prof. dr. philip scheltens treatment ad in the earliest stage: the role of medical nutrition
TRANSCRIPT
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
Aantal jong dementerende(<65) neemt toe
De impact van Alzheimer
1 op de 10 > 65 heeft Alzheimer 1 op de 3 > 80 heeft Alzheimer
De impact van Alzheimer
1 op de 10 > 65 heeft Alzheimer 1 op de 3 > 80 heeft Alzheimer
Iedere 15 minuten krijgt iemand Alzheimer
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 2040.
Terwijl de beroepsbevolking in aantal afneemt…...neemt de belasting voor de maatschappij
toe!
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
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
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
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
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