Patho of Dementia

Question 1

Alzheimer’s Disease - Familial Type
1. Early Onset
(<___ years old):

• ___ gene, ___-1, ____-2
• Account for only ____% of AD cases
• ____ (amyloid precursor protein) gene is on chromosome ___
• Normal protein function is ___
• Patients with __ ___(trisomy 21) develop dementia in ____ age. The amyloid precursor protein (APP) gene is located on Cr. ___

APP Protein

• Aβ peptides aggregate in tissue as ___ (amyloid), eliciting a ___ response in ___ and ___
• _____ tau protein is also present in AD

There is marked Atrophy w/ ___ ex Vacuo
2. Late Onset

(approximately ___ years earlier than nonfamilial Alzheimer’s):

• ___ alleles (chr ___)
• Most common form of familial AD
• Susceptibility factor

Answer 1

Alzheimer’s Disease - Familial Type
1. Early Onset
(<60 years old):

• Presenilin gene, PSEN-1, PSEN-2
• Account for only 0.1% of AD cases
• APP (amyloid precursor protein) gene is on chromosome 21
• Normal protein function is unknown
• Patients with DS (trisomy 21) develop dementia in middle age. The amyloid precursor protein (APP) gene is located on Cr. 21

APP Protein

• Aβ peptides aggregate in tissue as beta-pleated hseet (amyloid), eliciting a toxic response in astrocytes and microglia
• Hyperphosphorylated tau protein is also present in AD

There is marked Atrophy w/ hydrocephalus ex Vacuo

2. Late Onset

(approximately 5 years earlier than nonfamilial Alzheimer’s):

• ApoE4 alleles (chr 19)
• Most common form of familial AD
• Susceptibility factor

Question 2

Plaques and Tangles in AD:

Neuritic Plaques - Composed of ___ neurites and ____

• ____and ____ associated with ___ fibrils with a central core of __-____
• Increase in number with age

Distribution of neuritic plaques: Heavy involvement of h___, association cortex, posterior__ __ (memory of spatial awareness), and amygdala with relative sparing of primary ___, ___, and visual cortices. This is why you don’t see any sensory/motor loss in these pts

Neurofibrillay Tangles “___ shape” - Hyper-phosphorylated ___ protein

• Difficult to ___ ____ - can persist as “ghosts” after neuron dies

Answer 2

Plaques and Tangles in AD:

Neuritic Plaques - Composed of dystrophic neurites and mitochondria

• Astrocytes and microglia associated with amyloid fibrils with a central core of beta-amyloid
• Increase in number with age

Distribution of neuritic plaques: Heavy involvement of hippocampus, association cortex, posterior cingulate gyrus, and amygdala with relative sparing of primary sensory, motor, and visual cortices. This is why you don’t see any sensory/motor loss in these pts

Neurofibrillay Tangles ‘flame shape” - Hyper-phosphorylated tao protein

• Difficult to break down - can persist as “ghosts” after neuron dies

Question 3

**Vascular Dementia

• results in multiple ____ infarcts and/or chronic ischemia.**
• __-___ decline in cognitive ability with late onset memory impairment.
• ___ most common cause of dementia in the elderly
• Preventable by treating predisposing conditions.

MRI shows multiple in farcts in:

• ___
• ___
• ___

Answer 3

Vascular Dementia

• results in multiple arterial infarcts and/or chronic ischemia.
• step-wise decline in cognitive ability with late onset memory impairment.
• 2nd most common cause of dementia in the elderly
• Preventable by treating predisposing conditions.

MRI shows multiple in farcts in:

• cortical
• subcortical
• lacunar

Question 4

Synucleinopathies

• *1. Parkinsons**
• About ____% of patients with PD have clinically significant dementia.
• *2. Lewey Body Disease**
• Lewey body dementia: in addition to ___ Lewy bodies, similar inclusions are present in ___ neurons. ___ Lewy bodies are seen in Dementia with Lewy Bodies, not ____’s Disease!!!

3. Lewey Related Neurites

Lewy Bodies: Positive for α-synuclein

• ____ core surrounded by pale halo
• Found in ___ ___ in Parkinson’s disease
• Also seen in the ___ in Dementia with Lewy bodies

Answer 4

Synucleinopathies

• *1. Parkinsons**
• About 20% of patients with PD have clinically significant dementia.
• *2. Lewey Body Disease**
• Lewey body dementia: - in addition to brainstem Lewy bodies, similar inclusions are present in cortical neurons. Cortical Lewy bodies are seen in Dementia with Lewy Bodies, not Parkinson’s Disease!!!

3. Lewey Related Neurites

Lewy Bodies: Positive for alpha-synuclein

• Eosinophilic core surrounded by pale halo
• Found in substantia nigra in Parkinson’s disease
• Also seen in the cortex in Dementia with Lewy bodies

Question 5

Tauopathies:

1. __ __ and ___ linked to chromosome 17 (FTDP-17)
   - Group of autosomal ___, ____-onset, progressive neurodegenerative syndromes linked to chromosome 17q21-22 (___ gene).

• ___ disturbances, ___ impairment, and parkinsonism in varying combinations and in varying degrees of severity
• ____ of Aβ amyloid deposits, NFTs, or other disease-specific abnormalities
• Extensive deposition of intracellular ____ ___ protein in neurons and glia

2. ____ disease

• ____ atrophy: ____temporal
• Atrophy of ___ described as “__-___”
• Affects ____ limbic areas
• Atrophy may be ____
• Neuronal loss and ____ of outer layers of cortex, caudate nucleus, thalamus
• Gliosis of ___ ___ matter
• Spongiform change
• ____ bodies

–____ inclusions

–____+

3. ____ degeneration

4. ___ ___ palsy

5. _____ parkinsonism

Answer 5

Tauopathies:

1. Frontotemporal dementia and Parkinsons linked to chromosome 17 (FTDP-17)
   - Group of autosomal dominant, adult-onset, progressive neurodegenerative syndromes linked to chromosome 17q21-22 (Tao gene).

• Behavioral disturbances, cognitive impairment, and parkinsonism in varying combinations and in varying degrees of severity
• Lack of Aβ amyloid deposits, NFTs, or other disease-specific abnormalities but extensive deposition of intracellular hyperphosphorylated tao protein in neurons and glia

2. Pick’s disease

• Lobar atrophy: frontotemporal
• Atrophy of gyri described as “knife-edge”
• Affects anterior limbic areas
• Atrophy may be asymmetric
• Neuronal loss and gliosis of outer layers of cortex, caudate nucleus, thalamus
• Gliosis of subcortical white matter
• Spongiform change
• Pick bodies

–intracytoplasmic inclusions

–Tao+

3. PSP

4. Post excephalitic palsy

5. _____ parkinsonism

Question 6

**Dementia caused by Infectious Diseases

Dementia caused by HIV encephalopathy**

• HIV-associated dementia persists despite _____
• ____nodules and multinucleated __ ___ near __ ___
• Involves ____ matter, ____, and ____

Tertiary syphilis

• Progressive mental deterioration (paretic dementia), seizures, death
• Cerebral atrophy with thickened _____
• ____ neuronal loss and ___
• ___ and ___ inflammation
• Microglial proliferation that forms ___ ____.

CJD
Transmission

1. __to ___:
   - Contaminated neurosurgical instruments and EEG electrodes
   - Transplant (dura, cornea)
   - Human growth hormone
   - Blood transfusion (vCJD)
2. ___-to-human:
   - Oral transmission via contaminated meat (BSE)

• *Pathology:**
  1. ___ loss and __

2. ____ change
3. ____ plaques in _____ (10% of cases)
4. No ___ or ____ reaction - why?
   B/C it is a protein that is not recognized as foreign by the body

• *Presentation:**
  1. _____ progressive dementia (this is very unique to CJD)

2. Progression to death is ___, usually in less than __ year
3. Other symptoms – m____, ataxia, ___ abnormalities, m___

Types:

–____l: 10-15% of cases

–____ (sCJD) –> average age __

–_____ (vCJD):

•Bovine spongiform encephalopathy (“mad cow disease”) transmitted to humans –> average age ____

–____: caused by medical treatment

• *Tests:**
  1. ___ and __abnormalities

2. CSF: __-__-___ protein –> Increased levels in over 80% of cases of sCJD
3. Presence in ____ indicative of CJD, but not 100% specific

What are prions?
Prions Prion = proteinaceous infectious particle

___ ___ mutations in the PrP gene have been found in familial cases of CJD, GSS (Gerstmann-Sträussler-Scheinker), and FFI (familial fatal insomnia)

Function of normal PrP is unknown

Normal conformation (PrPc) is ___, which is changed to ___ in disease state (PrPp)

Abnormal prion protein facilitates ____ change in normal PrP molecules, which accumulate in the tissue

Abnormal prion protein form is relatively___ to digestion by proteases.

Answer 6

**Dementia caused by Infectious Diseases

Dementia caused by HIV encephalopathy**

• HIV-associated dementia persists despite HAART
• microglial nodules and multinucleated giant cells near perivascular vessels
• Involves white matter, diencephalon, and brainstem

Tertiary syphilis

• Progressive mental deterioration (paretic dementia), seizures, death
• Cerebral atrophy with thickened meninges
• Cortical neuronal loss and gliosis
• Meningial and perivascular inflammation
• Microglial proliferation that forms rod shapes

CJD

Transmission

1. human to human:
   - Contaminated neurosurgical instruments and EEG electrodes
   - Transplant (dura, cornea)
   - Human growth hormone
   - Blood transfusion (vCJD)
2. cattle-to-human:
   - Oral transmission via contaminated meat (BSE)

• *Pathology:**
  1. neuronal loss and gliosis

2. spongiform change
3. Amyloid plaques in cerebellum (10% of cases)
4. No immune rxn or inflammation - why?
   B/C it is a protein that is not recognized as foreign by the body

• *Presentation:**
  1. rapidly progressive dementia (this is very unique to CJD)

2. Progression to death is rapid, usually in less than one year
3. Other symptoms – myoclonus, ataxia, visual abnormalities, mutism

Types:

–familial: 10-15% of cases

–sporadic (sCJD) –> average age 65

–variant (vCJD):

•Bovine spongiform encephalopathy (“mad cow disease”) transmitted to humans –> average age 27

–iatrogenic: caused by medical treatment

• *Tests:**
  1. EEG and MRI abnormalities

2. CSF: 14-3-3 protein –> Increased levels in over 80% of cases of sCJD
3. Presence in CSF indicative of CJD, but not 100% specific

What are prions?
Prions = proteinaceous infectious particle

Autosomal dominant mutations in the PrP gene have been found in familial cases of CJD, GSS (Gerstmann-Sträussler-Scheinker), and FFI (familial fatal insomnia)

Function of normal PrP is unknown

Normal conformation (PrPc) is alpha-helix, which is changed to beta pleated sheets in disease state (PrPp)

Abnormal prion protein facilitates conformational change in normal PrP molecules, which accumulate in the tissue

Abnormal prion protein form is relatively resistant to digestion by proteases.

Question 7

Clinical syndrome of Wernicke’s Encephalopathy:
D___

N___

G__

Alcoholism or other settings associated with poor nutrition

____ (B1) deficiency - Treat with ___ (IV) thiamine

• In thiamine-deficient patients, giving ____ without thiamine can precipitate ____’s encephalopathy
• Untreated – fatal in 20% and leads to ____ syndrome in ___% of survivors

Korsakoff’s Syndrome - a result of ___

Amnestic syndrome:

• Retrograde amnesia (loss of past memories)
• Anterograde amnesia (inability to learn)
• Confabulation

Loss of neurons in the __ __ nucleus of the thalamus.

Answer 7

Clinical syndrome of Wernicke’s Encephalopathy:
Delirium

Nystagmus

Gait ataxia

Alcoholism or other settings associated with poor nutrition

Thiamine (B1) deficiency - Treat with parentral (IV) thiamine

• In thiamine-deficient patients, giving glucose without thiamine can precipitate wernicke’s encephalopathy
• Untreated – fatal in 20% and leads to korsakoff syndrome in 85% of survivors

Korsakoff’s Syndrome - a result of WE

Amnestic syndrome:

• Retrograde amnesia (loss of past memories)
• Anterograde amnesia (inability to learn)
• Confabulation

Loss of neurons in the medial dorsal nucleus of the thalamus.