Nutritional approach for prevention and treatment of dementia

Elio Scarpini

Università di MilanoU.V.A.

Fondazione Cà GrandaIRCCS Ospedale Maggiore Policlinico

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

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

AD pathogenesisthe amyloid cascade hypothesis

Aβ formation and deposition in AD and APP-transgenic mice

Nature, 1999

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

Double-blind clinical assessment maintained for 12 months:

significant differences in cognition favouring antibody responders compared

to placebo group

Gilman et al, 2005

Results after 6 yrs: clearance of amyloid plaques, but no evidence of increased survival

and no improvement in the time to severe dementia!

New approach: passive immunization

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

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)

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

Results: clearance of amyloid plaques, but no evidence of increased survival and no improvement

in the time to severe dementia!

- 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

BIOMARKERS STAGING

IN ALZHEIMER DISEASE

AGE

No β-amyloid

No atrophy

β-amyloid

No atrophy

β-amyloid

Atrophy

“Disease modifying” treatments

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

Mangialasche et al, 2010

I FARMACI: PRESENTE E FUTURO

Risultati insoddisfacenti ed effetti collaterali!

• 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)

Prevalence/Incidence in Africa

Rhyannon et al. Journal of global health 2013

CHINA

Kit Yee Chang, Lancet 2013;381, 2016-2023

Epidemiology of AD

persons 60+ years old

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)

PREVENZIONE

Contrastare i fattori di rischio

Approccio nutrizionale:

- dieta

- integratori alimentari specifici

In soggetti con MCI: dieta mediterranea dimezza il rischio di AD (follow up: 4,3 anni)

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

- The MeDi score: range 0 to 9- Mild to moderate alcohol consumption (>5g;<25g)

MeDi Score and Alzheimer

Ipotesi relazione dieta - AD

- Resistenza insulinica

- Stato pro-ossidante

- Stato pro-infiammatorio

- Ridotta generazione endoteliale di ossido

nitrico

- Accumulo di omocisteina

AAD and Diabetes

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.

-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

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

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

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

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

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 - -

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.

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)

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

Prevenzione: l’approccio nutrizionale

mediante integratori specifici

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.

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

Lower plasma levels of vitamin A in patients as compared with elderly controls (-20%, P<0.001)

Folate

Lower plasma levels of folate in patients as compared with elderly controls (-20%, P<0.001)

Vitamin B12

Lower plasma levels of vitamin B12 in patients as compared with elderly controls (-15%, P<0.001)

Same for vitamin E

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

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

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

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

Memory domain

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

Epigenetica, alimentazione e stile di

vita

Epigenetic alterations in AD

Mastroeni et al. Neurobiol Aging. 2011

- Histone modifications

- miRNAs

- DNA methylation

Increased methylation of LINE-1 and Alu repeated sequences in blood from patients

versus controls

Gene expression modulation?

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

The future:engeneered

sushi to treat AD?

“Fai che il cibo sia la tua medicina e che la medicina sia il tuo cibo”

Ippocrate di Kos (V sec A.C.)

Acknowledgements

Daniela GalimbertiChiara FenoglioMaria SerpenteRossana BonsiSara CioffiMarina Arcaro

Roberto VimercatiEmanuela RotondoPriscilla CortiMatteo Mercurio

Milena De RizAnna PietroboniAndrea ArighiGiorgio FumagalliLaura GhezziAlberto CalviPaola Basilico