Depressione e demenza nell'anziano:

legami neurobiologici e nuovi scenari terapeutici

Istituto di Gerontologia e GeriatriaIstituto di Gerontologia e GeriatriaUniversitUniversitàà degli Studi didegli Studi di PerugiaPerugia

Patrizia Mecocci

• Incidenza e prevalenza della demenza sono destinate a crescere nel corso dei prossimi anni

• La terapia farmacologica attualmente disponibile permette solo un modesto miglioramento della sintomatologia

UNICA POSSIBILE STRATEGIA: PREVENZIONE

IDENTIFICAZIONE E MODIFICAZIONE DEI FATTORI DI

RISCHIO

l’ ‘arma’ fondamentale finché non verrà provata l’efficacia di

DISEASE MODIFYING AGENTS

Middleton and Yaffe, Arch Neurol 2009

DEPRESSIONE IN ADDEPRESSIONE IN AD

- peggiore qualità di vita- ADL- declino cognitivo più rapido- mortalità

Lavretsky et al, Am J Psychiatry, 2010

DIAGNOSI DIFFERENZIALE TRA DEPRESSIONE E DEMENZA

PROBLEMA: sovrapposizione tra sintomi depressivi e sintomi di declino cognitivo e

funzionale

depressione si può presentare

con sintomi cognitivi

demenza si può presentare

con sintomi affettivi

difficoltà a gestire attività quotidiane

evidente ritiro dai rapporti sociali

Trattamento della depressione- E’ ben noto che, anche in età adulta, la presenza di

depressione riduce le capacità cognitive- Varie ipotesi sono state avanzate circa la relazione tra

depressione e demenza:- la depressione può essere un sintomo precoce o

prodromico di demenza- la diagnosi di depressione può talvolta agevolare quella di

demenza, specie negli stadi precoci- i soggetti con iniziali deficit cognitivi sono a maggior rischio

di sviluppare depressione

FATTORE DI RISCHIO

O SINTOMO PRODROMICO?

BIOMARKER NELLA DEPRESSIONE AD

INSORGENZA TARDIVA E NELLA

DEMENZA

integrità sostanza bianca nei circuiti fronto-striato-limbici

spessore di ginocchio e spleniodel corpo calloso

volume ippocampo

WMLA fattore rischio per demenza

NEUROIMAGING (MRI)

DEPRESSIONE

NEUROIMAGING(MRI)

↓ volume ippocampo e cortecciaentorinale

atrofia significativa corteccia temporale anteromediale e giro angolare sinistro

danno sostanza bianca a livello delle connessioni delle strutturelimbiche (DTI)

DEMENZA

vitamina B12 e folati, omocisteina (più

fattori di rischio chebiomarkers)

NUTRIZIONALI

ENDOCRINI patologie tiroide e asse ipotalamo-ipofisi-surrene

livelli di testosterone totale e libero nell’uomo

INFIAMMATORI IL-6 con = PCR

PROTEICI Ab42, Ab40/Ab42

DEPRESSIONE

MARKER PLASMATICI

possibili predittoridi deterioramento

cognitivo

↓ Ab42

↑ Ab40/Ab42

indicatori di disregolazione di sistema emopoietico, immunitario, apoptosi,

neurotrofismo identificherebbero MCI che convertono in AD

MARKERS INFIAMMATORI

IL-1 e TNFαverosimile associazione con conversione di MCI

in AD

18 PROTEINE REGOLATRICI DI

VARI SISTEMI

DEMENZA

MARKER PLASMATICI

MARKER GENETICI

POLIMORFISMO L/L PROMOTER

TRASPORTATORE DELLA SEROTONINA

associazionecon volume

ippocampo

POLIMORFISMO Val66Met BRAIN DERIVED

NEUROTROPHIC FACTOR (BDNF)

associazione coniperintensità della sostanza bianca e

vulnerabilità a danno vascolare

ALLELE APOE ε4 probabile ruolo nel sesso femminile

DEPRESSIONE

vari tipi di mutazione (gene APP su cromosoma 21,

presenilina 1 sul 14,presenilina 2 sull’1) responsabili di eAD

MUTAZIONI APP O

PRESENILINE

ALLELE APOE ε4

implicato nella forma sporadica di AD e suo

principale fattore di rischio genetico; predittivo di

progressione più rapida di AD

DELEZIONE NEL GENE DOPAMINA β-IDROSSILASI

probabile modificazione dell’effetto di ApoEε4 nel

sesso femminile

DEMENZAMARKER GENETICI

POSSIBILI MECCANISMI

dannineurobiologici

AD

capacitàdella riserva

cerebrale

MCI e rapida progressione

ad AD

danno circuito frontostriatale e frontolimbico

danno vascolare

depressione

Ipotesi vascolare-metabolicafattori di rischio vascolare

DEPRESSIONE

eccessoglicocorticoidi

noradrenalinae serotonina

danno cortecciadanno corteccia

Ipotesi neuroendocrina: asse IIS

atrofia ippocampoatrofia ippocampo

POSSIBILI MECCANISMI

DEMENZA

BDNFTGF β1

POSSIBILI MECCANISMIIpotesi infiammatoria

“sicknessbehavior”

IL-1IL-6 (Th1)TNFαIFNγ (Th1)

PGE2

⊕

IDO

⊕

5-HT

5-HIAA

IDO=indolamine 2,3 diossigenasi Triptofano Kinurenina Acido quinolinico apoptosi neurode-generazione

IL-4IL-10Θ⊕

⊕

CRH

Cortisolo

Depressione

NA, 5-HT NMDA attività

⊕

ULTERIORI SCENARI

TERAPEUTICI

POSSIBILE MECCANISMO COMUNE: POSSIBILE MECCANISMO COMUNE: disturbo delladisturbo della metilazionemetilazione a livello a livello

centrale centrale

Cerebrospinal fluid S-adenosylmethionine-indepression and dementia: effects of treatmentwith parenteral and oral S-adenosylmethionine

Bottiglieri et al, JNNP 1990

In cerebrospinal fluid (CSF) S-adenosylmethionine (SAM) levels were significantly lower in severely depressed patients than in a neurological control group. Theadministration of SAM either intravenously ororally is associated with a significant rise of CSF SAM, indicating that it crosses the blood-brain barrier in humans. These observations provide arational basis for the antidepressant effect of SAM, which has been confirmed in several countries. CSF SAM levels were low in a group ofpatients with Alzheimer's dementia suggesting apossible disturbance of methylation in such patients and the need for trials of SAM treatment.

METHOD: Participants were 73 serotonin reuptake inhibitor (SRI) nonresponders withmajor depressive disorder enrolled in a 6-week, double-blind, randomized trial ofadjunctive oral SAMe (target dose: 800 mg/twice daily). Patients continued to receive their SRI treatment at a stable dose throughout the 6-week trial. The primary outcome measure for the study was the response rates according to the 17-item Hamilton Depression Rating Scale (HAM-D).

RESULTS: The HAM-D response and remission rates were higher for patients treated with adjunctive SAMe (36.1% and 25.8%, respectively) than adjunctive placebo (17.6%versus 11.7%, respectively). The number needed to treat for response and remission was approximately one in six and one in seven, respectively.

CONCLUSIONS: These preliminary results suggest that SAMe canbe an effective, well-tolerated, and safe adjunctive treatmentstrategy for SRI nonresponders with major depressive disorderand warrant replication.

Papakostas et al., Am J Psychiatry, 2010

S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with

major depressive disorder: a double-blind, randomized clinical trial.

Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time.

Skarupski et al., Am J Clin Nutr. 2010

CONCLUSION: Our results support the hypotheses that hightotal intakes of vitamins B-6 and B-12 are protective of depressive symptoms overtime in community-residing older adults

Mental health literacy, folic acid and vitamin B12, and physical activity for the prevention of depression in older adults: randomised controlled trial.

Walker et al., Br J Psychiatry. 2010

CONCLUSIONS: Mental health literacy had a transient effect on depressive symptoms. Other than this, none of the interventions significantly reduced symptoms relative to their comparator at 6 weeks or subsequently. Neither folic acid plus B(12) nor physical activity were effective in reducing depressive symptoms.

Fava et al., J Clin Psychiatry 2009

Folate in depression: efficacy, safety,differences in formulations and clinical

issuesSupplementation with folate may help reduce depressive symptoms.

Folate is needed in the brain for the synthesis of norepinephrine, serotonin, and dopamine.

Three forms of folate are commonly used: folic acid, 5-methyltetrahydrofolate (5-MTHF) (also known as methylfolate), and folinic acid.

Some forms may be more bioavailable than others in patients with a genetic polymorphism and in those who take particular medications or use alcohol.

Folic acid augmentation in depressed patients may reduce residual symptoms.

The 5-MTHF formulation indicated efficacy as adjunctive therapy or monotherapy in reducing depressive symptoms in patients with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly patients with dementia and folate deficiency, and reducing depressive and somatic symptoms in patients with depression and alcoholism.

Adjunctive folinic acid reduced depressive symptoms in patients who were partially responsive or nonresponsive to a selective serotonin reuptake inhibitor.

ACIDO FOLICO

diidrofolato (DHF) da DHF-reduttasi

tetraidrofolato (THF)

5,10-metiltetraidrofolato (5,10-MTHF)

ACIDO FOLINICO

L-metilfolato (THF) da MTHF-reduttasi

BEE5-METILTETRAIDROFOLATO

(5-MTHF)

ATTIVAZIONE ENZIMI PER SINTESI DOPAMINA, NORADRENALINA, SEROTONINA

livelli sierici cianocobalamina (vit. B12)

omocisteinemia

espressione γ-secretasi e deposizione Aβ

produzione citochinepro-infiammatorie (TNFα,

IL-1, IL-6, IFN-γ)

neuroinfiammazione

esordio e progressione AD

CORRELAZIONE CON SVILUPPO BPSD?

IPOTESI

Politis et al., JAD 2010

Vitamin B12 Levels in Alzheimer’s Disease: Association with Clinical Features and Cytokine Production

Alzheimer’s disease (AD) has been associated with up-regulation of pro-inflammatory cytokines (e.g., specific gene variants for TFN-α; IL-6; IFN-γ) and low plasma levels ofcyanocobalamin (vitamin B12). Our goal was to relate B12 levels to AD symptoms andto expression of pro-inflammatory cytokines.Clinical manifestations were investigated for a case series of 55 outpatients

Ten patients (18%) had their B12 levels below <250 pg/ml. They did not statistically differ from those 45 who had normal levels in most demographic and clinical features;their MMSE scores were lower (14.7 vs 19.6 p = 0.03) but not after adjustment for disease duration .A greater basal production of IL-6 was reported in patients who had low B12 levels compared to normal B12 subjects (1333 pg/ml vs 976 p <0.01); this association was confirmed after controlling for age of onset and APOE genotype.

In conclusion, low B12 level is associated with greater production of IL-6 inperipheral blood mononuclear cells. Further reasearch is warranted to elucidate whether this neuroinflammatory effect of cobalamin is implicated in thepathophysiology of AD.

Cent Nerv Syst Agents Med Chem. 2009

Inflammatory biomarkers and depression

Muller et al., Neurotox Res, 2010

Collantes‐Estevezand Fernandez‐Perez (2003)

Muller et al. (2006)

Akhondzadeh etal. (2009)

Nery et al., (2008)

Begemann et al. (2008)

Depressivesyndrome,comorbid to osteoarthritis

MD

MD

Bipolar disorder, depressive ormixed episode

Bipolar depression,rapid cycling

Mean 33days

6 weeks

6 weeks

6 weeks

>5 months

343

50

28

1

Open

Randomized, double‐blind, placebo‐controlled add‐on

Randomized, double‐blind, placebo‐controlled add‐on

Randomized, double‐blind, placebo‐controlled

Open

Not specified

Reboxetine(flexible dose)

Fluoxetine(flexible dose)

Mood stabilizeror atypical antipsychotics

Not specified

Rofecoxib 12, 5 or 25 mg/day

Celecoxib400 mg/day

Celecoxib400 mg/day

Celecoxib400 mg/day

Celecoxib400 mg/day

Significant reduction of self‐reported depression

Significant superiority of the COX‐2 inhibitor

Significant superiority ofcelecoxib

Significant superiorityafter 1 week, nodifference at end‐point

Significant improvementof depressed andmanic symptoms

Authors Diagnosis Duration n Study design Concomitant COX‐2 Outcomeof trial drug inhibitor

CLINICAL STUDIES OF SELECTIVE COX‐2 INHIBITORS IN AFFECTIVE STATES

n= sample size; COX‐2= cyclooxygenase‐2; mg= milligram

IN CONCLUSIONE

è fondamentale che la ricerca individui ciò che le due patologie hanno in comune tra loro (biomarker, fattori di

rischio) per lo sviluppo di un programma terapeutico mirato

DEPRESSIONEDEMENZA

MOLTO FREQUENTI

FORTEMENTE INVALIDANTI GRANDE IMPATTO

SULLA SOCIETA’ VEROSIMILE CONTINUUM

CLINICO/ NEUROPATOLOGICO