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 Aβ42 (low level)* protein tau and phosphorilated protein tau (increased level)

vs. non-demented patients of similar agefrom 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

Investigaţiile neuroimagistice

- Rolul principal: * excluderea alte patologii cerebrale * sprijinirea diagnosticul tipului de demenţă neurodegenerativă

• în boala Alzheimer, atrofia cerebrală predominantă la nivelul hipocampului şi a lobului T• în DFT atrofia cerebrală predominantă la nivelul lobilor F şi T• în demenţa vasculară: evidenţierea leziunilor vasculare şi a tipului acestora, etc.

NB. Sunt însă şi situaţii în care simptomatologia este clinic evidentă pentru boala Alzheimer dar CT-ul nu este modificat pentru vârsta pacientului.

Deasemenea investigaţiile neuroimgistice nu sunt absolut necesare pentru diagnosticul bolii Alzheimer efectuat într-un stadiu deja avansat al bolii, cu manifestări clinice severe.

Examenul electroencefalografic (EEG) poate fi necesar uneori( grad de recomandare de nivel B )

- în cazuri selecţionate (spre exemplu în suspiciunea de CJD sau de encefalite)

Biopsia cerebrală - necesară numai în cazuri rare, selecţionate cu mare grijă, în care diagnosticul etiologic nu poate fi stabilit prin alte proceduri

- în centre de neurochirurgie cu experienţă

- 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 întâlnite:- dementa de tip Alzheimer- dementele vasculara- dementa din α-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 demenţă (alte boli neurodegenerative care asociază demenţă, boli inflamatorii/infecţioase, boli metabolice, boli neoplazice) sunt rare, reprezentând sub 10% din numărul cazurilor de demenţă

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. Wilson’s 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. Huntington’s disease2. Multiple sclerosis, Schilder’s disease, adrenoleukodystrophy and other diseases with CNS myelin lesions 3. Lipidoses4. Myoclonic epilepsy5. Creutzfeldt- Jacob disease ( classic & new variant ) Gerstmann-Strausler-Scheinker disease ( myoclonic, prionic dementia )6. Cortico-basal degeneration ( see FTD )7. Dementia with spastic paraplegia8. Progressive supranuclear palsy ( PSP → see FTD )9. Parkinson’s 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

External Capsule HI Extensive Periventricular HI

Deep White 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

February 2011

The Alzheimer’s Disease puzzleThe AD Network Puzzle

Cedazo-Minguez JCMM 2008

Bogdanovic & Winblad, Huddinge Brain Bank, 2006

• Intracellular• Hyperphosphorylated tau

- Neurofibrillary tangles

- Senile plaques

• Extracellular• Amyloid ß-peptide (Aß)

AD Neuropathology

- Neuronal and Synaptic loss- Inflammatory response- Vascular lesions

Modificari patologice in dementa Alzheimer• acumulari extracelulare de placi senile (SP)

- beta-amiloid (Aβ) • 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

Degenerescenteneurofibrilare

Placi amiloide

Creste productia si scade clearence-ul,

Aβ42

Placi difuzeAβ40

Tau

PHF-tau

Activitatea kinazelor si

fosfatezelor e alterata

Stress oxidativTulburari [Ca++]Inflamatie cronicaToxicitate glutamatergicaApoptozaDeteriorare structurala

Disfunctie si moarte neuronala

Dementa

oligomerizarea si depunerea Aβ42

Depozite Aβ

GeneFactori 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

Δt ↓ 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 PathologyTau Pathology

Tau proteinHyperphosphorylation

IncreasedKinase

GSK-3bCdk-5MAPK

DecreasedPhosphatase

PP2-APP2-B

PHF AND NFTformation

CellDeath

Tau stabilisationof microtubules

Microtubule instability

Dissociation of p-Taufrom microtubules

P

P

P

P

FOSFORILAREA SI DEFOSFORILAREAPROTEINEI 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

• Depression

PROTECTION FACTORS for AD• Genetic• Education

• NSAID ?

RESERVE - COGNITIVE - CEREBRAL ( structural )

• Vascular - HTA

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

• BMI

• Lifestyle• Diet• Intelectual activity• Physical activity

• Parmacologic interventions- Anti-HTA- Statins ( ? )

• Primary & secondary stroke prevention

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 Processes influencing clinical expression of dementiaexpression of dementia

Additional opportunities for interventions

Geneticallydetermineddisease process1. familial AD2. genetic RF – sporadic AD

Aging related decline

Neuronal repairand compensation mechanisms

DEMENTIA

Environmental risk factors + genetic risk factors Comorbidity

• 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 91–98%

– 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: 67–77

Is it possible to diagnose Alzheimer’s disease during thepredementia stage ?

Alzheimer D. Depression

Alzheimer D. VaD Depression

FTD

DLB VaD

Unique

domain

Multiple domains

Unique domain

Multiple domains

Amnestic

MCI

Non-amnestic

MCI

Clin

ical

cla

ssifi

catio

n

MCI SUBTYPES

Degenerative Vascular Psychiatric Medical conditions

ETIOLOGY

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 Alzheimer’s 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 Alzheimer’s disease and other dementias. U.S. Congress Office of Technology Assessment; U.S. Government Printing Office, 1987; p14

Progress of Symptom Development

TimeMobilityBehaviourCognitive functionMood

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

Dete

riora

tion

• Preclinical ADThe 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 ADThe 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 dementiaThe 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 Alzheimer‘s 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 functionAND2.   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 functionAND2.   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

• Dementia

Final commonFinal commonpathwaypathway

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

Cortical vs Subcortical DementiasCharacteristics Subcortical

Dementia Cortical DementiaExecutive function Very affected Consistent with other

impairments

Speed of cognitive processing

Early slowing Normal until late

Language No aphasia Early aphasia

Memory Impaired recallRetrieval>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

Management of VaD

Identify patients at risk of dementia Identify patients at risk of dementia due to CVDdue to CVD

Control vascular Control vascular risk factors and risk factors and

diseasedisease Targeted dementia Targeted dementia therapytherapy

Stabilization Stabilization of CVDof CVD Improvement in Improvement in

dementia symptomsdementia symptoms

Sachdev et al. 1999; Nyhenuis and Gorelick, 1998Sachdev et al. 1999; Nyhenuis and Gorelick, 1998

Identify patients Identify patients with dementiawith dementia

Control of Control of concomitent concomitent conditionsconditions

Improvement in Improvement in patients’ outcomes patients’ outcomes and caregiver QoLand caregiver QoL

DEMENTELE FRONTO-TEMPORALEProgresele 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 !!!!!!