Neurodegenerative Diseases - Cochran, Franczak, Hillard Flashcards Preview

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Flashcards in Neurodegenerative Diseases - Cochran, Franczak, Hillard Deck (77):
1

Alzheimer's dementia is described in three stages.

What impairments are apt to be seen in Stage I?

What timespan does this generally correspond to?

Impaired learning and remote recall. Some visuospatial impairment. Anomia (language problems), and perhaps depression or delusions.

1-2 years.

2

Alzheimer's dementia is described in three stages.

How does Stage II contrast with stage I?

Timespan?

Stage II has worse memory problems as well as visuospatial skills. Delusions become common.

Distinctive: Acalculia.

3

Alzheimer's dementia is described in three stages.

What are the hallmarks of late-stage (III) dementia?

Severe cognitive impairment

Urinary/fecal incontinence

Limb rigidity and flexion posture; many are bedridden and die from infection.

4

Summarize the gross appearance of the brain of a patient with Alzheimer's disease.

Diffuse gyral atrophy and widening of sulci.

Hydrocephalus ex vacuo--ventricles enlarge as tissue regresses.

5

Name 3-4 histologic hallmarks of Alzheimer's disease.

What comprises each finding? (ie composition)

Diffuse plaque - Accumulated Aß protein.

Neuritic plaque - Accumulated Aß protein and tau.

Cerebral amyloid angiopathy - Accumulated Aß protein.

NFTs - Phosphorylated Tau.

6

Describe the difference between a diffuse plaque and a neuritic plaque in Alzheimer's disease.

Both are comprised of Aß protein, but neuritic plaques also contain tau.

Neuritic plaques are more closely associated with cognitive decline than diffuse plaque.

7

Where are plaques generally found in Alzheimer's disease?

Mostly in the neocortex; initially in association cortices (affects executive & higher-order functions)

Later in the primary cortices.

8

What is cerebral amyloid angiopathy?

What is it indicative of?

Accumulation of Aß protein around cranial vessels. Can predispose to lobar hemorrhage!

Often associated with Alzheimer's but may be seen in the absence of clinical disease.

9

Describe the protein found in NFTs.

What causes it to misfold?

Tau; a microtubule associated protein that seems to be involved in maintaining microtubule stability.

The cause of unfolding is unknown, but it is not due to tau gene mutation.

10

How is Alzheimer's disease diagnosed?

Clinically, with exclusion of other possibilities.

Definitive diagnosis only possible with biopsy, usually done post-mortem.

11

How many cases of Alzheimer's are due to clear mendelian inheritance?

Contrast these familial ADs with sporadic AD.

1-5%.

Earlier onset (<60-65yrs), with high penetrance, but otherwise identical to late-onset AD in presentation. Autosomal dominant!

12

Describe how APP contributes to Alzheimer's pathogenesis.

Why do patients with Down syndrome get AD in their 30s?

APP is a precursor that can be aberrantly cleaved by beta or gamma-secretase to form Aß, which accumulates in plaques, NFTs, amyloid angiopathy etc.

APP is located in chr 21; this can be thought of as a gene dosing effect.

 

13

Besides from trisomy 21, what genetic abnormalities comprise the small subset of familial AD?

Presenilin 1 (PSEN1; chr-14) is most common.

Amyloid precursor protein (APP; chr-14) may itself be mutated, but this is rare.

Presenilin 2 (PSEN2; chr-1) is very rare.

14

What gene can act as a risk factor for AD?

Which alleles are risk increase, or risk reducing?

APOE (on chr-19) encodes Apolipoprotein E. It is unclear how this affects Alzheimer's, but the E4 allele increases risk (especially if homozygous), while the E2 allele decreases risk.

15

Since Alzheimer's involves loss of cortical cholinergic neurons, name 3 treatments that can offset this to treat Alzheimer's.

What are their mechanisms of action?

What are their side effects?

Donopezil, Rivastigmine, Galantamine.

Centrally active cholinesterase inhibitors.

GI problems, muscle cramping, abnormal dreams, and SLUDGE.

16

Memantine

Indication?

Mechanism of action?

Side effects?

 

Memantine

For AD (maybe other neurodegeneratives, too)

Blocks the NMDA channel (reduced excitotoxicity)

Headache, dizziness.

17

What is the prototypical frontotemporal degeneration?

What subtypes of FTD are there?

Pick's disease.

Behavioral (involving both frontal lobes) and primary progressive aphasic (further split into PNFA and semantic, involving broca's and wernicke's areas?)

18

Describe the etiology of most FTDs; are they sporadic or inherited?

About half are sporadic.

Familial inheritance has been seen (AutDom) in Tau, progranulin, and C9orf72 (last two increase TDP-43)

19

What symptoms are seen in the behavioral subtype of FTD?

In the primary progressive aphasic subtypes?

Socially inappropriate behavior; impulsive, careless, without empathy. Sterotyped or ritualistic, possibly with hyperorality.

Generally aphasia of fluency or comprehension (recall the third type of aphasia, repetitive)

20

There are a couple of pathophysiologies of FTDs.

Describe pathology of FTD resulting from Tauopathies (eg Pick's disease)

"Knife-edge" frontal & temporal atrophy (spares parietal & occipital lobes), with abundant astrocytosis and round tau inclusions ("Pick bodies").

21

There are a couple of pathophysiologies that can cause FTD.

Describe the pathology of TDP-43 accumulation.

Very similar to that of Tauopathies; atrophic frontal & temporal lobes with TDP-43 cytoplasmic inclusions.

22

What are the classic four signs in Parkinsonism?

Name 2 conditions that can cause Parkinsonism.

TRAP; Tremor (resting, pill-rolling), Rigidity, Akinesia (or bradykinesia), Postural instability. Also mask facies, festinating gait?

There is a long list in the slides, but most important are Parkinson's disease and Lewy body dementia.

23

Name the 3 poles and 6 lobes of the cerebral cortex

Name the size layers of (most of) the cerebral cortex from outer-to-inner

Poles: frontal, occipital, and temporal

Lobes: Frontal, parietal, temporal, occipital, insular, and limbic

Layers (outer to inner)

  • Molecular
  • External granular
  • External pyramidal
  • Internal granular
  • Internal pyramidal
  • Multiform

24

What is the function of the unimodal association cortices? Heteromodal? Give an example of each.

Unimodal: integration of function from a single area (example: Visual association cortex)

Heteromodal: higher order information processing and integration of function from multiple sensory and/or motor modalities (example: prefrontal associated cortex)

25

Describe Papez's circuit

Cingulate --> hippocampus --> fornix --> mammillary bodies --> anterior thalamix nucleus --> cingulate

26

Describe the chief function of each:

Outer core cortical components

  • Cingulate cortex
  • Orbital frontal lobe
  • Temporal lobe (hippocampus, parahippocampus, entorhinal cortex)

Inner core subcortical components

  • Hypothalamus
  • Amygdala
  • Septum pellucidum

Outer core cortical components

  • Cingulate cortex - rostral: emotions and motor; caudal: visual spatial and memory
  • Orbital frontal lobe - personality, behavioral control, self-awareness
  • Temporal lobe (hippocampus, parahippocampus, entorhinal cortex) - memory

Innter core subcortical components

  • Hypothalamus - pleasure, autonomic, endocrine integration
  • Amygdala - preservation-of-self behaviors
  • Septum - preservation-of-species behaviors (sex)

27

Lesions of which structures lead to defects in declarative memory?

Describe the two major subcategories of declarative memory.

Lesions of: hippocampus, dorsal medial nucleus of the thalamus, and mamillary nuclei

Episodic: personal events in one's life, associated with a time and place

Semantic: facts, known rather than actively recalled (the capital of Spain, etc)

28

Name the brain structure most closely associated with the following types of memory

  • Explicit (declarative), including facts and events
  • Priming
  • Procedural (skills and habits)
  • Associative learning and conditioning - emotional responses
  • Associative learning and conditioning - skeletal musculature
  • Nonassociative learning - habituation and sensitization

  • medial temporal lobe
  • neocortex
  • striatum
  • amygdala
  • cerebellum
  • reflex pathways

29

"Executive function" is controlled primarily by what lobe?

Primitive emotional responses?

Storage of emotional memories?

Frontal cortex

Hypothalamus

Amygdala and hippocampus

30

The striatum/neostriatum include what two major structures of the basal ganglia?

The lenticular nuclei include what two major structures of the basal ganglia?

Caudate nucleus and putamen

Putamen and globus pallidus

31

What are the direct and indirect pathways in the basal ganglia?

Describe the purpose of D1 and D2 receptors on these pathways

Direct: facilitates movement; Indirect: inhibits movement

D1 receptors excite the direct pathway (facilitate movement)

D2 receptors inhibit the indirect pathways, which (disinhibits movement -> facilitates movement)

32

Describe the concept of selective vulnerability in neurodegenerative disorders

Give the selective vulnerability seen in each of the following:

  • Parkinson's disease
  • Alzheimer's disease
  • Huntington's disease
  • ALS

Neurodegenerative disease tends to involve functionally-related (rather than spatially-related) neurons and tracts

  • extrapyramidal system
  • cerebral cortex
  • extrapyramidal system
  • pyramidal system

33

Misfolded and/or aggregated proteins are a common cellular hallmark of several neurodegenerative diseases. Name the misfolded protein(s) associated with the following:

  • Alzheimer's disease
  • Parkinson's disease
  • Frontotemporal lobar degeneration
  • Huntington's disease

  • beta-amyloid and tau
  • alpha-synuclein
  • tau, ubiquitin, TDP-43
  • polyglutamine

34

Most neurodegenerative disorders can have both sporadic and familal forms. Which disease only has a familal form?

Huntington's disease (autosomal dominant)

35

Give some major etiologies and cellular mechanisms that are possible factors in the development of neurodegenerative diseases

General etiologies

  • genetic mutations
  • genetic polymorphisms
  • aging
  • environmental toxins

Cellular mechanisms

  • oxidative stress and ROS generation
  • Inflammation
  • axonal transport dysfunction
  • synaptic dysfunction
  • dysfunctional waste clearance (especially ubiquination)
  • Mitochondrial dysfunction
  • apoptosis

36

What about normal neuronal metabolism makes it especially susceptible to oxidative degradation?

Neuronal metabolism is all oxidative

37

What aspect of aging increases the oxidative burden to neuronal cells?

Progressive mitochondrial dysfunction - inefficient electron transport "leaks" electroncs, leading to additional oxygen radicals. Free radicals cause lipid peroxidation (the CNS contains a lot of lipid and cholesterol)

38

How is excess degeneration of ROS in neurons related to calcium? Why does this relationship contribute to even more damage of neuronal cells?

Why is this a vicious cycle?

Superoxide persistently activated NMDA receptors, increasing intracellular calcium. Increased intracellular calcium activates Ca-sensitive proteases, leading to cell damage and depletion of ATP (then apoptosis)

Ca-activated damage and ATP depletion leads to cell death, which releases glutamate, which further activated NMDA cells, leading to further excess calcium

39

What is the most common form of dementia

By what age will approximately 50% of all individuals be affected?

Alzheimer's disease

85 years old

40

Give the clinical definition of Alzheimer's Disease

Gradual and progressive decline in cognitive function with impairments in recent memory and one additional cognitive domain that is not due to other medical or psychiatric illness, and results in a functional impairment socially or occupationally

41

What cognitive domains are commonly affected by Alzheimer's disease?

Memory

Language

Abstract thinking and judgement

Visuo-spatial or perceptual skills

Praxis

Executive function

42

Give the diagnostic criteria for each of the following forms of Dementia of Alzheimer's Disease (DAT)

  • Definite DAT
  • Probable DAT
  • Possible DAT

  • Definite DAT
    • Clinical criteria of probable DAT
    • Histopathologic evidence (biopsy or autopsy)
  • Probable DAT
    • Dementia
    • Two areas of cognitive impairment
    • Progression over time
    • Normal sensorium
    • Age of onset @ 40-90 years old
    • No other disease contributing to dementia
  • Possible DAT
    • Atypical onset, presentation, progression without known etiology
    • Systemic or other brain disease capable of producing dementia present
    • Gradually progressive decline in single intellectual function in the ancsence of any other indentifiable cause

43

Parkinson's Disease

How is PD inherited?

 

What genes are implicated and what do they mean for the disease progression?

 

What other factors are associated with PD?

 

Parkinson's is mostly sporadic, though it can be inherited.  

Parkin gene- associated with young onset

a-synuclein gene- autosomal dominant inheritance

 

Manganese, Carbon Monoxide (?), Well-water, Paper Mills, Pesticide use, Hydrocarbons

Basically impure water it sounds like 

44

 

What are the four clinical features of Parkinson's Disease?

 

What are some non-motor symptoms seen in Parkinson's?

Clinical/Motor Symptoms

  1. Resting Tremor- usually pill rolling, but chin tremor is pathognomonic
  2. Rigidity- increased resistance to passive movement
  3. Bradykinesia- lack of arm swinging while walking, decreased blink rate, hypophonia
  4. Gait/Balance- leg dragging or stooped posture

Non-Motor

  1. REM sleep disorders
  2. Olfactory loss
  3. Dysautonomia

45

 

How is Parkinson's diagnosed?

 

What are some criteria that support a diagnosis of Parkinson's?

 

No definitive diagnosis available

 

Unilateral onset

Resting Tremor

Response to Levodopa

Course of 10 years of longer

46

 

What is seen on gross pathology in Parkinson's disease?

 

What is seen on histology?

 

Pallor of the substantia nigra, loss of neurons 

 

Lewy Bodies (eosinophilic cytoplasmic inclusions containing alpha-synuclein)

47

Dementia with Lewy Bodies

What are the three core features?

 

What are the three suggestive features?

 

How many of each are needed for a diagnosis of DLB?

Core Features

  1. Fluctuating cognition, consciousness
  2. Visual Hallucinations
  3. Parkinsonian Motor Signs

Suggestive Features

  1. REM sleep disorders
  2. Neuroleptic sensitivity 
  3. Low Dopamine Uptake in Basal Ganglia

 

1 core feature + 1 suggestive feature OR 2 core features

DLB IS VERY SIMILAR TO PD

48

 

What are the gross pathology findings in DLB?

 

What is seen on histology?

 

Substantia Nigra degeneration

 

Lewy bodies are seen in both the substantia nigra AND the cortex

 

49

 

What is the rationale behind Parkinson's treatment?

 

Why are these cells uniquely vulnerable?

 

Replacing dopamine to compensate for the death of dopamine producing neurons in the substantia nigra

 

When dopamine is metabolized by MAO, it produces free radical hydroxyls and ionized iron, which cause damage.

50

 

How is levodopa localized to the brain?

 

How is it metabolized into dopamine? 

 

Amino acid transporters move levodopa across the BBB

 

Any neuron expressing L-aromatic amino acid decarboxylase (L-AAAD) can metbolize it to dopamine

51

 

What two drugs is L-dopa taken with?

 

Why?

 

Only 2% of levodopa gets to the brain, mostly because it's metabolized by peripheral L-AAAD or COMT

 

Carbidopa- L-AAAD inhibitor that can not cross the BBB

Entacapone- COMT inhibitor (COMT is strictly peripheral)

52

 

 

What are some side effects of taking L-dopa?

 

What are some contraindications for L-dopa?

 

Nausea, hypotension, arrhythmias, or hypertension (figure that one out) 

DECREASED WHEN TAKEN WITH CARBIDOPA

 

Glaucoma, Psychosis, Arrhythmias, or Malignant Melanoma

53

 

What new class of drugs are used instead of L-Dopa to treat Parkinson's?

 

What advantages do they have?

 

Domaine Receptor Agonists 

Pramipexole, ropinerole- selective D2 agonists

Apomorphine- D4>>D2, D3, D5

 

  1. Longer half life than L-dopa
  2. Higher specificity than L-dopa
  3. No enzymatic conversion 
  4. No oxidative stress from L-dopa metabolism

54

What are five potential side effects of direct DA agonists?

  1. Nausea (esp. bromocriptine)
  2. Fatigue
  3. Daytime sleep attacks
  4. CNS toxicity
    • More confusion (avoid in elderly pts), less dyskinesia than L-DOPA
  5. Apomorphine can cause QT prolongation

55

  1. What is the logic behind using MAO inhibitors for Parkinson's?
  2. What is the significant drawback of MAOIs?
  3. How is this drawback circumvented?

  1. Since MAO breaks down dopamine and releases free radicals in the process, inhibiting with will increase DA and decrease oxidative stress on the neuron.
  2. However, MAO is also essential in the liver to metabolize tyramine, which is a sympathomimemtic. MAOIs will increase tyramine levels = possible adrenergic storm.
  3. There are two isoforms of MAO: MAO-A in the GI tract & liver, and MAO-B in the brain. Selective MAO-B blockers provide the dopaminergic effects without as many sympathomimetic side effects.

56

Name two drugs specific for the brain isoform of MAO.

Which isoform is that, again?

Selegiline & Rasagiline

MAO-B isoform

[B for brain!]

57

How are MAOI used within a treatment regimen for Parkinson's?

What possibly beneficial side effect do MAOIs also provide?

  • Usually prescribed as soon as disease is diagnosed. Modest benefit, generally well tolerated in early disease.
  • In advanced disease, it is coupled with L-DOPA to prolong its effective t1/2. Have to monitor, however - in very advanced cases, MAOIs can worsen the S/Es of L-DOPA (too much DA?)
  • Modest effect on disease progression.

Also an antidepressant (increases NE)

58

What are the adverse effects of MAOIs?

What about drug interactions to look out for?

  • Metabolized to amphetamine and methamphetamine - stimulant S/Es
    • Reduced when given orally or as a patch (avoids first-pass effect)
  • Can lead to Serotonin Syndrome when given with:
    • Meperidine
    • Tricyclic antidepressants
    • Serotonin reuptake inhibitors

59

What are the symptoms of serotonin syndrome?

  • Stupor
  • Rigidity
  • Agitation
  • Hyperthermia

60

What is the mechanism of action of COMT inhibitors?

Name two COMT inhibitors and compare them.

COMT also metabolizes DA. Similar to MAOIs, these drugs inhibit the metabolism of DA (as well as L-DOPA).

  • Drugs:
    • Tolcapone
      • Long t1/2, inhibits both peripheral and central COMT
      • Significant hepatotoxicity, used as a last resort
    • Entacapone
      • Short t1/2, low CNS penetration so co-administered with L-DOPA to inhibit peripheral metabolism (just like carbidopa)

61

What are the side effects of Tolcapone and Entacapone?

  • Nausea, orthostatic hypotension, vivid dreams, confusion, hallucinations
  • Tolcapone has significant hepatotoxicity! (last resort)

62

What is the rationale for using antimuscarinic drugs in Parkinson's?

Name three drugs in this class used for Parkinson's.

Cholinergic interneurons are typically inhibited by DA. The loss of DA causes overactivity in these excitatory neurons. This can be blunted with anticholinergics.

  1. Trihexyphenidyl
  2. Benztropine
  3. Diphenhydramine (anti-muscarinic "side effects")

63

When are antimuscarinic agents used for Parkinson's?

  • Third choice, after L-DOPA and DA agonists
  • Used when dopaminergic therapy is contraindicated
  • However, can be used with L-DOPA/DA agonists so that their dose can be lower

64

What are the side effects of antimuscarinic drugs?

  • Sedation, confusion
  • Atropine-like perihperal effects (nausea, loss of balance, dry mouth, photophobia, blurred vision, dizziness, etc.)

65

What is the mechanism of action of Amantadine?

When is it used to treat Parkinson's?

Increases DA release. Mild anticholinergic. Blocks NMDA receptors.

  • Typically given as an add-on with L-DOPA or with anticholnergics
  • Less effective and shorter-lived benefits than other drugs
  • Not useful when L-DOPA is ineffective

66

What are the side effects of amantadine?

In what condition is it contraindicated?

  • Dizziness, lethargy, sleep distrubances
  • Peripheral edema
  • Sympathomimetic effects (due to catecholamine release)

Contraindicated in pts with congestive heart failure (should make sense looking at the 2nd and 3rd bullets)

67

How is Huntington's Disease inherited?

How common is it?

Autosomal dominant

4-8 per 100,000

68

When do symptoms typically present in Huntington's Disease?

Describe the progression of the disease.

4th-5th decade

Symptoms progress over several decades. Complete motor disability and dementia approximately 20 years after symptom onset.

69

Mutation of what gene causes Huntington's Disease? On which chromosome?

What type of mutation is it?

What is the pathogenesis stemming from the mutation?

huntingtin gene on Chr. 4

Trinucleotide repeat (CAG) causes structual abnormalities within the protein.

Not clearly understood: perhaps a toxic gain of function and/or protein aggregation. Formation of intranuclear inclusions in the basal ganglia.

70

What are the major symptoms of Huntington's Disease?

  • Motor sxs:
    • Chorea
    • Often present first
  • Cognitive sxs:
    • Progressive dementia
    • May occur before motor sxs
  • Behavioral sxs:
    • Neuropsych sxs in 98% of sxs
    • 10% of pts attempt suicide

71

What brain structures are affected in Huntington's Disease?

How do these structures tie into the major symptoms of the disease?

  • Loss of medium striatal neurons in the caudate and putamen
    • Loss of basal ganglia results in increased motor activity: chorea
  • Neuronal loss in cerebral cortex
    • Cognitive and behavioral sxs

72

If you were to inspect the brain of a Huntington's Disease pt upon autopsy, what gross pathology would you see?

What about histologically?

  • Gross
    • Atrophy of caudate & putamen
    • Ventricular enlargement
    • Mild/moderate atrophy of gyri
  • Histological
    • Neuronal loss & astrocytosis (within the caudata & putamen)

73

Name three drugs used to treat the symptoms of Huntington's Disease.

Can we treat the disease itself?

Can only treat the symptoms.

  • Fluoxetine for depression
  • Low dose antipsychotics for delusions & paranoia
  • Tetrabenzine (inhibits the vesicular monoamine transporter, VMAT) for movement control

74

How common is amyotrophic lateral sclerosis?

How is ALS inherited?

Is there a sex predisposition?

1-5 out of 100,000

Most cases are sporadic. 5-10% are familial. Typically autosomal dominant.

Males > Females

75

Mutations in how many genes can lead to ALS?

What is the most commonly mutated gene?

14 genes have been described.

SOD-1 (superoxide dismutase-1)

Also TDP-43

76

What components of the nervous system are affected in ALS?

What symptoms results from degeneration in each area?

  • Lower motor neurons (anterior horn cells & axons)
    • Muscle atrophy, weakness, & fasciculations ("amyotrophy")
  • Upper motor neurons (corticospinal tracts in lateral columns)
    • Spastic tone, hyperreflexia, & Babinski sign
  • Bulbar dysfunction
    • Dysarthria, dysphagia
  • Primary motor cortex atrophy also possible

In summary: progressive weakness (pt cannot move, eat, speak, or eventually breathe) but sensation remains intact.

77

What important drug from the lecture is used to treat ALS?

How does it work?

  • Riluzole
    • NMDA channel inhibitor
      • Inhibits glutamate release
    • Modest but genuine effects on ALS
      • Increases life span 2-3 months

(Lecture said to know just that riluzole is indicated for ALS)