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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
10
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
30
Senzitivity 80-85% demented vs. non-demented
Specificity 76-80%
Kahle-Wrobleski et al., 2007
Screening tests in dementia
31
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)
35
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
39
Cholinesterase inhibitors
- acetylcholinesterasis (brain - neurotransmission) – donepezil, galantamin, rivastigmin
- butyrylcholinestrasis
(brain – inflamation, neurodegeneration) rivastigmin
internal organs
41
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
53