I Sintomi Psicologici e Comportamentali nelle Varie Forme di Demenza:

Esiste una Peculiarità Sindromica e/o una Correlazione Genotipo/Fenotipo?

Gianfranco Spalletta

IRCCS Fondazione Santa Lucia, Roma

SINTOMATOLOGIA DELLA

DEMENZA

• Cognitiva

• Non-cognitiva

– Neuropsichiatrica

– Comportamentale

CARATTERISTICHE GENERALI

DELLA

SINTOMATOLOGIA NON-COGNITIVA

NELLA DEMENZA

• I sintomi non-cognitivi disturbano sia i pazienti che i caregivers

• I sintomi non-cognitivi sono la prima causa di istituzionalizzazione

• I sintomi non-cognitivi incrementano la spesa sanitaria

• I sintomi non-cognitivi causano un eccesso di disabilità

Approccio Sintomatologico-Dimensionale

• Depressione

• Mania

• Ansia

• Reazione catastrofica

• Modificazioni della personalità (Apatia)

• Alterazioni neurovegetative

• Alterazioni psicomotorie

• Deliri ed allucinazioni

Approccio Diagnostico-Categoriale

• Depressione della AD

• Psicosi della AD

• Apatia della AD

• GAD della AD

PREVALENZA DEI

SINTOMI NON-COGNITIVI

NELLE

DEMENZE NEURODEGENERATIVE

• Demenza di Alzheimer: 50-80%

• Demenze frontotemporali: > 80%

• Demenza con Corpi di Lewy: 40-75%

DEMENZA FRONTOTEMPORALE

E MALATTIA DI PICK

(Diagnosi)

• Rigorosa valutazione dei sintomi non-cognitivi

• Esordio precoce (50-60 anni)

• Alterazioni cognitive tardive

• Prevalenza: fino al 25% delle demenze neurodegenerative presenili

• Diagnosi difficile

• APATIA E/O AGGRESSIVITA’

RGM in Pazienti con

Depressione vs. Non Depressi

Overlay of significant decreases in regional glucose metabolism in AD patients with clinically

significant depression compared with AD patients free of depression on a MRI-template (n = 10;

statistical parametric mapping analysis, p ≤ .05, corrected). Left image displays the right

hemisphere; middle image displays the left hemisphere; right image displays the caudal view of the

brain. AD, Alzheimer’s disease; MRI, magnetic resonance imaging.

Holthoff et al. 2005

Regioni prefrontali dosrsolaterali, bilateralmente

RGM in Pazienti con

Apatia vs. Non Apatici

Overlay of significant decreases in regional glucose metabolism in AD patients with clinically

significant apathy compared with AD patients free of apathy on a MRI-template (n = 17; statistical

parametric mapping analysis, p ≤ .05, corrected). Left image displays the right hemisphere; middle

image displays the left hemisphere; right image displays the caudal view of the brain. AD,

Alzheimer’s disease; MRI, magnetic resonance imaging. Holthoff et al. 2005

Regione orbito-frontale sinistra

Diagnosi differenziale

Apatia in AD

Prevalenza fino al 90%

Più frequente della depressione

OBJECTIVE: The authors assessed and contrasted frontally mediated behavior changes in

patients diagnosed with Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). Apathy,

executive dysfunction, and disinhibition are common in AD, but these behaviors have not been

studied in MCI. METHODS: Participants were patients diagnosed with AD (n=25) or MCI

(n=20). Current behavior and behavior before the onset of cognitive impairment was rated by

knowledgeable informants on the Frontal Systems Behavior Scale (FrSBe). RESULTS: Apathy

and executive dysfunction exhibited the greatest increase in both MCI and AD, and both

increased significantly over baseline scores. No significant differences in behavior change were

found between the two groups. Behavior change was moderately correlated with a measure of

dementia severity, indicating that greater disease severity was associated with more abnormal

behavior. CONCLUSION: Changes in frontally-mediated behaviors are common in very

early and mild stages of cognitive impairment, even before functional decline in daily living

is evident. These behaviors deserve more study in MCI because they may have implications for

prognosis, treatment adherence, family distress, and patient quality of life.

Am J Geriatr Psychiatry, 2003

Apathy and Executive Dysfunction

in MCI and AD

OBJECTIVE: The purpose of this study was to examine the extent to which executive

cognitive dysfunction and frontally-mediated behavioral disturbances are associated with

functional impairment in patients with mild-to-moderate Alzheimer disease (AD).

METHODS: Patients with AD (N=45) completed the Mattis Dementia Rating Scale, and

patients' caregivers completed the Frontal Systems Behavioral Inventory and a modified

form of the Lawton and Brody Activities of Daily Living (ADLs) Questionnaire. RESULTS:

Multiple-regression analyses revealed that executive cognitive dysfunction and apathy

scores accounted for 44% of the variance in instrumental activities of daily living;

executive cognitive dysfunction alone explained 17% of the variance in instrumental ADLs,

and apathy scores explained an additional 27%. Executive dysfunction and frontal-

behavioral impairment explained 28% of the variance in basic ADLs (BADLs), and,

after accounting for executive dysfunction, apathy was the only symptom found to explain

additional unique variance in BADLs. CONCLUSION: These findings suggest that specific

cognitive and behavioral symptoms are associated with functional impairment in patients

with AD.

Am J Geriatr Psychiatry, 2003

Executive Dysfunction and Apathy

Predict Functional Impairment in AD

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872800/figure/f1-7370/

Apatia nella Demenza

Apatia Comuni Depressione Risposta emotiva appiattita Diminuzione dell’interesse Disforia

Indifferenza Rallentamento psicomotorio Ideazione suicidaria

Riduzione delle attività sociali Faticabilità/Ipersonnia Autocritica

Diminuzione dell’iniziativa Ridotto insight Sensi di colpa

Ridotta persistenza (motivazione) Pessimismo

Hopelessness

Sintomi

Apatia nella Demenza

Starkstein et al 2001

Dimensioni di Apatia nella Demenza

a) Criterio Sintomatologico: Perdita di motivazione e di iniziativa (almeno un sintomo per ogni punto 1, 2, 3)

1) Diminuzione dei comportamenti motori diretti a uno scopo (APATIA MOTORIA):

-- il paziente ha una minore capacità a mantenere l’energia su un compito (ad esempio, si stanca subito). -- il paziente è diventato più dipendente dagli altri nella pianificazione e nello svolgimento di attività.

2) Diminuita cognizione diretta ad uno scopo (APATIA COGNITIVA):

-- il paziente mostra una mancanza di interesse nell’apprendimento di nuove cose o di nuove esperienze.

-- il paziente mostra una mancanza di preoccupazione riguardo ai suoi problemi personali.

3) Diminuzione dei correlati emozionali del comportamento diretto ad uno scopo (APATIA AFFETTIVA):

-- il paziente mostra un appiattimento affettivo.

-- il paziente mostra una perdita di risposta emozionale di fronte ad eventi positivi o negativi.

b) Criterio Funzionale: I sintomi apatici causano un cambiamento rispetto al funzionamento precedente l’esordio dei sint. cognitivi.

1) Il paziente mostra una perdita di tenacia.

2) Il paziente mostra una indifferenza emozionale o una diminuita reattività emozionale.

3) Il paziente mostra una diminuita spinta sociale.

c) Criterio Temporale: Esordio dei sintomi apatici: - I sintomi apatici sono iniziati prima dell’esordio della demenza?

Se sì specificare quanti mesi prima ______________

- I sintomi apatici hanno avuto un esordio coincidente con la demenza? - I sintomi apatici hanno avuto un esordio successivo a quello della demenza? Se sì specificare quanti mesi dopo _______________

d) Criteri di Esclusione I sintomi sono dovuti all'effetto fisiologico diretto di una sostanza (es. abuso di sostanze psicoattive o farmaci)?

I sintomi causano distress o compromissione del funzionamento clinicamente significativi?

84%

Apatia ed Empatia

DEMENZA CON CORPI DI LEWY

• Caratteristiche diagnostiche principali

– Demenza (sviluppo precoce di sintomi cognitivi)

– Fluttuazione (Variazione temporale nelle abilità funzionali e cognitive)

– Parkinsonismo

– MANIFESTAZIONI PSICOTICHE (Allucinazioni visive)

DEMENZA VASCOLARE

• Elevato tasso di SINTOMI DEPRESSIVI

Questioni

1. Come valutare 2. Qual è il decorso 3. Novità

1. Come valutare

SCALE DA UTILIZZARE NELLA VALUTAZIONE

DEI SINTOMI NON-COGNITIVI

DELLA DEMENZA

• Behavioral Pathology in Alzheimer’s Disease (BEHAVE-AD) (1987) (18/25 items)

• Cohen-Mansfield Agitation Inventory (CMAI) (1989) (29 items)

• Disruptive Behavior Rating Scale (1989) (21 items)

• Dementia Behavior Disturbance Scale (1990) (22/28 items)

• Behavioral and Emotional Activities Manifested in Dementia (1992) (9/16 items)

• Nursing Home Behavior Problem Scale (1992) (23/29 items)

• Consortium to Establish a Registry for Alzheimer’s Disease – Behavior Rating Scale for Dementia (1995) (48 items)

• Agitate Behavior in dementia Scale (1999) (16 items)

• Neuropsychiatric Inventory (1994) (12 items)

• La valutazione dei sintomi neuropsichiatrici e

comportamentali della demenza è diventata una

pratica standard ed effettuata di routine in clinica

• Le scale più utilizzate hanno confermato

l’efficacia nel valutare la risposta al trattamento

farmacologico

• Mediante l’intervista clinica con pazienti e

parenti si possono ottenere molte informazioni

soggettive ma ………..

VALUTAZIONE DEI SINTOMI NON-COGNITIVI

DELLA DEMENZA

VALUTAZIONE DEI SINTOMI NON-COGNITIVI

DELLA DEMENZA

• Allo scopo di valutare l’efficacia dei trattamenti

sono necessarie misure valide ed oggettive e queste si

possono ottenere solo mediante l’utilizzo di scale di

valutazione valide ed affidabili

• Solo un’analisi di tali scale può permettere un

giudizio obiettivo sul miglioramento dei soggetti

BEHAVE-AD

• Scala semplice

• 2 parti: Sintomatologia e valutazione globale

• Sintomatologia: 7 cluster (25 sintomi)

Ideazioni deliranti

Allucinazioni

Aggressività

Disturbo dell’attività

Disturbo del ritmo diurno

Disturbi affettivi

Ansia e fobie

Valutazione: scala di 4 punti (precedenti 2 sett)

0=non presente; 1=presente; 2=presente con componente

emotiva; 4=presente con comp. emotiva e fisica

BEHAVE-AD

Valutazione globale della severità: caregivers

0=non crea problemi ai caregivers o è dannoso per i

pazienti

1=levemente problematico per i caregivers o dannoso per i

pazienti

2=moderatamente ….

3=severamente…….

BEHAVE-AD

(2 trial clinici: valutazioni al baseline)

Punteggi comparabili al MMSE

BEHAVE-AD

(La scala)

BEHAVE-AD

(La scala)

BEHAVE-AD

(Proprietà psicometriche)

•Affidabilità tra valutatori: eccellente

•Coefficiente di accordo : 0.65 – 0.91

•Affidabilità test-retest: lo strumento può

essere utilizzato per valutazioni ai follow-

up

•Punteggio massimo: 75

CMAI

• Valuta il comportamento agitato nei pazienti con

compromissione cognitiva

• Scala che indaga 29 comportamenti di agitazione con

7 livelli di severità (frequenza temporale: da mai a molte volte ogni ora)

• Per la somministrazione sono necessari 10-15 minuti

• Punteggio massimo: 203

CMAI

(La scala)

Sputare

Colpire

Afferrare

NPI

• Valuta 12 disturbi comportamentali

• Severità e frequenza sono determinati da una serie

di domande poste al caregiver del paziente • Gravità: 1=lieve; 2=moderato; 3=severo

• Frequenza: 1- 4 (occasionalmente - continuamente)

• Punteggio massimo per ogni disturbo = 12

(gravità X frequenza)

• Valuta lo stress dei caregiver con un punteggio da 0 a 5 per

ogni disturbo comportamentale

NPI

(Proprietà psicometriche)

• Tempo richiesto per la valutazione: circa 10 minuti

• Buone proprietà psicometriche (affidabilità tra

valutatori ed affidabilità test-retest)

NPI

(La scala)

Clusterizzazione dei NPS (Lawlor et al, 2001)

0

1

2

3

4

5

6

7

NP

I (A

pa

thy

)

NP

I (D

ep

res

sio

n/D

ys

ph

ori

a)

NP

I (A

nx

iety

)

NP

I (A

git

ati

on

)

NP

I (I

rrit

ab

ilit

y)

NP

I (A

be

rra

nt

Mo

tor

Be

ha

v)

NP

I (D

elu

sio

ns

)

NP

I (D

ish

inib

itio

n)

NP

I (H

allu

cin

ati

on

s)

NP

I (E

up

ho

ria

)

Depressione della

Demenza di Alzheimer (Miglioramento della validità diagnostica)

Olin et al. 2002; Lee et al. 2003

La Psicosi dell’AD

La Psicosi dell’AD

Cosa considerare di nuovo?

• L’aspetto più difficile da risolvere è la

caratterizzazione dei singoli sintomi:

– La natura osservazionale delle scale è un pregio così

come l’eleganza della loro semplicità.

– Purtroppo, la complessità derivata dalla co-occorrenza

dei sintomi ne rende difficile la caratterizzazione

soprattutto nelle fasi moderata e severa di malattia.

2. Qual è il decorso

MCI e BPSD: Review

• Quattro review:

– Ritchie e Touchon, 2000 Lancet (no BPSD)

– Petersen et al., 2001 Neurology (la depressione può

influenzare la performance cognitiva)

– Petersen et al., 2001 Arch Neurol (idem, per la valutazione

neuropsicologica)

– DeCarli, 2003 Lancet Neurology (no BPSD)

Conclusioni: I BPSD sono un fattore confondente

la diagnosi di MCI

MCI e BPSD: i Fatti

Sintomi depressivi in soggetti con MCI come fattore di rischio per demenza.

Pazienti con MCI e depressione sono 2 volte a rischio di sviluppare demenza.

Elevata prevalenza (43%) dei sintomi non-cognitivi nel MCI al momento della

valutazione. Il 29% con sintomi clinicamente significativi.

Il 50% con un sintomo comportamentale all’esordio dei sintomi cognitivi.

Depressione (20%), Apatia (15%), Irritabilità (15%).

MCI è frequentemente associato a sintomi neuropsichiatrici.

Depressione (39%), Apatia (39%), Irritabilità (29%), ansia (25%)

Conclusioni: il MCI è spesso associato a BPSD

Li et al., 2001; Modrego et al., 2004; Lyketsos et al., 2002; Hwang et al., 2004

Progressione da MCI ad AD

0

1

2

3

4

5

6

7

8N

PI (A

pa

thy)

NP

I (D

ep

ressio

n/D

ysp

ho

ria

)

NP

I (A

nxie

ty)

NP

I (A

gita

tio

n)

NP

I (I

rrita

bility)

NP

I (A

be

rra

nt M

oto

r B

eh

av)

NP

I (D

elu

sio

ns)

NP

I (H

allu

cin

atio

ns)

NP

I (D

ish

inib

itio

n)

NP

I (E

up

ho

ria

)

SevereModerateMild

1,5

2

2,5

3

3,5

4

4,5

5

5,5

Cell

Mean

NP

I depre

ssio

ne/d

isfo

ria 0

FxG

NP

I depre

ssio

ne/ dis

foria 1

FxG

NP

I depre

ssio

ne/d

isfo

ria 2

FxG

NP

I depre

ssio

ne/d

isfo

ria 3

FxG

NP

I depre

ssio

ne/d

isfo

ria 4

FxG

NP

I depre

ssio

ne/d

isfo

ria 5

FxG

Cell

Moderate-Severe

Mild

1 1,529 1,529 ,063 ,8018 ,063 ,057

99 2388,382 24,125

5 223,111 44,622 10,033 <,0001 50,166 1,000

5 69,487 13,897 3,125 ,0087 15,624 ,885

495 2201,474 4,447

DF Sum of Squares Mean Square F-Value P-Value Lambda Pow er

MILD DEMENTIA

Subject(Group)

Category for NPI DEP

Category for NPI DEP * MILD DEMENTIA

Category for NPI DEP * Subject(Group)

ANOVA Table for NPI DEP

1 9,396 9,396 ,475 ,4924 ,475 ,102

99 1958,779 19,786

5 192,739 38,548 9,676 <,0001 48,381 1,000

5 75,433 15,087 3,787 ,0022 18,935 ,946

495 1971,977 3,984

DF Sum of Squares Mean Square F-Value P-Value Lambda Pow er

MILD DEMENTIA

Subject(Group)

Category for NPI ANX

Category for NPI ANX * MILD DEMENTIA

Category for NPI ANX * Subject(Group)

ANOVA Table for NPI ANX

,5

1

1,5

2

2,5

3

3,5

4

4,5

Cell

Mean

NPI ansia 0 FxG NPI ansia 1 FxG NPI ansia 2 FxG NPI ansia 3 FxG NPI ansia 4 FxG NPI ansia 5 FxG

Cell

Moderate-Severe

Mild

0

1

2

3

4

5

6

7

8

9

10

11

Cell

Mean

NP

I apatia

/indiff

ere

nza 0

FxG

NP

I apatia

/indiff

ere

nza 1

FxG

NP

I apatia

/indiff

ere

nza 2

FxG

NP

I apatia

/indiff

ere

nza 3

FxG

NP

I apatia

/indiff

ere

nza 4

FxG

NP

I apatia

/indiff

ere

nza 5

FxG

Cell

Moderate-Severe

Mild

1 2,855 2,855 ,130 ,7194 ,130 ,064

99 2176,752 21,987

5 5419,445 1083,889 153,199 <,0001 765,997 1,000

5 52,158 10,432 1,474 ,1966 7,372 ,512

495 3502,136 7,075

DF Sum of Squares Mean Square F-Value P-Value Lambda Pow er

MILD DEMENTIA

Subject(Group)

Category for NPI APATHY

Category for NPI APATHY * MILD DEMEN...

Category for NPI APATHY * Subject(Gro...

ANOVA Table for NPI APATHY

3. Novità

Quale potrebbe essere

la vera innovazione?

• La specificità dei BPSD sia fenomenologica che rispetto ai loro correlati biologici ci suggerisce che la vera rivoluzione che si sta portando avanti nel campo della ricerca è quella che riparte dai sintomi stessi ridefiniti come Sintomi Neuropsichiatrici (NPS)

Overall, our findings of lack of efficacy and increased adverse events combined with existing literature lead us to conclude that SSRIs cannot be recommended

for the treatment of AD.

• Given that depression in AD is common and associated with a range of negative outcomes, there remains an urgent need for efficacious and effective

treatments for this condition.

Modificazioni Comportamentali e

Cognitive in Soggetti Asintomatici APOE e4+ e APOE e4-

180 soggetti: 93 e4- e 87 e4+

Età media: 60 anni

Follow-up medio: 33 mesi

MMSE: 29.6 Ham-D: 2.5

Caselli et al 2004

BPSD in AD

possibility of identifying distinct

behavioral phenotypes

on a genetic basis among AD patients?

• The construct of endophenotype is designed for identifying genes involved in

complex behaviors

• As opposed to exophenotypes (= external and apparent features of a

phenotype i.e., signs and symptoms that can be assessed during a standard

clinical evaluation) endophenotypes refer to internal traits, i.e. signs that

require neuropsychological, biochemical, electrophysiological and

neuroanatomical measures

• it fills the gaps in the causal chain between genes and behavioral phenotypes

Endophenotype of BPSD

Endophenotype of BPSD

Endophenotype:

• is associated with illness in the population.

• is heritable.

• co-segregates with the illness.

• is state-independent (i.e., it manifests in an individual whether or not illness

is active).

• is found in non-affected family members at a higher rate than in the general

population

(Gottesman and Gould, 2003)

Endophenotype of BPSD

As opposed to the rare ‘‘familial’’ early-onset form of the disease

(EOAD), which is known to follow a Mendelian pattern of

inheritance of highly penetrant mutations in three genes (APP,

PSEN1 and PSEN2), the etiology of the more prevalent

‘‘sporadic’’ LOAD seems more complex and largely

multifactorial, including a large number of genes with limited

penetrance.

Endophenotype of BPSD

Although a precise definition of the concept is rarely given in the literature, the

expression ‘‘endophenotype’’ is interchangeably used as ‘‘surrogate marker’’, suggesting that manifestation of the endophenotype in asymptomatic subjects foreshadows clinical decline and could be used as a ‘‘surrogate endpoint’’ for assessing prevention treatment efficacy

In the event that all subjects who present the endophenotype decline to AD (positive predictive accuracy), preclinical metabolic abnormalities should be considered a diagnostic (or state) marker for the disease (after considering the negative predictive accuracy or specificity)

Genetic bases of BPSD in AD (the case of the APOE)

- It has been suggested that neuropsychiatric symptoms in AD may be influenced by APOE genotype in various case–control studies (Levy et al., 1999; Craig et al., 2004; Borroni et al., 2006; Hollingworth et al., 2006)

however

- Longitudinal study show inconsistent findings: some found a substantial lack of association between the APOE ɛ4 allele and NPS after correction for multiple testing (Pritchard et al., 2007) others found that at baseline, ApoE genotype was not associated with any specific NPS rather it was associated with a peculiar neuropsychiatric profile (a wider range of NPS and higher scores for hallucinations and aberrant motor behaviors) the longitudinal results showed an increase/delayed onset in some symptoms and a parallel decrease in others, while non-carriers presented an undifferentiated worsening of symptomatology (Del Prete et al., 2009)

• While some studies failed to find a significant

association between the APOE polymorphism and

NPS as a whole in AD, other studies reported a

significant association between the APOE ɛ4 allele

and an increase in agitation/aggression, hallucinations,

delusions, and late-life depression or anxiety;

• Some negative studies that focused on the distribution

of APOE genotypes between AD patients with or

without NPS further emphasized the importance of

sub-grouping NPS in

distinct neuropsychiatric syndromes

Genetic bases of BPSD in AD

Apathy

• The relationship between the APOE 4 allele and the apathetic

syndrome and/or the apathy symptom was studied although it

has not been as thoroughly investigated as for depression and

psychosis (Table 2)

(Panza et al., 2012, Ageing Research Reviews)

Apathy

- The presence of apathy was significantly cross-sectionally

associated with the APOE 4 allele independently from age,

education, sex, duration of disease, MMSE score and other

symptoms (Monastero et al., 2006)

- No longitudinal report confirmed these suggestions, and other

cross-sectional studies did not show any association of apathy

endophenotypes (Borroni et al., 2006; Hollingworth et al., 2006)

or NPI apathy symptom (van der Flier et al., 2007) with APOE

genotypes

Apathy

David et al. (2011):

- tested the hypothesis that single nucleotide polymorphisms (SNPs) in catechol-O-methyltransferase (COMT) are associated with apathy in individuals with Alzheimer's disease (AD)

- Polymorphisms in seventeen SNPs COMT

- 281 Caucasian AD individuals with apathy

- None of the candidate gene SNPs were significantly associated with the presence of apathy

Depression

A relevant number of studies showed an association between APOE polymorphism and depression (Ramachandran et al., 1996; Murphy et al., 1997; Müller-Thomsen et al., 2002; Delano-Wood et al., 2008; D’Onofrio et al., 2010b),

However

several other reports have not supported the notion that APOE ɛ4 genotype may influence depression in AD

(Cantillon et al., 1997; Lopez et al., 1997; Harwood et al., 1999; Levy et al., 1999; Liu et al., 2002; Scarmeas et al., 2002; Gabryelewicz et al., 2002; Craig et al., 2004; Pritchard et al., 2007)

Depression

Variable findings:

- APOE ɛ2-carriers may be at higher risk of depressive symptoms in AD

(Holmes et al., 1996, 1997, 1998)

- the APOE ɛ4 allele may be protective against the development of major

depressive disorder (MDD) in AD (Ballard et al., 1997, Lyketsos et al.,

1997)

- there are trends of association between APOE genotype and depression but

have rendered conclusions of no relationship (Cacabelos et al., 1996, 1997;

Forsell et al., 1997; Chopra et al., 2009).

Depression

Liu et al. (2002):

- evaluated the association between apo E genotypes

and depression in patients with AD

- 149 patients with AD: 0 in epsilon 2/3, 2 in epsilon2/4,

74 in epsilon3/3, 46 in epsilon3/4, and 17 in epsilon4/4

- no association between depression and the presence

or absence of the epsilon4 or epsilon2 allele

- The HDRS scores were not different in patients with

AD with the epsilon4 or epsilon2 allele or in those

patients without them

Depression

Craig et al. (2005):

- hypothesis that genetic variants of apolipoprotein E influence the risk for depressive symptoms in 404 AD patients

- No statistically significant association between genotypes or alleles of apolipoprotein E and depression/dysphoria in AD was observed, nor was any association noted between the presence of severe symptoms and genotypes/alleles of apolipoprotein E.

- apolipoprotein E genotype creates no additional risk for depressive symptoms in AD

Depression

D’Onofrio et al., 2011:

• No difference in the distribution of APOEε4 genotypes was found between AD patients with vs. without neuropsychiatric symptoms as a whole

However

in APOE ε4-carriers AD patients, there was an increased risk of affective and apathetic syndromes when considered indivudually

Depression

Fritze et al., 2011

• In AD: depression was more likely to be reported in patients if at least one copy of the APOEe4 allele was present.

• No effect for gender

• In DLB: no relationship between APOE ε4 and depression

Depression:

Patogenic Hypotheses

• APOE ε4 allele

• low efficiency at inducing cholesterol transport

• poor maintainance of the integrity of membranes

• impaired response to cerebral damage and diminished capacity for neuronal repair (Arendt et al., 1997; Crawford et al., 2002)

• development of cognitive decline and depression in older adults with the APOE ε4 genotype.

Depression:

Patogenic Hypotheses

- APOE may be linked to vascular risk factors in late life and, in turn, may be associated with depression

- some late-life depressive syndromes might predispose, precipitate, or perpetuate by CVD, the so called “vascular depression” hypothesis (Alexopoulos et al., 1997) This notion is based on the comorbidity of depressive syndromes with cerebrovascular lesions and cerebrovascular risk factors (Alexopoulos et al., 2005)

- In addition, the APOE ε4 allele may increase the odds that older depressed patients develop MCI (Geda et al., 2006)

Anxiety • APOE ε4 mice showed decreased activity levels and higher measures of

anxiety than mice expressing APOE ε2 or APOE ε3 isoform across all ages

(Siegel et al., 2010) Consistent with the mouse studies (Robertson et al.,

2005; Siegel et al., 2010), APOE also has isoform dependent effects on

measures of anxiety in probable AD patients (Robertson et al., 2005)

• male APOE 4/4 subjects had higher anxiety scores than gender-matched

APOE 3/3 subjects; in males, but not in females, subjects with APOE 4/4

had also higher anxiety scores than those with APOE 3/4 (Robertson et al.,

2005)

• Pritchard et al, 2007: (longitudinal study) association with the APOE 3/4

genotype, but not with the APOE 4/4 genotype or the ε4 allele anxiety

appeared more frequently in APOE 3/4 demented patients (Cacabelos et al.,

1996, 1997)

Psychotic symptoms

- A number of investigations have examined whether the APOE 4

allele might contribute to the

AD+Psychosis (AD+P) endophenotype

- Most of studies compares AD+P against AD-P

- high variability in findings

- it may be necessary to operate a distinction among different

psychotic symptoms in AD in relation to APOE polymorphism

Psychotic symptoms: hallucinations

Main findings:

-two copies of ε4 being reported as protective (Scarmeas et al., 2002)

-ε4 being associated with increased risk (Chang et al., 2004)

-hallucinations appeared to increase with more ε4 alleles (Weiner et al., 1999)

Psychotic symptoms: delusions

In cross-sectional studies, the presence of the APOE 4

allele was associated with

-increased levels of delusions within the last month from the first visit and with

the presence of categorical delusions at the early stage (Spalletta et al., 2006)

-delusions appeared to increase with more 4 alleles (Weiner et al., 1999) and 4/4

genotype (van der Flier et al., 2007)

-4 allele was preferentially associated with delusions also in a large sample of AD

patients from US (Zdanys et al., 2007)

Psychotic symptoms: delusions

Thus, APOE genotype could have a role in the development of

delusions in AD patients, also after controlling for disease

duration (Scarmeas et al., 2002)

However

cross sectional and longitudinal studies suggest that APOE does

not appear to contribute to the risk of psychosis as a whole in AD

Psychotic symptoms

Di Maria and coll (2009)

- tested the hypothesis that the occurrence of delusions

and hallucinations in AD is associated with variations

in the G72/DAOA gene, which is supposed to play a

key role in the glutamate pathway regulated through

the NMDA receptors

- A panel of single nucleotide polymorphisms were

genotyped in a cohort of 185 AD patients

- multivariate regression showed that the rs2153674

genotype accounts for up to 15% of the variance in

delusions severity

Psychotic symptoms

Holmes et al (2001):

- possible associations between selected polymorphisms in the dopamine receptor genes DRD1 and DRD3 with the presence of psychotic phenomena or aggressive behaviour in a community based cohort of 134 patients with late onset AD An association was found between:

- The presence of psychotic symptoms and aggressive behaviour and the DRD1 polymorphism;

- the presence of psychosis, but not aggression, and the DRD3 polymorphism;

- carriers of the DRD1 B2 allele were more likely to be aggressive or experience hallucinations whereas homozygous carriers of the DRD3 1 allele were more likely to experience delusions

• 1299 AD with psychosis (AD+P), 735 AD cases

without psychosis (AD–P) and 5659 controls

• combined analysis of three genome-wide

association studies (GWASs) to identify loci

(1) that increase susceptibility to an AD and

subsequent psychotic symptoms

(2) that modify risk of psychotic symptoms in

the presence of neurodegeneration caused by

AD.

Results:

AD+P - intergenic region on chromosome 4

- SNPs upstream of SLC2A9 and

within VSNL1

Conclusions:

this study does not identify any SNPs that meet strict criteria for genome-wide significant association with AD+P when compared with controls or AD–P cases

However:

a number of sub-threshold associations were observed that

-show patterns of effect that are stronger than those generally observed in AD GWAS

- are interesting biological and position candidates for AD+P

- show some overlap with other psychiatric disorders with psychotic features

Psychotic symptoms: pathogenic hypotheses

ε4 allele has been associated with deficits in

cholinergic neurons, in particular in the frontal cortex and medial temporal lobe

the development of NPS in AD appears to be related to specific neurotransmitter imbalances, notably acetylcholine

the presence of the ε4 allele could favor a preferential pathologic involvement of the cholinergic system, which in turn might result in more frequent psychotic manifestations (Panza et al., 2012)

Psychotic symptoms: pathogenic hypotheses

Pritchard et al, 2008: Role of polymorphisms within serotonin receptors

- large cohort of 394 AD patients NPI measures were related to the 5HT(2A) T102C and 5HT(2C) cys23ser genotype and allele frequencies

Results:

- increased frequency of the C allele and CC genotype of the T102C variant of 5HT(2A) with hallucinations, delusions, psychosis and aberrant motor behaviour, however, we dispute previous associations with depression and aggression

- increase in the C allele and CC genotype frequencies of the cys23ser variant of 5HT(2C) with anxiety and support previous associations with appetite disturbances in females.

Psychotic symptoms:pathogenic hypotheses

Angelucci et al. (2009): alterations in serotonergic neurotransmission hypothesis a 3-year follow-up study association of serotonin (5-HT) receptor 5-HT2a 102T/C polymorphism (allelic variants CC, CT and TT) with psychotic symptom severity and response to treatment with atypical antipsychotics (risperidone, olanzapine and quietapine) in 80 patients with a diagnosis of probable AD

Results:

- patients carrying the TT genotype were the most delusional during the follow-up period

- NPI FxS delusion score was higher in TT than in CC genotype at year 2

- patients with delusion symptoms carrying the CT and TT genotypes were resistant to the treatment with antipsychotic drugs

The presence of T allele of the 102T/C polymorphism in patients with AD is associated with both increased presence of delusion symptoms and treatment-resistance to second generation antipsychotic drugs.

Agitation/aggressiveness

ε4 allele was associated with increased combativeness,

agitation, wandering, and confusion (Murphy et al.,

1997), restlessness and vocalizations, in nursing home

residents (Woods et al., 2009)

However

when AD patients were grouped in neuropsychiatric

syndromes, for hyperactive syndrome, including AD

patients with agitation, euphoria, disinhibition,

irritability, and aberrant motor behaviour, no

association was found with APOE genotype

(D’Onofrio et al., 2010a)

Agitation/aggressiveness

Van der Flier et al (2007):

- sample: 27 APOE-epsilon4-negative patients,

65 heterozygous patients and 18 homozygous

patients

- agitation/aggression, which were more

common and severer among homozygous

APOE epsilon4 carriers than among

heterozygous or APOE-epsilon4-negative

patients

Agitation/aggressiveness

Craig et al. (2004):

- the A218C intronic polymorphism of the tryptophan

hydroxylase gene influences aggression and anger in

non-demented individuals influence of A218C

on symptoms of agitation/aggression in

396 Alzheimer's diseasepatients using the NPI?

- male patients with a history of agitation/aggression

were more likely to possess C-containing genotypes

ggression in male subjects

with Alzheimer's disease may be genetically linked to

polymorphic variation at the tryptophan hydroxylase

gene

Agitation/aggressiveness:mouse models

The amyloid precursor protein (APP) 23 transgenic mouse model develops amyloid plaques from the age of 6 months onward and exhibits tau pathology, which is absent in most other amyloid-based models Besides mimicking the demented patients' memory deficits, these transgenic mice present with various behavioral disturbances, thereby approximating the clinical situation remarkably well The presence of aggressive disturbances in this valuable mouse model opens perspectives to evaluate aggression-modulating therapies.

Agitation/aggressiveness:mouse models

Alexander and coll (2011)

- used a transgenic mouse model, denoted Tg2576, which over-expresses a mutated human amyloid precursor protein (APP) gene implicated in familial AD, to investigate aggressive behaviour of males at the stage of amyloid beta pathology preceding overt amyloid plaque deposition in the brain

- 7-month-old Tg2576 resident males demonstrated significantly higher levels of aggression towards intruders as compared to non-transgenic controls

- usefulness of the Tg2576 mouse model of AD underscoring its in studying non-mnemonic changes in behaviour related to AD

Agitation/aggressiveness:mouse models

Pugh et al., 2007:

- non-cognitive behaviour of the hAPP/PS1 transgenic mouse model (TASTPM) was observed at ages spanning the rapid progression of amyloid neuropathology

- TASTPM transgenic mice, of both genders, exhibited decreased spontaneous motor activity, disinhibition, increased frequency and duration of feeding bouts, reduced body weight

- In addition to the aforementioned behaviours, male transgenic mice also displayed enhanced aggression relative to wildtype controls

- these data reveal previously unreported disease relevant behavioural changes that demonstrate the value of measuring behaviour in APP/PS1 transgenic models.

Agitation/aggressiveness: pathogenic hypotheses

APOE association with higher tangle burden in the brain (Gomez-Isla et al., 1996; van Dyck et al., 1998; Kanai et al., 1999; McNamara et al., 1998)

• aggression and agitation disruption of the serotonergic and dopaminergic systems

• aggression and agitation bilateral

orbitofrontal and left anterior cingulated tangle burden (Tekin et al., 2001), and with left fronto-temporal hypoperfusion (Hirono et al., 2000).

Sleep disorders

Craig et al. (2006):

- investigated the role of a monoamine A oxidase promoter polymorphism in sleep disruption in AD

- NPI; Genotyping of apolipoprotein E (APOE) and of the 30 bp variable number tandem repeat of the MAO-A promoter was by standard methods

Results:

- high-activity 4-repeat allele of the MAO-A VNTR promoter polymorphism confers increased susceptibility to sleep disturbance

- A quantitative sleep disturbance score was significantly higher in the patients possessing MAO-A 4-repeat allele genotypes

- APOE had no influence on the development of an altered sleep phenotype.

Sleep disorders Yesavage et al (2011):

- to report indices of sleep–wake function

collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes

- 300 probable AD patients

- 122 circadian related single-nucleotide polymorphisms (SNPs) were examined. In 124 pts. an additional polymorphism (variable-number tandem repeat in per3) was also determined

- none of the candidate gene SNPs were significantly

associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation

Conclusions

• Several studies have investigated whether the main

recognised genetic risk factor for late-onset AD,

namely the apolipoprotein E gene, is associated with

BPSD, with conflicting results

• The involvement of dopamine- or serotonin-related

pathways and associated genetic variabilities has been

demonstrated as being interesting candidates for the

neuropsychiatry manifestations of dementia

• Genetic variations of neurotrophins, such as brain-

derived neurotrophic factor (BDNF), have been related

to depression susceptibility in AD.

Conclusions

High variability in findings:

- Varying schemes for diagnosing BPSD in AD

- the use of very brief inventories of symptoms, and/or

low diagnostic measures for determining symptoms

could be leading to poorer diagnostic accuracies and

thus different prevalence rates of BPSD in AD (Forsell

et al., 1997; Levy et al., 1999; Delano-Wood et al.,

2008)

- small sample sizes generating false positives that

cannot be consistently replicated

Conclusions

- differences in patient populations

- possible lack of statistical power to detect associations in the negative studies

- mainly cross-sectional studies, whereas it would be of paramount importance to evaluate the risk for incident BPSD in relation to the APOE genotype in prospectively followed cohorts of patients identifying predisposing genetic risk factors may allow us to understand the pathophysiological features of neuropsychiatric syndromes or symptoms, so optimizing possible therapeutic options.

Conclusions

Although APOE genotype is currently a non-

modifiable risk factor, it has potential for

modifying the impact of other factors, in

particular vascular and lifestyle-related factors

(Solfrizzi et al., 2008), implying that some

interventions may perhaps best be restricted to

people at genetic risk