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STEP 5: Neuro PATHOMA > Dementia Denerative D/o > Flashcards

Dementia Denerative D/o Flashcards

1
Q

What is the classification of damaging CORTICAL GRAY MATTER? Damaging DEEP STRUCTURE (basal ganglia + brainstem) gray matter?

A 
CORTICAL = DEMENTIA
DEEP STRUCTURE (basal ganglia**+brainstem) = MOVEMENT D/o
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2
Q

ALZHEIMERS DISEASE results as a deposit of ___?

How does this occur?

A

NORMAL: AMYLOID PRECURSOR PROTEIN (APP, Chrom21) - Gets cleaved by ALPHA secretase cleaving enz -> NORMAL TURN OVER

AD: APP gets cleaved by BETA secretase cleaving enz instead -> NO Turnover -> Abeta amyloid deposits in the brain

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3
Q

What are the components of DEMENTIA in ALZHEIMER’S DISEASE?

A

DEMENTIA = MEMORY LOSS + COGNITIVE DYSFN (Intact consciousness)

  1. Memory Loss: SLOW PROGRESSION (takes years to develop) - First short-term memory loss followed by long-term memory
  2. Cognitive Dysfn: Loss of MOTOR SKILLS + LANGUAGE
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4
Q

What is the MAIN DISTINGUISHING feature of AD that differentiates it from PARKINSON’s or HUNTINGTON’S EARLY on in the disease?

A

AD: NO FOCAL NEUROLOGIC DEFICITS early on as seen in PARKINSON’S (akinesia, expressionless face, pill rolling tremor) or HUNTINGTON (chorea)

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5
Q

What is a common cause of death in AD pts?

A

INFECTION

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6
Q

What chromosome is AMYLOID PRECURSOR PROTEIN on? Thus, what other pathology is ALZHEIMER’S most closely associated with?

A 
Chrom 21
TRISOMY 21 (DOWN SYNDROME)
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7
Q

What are the 2 forms of ALZHEIMER’S DISEASE?

A

SPORADIC

EARLY-ONSET AD

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8
Q

What are the two RISK FACTORS of SPORADIC ALZHEIMER’S? What factor DECREASES the risk?

A
  1. AGE (Occurs in the ELDERLY)
  2. E4 allele of APLIPOPROTEIN E -> Encodes for beta cleavage of AMYLOID PRECURSOR PROTEIN: Resulting in Abeta amyloid deposits in the brain

DECREASES RISK: E2 allele of APOLIPOPROTEIN E

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9
Q

What are 2 associations of EARLY ONSET AD?

[Hint: 1 inherited gene mutation, 1 chromosomal]

A
  1. FAMILIAL - Inherited mutation of PRESENILIN 1**or presenilin 2
  2. TRISOMY 21 [DOWN SYNDROME] - Mostly associated since Amyloid precursor protein (APP) is on Chrom 21 - More of it can undergo beta cleavage -> Abeta amyloid deposits
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10
Q

What are the 4 morphological changes seen on the brain with ALZHEIMER’S? [Think cerebral, gyrus, sulci, ventricles]

A
  1. DIFFUSE** cerebral atrophy
    2-3. NARROWING OF GYRI, resulting in WIDENING OF SULI
  2. HYDROCEPHALUS EX VACUO - Loss of brain parenchyma -> Dilation of ventricles (note this hydrocephalus is NOT due to increase in ICP but loss of cortical mass)
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11
Q

What are 2 histological changes seen with ALZHEIMER’S DISEASE?

A

NEURITIC PLAQUES

NEUROFIBRILLARY TANGLES

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12
Q

What are ALZHEIMER’S NEURITIC PLAQUES comprised of?

A

NEURITIC PLAQUES = EXTRACELLULAR Abeta amyloid protein + INTRACELLULAR entangled neuritic processes

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13
Q

What is another possible fatal complication of ALZHEIMER’S as a result of NEURITIC PLAQUE FORMATION?

A

ALZHEIMER’S AMYLOID DEPOSITS can also form around BV -> CEREBRAL AMYLOID ANGIOPATHY

Increases risk of HEMORRHAGE

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14
Q

What are ALZEIMER’S NEUROFIBRILLARY TANGLES composed of?

A

NFT = INTRACELLULAR HYPERPHOSPHORYLATED TAU PROTEIN

Tau = microtubule-associated protein that organizes the cytoskeletaon
AD: HYPERPOSPHORYLATED TAU -> No longer organizes cytoskeleton -> Looks triangular

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15
Q

How is the final diagnosis of ALZHEIMER’S MADE?

A

CLINICALLY + PATHOLOGY
Clinical: Presumptive diagnosis after excluding other causes
Pathology: Confirmed by autopsy (4 morphological changes) POST-MORTEM

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16
Q

What is the most common cause of dementia? Which form of this pathology is most common?

A

ALZHEIMER’S DISEASE

95% are SPORADIC - seen in the elderly, E4 allele of apolipoprotein E

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17
Q

What is the 2nd most common cause of DEMENTIA? What is it a consequence of?

A

VASCULAR DEMENTIA = Consequence of MODERATE GLOBAL ISCHEMIA
Think dementia = memory loss + loss of cognitive fn (motor skills/language)

MEMORY LOSS: Ischemia to vulnerable region (pyramidal neurons of hippocampus in temporal lobe)
COGNITIVE FN: Ischemia to vulnerable region (Pyramidal neurons of cortical layers 3,5,6 - CORTICAL LAMINAR NECROSIS)

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18
Q

What are the 3 most common causes of VASCULAR DEMENTIA?

A

Decrease in BLOOD FLOW resulting in MULTIFOCAL INFARCTION of particularly susceptible regions (hippocampus + cortical layers 3,5,6) =

  1. HTN
  2. ATHEROSCLEROSIS
  3. VASCULITIS
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19
Q

How does PICK DISEASE (FRONTOTEMPORAL LOBAR DEMENTIA) differ from ALZHEIMER’S DEMENTIA?

A

ALZHEIMER’S: DIFFUSE cerebral atrophy, NO focal neurologic deficits early on
PICK DISEASE: SELECTIVE atrophy of frontal lobe + temporal lobe, YES focal neurologic deficits early on (frontal lobe k/o = profound dis-inhibition, temporal lobe k/o = apathy + language difficulties)

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20
Q

What is seen on histology of PICK DISEASE? Which pathology do you also see this?

A

ROUND AGGREGATES of TAU PROTEIN

Also seen with ALZHEIMER’S (hyperphosphorylated aggregates)

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21
Q

What type of neurons are degenerated in PARKINSON’S? What pathway is it involved in?

A

DOPAMINERGIC NEURONS of the SUBSTANTIA NIGRA pars compacta (MIDRAIN) are degenerated -> Loss of dopamine release to BASAL GANGLIA (VENTRAL STRIATUM) = NIGROSTIATAL PATHWAY

22
Q

What are the 2 dopaminergic responses from SUBSTANTIA NIGRA -> BASAL GANGLIA -> CORTEX?

A

PATH 1: SUBSTANTIA NIGRA PARS COMPACTA -> Release of Dopamine -> Binds to D1-R in BASAL GANGLIA (ventral striatum) -> Stimulation of DIRECT PATH to cortex = INCREASE movement initiation

PATH 2: SUSTANTIA NIGRA PARS COMPACTA -> Release of dopamine -> Binds to D2-R in BASAL GANGLIA (ventral striatum) -> DECREASE INDIRECT INHIBITORY path to cortex = DECREASE inhibition of movement initiation = INCREASE movement initiation

23
Q

What is the most common risk factor of PARKINSON’S DISEASE? What is the rare, but HIGH YIELD environmental risk factor?

A

AGE

Environmental risk factor = MPTP exposure [common in illicit drugs]

24
Q

What are the 4 clinical features of PARKINSON’S?

A

PARKINSON’S TRAP
T: Tremor - Pill rolling tremor AT REST, disappears with movement
R: Rigidity - Cogwheel rigidity in extremities
A: Akinesia/Bradykinesia - Expressionless face
P: Postural instability/ shuffling gait

25
What is a morphological change seen on biopsy of a PARKINSON'S pt?
LOSS OF PIGMENTED NEURONS (Dopaminergic) of the SUBSTANTIA NIGRA PARS COMPACTA
26
What is the HISTOLOGIC change seen on biopsy of a PARKINSON'S pt?****
LEWY BODIES = Eosinophilic inclusions of ALPHA SYNUCLEIN in affected dopaminergic neurons
27
How do you differentiate (2) between LEWY BODY DEMENTIA and PARKINSON'S? [HINT: Think Symptomatology and histology]
LEWY BODY DEMENTIA: See parkinsonian features (TRAP) + hallucination + ***EARLY ONSET DEMENTIA (within
28
What type of neurons are degenerated in HUNTINGTON DISEASE?
Degeneration of GABA-ergic neurons in DORSAL STRIATUM OF BASAL GANGLIA (specifically the CAUDATE NUCLEUS) DORSAL STRIATUM of Basal ganglia = CAUDATE + PUTAMEN + INTERNAL CAPSULE IN BETWEEN
29
What is the inheritance pattern of HUNTINGTON DISEASE? What type of mutation is passed along? What protein is mutated?
AUTOSOMAL DOMINANT Trinucleotide repeat of CAG (HUNTINGTIN GENE on Chrom4) - Expect ANTICIPATION (each successive generation contracts the disease at an earlier age)
30
When does TNR (CAG) expansion occur for HUNTINGTON'S DISEASE? ****
SPERMATOGENESIS
31
What are the 2 motor signs that typically present with HUNTINGTON'S? What are 2 other signs can present later with HUNTINGTON'S (psych, cognitive)
1. CHOREA: Involuntary movements due to LACK OF inhibitory control over movement 2. ATHETOSIS: Snake-like, slow, involuntary movement of fingers 2 other signs = DEPRESSION + DEMENTIA (later progression)
32
What morphological change can be seen on biopsy of a HUNTINGTON DISEASE Pt?
1. DEGENERATION OF CAUDATE NUCLEUS 2. HYDROCEPHALUS EX VACUO (dilation of LATERAL ventricles) - Due to lack of caudate mass pressing on the lateral ventricles
33
Which two dementia/degenerative disorders can result in HYDROCEPHALUS EX VACUO?
ALZHEIMER'S: Diffuse cerebral atrophy -> Loss of cortical mass -> Overall hydrocephalus HUNTINGTON'S: Atrophy of caudate nucleus -> Loss of deep structure compressing on lateral ventricles -> DILATED LATERAL VENTRICLES
34
What type of HYDROCEPHALUS is NORMAL PRESSURE HYDROCEPHALUS (communicating or non-communicating)?
COMMUNICATING | Defect in CSF resorption at arahnoid granulations - CSF RESORPTION CAN NOT KEEP UP WITH CSF PRODUCTION
35
What is the pathophysiology of NORMAL PRESSURE HYDROCEPHALUS? Specifically what gets STRETCHED**?
Idiopathic Normal pressure hydrocephalus -> Defective CSF resorption with NORMAL CSF production -> INCREASED CSF -> Dilation of ventricles -> Stretching of CORONA RADIATA (sheet of the majority of white matter = ascending and descending axons to and from cerebral cortex) -> WET WACKY WOBBLY
37
Name the 2 degenerative disorders with RAPID ONSET DEMENTIA, and EARLY ONSET DEMENTIA.
CREUTZFELDT-JAKOB DISEASE (CJD) = rapid onset dementia (within wks to months) + death LEWY BODY DEMENTIA = early onset dementia within a yr
38
What is the classical presentation of NORMAL PRESSURE HYDROCEPHALUS?
NORMAL PRESSURE HYDROCEPHALUS: Defective CSF resorption = Increased CSF = WET WACKY WOBBLY WET = Urinary incontinence, WACKY = dementia, WOBBLY = gait instability
39
What is the degenerative disease due to accumulation of PRION PROTEIN? What is the pathological and normal form?
SPONGIFORM ENCEPHALOPATHY Normal Form = Prion protein (CNS): ALPHA HELICAL Pathological form = Prion protein (CNS): BETA-PLEATED
40
How does the formation of Prion protein (PRPsc - BETA PLEATED) result in SPONGIFORM ENCEPHALOPATHY? Where does it accumulate?
PRPsc - ALPHA HELICAL (normal) gets converted to PRPsc - BETA PLEATED Result 1: Can be converted back into PRPc (alpha-helical) to form MORE PRPsc (beta-plated) Result 2: PRPsc (beta) can NOT be degraded -> Accumulates in NEURONS + GLIAL CELLS
41
What is the histological hallmark of SPONGIFORM ENCEPHALOPATHY?
Intracellular vacuoles (SPONGY DEGENERATION) of neurons and glial cells due to accumulation of PRPsc (BETA PLEATED FORM)
42
What are the 3 etiologies of SPONGIFORM ENCEPHALOPATHY and associated forms?
1. SPORADIC: random conversion to beta pleated = CJD 2. INHERITED: familial form = FAMILIAL FATAL INSOMNIA 3. TRANSMITTED: Due to exposure of PRPsc (beta) and thus considered "infectious" = CJD + VARIANT CJD
43
What are the 3 types of SPONGIFORM ENCEPHALOPATHY?
1. CJD: CREUTZFELDT-JAKOB DISEASE 2. VARIANT CJD: MAD COW DISEASE 3. FAMILIAL FATAL INSOMNIA
44
What are the two most common causes of CREUTZFELDT-JAKOB DISEASE?
1. SPORADIC*** = most common | 2. EXPOSURE TO INFECTED TISSUE (By Hu Growth hormone derived from someone infected, Corneal Tx)
45
What are the 3 most typical Sx of CJD?
Think CJD - spongiform = spastic, quick (rapid dementia, startle myoclonus, lose balance [ataxia]) 1. RAPIDLY PROGRESSIVE DEMENTIA** with death
46
What is the most diagnostic feature of CJD using an EEG?
Periodic SHARP WAVES (spike wave complexes) due to STARTLE MYOCLONUS [muscle contractions with minimal stimuli]
47
COMPARED TO CJD, what are the two distinguishing features of VARIANT CJD? (HINT: think pt population, etiology)
1. Affects younger pts | 2. Etiology = TRANSMISSION from mad cow (bovine)
48
Compared to CJD and VARIANT CJD, what are the 2 distinguishing features of FAMILIAL FATAL INSOMNIA? [HINT: Think etiology, Clinical Sx (2)]
1. Etiology = Inherited form of prion disease | 2. Clinical Sx = SEVERE INSOMNIA + EXAGGERATED STARTLE RESPONSE
49
What can improve the Sx of NORMAL PRESSURE HYDROCEPHALUS? What procedure is done to treat it?
Sx improvement = LUMPAR PUNCTURE - Drain some of the CSF from subarachnoid space Tx = VENTRICULOPERITONEAL SHUNT - Shunt some of the CSF in the ventricles to the peritoneum
50
Name the 5 DEGENERATIVE DISEASES. | Top 2 causes, 1 behavioral, 2 Loss of neurons related to movement, infectious-like cause
1. ALZHEIMER'S (#1 cause of dementia) = Abeta amyloid - Diffuse cerebral atrophy + Neuritic plaque + NFT (hyperphosphrylated tau) + hydrocephalus ex vacuo + Increased risk of hemorrhage (Abeta amyloid protein), LATE onset dementia, Down syndrome (Trisomy 21 - you're carrying Amyloid precursor protein APP) 2. VASCULAR DEMENTIA (#2 cause of dementia) = Consequence of MODERATE global ischemia in pyramidal neurons of cortical layers 3,5,6 + hippocampus 3. PICK DISEASE = Selective dementia of FRONTAL TEMPORAL LOBES, profound disinhibition and apathy FIRST, dementia later, ROUND TAU aggregates 4. PARKINSON'S = TRAP, Loss of dopaminergic neurons of SNpc, LATE onset dementia, LEWY bodies (alpha synuclein) in SNpc compared to LEWY BODY DEMENTIA (early dementia, lewy bodies in cortex) 5. HUNTINGTON'S = CHOREA, ATHETOSIS, Loss of GABA-ergic neurons of CAUDATE, HYDROCEPHALUS ex vacuo, TNR (CAG repeat) Chrom 4 6. SPONGIFORM ENCEPHALOPATHY (Prionprotein beta pleated) = CJD + VARIANT CJD + FAMILIAL FATAL INSOMNIA
51
UWORLD: During an acute mental status change, pt clinical presentation says "NO FOCAL FINDINGS" What type of dementia can be ruled out?
VASCULAR DEMENTIA

STEP 5: Neuro PATHOMA (6 decks)

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