DIAGNOSTICUL

PRIN PRISMA SPECTRULUI

CLINICO-BIOLOGIC AL DEMENTELOR
Prof. Dr. Ovidiu Bajenaru

UMF Carol Davila Bucuresti
Spitalul Universitar de Urgenta Bucuresti Clinica de Neurologie
Dementele provocarea viitorului
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*
Estimare a numrului de persoane suferind de dementa, 2005-2050*
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An
1. Green Paper on Demographic change, Brussels 2005;12(suppl 1):1-27
*Sursa: Datamonitor, publicat Martie 2008
Lim, et al. J Am Geriatr Soc. 1999 May;47(5):564-9
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
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 )
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

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
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. Dementele fronto-temporale ( inclusiv sd. afazice primare progresive)
si cele de lob frontal
F. Boli degenerative nespecificate
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 ! ) va disparea 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 DSM-IV
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
Neurocognitive Disorder
- new reccomended criteria by APA -
Terminology for the cognitive domains has been updated to reflect
current usage in neuropsychology and neurology

Evidence of significant cognitive decline from a previous level of
performance in one or more of the domains based on:
Complex attention (sustained attention, divided attention, selective
attention, processing speed)
Executive ability (planning, decision-making, working memory, responding to
feedback/error correction, overriding habits, mental flexibility)
Learning and memory (immediate memory, recent memory [including free recall,
cued recall, and recognition memory])
Language (expressive language [including naming, fluency, grammar and syntax]
and receptive language)
Visuoconstructional-perceptual ability (construction and visual perception)
Social cognition (recognition of emotions, theory of mind, behavioral regulation)

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).
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, Minor and Major may be earlier and later
stages of the same disorder
S 24 - 35 Major 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 - 23 Mild Neurocognitive 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
DSM-5 Neurocognitive Criteria, Draft 1/7/10
M E M O R I A

DECLARATIVA
( EXPLICITA )
NON-DECLARATIVA / PROCEDURALA
( IMPLICITA )
Fapte
Evenimente
COMPORTAMENTALA
(abilitati, obiceiuri)
De IDENTIFICARE
(DETECTARE)
De INVATARE
ASOCIATIVA
DE BAZA
De INVATARE
NON-ASOCIATIVA
RASPUNSURI
EMOTIONALE
RASPUNS
MUSCULAR
SCHELETIC
HIPOCAMP
LOB T MEDIAL
DIENCEFAL
STRIAT
CORTEX MOTOR
CEREBEL
NEOCORTEX
SISTEM
LIMBIC
CEREBEL
CAI
REFLEXE
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

B. Alzheimer Depresie
B. Alzheimer VaD Depresie
DFT
DLB VaD
Domeniu
unic
Domenii
multiple
Domeniu
unic
Domenii
multiple
MCI
amnestic
a
MCI
non-amnestica
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SUBTIPURI de MCI
Degenerativa Vasculara Psihiatrica Conditii medicale
ETIOLOGIE

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
investigarea funciei tiroidiene
nivelul seric de vitamin B12

- pot fi necesare analize specifice:
* teste serologice pentru boli infecioase
( HIV, 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 (ex. 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.
PET cu PIB ( Pittsburg Compound B )


PDD: incarcare mica cu amiloid
DLB: incarcare semnificativa cu amiloid !


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 c4: asociere cu b. Alzheimer ( homozigotia c4=f.risc)
* relatie cu transportul colesterolului
Bogdanovic & Winblad, Huddinge Brain Bank, 2006
Intracellular
Hyperphosphorylated tau

- Neurofibrillary tangles
- Senile plaques
Extracellular
Amyloid -peptide (A)
AD Neuropathology
- Neuronal and Synaptic loss
- Inflammatory response
- Vascular lesions
Boller F. et al - Cortex, (2007) 43, 565-569
Marinesco G, tude anatomique et clinique des plaques dites
sniles, Encphale (Paris), 1er semestre, 1912, 105132.
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. - J ournal of Aging Research Volume 2012, Article ID 324968,
doi:10.1155/2012/324968

Ipoteza cascadei amiloide
Degenerescente
neurofibrilare
Placi amiloide
Creste productia
si scade clearence-ul,
A
42
Placi difuze
A
40
Tau
PHF-tau
Activitatea
kinazelor si
fosfatezelor
e alterata
Stress oxidativ
Tulburari [Ca
++
]
Inflamatie cronica
Toxicitate glutamatergica
Apoptoza
Deteriorare structurala
Disfunctie si moarte
neuronala

Dementa
oligomerizarea si
depunerea A
42
Depozite A
Gene
Factori de mediu
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
t
moarte neuronala




FOSFORILAREA SI DEFOSFORILAREA
PROTEINEI TAU
Querfurth HW, LaFerla FM. NEJ M 2010
Degenerescentele neurofibrilare - NFT
Degenerescentele neurofibrilare intraneuronale sunt
compuse din filamente helicoidale in perechi, derivate din
agregate de proteina tau produse prin procesul de
hiperfosforilare





A and BBB
Brain
Capillary
A|
LRP-
1
RAG
E
LRP-1 = low density lypoprotein receptor-related protein
RAGE = receptor for advanced glycation end-products
Drawing following the concept of Deane et al., Nature Med, 2003
A| in:
-blood
-vessels (CAA)
-brain tissue

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

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


February 2011
The Alzheimers Disease puzzle
The AD Network Puzzle
Cedazo-Minguez JCMM 2008
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
Pathophysiological Processes Leading to
DEMENTIA
Possible Targets for Therapy
Aging
Neurotransmitters
deficits
Micro- & astroglia
activation
Inflammation
Cognitive dysfunction
Oxidative stress
Disbalance:
calcium

energy antioxidant
triangle
APP & presenilin
mutations (AD)
Increased A|
production
Tau protein
hyperphosphorilation
Synaptic damage
Neurodegeneration
Neuronal death
Current approaches
to drug therapy
Future
treatment
strategies
VASCULAR (VAD, AD)
Accumulation of
peptides
(A, -synuclein) DLB
degradation
(proteasomal) deficit?
Tau mutations
(FTD)
Human and experimental
animal studies revealed that
neurodegeneration associated
with peripheral insulin
resistance is likely effectuated
via a liver-brain axis whereby
toxic lipids, including
ceramides, cross the blood
brain barrier and cause brain
insulin resistance, oxidative
stress, neuro-inflammation,
and cell death.


In essence, there are dual
mechanisms of brain insulin
resistance leading to AD-type
neurodegeneration:
one mediated by
endogenous, CNS factors;
the other: peripheral insulin
resistance with excess
cytotoxic ceramide
production.

[BMB reports 2009; 42(8): 475-481]

del Monte SM, 2009
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.

FIZIOLOGIC:
- Insulina ( via GSK 3 ) inhiba HIPERFOSFORILAREA PROTEINEI TAU

inhiba formarea degenerescentelor neuro-fibrilare

- Rezistenta crescuta la insulina ~ accelereaza formarea placilor
neuritice ( crescuta suplimentar la purtatorii APOE 4 )

HIPERINSULINISMUL CRONIC:
insulina exacerbeaza raspunsul inflamator cronic si creste stress-ul
oxidativ ( posibil rol: ceramidele rezultate din alterarea metabolismului
lipidic periferic ( axa ficat creier trec BHE efecte neurotoxice si
proinflamatorii prin citokine pro-inflamatorii )

inflamatia: promotor al patogeniei b.A.
Facchini FS, Hua NW, Reaven GM, Stoohs RA. - Free Radic Biol Med 2000; 29: 1302-1306;
Axelrod L. - Diabetes 1991; 40: 1223-1227; Laight D, Desai K, Gopul N - Eur J Pharmacol
1999; 377: 89-92; Soop M, Duxbury H, Agwunobi A - Am J Physiol Endocrinol Metab
2002; 282: E1276-E1285; del Monte SM - BMB reports 2009; 42(8): 475-481;
Matsuzaki T - Neurology, 2010, 75 ( 9 ): 764-770
TNF inhiba clearance-ul A
Insulina previne acumularea A intracelular facilitand eliberarea sa
Insulina & IGF-1 faciliteaza intrarea crescuta in SNC a proteinelor de
transport ( albumina & transthyretine ) legarea A transportul A
catre LCR si sange

TNF inhiba IRS reduce trecerea
proteinelor de transport in SNC
Gasparini L, Xu H - Trends Neurosci 2003; 26: 404-406;
White MF - Am J Physiol Endocrinol Metab 2002, 283:E413E422

METABOLIC
SYNDROME
LIFESTYLE
GENETICS ?
ATYPIC
ANTIPSYCHOTICS
OSHAS
CHRONIC SLEEP
DEPRIVATION
STROKE
CHD
COGNITIVE IMPAIRMENT/
/ DEMENTIA ( AD )
VASCULAR DEATH
BRAIN
(Metabolic control)
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
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

Frisoni GB, et al. Nat Rev Neurol 2010; 6: 6777
Is it possible to diagnose Alzheimers disease during the
predementia stage ?
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
( A CJD )
* crize epileptice generalizate ( posibile )

- deces: tulburari de nutritie, infectii, IMA

DURATA MEDIE TIPICA: 8 10 ani ( extreme: 1 25 ani! )
Progress of Symptom Development
Time
Mobility
Behaviour
Cognitive function Mood
Gauthier (1999); Feldman, Kertesz (2001); Auer et al. (1996); Reisberg et al. (1996); Barclay et al.(1985)
D
e
t
e
r
i
o
r
a
t
i
o
n

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
Genetici
Educatia
Stilul de viata
Dieta
Activitatea cerebrala
Activitatea fizica
Interventii farmacologice
Anti-HTA
Statine
preventia primara & secundara a
AVC
AINS ?
Estrogeni ?!
REZERVA
- COGNITIVA
- CEREBRALA
( structurala )
FACTORI DE RISC

BOALA ALZHEIMER & DEMENTE VASCULARE
* VARSTA
* AS CAROTIDIANA
* FIBRILATIA ATRIALA
* SINDROMUL METABOLIC
&
* DIABET ZAHARAT ( TAGE, rezistenta la insulina )
* FUMAT
* FACTORI GENETICI ApoE4 ( b.A. > DVa )
* HTA ( x 4 )
* AVC
* HIPERCOLESTEROLEMIA
* HIPERHOMOCISTEINEMIA
* DISFUNCTIA VENTRICULARA

Diabetul zaharat asociat cu ApoE4 creste > x 2 riscul b. Alzheimer
( |nr. placi amiloide & NFT, probabil si prin intermediul bcv )
New approach of AD and VaD

VaD
AD with/ CVD
CVD is the pathology; VaD is the clinical disease
VaD without AD pathology is relatively rare
Most patients have significant overlap between AD and CVD
This overlap is AD w/CVD
AD
Risk factors and markers in Dementia:
Continuum between AD and VaD
Definite AD
Probable
AD
Possible
AD
Possible
VaD
Probable
VaD
AD +
CVD
Definite VaD
Hypertension
Stroke/TIA
Hypercholesterolemia
Heart
Disease
Hypercholesterole
mia
Amyloid Plaques
Genetic
s
AD VaD
Neurofibrillary Tangles
Diabetes
Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13:S115-123
Hypertension
Cholinergic deficits
Brain Infarcts
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

Relationship among AD,
VaD and other dementias
AD
VaD
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 J ournal 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
TULBURAREA COGNITIVA
VASCULARA ( VCI )
BCV = a 2-a cauza a dementelor

25% dintre supravietuitorii unui prim AVC
dezvolta o forma de dementa la 5 ani dupa
evenimentul acut

Factorii de risc comuni pentru DA si VaD

BCV detectabila si tratabila !
MECANISME :
1. Boala de vase mari ( trombotic, tromboembolic )

2. Boala de vase mici
- HTA * tip I: ischemie / edem
* tip II: lacune
- alte microangiopatii (inflamatorii, DZ, CAA )

3. Alte arteriopatii specifice

4. Hemodinamic

5. Embolii la distanta ( cord, aorta )

6. Hemoragii

7. Factori hematologici

8. Boli hereditare ( CADASIL, etc. )

SUBTIPURI de DEMENTE VASCULARE:

1. INFARCTE TERITORIALE MULTIPLE ( MID )

2. INFARCT UNIC STRATEGIC

3. DEMENTA VASCULARA SUBCORTICALA

- INFARCTE LACUNARE MULTIPLE

- LEZIUNI DIFUZE ALE SUBSTANTEI ALBE

4. POST- HEMORAGIE CEREBRALA

5. LEZIUNI VASCULARE MIXTE (cortico-subcorticale)
Pathophysiology of dementia with CVD
Dementia
Final common
pathway
Damage to critical
cortical and subcortical
structures
Damage/interruption
of subcortical circuits
and projections
+ Cholinergic
transmission
Cardiovascular risk factors
Hypertension Diabetes Smoking Hypercholesterolemia Heart disease
Genetics
Damage to cerebral blood supply
(common denominator)

Large-vessel infarcts Small-vessel infarcts Hemorrhage Hypoperfusion
Multiple distinct pathophysiologies
Hyperintensities (HI) Affecting
ACh WM Tracts
External Capsule HI Extensive Periventricular HI
Deep White HI
Selden NR, et al. Brain. 1998;121:2249-2257
Cortical vs Subcortical Dementias
Characteristics
Subcortical
Dementia
Cortical Dementia
Executive function Very affected Consistent with other
impairments
Speed of cognitive
processing
Early slowing Normal until late
Language No aphasia Early aphasia
Memory Impaired recall
Retrieval>recognition
Recall and recognition
impaired
Attention Impaired Impaired
Visuospatial skills Impaired Impaired
Calculation Preserved until late Involved early
Personality and mood Apathetic, inert, depressed,
crying/laughing spells
Unconcerned, euthymic
Speech Dysarthric Articulate until late
Coordination and gait Impaired Normal until late
Motor speed and control Slowed Normal
Abordarea noua a VaD si B.A.

VaD
BA cu/BCV
BCV este patologia; VaD is boala clinica
VaD fara patologie de BA este relativ rara
Multi pacienti au suprapunere de BA si BCV semnificativa
Aceasta suprapunere este BA cu BCV ( AD w/CVD )
BA
Management of VaD
Identify patients at risk of VCI due to
CVD
Control vascular
risk factors and
disease Targeted dementia
therapy
Stabilization
of CVD
Improvement in
dementia symptoms
modificat dupa Sachdev et al. 1999; Nyhenuis and Gorelick, 1998
Identify patients
with VCI
Control of
concomitent
conditions
Improvement in
patients outcomes
and caregiver QoL
Dementia (DSM IV)
With stroke
Without stroke
Total



Severe cognitive decline (MMSE)
With stroke
Without stroke
Total
Events
active placebo
Favours
active
Favours
placebo
Risk reduction
(95%CI)

43
150
193




48
228
276

65
152
217




86
248
334

34% (3 to 55%)
1% (-24 to 22%)
12% (-8 to 28%)



45% (21 to 61%)
9% (-10 to 84%)
19% (4 to 32%)
0.5
2.0
Odds ratio
1.0
Dementia and severe cognitive decline
PREVENTIA PRIMARA
PREVENTIA SECUNDARA
DEMENTELE FRONTO-TEMPORALE
Progresele in epidemiologie, neuroimagistica, neuropatologie, genetica
moleculara

Clasificari traditionale
1. Sindroame fara implicatii biologice specifice
- AFAZIA PROGRESIVA
- DEMENTA SEMANTICA
- DEMENTA DE TIP FRONTAL
2. Entitati neuropatologice specifice
- B. PICK
- TAUPATIA FAMILIALA
3. Entitati familiale
- FTD cu PARKINSONISM LEGATA DE CRZ. 17

* Clinic, neuropatologic, genetic:
- GRUP HETEROGEN DE AFECTIUNI NEURODEGENERATIVE
DEMENTELE FRONTO-TEMPORALE
Se prefera
CLASIFICAREA BAZATA PE PREZENTAREA CLINICA:

1. FTD varianta frontala / comportamentala ( bv-FTD )
2. DEMENTA SEMANTICA ( SD )
3. AFAZIA PRIMARA PROGRESIVA NON-SEMANTICA ( PNFA )









DEMENTA FRONTO-TEMPORALA
COMPORTAMENTAL
A
CU TULBURARE DE
LIMBAJ
bv-FTD SD PNFA
Kippo CM, Hodges J R, 2007
FORME CLINICE ale DFT
DFT varianta COMPORTAMENTALA ( bvDFT )
3 componente majore ( apar impreuna sau separat ):


1. Debut insidios, nespecific:
( intre decada a 3-a a 6-a de varsta )
- disfunctie executiva
- alterarea judecatii, rigiditate mentala
- memoria de lucru mai afectata decat
memoria episodica ( de BA )
- lipsa de alterare a functiei vizuo-
spatiale ( de BA )
- alterarea introspectiei
- apatie si dezinteres ( confuzie cu
depresia )
- hipoprosexie, distractibilitate
- indecizie
- impulsivitate si distractibilitate

NB. Un scor MMSE ridicat nu exclude FTD !!!!!!
( hiperoralitate +hipersexualitate +comportament
de utilizare : sd. Kluver-Bucy )


2. Dezinhibitie ( valoare dg. )

: psihoza maniacala, tulb. obsesiv-compulsiva,
tulb. sociopatica de personalitate
- comportament infantil, grosolan
- pierderea capacitatii empatice
- remarci inadecvate cu tema sexuala
- nerabdare
- conducere auto neglijenta
- cheltuieli excesive, colectionare de diverse
obiecte
- glume inadecvate
- perseverare in activitati de rutina
- hoinareala compulsiva
- aport alimentar nestapanit
- neglijarea igienei personale
- pierderea interesului pt. familie



FORME CLINICE ale DFT
DFT varianta COMPORTAMENTALA ( bvDFT )
3 componente majore ( apar impreuna sau separat ):


3. Modificarea structurii de personalitate
( sesizata de familie / anturaj ):
- furtisaguri
- furturi din magazine
- injuraturi
- dezbracare in public
- urinare frecventa
- incontinenta fecala rapid progresiva

Adesea se asociaza si afazie progresiva ( valoare dg. )



Tartaglia MC, Rosen HJ , Miller BL - Neurotherapeutics: The J ournal of the American Society for Experimental
Neurotherapeutics 2011; 8: 82 - 92
Top row: Sagittal view of a patient with the behavioral variant of frontotemporal dementia (bvFTD); note
the anterior atrophy with relative sparing of the parietal and occipital regions. The anterior corpus
callosum is also thinned compared to posterior. Coronal view of patient with semantic dementia showing
significant left temporal atrophy. Coronal view of patient with nonfluent variant of FTD showing
significant left insular atrophy.

Bottom row: VBM study showing that in patients with bvFTD, frontal lobe volumes are reduced
compared with age-matched controls. There is volume loss in the ventromedial frontal cortex, the
posterior orbital frontal regions, the insula, and the anterior cingulate cortex.
DEGENERESCENTA CORTICO-BAZALA si
PARALIZIA SUPRANUCLEARA PROGRESIVA
Dementa Pick ( anii 30 ): asociaza semne extrapiramidale !
degenerescenta cortico-dentato-nigrala: aceeasi patologie cu b. Pick !
degenerescenta cortico-bazala ( grupul de boli Mov. Dis )
TABLOU CLINIC:
1. CBD
rigiditate unilaterala
+ apraxie evidenta, paralizia privirii, mioclonus reflex, sd. de mana straina
- pot asocia afazie primara progresiva / alte variante de FTD

2. PSP
- sd. extrapiramidal simetric: distonie axiala, bradikinezie, caderi frecvente,
disfagie, paralizia de verticalitate a privirii
- adesea asociata cu CBD ( cu paralizie de verticalitate a privirii )
- poate preceda sau succeda tabloului clinic de FTD sau/ si PPA ( au acelasi
substrat patologic )
BOALA NEURONULUI MOTOR si FTD
asociere frecventa: DEMENTA + SLA ( MND ) - cca. 50% din cazurile de SLA
orice forma clinica de SLA dar VARI ANTA BULBARA mai frecvent !
uneori se observa aspect tipic de bvFTD sau PPA
10% cazurile de bvFTD sau PPA dezvolta SLA
substrat comun in majoritatea cazurilor:
incluzii ubiquitin-pozitive, tau-negative in cortex ( descrise initial in SLA ! )

anomalii ale proteinei TDP-43 ( in SLA si varianta ubiquinata a FTD: FTLD-U )

CONCLUZII PRACTICE:
* Orice pacient cu SLA trebuie evaluat cognitiv si comportamental ( clinic si
neuropsihologic )

* Orice pacient cu FTD trebuie evaluat neuromuscular ( clinic si electrofiziologic )
CLASIFICAREA NEUROPATOLOGICA ACTUALA
Bazata pe constituentul proteic al incluziilor neuronale si/ sau gliale:
* proteina TAU : FTDL-tau

* TDP-43 ( TAR DNA-binding protein of 43 kD ): FTDL-TDP
Subtipuri:
- FTDL-TDP tip 1: incluzii citoplasmatice neuronale, neurite distrofice
scurte in cortexul superficial
- FTDL-TDP tip 2: neurite distrofice lungi in cortexul superficial si profund
- FTDL-TDP tip 3: predominanta incluziilor citoplasmatice neuronale si
saracie in neurite distrofice
- FTDL-TDP tip 4: frecvente incluzii, asociata cu mutatii ale genei pentru
valosina ( proteina )

* FUS (fused in sarcoma): FTDL - FUS
Modificari comune ale acestor proteine: fosforilare anormala, ubiquitinare anormala,
clivaj proteic
FTLD si SLA au mecanism comun patogenic in relatie cu proteinele TDP-43 si FUS
Clinical, genetic and pathological spectrum of frontotemporal lobar degeneration.
Seelaar H et al. J Neurol Neurosurg Psychiatry
2011;82:476-486
Categorii de complicatii neurologice
la pacientii imfectati HIV
Primare
mai frecvente
tulburarile neurocognitive
[ minore+deficit motor (MCMD)
dementa asociata HIV (HAD)]
mielopatia vacuolara
neuropatii periferice

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

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).

J anssen 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)


Antinori A. et al, Neurology 2007, 69 (18 ): 1789-1799
A limitation of the existing AAN criteria is that they do not recognize a
subgroup of HIV-infected patients (<15%) who actually have
neurocognitive impairment despite the absence of overt functional decline in
ADLs

There have been substantial changes to HIV disease with the introduction
of HAART which have affected cognitive impairment in a number of areas

In 2007, the National Institute of Mental Health and the National Institute
of Neurological Diseases and Stroke ( NINDS ) have charged a working
group to critically review the adequacy and utility of these definitional
criteria and to identify aspects that require updating


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



Diagnosis
CHARTER Neurocognitive Test Battery
Verbal Fluency
Letter Fluency
Category Fluency

Speed of Information Proc.
WAIS-III Symbol Search
WAIS-III Digit Symbol
Trail Making Test Part A

Attention/Working Memory
Paced Auditory Serial Addition Test -
50
WAIS-III Letter-Number Sequencing
Motor
Grooved Pegboard

Abstraction/Executive
Wisconsin Card Sorting Test 64
Trail Making Test Part B

Learning and Memory
Hopkins Verbal Learning Test-R
Brief Visuospatial Memory Test-R
Story Memory Test
Figure Memory Test
Everyday Functioning: Patients Assessment of Own
Functioning Inventory Activities of Daily Living Scale
scale
International HIV Dementia Scale


Naming four objects

Fingertapping

Luria psychomotor learning task

Recall of names
Sacktor et al. - Neurology 2003 60;1:A186-187