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)

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Alzheimer's Disease (AD)

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• 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?

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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

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senile

plaques

neurofibrilary

tangles

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Courtesy of doc. Bartos

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ß-secretasis

g-secretasis

a-secretasis

21

Tau protein

22

Clinical course in AD

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time

Imp

airm

en

t memory only

Clinical course in AD

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time

Imp

airm

en

t memory +

attention

Clinical course in AD

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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)

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Dubois et al, 2007, DSM V - 2011

MRI volumetry

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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

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MOCA sensitivity 90% specificity 90%

Nasreddine et al., 2005

Earlier and cheaper diagnosis?

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EFNS guidelines 2010

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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)‏

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A

NFT

Neurons/ synapses

prodromal MCI AD

Neurons/ synapses

NFT A

ageing

Normal ageing?

Preclinical AD?

MCI

prodromal AD

dementia

Who?

Earlier diagnostics

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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

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NMDA receptor

AMPA receptor

Glutamate

Magnesium

+ -

+ Na

- + Ca2+

Ca 2+

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

week

decline

improvement

SIB

sco

re

Monotherapy - memantine

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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

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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)

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Level A evidence for AD

no Level A evidence

Non-evidence based medications

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Net cost of care per AD patient over 3 years

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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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