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

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Presentation on theme: "Prof. Dr. Philip Scheltens Treatment AD in the earliest stage: The role of medical nutrition."— Presentation transcript:

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

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

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

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

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

7 De impact van Alzheimer 1 op de 10 > 65 heeft Alzheimer  1 op de 3 > 80 heeft Alzheimer  Iedere 15 minuten krijgt iemand Alzheimer Aangenomen dat per patiënt 3 zorgverleners (part time) betrokken zijn; zijn er 1.5 miljoen zorgverleners nodig in Terwijl de beroepsbevolking in aantal afneemt…...neemt de belasting voor de maatschappij toe!    

8 ‘98‘99’00’01’02’03’04’05’06’07‘08‘09’10’11‘12 … Prof. Scheltens VUMc, NL Prof. Soininen UEF, Finland > 10 Years of Research Prof. Scheltens VUMc, NL Prof. Bennett Rush, USA Souvenir I received funding from Stichting Technische Wetenschappen, Souvenir II received funding from the NL Food & Nutrition Delta project, FND #10003, LipiDiDiet: Funded by the EU FP7 project LipiDiDiet, Grant Agreement # Prof Wurtman, MIT Various national and international preclinical research consortia including ‘Dementia’ and ‘Neuronutrients’

9 Alzheimer: 3 fundamentele processen Seniele plaques Neurofibrillaire kluwens Synapsverlies

10 Synaptic Failure in Alzheimer’s disease ControlMCIAD * -13% - 44 % # Synapses dentate gyrus (x10 10 ) Scheff et al., Neurobiol Aging, 2006 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

11 Synapse Loss in AD is an early event Synapse loss is an early event in the AD continuum Sperling et al., Alz & Dement, 2011

12 Nutritional precursor control of neuronal membrane synthesis Axon neurite dendritic spine Saturated fatty acid Glycerol Phosphate Choline PUFA

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

14 Different nutritional status in patients with mild AD J.W. Sijben, M.G.M Olde Rikkert et al. Poster EFNS 2012 Stockhom No significant differences were observed for plasma folate, vitamins B6 and B12, choline, vitamins A and E, plasma fatty acids, BMI, and calf circumference.

15 Onverzadigde vetzuren Verzadigde vetzuren

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

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

19 Sakamoto et al. (2007) Brain Res Spine Density hippocampus (for 50µM) Control (choline) UMP UMP DHA DHA ** * Nutritional precursors increase membrane dependent structures (dendritic spines in gerbil hippocampus)

20 Cognition (ADAS-cog) Cognition (NTB) Biomarker MRI & CSF Memory (WMS-r) & Cognition (ADAS-cog) Memory (NTB) Biomarker EEG & MEG MildProdromalModerate Clinical Trials Trials are registered in the ICMJE compliant

21 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-primary outcomes: WMS-r delayed verbal recall ADAS-cog-13 Baseline Characteristics Control (n = 106) Active (n = 106) Sex (male/female; counts)52 / 5454 / 52 Age (y)73.3 ± ± 7.2 BMI (kg/m2)26.2 ± ± 4.8 Years of education on top of primary school 6.0 ± ± 3.9 Days since AD diagnosis (median) 31.5 (0 – 1036) 30.0 (0 – 1932) Total MMSE score24.0 ± ± 2.7 Values are mean ±SD, unless stated otherwise t ≤-3 t= wks n=212 Souvenaid (n=106) Control (n=106) Outcome parameters

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

23 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 No difference in AEs and Compliance

24 Wechsler Memory Score Logisch geheugen  b) Uitgestelde herinnering (na 30 minuten) Verhaal A Anna / Jansen /uit Amsterdam / Zuid / die werkte/ als werkster / op een kantoorgebouw / deed aangifte / op het politiebureau / Singel, / dat zij de vorige avond/ in de Spuistraat / was aangehouden / en van 115 € / was beroofd. / Zij had vier / kleine kinderen /de huur / was nog niet betaald / en ze hadden reeds twee dagen / niet gegeten. / De agenten waren zeer getroffen / door dit verhaal / en hielden een geldinzameling / voor haar. Max. = 25 Totaal verhaal A

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

26 Co-Primary Outcome: ADAS-cog ITT, MMRM, data are mean ± SE Primary analysis: No significant (p=0.826) effect 1 1 Scheltens et al. Alzheimers Dement (1): Kamphuis et al. J Nutr Health Aging (8):720-4.

27 Cognition (ADAS-cog) Cognition (NTB) Biomarker MRI & CSF Memory (WMS-r) & Cognition (ADAS-cog) Memory (NTB) Biomarker EEG & MEG MildProdromalModerate Clinical Trials Trials are registered in the ICMJE compliant

28 S-Connect study: Mild to Moderate AD using AD medication Principle investigators: David Bennett and Raj Shah, Rush, Chicago Multi-centre (48 sites in the US), randomized, controlled trial Intervention 24 weeks Primary outcome: ADAS-cog-11 n=527 n=265 Active t ≤ wk Outcome parameters n=262 Control Values are mean±SD, unless stated otherwise Baseline Characteristics Control (n = 262) Active (n = 265) Age (y)76.9 (8.2)76.6 (8.2) Sex: males (n[%])127 (48.5%)126 (47.5%) Years of education on top of primary school 6.4 (3.5)6.7 (3.6) Total MMSE score19.3 (3.0)19.5 (3.2) Duration AD since diagnosis (months)34.9 (29.6)32.7 (25.0) Acetylcholinesterase inhibitors243 (92.7%)251 (94.7%) NMDA antagonist170 (64.9%)177 (66.8%) BMI (kg/m2)26.64 (4.56)26.19 (4.51)

29 No difference in Adverse Events Body System Control (n=262) Active (n=265) p-value Any AE165 (60.1)150 (56.8)0.130 Body as a whole33 (12.7)24 (9.1)0.208 Nervous system21 (8.1)27 (10.2)0.450 Gastro-intestinal38 (14.6)41 (15.5)0.808 Metabolic & nutritional19 (7.3)19 (7.2)1.000 Musculo-skeletal15 (5.8) 24 (9.1)0.183 Psychiatric43 (16.5)32 (12.1)0.170 Respiratory system42 (16.2)50 (18.9)0.423 Skin and appendages18 (6.9)8 (3.0)0.045 Urinary system19 (7.3)25 (9.5)0.432 Other27 (10.4)20 (7.6)0.287 Occurrence of > 5% in total subjects Overall compliance during 24 weeks was 94% and not different between the groups

30 No significant effect* (p=0.513) during 24 weeks Primary Outcome: ADAS-cog 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

31 Cognition (ADAS-cog) Cognition (NTB) Biomarker MRI & CSF Memory (WMS-r) & Cognition (ADAS-cog) Memory (NTB) Biomarker EEG & MEG MildProdromalModerate Clinical Trials Trials are registered in the ICMJE compliant

32 Souvenir II study: Drug-Naive Mild AD Multi-country (NL, Ger, Bel, Fr, It, Sp), randomized, controlled trial Intervention 24 weeks Primary outcome: Memory Domain NTB (z-score): RAVLT immediate, delayed, recognition and VPA immediate and delayed n=259 n=130 Active t ≤ wk n=129 Control Outcome parameters Values are mean±SD, unless stated otherwise Baseline Characteristics Control (n = 129) Active (n = 130) Age (y) 73.2 (8.4)74.4 (6.9) Sex: males (n[%]) 64 (49.6)68 (52.3) Years of education on top of primary school 6.6 (4.6)6.5 (4.8) Total MMSE score 25.1 (2.9)25.1 (2.8) Duration AD since diagnosis (months) (median[range]) 2.0 ( )1.0 ( ) BMI (kg/m2) 26.7 (4.2)26.1 (4.1)

33 No Difference in Adverse Events Body systemExamples Control (n=129) Active (n=130) p-value Body as a wholeFatigue, influenza-like symptoms20 (15.5%)11 (8.5%)p=0.125 Central and peripheral nervous system disorders Dizziness, headache18 (14.0%)11 (8.5%)p=0.237 Gastro-intestinal system disorders Constipation, diarrhoea, flatulence, nausea 30 (23.3%)22 (17.1%)p=0.277 Metabolic and nutritional disorders Hyperglycaeemia, weight increase 9 (7.0%)13 (10.1%)p=0.505 Musculo-skeletal system disorders Arthralgia, ischial neuralgia9 (7.0%)10 (7.8%)p=1.000 Psychiatric disordersAnxiety, depression, insomnia16 (12.4%)15 (11.6%)p=1.000 Respiratory system disordersPharyngitis, bronchitis15 (11.6%)10 (7.8%)p=0.400 Skin and appendages disordersRash, skin dry10 (7.8%)4 (3.1%)p=0.168 OtherFall, surgical intervention8 (6.2%) p=1.000 Occurrence of > 5% in total subjects Overall compliance during 24 weeks was 97% and not different between the groups

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

35 ITT, MMRM, 2 df contrast, data are mean ±SE 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) Scheltens et al. J Alzheimers Dis (1):

36 Control (N) Active (N) Week 0, 12, 24 -> SII ITT; Week 36, 48 -> OLE ITT, all subjects Raw means and SE; change from baseline Double-blind treatmentOpen-label extension Exploratory – Memory domain z-score

37 Electrical Activity at the Synapse – EEG: Biomarker for Functional Connectivity 1.Basic quantitative EEG analysis - Relative power and Peak Frequency  In AD disturbed signal strength 1 1 Stam CJ et al. Brain , Stam CJ, van Straaten ECW. Clin Neurophysiol 2012 doi: /j.clinph Phase Leg Index (PLI) as Functional Connectivity measure  In AD loss of PLI 1 3.Clustering & Path length are measures of Network Organization  In AD disrupted Organization 2 PLI HealthyAD

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

39 Cognition (ADAS-cog) Cognition (NTB) Biomarker MRI & CSF Memory (WMS-r) & Cognition (ADAS-cog) Memory (NTB) Biomarker EEG & MEG MildProdromalModerate Clinical Trials Trials are registered in the ICMJE compliant

40 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

41 Very limited intervention studies in an exclusively mild AD population have been reported 1 Van Gool WA et al., Lancet 2001; 358: 455–60. (hydroxychloroquine) Seltzer B et al., Arch Neurol 2004; 61: 1852–6. (Donepezil) Lannfelt L et al., Lancet Neurol 2008; 7: 779–86. (PBT2) Kessler H et al., J Neural Transm 2008; 115: 1181–7. (copper) Green RC et al., J Am Med Assoc 2009; 302: 2557–64. (Tarenflurbil) Hampel H et al., J Clin Psych 2009; 70: 922–31. (lithium) Scheltens P et al., Alzheimers Dement 2010; 6: 1–10. (Souvenaid) Souvenir II is the first study to suggest memory improvement as a predefined primary outcome measure Scheltens P et al., J Alzheimers Dis 2012; 31(1): (Souvenaid) Mild AD is a New Target 1 Medline search string: English up to June 2012, Searches were restricted to randomized controlled clinical trials performed in an exclusively mild AD study population. "mild/early Alzheimer's" or "very mild Alzheimer's" or "cognition testing and outcome and Alzheimer’s" and randomized/controlled/single blind/double blind/intervention study/trial" including nutritional intervention studies.

42 Abnormal Normal Time Presymptomatic Dementia CSF Aβ 42 Amyloid imaging FDG-PET MRI hippocampal volume CSF Tau Cognitive performance Function (ADL) FDG-PET (Synaptic Dysfunction) MRI hippocampal volume CSF Aβ 42 Amyloid imaging Cognitive performance Function (ADL) CSF Tau Prodromal The AD Continuum Modified from Aisen PS Alzheimers Dement. 2010

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

44 VUmc Alzheimer Center


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