OS 211 [A]: Integration, Coordination, and Behavior
Lec 01: Dementia and Other Neurological Disorders
Michelle Anlacan, MD, FPNA
TOPIC OUTLINE
I.
II.
III.
IV.
V.
VI.
Cortical Dementia
A. Alzheimer’s Dementia
B. Frontotemporal Dementia
C. Lewy Body Dementia
Subcortical Dementia
A. Parkinson’s Disease Dementia
B. Huntington’s Disease
C. Progressive Supranuclear Palsy
D. Normal Pressure Hydrocephalus
E. White Matter Disease
F. Multiple System Atrophy
G. Other Subcortical Dementias
H. Distinguishing Cortical from Subcortical Dementias
Toxic Metabolic Dementias
A. Systemic Illness
B. Metabolic and Toxic Causes
Reversible Dementias
Rapidly Progressing Dementias
A. Non Prion Diseases
B. Prion Diseases
Approach to a Patient with Dementia
1
August 3, 2013
o
May already exhibit hallucinations and delusions (defend their
delusions)
3. Severe Alzheimer’s Disease
o Cannot use or understand words
o Cannot recognize who they are when they look in the mirror
o Cannot recognize family members
o Cannot care for themselves
I. CORTICAL DEMENTIA
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Types of dementia (for age group > 65)
o Alzheimer’s disease
43%
o Frontotemporal
11%
o Lewy Body
15%
o Vascular (stroke related, etc.)
30%
A. ALZHEIMER’S DISEASE
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Most common type of dementia worldwide (affects elderly patients
60 years old and above)
Almost half of people above 85 years old have Alzheimer’s disease
Impaired cognitive functioning and activities of daily living (difficulty
handling money, taking public transportation)
Neurodegenerative disease with no known cure
Insidious onset (gradual and progressive, months to years unlike
stroke/vascular dementia – sudden)
ABCs of Alzheimer’s
o Activities of daily living impaired
o Behavioral and Psychiatric symptoms (usual reason for consult)
o Cognitive impairment (usually the first one to manifest)
Cognitive loss in 2 or more domains: memory (recent memory
affected first), language, calculation, orientation, and judgment
o Memory is erased backwards
Sufficiently severe to cause social or occupational disability
o Difficulty bathing, grooming, toileting, can’t count change, loses
wallet
Figure 1. Natural history of Alzheimer’s Disease. Medication slows
down loss of functional independence due to AD. However, the course
still remains the same across cultures. Patient is symptomatic for 1-2
years and experiences mild cognitive impairment. There is a gradual
progressive decline but early intervention can lead to period of longer
functional independence.
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Death from complications
o Progressive debilitation, bedsores (usually bedridden at end
stage)
o Malnutrition
o Dehydration
o Pneumonia
o Urinary infections
o Alzheimer’s itself can kill – neurons of respiratory center die out
GROSS BRAIN ATROPHY
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Gross cortical atrophy, prominent gyri, and deep sulci
Often affects the temporal, parietal and frontal
Usually, first manifestation is bitemporal hypometabolism
More prominent atrophy of hippocampus, entorhinal complex, and
limbic structures
Note: without a hippocampus, there is no formation of new memory
Starts from hippocampus  frontal  parietal  temporal
CLINICAL COURSE
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Mean survival after onset: 10.3 years
Survival range: 2 - 20 years
Gradual cognitive decline
Most patients evolve through stages:
1. Mild Alzheimer’s Disease
o Say the same thing over and over
o Lose orientation even in familiar places (e.g. at the home, at the
mall)
o Lose interest in things they once enjoyed (e.g. bathing)
o Have trouble finding names for common items
o Lose things more often than normal (esp. money)
o Undergo personality changes (have simplistic thoughts)
2. Moderate Alzheimer’s Disease
o More confused about recent events
o Have difficulty with simple daily activities like dressing, eating
o Argue more often than usual
o Believe things are real when they are not
o Require close supervision
o Display anxiety or depression
TRANSER, TRANSER, TRANSER
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Lec 1: Dementia and Other Neurological Disorders
Figure 2. Brain of a normal individual and a patient with
Alzheimer’s Disease. Note the deepening of the sulci and loss of brain
matter (cortical atrophy).
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Figure 3. Hippocampal atrophy. These are MRI scans showing
hippocampal atrophy can still be present even if memory gap is not
severe, and this is usually the first sign of mild AD. To be symptomatic,
at least 50% of neurons must have died. The hippocampus is critical for
the formation of new memories and consolidation of information from
short term to long term memory.
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 Amyloid forms tangles  caspases are activated and induce
cell death
 Always asked!
o Neuritic plaques (outside neuron)
 Amyloid plaque outside neuron induces inflammation
 Always asked!
o Granulovacuolar degeneration and amyloid angiopathy
 Amyloid is abnormally accumulated in AD (don’t know yet if
it’s due to abnormal production, folding, or degeneration)
o Neurofibrillary tangles and amyloid plaques from outside
neurons will eventually:
 Choke the cells until they can no longer function well
 Attract interleukins  inflammation  cells eventually die
 Activate caspases  cells programmed to die
“Wherever there is amyloid, there is death and damage to neuron.”
(Anlacan, 2011 and 2013)
o The more amyloid, the worse the AD
Controlling hypertension, DM, and dyslipidemia decreases chances
of getting AD.
Figure 5. Neuropathological finding. Left: neurofibrillary tangle
(arrow). Right: neuritic plaques.
PATHOLOGICAL FEATURES
Trivia: Famous people who had Alzheimer’s include Ronald Reagan and
Margaret Thatcher.
B. FRONTOTEMPORAL DEMENTIA
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Personality change is the primary manifestation, not memory loss.
Memory problems develop later on.
Usual psychiatric patients (psych problems manifest first).
Strikes relatively young patients (40-60 y/o)
Behavioral features include:
o Personality changes
o Disinhibition
o Psychosis
Cognitive features (executive dysfunction) include:
o Loses ability to plan and organize
o Forgets the steps in bathing and other activities of daily living
o Prone to repetitive behaviors and collection mundane items (e.g.
nail biting, collecting broken bottles, hoarding tansans)
Symptomatic treatment only; no known cure
GROSS BRAIN FINDINGS
Figure 4. Pathophysiology of Alzheimer’s Disease. Accumulation of A-beta has
several effects on neurons and neuronal function. Small aggregates of A-beta can
alter neurotransmission, and the aggregates can be toxic to neurons and synaptic
endings. Larger deposits, in the form of plaques, also lead to neuronal death
through activation of caspases, elicit a local inflammatory response that can result
in further cell injury, and may cause altered region to region communication
through mechanical effects on axons and dendrites. The presence of A-beta also
leads neurons to hyperphosphorylate the microtubule binding protein tau. With this
increase level of phosphorylation, tau redistributes within the neuron from the axon
into dendrites and cell body and aggregates into tangles. This process also results
in neuronal dysfunction and cell death. The anatomic distribution of these changes,
which occur roughly in parallel, are responsible for the clinical signs and
symptoms. They appear to develop well in advance of clinical presentation.
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The process of degeneration from Alzheimer’s is as follows:
o Beta-secretase cleaves the APP molecule producing amyloid,
which then accumulates  Amyloid causes activation of
caspases resulting in the cleavage of tau protein  Tau proteins
aggregate to form NF tangles  NF tangles cause neuronal cell
death.
Microscopic features include:
o Neurofibrillary tangles (inside neuron)
AICA, LEA, JEBBICK
Figure 6. Frontotemporal dementia. A brain scan shows severe
atrophy of the frontotemporal lobe.
C. LEWY BODY DEMENTIA
CORE FEATURES
 Parkinsonism with dementia
o Parkinsonism may be concurrent or it may precede dementia
o Onset of dementia at a point within a year of Parkinsonism
 Onset: any age
 Parkinsonism has milder symptoms, especially in the
morning/waking hours, compared to true Parkinson’s disease
 Visual hallucinations of people and animals: most striking finding
because hallucinations are very vivid and repetitive
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Lec 1: Dementia and Other Neurological Disorders
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Fluctuating attention and cognition (awake for 2 days and asleep for
the next 2 days)
Prognosis: rapid decline
Other suggestive symptoms include:
o REM movement disorder
 Shouting, biking in the air, bites caregiver while sleeping, etc.
 Important to rule out seizures
o Parkinsonism: bilateral manifestation
o Parkinson’s Disease: starts from one side, then crosses
HISTOPATHOLOGY
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Single, multiple, intracytoplasmic, eosinophilic, round to elongated
inclusions that often have a dense core surrounded by a pale halo
(Lewy body)
Ultrastructurally, Lewy bodies are composed of fine filaments,
densely packed in the core but loose at the rim
Lewy bodies may also be found in the cholinergic cells of the Basal
Nucleus of Meynert, as well as in other brainstem nuclei
Figure 8. Features of Parkinson’s Disease. Stooped-over posture,
speaks in whispers, takes small steps
PATHOPHYSIOLOGY
Figure 7. Gross and histologic presentation of Lewy Body
Dementia. On the left, note loss of substantia nigra (which explains
Parkinsonism), and the presence of Lewy bodies (arrow) on the right.
II. SUBCORTICAL DEMENTIA
A. PARKINSON’S DISEASE DEMENTIA (PDD)
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Incidence of dementia in PD may be as high as 6 times more than in
the general non-PD population
25% of patients will develop dementia of the AD type due to overlap
of these two pathologies
PDD patients are more likely to have akinetic/rigid PD phenotype
rather than the tremor-predominant phenotype
It will usually take at least 5 years for a patient with PD to have
memory deficits. The executive functions are the first to go.
Trivia: Prominent people who have atypical Parkinson’s disease include
Michael J. Fox (diagnosed with juvenile Parkinson’s; he had no facial
expressions) and Muhammad Ali, who acquired the disease from boxing
(chronic traumatic encephalopathy with development of dementia
fugilistica).
Figure 9. Parkinson’s Disease. Substantia nigra as seen in
Parkinson’s Disease.
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In LBD and PDD, abnormal protein (alpha synuclein) deposits
disrupt the brain’s normal functioning. These Lewy body proteins are
found in an area of the brainstem where they deplete the
neurotransmitter dopamine, causing Parkinsonian symptoms. In
Lewy body dementia, these abnormal proteins are diffuse
throughout other areas of the brain, including the cerebral cortex
(basically same abnormal protein in both diseases but accumulate in
different areas).
FEATURES OF PARKINSON’S DISEASE DEMENTIA
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Tremor (resting tremor, postural tremor)
Rigidity
Bradykinesia
Unilateral (as compared to Parkinsonism which is bilateral)
Postural instability (flexed posture, impaired postural reflex)
Other features include expressionless face (hypomimia), greasy
skin, and soft rapid indistinct speech
Tremor, rigidity, and bradykinesia respond well to therapy unlike
postural instability
Give Levodopa and Carbidopa
Figure 10. Parkinson’s Disease. During movement, signals pass from
the brain’s cortex, via reticular formation and spinal cord (pathway A), to
muscles, which contract. Other signals pass, by pathway B, to the basal
AICA, LEA, JEBBICK
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Lec 1: Dementia and Other Neurological Disorders
ganglia; these damp the signals in pathway A, reducing muscle tone so
that movement is not jerky. Dopamine, a nerve transmitter made in the
basal ganglia, is needed for this damping effect. In Parkinson’s disease,
degeneration of parts of the basal ganglia causes a lack of dopamine
within this part of the brain. The basal ganglia are thus prevented from
modifying the nerve pathways that control muscle contraction. As a
result, the muscles are overly tense, causing tremor, joint rigidity, and
slow movement. Most drug treatments increase the level of dopamine in
the brain or oppose the action of acetylcholine.
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OS 213
Dementia (mild to moderate)
Incontinence
Triad of dementia, ataxia, and incontinence
o Do not wait for full triad before treating
May respond to shunting (prognosis better if symptoms are reduced
by relief of pressure). Thus partially reversible.
May be a post traumatic sequelae
Presumed to be caused by obstruction to normal flow of CSF over
the cerebral convexity and delayed absorption into the venous
system resulting to enlarged lateral ventricles and stretching and
distortion of white matter tracts in corona radiata
In contrast to AD, NPH patient has early and prominent gait
disturbance and has no evidence of cortical atrophy on CT or MRI
GROSS BRAIN FINDINGS
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Neuroimaging studies reveal enlarged lateral ventricles with little or
no cortical atrophy
o Communicating hydrocephalus with patent aqueduct of Sylvius
o Ventriculomegaly
Lumbar puncture opening pressure is in the high normal range
Figure 11. Dopaminergic cell death. Accumulation of alpha-synuclein
leads to death of dopaminergic neurons.
B. HUNTINGTON’S DISEASE
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Not very common
Affectation of the caudate nucleus
Autosomal dominant form of inheritance
o If none is inherited, then you’re probably safe from this disease
o Since it’s autosomal dominant, usually parents with Huntington’s
are advised not to have children anymore
Movement disorder: choreiform movements (“shaker”)
Progressive dementia, with psychotic symptoms
Characterized by motor abnormalities and fewer language
abnormalities
Psychomotor slowing and difficulty with complex tasks, but memory,
language, and insight remain relatively intact in the early and middle
stages of the illness
Distinguished from AD type with the ff:
o High incidence of depression and psychosis
o Classis choreoathetoid movement disorder
Important differential is X-linked dystonia; inquire family history or if
clan hails from Panay island
Figure 12. Normal pressure hydrocephalus. CSF has no way out so a
shunt must be placed. This can bring them back to functional level.
However, in very severe cases, shunting could not be done.
E. WHITE MATTER DISEASES
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Dementia is a common occurrence in patients with disorders
affecting cerebral hemispheric white matter (e.g. strokes, multiple
sclerosis, HIV encephalopathy, leukodystrophies)
o White matter hyperintensities on MRI are hallmark of HIV
encephalopathy
Pathological findings include numerous ischemic areas prone to
stroke (due to very “bad” vessels) with loss of myelin
C. PROGRESSIVE SUPRANUCLEAR PALSY
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Also known as Steele-Richardson-Olszewski Syndrome
Uncommon type of dementia
Loss of balance (falls)
Vertical gaze difficulties usually come first (can’t look up or down)
o Note: if there are problems in vertical gaze, think midbrain; if in
horizontal gaze, think pons
o Rule out pineal/quadrigeminal plate tumor which can also cause
impaired vertical gaze
Dementia, slurring, choking (cause of death: choking)
Brain MRI reveals midbrain atrophy (superior colliculus) due to
widespread neuronal loss which also affects globus pallidus,
subthalamic nucleus, substantia nigra, periaqueductal gray matter,
and dentate nucleus of the cerebellum
PET studies show symmetric frontal and striatal hypometabolism
Figure 13. HIV Leukoencephalopathy. The MRI shows atrophy and
white matter hyperintensity on T2 not involving U-fibers. This 40-year old
female patient is diagnosed with HIV and presented with confusion,
decline in memory without focal findings, and dehydration
E. MULTIPLE SYSTEM ATROPHY
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FEATURES WITH MSA
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D. NORMAL PRESSURE HYDROCEPHALUS
FEATURES OF NORMAL PRESSURE HYDROCEPHALUS
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Gait problems (ataxia/apraxia, with wide based/”magnetic” gait)
AICA, LEA, JEBBICK
Also known as olivopontocerebellar atrophy
Include all other syndromes that could not be classified back in the
days (i.e. Shy-Drager syndrome)
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Ataxia is a manifestation
Relatively rapid progression
Autonomic dysfunction
o Orthostatic hypotension (all patients will have this)
o BP of patient from lying to sitting/standing should increase but in
orthostatic hypotension, it decreases
o Incontinence
Parkinsonism
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Lec 1: Dementia and Other Neurological Disorders
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Group of disorders with the presence of glial cytoplasmic inclusions
typically within the cytoplasm of oligodendrocytes, that can have
different patterns of clinical presentation
No medications to stop the atrophy
OS 213
ENDOCRINOPATHIES
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Hyper/hypothyroidism
o Hypothyroidism is very common in patients who undergo
thyroidectomy but fail to follow up
Parathyroid/adrenal disturbances
GROSS BRAIN FINDINGS
B. TOXIC AND METABOLIC CAUSES
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Figure 14. Multiple system atrophy. In cerebellar forms, there is
typically atrophy of cerebellum, including the cerebellar peduncles, pons
(especially the basis pontis), and medulla (inferior olive), while in
Parkinsonian forms, the atrophy involves both the substantia nigra and
striatum (putamen).
G. SUBCORTICAL DEMENTIAS
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Spinocerebellar degenerations
Cerebellar + memory + frontal dysfunctions
Idiopathic basal ganglia calcifications (may be asymptomatic)
Cortico-basal ganglionic degeneration (“alien hand syndrome”; can’t
recognize half of the body)
Pseudodepression
Wilson’s disease, along with Sydenham’s Chorea of Rheumatic
Fever, is a differential diagnosis for very young children who move
too much and is caused by a ceruloplasmin problem
Vascular dementia (e.g. from hypoxic encephalopathy)
Vitamin deficiencies (deficiencies in B1, B12, folate, niacin)
o Vitamin B12 deficiency is not common in the Philippines
because most of us are not vegetarians who need vitamin B12
supplementation
o B1 deficiency – alcoholics
Drugs that cause dementia include:
o Psychotropic agents
o Anticholinergics
o Anti-convulsants
Heavy metals and toxins (esp. common in those from the mining and
gold rush districts or those exposed to lead)
IV. REVERSIBLE DEMENTIAS
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Drugs and toxins
Metabolic dementias
Normal pressure hydrocephalus
Tumors
Infections
SLE
Endocrinopathies
Vitamin deficiencies
Alcoholism (mammillary bodies shrink)
Pseudodementia (like those seen in depression)
V. RAPIDLY PROGRESSING DEMENTIAS
H. DISTINGUISHING CORTICAL FROM SUBCORTICAL DEMENTIA
Figure 15. Various forms of rapidly-progressing dementia.
 The terminology prion refers to an infections protein agent that
“replicates” by inducing the misfolding of the native polypeptides
which leads it to take on a dysfunctional form
A. NON-PRION DISEASES
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These include:
o Corticobasal ganglionic degeneration
o Frontotemporal dementia
o Lewy Body dementia
o Alzheimer’s disease
o Progressive Supranuclear Palsy
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Creutzfeldt-Jakob disease is not synonymous to Mad Cow Disease
CJD has been present even before MCD. CJD has been
demonstrated in the Kuru tribe in Papua New Guinea where they
open skulls of cows and eat the brains.
MCD is under Variant CJD. It is a disease of cows that has been
transmitted to people. It has younger age of onset, more rapid
progression, and leads to ataxia and earlier death.
B. PRION DISEASES
III. TOXIC METABOLIC DEMENTIAS
A. ETIOLOGY FROM SYSTEMIC ILLNESS
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Chronic hypoxia - can be caused by too much smoking
Hepatic encephalopathy - can be caused by hyperammonemia
Uremia (elevated creatinine)
Persistent electrolyte imbalance (i.e. hyper/hyponatremia)
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SPORADIC CREUTZFELDT-JAKOB DISEASE
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AICA, LEA, JEBBICK
Occurs between 50-70 years old
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Lec 1: Dementia and Other Neurological Disorders
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Mean survival of 5 months
85% die witching a year of diagnosis
Prion disease is not the same as mad cow disease
Dementia + 2 of the ff:
o Pyramidal or extrapyramidal symptoms
o Visual/cerebellar dysfunction (mainly)
o Myoclonus
 Startle myoclonus using clap as stimulus - feet/whole body
jerks when startled
 Most common in Filipino patients
o Akinetic mutism
o EEG: periodic sharp waves
 This is diagnostic of SCJD
 Different from epilepsy since it does not respond to AEDs
o CSF 14-3-3 protein elevation
 A very expensive diagnostic test
 Confirm to prognosticate
VARIANT CREUTZFELDT-JAKOB DISEASE
 Transmitted from cows to humans
 Occurs in 12-74-year olds
 Includes Mad Cow Disease
 Early and profound psychiatric illness which is followed by:
o Ataxia (e.g. some die by head injury)
o Dementia
o Movement disorder (myoclonic jerks)
o EEG: no periodic sharp waves (usually normal)
o MRI: Pulvinar sign can be seen (unlike SCJD which is usually
normal)
Figure 16. Pulvinar sign. 33-year old woman with VCJD. Axial fluidattenuated inversion recovery MRI shows high signal intensity bilaterally
in pulvinar and medial aspects of thalamus (arrows).
VI. APPROACH TO PATIENT WITH DEMENTIA
HISTORY
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Check patient’s instrumental and daily activities:
o Everyday problem solving
o Handling business and financial affairs
o Job responsibilities
o Shopping
o Participation in volunteer and social groups
o Home activities, hobbies
o Maintenance of personal hygiene
o Intake of medications
o Phone dialing
o Traveling alone; knowing destination
o Handling money
Important to assess is impact on patient’s daily activities, which will
help differentiate between normal and pathologic forgetfulness
Alzheimer’s can occur as early as 40s if there is history of trauma
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Early mutism
Lateralizing signs
o e.g. hemiplegia (caused by vascular dementia) and stroke or
subdural hematoma on one side
Refer dementia patients with red flags
WORK-UP
 CBC with platelet count
 ESR
 Urinalysis
 Cholesterol, lipids
 VDRL/TPA – neurosyphilis but no cases the past 5 years
 HgbA1c, electrolytes
 BUN, creatinine
 Serum B12, folate
 LFTs, TFTs
 ECG
 2D Echo
 Carotid/Vertebral Doppler
 Cranial MRI
 Toxic screening
NOTE: The most important procedure to be done is the MRI. If it cannot
be performed, CT-Scan will do. These are important because the patient
may have had trauma or vehicular accidents.
TEST
EEG
Lumbar Puncture (Neurosyphilis,
TB meningitis)
Heavy metal screen
HIV screen
Ceruloplasmin
ApoE4 (susceptibility gene) /
Genetic testing
INDICATION
Possible seizures: CJD
Onset before 55 y/o: rapid
progression of dementia
History of potential exposure
History of potential exposure
Wilson’s disease
To strengthen diagnosis; strong
family history
ApoE4 is a susceptibility gene. It
doesn’t mean that if you have it,
you have dementia.
PET Scan with amyloid screening
Diagnostic test for Alzheimer’s
disease
Table . Optional laboratory work-ups. Only done when other
comorbids/etiologies are suspected. Biomarkers: PET Scan with amyloid
screening, CSF testing
PREVENTION
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Ballroom dancing (you use your body and your mind)
Low fat diet, high in omega 3
Memoplus Gold = NO approved therapeutic claims
Sufficient hours of sleep
After 26 years, difficult to memorize things already
Question: What if there are normal findings but presented with signs of
cognitive degradation?
Answer: Probably Alzheimer’s!
END OF TRANSCRIPTION
Greetings
Aica: Hi Phive Star! Hello Harvey and Extra D’yiz! 
Lea: Punta kayo IMDC please and support our class! Yay!
NEUROLOGIC EXAMINATION
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Check for the ff:
o Aphasia (speech)
o Apraxia (motor memory)
o Agnosia (sensory recognition)
o Executive functioning (complex behavior sequencing)
o Judgment and insight (MSE)
o Complete cranial nerve testing
o Complete motor testing
o Tremors, gait disturbances
o Orthostatic hypotension (check for multiple system atrophy)
RED FLAGS
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Early gait disturbances – comes late in Alzheimer’s
Early incontinence – comes just before patients become bedridden
AICA, LEA, JEBBICK
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APPENDIX. Diagnostic work-up for dementia. Screen for treatable
causes of dementia. If treatable, treat.
o
Example of atypical features:
 hemiparesis, which could indicate stoke leading to vascular
dementia
 bad gait, but this occurs at later stages of Alzheimer’s
AICA, LEA, JEBBICK
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