TULBURARILE NEUROCOGNITIVE

Prof. Dr. Ovidiu Bajenaru

UMF Carol Davila Bucuresti
Spitalul Universitar de Urgenta Bucuresti Clinica de Neurologie

Dementele provocarea viitorului

Persoane suferind de boala

Alzheimer (milioane)

Estimare a numrului de persoane suferind de dementa, 2005-2050*

An

Numrul persoanelor cu vrst peste 65 de ani se va dubla pn n 2030 1

Numrul persoanelor suferind de boala Alzheimer se va dubla pn n 2050*

1. Green Paper on Demographic change, Brussels 2005;12(suppl 1):1-27

*Sursa: Datamonitor, publicat Martie 2008

 DEMENTA reprezinta un sindrom clinic

neurolgic caracterizat printr-o deteriorare
cognitiva globala, care implica un declin fata
de nivelul anterior de functionare si care
asociaza o gama larga de simptome psihice,
psihologice si comportamentale.

 Tulburarile functiilor cognitive sunt uneori

precedate si aproape ntotdeauna nsotite de:
- tulburari ale controlului emotional
- modificari ale personalitatii
- alte simptome psihiatrice:
* apatie, depresie, tulburari psihotice
* tulburari comportamentale

CRITERII DE DIAGNOSTIC
DSM IV TR ( nu mai este de actualitate, incepand cu mai 2013):
Criteriile diagnosticului de demen, indiferent de cauza:
1. Dezvoltarea mai multor deficite cognitive, dintre care obligatoriu:
Afectarea memoriei (scderea capacitii de a nva informaii noi sau de a
evoca informaii nvate anterior)
si,
Cel puin una dintre urmtoarele:

Afazie (tulburare de limbaj)

Apraxie (afectarea abilitii de a executa activiti motorii ntr-o anume
secven i care servesc unui scop, n lipsa afectrii funciei motorii)
Agnozie (incapacitatea de a recunoate sau identifica obiecte n lipsa afectrii
funciilor senzoriale)
Perturbarea funcionrii excutive (planificare, organizare, secvenializare,
abstractizare).

CRITERII DE DIAGNOSTIC
2. Deficitele cognitive menionate mai sus reprezint un declin fa de
nivelul anterior de funcionare i cauzeaz, fiecare, afectarea
semnificativ a funcionrii sociale sau ocupaionale
3. Deficitele cognitive menionate mai sus nu apar exclusiv n cursul
unui episod de delirium
4. Criterii de diagnostic specifice se adaug pentru stabilirea
diferitelor etiologii ale demenei
5. Afectarea memoriei trebuie obligatoriu s fie prezent ns uneori
poate s nu fie simptomul predominant ( f-ctie de forma
etiopatogenica ! ) disparuta in DSM5
6. Pentru a se putea stabili diagnosticul de demen, deliriumul* i
orice alt tip de tulburare confuzional trebuie exclus prin
diagnostic diferenial.

NEUROCOGNITIVE DISORDERS
A proposal from the DSM-5 Neurocognitive
Disorders Work Group
Neurocognitive Disorders - a new category to replace the DSMIV Category of Delirium, Dementia, Amnestic, and Other
Geriatric Cognitive Disorders
The defining characteristics of these disorders are that their core or
primary deficits are in cognition and that these deficits represent a
decline from a previously attained level of cognitive functioning
This section includes three broadly defined syndromes:
(1) Delirium
(2) Major Neurocognitive Disorder
(3) Mild Neurocognitive Disorder

Figure 2 Neurocognitive domains

Sachdev, P. S. et al. (2014) Classifying neurocognitive disorders: the DSM5 approach

Nat. Rev. Neurol. doi:10.1038/nrneurol.2014.181

MEMORIA

NON-DECLARATIVA / PROCEDURALA
( IMPLICITA )

DECLARATIVA
( EXPLICITA )

Fapte

Evenimente

COMPORTAMENTALA
(abilitati, obiceiuri)

De IDENTIFICARE
(DETECTARE)

De INVATARE
ASOCIATIVA
DE BAZA

RASPUNSURI
EMOTIONALE

HIPOCAMP
LOB T MEDIAL
DIENCEFAL

STRIAT
CORTEX MOTOR
CEREBEL

NEOCORTEX

SISTEM
LIMBIC

De INVATARE
NON-ASOCIATIVA

RASPUNS
MUSCULAR
SCHELETIC

CEREBEL

CAI
REFLEXE

Major Neurocognitive Disorder

A. Evidence of significant cognitive decline from a previous level of
performance in one or more of the domains outlined above based on:
1. Concerns of the patient, a knowledgeable informant or the clinician
that there has been a significant decline in cognitive function
AND
2. Clear decline in neurocognitive performance, typically 2 or more
standard deviations below appropriate norms on formal testing,
or equivalent clinical evaluation.
B. The cognitive deficits are sufficient to interfere with independence (i.e.,
requiring assistance at a minimum with instrumental ADL [more complex tasks
such as paying bills or managing medications]).
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not wholly or primarily attributable to another Axis I
disorder (e.g., Major Depressive Disorder, Schizophrenia)

Mild Neurocognitive Disorder

A. Evidence of minor cognitive decline from a previous level of performance in
one or more of the domains outlined above based on:
1. Concerns of the patient, a knowledgeable informant or the clinician that
there has been a mild decline in cognitive function
AND
2. Mild decline in neurocognitive performance, typically between
1 and 2 standard deviations below appropriate norms on formal
testing, or equivalent clinical evaluation.
B. The cognitive deficits are insufficient to interfere with independence (i.e.,
instrumental ADL [more complex tasks such as paying bills or managing
medications] are preserved), but greater effort, compensatory strategies, or
accommodation may be required to maintain independence.
C. The cognitive deficits do not occur exclusively in the context of a delirium.
D. The cognitive deficits are not wholly or primarily attributable to another Axis I
disorder (e.g., Major Depressive Disorder, Schizophrenia).

S 24 - 35 Major Neurocognitive Disorder

S 12 - 23 Mild Neurocognitive Disorder

S 24 Major Neurocognitive Disorder

S 25 Major Neurocognitive Disorder Associated with Alzheimer's
Disease
S 26 Major Neurocognitive Disorder Associated with Vascular
Disease
S27 Major Neurocognitive Disorder Associated with Fronto-Temporal
Lobar Degeneration
S 28 Major Neurocogntive Disorder Associated with Traumatic Brain
Injury
S 29 Major Neurocognitive Disorder Associated with Lewy Body
Disease
S 30 Major Neurocognitive Disorder Associated with Parkinson's
Disease
S 31 Major Neurocognitive Disorder Associated with HIV Infection
S 32 Major Neurocognitive Disorder Associated with Substance Use
S 33 Major Neurocognitive Disorder Associated with Huntington's
Disease
S 34 Major Neurocognitive Disorder Associated with Prion Disease
S 35 Other Specified Major Neurocogntive Disorder

S 12 Mild Neurocognitive Disorder

S 13 Mild Neurocognitive Disorder Associated with Alzheimer's
Disease
S 14 Mild Neurocognitive Disorder Associated with Vascular
Disease
S 15 Mild Neurocognitive Disorder Associated with Fronto-Temporal
Lobar Degeneration
S 16 Mild Neurocognitive Disorder Associated with Traumatic Brain
Injury
S 17 Mild Neurocognitive Disorder Associated with Lewy Body
Disease
S 18 Mild Neurocognitive Disorder Associated with Parkinson's
Disease
S 19 Mild Neurocognitive Disorder Associated with HIV Infection
S 20 Mild Neurocognitive Disorder Associated with Substance Use
S 21 Mild Neurocognitive Disorder Associated with Huntington's
Disease
S 22 Mild Neurocognitive Disorder Associated with Prion Disease
S 23 Other Specified Mild Neurocogntive Disorder

The distinction between Major and Mild disorders is primarily one of severity, with the
threshold for Major Neurocognitive Disorder encompassing a greater degree of cognitive
impairment and hence a loss of independence in instrumental activities of daily living
In most progressive disorders such as the neurodegenerative disorders and some
forms of vascular cognitive impairment, Mild and Major may be earlier and later stages
of the same disorder
DSM-5 Neurocognitive Criteria, Draft 1/7/10

ETIOLOGIE
dementele = un grup heterogen de afectiuni neurologice primare sau
secundare asociate unor boli sistemice cu afectare a
sistemului nervos central
formele cele mai ntlnite:
- dementa din boala Alzheimer
- dementele vasculare
- dementa din -sinucleinopatii
* dementele cu corpi Lewy
* dementa asociata bolii Parkinson
- formele mixte
* boala Alzheimer asociata cu boala cerebro-vasculara
* boala Alzheimer asociata cu dementa cu corpi Lewy
- dementele fronto-temporale

I. Boli in care dementa este asociata cu semne clinice si

de laborator ale altor afectiuni medicale:
A. Infectia HIV / SIDA
B. Afectiuni endocrine: hipotiroidism, sd. Cushing, hipopituitarism
C. Carente nutritionale: sd. Wernicke-Korsakov, degenerescenta combinata
subacuta ( carenta de vit. B12 ), pelagra
D. Meningoencefalite cronice: paralizia generala progresiva, sifilisul
meningo-vascular, criptococcoza
E. Degenerescenta hepato- lenticulara familiala ( b. Wilson ) si dobandita
F. Intoxicatii cronice ( inclusiv statusul dupa intoxicatie cu CO )
G. Hipoglicemia sau hipoxia prelungita
H. Encefalita limbica paraneoplazica
I. Expunera la metale grele: As, Bi, Au, Mn, Hg
J. Dementa dialitica ( rara in prezent, datorita evolutiei tehnologiilor de
dializa )
modificat dupa Ropper AH, Samuels MA, Klein JP - Adams and Victors Principles of Neurology, 10-th ed,
McGrawHill Education, 2014

Pacienta cu sd. demential encefalita limbica paraneoplazica asociata cu

adenocarcinom pulmonar: debut neurologic inainte de diagnosticul oncologic

II. Boli in care dementa este asociata cu alte semne

neurologice, dar fara alte afectiuni medicale evidente(1):
A. Invariabil asociate cu alte semne neurologice:
1. Boala Huntington
2. Scleroza multipla, boala Schilder, adreno-leucodistrofia
si alte boli inrudite care afecteaza mielina SNC
3. Lipidozele
4. Epilepsia mioclonica
5. B. Creutzfeldt- Jacob ( clasica si noua varianta )
b.Gerstmann-Strausler-Scheinker
(dementele mioclonice, prionice)
6. Degenerescenta cerebro-cerebeloasa
7. Degenerescentele cortico-bazale DFT
8. Dementa cu paraplegie spastica
9. Paralizia supranucleara progresiva ( PSP ) DFT
10. Boala Parkinson
11. Boala difuza cu corpi Lewy
12. Scleroza laterala amiotrofica & dementaDFT
13. Complexul Parkinson-SLA-dementa
14. Alte boli metabolice ereditare rare
modificat dupa Ropper AH, Samuels MA, Klein JP - Adams and Victors Principles of Neurology, 10-th ed,
McGrawHill Education, 2014

II. Boli in care dementa este asociata cu alte semne

neurologice, dar fara alte afectiuni medicale evidente (2):
B. Adesea asociate cu alte semne neurologice:
1. AVC multiple ( ischemice/ hemoragice )
si b. Binswanger
2. Tumorile ( primare/ secundare ) sau abcesele cerebrale*
3a. Hematoamele intracraniene cronice*
3b. Leziuni dupa traumatisme cranio-cerebrale
( de regula tipuri de leziuni insotite de diferite forme de
sangerare cerebrala )
4. Boala difuza cu corpi Lewy
5. Hidrocefaliile comunicante normotensive sau
hidrocefaliile obstructive*
6. Leucoencefalita multifocala progresiva ( LEMP )
7. Boala Marchiafava Bignami
8. Granulomatozele si vasculitele cerebrale
9. Encefalitele virale
modificat dupa Ropper AH, Samuels MA, Klein JP - Adams and Victors Principles of Neurology, 10-th ed,
McGrawHill Education, 2014

III. Boli in care de obicei dementa este singura manifestare

evidenta a unei afectiuni neurologice sau medicale:
A. Boala Alzheimer
B. Unele cazuri de SIDA
C. Degenerescentele lobare fronto-temporale
( inclusiv sd. afazice primare progresive) si cele de lob frontal
F. Boli degenerative nespecificate

modificat dupa Ropper AH, Samuels MA, Klein JP - Adams and Victors Principles of Neurology, 10-th ed,
McGrawHill Education, 2014

MILD COGNITIVE IMPAIRMENT ( MCI )

Criterii clinice pentru MCI:
( Mayo Alzheimer Disease Center, Petersen et al., 1999,
modificate in 2001 )
1. Acuze privind tulburari cognitive (de obicei de memorie), de
preferat sesizate si de o persoana din anturaj
2. Tulburari cognitive (de obicei de memorie) obiective, in raport
cu varsta si nivelul de instruire
3. Functiile cognitive generale intacte in cea mai mare masura
4. Conservarea in esenta a activitatilor din viata cotidiana
5. Absenta dementei

SUBTIPURI de MCI
ETIOLOGIE
Degenerativa

Vasculara

B. Alzheimer

Psihiatrica

Depresie

Clasificare clinica

Domeniu
unic

MCI
amnestic
Domenii
a
multiple

B. Alzheimer

VaD

DFT

MCI

Domeniu
unic

non-amnesticaDomenii
multiple

DLB

VaD

Depresie

Conditii medicale

Examenul clinic general - obligatoriu

- semne care s orienteze ctre diagnosticul unei
afeciuni generale care se nsoete de demen
( tumor malign, afeciune metabolic, SIDA, hipotiroidism,
anemie sever, etc.)

Examenul neurologic obligatoriu

- poate decela semne neurologice specifice care s orienteze
diagnosticul ctre boli neurologice primare care se asociaz
cu demen (boala Wilson, boala Creutzfeldt-Jacob, etc.).
* Ex. : examenul neurologic este foarte important pentru
a deosebi o demen de tip Alzheimer de o demen vascular.

Examenul psihiatric obligatoriu

poate depista tulburri non-cognitive:
- simptome psihiatrice ( adeseori prezente din primele stadii evolutive ):
* depresia
* fenomene psihotice
* stri confuzionale
* episoade obsesive
* anxietate
* iritabilitate
* dezinhibiie
* agitaie
scop: asigurarea unui management optim al bolii

Examenul neuropsihologic
- obligatoriu n caz de demen usoar sau probabil
- teste pentru aprecierea deficitului cognitiv
- scale specifice pentru evaluarea depresiei
(depresia poate mima o demen sau se poate asocia unei demene).

Analize de laborator
- obligatoriu cele uzuale
( hemoleucogram, uree, creatinin, VSH, glicemie, transaminaze,etc.)
- se recomand: ionograma i investigarea funciei tiroidiene
- pot fi necesare analize specifice:
* teste serologice pentru boli infecioase
( SIDA, sifilis, borelioz, encefalita herpetic, etc.)
* teste imunologice (diagnosticul vasculitelor, a lupusului sistemic, etc.)
* probe toxicologice (intoxicaii cu metale grele)
* teste genetice
(identificarea bolii Alzheimer precoce familiale, DFT, CADASIL, etc.)
* alte determinari (nivelul seric de vitamin B12 sau homocistein)
* alte teste specifice.

Examenul lichidului cefalorahidian

- n cazuri selecionate de diagnostic diferenial
- in boala Alzheimer:
* peptidul A42 are un nivel sczut
* proteina tau & proteina tau fosforilata - nivel crescut
vs. non-demeni de aceeai vrst
( grad de recomandare de nivel B )
- in cazul suspiciunii de boal Creutzfeldt-Jakob:
* proteina 14-3-3 este important pentru diagnostic
( grad de recomandare de nivel B )

Investigaiile neuroimagistice
- Rolul principal:
* excluderea alte patologii cerebrale
* sprijinirea diagnosticul tipului de demen neurodegenerativ
n boala Alzheimer, atrofia cerebral predominant la nivelul
hipocampului i a lobului T
n DFT atrofia cerebral predominant la nivelul lobilor F i T
n demena vascular: evidenierea leziunilor vasculare i a
tipului acestora, etc.
NB. Sunt ns i situaii n care simptomatologia este clinic evident
pentru boala Alzheimer dar CT-ul nu este modificat pentru
vrsta pacientului.
Investigaiile neuroimgistice nu sunt absolut necesare pentru
diagnosticul bolii Alzheimer efectuat ntr-un stadiu deja avansat
al bolii, cu manifestri clinice severe.

Investigaiile neuroimagistice
- ajuta la stabilirea diagnosticului de demen
- cel putin CT cerebrala fr contrast (grad de recomandare de nivel A)
- in cazuri selecionate:IRM cerebral (grad de recomandare de nivel A)
sau examinri imagistice cu contrast
- in cazuri selecionate: SPECT cerebrala
* diagnosticul etiologic al demenei
* diagnostic diferenial: demen Alzheimer i demen vascular
(grad de recomandare de nivel B)
- PET cu PIB ( Pittsburg Compound B ): gradul de incarcare cerebrala
cu amiloid: d. Alzheimer, DLB vs PD-D

Forsberg A, et al. Neurobiol Aging 2008; 29: 14561465.

Examenul electroencefalografic (EEG) poate fi necesar uneori

( grad de recomandare de nivel B )
- n cazuri selecionate (spre exemplu n suspiciunea de CJD sau de
encefalite)

Biopsia cerebral
- necesar numai n cazuri rare, selecionate cu mare grij,
n care diagnosticul etiologic nu poate fi stabilit prin alte proceduri
- n centre de neurochirurgie cu experien
- numai la recomandarea neurologului sau psihiatrului curant
si
- cu acordul scris al familiei sau reprezentantului legal al bolnavului.
- pt. b. Alzheimer: substituita astazi de markerii biologici in LCR

BOALA ALZHEIMER
- cea mai frecventa boala neurodegenerativa, 2/3 dintre demente
- 10% peste 60 ani, 1 din 3 peste 85 ani

MODIFICARI GENETICE CUNOSCUTE:

- gena APP de pe cromozomul 21
- PS 1 de pe cromozomul 14 ( proteina S 182 ): > 40 mutatii
(clivaj al APP in situsul pt. -secretaza ); 40 70% dintre
bolnavii cu b. Alzheimer cu debut precoce si evolutie mai
rapida: 6 7 ani ( forma mai rara )
- PS 2 de pe cromozomul 1 ( STM 2 ): debut mai tardiv si
evolutie mai lunga ( 11 ani )
* PS rareori implicate in formele cele mai comune, sporadice
- gena ApoE de pe cromozomul 19 (formele sporadice comune)
alelele 4: asociere cu b. Alzheimer ( homozigotia 4=f.risc)
* relatie cu transportul colesterolului

AD Neuropathology

- Senile plaques
Extracellular
Amyloid -peptide (A)

- Neurofibrillary tangles
Intracellular
Hyperphosphorylated tau

- Neuronal and Synaptic loss

- Inflammatory response
- Vascular lesions

Bogdanovic & Winblad, Huddinge Brain Bank, 2006

Boller F. et al - Cortex, (2007)

43, 565-569

Blocq P, Marinesco G, Sur les lsions et la

pathologie de
lpilepsie dite essentielle, La Semaine
mdicale, novembre
1892, 445446 (travail du laboratoire du Pr
Charcot).
Marinesco G, Nouvelles recherches sur les
plaques sniles
(1928). In: ***, OEuvres choisies (1963), vol. II,
Masson, Paris,
1897, 133.

Continutul unei placi amiloide

Nucleu de amiloid, inconjurat de leziuni degenerative
- in placa exista si alte substante: apoE

Cu timpul, neuronii din jur degenereaza si acumuleaza proteina tau

hiperfosforilata

Procesarea APP

modificat dupa Querfurth H and LaFerla F.- N Engl J Med 2010;362:329-344

Zheng and Koo Molecular Neurodegeneration 2011 6:27 doi:10.1186/1750-1326-6-27

Zheng and Koo Molecular Neurodegeneration 2011 6:27 doi:10.1186/1750-1326-6-27

Spuch C.,Ortolano S.,Navarro C. - Journal of Aging Research Volume 2012, Article ID 324968,
doi:10.1155/2012/324968


Axa ficat creier
Insulina plasmatica faciliteaza clearance-ul hepatic al
amiloidului plasmatic (1-40) prin translocarea intracelulara a
LDL Receptor-related Protein-1 ( LRP-1) catre
membrana plasmatica a hepatocitelor

Previne acumularea cerebrala a A ( 1-40)

DZ tip 2 & MetSy

( REZISTENTA CRESCUTA la INSULINA )

FACTORI DE RISC pentru BA

Tamaki C. et al, Molecular Pharm, 2007

Ipoteza cascadei amiloide

Creste productia
si scade clearence-ul,
A42

Factori de mediu

Tau

oligomerizarea si
depunerea A42

Placi difuze
Depozite A

Gene

A40

Activitatea
kinazelor si
fosfatezelor
e alterata

PHF-tau
Degenerescente
neurofibrilare

Placi amiloide

Stress oxidativ
Disfunctie si moarte
Tulburari [Ca++]
neuronala
Inflamatie cronica
Toxicitate glutamatergica
Apoptoza
Deteriorare structurala

Dementa

Hiperfosforilarea tau & NFT

Microtubulii = parti din citoscheletul neuronal

- formati din subunitati de tubulina (proteina) stabilizata de:
- 2 proteine unice asociata microtubulilor (MAP)
* proteina tau = una din aceste proteine

Tau = MAP ce stabilizeaza microtubulii in configuratia neuronala normala

- permite transportul axonal normal al factorilor nutritivi si altor molecule
in interiorul neuronului

Hiperfosforilarea tau * destabilizarea microtubulilor,

* agregarea proteinei tau / formarea NFT

moarte neuronala

FOSFORILAREA SI DEFOSFORILAREA
PROTEINEI TAU

The AD Network Puzzle

TheAlzheimersDiseasepuzzle

CedazoMinguezJCMM2008

February 2011

Hypercholesterolemia

However:
NORMAL Ch is essential for many physiologic processes
modulates fluidity of cell membranes & is essential for basic synaptic
integrity and neurotransmission

All these processes - are compromised with aging

- have been shown to be dysfunctional in AD

N Ch could have a protective effect in patients with AD !

Mielke MM et al, Neurology, 2005

HIGH MIDLIFE serum Ch is a RF for subsequent dementia/ AD

but spontaneously decreasing serum Ch after midlife reflect ongoing
disease processes and may represent a risk marker for late-life cognitive
impairment (21 y follow-up of 1449 individuals )
Solomon A. et al. Neurology 2007

Ltjohann D et al - Clin Lipidology. 2012;7(1):65-78

 In Alzheimer disease and CAA, accumulation of A in the media of

cortical arterioles weakens the vessel wall and increases the chance of
lobar hemorrhages
The major risk factors for VCI and Alzheimer disease hypertension,
aging, and diabetes impair endothelium-dependent responses in the
cerebral microcirculation and blunt functional hyperemia
A is a potent vasoconstrictor and suppresses endothelium-dependent
responses, functional hyperemia, and cerebrovascular autoregulation.
Cerebral smooth muscle cells of patients with Alzheimer disease have
increased constrictor tone, which may contribute to the CBF reduction
observed in this condition.
Vascular oxidative stress and inflammation are key pathogenic factors
in neurovascular dysfunction

Cerebrovascular atherosclerosis correlates with

Alzheimer pathology
in neurodegenerative dementias

The combination between cerebrovascular lesions and Alzheimer-type pathology is the most
common neuropathological finding in elderly patients with dementia.

More than 77% of subjects with Alzheimer's disease had grossly apparent circle of Willis
atherosclerosis, a percentage that was significantly higher than normal (47%), or other
neurodegenerative diseases (43-67%). Age- and sex-adjusted atherosclerosis ratings were highly
correlated with neuritic plaque, paired helical filaments tau neurofibrillary tangle and cerebral
amyloid angiopathy ratings in the whole sample and within individual groups.

These results provide further confirmation and specificity that vascular disease and Alzheimer's
disease are interrelated and suggest that common aetiologic or reciprocally synergistic
pathophysiological mechanisms promote both vascular pathology and plaque and tangle pathology

Increased cardiovascular risk was associated with reduced gray matter volume and thickness in
regions also affected by Alzheimer disease independent of infarcts and apolipoprotein E genotype.
These results suggest a "double hit" toward developing dementia when someone with incipient
Alzheimer disease also has high cardiovascular risk
Yarchoan M et al - Brain. 2012 Nov 30. [Epub ahead of print]
Cardenas VA et al - Stroke. 2012 Nov;43(11):2865-70
Diehl J, Kurz A. - Fortschr Neurol Psychiatr.2002;70(3):145-54

LESIONS in ALZHEIMERs DISEASE and VASCULAR

DEMENTIA
(Kalaria R.N., 2001)
A.D. (%)
Va .D.(%)
- amyloid cerebral angiopathy.98..30
- microvascular degeneration....100......30
- complete infarcts......36........100
- microinfarcts.............31..........65
- hemorrhagic brain lesions......7..........15
- white matter lessions.........35......70
- cholinergic neurons loss....70......40
- cardiovascular diseases.....77......60

Epidemiological findings of vascular risk factors in

Alzheimer's disease:
implications for therapeutic and preventive intervention

Systematic reviews and meta-analyses of population-based prospective studies have concluded from
the life-course perspective (supported by population-based neuroimaging and neuropathological
studies ) an age-dependent association with the risk of AD for several vascular factors, such as :

high blood pressure

obesity
high total cholesterol

Possessing these factors in midlife is associated with an increased risk of late-life AD, whereas having
a low level in late life or a decline after middle age in these factors may anticipate clinical onset of AD

Practicing clinicians can reasonably state to patients that, although more definitive research is clearly
needed, the management and treatment of vascular disease risk factors are likely
beneficial not only to prevent heart disease and stroke, but also common forms of
dementia in the community
Romn GC, Nash DT, Fillit H - Alzheimer Dis Assoc Disord. 2012 Oct;26(4):295-9

REZISTENTA LA INSULINA IN
BOALA ALZHEIMER
Studii epidemiologice:
asociere semnificativa a dementelor din boala
Alzheimer si posibil a dementelor vasculare, cu:
diabetul zaharat
sd. metabolic

Craft S et al - Arch Gen Psychiatry 1999; 56: 1135-1140; Kern W et al - Neuroendocrinology

2001; 74: 270-280; Craft S et al - Neuroendocrinology 1999; 70: 146-152.

Pathophysiological Processes Leading to

DEMENTIA Winblad B - 2008
Possible Targets for Therapy
Aging
Disbalance:
calcium
energy

antioxidant
triangle

Accumulation of
peptides
(A, -synuclein) DLB
degradation
(proteasomal) deficit?
Neurotransmitters
deficits

VASCULAR (VAD, AD)

APP & presenilin

mutations (AD)
Increased A
Tau mutations
production
(FTD)

Oxidative stress
Synaptic damage
Neurodegeneration
Neuronal death
Cognitive dysfunction

Current approaches
to drug therapy

Tau protein
hyperphosphorilation

Future
treatment
strategies
Micro- & astroglia
activation
Inflammation

 Alzheimer's disease is a pathological diagnosis using a series of

standardised criteria
Alzheimer's dementia is a clinical syndrome that is possibly or probably
as a consequence of Alzheimer's disease ( progressive
neurodegenerative disease )
Alzheimer's dementia is most commonly defined in a research setting using the
NINCDS-ADRDA criteria which compared to results at autopsy, detects Alzheimer's
disease with a sensitivity of 9198%

Years before the onset of clinical symptoms of demential syndrome, there is

an AD process evolving along a predictable pattern of progression in the brain
Braak H, Braak E. - Acta Neuropathol (Berl), 1991; Delacourte A et al. Neurology, 1999
Dubois B. et al, Lancet Neurology, 2007

Is it possible to diagnose Alzheimers disease during the

predementia stage ?

Frisoni GB, et al. Nat Rev Neurol 2010; 6: 6777

Forsberg A, et al. Neurobiol Aging 2008; 29: 14561465.

BOALA ALZHEIMER
MANIFESTARI CLINICE
* boala neurologica progresiva cu pierdere ireversibila de
sinapse si neuroni, predominent corticala (hipocamp
si neocortex )
- elementele clinice esentiale ( in stadiul demential ):
* afectarea progresiva a memoriei, judecatii, a capacitatii
de decizie
* afectarea capacitatii de orientare in mediul fizic
* afectarea limbajului

ELEMENTE NEUROPATOLOGICE ESENTIALE:

* pierderea sinaptica si neuronala
* placile senile extracelulare ( care contin -amiloid )
* degenerescentele neurofibrilare ( NFT )
( cu proteina tau microtubulara hiperfosforilata )

MANIFESTARI CLINICE
- semnele precoce sunt subtile, adesea ignorate:
* lipsa de initiativa, scaderea interesului fata de activitatile
profesionale, neglijarea sarcinilor de rutina, disparitia
interesului fata de activitatile care faceau placere
("oboseala");
sau,
* instabilitate emotionala, tulburari afective ( depresie, cel mai
frecvent ), apatie ( rareori exaltare nejustificata ), fluctuatii
nejustificate ( ras plans ).
- progresiv, dezvoltare graduala a tulburarilor mnezice ( nume
proprii, intalniri fixate, conversatii recente, evenimente sociale,
repeta aceleasi intrebari uitand raspunsurile);
- distractibilitate usoara determinata de orice eveniment trecator;
- conversatia pierde din claritate, nu mai intelege toate nuantele
si aspectele conversatiei, unei situatii;
- preocupare excesiva pt. aspecte neimportante;
- sarcini care implica mai multi timpi nu mai pot fi realizate;

- apar dezorientari, chiar in mediul obisnuit ( mai tarziu rataciri);

- acuze somatice: ameteli, neclaritate mentala, cefalee
nesistematizata;
- uneori stare confuzionala acuta determinata de o boala febrila,
un traumatism, o operatie, un nou medicament, schimbarea
mediului obisnuit, etc.
- mai tarziu:
* pierderea abilitatilor sociale si interferenta cu obiceiurile
sociale;
* alterarea judecatii;
* suspiciozitate crescuta, manifestari paranoiace;
* alterare severa antero / retrograda a memoriei ( nu mai
recunoaste rudele apropiate, numele copiilor, etc.);
* apraxii si agnozii interfera cu realizarea unor sarcini
simple;

- afectarea limbajului:
* in unele demente ( altele decat AD, in particular FTD ):
de la inceput
* pierderea intelegerii nuantelor de limbaj ( vorbit, scris );
* restrangerea vocabularului, vorbire cu repetitii
* nu se mai exprima in fraze si propozitii lungi, bine constituite
* tendinta de folosi formule verbale stereotipe, exclamatii
* parafazii, dificultate de a intelege fraze complexe
* agravare in timp palilalie, echolalie, nu-si mai pot exprima
verbal sentimentele concomitent cu degradare
comportamentala, etc.
- nu mai pot face calcule, nu mai recunosc ceasul
- in stadii avansate pot ramane ambulatori, dar se deplaseaza
fara un scop; au complet pierdute abilitatile cognitive, ratiunea,
judecata; pierderea inhibitiei, comportament agresiv, beligerant
alternand cu pasivitate si retragere sociala
- perturbarea ritmului veghe-somn, cu inversiune, adesea cu
agitatie psiho-motorie vesperala ( " sun-down syndrome" );

- tulburari de mers, cu nesiguranta si rigiditate musculara

generalizata asociata cu lentoare si lipsa de spontaneitate
a miscarilor ( parkinsonism ! );
- in stadiile finale:
* rigiditate, mutism, incontinenta, imobilizati la pat
( frecvent, dar nu obligatoriu )
* necesita ajutor pentru cele mai elementare sarcini
( hranire, imbracat, toaleta, etc )
* ROT exagerate, dezinhibitia unor reflexe ancestrale
( r. Toulouse, supt, s.a. )
* tresariri mioclonice la stimuli senzitivi, auditivi
( CJD )
* crize epileptice generalizate ( posibile )
- deces: tulburari de nutritie, infectii, IMA
DURATA MEDIE TIPICA: 8 10 ani ( extreme: 1 25 ani! )

Deterioration

Progress of Symptom Development

Mood

Cognitive function Behaviour Mobility

Time

Gauthier (1999); Feldman, Kertesz (2001); Auer et al. (1996); Reisberg et al. (1996); Barclay et al.(1985)

Miia Kivipelto, MD, PhD and Alina Solomon, MD - NEUROLOGY 2009;73:168-169

Factori de risc si de protectie in

patogenia bolii Alzheimer
modificat dupa Arrizaga R. Congres SSNN, Cracovia 2011
Roe CM et al. Neurology 2011; 76:501-510

FACTORI DE RISC in BA

Genetici
Varsta
Vasculari

HTA
H-colesterolemie
H-trigliceridemie
Diabetul zaharat
Sd. metabolic
AVC
Homocisteinemia
Fumatul

BMI
Depresia

FACTORI DE PROTECTIE in BA

REZERVA

Genetici
Educatia
Stilul de viata

- COGNITIVA
- CEREBRALA
( structurala )

Dieta
Activitatea cerebrala
Activitatea fizica

Interventii farmacologice

Anti-HTA
Statine
preventia primara & secundara a
AVC
AINS ?
Estrogeni ?!

Risk factors and markers in Dementia:

Continuum between AD and VaD

AD

VaD
Hypertension

Hypertension
Cholinergic deficits

Amyloid Plaques
Definite AD

Probable Possible
AD
AD

Hypercholesterole
mia

Genetic
s
Neurofibrillary
Tangles

AD +
CVD

Stroke/TIA Diabetes

Possible Probable
VaD
VaD

Definite VaD

Hypercholesterolemia
Brain Infarcts

Heart
Disease

Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13:S115-123

Relationship among AD,

VaD and other dementias

VaD
AD
Other
(PDD,
DLBD,FTD, etc. )

Cras, 1998

Processes influencing clinical expression of

dementia
Additional opportunities for interventions

Sperling RA et al - Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2011, 7 (3): 280-292

MODIFICARI IN NEUROTRANSMISIE:
( fenomene secundare leziunilor neuronale )

- afectare predominenta a sistemului colinergic

* diminuare marcata a ACh, CAT, receptori nicotinici
* diminuarea ChE, cresterea BuChE ( asociata placilor senile si NFT )
degenerescenta nc. basalis Meynert
Baza terapiei simptomatice cu ChEI:
- donepezil
- rivastigmine
- galantamine

- reducere a activitatii sistemului noradrenergic

- sistemul glutamatergic (nivel crescut de glutamat)
Baza terapiei simptomatice cu ANTAGONISTI PARTIALI rNMDA:
- memantine

TRATAMENT SIMPTOMATIC
A. Inhibitori de cholinesteraza ( AchEI )
-

DONEPEZIL
RIVASTIGMINE
GALANTAMINE

B. Antagonisti partiali de receptori NMDA ( pt. glutamat )

-

MEMANTINE

C. Terapii in dezvoltare

Categorii de complicatii neurologice

la pacientii infectati HIV
Primare
mai frecvente
tulburarile neurocognitive
[ minore+deficit motor (MCMD)
dementa asociata HIV (HAD)]
mielopatia vacuolara
neuropatii periferice

Secundare imunosupresiei

encefalita cu toxoplasma
meningita criptococcozica
encefalita cu CMV
radiculita cu CMV
limfomul primar SNC
LEMP
neurotuberculoza

alte manifestari neurologice

(mai frecvente la infectatii HIV vs. neinfectati,
dar nu neaparat direct cauzate de HIV)

neuropatii de incarcerare
cefalee
crize epileptice
AVC
miopatii

Asociate cu tratamentul
neuropatii toxice
sd. metabolic & consecintele
vasculare si neurodegenerative
modificarea clinica a tulb.
neurocognitive

Afectarea SNC
Sindroamele neurocognitive
evolutie clinica progresiva HAD
este o forma definitorie de SIDA
debut: de obicei cand nr. cel.T CD4+ scade sub < 200/L
HAART HAD poate apare si la CD4+ > 200/L
HAD prognostic prost de supravietuire cu/ fara HAART
asocierea infectiei cu HCV poate agrava disfunctia
neurocognitiva mai ales disfunctia executiva

AAN (American Academy of Neurology)

AAN criteria defined 2 levels of neurologic manifestations of HIV infection:
- HIV-associated dementia (HAD)
- Minor cognitive motor disorder (MCMD)

AAN criteria for HAD were:

1) an acquired abnormality in at least two cognitive (nonmotor) areas
causing impairment in work or activities of daily living (ADLs)
and
2) either an abnormality of motor function or specified
neuropsychiatric or psychosocial functions (e.g., motivation,
emotional control, social behavior).
Janssen RS et al Nomenclature and research case definitions for neurological manifestations of human
immunodeficiency virus type-1 (HIV-1) infection. Report of a Working Group of the American Academy of
Neurology AIDS Task Force. Neurology 1991;41:778785.

HAD (HIV-associated dementia) defined

by AAN
AAN diagnostic scheme defined 3 subtypes of HAD:
1) HAD with motor symptoms (criterion 1 met fully, but only motor
symptoms meeting criterion 2)
2) HAD with behavioural or psychosocial symptoms (criterion 1 met
fully,but only behavioral symptoms meeting criterion 2)
3) HAD with both motor and behavioral/psychosocial symptoms
(criteria 1 and 2 met fully)

The three conditions comprising

HAND ( HIV Associated Neurocognitive Disorders ):
ANI ( Asymptomatic Neurocognitive Impairment )
The recognition of ANI might promote the initiation of antiretroviral
therapy, independent of CD4 count or plasma HIV RNA levels. These
issues / questions are unresolved and require future study

MND ( HIV-Associated Mild Neurocognitive Disorder)

HAD ( HIV- Associated Dementia )
may be classified using a variety of specific clinical and laboratory-based methods

Antinori A. et al, Neurology 2007, 69 (18 ): 1789-1799

Caracteristici clinice ale HAD

( de obicei precedate de tulburari minore cognitive si motorii )

Declin neurocognitiv
Tulburari afectiv-comportamentale
Tulburari motorii progresive
FACTORI DE RISC:
Nr. scazut de cel.CD4+ & incarcare virala plasmatica
mare
Anemie
Toxicomanii ( cu droguri i.v. ) progresie rapida
Varste extreme: varstnici & copii
Incarcare virala crescuta in LCR

Tulburari cognitive
acuze subiective de lentoare mentala
progresiva
tulburari mnestice initial minore
declin mnestic progresiv
hipoprosexie ( f. adesea in HAD )
pierderea capacitatii de concentrare
pt. activitati cotidiene uzuale ( citit, TV,
s.a. )

tulburari vizuo-spatiale
discoordonare vizuo-motorie
NB: MMSE nu este util in stad. incipiente
( manifestari de tip frontal )

Tulburari comportamentale
apatie marcata si retragere sociala
fara depresie
iritabilitate marcata
inflexibilitate mentala accentuata
scaderea libidou-lui
manifestari psihotice maniacale
( nu sunt comune )

Tulburari motorii
scadere globala a fortei
musculare
tulburari de echilibru
mers nesigur
bradikinezie, parkinsonism
motor
semne de sd. bipiramidal
miscari sacadice de urmarire
ale globilor oculari
semne de eliberare frontala
( stadii avansate )
mioclonii ( stadii avansate )