part
Time up and go TUG standardized version
Hoehn & Yahr stage
Fingertapping ?
Autonomic dysfunction
Orthostatic blood pressure and pulse measurements in supine position after 5 minutes rest, immediately after standing, after 1 and 3 minutes.
ECG
Quality of life
Quality of life in AD (QOL-AD).
Carer burden
Zarit burden interview
Prognostic milestones
Time to severe dementia: CDR: 3, MMSE: 0
Time to nursing home admission
Time to death

15. Neuropsychological assessment
Level 1
Level 2*
Global
MMSE, MoCA
Memory
Hopkins verbal learning tests
Benton visual retention test
Visuospatial
Degraded letter test (VOSP)
Judgement of line orientation test (Benton)
Executive
Similarities (WAIS)
Stroop
Attention
Adaptative-digit ordering test
Trail making test A+B
Language
Category fluency-animals
Boston naming test-CERAD 15-item version
*Level 2: means Level 1 test + Level 2 test

16. Biomarkers Neuroimaging EEG Samples MRI: T1. T2. FLAIR. fMRI. DTI.
DaTSCAN.
EEG
20 min of registre without artefacts, 21 derivations.
Electrooculography.
ECG.
Samples
CSF.
Blood samples.
Genetics.

17. Summary of the proposal
Level 1
Arterial pressure, heart rate.
Neuroimaging: Dat SCAN: just for diagnosis. MIGB, SPECT. MRI*: T1, T2, FLAIR, fMRI.
Samples: CSF: Aβ42, tau, p-tau. Just 1 sample. DNA.
EEG.
Level 2
Neuroimaging: MRI DTI*. FDG-PET*.
Level 3
Arterial pressure 24 h registre.
Neuroimaging: MRI spectroscopy,* ASL*, DKI*. PiB PET, or in the future alfa synuclein PET.
Samples: CSF: alfa synuclein.
EEG 24 h registre. Polisomnography.
Skin biopsy.
* Every 2 years

18. Budget plan
JPND call: Risk and protective factors, longitudinal cohort approaches and advanced experimental models
Last name
Country
Funding org.
Personnel
Consumables
Equipment
Travel
Other costs2
Overheads3
Total budget4
Coordinator
Åarsland
Norway
RCN
€ 280,000
€ 55,000
€ 14,000
€ 95,000
€ 70,000
€ 514,000
Partner 2
Ballard UK
MRC
€ 184,000
€ 42,000
€ 105,000
€ 147,000
€ 478,000
Partner 3
Biundo
Italy
MOH-IT
€ 110,000
€ 80,000
€ 20,000
€ 4,500
€ 21,500
€ 236,000
Partner 4
Lemstra
Netherlands
ZonMW
€ 178,000
€ 120,000
€ 5,000
€ 17,400
€340,400*
Partner 5
Winblad
Sweden
SRC
€ 170,000
€ 90,000
€ 10,000
€ 100,000
€ 81,000
€ 451,000
Partner 6
Falup- Pecurariu
Romania
NASRI
€ 57,000
€ 43,000
€ 16,000
€ 4,000
€ 30,000
€ 150,000
Partner 7
Mollenhauer
Germany
BMBF
€ 84,000
€ 6,000
€ 200,000
€ 66,400
€ 398,400
Partner 8
Castell-Conesa
Spain
ISCIII
€ 24,500
€ 21,000
Total
€ 2,667,800

19. Until now…
CLINICAL COURSE OF DLB: RESULTS FROM A LARGE LONGITUDINAL MULTICENTRE COHORT STUDY Milica G Kramberger, Carla Abdelnour, Josep Garre Olmo, Zuzana Walker, Evelin Lemstra, Elisabet Londos, Laura Bonanni, Flavio Nobili, Greg Elder, Bengt Winblad, Frank Jan de Jong, Elka Stefanova, Maria Petrova, Cristian Falup-Pecurariu, Irena Rektorova, Sevasti Bostantjopoulou, Roberta Biundo, Daniel Weintraub and Dag Aarsland. Objective. Dementia with Lewy bodies (DLB) is the second most common degenerative dementia in older people following Alzheimer’s disease (AD) but remains under-recognized in clinical settings, and relatively little is known about its clinical course. By using data collected from a new pan-European consortium on DLB we describe here disease course. Methods. From 18 centers in 12 European countries data from 1115 patients with clinical diagnosis of DLB, 576 patients with Parkinson’s disease with dementia (PDD) and 301 patients with AD were collected prospectively. Baseline clinical data, demographics, cognitive (Mini-Mental State Examination-MMSE) and motor assessment (Unified Parkinson’s Disease Rating Scale III-UPDRS III) were included, and up to two year follow-up MMSE scores were analyzed. Results. There were significant between groups (Table 1) and between-center differences in MMSE and UPDRS III at baseline (p. 0001). There was a significant MMSE decline for the DLB patients during two-year follow up (baseline=21.3±4, follow-up=16.9 7, 4.4  6 point decline; n=268, Wilcoxon signed rank test p. 0001). There was a slower decline in PDD during the second year compared to DLB, (1.5 ±4.2, p .008), but no significant between groups differences in rate of decline at year 2 were found (Table 2). In the DLB group multivariate regression analysis showed that greater MMSE decline was predicted by lower MMSE at baseline (B: 0.243, p. 001), whereas neither sex, age at onset, duration of cognitive symptoms, nor UPDRS III were associated with rate of decline. Conclusion: In the largest DLB cohort to date we report diversity in clinical profile of DLB patients across European countries. A significant cognitive decline over two years was observed, and changes were similar to those seen in PDD and AD. In DLB, a more rapid rate of decline is predicted by more severe cognitive symptoms at baseline. Larger prospective studies on longitudinal course and prognostic values of different clinical and biomarker characteristics in DLB are needed.

20. Thanks for your attention
Alzheimer with his co-workers Nervenklinik Munich
Front row, from left: Mrs. Adele Grombach, Ugo Cerletti, unknown, Francesco Bonfiglio, Gaetano Perusini. Top row from left: Fritz Lotmar, unknown, Stefan Rosental, Allers (?), unknown, Alois Alzheimer, Nicolás Achúcarro, Friedrich Heinrich Lewy.