nutritional approach for prevention and treatment of dementia · nutritional approach for...
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Nutritional approach for prevention and treatment of dementia
Elio Scarpini
Università di MilanoU.V.A.
Fondazione Cà GrandaIRCCS Ospedale Maggiore Policlinico
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La malattia di Alzheimer
É la causa più frequente di demenza
Colpisce circa il 6% della popolazione sopra i 65 anni
È una delle cause principali
di disabilità e di morte
negli anziani
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Terapia: approccio farmacologico
- unici farmaci attualmente disponibili: inibitori della colinesterasi e memantina
- farmaci sintomatici
- rallentano la progressione dei sintomi in circa il 1/3 dei pazienti trattati
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AD pathogenesisthe amyloid cascade hypothesis
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Aβ formation and deposition in AD and APP-transgenic mice
Nature, 1999
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Active immunizationHUMAN TRIAL: AN1792 + AS21 adjuvant
� phase IIa study- 372 probable AD (mild to moderate)
Study discontinuation!
Aseptic meningoencephalitis in 18 of 300 (6%) immunized patients
By the time of discontinuation:- 24 patients received 3 immunizations- 274 received 2 immunizations
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Double-blind clinical assessment maintained for 12 months:
significant differences in cognition favouring antibody responders compared
to placebo group
Gilman et al, 2005
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Results after 6 yrs: clearance of amyloid plaques, but no evidence of increased survival
and no improvement in the time to severe dementia!
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New approach: passive immunization
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Anti-A β antibodies: Fc-receptor- mediated phagocytosis (“central” hypothesis)
Liver clearance
CSF
Plasma
AβBrain
Blood-brain barrier
Intracellular
Aβ
Aβ
Aβ antibody
γ secretase
Interstitial space
sAPP β
AICD
β secretase
Oligomers
Amyloid plaque
APP
Amyloid plaque
Phagocytosis
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Aβ antibody Liver clearance
CSF
Soluble A βBrain
Blood-brain barrier
Intracellular
Aβ
PlasmaAβ
γ secretase
Interstitial space
sAPP β
AICD
β secretase
Oligomers
Amyloid plaque
APP
Anti-A β antibodies: facilitated peripheral clearance (“sink” hypothesis)
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Ostrowitzki, S. et al. Arch Neurol 2012
Effect of gantenerumab on amyloid load
as indexed by standard uptake value ratios (SUVRs) using carbon 11-labeled ([11C] PiB) PET
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Results: clearance of amyloid plaques, but no evidence of increased survival and no improvement
in the time to severe dementia!
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- Extracellular beta-amyloid plaques (“senile plaques”)
- Intracellular neurofibrillary tangles (NFTs)
Birth 40 60 80 Death
AD brain changes may start decadesbefore symptoms show
Amnestic MCI: memory problems; other cognitive functions OK; brain compensates for changes
Cognitive decline accelerates after AD diagnosis
Normal age-related memory loss
Total loss of independent function
Healthy aging Amnestic MCI Clinically diagnosed AD
Life Course
MODELLO ATTUALE
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BIOMARKERS STAGING
IN ALZHEIMER DISEASE
AGE
No β-amyloid
No atrophy
β-amyloid
No atrophy
β-amyloid
Atrophy
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“Disease modifying” treatments
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Fase pre-demenza
Mild Cognitive Impairment (Petersen et al.)
Prodromal AD (Dubois et al.)
In assenza di terapie efficaci:necessità di sviluppare nuove strategie
per prevenire la progressione da MCI ad AD
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Mangialasche et al, 2010
I FARMACI: PRESENTE E FUTURO
Risultati insoddisfacenti ed effetti collaterali!
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• 1/9 age ≥65 (11%)• 1/3 age≥85 (32%)• 5,2 million Americans (5mil age ≥65 aa; 200mila age<65aa)• 53/1000 age 65-74; 170/1000 age 75-84; 231/1000 age≥85.• Almost two-thirds of Americans with AD are women• the annual number of new cases of Alzheimer’s and other
dementias is projected to double by 2050
4%13%
45%
38%
Distribuzione per età
≤65 65-74 75-84 ≥85
Epidemiology of Alzheimer (USA)2010 U.S. Census and the Chicago Health and Aging Project (CHAP)
Aging, Demographics, and Memory Study (ADAMS)
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Prevalence/Incidence in Africa
Rhyannon et al. Journal of global health 2013
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CHINA
Kit Yee Chang, Lancet 2013;381, 2016-2023
Epidemiology of AD
persons 60+ years old
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ORIGINE DELLA MALATTIA
È una malattia MULTIFATTORIALE
Nella sua insorgenza sono coinvolti molti fattori, alcuni MODIFICABILI, altri NON MODIFICABILI
NON MODIFICABILI
Età
Corredo genetico (APOE)
MODIFICABILI
Livello di istruzione (?)
Rischio cardiovascolare
Stile di vita (fumo, alcol, alimentazione, attività fisica…)
Farmaci (FANS, estrogeni?)
Altri fattori non noti (genetici e ambientali)
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PREVENZIONE
Contrastare i fattori di rischio
Approccio nutrizionale:
- dieta
- integratori alimentari specifici
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In soggetti con MCI: dieta mediterranea dimezza il rischio di AD (follow up: 4,3 anni)
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Mediterranean Diet
Alimenti preventivi: cereali integrali, pasta di grano duro,
legumi, prodotti di soia, verdure, frutta, semi
oleoginosi, olio d’oliva e pesce
Alimenti che peggiorano l’ equilibrio metabolico: pane bianco e farine raffinate, zucchero, patate, latte,
formaggi, burro, carni rosse, bianche e conservate
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- The MeDi score: range 0 to 9- Mild to moderate alcohol consumption (>5g;<25g)
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MeDi Score and Alzheimer
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Ipotesi relazione dieta - AD
- Resistenza insulinica
- Stato pro-ossidante
- Stato pro-infiammatorio
- Ridotta generazione endoteliale di ossido
nitrico
- Accumulo di omocisteina
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AAD and Diabetes
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A cross talk between brain and pheripheral tissues: a central role in triggering the onset of sporadic AD.
AD is caused by a metabolic dyshomeostasis. Result of cumulative, lifelong impact in peripheral tissues and brain.
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-An unhealthy lifestyle (lack of or insufficient physical activity, inadequate nutrition), which may start in the first years of life and increase the prevalence of type 2 diabetes in youth, might have an important role in susceptibility to AD later
-An unhealthy lifestyle triggers deleterious processes in peripheral tissue, leading to the activation of pathways related to chronic metabolic syndrome (including obesity,
insulin resistance, and type 2 diabetes).
Unhealthy lifestyle an risk of AD
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Dieta povera di grassi insaturi, con basso indice glicemico
aumento concentrazioni liquorali Aβ42
DIET may be a powerful environmental factorthat modulates AD risk
through its effects on CNS concentrations ofAβ42, lipoproteins, oxidative stress, and insulin
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In unadjusted models that simultaneously included a ll nutrients:higher intake of ω-3 polyunsaturated fatty acid associated with lower levels of Aβ40 and lower levels of Aβ42.
ω-3 polyunsaturated fatty acid: strong predictor of Aβ42, whereas its association with Aβ40 is attenuated.
Other nutrients: not associated with plasma Aβ levels.
Conclusions:
higher dietary intake of ω-3 polyunsaturated fatty acid is associated with lower plasma levels of Aβ42, a
profile linked with reduced risk of incident AD and slower cognitive decline
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Progetto AliDem
PREVENIRE LA DEMENZA DI ALZHEIMER CON L’ALIMENTAZIONE
• Fondazione IRCCS Istituto Neurologico C.Besta
• Fondazione IRCCS Istituto Nazionale dei Tumori
• Fondazione IRCCS Ca’ Granda OspedaleMaggiore Policlinico
• Fondazione San Raffaele del Monte Tabor
• Azienda di Servizi alla Persona Golgi-Redaelli
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Progetto AliDem
PREVENIRE LA DEMENZA DI ALZHEIMER CON L’ALIMENTAZIONE
STUDIO INTERVENTISTICO NON FARMACOLOGICO MULTICENTRICO
RANDOMIZZATO NON CONTROLLATO IN APERTO
prevede:
• Selezione di soggetti Mild Cognitive Impairment amnestico e multidominio
• Selezione di soggetti con concentraz. liquorale di Aβ42 <500 ng/L
• Randomizzazione per costituzione del gruppo di intervento e del gruppo di controllo
• Intervento alimentare sul gruppo intervento
• Follow-up con monitoraggio della compliance e registrazione delle progressioni in demenza di Alzheimer
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Razionale Classe di alimenti Iper-
Glicemia iper- insulinemia
infiam- mazione
dis- lipidemia
stato ossidativo
iper-tensione
Pane bianco e farine raffinate
+ + +
Zucchero e soft drinks + + + Patate + Latte + Formaggi + + + + Burro, margarine + + + Carni rosse, carni conservate
+ + + + +
Carni bianche + Cereali integrali - - - - - - Pasta (di grano duro) - - Legumi - - - Prodotti di soia - - - - - Verdure - - - Frutta - Semi oleaginosi - - Olio di oliva - - Pesce - -
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Progetto AliDem
PREVENIRE LA DEMENZA DI ALZHEIMER CON L’ALIMENTAZIONE
OBIETTIVO PRIMARIO
K Valutare l’efficacia della dieta mediterraneatradizionale, integrata da principi della
macrobiotica, per la prevenzione della Demenza
di Alzheimer nelle persone con lieve deficitcognitivo con compromissione delle funzionimnesiche (MCIa, MCImd) attraversol’organizzazione e la gestione di unasperimentazione clinica randomizzata.
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Progetto AliDem
PREVENIRE LA DEMENZA DI ALZHEIMER CON L’ALIMENTAZIONE
OBIETTIVI SECONDARI
檾Meccanismi patogenetici ipotizzabili e da valutare:
⫋ - azione anti-aterosclerotica
K - azione anti-ossidante
K - azione anti-infiammatoria
K - azione anti-diabetica
K - azione anti-ipertensiva
K - modifica della scala ADAS-Cog
K Valutazione di: esami ematochimici, parametri sindrome metabolica, esami antropometrici (impedenziometria)
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PREVENIRE LA DEMENZA DI ALZHEIMER CON L’ALIMENTAZIONE
Gruppo controllo:1. Dieta sana 2. Esercizio regolare 3. Attività mentale 4. Igiene del sonno 6. Riduzione dello stress 5. Vita attiva
Progetto AliDem
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Prevenzione: l’approccio nutrizionale
mediante integratori specifici
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Structural loss of synapse basis of functional
deficits in AD
Reduced number of synapses
Control MCI AD0
5
10 *
-13% -44%
# sy
naps
es d
enta
te g
yrus
(x1
010
)
New approaches to prevent and treat AD are urgently needed!
Because cognitive disturbances of AD best correlate with loss of hippocampal and cortical synapses [2], a possible therapeutic strategy might involve steps to restore such synapses.
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Low intake of some nutrients: associated with a loss of cognitive
function and increased risk of AD
Fish consumption
0
1
2
3
4
5
6
7
daily > weekly < weekly never
Inci
denc
e(p
er 1
00 p
erso
ns y
ear)
AD Dementia
Barberger-Gateau et al. (2002) BMJ; Engelhart et a l. (2002) JAMA
Vitamin C intake<95 96-133 >133 mg/d
0
1
Rel
ativ
e R
isk
Rotterdam study
Low intake of nutrients is associated with cognitive decline
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Lower plasma levels of vitamin A in patients as compared with elderly controls (-20%, P<0.001)
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Folate
Lower plasma levels of folate in patients as compared with elderly controls (-20%, P<0.001)
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Vitamin B12
Lower plasma levels of vitamin B12 in patients as compared with elderly controls (-15%, P<0.001)
Same for vitamin E
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Other nutrients
No (significant) differences in:
- Vitamin D
- Zinc
- Copper
- Iron
Conflicting results:
- Fatty acids
- Calcium
- Magnesium
- Manganese
- Selenium
- Copper
Additional research needed toinvestigate the changes in AD-specific eating behavior, nutrient metabolism, and pathophysiology causing the lower nutrient levels in AD and to determine when in the disease spectrum the lower levels start to manifest
The highly significant effects acrossa range of nutrients provide conclusive evidencethat plasma nutrients levels are lower in AD, andthe lower levels may occur in the absence of, or precede, signs of protein and energy malnutrition → nutritional strategies in AD
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Dietary precursor control of neural membrane synthesis
The Kennedy pathway for biosynthesis neuronal membrane
Membranes are main constituents of synapses
Phosphocholine
CDP-choline
Phosphatidylcholine
New neuronal membraneNew neuronal membrane
PhospholipidsCholine
PhospholipidsCholine
UridineUridine
Omega-3 fatty acidsOmega-3 fatty acids
Axon
neurite
dendriticspine
Axon
Axon terminal
dendriticspine
Preclinical studies indicate that such an effect can be induced by co-administration of rate-limiting precursors for membrane phosphatide synthesis, such as:the nucleotide uridine, omega-3 polyunsat. fatty
acids, choline
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Dietary precursors increase membrane
dependent structures: neurite outgrowth
Pooler et al. (2005) Neuroscience
Control
Uridine 150 µM
Increase of hippocampal dendritic spines, the anatomical precursor and surrogate marker of new synapses
1 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 stimulate neurite outgrowth in vitro 1
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Fortasyn reduces Abeta-induced toxicity in vivo: protection cholinergic cells & behaviour
ICV Abeta1-42 infusionResembling AD pathology
Neuroprotective: behaviour normalised
•Abeta 1-42
0
100
200
300
400
500
Sham Abeta Sham Abeta
ChA
T p
ositi
ve c
ells
NB
M
Control Fortasyn TM Connect*
*
Choline acetyl-transferase
VA
ChT
pos
itive
cel
lsN
BM
0
50
100
150
200
250
300
350
Sham Abeta Sham Abeta
Control
*Vesicular ACh transporter
Neurodegenerative markers
Fortasyn TM Connect*
De Wilde, 2011, J Alz Dis
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Memory domain
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Results I
NTB memory domain
interventional period: 24 weeks
Significant difference
between active and controlgroups
(p=0.023)
Primary outcome
NTB memory domainNTB memory domain
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Epigenetica, alimentazione e stile di
vita
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Epigenetic alterations in AD
Mastroeni et al. Neurobiol Aging. 2011
- Histone modifications
- miRNAs
- DNA methylation
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Increased methylation of LINE-1 and Alu repeated sequences in blood from patients
versus controls
Gene expression modulation?
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Nutrients
are part of methyl-group metabolism
can significantly influence epigenetics
dietary methyl-group intake (choline, methionine, and folate) can alter DNA and
histone methylation
Zeisel. Am J Clin Nutr 2009
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The future:engeneered
sushi to treat AD?
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“Fai che il cibo sia la tua medicina e che la medicina sia il tuo cibo”
Ippocrate di Kos (V sec A.C.)
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Acknowledgements
Daniela GalimbertiChiara FenoglioMaria SerpenteRossana BonsiSara CioffiMarina Arcaro
Roberto VimercatiEmanuela RotondoPriscilla CortiMatteo Mercurio
Milena De RizAnna PietroboniAndrea ArighiGiorgio FumagalliLaura GhezziAlberto CalviPaola Basilico