Potential of metabolome analysis for early diagnosis of Alzheimer s disease

Transkript

1 Potential of metabolome analysis for early diagnosis of Alzheimer s disease Christian Humpel Laboratory of Psychiatry and Exp. Alzheimer Res. Medical University Innsbruck (December, 2015)

2 Alzheimer s Disease Extracellular beta-amyloid Plaques Intraneuronal neurofibrillary Tau Inclusion Cerebral Amyloid Angiopathy Neurodegeneration of cholinergic neurons Memory loss Small vascular bleedings Inflammation ba ba ba-caa Tau

3 DIAGNOSIS Alzheimer 100% sure Postmortem pathology Anamnesis (Own-, External-, Family-, Social-) Neurological Status Psychiatric Status Internal Med. Status Neuropsychology (Cognitive Tests, Depression Scale) Laboratory (Blood) EEG Imaging MRT/PET Genetics (ApoE4) LIQUOR ANALYSIS Search for BLOOD BIOMARKERS

4 CSF BIOMARKER: This analysis suggests... Marker [pg/ ml] Amyloidß (<500) Total-TAU 880 (>550) High probability for Alzheimers disease (>90% security) Phospho-Tau (>60) Only when all 3 are changed!! Only Innogenetics/Fujirebio ELISA >60 years validated We support clinical diagnosis

5 Tiroler Landeskrankenanstalten Ges.m.b.H., Landeskrankenhaus Universitätskliniken Univ. Klinik f. allg. Psychiatrie & Sozialpsychiatrie (Univ. Prof. D r. W.W. Fleischhacker) Psych. Labor für Exp. Alzheimerforschung (ao.univ. Prof. M ag. D r. Christian H umpel) Tel: ; ZUWEISUNG LIQUOR DIAGNOSTIK - DEM ENZ PatientIn (Name, GebDatum, SVNr.) Zuweisende Stelle (Adresse) Liquorabnahme am, um:... Wie wünschen Sie die Befundzusendung? o Post (Arzt) o FAX o Vom Labor auszufüllen: Probe übernommen am, um:... AnalyseNr.... Die Sendung sollte 2 Tage bei RT nicht überschreiten kein Glasröhrchen verwenden SAP Marker Normalwert (M±SEM) CUT-OFF Patient Gesamtprotein 481±29 µg/ml >800 ßAmyloid(1-42) 744±20 pg/ ml <500 Gesamt- TAU 292±149 pg/ ml >550 Phospho-Tau ±5 pg/ ml >60 Die Werte sind im Normalbereich Verdacht auf neurodegenerativen Prozess, z.b. Demenz, MCI, vaskulär Verdacht auf Alzheimerdemenz Verdacht auf Creutzfeldt Jacob (Tau >3500 pg/ ml) Erhöhtes Eiweiss (Abklärung empfohlen) Diese Werte unterstützen die klinische Diagnose Aussagen über Demenz gelten für Patienten >60 Jahre Datum:... Labor: Version 09-12/CH

6 Advantage and disadvantage of the 3 combined CSF Biomarkers Specificity Sensitivity Stability Validated for 90-97% (=> correct healthy) 85-95% (=> correct not healthy) 2-3 days RT >60 years Reproducibility Cheap Invasive Screening Multiple Testing Other forms of dementia YES (many centers worldwide) NO (3 Elisas = ca = ca. 40 samples) YES- Lumbalpuncture NO NO NO

7 AIMS for Blood biomarkers Reproducible objective measurements Specificity > 90% to differentiate a disease Sensitivity >90% Cheap Simple use (Transport, Storage, Stability) Non-invasive for patients

8 Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. Klavins K, Koal T, Dallmann G, Marksteiner J, Kemmler G, Humpel C (2015) The ratio of phosphatidylcholines to lysophosphatidylcholines in plasma differentiates healthy controls from patients with Alzheimer s disease and mild cognitive impairment. Alzheimer s & Dementia: Diagnosis, Assessment & Disease Monitoring 1:

9 METABOLOMICS - LIPIDOMICS Mean±SD µm n male [%] Age [years] 77±7 75±7 ns 81±5 MMSE 29.0± ±1.2 * 20.6±4.4 ***

10 Ratio between PC aa C34:4/lyso PC a C18:2 MCI => ratio < AD => ratio < 0.071

11 MCI AD

12 Stability of Lipids Intra-assay variation 3.8±0.8 % (n=32) Inter-assay variation: 4.4±1.1 % (n=32) Mean blood processing time: 4.3±0.2 hours (74%) 10.3±1.8 hours (all): MCI and AD not significant from controls Blood should be processed within 3 hours!

13 Noviplex Dried Plasma Spots Mitra Dried blood spot

14 Patient Specific Signature Analysis of many parameters from blood Proteomics, Metabolomics, Genomics, RNomics Expensive and complex Bioinformatics Computer-assisted Analysis

15 Med. Univ. Innsbruck Laboratory of Psychiatry and Exp. Alzheimer Research (Head: W. W. Fleischhacker) Josef Marksteiner Georg Kemmler Biocrates Innsbruck Memory Clinics: Innsbruck/Hall Blasko, I Defrancesco, M Deisenhammer, EA Imarhiagbe, D Weiss, E christian.humpel@i-med.ac.at Supported by the Austrian Science Funds and Austrian Nationalbank