cognitive functions and dementia · cognitive functions and dementia doc. mudr. jakub hort, phd....

Cognitive functions and dementia

Doc. MUDr. Jakub Hort, PhD. Dept. of Neurology, 2nd Medical

Faculty, Charles University and Motol Teaching Hospital

What is dementia?

• DE-MENTIA = „without mind“

• acquired memory dysfunction (= set of signs and symptoms) and other cognitive domains beyond normal aging

→ attention

→ language

→ executive functions (decision making)

• duration of at least 6 month (shorter = delirium)

2

Clinical manifestation of dementia

• Cognitive dysfunction memory, thinking and learning disturbances,

visuo-spatial impairment

executive functions impairment

failure of symbolic functions

3

• Behavioral disorders personality changes

emotional changes, depression and anxiety, hallucinations and delusions

irritatability, aggressiveness, apathy, sleep disturbances

• Limitation in everyday Activities homework

grooming, continence, walking

complex activities (employment, driving, etc.)

Dementia is about forgeting, but forget it!

4

Incidence of dementia - increases with age

6

Growdon, 2007

Pre

vale

nce

(%

‏(

age

New dementia cases per year in EU compared with other diseases

7

600,0001

575,0002

500,0003

350,0004

0

250,000

500,000

750,000

1,000,000

Dementia Stroke Diabetes Breast Cancer

An

nu

al In

cid

en

ce

1. Iliffe S, et al. Fam Pract. 2003;20:376-381. 2. European Stroke Initiative. Available at: http://www.eusi-stroke.com. 3. Wild S, et al. Diabetes Care. 2004;27:1047-1053. 4. Ferlay J, et al. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide. Lyon, France;

IARCPress, 2001.

Types of dementias

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Parkinson's disease

Lewy body

Alzheimer's Disease

Vascular dementia

Mixed dementia

Frontotemporal

dementia

Frontotemporal dementia • 5-10%

• peak 45-65 years

• neuronal loss changes in frontal and temporal region → mutation of the tau protein

• Frontal variant → personality changes, behavioral dysfunctions, failure in executive functions

• Temporal variant → semantic dementia, speech impairment, (anomia), failure of understanding

11

Dementia with Lewy bodies

• 10-20%

• neuronal changes due to synucleopathy → brain stem, diencefalon, anterior cingulum, amygdala, cortex

→ fluctuating cognitive impairment

→ persistent visual halucinations

→ extrapyramidal symptoms

→ neuroleptic sensitivity

12

Vascular dementia • 10-15%

• heterogenous group → cognitive impairment due to vascular changes (ischemia, hemorhagy) with various clinical symptoms

• cortical dementia

• subcortical dementia

• posthemorhagical dementia

• hereditary dementia (CADASIL)

13

Alzheimer's Disease (AD)

15

• progressive neurological disease

• most common type of dementia

• risk factors

age

apolipoprotein E4 (APOE-4)

female

low education

family history of AD or Down syndrome

head trauma

cerebrovascular disease (hypertension)

diabetes, hyperhomocysteinemia, high fat level in diet

• protecting factors → antioxidants, NSA, hypolipidemics

How was it?

16

Alois Alzheimer (1864-1915) Oskar Fischer (1876 – 1942)

17

37 meeting of psychiatrists from south Germany in Tübingen, 1906 Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiat 1907;64:146-148 1. patient

Fischer O. Miliare nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz. Monatssch Psychiat Neurol 1907;22:361-372 12 pacients

10 controls, 10 psychosis, 45 neurosyphilis

18

senile

plaques

neurofibrilary

tangles

19

Courtesy of doc. Bartos

20

ß-secretasis

g-secretasis

a-secretasis

21

Tau protein

22

Clinical course in AD

23

time

Imp

airm

en

t memory only

Clinical course in AD

24

time

Imp

airm

en

t memory +

attention

Clinical course in AD

25

time

Imp

airm

en

t memory +

aphasia

visuospatial

attention

Can we diagnose AD before the onset of dementia?

What are the early signs of the disease?

26

New diagnostic criteria for AD

• Memory impairment combined with

- typical findings in CSF (beta-amyloid, tau protein)

- MRI volumometry (hippocampal atrophy)

- perfusion on SPECT or metabolism on PET (hypoperfusion in temporoparietal and frontal brain regions)

27

Dubois et al, 2007, DSM V - 2011

MRI volumetry

29

HOŘÍNEK, Daniel, PETROVICKÝ, Pavel, HORT, Jakub et al. Amygdalar volume and psychiatric symptoms in Alzheimer´s disease: an MRI analysis, ACTA NEUROL SCANDINAVICA113, 2006, No.1., p. 40-45

HOŘÍNEK, Daniel , VARJASSYOVÁ, Alexandra and HORT, Jakub. Magnetic Resonance analysis of Amygdalar volume in Alzheimer's Disease. CURR OPIN PSYCHIATRY, 20, 2007, No. 3, p.273-277

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Senzitivity 80-85% demented vs. non-demented

Specificity 76-80%

Kahle-Wrobleski et al., 2007

Screening tests in dementia

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Mini Mental State Examination

32

MOCA sensitivity 90% specificity 90%

Nasreddine et al., 2005

Earlier and cheaper diagnosis?

33

EFNS guidelines 2010

34

AD – insidiously progressive disease

• Dementia syndrome in AD is preceded by amyloid deposition in the brain (1 decade earlier)

• 20%-30% of cognitively normal elderly persons have brain AD pathology

• 50%-70% of patients with MCI have AD pathology (conversion 15% per year)

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Hansson O, et al. Lancet Neurol. 2006;5:228-234; Okello A, et al. Neurology. 2009;73:754-760 ; Jack CR Jr, et al. Lancet Neurol. 2010;9:119-128

Progression of neuropathology in AD (years)‏

36

A

NFT

Neurons/ synapses

prodromal MCI AD

Neurons/ synapses

NFT A

ageing

Normal ageing?

Preclinical AD?

MCI

prodromal AD

dementia

Who?

Earlier diagnostics

38

AD – management strategies

• normal ageing – (no symptoms), AD pathology not present

influencing risk factors +,-

• preclinical AD – (no symptom), AD pathology present

primary prevention

• prodromal AD ( MCI syndrome)

secondary prevention

• full blown AD (dementia syndrome)

treatment of established AD

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Cholinesterase inhibitors

- acetylcholinesterasis (brain - neurotransmission) – donepezil, galantamin, rivastigmin

- butyrylcholinestrasis

(brain – inflamation, neurodegeneration) rivastigmin

internal organs

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Acetyl CoA

Choline

ACh

ACh

Cholin acetyltransferasis

M2, M3 N - +

M1, M3 N

Ionotropic

M2, M4

cAMP

Presynaptic part

Postsynaptic part

ACh

ACh

AChE

DONEPEZIL

N = nicotinic ACh receptors M = muscarinic Ach receptors

ACh ACh

+

Cholin

+ acetate

GALANTAMIN

BuChE

GLIE

RIVASTIGMIN

GLIA

Cholinergic synapse

42

NMDA receptor

AMPA receptor

Glutamate

Magnesium

+ -

+ Na

- + Ca2+

Ca 2+

43

MMSE = 3-14. Reisberg et al. N Engl J Med. 2003;348:1333-1341.

week

decline

improvement

SIB

sco

re

Monotherapy - memantine

44

MMSE = 5-14. Tariot et al. JAMA. 2004;291:317-324.

Combined therapy memantine + IChE

45

SIB

sco

re

week

decline

improvement

Adherence to therapy – motivation seeing the

improvement • symptomatic (IAChE) - delayed decline

• disease modifying - slowing of the decline

47

Gauthier S. Brain Aging 2002;2:9–22

Ch

ange

fro

m b

asel

ine

untreated

Initial improvement - IAChE

disease modifying

symptomatic

What improvement is possible today?

• Rivastigmin patch

• Donepezil oro-tabs

• Memantine once daily

• Higher dose of inhibitors - donepezil 23 mg • Combination therapy ChEI + memantine

• Severe dementia – theory versus practice

• Avoid non-evidence based (nootropics)

48

Level A evidence for AD

no Level A evidence

Non-evidence based medications

49

Net cost of care per AD patient over 3 years

50

Fagnani et al., 2004

Conclusions

• forget dementia

• AD is insidiously progressive disease

• cholinesterase inhibitors, butyrylcholinesterasis • don't forget they will hardly ever disappear

• disease modifying therapies

• investment in treatment should go with investments in diagnostics

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