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

Prof. Dr. Philip Scheltens

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

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

Alzheimer: de getallenNu: ~ 250.000 patiënten in Nederland

Belangrijkste risicofactor: Leeftijd

Dubbele vergrijzing: méér ouderenworden ouder snelle toename!

Schatting 2040: 500.000

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De impact van Alzheimer

1 op de 10 > 65 heeft Alzheimer 1 op de 3 > 80 heeft Alzheimer



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Terwijl de beroepsbevolking in aantal afneemt…...neemt de belasting voor de maatschappij

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Alzheimer: 3 fundamentele processen

Seniele plaques

Neurofibrillaire kluwens

Synapsverlies

Synaptic Failure in Alzheimer’s disease

Control MCI AD0

5

10 *

-13% -44%

# S

ynap

ses

dent

ate

gyru

s (x

101

0)

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

Nutritional precursor control of neuronal membrane synthesis

Axon

neurite

dendriticspine

Sa

tura

ted

fa

tty

ac

id

Glycerol

Phosphate

Choline

PUFA

Phospholipids are synthesized by the Kennedy Pathway

Sat

ura

ted

fat

ty a

cid

Glycerol

Phosphate

Choline

PUFA

e.g. DHA

KENNEDY EP, WEISS SB (1956). J. Biol. Chem. 222 (1): 193–214

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.

Onverzadigde vetzuren Verzadigde vetzuren

UMPDHA, EPACholinePhospholipidsB vitaminsAnti-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:

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

Control Uridine 50 µM

Sakamoto et al. (2007) Brain Res

Sp

ine

De

nsi

ty h

ipp

oca

mp

us

(fo

r 5

0µ

M)

Control (choline)

UMP UMP DHA

DHA

***

0

20

40

60

80

100

Nutritional precursors increase membrane dependent structures(dendritic spines in gerbil hippocampus)

http://en.wikipedia.org/wiki/Dendritic_spine

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-13Baseline Characteristics

Control

(n = 106)

Active

(n = 106)

Sex (male/female; counts) 52 / 54 54 / 52

Age (y) 73.3 ± 7.8 74.1 ± 7.2

BMI (kg/m2) 26.2 ± 3.5 26.2 ± 4.8

Years of education on top of primary school

6.0 ± 4.0 5.5 ± 3.9

Days since AD diagnosis (median)

31.5 (0 – 1036)

30.0 (0 – 1932)

Total MMSE score 24.0 ± 2.5 23.8 ± 2.7

Values are mean ±SD, unless stated otherwise t ≤-3 t=0 6 12 wks

n=212

Souvenaid (n=106)

Control (n=106)

Outcome parameters

• Significant changes (p<0.001) in vitamin E and EPA

Blood Nutritional Parameters

ITT, data are mean ± SE

0 6 1230.0

35.0

40.0

45.0

Control

Active

Time (weeks)

Vita

min

E (

µm

ol/L

)

0 6 120.8

1.0

1.2

1.4

1.6

1.8

2.0

Control

Active

Time (weeks)

EP

A in

tota

l fa

tty a

cid

s o

fe

rytr

ho

cyte

me

mb

ran

es

(%)

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

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. = 25Totaal verhaal A

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

0

10

20

30

40

50

worsened unchanged improved

Pre-defined subgroup MMSE 24 - 26, Chi-square

Scheltens et al. Alzheimers Dement. 2010 6 (1):1-10.

0

10

20

30

40

50

worsened unchanged improved

% o

f pat

ient

s

Control Active

(p=0.019)(p=0.021)

Co-Primary Outcome: ADAS-cog

0 6 12

-1.5

-1

-0.5

0

0.5

1

Control

Active

Weeks

AD

AS

-co

g m

ean

ch

ang

e f

rom

bas

elin

e

ITT, MMRM, data are mean ± SE

Primary analysis:No significant (p=0.826) effect1

1Scheltens et al. Alzheimers Dement. 2010 6 (1):1-10.2Kamphuis et al. J Nutr Health Aging. 2011 15(8):720-4.

Cognition (ADAS-cog)

Cognition (NTB) Biomarker MRI & CSF

Memory (WMS-r) & Cognition (ADAS-cog)

Memory (NTB) Biomarker EEG & MEG

MildProdromal Moderate

Clinical Trials

Trials are registered in the ICMJE compliant www.trialregister.nl

S-Connect study: Mild to Moderate ADusing 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 ≤-3 0 12 24 wk

Outcome parameters

n=262 Control

Values are mean±SD, unless stated otherwise

Baseline CharacteristicsControl

(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 score 19.3 (3.0) 19.5 (3.2)

Duration AD since diagnosis (months) 34.9 (29.6) 32.7 (25.0)

Acetylcholinesterase inhibitors 243 (92.7%) 251 (94.7%)

NMDA antagonist 170 (64.9%) 177 (66.8%)

BMI (kg/m2) 26.64 (4.56) 26.19 (4.51)

No difference in Adverse Events

Body SystemControl(n=262)

Active(n=265)

p-value

Any AE 165 (60.1) 150 (56.8) 0.130

Body as a whole 33 (12.7) 24 (9.1) 0.208

Nervous system 21 (8.1) 27 (10.2) 0.450

Gastro-intestinal 38 (14.6) 41 (15.5) 0.808

Metabolic & nutritional 19 (7.3) 19 (7.2) 1.000

Musculo-skeletal 15 (5.8) 24 (9.1) 0.183

Psychiatric 43 (16.5) 32 (12.1) 0.170

Respiratory system 42 (16.2) 50 (18.9) 0.423

Skin and appendages 18 (6.9) 8 (3.0) 0.045

Urinary system 19 (7.3) 25 (9.5) 0.432

Other 27 (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

No significant effect* (p=0.513) during 24 weeks

Primary Outcome: ADAS-cog

Baseline Week 12 Week 240

0.5

1

1.5

2

2.5

Active

Control

AD

AS

-co

g c

han

ge

fro

m b

asel

ine

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






Clinical Trials


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=259n=130 Active

t ≤-3 0 12 24 wk

n=129 Control

Outcome parameters

Values are mean±SD, unless stated otherwise

Baseline CharacteristicsControl

(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 (0.0 - 88.0) 1.0 (0.0 - 70.0)

BMI (kg/m2) 26.7 (4.2) 26.1 (4.1)

No Difference in Adverse Events

Body system ExamplesControl (n=129)

Active (n=130)

p-value

Body as a whole Fatigue, influenza-like symptoms 20 (15.5%) 11 (8.5%) p=0.125

Central and peripheral nervous system disorders

Dizziness, headache 18 (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 neuralgia 9 (7.0%) 10 (7.8%) p=1.000

Psychiatric disorders Anxiety, depression, insomnia 16 (12.4%) 15 (11.6%) p=1.000

Respiratory system disorders Pharyngitis, bronchitis 15 (11.6%) 10 (7.8%) p=0.400

Skin and appendages disorders Rash, skin dry 10 (7.8%) 4 (3.1%) p=0.168

Other Fall, surgical intervention 8 (6.2%) 8 (6.2%) p=1.000

Occurrence of > 5% in total subjects

• Overall compliance during 24 weeks was 97% and not different between the groups

Primary Efficacy: Memory Domain Score (z-score) of the NTB

0 12 240

0.05

0.1

0.15

0.2

0.25

Control

Active

Time (weeks)

Me

an

ch

an

ge

fro

m b

ase

line

in N

TB

Me

mo

ry d

om

ain

z-s

core

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. 2012 31(1):225-36.

0 12 24-0.05

0

0.05

0.1

0.15

0.2

Control

Active

Time (weeks)

Me

an

ch

an

ge

fro

m b

ase

line

inN

TB

exe

cutiv

e d

om

ain

z-s

core

ITT, MMRM, 2 df contrast, data are mean ±SE

0 12 24-0.05

0

0.05

0.1

0.15

0.2

Control

Active

Time (weeks)

Me

an

ch

an

ge

fro

m b

ase

line

into

tal N

TB

co

mp

osi

te z

-sco

reSecondary 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. 2012 31(1):225-36.

0 12 24 36 480.00

0.10

0.20

0.30

0.40

Control - ActiveActive - Active

Time (weeks)

Mea

n ch

ange

from

bas

elin

e in

N

TB m

emor

y do

mai

n z-

scor

e

0 12 24 36 48

Control (N) - 100 103 85 83

Active (N) - 107 103 83 83

Week 0, 12, 24 -> SII ITT;Week 36, 48 -> OLE ITT, all subjectsRaw means and SE; change from baseline

Double-blind treatment Open-label extension

Exploratory – Memory domain z-score

Electrical Activity at the Synapse – EEG: Biomarker for Functional Connectivity

1. Basic quantitative EEG analysis -Relative power and Peak Frequency

In AD disturbed signal strength1

1Stam CJ et al. Brain 2009 132, 213-242Stam CJ, van Straaten ECW. Clin Neurophysiol 2012 doi:10.1016/j.clinph.2012.01.011

2. Phase Leg Index (PLI) as Functional Connectivity measure

In AD loss of PLI1

3. Clustering & Path length are measures of Network Organization

In AD disrupted Organization2

PLI

Healthy AD

0 12 240.915

0.920

0.925

0.930

0.935

Time (weeks)

No

rma

lise

d p

ath

len

gth

in b

eta

ba

nd

0 12 248.20

8.40

8.60

8.80

9.00

9.20ControlActive

Time (weeks)

Pea

k fr

eque

ncy

(Hz)

0 12 241.010

1.015

1.020

1.025

1.030

ControlActive

Time (weeks)

Nor

mal

ised

clu

ster

ing

coe

ffic

ient

in b

eta

band

0 12 240.12

0.13

0.14

0.15ControlActive

Time (weeks)

Ph

ase

La

g I

nd

ex

(PL

I)in

de

lta b

an

d

3. Brain Network organization*1. Peak Frequency

p=0.053

p=0.009

2. Phase Leg Index

p=0.011

p=0.019

Network Parameters suggest PreservedSynaptic Formation, Function and Network

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






Clinical Trials


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

Abnormal

Normal TimePresymptomatic Dementia

CSF Aβ42

Amyloid imagingFDG-PETMRI hippocampal volumeCSF TauCognitive performanceFunction (ADL)

FDG-PET (Synaptic Dysfunction)

MRI hippocampal volume

CSF Aβ42

Amyloid imaging

Cognitive performance

Function (ADL)

CSF Tau

Prodromal

The AD Continuum

Modified from Aisen PS Alzheimers Dement. 2010

CARE

SYMPTOMATIC APPROACH

LOWERING AMYLOID ?

IMMUNISATION ?

MEDICAL FOOD

Multi Level Approach: no single magic bullit for AD

VUmc Alzheimer Center

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

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