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Treatment AD in the earliest stage: The role of medical nutrition

Treatment AD in the earliest stage: The role of medical nutrition. Prof. Dr. Philip Scheltens. Disclosures. The Alzheimer Center has received funding from:

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Treatment AD in the earliest stage: The role of medical nutrition

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  1. Treatment AD in the earliest stage:The role of medical nutrition Prof. Dr. Philip Scheltens

  2. Disclosures The Alzheimer Center has received funding from: AEGON, ZONMW, Alzheimer Nederland, Heineken Nederland, ING, Stichting VUmc Fonds, AHAF, ISOA, ISAO, Pfizer, Jansen, Novartis, KLM Royal Dutch Airlines, KPN, KPMG, Twentse Kabel Holding, Stichting Zabawas, RABO Bank Image analysis research and clinical trials are carried out with Nutricia Advanced Medical Nutrition, Jansen Research Foundation, Novartis, Roche, Merck, Lundbeck, Pfizer Dr Scheltens receives no personal compensation from any of the above or others except from the VUmc

  3. Alzheimer: de getallen Nu: ~ 250.000 patiënten in Nederland Belangrijkste risicofactor: Leeftijd Dubbele vergrijzing: méér ouderen worden ouder  snelle toename! Schatting 2040: 500.000 Aantal jong dementerende (<65) neemt toe

  4. De impact van Alzheimer 1 op de 10 > 65 heeft Alzheimer  1 op de 3 > 80 heeft Alzheimer 

  5. De impact van Alzheimer 1 op de 10 > 65 heeft Alzheimer  1 op de 3 > 80 heeft Alzheimer  Iedere 15 minuten krijgt iemand Alzheimer

  6. De impact van Alzheimer 1 op de 10 > 65 heeft Alzheimer  1 op de 3 > 80 heeft Alzheimer  Iedere 15 minutenkrijgtiemand Alzheimer Aangenomendat per patiënt 3 zorgverleners (part time) betrokkenzijn; zijner 1.5 miljoenzorgverlenersnodig in 2040. Terwijl de beroepsbevolking in aantalafneemt… ...neemt de belastingvoor de maatschappij toe!    

  7. Alzheimer: 3 fundamentele processen Neurofibrillaire kluwens Synapsverlies Seniele plaques

  8. * 10 # Synapses dentate gyrus (x1010) 5 -13% -44% 0 Control MCI AD Synaptic Failure in Alzheimer’s disease • Synapse loss is an early event in the disease process • Synaptic loss is strongest structural correlate with cognitive decline • Failure to replace the loss of synaptic contacts leads to the decline in memory Scheff et al., Neurobiol Aging, 2006

  9. Choline Phosphate Glycerol Saturated fatty acid dendritic spine PUFA neurite Axon Nutritionalprecursor control of neuronalmembranesynthesis

  10. Choline Phosphate Glycerol Saturated fatty acid PUFA Phospholipids are synthesized by the Kennedy Pathway e.g. DHA KENNEDY EP, WEISS SB (1956). J. Biol. Chem. 222 (1): 193–214

  11. Different nutritional status in patients with mild AD No significant differenceswereobservedfor plasma folate, vitamins B6 and B12, choline, vitamins A and E, plasma fattyacids, BMI, and calfcircumference. J.W. Sijben, M.G.M OldeRikkert et al. Poster EFNS 2012 Stockhom

  12. Verzadigde vetzuren Onverzadigde vetzuren

  13. UMP DHA, EPA Choline Phospholipids B vitamins Anti-oxidants Providing the Nutritional Precursors and Co-Factors for Neuronal Membrane Formation Hypothesized to: Increase the formation of neuronal membranes Much of early developmental work was conducted By Professor Richard Wurtman at MIT, Boston, USA

  14. Nutritional precursors increase membrane dependent structures: Neurite outgrowth Control Uridine 50 µM Pooler et al (2005) Neuroscience B-vitamins, choline and omega-3 fatty acids also stimulate neurite outgrowth in vitro Darioset al. (2006) Nature; Wang et al. (2000) NeurosciLett; Calderon et al. (2004) J Neurochem

  15. Nutritional precursors increase membrane dependent structures (dendriticspines in gerbil hippocampus) ** 100 * 80 60 Spine Density hippocampus (for 50µM) 40 20 0 Control (choline) UMP DHA UMP DHA http://en.wikipedia.org/wiki/Dendritic_spine Sakamotoet al. (2007) BrainRes

  16. Souvenir I: Proof of Concept Study in Drug-Naive mild AD • Multi-country (NL, Bel, Ger, UK, US), randomized, controlled trial • Intervention 12 weeks (+ optional 12 wk extension) • Co-primaryoutcomes: • WMS-r delayed verbal recall • ADAS-cog-13 Outcome parameters Souvenaid (n=106) n=212 Control (n=106) t ≤-3 t=0 6 12 wks Values are mean ±SD, unless stated otherwise

  17. Blood Nutritional Parameters • Significant changes (p<0.001) in vitamin E and EPA ITT, data are mean ± SE

  18. No difference in AEs and Compliance Safety • No significant differences in the number of (Serious) Adverse Events (S)AEs • No clinically relevant differences in blood safety parameters • No difference in dropouts (# patients) due to (S)AEs Tolerance • No difference in product appreciation (taste and amount) between the Control and Active group • Overall product compliance was very high at 95% with no difference between the groups

  19. Wechsler Memory Score

  20. Co-Primary Outcome: WMS-r Delayed Verbal Recall Score Very MildAD after 12 weeks mild AD after 12 weeks (p=0.021) (p=0.019) Pre-defined subgroup MMSE 24 - 26, Chi-square ITT, Chi-square *At baseline 40% scored 0 [lowest score], planned MMRM substituted by nonparametric analyses, MWU and Chi-square gave similarresults Scheltens et al. Alzheimers Dement. 2010 6 (1):1-10.

  21. Co-Primary Outcome: ADAS-cog Primary analysis: No significant (p=0.826) effect1 ITT, MMRM, data are mean ± SE 1Scheltens et al. Alzheimers Dement. 2010 6 (1):1-10. 2Kamphuis et al. J Nutr Health Aging. 2011 15(8):720-4.

  22. Clinical Trials Prodromal Mild Moderate Memory (WMS-r) & Cognition (ADAS-cog) Memory (NTB) Biomarker EEG & MEG Cognition (ADAS-cog) Cognition (NTB) Biomarker MRI & CSF Trials are registered in the ICMJE compliant www.trialregister.nl

  23. S-Connect study: Mild to Moderate AD using AD medication Outcome parameters • Principle investigators: David Bennett and Raj Shah, Rush, Chicago • Multi-centre (48 sites in the US), randomized, controlled trial • Intervention 24 weeks • Primaryoutcome: • ADAS-cog-11 n=265 Active n=527 n=262 Control t ≤-3 0 12 24 wk Values are mean±SD, unless stated otherwise

  24. No difference in Adverse Events Occurrence of > 5% in total subjects • Overall compliance during 24 weeks was 94% and not different between the groups

  25. Primary Outcome: ADAS-cog No significant effect* (p=0.513) during 24 weeks ITT, MMRM, data are mean ±SE *Statistical analysis run by Rush Alzheimer’s Disease Centre, Rush University Medical Centre Shah et al., J Nutr Health Aging, 2011;15; Suppl 1:S30, Manuscript in preparation

  26. Clinical Trials Prodromal Mild Moderate Memory (WMS-r) & Cognition (ADAS-cog) Memory (NTB) Biomarker EEG & MEG Cognition (ADAS-cog) Cognition (NTB) Biomarker MRI & CSF Trials are registered in the ICMJE compliant www.trialregister.nl

  27. Souvenir II study: Drug-Naive Mild AD Outcome parameters • Multi-country (NL, Ger, Bel, Fr, It, Sp), randomized, controlled trial • Intervention 24 weeks • Primaryoutcome: Memory Domain NTB (z-score): • RAVLT immediate, delayed, recognition and VPA immediate and delayed n=130 Active n=259 n=129 Control t ≤-3 0 12 24 wk Values are mean±SD, unless stated otherwise

  28. No Difference in Adverse Events Occurrence of > 5% in total subjects • Overall compliance during 24 weeks was 97% and not different between the groups

  29. Primary Efficacy: Memory Domain Score (z-score) of the NTB (p=0.023) ITT, MMRM 2df contrast, data are mean ±SE *Statistical analysis re-run by Rush Alzheimer’s Disease Center Scheltens et al. J Alzheimers Dis. 2012 31(1):225-36.

  30. Secondary Efficacy: NTB Total and NTB Executive Domain (z-score) NTB executive domain score no significant effect (p=0.686) NTB composite score trend (p=0.053) ITT, MMRM, 2 df contrast, data are mean ±SE Scheltens et al. J Alzheimers Dis. 2012 31(1):225-36.

  31. Exploratory – Memory domain z-score Week 0, 12, 24 -> SII ITT; Week 36, 48 -> OLE ITT, all subjects Raw means and SE; change from baseline Double-blind treatment Open-label extension

  32. PLI Electrical Activity at the Synapse – EEG: Biomarker for Functional Connectivity • Basic quantitative EEG analysis - • Relative power and Peak Frequency • In AD disturbed signal strength1 • Phase Leg Index (PLI) as Functional Connectivity measure • In AD loss of PLI1 Healthy AD • Clustering & Path length are measures of Network Organization • In AD disrupted Organization2 1Stam CJ et al. Brain 2009 132, 213-24 2Stam CJ, van Straaten ECW. ClinNeurophysiol2012 doi:10.1016/j.clinph.2012.01.011

  33. Network Parameters suggest Preserved Synaptic Formation, Function and Network 1. Peak Frequency 3. Brain Network organization* p=0.019 p=0.009 2. Phase Leg Index p=0.053 p=0.011 Scheltens et al. J Alzheimers Dis. 2012 31(1):225-36. *Manuscript in preparation, Developing topics P4-363 ITT, MMRM, 2 df contrast, data are mean ±SE

  34. Clinical Trials Prodromal Mild Moderate Memory (WMS-r) & Cognition (ADAS-cog) Memory (NTB) Biomarker EEG & MEG Cognition (ADAS-cog) Cognition (NTB) Biomarker MRI & CSF Trials are registered in the ICMJE compliant www.trialregister.nl

  35. EU – Funded* LipiDiDiet: Proof of Concept Study in Prodromal AD • Principle investigator: H. Soininen (UEF, Kuopio, Finland) • 24-Month randomized, controlled, multicenter (11 sites in Fin, Swe, Ger, NL) • Drug-naive prodromal AD patients (Dubois et al., 2007) (recruited 240 / 300) • Primary Outcome: Neuropsychological Test Battery (NTB) • Secondary Outcomes: • Progression to AD • Functional Abilities • CSF and MRI *Funded by the EU FP7 project LipiDiDiet, Grant Agreement #211696

  36. The AD Continuum CSF Aβ42 Amyloid imaging FDG-PET MRI hippocampal volumeCSF Tau Cognitive performance Function (ADL) Abnormal FDG-PET (Synaptic Dysfunction) MRI hippocampal volume Cognitive performance CSF Aβ42 Amyloid imaging Function (ADL) CSF Tau Normal Time Prodromal Dementia Presymptomatic Modified from Aisen PS Alzheimers Dement. 2010

  37. Multi Level Approach: no single magic bullit for AD IMMUNISATION ? LOWERING AMYLOID ? MEDICAL FOOD SYMPTOMATIC APPROACH CARE

  38. VUmc Alzheimer Center

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