Alzheimer’s vs Vascular

Dementia
Kiara G. Rivera Guevara, MS3
February 6, 2018 Author Note:
San Juan Bautista School of Medicine Presentation prepared for Psychiatry Didactics
An 80 y/o man with long standing hypertension is brought into the ED after
police found him confused and wandering around the park at night with a
small laceration to the forehead. Upon arrival to the ED, the patient became
physically and verbally aggressive to which the nursing staff had to
administer haloperidol IM. The next morning, the patient is calm and
cooperative, but is found to be disoriented to time and place and can only
recall 1 of 3 items on a short term memory test. No focal neurologic deficits
are present on testing. MRI of the brain reveals diffuse cortical and
hippocampal atrophy with no other abnormalities. This patient would benefit
from treatment with which of the following:

a) Vitamin A
b) Sertraline
c) Lorazepam
d) Desipramine
e) Donepezil
An 80 y/o man with long standing hypertension is brought into the ED after
police found him confused and wandering around the park at night with a
small laceration to the forehead. Upon arrival to the ED, the patient became
physically and verbally aggressive to which the nursing staff had to
administer haloperidol IM. The next morning, the patient is calm and
cooperative, but is found to be disoriented to time and place and can only
recall 1 of 3 items on a short term memory test. No focal neurologic deficits
are present on testing. MRI of the brain reveals diffuse cortical and
hippocampal atrophy with no other abnormalities. This patient would benefit
from treatment with which of the following:

a) Vitamin A
b) Sertraline
c) Lorazepam
d) Desipramine
e) Donepezil
Dementia “Dementia describes a group of
acquired symptoms affecting
memory, thinking, and social
abilities severe enough to
interfere with daily functioning”
(Mayo Clinic Staff, 2017).

• Onset is gradual (months to

years)
• Consciousness remains intact
• Characterized by a
progressive deterioration in
global intellectual ability
• Usually irreversible
• Remote memory usually
Figure 1: Most Common Types of Dementia (Alzheimer's spared
Disease & Dementia, 2016)
DSM-V Criteria for Major Neurocognitive
Disorder (Dementia)

Evidence of significant cognitive decline from a previous level or

performance in one or more cognitive domains:
▪ Learning and memory
▪ Language
▪ Executive function
▪ Complex attention
▪ Perceptual-motor
▪ Social cognition
 DSM-V Criteria for Major Neurocognitive
Disorder (Dementia)

▪ Cognitive deficits interfere with independence in everyday activities.

– Assistance should be required with complex Instrumental Activities of Daily
Living (IADL), such as paying bills or managing medications.

▪ The cognitive deficits do not occur exclusively in the context of

delirium.
▪ The cognitive deficits are not better explained by another mental
disorder (eg, MDD, schizophrenia).

Note: IADLs include shopping, preparing meals, using the telephone, managing transportation needs, managing
medications, managing finances. These typically require a cognitive component in addition to physical ability.
Alzheimer’s Disease
 Alzheimer’s Dementia – Pathophysiology

▪ Diagnosis of exclusion that requires

neuropathological examination of the brain for final
diagnosis.

▪ Most important biochemical abnormality implicated

in the development of AD is ↓ ACh levels in the CNS
due to choline acetyltransferase deficiency.
– In the CNS, ACh is involved primarily with arousal,
memory, and learning; therefore, degeneration of
cholinergic neurons leads to AD.
Figure 2: Synthesis of ACh from acetyl
coenzyme A and choline through the action of
choline acetyltransferase (Gauthier, 2002)
NE is also hypothesized to be hypoactive in AD as evidenced by
the decrease in NE-containing neurons in the locus ceruleus of
some pathological specimens (Sadock & Ruiz, p. 706).
 Alzheimer’s Dementia – Pathophysiology

▪ Most notable ACh decline is seen in:

– Nucleus basalis of Meynert
▪ Located at the base of the forebrain
and widely projects to neocortex
▪ Involved in memory and cognition

– Hippocampus
▪ Located in the medial temporal lobe
(part of the limbic system)
▪ Involved in the formation of new
memories
▪ Damage leads to anterograde Figure 3: Projections from the nucleus basalis of
amnesia Meynert and other cholinergic cell groups in the
septum pellucidum to the hippocampus and neocortex
(Gauthier, 2002)
“Alzheimer’s disease begins in the
entorhinal region of the medial temporal
lobe, spreads to the hippocampus, and
then moves to lateral and posterior
temporal and parietal neocortex,
eventually causing a more widespread
degeneration” (Seeley & Miller, 2015).
 Alzheimer’s Dementia – Pathophysiology

▪ On macroscopic
examination of the
neuropathologic
specimen, mild-to-
moderate generalized
cortical brain atrophy
can be seen.

Figure 4: Cortical Atrophy

seen in Advanced Alzheimer’s
Disease (Agamanolis, 2016)
Alzheimer’s Dementia – Histopathology

Neurofibrillary Tangles

– Intracellular
– Aggregates of
hyperphosphorylated tau
proteins

Figure 5: Neurofibrillary Tangles in the

Hippocampus of an Old Person with Alzheimer-
related Pathology (Wikimedia Commons, 2012)
 Alzheimer’s Dementia – Histopathology

Senile Plaques

– Extracellular
– Abnormally folded (insoluble) fibrillar
protein deposits composed of a β-amyloid
core surrounded by dystrophic neurites
▪ Loss of α-helical configuration via 2° protein
structure disruption of hydrogen bonds
– In AD, amyloid deposits are seen
exclusively in brain tissue
– In early AD, senile plaques are often found
in the medial temporal lobe (hippocampus,
Figure 6: Neuritic (Senile) Plaques Seen in amygdala, entorhinal cortex)
Bielschowski silver stain (Agamanolis, 2016)
 Amyloid Angiopathy

– β-amyloid deposits in the media/adventitia of cerebral arteries’ walls causing vessel

weakening which may lead to intracranial hemorrhage
– β-amyloid is formed by the cleavage of a transmembrane glycoprotein: amyloid
precursor protein (APP)
– Seen as apple-green birefringence when stained with Congo Red stain and viewed
under polarized light

Figure 7: Cerebral blood

vessels with cerebral
amyloid angiopathy in
Congo Red staining viewed
with polarization (a), and
immunohistochemistry
against amyloid beta
peptide (b) (Tanskanen,
Makela, & Myllykangas,
2011)
Alzheimer’s Disease – Genetic Basis

▪ Down Syndrome (Trisomy 21)

– The gene for the amyloid precursor protein (APP) is on chromosome 21
– AD onset around age 35

▪ Autosomal Dominant AD
– Mutations of the APP gene and of the presenilin 1 and 2 genes on chromosomes
14 and 1, respectively
▪ Presenilins are catalytic components of γ-secretase

▪ Apolipoprotein E4
– Chromosome 19
– Increases risk of sporadic form
 Alzheimer’s Disease - Symptoms

▪ Mild confusion (early in the course)

▪ Difficulty remembering/ increasing forgetfulness of recent events
– Forget conversations, appointments or events, and not remember them later

▪ Trouble organizing thoughts

▪ Repeat statements and questions over and over, not realizing that they’ve
asked the question before
▪ Routinely misplace possessions, often putting them in illogical locations
▪ Get lost in familiar places

(Alzheimer’s Disease, 2017)

 Alzheimer’s Disease - Symptoms

▪ Eventually forget the names of family members and everyday objects

▪ Have trouble finding the right words to identify objects, express thought or
take part in conversations
▪ Difficulty concentrating and thinking, especially about abstract concepts like
numbers
– Difficulty balancing checkbooks and paying bills on time

▪ Insight into their own disease is typically lost

(Alzheimer’s Disease, 2017)

 Alzheimer’s Disease - Symptoms

▪ Difficulty making judgments and decisions

– Ex: Responding effectively to food burning on the stove

▪ Later in the course, patients may have difficulty performing basic sequential tasks
such as dressing and bathing
▪ Skills and habits learned early in life are among the last abilities to be lost as the
disease progresses

(Alzheimer’s Disease, 2017)

 Alzheimer’s Disease - Symptoms

▪ Changes in personality and behavior

– Depression
– Apathy
– Social withdrawal
– Mood swings
– Distrust in others
– Irritability and aggressiveness
– Changes in sleeping habits
– Wandering
– Loss of inhibitions
– Delusions, such as believing something was stolen

(Alzheimer’s Disease, 2017)

 Therapy for Alzheimer’s Disease
▪ Cholinesterase inhibitors
– Enhance cholinergic neurotransmission by preventing ACh breakdown by AChE
in the CNS
– Used in mild to moderate neurocognitive disorders
▪ Donepezil (Aricept®)
▪ Galantamine (Razadyne®)
▪ Rivastigmine (Exelon®)

§ These drugs are useful in:

• Improving behavior, cognition, and functioning in activities of daily living
• Delaying the institutionalization and mortality in AD patients

• Note: These drugs do NOT prevent the ultimate progression of

cerebral neurodegeneration
 Therapy for Alzheimer’s Disease

▪ Neuroprotection via antioxidants

– “Oxidative stress has been demonstrated to be involved in the pathogenesis of the two
major types of dementia: AD and vascular dementia” (Luca, Antonia, & Calandra, 2015)
– May slow functional losses in AD
– Vitamin E (α-tocopherol)

▪ NMDA receptor antagonism

– CNS NMDA receptor overstimulation by glutamate (excitotoxicity) contributes to AD
symptoms
– Used in moderate to severe neurocognitive disorders in conjunction to cholinesterase
inhibitors
▪ Memantine (Namenda®)
Therapy for Alzheimer’s Disease

▪ Atypical Antipsychotics
– For behavioral disturbances (aggression or psychosis)
– Olanzapine (Zyprexa®)
– Risperidone (Risperdal®)
– Used with caution as there have been studies linking the use of atypical
antipsychotics with a higher risk of death among elderly patients with dementia.

▪ Respite
– Provide support and respite to the caregivers
Vascular Dementia
 Vascular Dementia

Sudden/stepwise
decline in
cognitive ability
with late-onset
memory
impairment due
to reduced blood
supply to a part
of the brain

Figure 8: Vascular Cognitive Impairment (VCI) caused by the blockage of blood supply
to the brain (What You Ought to Know About Vascular Dementia?, 2015)
Vascular Dementia

▪ Associated with focal neurologic signs

▪ Does not impair consciousness in the early stages
▪ Glial scar formation seen on autopsy
▪ Result of multiple arterial infarcts and/or chronic ischemia
▪ Multiple lacunar infarcts
▪ Large areas of encephalomalacia
▪ Approximately 10% of patients with AD also have pathologic findings
of vascular dementia and may be considered to have mixed dementia.
Neuroimaging
shows multiple
areas of
infarction
(multiple patchy
perfusion
defects)

Figure 9: PET imaging in

the differential diagnosis of
vascular dementia (Heiss &
Zimmermann-Meinzingen,
2012)
Vascular Dementia - Symptoms

▪ Seen in the setting of HTN, a-fib, peripheral vascular

disease, diabetes, and tobacco use.
▪ Focal damage in a variable patchwork of cortical and
subcortical regions of white matter tracts that disconnect
nodes within distributed networks.
“In patients suffering from cerebrovascular
disease, it can be difficult to determine
whether the dementia is due to AD, vascular
disease or a mixture of the two because many
of the risk factors for vascular dementia,
including diabetes, high cholesterol,
elevated homocysteine, and low exercise, are
also putative risk factors for AD” (Seeley &
Miller, 2015).
 Vascular Dementia - Symptoms
▪ Discreet episode of sudden neurologic
deterioration
▪ Focal neurologic deficits:
– Hemiparesis
– Unilateral Babinski sign
– Visual field defect
– Pseudobulbar palsy

▪ Mixture of executive control and

visuospatial deficits, with prominent
psychomotor slowing
▪ Can present with psychiatric symptoms
such as depression, anxiety, delusions,
disinhibition, or apathy
Figure 10: Common Symptoms of Vascular Dementia
(What You Ought to Know About Vascular Dementia?,
2015)
 Vascular Dementia - Symptoms

▪ Mild confusion
▪ Anxiety
▪ Psychosis
▪ Marked difficulties in judgment, orientation, and dependence on others for daily
activities develop later
▪ Euphoria, elation, depression, or aggressive behaviors are common as the disease
progresses
▪ Pyramidal and cerebellar signs may be present
▪ Gait disorder is seen in at least half of the patients
 Vascular Dementia - Symptoms

▪ Advanced disease:
– Urinary incontinence and dysarthria with or without other pseudobulbar features
(dysphagia, emotional lability) are frequent

▪ Trouble paying attention and concentrating

▪ Reduced ability to organize thoughts or actions
▪ Patients tend to have more somatic complaints than do patient's who have
Alzheimer's disease
Treatment of Vascular Dementia

▪ Focused on preventing new ischemic injury by stabilizing or removing

the underlying causes, such as HTN, diabetes, smoking, or lack of
exercise
▪ Recovery of lost cognitive function is not likely, although fluctuations
with periods of improvement are common
 References
▪ 21.3 Dementia (Major Neurocognitive Disorder). (2015). In B. J. Sadock, V. A. Sadock, & P. Ruiz, Kaplan &
Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry (p. 706). Philadelphia: Wolters
Kluwer.
▪ Agamanolis, D. P. (2016, August). Alzheimer's Disease. Retrieved from Neuropathology: An Illustrated
Interactive Course for Medical Students adn Residents: http://neuropathology-
web.org/chapter9/chapter9bAD.html
▪ Alzheimer's Disease & Dementia. (2016). Retrieved from Alzheimer's Services of the Capital Area:
http://alzbr.org/alzheimers-disease-dementia/
▪ File:Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer-related pathology, HE
3.JPG. (2012, June 10). Retrieved from Wikimedia Commons:
https://commons.wikimedia.org/wiki/File:Neurofibrillary_tangles_in_the_Hippocampus_of_an_old_person
_with_Alzheimer-related_pathology,_HE_3.JPG
▪ Gauthier, S. (2002). Advances in the pharmacotherapy of Alzheimer's disease. Canadian Medical Association
Journal, 616-623.
▪ Heiss, W.-D., & Zimmermann-Meinzingen, S. (2012). PET imaging in the differential diagnosis of vascular
dementia. Journal of Neurological Sciences, 268-273.
 References
▪ Luca, M., Antonia, L., & Calandra, C. (2015). The Role of Oxidative Damage in the Pathogenesis and
Progression of Alzheimer's Disease and Vascular Dementia. Oxidative Medicine and Cellular Longevity, 1-8.
▪ Mayo Clinic Staff. (2017, August 2). Dementia. Retrieved from Mayo Clinic:
https://www.mayoclinic.org/diseases-conditions/dementia/symptoms-causes/syc-20352013
▪ Seeley, W. W., & Miller, B. L. (2015). Dementia. In D. L. Kasper, A. S. Fauci, S. L. Hauser, D. L. Longo, J. L.
Jameson, & J. Loscalzo, Harrison's Principles of Internal Medicine (pp. 170-172). Chicago: McGraw-Hill
Education.
▪ Staff, M. C. (2017, December 30). Alzheimer's Disease. Retrieved from Mayo Clinic:
https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447
▪ Tanskanen, M., Makela, M., & Myllykangas, L. (2011, September). Retrieved from ResearchGate:
https://www.researchgate.net/figure/Cerebral-blood-vessels-with-cerebral-amyloid-angiopathy-CAA-The-
results-of_51642693
▪ What You Ought to Know About Vascular Dementia? (2015, September 23). Retrieved from Med India
Network for Health: http://www.medindia.net/patients/patientinfo/vascular-dementia.htm