17.7 Dementia and degenerative disorders

Question 1

Alzheimer’s disease

-how to dx

Answer 1

• dx with clinical and pathological correlation
  1. clinical–diagnosis of exclusion
  2. pathology–requires autopsy

Question 1

Pick disease

-characterized by what, histologically

Answer 1

Pick bodies–round aggregates of tau protein in cortex neurons (as opposed to NFTs in alzheimers)

Question 2

Down’s syndrome

-assoc with what CNS disorder and why

Answer 2

Alzheimer’s

-the gene for APP (amyloid precursor protein) is on c21, so 3 c21s results in increased production

Question 2

Lewy bodies

Answer 2

-round, eosinophilic inclusions of alpha-synuclein in affected neurons. Characteristic of parkinson disease.

Also present in Lewy body dementia. Presence of cortical Lewy bodies

Question 3

Alzheimer’s disease

-morphologic features include: (4)

Answer 3

1. cerebral atrophy
2. neuritic plaques–comprised of AB amyloide with entangled neuritic processes
3. neurofibrillary tangles–intracellular aggregates of fibers composed of hyperphosphorylated Tau protein
4. loss of cholinergic neurons in the nucleus basalis of Meynert

Question 4

Parkinson’s disease

-etiology

Answer 4

-unknown. rare cases related to MPTP exposure (comtaminant found in illicit drugs)

Question 5

Alzheimer’s disease

-important to recognize absence of what symptom early in the disease?

Answer 5

Absence of focal neurologic defects early in disease.

Question 6

Creutzfeldt Jakob disease (CJD)

-prognosis

Answer 6

-Results in death, usu

Question 7

Huntington’s disease

-what brain pathways affected and how?

Answer 7

• Loss of GABAergic neurons in the caudate nucleus of basal ganglia
• these neurons inhibit the cortex movements, so loss of inhibition means uncontrolled movements.

Question 7

Creutzfeldt Jakob disease (CJD)

-characteristic diagnostic test finding

Answer 7

-EEG: periodic sharp waves

Question 8

Alzheimer’s disease

• divided into what 2 types
• what are their risk factors (2 each)

Answer 8

1. sporadic (95%)
   - age
   - E4 APOE allele higher risk, E2 is lower risk
2. Early-onset
   - Presenilin gene mutations
   - Down’s syndrome (b/c gene for precursor of A beta amyloid is on c21)

Question 8

Alzheimer’s disease

-mechanism

Answer 8

APP —> A beta amyloid (cannot be degraded)

–> alpha (can be recycled)

APP (amyloid precursor protein) is a receptor on neurons. Normally alpha cleavage results in degradable material, but beta cleavage results in accumulation of A beta amyloid.

Question 8

You see a pt with new clinical symptoms consistent with early Parkinson’s. She also has new dementia symptoms.

Think what?

Answer 8

Dementia is a late (years later) complication of Parkinsons.

early-onset dementia with parkinsonian symptoms suggests Lewy body dementia.

Question 9

Creutzfeldt Jakob disease (CJD)

-mech, etiology

Answer 9

• most common spongiform encephalopathy.
• usu sporadic, but can be transmitted through exposure to prion-infected tissue (eg human growth hormone, or corneal transplant)–infected with PrPsc (beta pleated conformation)

Question 10

Creutzfeldt Jakob disease (CJD)

-clinical symptoms (3)

Answer 10

• rapidly progressing dementia (weeks to months), and assoc with:
• ataxia (cerebellum)
• startle myoclonus–involuntary muscle contractions to minimal stimuli

Question 11

Parkinson’s disease

-clinical symptoms (4)

Answer 11

“TRAP”
Tremor–pill rolling, disappears with movement

Rigidity

Akinesia/Bradykinesia–slowing of movement

Postural instability, shuffling gait

Question 12

Tau protein

• function
• what diseases does it play a role (2)

Answer 12

microtubule associated protein important in the arrangement of cytoskeletal microtubules

1. Alzheimer’s–neurofibrillary tangles composed of hyperphosphorylated Tau
2. Pick disease–round aggregates of Tau protein (Pick bodies)

Question 13

Dementia

• most common cause
• second most common

Answer 13

1. alzheimer’s
2. vascular dementia (from global cerebral ischemia)

Question 14

Parkinson disease

-histology and gross appearance

Answer 14

gross: loss of pigmented neurons in substantia nigra
histology: Lewy bodies–round, eosinophilic inclusions of alpha-synuclein. In affected neurons

Question 15

Spongiform encephalopathy

-how can someone get this disease (3)

Answer 15

1. sporadic
2. inherited
3. transmitted

Question 16

Normal pressure hydrocephalus

-clinical presentation (3)

Answer 16

-increased CSF leads to dilated ventricles, which stretch the corona radiata, causes symptoms.

“Wet, wobbly, and wacky”

1. urinary incontinence
2. gait instability
3. dementia

Question 18

Pick disease

• disease affects what?
• clinical presentation

Answer 18

• degenerative disease of:
  1. frontal cortex–behavioral symptoms
  2. temporal cortex–language symptoms

eventually progresses to dementia.

“Picks” the frontal and temporal, not parietal and occipital.

Question 19

Mad cow disease

Answer 19

“Variant Creutzfeld Jakob disease”

-related to exposure to bovine spongiform encephalopathy

Question 21

Alzheimer’s disease

-neurofibrillary tangles

Answer 21

-intracellular aggregates of fibers, composed of hyperphosphorylated Tau protein

Question 22

Creutzfeldt Jakob disease (CJD) -gross appeaerance

Answer 22

-damage to neurons and glial cells results in intracellular vacuoles (spongy degeneration)

Question 23

Lumbar puncture improves symptoms of what?

Answer 23

Normal pressure hydrocephalus

Question 24

startle myoclonus - what is it - assoc with what disease (pathoma)

Answer 24

- involuntary muscle contractions with minimal stimuli - assoc with Creutzfeld Jakob disease (along with rapidly progressing dementia and ataxia)

Question 25

Huntington's disease - genetic inheritance pattern - what chromosome, describe genetics

Answer 25

- auto dom - expanded trinucleotide CAG repeats in huntingtin gene on c4. Anticipation--expansion of repeats occurs through spermatogenesis. Offspring experience Hungtinton's earlier in life.

Question 26

Vascular dementia -cause

Answer 26

result of moderate GCI--global cerebral ischemia -moderate GCI leads to multifocal infarct/injury due to HTN, atherosclerosi, or vasculitis

Question 27

Alzheimer's disease - clinical presentation over time (how do symptoms progress) - common cause of death?

Answer 27

- Slow-onset memory loss, starts with short term and then long term memory loss with progressive disorientation - loss of motor skills, language - changes in bx and personality - mute and bedridden - infection is common cause of death

Question 28

Familial fatal insomnia

Answer 28

- inherited form of prion disease - charaterized by severe insomnia, exaggerated startle response

Question 30

Dementia, Degenerative disorders -general principles

Answer 30

(see picture) Typically due to loss of gray matter neurons from accumulation of protein that damages neurons - degeneration of gray matter in cortex leads to dementia - gray matter in brainstem and basal ganglia leads to movement disorders

Question 31

Normal pressure hydrocephalus -tx

Answer 31

- Must reduce CSF to reduce pressure. Use ventriculoperitoneal shunting of CSF. (note: LP decreases symptoms )

Question 33

APOE

Answer 33

Apolipoprotein E - This is associated with Alzheimer's disease, sporadic type - APOE E4 allele increases risk - APOE E2 decreases risk

Question 34

Spongiform encephalopathy -describe mech/etiology

Answer 34

- degnerative disease due to prion protein - PrP usually in alpha-helical formation (PrPc) - however, disease occurs with beta-pleated formation (PrPsc) PrPsc protein is not degradable and converts normal PrP to PrPsc, causing vicious cycle.

Question 36

Presenilin

Answer 36

gene assoc with Alzheimer's disease, early-onset type. -mutations in presenilin increase risk

Question 37

Huntington's disease - clinical presentation (early vs later symptoms) - average age of 1st presentation? - common cause of death

Answer 37

- early: chorea and athetosis (slow, involuntary snake like movements) - Later: progresses to dementia and depression - 40 yo is average age suicide is common cause of death

Question 38

Alzheimer's disease - neuritic plaques--what are they - where else can amyloid deposit?

Answer 38

- Plaques with extracellular core comprised of AB amyloid with entangled neuritic processes - Amyloid may deposit around vessels, increasing risk of hemorrhage ("Cerebral Amyloid Angiopathy")

Question 39

Parkinson's disease -mechanism and neural pathways to know

Answer 39

(see picture) Basal ganglia striatum modulates cortex movements through: 1. stimulatory signals (with D1 receptors) 2. nhibitory receptors (with D2 receptors) Substantia nigra uses DA to initiate movement--it increases stimulation and decreases inhibition of cortex movement. (nigrostriatal pathway) Degenerative of dopaminergic neurons of substantia nigra results in inability to initiate movements

Question 40

Normal pressure hydrocephalus -mech, etiology

Answer 40

- caused by a decrease in arachnoid granulations, which move CSF into venous space, causing backup of CSF into ventricles - expanded ventricles push on corona radiata, resulting in symptoms (wet, wobbly, wacky)

Question 41

Parkinson disease -does it cause dementia?

Answer 41

Yes, dementia is a common feature of late disease, years later

Question 42

Lewy body dementia - clinical presentation - how does this compare with Parkinson's?

Answer 42

-dementia, hallucinations, parkinsonian features. Early-onset dementia is suggestive of Lewy body dementia and not Parkinson's.