NEUROPATHOBIOLOGICAL

BASIS OF

DEMENTIA
M. Sajid Darmadipura
DEPT. OF NEUROSURGERY
NEUROSURGICAL FORUM, MARCH 2005

DEMENTIA
DE = OUT OF
MEN = MIND
TIA = STATE OF
A STATE OF BEING OUT OF ONES
MIND
AN ACQUIRED COGNITIVE
IMPAIRMENT INVOLVING MULTIPLE
DOMAINS OF FUNCTION IN THE
ABSENCE OF A CLOUDING OF
CONSCIUSNESS

DEMENTIA
A syndrome consisting of progressive impairment
in two or more areas of cognition
- memory
- language
- visuospital
- thinking & problem solving
- behaviour
Sufficient to interfere with work, social function,
relationship
in the absence of delirium or major non organic
psychiatric disorders
( AM. PSYCHIATRIC ASSOCIATION IN
DIAG. & STATISTICAL MANUAL OF
MENTAL DISORDERS, DSM IV )

Glossary, Functions Related To

Dementia
AMNESIA : disturbance of learning / memory due to
structural damage.
LEARNING
: the acquisition of new
knowledge of information
MEMORY : the process whereby newly acquired
information is stored and retrieved for future use
recall is part of memory
short term (seconds, minutes to 1 hour)
long term memory : retention for extended period
of time
Organic Brain Syndrome, Sindroma Otak Organik (SOO) :
general term that means physical disturbance of the brain
causing mental function deficit.

Causes of Dementia
Primary Degenerative Disease
Cortical
: Alzheimers Dis.
FT Dementia (Picks Dis)
Subcortical
: Progr. Supranucl. Palsy
Huntingtons Dis.
Parkinsons Dis.
Cortical & SubCortical :
Dementia with Lewy bodies
Corticobasal Deg.
Vascular Dementia
Multi infarct
Biswangers Dis.
Primary Cerebral Amyloid Angiopthy
CADASIL ( cerebral autosomal dominant arteriopathy with
subcortical infarcts and leucoencephalopathy )
Anoxia ( secondary )
Vasculitides
Others

FTD
12%

Others
29%

AD
34%

DLB
7%
VaD
18%

Younger than 65 years

VaD
20%

Others
5%

DLB
20%

AD
55%

Older than 65 %

Behaviour
Sum of actions and psychomotor reactions
that can be objectively observed and
interpreted and that interfere with the
subjects environment.
Includes :
Motor activity
Language
Socially oriented actions
Affectively expression

Harmoniously
Goal oriented /
Individual Specific plan

Lymbic System

PREFONTAL
CORTEX

ASSOCIATION
CORTEX

ANTERIOR CINGULATE
GYRUS

LIMBIC CIRCUIT
The inner loop =
PAPEZS CIRCUIT
involved in memory
processes
The outer loop =
centered by
AMIGDALA,
and process emotional
patterns, links with
experience coming
from

ENTORHINAL
CORTEX

THALAMUS

AMYGDALA
HIPPOCAMPUS
MAMILLAR
BODY
HIPPOTHALAMUS

Acetylcholine
BM = Basal nucleus
of Meynert
DB = Diagonal band
of Broca
H
= Hipothalamus
HIPP = Hippocampal
formation
PA & SO =
Paraventricular and
supraoptic nuclei of
the hypo-thalamus
PPT & LTD =
Pedunculopontine
tegmental nucleus
and laterodorsal
tegmental nucleus
RF = Reticular
Formation
S
= Septum
SNc = Subtantia nigra
pars compacta
THAL= Thalamus

DOPAMINE
NUC. ACC = nucleus accumbens
SN
= subtantia nigra
VTA
= ventral tegmental area

GLUTAMATE

AMYG
PAG

= amygdala
= periaqueductal gray area

HYPO
THAL

= hypothalamus
= thalamus

Dementias
Normal Aging
Vascular Dementia
Biswangers disease
Multiple Lacunar infarcts
CADASIL

DLB, Dementia with Lewy Bodies

DLBD, Diffuse Lewy Body Disease
PD with Dementia

ALZHEIMERS DISEASE

Alzheimers Disease
(Alois Alzhemier 1864 1915)
German Neuropathologist Neurologist
An extraordinary high prevalence malignancy,
dramatically reduces QOL & Survival
One of the most important disease in medicine
today
In USA 1.5 4 millions pop, increasing with age
Tremendous burden on families and health care
system

( Murray, 1996; Greicius et al., 2003)

Ach exerts its activation

From 1 the basal forebrain system
(nucl :Meynerts n.med. setpti)
widespread projections to
c. cortex etc.
2 the pedunculo ponto tegmental
complex projections ach neurons etc.
1. Form an Important Part of Cortical Arousal
during :

Attention
Learning
Memory

Deficit of this system

AD

2. Constitute important links in RAS, participate in

arousal & wakefullness

Diagnosis of AD
History
Complete GENERAL NEUROLOGICAL
EXAMINATION
There is overlap
- time of appearance
- severity, degree and extend of specific
region(s) affected
allow, not always, one dementia to be
DISTINGUISHED from another
MRI, SPECT, PET Scan
Biopsy / Autopsy

AD is characterized by
Amyloid plaques, clumps of amyloid,
between neurons
NFT, bundles of twisted filaments within
neurons, made up of tau

Neuro Fibrillatory Tangle (NFT)

( Aminoff and Daroff, 2003 )

Amyloid Plaques
( Aminoff and Daroff, 2003 )

TAU = A hyper phosphorylated

form of tubule associated protein
Amyloid Protein (AP) =
major constituent plaques in AD

Treatment
AD & other dementias
NS cases, Neurosurgically considered
EXCLUDE METAB diseases
AD ( in AD, a marked reduction in choline
acetyltransferase and Ach)
Ach E catalyzes degradation of Ach.
Drugs that inhibit Ach E, effectively
increase concentration of
neurotransmitters at post synaps / motor
end plate

Treatment of AD
Drugs that slow progression of disease
Drugs that treat particular neuropsychiatric
symptoms
Drugs that prevent the disease
NOTE : cholinergic projections from the basal forebrain

 Ach E inhibitors
TARCINE
: non selective Ach E inhibitor
short half life 4 dd,
prominent cholinergic effect,
LFT disturbed
DONEPEZIL : approved 1996, selective,
longer half live,
milder cholinergic effect
RIVASTIGMINE
:
recently approved in US
less drop outs
better as evaluated by ADAS sub scale
GALANTAMINE
: approved in US

approved 1993,

Memantine : glutamate activity is often

disrupted in AD; combine
with Ach E inhibitors

Ach E inhibitor for dementias

other than AD ?
Note : overlaps among dementias
PD dementia like disorders include :
- AD
- AD with LB
- FT D / Picks D
- VD
(NINDS, 2005)

Why not ?

Ach E inhibitor for traumatic

mental dysfunction ?
SURE !
In animal (Chen at al, 1998)
In patients (Tenovuo, 2004)