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DEMENTIA

DEMENTIA = clinical neurological syndrome characterized by global cognitive deterioration (which implies a decline compared to the anterior level) and associates a large variety of psychological and behavioral changes.

Cognitive dysfunctions are sometimes preceded and almost always accompanied by : - emotional control disorders - personality changes - other psychiatric symptoms: * apathy, depression, psychotic disorders * behavioral disorders

Clinical examination
General exam
Other diseases which can cause dementia: hypothyroidism, AIDS, neoplasms

Neurological exam
Sign and symptoms suggestive for neurological diseases associated with dementia (Creutzfeld Jakob disease, Wilson disease)

Psychiatric exam
Depression, anxiety, irritability, obsession, confusion, dissinhibition

Neuropsychological exam
specific tests for evaluating depression, cognition a.s.o

Lab analysis Mandatory : FBC, BUN, creatinine, ESR, glycemia, Na, K, transaminases, a.s.o.) Recommended: thyroid function

Selected cases: * tests for infectious diseases ( AIDS, siphilis, borreliosis, herpes virus encefalitis a.so.) * tests for immunologic disorders (vasculitis, LE, a.s.o) * Toxicology (intoxications with heavy metals) * genetic tests (identification of familial form of Alzheimer disease, FTD, CADASIL, etc.) * other ( vitamine B12 or homocisteine) * other specific tests.

CSF (selected cases)


- Alzheimer Disease (AD): * peptide A42 (low level) * protein tau and phosphorilated protein tau (increased level) vs. non-demented patients of similar age from 2011: recommended for the dg of AD in predemential stages

- in case of suspicion of Creutzfeldt-Jakob disease: * protein 14-3-3 ( recommendation level B )

Neuroimagistic
- exclusion of other diseases - contributes to the diagnosis of dementia - minimal request : non- enhanced contrast CT (recommendation level A) - selected cases : contrast CT or MRI (recommendation level A) SPECT * etiological diagnosis of dementia * differential diagnosis: AD versus Vascular Dementia (recommendation level B)

- PET with PIB ( Pittsburg Compound B ): evaluates the level of amyloid loading in AD: d. Alzheimer, DLB vs PD-D since 2011: recommended for the diagnosis of AD in predemential phase

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. Deasemenea investigaiile neuroimgistice nu sunt absolut necesare pentru diagnosticul bolii Alzheimer efectuat ntr-un stadiu deja avansat al bolii, cu manifestri clinice severe.

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.

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 de tip Alzheimer - dementele vasculara - 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

Celelalte forme de demen (alte boli neurodegenerative care asociaz demen, boli inflamatorii/infecioase, boli metabolice, boli neoplazice) sunt rare, reprezentnd sub 10% din numrul cazurilor de demen

I. Diseases associating dementia with clinical and laboratory data for other medical conditions:
A. HIV infection/ AIDS B. Endocrine: hypothyroidism, Cushing sd., hypopituitarism C. Nutritionale: Wernicke-Korsakov sd., subacute combined degeneration ( vit. B12 deficiency ), pellagra D. Chronic meningoencephalites: neurosyphilis, criptococcosis E. Wilsons disease & aquired hepatolenticular degeneration F. Chronic intoxications ( including status post- CO intoxication ) G. Hypoglycaemia, prolonged hypoxia H. Lymbic paraneoplastic encephalitis I. Heavy metals exposure: As, Bi, Au, Mn, Hg J. Dialytic dementia ( hystorical nowadays )

Pacienta cu sd. demential encefalita limbica paraneoplazica asociata cu adenocarcinom pulmonar: debut neurologic inainte de diagnosticul oncologic

II. Diseases with dementia associated with other neurological signs, but without other obvious medical conditions (1):
A. Always associated with other neurological signs:
1. Huntingtons disease 2. Multiple sclerosis, Schilder s disease, adrenoleukodystrophy and other diseases with CNS myelin lesions 3. Lipidoses 4. Myoclonic epilepsy 5. Creutzfeldt- Jacob disease ( classic & new variant )

Gerstmann-Strausler-Scheinker disease
( myoclonic, prionic dementia ) 6. Cortico-basal degeneration ( see FTD ) 7. Dementia with spastic paraplegia

8. Progressive supranuclear palsy ( PSP see FTD )


9. Parkinsons disease 10. ALS forms with associated dementia( see FTD ) & Parkinson-ALS-dementia complex ( Guam ) 11. Other hereditary metabolic diseases ( 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. Vascular dementia ( multiple strokes/ strategic strokes ) & Binswanger s disease

2. Tumours ( primary/ secondary ) or brain abcesses*


3. Post-traumatic brain injuries ( usually with bleeding lesions ) - Chronic subdural / epidural hematoma * 4. Diffuse Lewy bofies disease

5. Communicating normotensive hydrocephalus & obstructive


hydrocephalus* 6. Progressive multifocal leukoencephalopathy ( PML ) 7. Marchiafava Bignami disease

8. Brain granulomatosis & vasculitis


9. Viral encephalitis

Hyperintensities (HI) Affecting ACh WM Tracts


Deep White HI

External Capsule HI

Extensive Periventricular HI

Selden NR, et al. Brain. 1998;121:2249-2257

III. Diseases with dementia as the only clinical expression of a neurological or medical condition:
A. Alzheimer s disease B. AIDS ( some variants ) C. Frontotemporal dementia ( FTD )

- behavioural form
- progressive primary aphasia ( semantic / non-fluent ) - associated with: ALS, PSP, CBD F. Non-specified degenerative diseases

Neurodegenerarea in boala Alzheimer


CAUZA ? ( foarte putine forme familiale genetice ) Modificari proteice
beta-amiloid tau

Alterari sinaptice Alterari ale functiei NTF Deficit de neurotransmitatori Disfunctie mitocondriala Stress oxidativ Alterari in functia insulinei Modificari in metabolismul colesterolului Factori vasculari Inflamatia Alterari ale functiei celulare a Ca++ Deficit de transport axonal

The AD Network Puzzle The Alzheimers Disease puzzle

Cedazo-Minguez JCMM 2008

February 2011

AD Neuropathology

- Senile plaques
Extracellular Amyloid -peptide (A)

- Neurofibrillary tangles
Intracellular Hyperphosphorylated tau

- Neuronal and Synaptic loss - Inflammatory response - Vascular lesions


Bogdanovic & Winblad, Huddinge Brain Bank, 2006

Modificari patologice in dementa Alzheimer


acumulari extracelulare de placi senile (SP) - beta-amiloid (A) acumulari intracelulare de degenerescente neurofibrilare (NFT) - proteina tau

modified after Querfurth HW, LaFerla FM. NEJM 2010

Amyloid plaque
Core of amyloid, surrounded by degenerative lesions
- contains also other substances, such as: apoE

In time, the neurons from vicinity degenerate and accumulate hyperphosphorilated protein tau

PET cu PIB ( Pittsburg Compound B )


PDD: low level of amyloid loading DLB: high level of amyloid loading !

Ipoteza cascadei amiloide


Factori de mediu Creste productia si scade clearence-ul, A42 Tau Gene
Activitatea kinazelor si fosfatezelor e alterata
oligomerizarea si depunerea A42

Placi difuze
Depozite A A40

PHF-tau

Placi amiloide

Degenerescente neurofibrilare

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

Dementa

Hiperfosforilarea tau & NFT


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

Tau = MAP ce stabilizeaza microtubulii in configuratia neuronala normala


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

Hiperfosforilarea tau * destabilizarea microtubulilor, * agregarea proteinei tau / formarea NFT

moarte neuronala

Degenerescentele neurofibrilare - NFT


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

Tau Pathology
Microtubule instability

Tau stabilisation of microtubules

Dissociation of p-Tau from microtubules P

Tau protein Hyperphosphorylation


Increased Kinase GSK-3b Cdk-5 MAPK Decreased Phosphatase PP2-A PP2-B

Cell Death
P
PHF AND NFT formation P

FOSFORILAREA SI DEFOSFORILAREA PROTEINEI TAU

Querfurth HW, LaFerla FM. NEJM 2010

Risk and protection factors in AD


modified after Arrizaga R. SSNN Congress, Krakow 2011 Roe CM et al. Neurology 2011; 76:501-510

RISK FACTORS for AD


Genetic Age

PROTECTION FACTORS for AD


Genetic Education

Vascular
- HTA - H-cholesterolemia - H-triglyceridemia - Diabetes mellitus - Metabolic syndrome - Stroke Hyperhomocysteinemia - Smoking

RESERVE
- COGNITIVE - CEREBRAL ( structural )

BMI
Depression

Lifestyle Diet Intelectual activity Physical activity Parmacologic interventions - Anti-HTA - Statins ( ? ) Primary & secondary stroke prevention
NSAID ?

Familial genetic mutations (1 )


3 autosomal dominant mutations that cause familial AD :
on chromosome 21 (amyloid precursor protein), on chromosome 14 (presenilin 1) on chromosome 1 (presenilin 2)
the presence of a proband with genetic-testing evidence of one of these mutations can be considered as strongly supportive for the diagnosis of AD

Processes influencing clinical expression of dementia


Additional opportunities for interventions Aging related decline Environmental risk factors + genetic risk factors Comorbidity Neuronal repair and compensation mechanisms

Genetically determined disease process


1. familial AD 2. genetic RF sporadic AD

DEMENTIA

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

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

Is it possible to diagnose Alzheimers disease during the predementia stage ?

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

MCI SUBTYPES
ETIOLOGY
Degenerative Vascular Psychiatric Medical conditions

Alzheimer D. Unique Clinical classification Amnestic domain

Depression

MCI

Multiple domains

Alzheimer D.

VaD

Depression

Non-amnestic

Unique domain Multiple domains

FTD

MCI

DLB

VaD

Potential evolution of MCI


Continued deterioration in cognition and functional decline to satisfy criteria for Alzheimer's dementia Conversion to another subtype of dementia

Continued deterioration in cognition which does not go on to satisfy criteria for a dementia
No conversion, but stability of deficit with no recovery or progression Recovery of cognitive abilities
Mason SE et al.- Int J Alzheimer Dis. 2010

Symptoms of Alzheimers Disease1


Mild AD Forgetfulness Fatigue Difficulty recalling familiar words Inability to learn new things Deterioration in judgment and behaviour Diminished orientation to time, place, date Moderate AD Loss of logic, memory and motor abilities Diminished ability to carry out daily tasks (e.g. washing, dressing, meal preparation, use of the telephone) Impatience, restlessness, wandering, disorientation Physical or verbal aggression in response to frustration Decline in speech, verbal skills and ability to calculate Decline in social skills Paranoia Severe AD Loss of bladder and bowel control Reduced ability to speak or follow simple commands Manifestation of emotional disturbances; patients may become abusive or passive Shuffling walk, and slow, awkward movements

Final AD Bedridden Inability to think, speak, perceive or move Death usually from viral or bacterial infection

1. Losing a million minds: Confronting the tragedy of Alzheimers disease and other dementias. U.S. Congress Office of Techno logy Assessment; U.S. Government Printing Office, 1987; p14

Progress of Symptom Development

Deterioration

Mood

Cognitive function Behaviour Mobility

Time

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

Preclinical AD
The long asymptomatic period between the first brain lesions and the first appearance of symptoms and which concerns normal individuals that later fulfil AD diagnostic criteria

Prodromal AD
The symptomatic predementia phase of AD, generally included in the mild cognitive impairment category; this phase is characterised by symptoms not severe enough to meet currently accepted diagnostic criteria for AD

AD dementia
The phase of AD where symptoms are sufficiently severe to meet currently accepted dementia and AD diagnostic criteria

American Psychiatric Association - 2010


The previous criteria for dementia used Alzheimers disease as their prototype and thus required memory impairment as a criterion for all dementias (!!!) There is growing recognition that, in other neurocognitive disorders (e.g., HIV-related cognitive decline, cerebrovascular disease, frontotemporal degeneration, traumatic brain injury, etc.), other domains such as language or executive functions may be impaired first, or exclusively, depending on the part of the brain affected and the natural history of the disease In addition, the terminology for the cognitive domains has been updated to reflect current usage in neuropsychology and neurology

Major Neurocognitive Disorder new reccomended criteria by APA (2010)


A. Evidence of significant cognitive decline from a previous level of performance in one or more of the domains outlined above 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),and 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 (i.e., below the 3rd percentile) 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 (i.e., between the 3rd and 16th percentile) 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).

Symptomatic treatment in AD
A. Cholinesterase Inhibitors ( AchEI ):
DONEPEZIL RIVASTIGMINE GALANTAMINE

B. NMDA Receptors (partial) antagonists


MEMANTINE

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 !

Pathophysiology of dementia with CVD

Cardiovascular risk factors


Hypertension Diabetes Smoking Hypercholesterolemia Heart disease Genetics

Damage to cerebral blood supply


(common denominator)

Multiple distinct pathophysiologies


Large-vessel infarcts Small-vessel infarcts Hemorrhage Hypoperfusion

Final common pathway


Damage to critical cortical and subcortical structures

Cholinergic
transmission

Damage/interruption of subcortical circuits and projections

Dementia

Cortical vs Subcortical Dementias


Characteristics
Executive function

Subcortical Dementia
Very affected

Cortical Dementia
Consistent with other impairments Normal until late

Speed of cognitive processing Language

Early slowing

No aphasia

Early aphasia

Memory

Impaired recall Retrieval>recognition


Impaired Impaired Preserved until late

Recall and recognition impaired


Impaired Impaired Involved early

Attention Visuospatial skills Calculation

Personality and mood

Apathetic, inert, depressed, crying/laughing spells


Dysarthric Impaired Slowed

Unconcerned, euthymic

Speech Coordination and gait Motor speed and control

Articulate until late Normal until late Normal

Management of VaD
Identify patients at risk of dementia
due to CVD

Control vascular risk factors and disease

Identify patients with dementia


Control of concomitent conditions Improvement in patients outcomes and caregiver QoL Targeted dementia therapy

Stabilization of CVD

Improvement in dementia symptoms

Sachdev et al. 1999; Nyhenuis and Gorelick, 1998

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

Fronto- Temporal Dementia (FTD)


Clinical aspects-FTD (FRONTAL variant)
- Progressive onset of symptomatology - Apathy - Altered capacity of introspection - Disinhibition - Distractibility - Abnormal feeding behaviour - Mental Rigidity - Stereotype and ritual behaviour - self neglect - loose of empathy - emotional recognition altered - altered judgement and capacity of planning NB. An elevated MMSE score does not exclude FTD !!!!!!