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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
Q

What is a morphological change seen on biopsy of a PARKINSON’S pt?

A

LOSS OF PIGMENTED NEURONS (Dopaminergic) of the SUBSTANTIA NIGRA PARS COMPACTA

26
Q

What is the HISTOLOGIC change seen on biopsy of a PARKINSON’S pt?**

A

LEWY BODIES = Eosinophilic inclusions of ALPHA SYNUCLEIN in affected dopaminergic neurons

27
Q

How do you differentiate (2) between LEWY BODY DEMENTIA and PARKINSON’S?
[HINT: Think Symptomatology and histology]

A

LEWY BODY DEMENTIA: See parkinsonian features (TRAP) + hallucination + ***EARLY ONSET DEMENTIA (within

28
Q

What type of neurons are degenerated in HUNTINGTON DISEASE?

A

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
Q

What is the inheritance pattern of HUNTINGTON DISEASE? What type of mutation is passed along? What protein is mutated?

A

AUTOSOMAL DOMINANT
Trinucleotide repeat of CAG (HUNTINGTIN GENE on Chrom4) - Expect ANTICIPATION (each successive generation contracts the disease at an earlier age)

30
Q

When does TNR (CAG) expansion occur for HUNTINGTON’S DISEASE? **

A

SPERMATOGENESIS

31
Q

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)

A
  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
Q

What morphological change can be seen on biopsy of a HUNTINGTON DISEASE Pt?

A
  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
Q

Which two dementia/degenerative disorders can result in HYDROCEPHALUS EX VACUO?

A

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
Q

What type of HYDROCEPHALUS is NORMAL PRESSURE HYDROCEPHALUS (communicating or non-communicating)?

A

COMMUNICATING

Defect in CSF resorption at arahnoid granulations - CSF RESORPTION CAN NOT KEEP UP WITH CSF PRODUCTION

35
Q

What is the pathophysiology of NORMAL PRESSURE HYDROCEPHALUS? Specifically what gets STRETCHED**?

A

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
Q

Name the 2 degenerative disorders with RAPID ONSET DEMENTIA, and EARLY ONSET DEMENTIA.

A

CREUTZFELDT-JAKOB DISEASE (CJD) = rapid onset dementia (within wks to months) + death

LEWY BODY DEMENTIA = early onset dementia within a yr

38
Q

What is the classical presentation of NORMAL PRESSURE HYDROCEPHALUS?

A

NORMAL PRESSURE HYDROCEPHALUS: Defective CSF resorption = Increased CSF = WET WACKY WOBBLY
WET = Urinary incontinence, WACKY = dementia, WOBBLY = gait instability

39
Q

What is the degenerative disease due to accumulation of PRION PROTEIN? What is the pathological and normal form?

A

SPONGIFORM ENCEPHALOPATHY
Normal Form = Prion protein (CNS): ALPHA HELICAL
Pathological form = Prion protein (CNS): BETA-PLEATED

40
Q

How does the formation of Prion protein (PRPsc - BETA PLEATED) result in SPONGIFORM ENCEPHALOPATHY? Where does it accumulate?

A

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
Q

What is the histological hallmark of SPONGIFORM ENCEPHALOPATHY?

A

Intracellular vacuoles (SPONGY DEGENERATION) of neurons and glial cells due to accumulation of PRPsc (BETA PLEATED FORM)

42
Q

What are the 3 etiologies of SPONGIFORM ENCEPHALOPATHY and associated forms?

A
  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
Q

What are the 3 types of SPONGIFORM ENCEPHALOPATHY?

A
  1. CJD: CREUTZFELDT-JAKOB DISEASE
  2. VARIANT CJD: MAD COW DISEASE
  3. FAMILIAL FATAL INSOMNIA
44
Q

What are the two most common causes of CREUTZFELDT-JAKOB DISEASE?

A
  1. SPORADIC*** = most common

2. EXPOSURE TO INFECTED TISSUE (By Hu Growth hormone derived from someone infected, Corneal Tx)

45
Q

What are the 3 most typical Sx of CJD?

A

Think CJD - spongiform = spastic, quick (rapid dementia, startle myoclonus, lose balance [ataxia])
1. RAPIDLY PROGRESSIVE DEMENTIA** with death

46
Q

What is the most diagnostic feature of CJD using an EEG?

A

Periodic SHARP WAVES (spike wave complexes) due to STARTLE MYOCLONUS [muscle contractions with minimal stimuli]

47
Q

COMPARED TO CJD, what are the two distinguishing features of VARIANT CJD? (HINT: think pt population, etiology)

A
  1. Affects younger pts

2. Etiology = TRANSMISSION from mad cow (bovine)

48
Q

Compared to CJD and VARIANT CJD, what are the 2 distinguishing features of FAMILIAL FATAL INSOMNIA?
[HINT: Think etiology, Clinical Sx (2)]

A
  1. Etiology = Inherited form of prion disease

2. Clinical Sx = SEVERE INSOMNIA + EXAGGERATED STARTLE RESPONSE

49
Q

What can improve the Sx of NORMAL PRESSURE HYDROCEPHALUS? What procedure is done to treat it?

A

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
Q

Name the 5 DEGENERATIVE DISEASES.

Top 2 causes, 1 behavioral, 2 Loss of neurons related to movement, infectious-like cause

A
  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
Q

UWORLD: During an acute mental status change, pt clinical presentation says “NO FOCAL FINDINGS” What type of dementia can be ruled out?

A

VASCULAR DEMENTIA

STEP 5: Neuro PATHOMA (6 decks)

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