Basic Science applied to medicine

1. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
INTRODUCTION
● Alzheimer disease (AD) is the most common cause of dementia
PATHOLOGY
● Essential neuropathologic changes
○ Neuritic plaques
○ Extracellular deposits of amyloid beta peptides
○ Neurofibrillary degeneration
■ Intracellular
● Additional features
○ Cerebral amyloid angiopathy
○ abnormal alpha-synuclein accumulation, known as Lewy bodies
○ Vascular brain injury
○ Hippocampal sclerosis
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by Dr. Eashan Srivastava

2. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
PATHOGENESIS
● Exact pathogenesis remains unclear
● Genetic factors
● Environmental factors
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by Dr. Eashan Srivastava

3. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
HYPOTHESIS
● Amyloid hypothesis
● Tau hypothesis
○ Tau is a microtubule-associated protein
○ microtubule assembly and stabilization
○ In AD, tau becomes hyperphosphorylated and aggregates to form neurofibrillary
tangles within the neuronal cytoplasm
○ accumulation of this altered protein is toxic to neurons
● Plasmin hypothesis
○ Lower levels of plasmin responsible for endothelial dysfunction
● Calcium hypothesis
● Free radical hypothesis
● Neurotransmitter hypothesis
○ Depletion of NA, Serotonin, Ach
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by Dr. Eashan Srivastava

4. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
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- Created with love
by Dr. Eashan Srivastava

5. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
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- Created with love
by Dr. Eashan Srivastava

6. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
GENETICS OF EARLY ONSET AD
● Amyloid precursor protein
○ APP​ gene
○ chromosome 21q
○ function of APP in neurons is not well understood
○ APP is cleaved proteolytically by three enzymes, known as α-, β-, and
γ-secretase
○ amyloidogenic pathway
■ β-secretase and later γ-secretase
■ amyloid-beta 42 (Aβ42) prone to fibril formation
● Presenilin 1
○ chromosome 14q
○ protein product, PSEN1
○ accounting for up to 50 percent of early-onset familial AD
○ Function
■ regulation of intracellular calcium signaling
■ cell cycle and cell death
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by Dr. Eashan Srivastava

7. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
■ trafficking of membrane proteins
■ responsible for γ-secretase cleavage of APP
● Presenilin 2
○ chromosome 1q
○ protein product, PSEN2
○ Function = not known
● Trisomy 21/Down syndrome
○ extra copy of the ​APP​ gene
GENETICS OF LATE ONSET AD
● Apolipoprotein E
○ chromosome 19
○ 3 alleles: epsilon 2, 3, and 4
○ The ​APOE​epsilon 4 (ε4) = risk factor for LOAD
Epidemiology
● increasingly prevalent with advancing age
● M/c cause of dementia in developed countries
● M/c cause of dementia in developing countries = vascular dementia
● F>M
Risk factors
● Family history of dementia is a risk factor
● African Americans
● hypertension
● Dyslipidemia
● Cerebrovascular disease
● Atherosclerosis
● Obesity
● type 2 diabetes
● Physically active individuals have lower incidence and prevalence
● Brain trauma
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by Dr. Eashan Srivastava

8. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
● Opioids, cocaine, Benzodiazepines
● smoking
CLINICAL FEATURES
● Age of onset
○ LOAD = > 65 yrs
○ Early-onset AD = onset of symptoms before 65 years of age
● Cardinal symptoms
○ Memory impairment is the most common initial symptom
○ other cognitive domains
○ Executive dysfunction
○ visuospatial impairment
○ deficits in language and behavioral symptoms often manifest later
● Memory impairment
○ Declarative episodic memory (memory of events occurring at a particular time
and place) is usually profoundly affected in AD
○ semantic memory becomes impaired somewhat later
○ described as anterograde long-term episodic amnesia
○ develop insidiously
○ progress slowly over time
○ MMSE - recall after 5-10 minutes
● Executive function and judgment/problem solving
○ less organized
○ less motivated
○ multitasking is particularly compromised
○ poor insight
● Behavioral and psychologic symptoms
○ Apathy
○ social disengagement
○ Irritability
● Apraxia
○ difficulty performing learned motor tasks
○ occurs later
○ Eg. pantomime the use of tools
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by Dr. Eashan Srivastava

9. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
● Sleep disturbances
○ more fragmented sleep
EVALUATION
● Clinical assessment
○ History
○ Examination
○ Neurological assessment
○ MMSE
● Role of neuropsychologic testing
○ provide a baseline in order to follow up
○ differentiate among different forms of neurodegenerative dementias
○ To assess competencies and guide recommendations pertaining to driving,
financial decisions
○ R/o depression etc
● Neuroimaging
○ MRI
■ diffuse atrophy
■ reduced hippocampal volume
■ medial temporal lobe atrophy
○ FDG-PET
○ SPECT
○ fMRI
● Role of biomarkers
○ Molecular biomarkers of Aβ protein deposition include
■ Low cerebrospinal fluid (CSF) Aβ42
■ Positive amyloid PET imaging using one of the amyloid PET tracer
○ Biomarkers of tau deposition
■ Increased CSF total tau and phospho-tau
■ Evidence of cerebral tau using a tau-specific PET tracer
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by Dr. Eashan Srivastava

10. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
Pathophysiologic
marker
Topographic
marker
Marker of neuronal
injury/degeneration
Cerebrospinal fluid
Aβ42 or Aβ42:Aβ40 ratio Yes No No
Total tau, phospho-tau Yes No Ye
s
PET
Amyloid tracer uptake Yes No No
Fluorodeoxyglucose No Yes Ye
s
Structural MRI
Medial temporal lobe
atrophy
No Yes Ye
s
● Other laboratory testing
○ To exclude contributing secondary causes
■ TFT
■ vitamin B12
■ VDRL
■ HIV
● Genetic testing
○ not recommended routinely
○ Only in early onset/familial cases
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by Dr. Eashan Srivastava

11. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
DIAGNOSIS
DSM 5 Criteria
DSM-5 criteria for major neurocognitive disorder due to Alzheimer
disease
A.​​ Evidence of significant cognitive decline from a previous level of performance in one or more
cognitive domains*:
Learning and memory.
Language.
Executive function.
Complex attention.
Perceptual-motor.
Social cognition.
B.​​ The cognitive deficits interfere with independence in everyday activities. At a minimum,
assistance should be required with complex instrumental activities of daily living, such as paying
bills or managing medications.
C.​​ The cognitive deficits do not occur exclusively in the context of a delirium.
D.​​ The cognitive deficits are not better explained by another mental disorder (eg, major depressive
disorder, schizophrenia).
E.​​ There is insidious onset and gradual progression of impairment in at least two cognitive domains.
F.​​ Either of the following:
Evidence of a causative Alzheimer disease genetic mutation from family history or genetic
testing.
All three of the following are present:
1) Clear evidence of decline in memory and learning and at least one other cognitive domain.
2) Steadily progressive, gradual decline in cognition, without extended plateaus.
3) No evidence of mixed etiology (ie, absence of other neurodegenerative disorders or
cerebrovascular disease, or another neurological, mental, or systemic disease or condition
likely contributing to cognitive decline).
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by Dr. Eashan Srivastava

12. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
DIFFERENTIAL DIAGNOSIS
● Vascular dementia
● DLB
● FTD
● Prion disease
● Huntington
● NPH
● Wernicke’s
● Pellagra
● Hypothyroid
● B12 def
● Chronic meningitis
● Chronic lead poisoning
● Chronic traumatic encephalopathy
● Fugue state
Rx
● Compliance issue
● Unable to report adverse effects
● caregiver history is essential
CHOLINESTERASE INHIBITORS
● degree of expected benefit is modest
● therapy should not be continued indefinitely in patients who do not appear to be
benefiting or who have significant side effects
● not neuroprotective
● No role in Non AD dementia
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by Dr. Eashan Srivastava

13. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
nesterase inhibitors used for treatment of dementia: Dose and
administration
Drug Formulations Starting dose Maintenance dose Comments
Donepezil Tablet 5 mg OD 10 mg OD
Galantamine tablet 4 mg BD 12 mg BD Give with meals
Do not use with severe renal
or liver impairment.
Rivastigmine Capsule 1.5 mg BD 6 mg BD Give with meals
Slow and cautious titration
with renal or liver
impairment
Transdermal
patch
4.6 mg/24 hours Can cause rash; rotate
sites. Fewer side effects
than capsule.
● Contraindications and precautions
○ bradycardia
○ heart block
○ Adjustments for renal/hepatic disease
○ Sleep disturbances
○ GI symptoms (nausea, vomiting, diarrhea)
● Duration of therapy​​ — There is no consensus on how long to continue cholinesterase
inhibitors
MEMANTINE
● N-methyl-D-aspartate (NMDA) receptor antagonist
● proposed to be neuroprotective
● Glutamate is the principal excitatory amino acid neurotransmitter
● fewer side effects
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by Dr. Eashan Srivastava

14. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
ANTIOXIDANTS
● Vitamin E (alpha-tocopherol)
● selegiline (a monoamine oxidase inhibitor)
● Not recommended
NONPHARMACOLOGIC THERAPY AND SUPPORTIVE CARE
● Behavioral disturbance
○ Delusions
○ Hallucinations
○ Depression
○ Agitation
○ Aggression
○ sleep disturbances
○ Rx
■ SSRI
■ SNRI
■ Antipsychotics
● Nutrition
○ nutritional supplements may improve weight and fat-free mass
● Cognitive rehabilitation
○ to help patients in the early stages
○ devise strategies to compensate for declining function
● Exercise programs
● Occupational therapy
● Alcohol
○ drink to excess because they lose track of how many drinks have been
consumed
○ limit alcohol
- Created with love
by Dr. Eashan Srivastava

15. Science is a differential equation. Religion is a boundary condition.
- Alan Turing
Under study
● HRT
● Ginkgo biloba
● Statins
● Vitamin B
● Omega-3 fatty acids
- Created with love
by Dr. Eashan Srivastava