Case Review

Mr. Demizi, 69 y.o

D: Dementia and Alzheimer Disease
CC: Loss way back home and frequently forget new event

Anamnesis:
-has to be reminded for
his appointment
-behavioural changes
prejudice, frequently
angry and aggressive,
showed odd behavior

MSE:
-Disorientation
-decreased immediate
and recent memory
-visual illusion and
hallucination, delusion
-irritable, agitation,
decrease intellectual

Other Exam:
-Mild Aphasia
-MMSE: 15
-CDT: 3
-ADL/IADL
decreased
-MRI: Bilateral
medial temporal
lobe and
hippocampus

Management:
Pharmaco: Donepezil 5mg 1x/day at bed time and Haloperidol 0.5mg 2x/day for 2 mo
Non-pharmaco: family counseling
Prognosis:
Adbonam

CEREBRAL CORTEX
a. Anatomy
Gray matter area that covers the cerebral hemisphere.
To increase surface area of cerebral cortex cerebral hemisphere is thrown into folds or gyri that
separated each other by: sulcus or fissure (more deeper than sulcus)
Main sulci : Central sulcus (between 2 parallel gyri), Lateral sulcus (deep cleft mainly on the inferior
and lateral surfaces of cerebral hemisphere), Parietooccipital sulcus, calcarine sulcus (on medial
surface of hemisphere)
Lobes of cerebral hemisphere : frontal, temporal, parietal and occipital lobe.
b. Histology
Types of cells:
1. Pyramidal cells giant pyramidal cells in motor precentral gyrus = Betz cell
2. Stellate cell/granule cell small and polygonal cell, multiple branching dendrites
3. Fusiform cell at deepest layer of cortex. Inferior dendrites branches in same layer; superior
one will ascend.
4. Horizontal cell of Cajal small, fusiform, horizontally-oriented cell, found at surface of
superficial cortex.
5. Cell of martinotti small and multipolar cell, in every layer of cortex, have short dendrites.
Nerve fiber of cerebral cortex : radial (right angle to cortex) and tangential (parallel to cortex
inner and external band of Baillanger)
Cerebral cortex is mainly neocortex; consists of 6 layers:
a. Molecular layer = most superficial layer, contain dense-connective tissue of nerve fibers,
dendrite from: pyramidal and fusiform cells, axons from: stellate and cell of martinotti.
Horizontal cells of Cajal also present.
b. External granular layer = contain large numbers small pyramidal cells and stellate cells,
dendrite towards the molecular layer and axons to the deeper layer.
c. External pyramidal layer = larger (in size) pyramidal cell.
d. Internal granular layer = dense stellate cell and external band of Baillanger.
e. Ganglionic / internal pyramidal layer = very large and medium-size pyramidal cells + stellate
and Martinotti cells. Inner band of Baillanger.
f. Multiform layer = fusiform cells and modified-pyramidal cell.
c. Physiology
Generally, cerebral cortex consists of:
- sensory area: receive sensory information from receptor, awareness of sensation
- motor area: regulate the execution of voluntary movement
- association area: area that receive and analyze the signal simultaneously from multiple region
(motor and sensory cortex area)
Based on lobes:
1. frontal lobe
a. Primary motor area (broadmann area 4): posterior precentral area, which function is for
producing movement. Afferent fiber from premotor and sensory cortex, hypothalamus,
cerebellum and basal gangliafinal place before the execution of movement
b. Premotor/ secondary motor area (broadmann area 6,8,4,45): anterior precentral area, which
function is for saving motoric program and activity (result from the past experience)
c. Supplementary motor area (SMA)
d. Frontal eye field (broadmann area 6,8,9): regulate voluntary scanning movement from the
eye and not dependent to a visual stimuli.
e. Motor speech area of Broca (broadmann area 44 and 45) formation of words through its
connection with primary motor area (muscle of larynx, respiratory, and mouth)
f. Prefrontal area regulate individual personality and regulator of person that has a depth
feeling
2. Temporal lobe
a. Primary auditory area (broadmann area 41 and 42): receive sound stimuli
b. Secondary auditory area (area brodmann 22): has an important role for sound interpretation
and auditory input association with sensory information
c. Sensory speech area of Wernicke most commonly at left hemisphere and superior to
temporal gyrus.

Function: produce language understanding (written or verbal) and therefore, someone can
read and make a sentence, understanding and say it
3. Occipital lobe
a. Primary visual area (area Brodmann 17): receive visual stimuli
b. Secondary visual area (area Brodmann 18,19): which connects visual information that
received by primary visual area and former visual experience
c. Occipital eye field (in secondary visual area): to reflex and associated with movement of the
eye; dependent to visual stimuli
4. Parietal lobe
a. Primary somesthetic area (Area Brodmann 3,1,2): receive sensory stimuli
b. Secondary someshtetic area
c. Somesthetic associations area (area Brodmann 5,7): receive and integrate different sensory
modalities; help us to know shape and things without visual stimuli

LIMBIC SYSTEM

Limbic system : a group of structures that lie in the border zone between the cerebral cortex and
the hypothalamus
The limbic structures include the subcallosal, the cingulate, and the parahippocampal gyri, the
hippocampal formation, the amygdaloid nucleus, the mammillary bodies, and the anterior thalamic
nucleus
The alveus, the fimbria, the fornix, the mammillothalamic tract, and the stria terminalis constitute
the connecting pathways of this system.

Hippocampal formation

The hippocampal formation consists of the hippocampus, the dentate gyrus, and the
parahippocampal gyrus
The hippocampus is a curved elevation of gray matter that extends throughout the entire length of
the floor of the inferior horn of the lateral ventricle. Its anterior end is expanded to form the pes
hippocampus.
The convex ventricular surface is covered with ependyma, beneath which lies a thin layer of white
matter called the alveus. The alveus consists of nerve fibers that have originated in the
hippocampus, and these converge medially to form a bundle called the fimbria. The fimbria, in turn,
becomes continuous with the crus of the fornix.
The hippocampus terminates posteriorly beneath the splenium of the corpus callosum
The dentate gyrus is a gray matter that lies between the fimbria of the hippocampus and the
parahippocampal gyrus
Posteriorly, the gyrus continuous with the indusium griseum. The indusium griseum is a thin,
vestigial layer of gray matter that covers the superior surface of the corpus callosum
Anteriorly, the dentate gyrus is continued into the uncus.
The parahippocampal gyrus lies between the hippocampal fissure and the collateral sulcus and is
continuous with the hippocampus along the medial edge of the temporal lobe (collateral sulcus :
memisahkan parahippocampal gyrus dengan gyrus dibawahnya yaitu fusiform gyrus)
Parahippocampal gyrus is a major jucntional region between neocortex and allocortex. Its anterior
part is the entorhinal cortex. The entorhinal cortrx face in two directions, its neocortocal face
connect with all association area and allocortical face connect with hippocampus. Its function is to
receive a constant stream of cognitive and sensory information from the association area transmit it
to the hippocampal formation for consolidation and returns it to to the association area where it
encoded in the form of memory traces

Amygdaloid Nucleus
The amygdaloid nucleus is almond shape nucleus.
It is fused with the tip of the tail of the caudate nucleus. The stria terminalis emerges from its
posterior aspect.
The amygdaloid nucleus consists of a 2 complex nuclei :
1. larger basolateral group : lateral basal nuclei and accessory basal nuclei
2. smaller corticomedial group : anterior area, lateral olfactory nucleus, medial amygdaloid
nucleus &cortical nucleus.

Has abundant bidirectional connection with hypothalamus.

Connecting Pathway of the Limbic System

Alveus -> Fimbria -> crus of the fornix -> body of the fornix -> column of the fornix
->mammilary body

Histology of Limbic System

1. Hippocampus -> 3 layered/ allocortex. Consist of molecular layer, pyramidal layer and polymorphic
layer
2. Parahippocampal gyrus, cingulated gyrus ->mesocortex/transitional zone, has 6 layered
Physiology of Limbic System :
Function :
o influence many aspect of emotional behavior. Particularly, the reaction of fear and anger and sexual
behavior.
o Reward and punishment function :
stimulation in these respective areas gives rise to pleasant or unpleasant sensations.
- Major reward centres located in lateral and ventromedial nuclei of hypothalamus.
- Major punishment centre located in the central gray area surrounding the aqueduct Sylvius and
extending upward into periventricular zone in hypothalamus
- Reward and punishment centre select the information that we learn, if stimulus cause either
reward or punishment centre, cerebral cortex response become more and more intense during
repeated stimulation (memory traces), the response is said to be reinforced.
- Another function : control of our body activities, our drives, our motivation.
1. Hippocampus
- play a role in consolidation of memory and learning.
- Hippocampus transmit signals that make the mind rehearse over and over until permanent
storage takes place, without hippocampus consolidation of memory is very poor or does not
take place.
- has afferent and efferent connection. The largest afferent connection is preforant path (from
entorhinal cortex to the hippocampus). The largest efferent connection is projection from
entorhinal cortex to neocortex.
- Papez circuit :
Entorhinal cortex -> hippocampus -> fimbriae -> fornix ->mammilary body
->mammilothalamic tract -> anterior thalamic nuclei -> cingulated cortex ->back into
entorhinal cortex.
2. Amygdala
- Recieves neuronal signals from all part of limbic cortex and neocortex.
- Transmit signal back into the same cortical area, into hippocampus, septum, thalamus and
hypothalamus
- Primarily associated with emotion of fear, anger, anxiety and depression
- Afferent connection :
Nuclear groups receiving afferents : lateral nucleus (mostly)

All sensory association area of the cortex have direct access to the lateral nucleus of
amygdale.
Efferent connection :
Stria terminalis send fibers to septal area(anterior of anterior commisure) and
hypothalamus. (Makanya kalo stress cortisol keluar)
Effect amygdale melalui hypothalamus
1. Increase/decrease arterial pressure
2. Increase/decrease herart rate
3. Increase/decrease motility of GI tract
4. Dilatasi/konstriksi pupil
5. Secretion anterior pituitary hormone (gonadotropins and adrenocorticotropic)
Effect involuntary movement :
1. tonic movements ; raising the head or bending the body
2. circling movement
3. clonic movement

MEMORY
o Definition of Memory : The ability to recover information about past events or knowledge.
o Memories are stored in the brain by changing the basic sensitivity of synaptic transmission between
neurons as a result of previous neural activity. The new or facilitated pathways are called memory
traces
o The brain has the capability to learn to ignore information that is of no consequence.This results
from inhibition of the synaptic pathways for this type of information (rapid closure of calcium
channel ); the resulting effect is called habituation.
o Habituation : decreased responsiveness to repetitive stimulus
o The brain has the capability to store the memory, this process called sensitization.
o Sensitization : increased responsiveness to mild stimuli following a strong or noxious stimuli
Classification of Memories
A. Berdasarkan jangka waktu :
1. Short term Memory : memories that last for seconds or at most minutes unless the are
converted into longterm
2. Intermediate long term Memory : last for dayst to weeks
3. Long term memory : once stored, can be recalled up to years or even a lifetime later
B. Type of information
1. Declarative memory : basically means a memoryof the various detail of an integrated thought,
such as memory of an important experience that include memory of surrounding, time
relationship, meaning of the experience
2. Skill memory : associated with motor activity. Example : skills developed from hitting tennis ball.
o Working memory : interrelates various piece of information relevant to a current mental task
o Mechanism of short term memory : transient modification in function of presynaptic, such as
altering amount of neurotransmitter
o Mechanism of long term memory : involves relatively permanent functional or structural
changes between presynaptic and postsynaptic, such as formation of new synapse, synthesis of
new protein
Mechanism of Habituation : Repetitive stimuli -> Calcium channel do not open -> Calcium influx
decrease -> Decrease exocytosis of neurotransmitter
Mechanism of Sensitization :
Strong/noxious stimulius

Release of serotonin to presynaptic neuron from facilitating interneuron

Activation of adenylyl cyclase

Increased cAMP in presynaptic neuron

Activation of protein kinase

Phosphorilasion of protein that itself is part of the potassium channels in the sensory
synaptic terminal

Blockage of potassium channel

Prolonged action potential

Exocytosis neurotransmitter increase

Mechanism of Consolidation (perubahan short term memory jadi long term memory)
1. Presynaptic neuron release glutamate (common excitatory neurotransmitter)
2. Gluamate will bind to 2 types of receptor on post synaptic neuron
a. AMPA receptor : permits net entry of Sodium, leading to formation of excitatory postsynaptic
potential in postsynaptic neuron.
b. NMDA receptor : permits entry of calcium ions, This receptor both gated and closed by a
magnesium ion. Mg physically block the channel opening at resting potential.
3. Eventhough glutamate binds with NMDA receptor, the receptor doesnt open unless the
postsynaptic cells is sufficiently depolarized as a result of other excitatory act. Additional
depolarization is needed to depolarize the postsynaptic neuron enough to force magnesium out of
channel
4. When NMDA receptor open (Magnesium out of channel) calcium ions enter postsynaptic channels
5. Calcium influx activates second-messenger pathway
6. Second messenger pathway leads to formation of new AMPA receptor (additional receptor)
7. Because of the increased availability of AMPA receptor, the postsynaptic neuron exhibits a greater
response to subsequent release of glutamate.
NEUROTRANSMITTER IN COGNITION AND MEMORY
Acetylcholine
1. Class : 1, small molecule, rapid acting transmitter
2. Effect : excitatory
3. Cholinergic tracts :
Nucleus basalis of Meynert in basal forebrain -> project a group of cholinergic neurons ->cerebral
cortex & limbic system
Reticular system project cholinergic neurons ke cerebral cortex, thalamus, hypothalamus and limbic
system
4. Synthesis :
- Synthesized in cholinergic axon terminal
Acetyl coA + choline -> acetylcholine . Enzyme : choline acetyltransferase
- Packaged in secretory vesicles
- Released when triggered by action potential
5. Metabolized in synaptic cleft
- Acetylcholine -> choline + acetic acid. Enzyme : acetylcholinesterase
- Choline is taken back up into presynaptic and recycled to make new acetylcholine
6. Receptor
1. Muscarinic (M1, M2, M3, M4, M5) : nerve, heart, smooth muscle, glands & endothelium
2. Nicotinic (Nm&Nn) : neuromuscular junction, skeletal muscle, autonomic ganglion cells
DELIRIUM
Definition : a syndrome of acute onset of fluctuating cognitive impairment and a disturbance of
consciousness
Epidemiology :
- 0,4 percent for people 18 years of age and older
- 1,1 percent for people 55 and older
- The highest rate is in postcardiotomy patients ( >90%)
- 80% in terminally ill patients
- 40-50% in patients who recovering for hip fractures
- 30-40 % patients with AIDS

30 % patients in surgical intensive care

Etiology :
- Major causes : nervous system disease ( example : epilepsy, head trauma, brain tumor,
subarachnoid hemorrhage, subdural, epidural hematoma), systemic disease (cardiac failure,
infection), intoxication from pharmacological or toxic agents or its withdrawal
- Metabolic disorder : electrolyte abnormalities, diabetes, hypo-hyperglycemia
- Medication : pain medication, antibiotics, antiviral, steroid, anesthesia, cardiac medication,
antihypertensive etc.
- Endocrine : adrenal crisis or adrenal failure, thyroid abnormality
Risk Factors :
- Major risk factor : advanced age (older than 70 years old)
- Preexisting brain damage ( dementia, tumor, cerbrovascular disease)
- History of delirium
- Smoking History
- Alcohol dependence
- Abnormal potassium, glucose and sodium level
- Diabetes
- Functional limitation
- Visual sensory impairment
- Use of bladder catheter
- Malnutrition
- Alcohol abuse
- Male gender
- Hypertension
Clinical features :
Yang umum : berkurangnya kesadaran, altered attention (diminished ability to focus, diminished
ability to maintain attention or shift attention), impairment cognitive function ( disorientation ;
especially time and place, decreased memory, rapid onset, brief duration, unpredictable fluctuation
in severity
Associated clinical features : disorganization of though process, perceptual disturbances such as
illusion and hallucination, psychomotor hyperactivity and hypoactivity, disruption of sleep-wake
cycle, mood alterations
Diagnostic Criteria :
Diagnostic criteria for each type of delirium : delirium due to medical condition, substance intoxication,
substance withdrawal, delirium due to multiple etiologies and delirium not otherwise specified
Untuk yang krn medical condition, substance intoxication, withdrawal and multiple etiologies
criteria yang sama adalah :
1. Disturbance of consciousness (reduced clarity of awareness) with reduced ability to focus,
maintain attention or shift attention
2. Change in cognition : memory deficit, disorientation, language disturbance
3. These disturbance develop over a short period of time (hours to days) and tends to fluctuating
during the day
Yang beda
1. Due to General medical condition : there is evidence from the history, PE or Lab findings that
disturbance is caused by the direct consequences of medical condition
2. Due to substance intoxication : there is evidence from history, PE and lab findings those
symptoms develop during substance intoxication or if patient use some medication, the
medication use is etiologically related to the disturbance
3. Due to substance withdrawal : there is evidence the symptoms developed during or shortly after
withdrawal syndrome
4. Multiple etiologies : there is evidence that the delirium has more than one etiology
Delirium Not Otherwise Specified
- This category doesnt meet criteria for any of the specific types of delirium
Physical Examination
- Mini mental Status Examination and neurological sign can be used to document the cognitive
impairment
- A physical examination reveals clue to the cause of delirium (Contoh : klo demam kemungkinan
penyebabnya sepsis, klo tachycardia kemungkinanya bisa infeksi, hyperthyroidism atau heart
failure)

Presence of known physical illness or history of head trauma or alcohol dependence increase
the likelihood of diagnosis.
Lab Exam
- EEG : in delirium shows a generalized slowing of activity and useful in differentiating delirium
from depression or psychosis

Differential Diagnosis
Deirium vs Dementia, Schizophrenia and Depression
Delirium
Dementia
Time
Development
condition
(Impairment
cognition)

to
of

Short,
fluctuating
changes

Longer,
more
stable over time,
changes do not
fluctuae

Consciousness

Has episodes
decreased
consciousness

Usually alert

Level of attention

Fluctuating

Hallucination
Dellusion

Less constant

of

and

Others symptoms

of

Hypoactive
symptoms
(differentiate with
depression
using
EEG)

Relative
consistent
Less constant

Schizophreni
a
Associated
with
some
intellectual
impairment
but
less
severe
No change
in their level
of
consciousne
ss

Depression
More
prominent
depressive symptoms

to

Diminished
ability
concentrate and think

to

Well preserved
More
constant
and
better
organized

Usually
there
is
no
hallucination and delusion

Hypoactive symptoms

Management of Delirium
Primary goal is to treat the underlying causes
Other goal is to provide sensory, physical and environmental support. Delirium patients helped by
having friends or relative in the room.
Pharmacotherapy : Haloperidol (to treat psychosis) dose may range depend on a patients age,
weight and physical condition and benzodiazepines to treat insomnia
Course and Prognosis
Symptoms of delirium usually persist as long as the causative factors are present, after
identification and removal of the causative factors, the symptoms usually recede over 3-7 days
although some symptoms may take up to 2 weeks to resolve
The older patient and the longer the patient has been delirious, the longer delirium takes to resolve.
DEMENTIA
Definition : progressive impairment of cognitive function without disturbance of consciousness
Epidemiology :
- 5 percent in patients older than 65, 20-40% in patients older than 85, 50% in chronic care
facilities
- Of all patient with dementia, 50-60% have dementia of Alzheimer type, 2 nd most common type
is vascular dementia
Etiology :

1. Alzheimers disease (Dementia of the Alzheimers type)

- Molecular basis of amyloid deposition (Genetic Factors)
2. Vascular dementia
- Hypertension -> occlusion of the vessels -> infarction -> multiple lesion
3. Biswangers disease
- Characterized by Many small infarction of the white matter
4. Picks disease
- Athropy in frontotemporal region, these region also have neuronal loss, gliosis and neuronal
picks body. The cause is unknown.
5. Lewy body disease
- Present of lewy inclusion body in cerebral cortex
6. Huntington disease
7. Parkinson disease
8. HIV-Related Dementia
9. Head trauma related dementia
Risk Factor : Advance age (>65 years of age), hypertension for vascular dementia, familial for Alzheimers
type,
Classification : Alzheimers disease, vascular, frontotemporal dementia, dementia with lewy bodies
Psychiatric and Neurological changes in Dementia
Personality : become introvert, less concerned and have paranoid delusion
Hallucination (20-30%) and Dellusion ( 30-40%)
Mood : depression and anxiety (40-50%)
Cognitive change :
- Apraxias, aphasia and agnosias are common in dementia patient. Primitive reflex may
reappear and myoclonial jerks are present in 5-10% of patients.
- Patients with vascular dementia : headaches, dizziness, faintness, weakness and sleep
disturbances
Catastropic Reaction :
- Patients have difficulty in forming concepts and grasping similarities and difference among
concept
- Ability to make judgement, solve problem and to reason logically is compromised
Sundowner syndrome
- Drowsiness, confusion, ataxia, and accidental falls
- Sensory reaction decreased
Diagnostic Criteria and Tool for diagnostic
1. Memory impairment (ipaired ability to learn new information or to recall previously learne
information)
2. One or more cognitive disturbance : aphasia (language disturbances), apraxia (impaired ability to
carry out motor activities), agnosia (failure to recognize usual object) and disturbance in executive
functioning (planning, sequencing, organizing)
3. Cognitive deficit each cause significant impairment in social or occupational functioning
4. Course is characterized by gradual onset continuing cognitive decline
5. Deficit do not occur in course of delirium
Tool for diagnostic
1. Anamnesis : untuk dapet chief complain biasanya gangguan memori (75% chief complain),
gangguan orientasi, gangguan persepsi dan intelektual. Penyerta nya perubahan behavior,
personality
2. MMSE : skor nya kurang dari normal. 24 keatas normal
3. MRI : penemuan yang khas atrophy hippocampus dan medial temporal lobe nya, ditambah
perbesaran ventricle
Management

Accurate diagnosis as soon as possible to halted progression of the disease or even reversed if
appropriate therapy is provided
General treatment : provide supportive medical care, emotional support for the patients, family and
caregiver.
Educational psychotherapy, in which their illness is clearly explained
Assistance in grieving and accepting the extent of their disability
Pharmacotherapy : (Principle : anticholinergic should be avoided)
- Donepezyl (acetylcholinesterase inhibitors)
MOA : inhibit acetylholine breakdown
Effect : Improvement in memory and cognitive function
Indication : dementia of Alzheimers type
Contraindication : Hypersensitivity
Adverse effect : nausea, diarrhea, vomiting
- Haloperidol (Antipsychotic)
MOA : block dopamine receptor in CNS
Effect : antipsychotic, decreased hallucination and delusion
Indication : psychotic disorder, hallucination, delusion
Contraindication : depression
Adverse effect : Parkinson, drowsiness

Course and Prognosis : 85% dementia is irreversible, Alzheimer type is usually irreversible
Gradual deterioration of cognitive over 5-10 years
Average survival expectation is 8 years with a range 1-20 years
Comparison of Dementia, Delirium, Pseudodementia and Benign senescent forgetfulness
Delirium
Dementia
Benign
senescent Depression
forgetfulness
Rapid onset
Slow onset
Minor severity
Fatigue/loss of energy
Fluctuating attention
Attention is preserved
Age related memory loss as Diminished ability to think
apart of ageing
and concentrate
Reduced awareness
Unchanged awareness
Diminished interest at all
Interfere
with Interfere
with Does not interfere with Interfere
with
social/occupational
social/occupational
social/occupational function
social/occupational
function
function
function
Disruption in sleep Fragemented
sleep Does
not
progress
to Insomnia nearly everyday
patterns
patterns
dementia
Staging of Alzeimer disease
Mild Cognitive Early Stage
Middle Stage
Late Stage
End Stage
Impairment
Cognitive
Mild memory Measurable
Moderate
to Little cognitive No
significant
loss
short
term Severe
ability,
cognitive function
memory loss, cognitive
language not
other
problem
clear
cognition
problem
Function
Mild anxiety
Mild
IADLADL
Nonambulatory/bedb
Instrumental
dependent,
dependent
ound, unable to eat
Acitivities
of Activities
of
Daily
Living Daily
Living
(IADL) problem (ADL)
problems

Special Thanks to: Stefanie Yuliana Usman, Maria Christina Sycha