DIAGNOSTICUL PRIN PRISMA SPECTRULUI CLINICO-BIOLOGIC AL DEMENTELORProf. Dr. Ovidiu Bajenaru

UMF Carol Davila BucurestiSpitalul Universitar de Urgenta Bucuresti Clinica de Neurologie

Dementele provocarea viitoruluiNumrul persoanelor cu vrst peste 65 de ani se va dubla pn n 20301Numrul persoanelor suferind de boala Alzheimer se va dubla pn n 2050*Estimare a numrului de persoane suferind de dementa, 2005-2050*Persoane suferind de boala Alzheimer (milioane)An1. 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

ETIOLOGIEdementele = 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

Boli in care dementa este asociata cu semne clinice si de laborator ale altor afectiuni medicale:

A. Infectia HIV / SIDAB. Afectiuni endocrine: hipotiroidism, sd. Cushing, hipopituitarismC. Carente nutritionale: sd. Wernicke-Korsakov, degenerescenta combinata subacuta ( carenta de vit. B12 ), pelagraD. Meningoencefalite cronice: paralizia generala progresiva, sifilisul meningo-vascular, criptococcozaE. Degenerescenta hepato- lenticulara familiala ( b. Wilson ) si dobanditaF. Intoxicatii cronice ( inclusiv statusul dupa intoxicatie cu CO )G. Hipoglicemia sau hipoxia prelungitaH. Encefalita limbica paraneoplazicaI. Expunera la metale grele: As, Bi, Au, Mn, HgJ. 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 Huntington2. Scleroza multipla, boala Schilder, adreno-leucodistrofia si alte boli inrudite care afecteaza mielina SNC3. Lipidozele4. Epilepsia mioclonica5. B. Creutzfeldt- Jacob ( clasica si noua varianta ) b.Gerstmann-Strausler-Scheinker (dementele mioclonice, prionice)6. Degenerescenta cerebro-cerebeloasa7. Degenerescentele cortico-bazale DFT8. Dementa cu paraplegie spastica9. Paralizia supranucleara progresiva ( PSP ) DFT10. Boala Parkinson11. Boala difuza cu corpi Lewy 12. Scleroza laterala amiotrofica & dementaDFT13. Complexul Parkinson-SLA-dementa14. 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. Binswanger2. 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 Lewy5. Hidrocefaliile comunicante normotensive sau hidrocefaliile obstructive*6. Leucoencefalita multifocala progresiva ( LEMP )7. Boala Marchiafava Bignami8. Granulomatozele si vasculitele cerebrale9. Encefalitele virale

III. Boli in care de obicei dementa este singura manifestare evidenta a unei afectiuni neurologice sau medicale:

A. Boala AlzheimerB. Unele cazuri de SIDAC. Dementele fronto-temporale ( inclusiv sd. afazice primare progresive) si cele de lob frontal F. Boli degenerative nespecificate

CRITERII DE DIAGNOSTICDSM 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 DIAGNOSTIC2. 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 DISORDERSA proposal from the DSM-5 Neurocognitive Disorders Work GroupNeurocognitive 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 functionAND2. 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 DisorderA.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 functionAND2. 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 disorderS 24 - 35 Major Neurocognitive DisorderS 24 Major Neurocognitive DisorderS 25 Major Neurocognitive Disorder Associated with Alzheimer's DiseaseS 26 Major Neurocognitive Disorder Associated with Vascular DiseaseS27 Major Neurocognitive Disorder Associated with Fronto-Temporal Lobar DegenerationS 28 Major Neurocogntive Disorder Associated with Traumatic Brain InjuryS 29 Major Neurocognitive Disorder Associated with Lewy Body DiseaseS 30 Major Neurocognitive Disorder Associated with Parkinson's DiseaseS 31 Major Neurocognitive Disorder Associated with HIV InfectionS 32 Major Neurocognitive Disorder Associated with Substance UseS 33 Major Neurocognitive Disorder Associated with Huntington's DiseaseS 34 Major Neurocognitive Disorder Associated with Prion DiseaseS 35 Other Specified Major Neurocogntive DisorderS 12 - 23 Mild Neurocognitive DisorderS 12 Mild Neurocognitive DisorderS 13 Mild Neurocognitive Disorder Associated with Alzheimer's DiseaseS 14 Mild Neurocognitive Disorder Associated with Vascular DiseaseS 15 Mild Neurocognitive Disorder Associated with Fronto-Temporal Lobar DegenerationS 16 Mild Neurocognitive Disorder Associated with Traumatic Brain InjuryS 17 Mild Neurocognitive Disorder Associated with Lewy Body DiseaseS 18 Mild Neurocognitive Disorder Associated with Parkinson's DiseaseS 19 Mild Neurocognitive Disorder Associated with HIV InfectionS 20 Mild Neurocognitive Disorder Associated with Substance UseS 21 Mild Neurocognitive Disorder Associated with Huntington's DiseaseS 22 Mild Neurocognitive Disorder Associated with Prion DiseaseS 23 Other Specified Mild Neurocogntive DisorderDSM-5 Neurocognitive Criteria, Draft 1/7/10

M E M O R I A

DECLARATIVA( EXPLICITA )NON-DECLARATIVA / PROCEDURALA( IMPLICITA )FapteEvenimenteCOMPORTAMENTALA(abilitati, obiceiuri)De IDENTIFICARE(DETECTARE)De INVATAREASOCIATIVADE BAZADe INVATARENON-ASOCIATIVARASPUNSURIEMOTIONALERASPUNS MUSCULARSCHELETICHIPOCAMPLOB T MEDIALDIENCEFALSTRIATCORTEX MOTORCEREBELNEOCORTEXSISTEM LIMBICCEREBELCAIREFLEXE

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

Domeniu unicDomenii multipleDomeniu unicDomenii multipleMCI amnesticaMCI non-amnesticaClasificare clinicaSUBTIPURI de MCIDegenerativaVascularaPsihiatricaConditii medicaleETIOLOGIE

B. AlzheimerDepresieB. AlzheimerVaDDepresieDFTDLBVaD

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 amiloidDLB: 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 4: asociere cu b. Alzheimer ( homozigotia 4=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, 565-569Blocq P, Marinesco G, Sur les lsions et la pathologie delpilepsie dite essentielle, La Semaine mdicale, novembre1892, 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;362:329-344Zheng 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

Ipoteza cascadei amiloideDegenerescenteneurofibrilarePlaci amiloideCreste productia si scade clearence-ul, A42Placi difuzeA40TauPHF-tauActivitatea kinazelor si fosfatezelor e alterataStress oxidativTulburari [Ca++]Inflamatie cronicaToxicitate glutamatergicaApoptozaDeteriorare structuralaDisfunctie si moarte neuronala Dementaoligomerizarea si depunerea A42Depozite AFactori de mediu

Hiperfosforilarea tau & NFTMicrotubulii = 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 neuronuluiHiperfosforilarea tau * destabilizarea microtubulilor, * agregarea proteinei tau / formarea NFTt

moarte neuronala

FOSFORILAREA SI DEFOSFORILAREAPROTEINEI TAU

Querfurth HW, LaFerla FM. NEJM 2010

Degenerescentele neurofibrilare - NFTDegenerescentele neurofibrilare intraneuronale sunt compuse din filamente helicoidale in perechi, derivate din agregate de proteina tau produse prin procesul de hiperfosforilare

Ab and BBBBrainCapillaryAbLRP-1RAGELRP-1 = low density lypoprotein receptor-related proteinRAGE = receptor for advanced glycation end-productsDrawing following the concept of Deane et al., Nature Med, 2003Ab 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 hemorrhagesThe major risk factors for VCI and Alzheimer disease hypertension, aging, and diabetes impair endothelium-dependent responses in the cerebral microcirculation and blunt functional hyperemiaA 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 dementiasThe 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 2011The Alzheimers Disease puzzleThe AD Network PuzzleCedazo-Minguez JCMM 2008

HypercholesterolemiaHowever: 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 DEMENTIAPossible Targets for TherapyAgingCurrent approachesto drug therapyFuture treatmentstrategiesVASCULAR (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 zaharatsd. 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 AInsulina previne acumularea A intracelular facilitand eliberarea saInsulina & IGF-1 faciliteaza intrarea crescuta in SNC a proteinelor de transport ( albumina & transthyretine ) legarea A transportul A catre LCR si sangeTNF inhiba IRS reduce trecerea proteinelor de transport in SNCGasparini L, Xu H - Trends Neurosci 2003; 26: 404-406; White MF - Am J Physiol Endocrinol Metab 2002, 283:E413E422

METABOLICSYNDROMELIFESTYLEGENETICS ?ATYPICANTIPSYCHOTICSOSHASCHRONIC SLEEP DEPRIVATIONSTROKECHDCOGNITIVE IMPAIRMENT// DEMENTIA ( AD )VASCULAR DEATHBRAIN(Metabolic control)

Epidemiological findings of vascular risk factors in Alzheimer's disease: implications for therapeutic and preventive interventionSystematic 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 pressureobesity 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, 1999Dubois B. et al, Lancet Neurology, 2007

Frisoni GB, et al. Nat Rev Neurol 2010; 6: 6777Is it possible to diagnose Alzheimers disease during thepredementia stage ?

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

BOALA ALZHEIMERMANIFESTARI 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! )

Progress of Symptom DevelopmentTimeMobilityBehaviourCognitive functionMoodGauthier (1999); Feldman, Kertesz (2001); Auer et al. (1996); Reisberg et al. (1996); Barclay et al.(1985)Deterioration

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 2011Roe CM et al. Neurology 2011; 76:501-510FACTORI DE RISC in BAGeneticiVarstaVasculariHTAH-colesterolemieH-trigliceridemieDiabetul zaharatSd. metabolicAVCHomocisteinemiaFumatulBMIDepresia

FACTORI DE PROTECTIE in BAGeneticiEducatiaStilul de viataDietaActivitatea cerebralaActivitatea fizicaInterventii farmacologiceAnti-HTAStatinepreventia primara & secundara a AVCAINS ?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 VaDAD with/ CVDCVD is the pathology; VaD is the clinical diseaseVaD without AD pathology is relatively rareMost patients have significant overlap between AD and CVDThis overlap is AD w/CVD AD

Risk factors and markers in Dementia:Continuum between AD and VaDDefinite ADDefinite VaDHypertensionStroke/TIAHypercholesterolemiaHeart DiseaseHypercholesterolemiaAmyloid PlaquesGeneticsADVaDNeurofibrillary TanglesDiabetesKalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13:S115-123HypertensionCholinergic deficitsBrain 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 dementiasADVaDOther(PDD, DLBD,FTD, etc. )Cras, 1998

Processes influencing clinical expression of dementiaAdditional 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 MeynertBaza 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 SIMPTOMATICInhibitori de cholinesteraza ( AchEI )DONEPEZILRIVASTIGMINEGALANTAMINE

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 specifice4. Hemodinamic

5. Embolii la distanta ( cord, aorta )

6. Hemoragii

7. Factori hematologici8. 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

Hyperintensities (HI) Affecting ACh WM TractsExternal Capsule HI Extensive Periventricular HIDeep White HISelden NR, et al. Brain. 1998;121:2249-2257

Cortical vs Subcortical Dementias

CharacteristicsSubcortical DementiaCortical DementiaExecutive functionVery affectedConsistent with other impairmentsSpeed of cognitive processingEarly slowingNormal until lateLanguageNo aphasiaEarly aphasiaMemoryImpaired recall Retrieval>recognitionRecall and recognition impairedAttentionImpairedImpairedVisuospatial skillsImpairedImpairedCalculationPreserved until lateInvolved earlyPersonality and moodApathetic, inert, depressed, crying/laughing spellsUnconcerned, euthymicSpeechDysarthricArticulate until lateCoordination and gaitImpairedNormal until lateMotor speed and controlSlowedNormal

Abordarea noua a VaD si B.A. VaDBA cu/BCVBCV este patologia; VaD is boala clinicaVaD fara patologie de BA este relativ raraMulti pacienti au suprapunere de BA si BCV semnificativaAceasta suprapunere este BA cu BCV ( AD w/CVD )BA

Management of VaDIdentify patients at risk of VCI due to CVDControl vascular risk factors and diseaseTargeted dementia therapyStabilization of CVDImprovement in dementia symptomsmodificat dupa Sachdev et al. 1999; Nyhenuis and Gorelick, 1998Identify patients with VCIControl of concomitent conditionsImprovement in patients outcomes and caregiver QoL

Dementia (DSM IV) With stroke Without stroke Total

Severe cognitive decline (MMSE) With stroke Without stroke TotalEvents active placeboFavoursactiveFavoursplaceboRisk reduction(95%CI)

43 150 193

48228276

65152217

86248334

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 Odds ratio1.0Dementia and severe cognitive decline

PREVENTIA PRIMARAPREVENTIA SECUNDARA

DEMENTELE FRONTO-TEMPORALEProgresele in epidemiologie, neuroimagistica, neuropatologie, genetica moleculara

Clasificari traditionale1. Sindroame fara implicatii biologice specifice- AFAZIA PROGRESIVA- DEMENTA SEMANTICA- DEMENTA DE TIP FRONTAL2. Entitati neuropatologice specifice- B. PICK- TAUPATIA FAMILIALA3. Entitati familiale- FTD cu PARKINSONISM LEGATA DE CRZ. 17 * Clinic, neuropatologic, genetic: - GRUP HETEROGEN DE AFECTIUNI NEURODEGENERATIVE

DEMENTELE FRONTO-TEMPORALESe 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-TEMPORALACOMPORTAMENTALACU TULBURARE DE LIMBAJbv-FTDSDPNFAKippo CM, Hodges JR, 2007

FORME CLINICE ale DFTDFT 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 DFTDFT 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 Journal of the American Society for Experimental Neurotherapeutics 2011; 8: 82 - 92Top 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 PROGRESIVADementa 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. CBDrigiditate unilaterala + apraxie evidenta, paralizia privirii, mioclonus reflex, sd. de mana strainapot asocia afazie primara progresiva / alte variante de FTD

2. PSPsd. extrapiramidal simetric: distonie axiala, bradikinezie, caderi frecvente, disfagie, paralizia de verticalitate a priviriiadesea 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 FTDasociere frecventa: DEMENTA + SLA ( MND ) - cca. 50% din cazurile de SLAorice forma clinica de SLA dar VARIANTA BULBARA mai frecvent !uneori se observa aspect tipic de bvFTD sau PPA10% cazurile de bvFTD sau PPA dezvolta SLAsubstrat 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 ACTUALABazata pe constituentul proteic al incluziilor neuronale si/ sau gliale:* proteina TAU : FTDL-tau

* TDP-43 ( TAR DNA-binding protein of 43 kD ): FTDL-TDPSubtipuri:- 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 proteicFTLD 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 neurologicela pacientii imfectati HIVPrimare mai frecventetulburarile neurocognitive [ minore+deficit motor (MCMD) dementa asociata HIV (HAD)]mielopatia vacuolaraneuropatii periferice

alte manifestari neurologice (mai frecvente la infectatii HIV vs. neinfectati, dar nu neaparat direct cauzate de HIV)neuropatii de incarcerarecefaleecrize epilepticeAVCmiopatii Secundare imunosupresieiencefalita cu toxoplasmameningita criptococcozicaencefalita cu CMVradiculita cu CMVlimfomul primar SNCLEMPneurotuberculoza

Asociate cu tratamentulneuropatii toxicesd. metabolic & consecintele vasculare si neurodegenerativemodificarea clinica a tulb. neurocognitive

Afectarea SNCSindroamele neurocognitive

evolutie clinica progresiva HADeste o forma definitorie de SIDAdebut: de obicei cand nr. cel.T CD4+ scade sub < 200/LHAART HAD poate apare si la CD4+ > 200/LHAD 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)

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 (

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 mareAnemieToxicomanii ( cu droguri i.v. ) progresie rapidaVarste extreme: varstnici & copiiIncarcare virala crescuta in LCR

Tulburari cognitiveacuze subiective de lentoare mentala progresivatulburari mnestice initial minore declin mnestic progresivhipoprosexie ( f. adesea in HAD )pierderea capacitatii de concentrare pt. activitati cotidiene uzuale ( citit, TV, s.a. )tulburari vizuo-spatiale discoordonare vizuo-motorieNB: MMSE nu este util in stad. incipiente ( manifestari de tip frontal )

Tulburari comportamentaleapatie marcata si retragere sociala fara depresieiritabilitate marcatainflexibilitate mentala accentuatascaderea libidou-luimanifestari psihotice maniacale ( nu sunt comune )

Tulburari motoriiscadere globala a fortei muscularetulburari de echilibrumers nesigurbradikinezie, parkinsonism motorsemne de sd. bipiramidalmiscari sacadice de urmarire ale globilor ocularisemne de eliberare frontala ( stadii avansate )mioclonii ( stadii avansate )

DiagnosisCHARTER Neurocognitive Test BatteryVerbal FluencyLetter FluencyCategory Fluency

Speed of Information Proc.WAIS-III Symbol SearchWAIS-III Digit SymbolTrail Making Test Part A

Attention/Working MemoryPaced Auditory Serial Addition Test - 50WAIS-III Letter-Number SequencingMotorGrooved Pegboard

Abstraction/ExecutiveWisconsin Card Sorting Test 64Trail Making Test Part B

Learning and MemoryHopkins Verbal Learning Test-RBrief Visuospatial Memory Test-RStory Memory Test Figure Memory TestEveryday 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 namesSacktor et al. - Neurology 2003 60;1:A186-187

*Trendul actual de imbatranire a populatiei va duce la o veritabila explozie a numarului de pacienti suferind de boala Alzheimer. Conform unor estimari recente acest numar se va dubla pana in anul 2050.***********Recent autopsy studies of brain specimens from dementia patients suggest that pure AD and pure VaD are relatively uncommon, and that most individuals with dementia have AD w/CVD.13 In one of these studies (the Nun study), the occurrence of vascular lesions in patients with AD significantly increased the risk of developing clinical symptoms.1 This supports the hypothesis that vascular pathology is an important component of clinically expressed dementia in both VaD and AD.

References1. Snowdon DA et al. JAMA 1997; 277: 8137. 2. Barker WW et al. Alzheimer Dis Assoc Disord 2002; 16: 20312. 3. Nagga K et al. Dement Geriatr Cogn Disord 2004; 18: 5966.

**The risk factors for AD and VaD overlap note the presence of both hypertension and hypercholesterolemia in both diseases. Diagnosis of these diseases can, therefore, be challenging.**This slide outlines the pathophysiology of dementia with CVD. This highlights how vascular risk factors and events lead to a final common pathway of reduced cholinergic transmission that manifests itself in dementia.****Recent autopsy studies of brain specimens from dementia patients suggest that pure AD and pure VaD are relatively uncommon, and that most individuals with dementia have AD w/CVD.13 In one of these studies (the Nun study), the occurrence of vascular lesions in patients with AD significantly increased the risk of developing clinical symptoms.1 This supports the hypothesis that vascular pathology is an important component of clinically expressed dementia in both VaD and AD.

References1. Snowdon DA et al. JAMA 1997; 277: 8137. 2. Barker WW et al. Alzheimer Dis Assoc Disord 2002; 16: 20312. 3. Nagga K et al. Dement Geriatr Cogn Disord 2004; 18: 5966.

**This slide shows the opportunities for early intervention in patients with dementia due to CVD. Management of vascular risk factors may prevent further vascular events thus preventing worsening of the disease. Targeted dementia therapy will improve a patients dementia symptoms. In addition, secondary conditions can be managed eg. Depression or behavioral problems will improve patients outcomes and caregiver QoL.****HOPE: Reduced risk of cognitive and motor changesContent points:Tritace also blunted development of functional impairment in nonfatal stroke.66 As shown, significantly fewer patients in the Tritace arm experienced adverse cognitive or motor changes than those in the placebo arm.*Clinical, genetic and pathological spectrum of frontotemporal lobar degeneration.**