Neurodegenerative Disease

Question 1

Alzheimer Disease

1. Age
2. symptom progression
3. proteins involved:
4. pathologic hallmarks:

Answer 1

Alzheimer Disease

1. Age: older adults
2. symptom progression: memory, visuospatial orientation, judgement personality and language
3. proteins involved: Aß and Tau
4. pathologic hallmarks:
   
   1. ​plaques- deposits of aggregated Aß peptides in neuropil
   2. Tangles- aggregates of microtuble binding protein tau

Question 2

AD

1. Amyloid beta is formed by:
2. what is a characteristic of this protein?
3. what is the precursor protein
   
   1. what chromosome is it on?

Answer 2

AD

1. Amyloid beta is formed by: Beta-secretase
2. what is a characteristic of this protein? its very sticky so it is prone to aggregation
3. what is the precursor protein: Amyloid Precursor Protein
   
   1. what chromosome is it on? 21- especially important in patients with down syndrome because they have 3 copies of theis chromosome

Question 3

AD

1. what is Tau?
   
   1. what is it a component of?

Answer 3

AD

1. Tau is a microtubule associated protein that is present in axons
   
   1. Tau is a component of neurofibrillary tangles which lead to neuronal damage

Question 4

AD

1. Other Genetic Factors:

Answer 4

AD

1. Other Genetic Factors:
   
   1. Apolipoprotein E (ApoE) - promotes the generation of amyloid beta and its deposition
   2. conveys 25% of the risk for late-onset AD

Question 5

AD- Molecular Genetic and Pathogenesis

1. What role does inflammation play?
2. What biomarkers correlate to dimentia?

Answer 5

AD- Molecular Genetic and Pathogenesis

1. inflammation elicided by both small and large Amyloid beta from microglia and astrocytes may increase clearance of peptides, but also increase mediators that cause damage
   
   1. the inflammatory effect worsens the disease state
2. Neurons are subjected to oxidative injury

Question 6

AD

How can we identify preclinical AD?

Answer 6

Preclinical AD can be found by using radio labeled amyloid binding proteins to identify A beta deposition in the brain

we can also see an increase in phosphorylated tau

as wel as Reduced Amyloid beta in the CSF

**the goal is to catch AD early and focus on pharmacologic decrease in progression

Question 8

AD

Histology findings gross/microscopic

Answer 8

in AD we have a variable degree of cortical atrophy marked by widening of the cerebral sulci, most pronounced in the frontal, temporal, and parietal lobes. With this atrophy, we will often have compensatory ventriular enlargement (hydrocephalous ex vacuo) secondary to the reduced brain enlargement.

Microscopically we will see plaques and tangle

Question 9

Answer 9

A plaques

B plaques (IHC)

C tangle within a neuron

D tangle on a silver stain

tangle (IHC)

Question 10

What disease is this?

Answer 10

AD

Characteristic widening of the sulci because of the loss of gyri in the frontal and temporal lobes

Question 11

Clinical Features of AD

Answer 11

Clinical features

1. slow but relentlessly progressie
2. asymptomatic course lasting 10+ years
3. initial symptoms are forgetfullness and memory loss
4. progressive symptoms include the prior and addition of language deficits, loss of mathematics skills, loss of learned motor skills
5. Final stages include incontinence, mute, little motor skills
6. Terminal event is often pneumonia

Question 12

Frontotemporal Lobar Degenerations (FTLD)

1. progression of symptoms
2. one of the more common causes of _____.

Answer 12

Frontotemporal Lobar Degenerations (FTLD)

heterogeneous set of disorders associated with focal degeneration of frontal and/or temporal lobes

1. progression of symptoms
   
   1. personality, behavior and language (aphasia) preceed memory loss
      
      1. memory alterations occur last (compared with AD when memory loss is first)
2. one of the more common causes of early dimentia.

Question 13

FLTD- Tau (Broad Category)

1. histology
2. Under the broad category, a specific stereotypic lobar distribution and distinctive inclusions can be seen. What is this disease called?

Answer 13

FLTD- Tau (Broad Category)

affected cortical regions demonstate progressive neuronal loss and reactive gliosis, along with the presence of tau-containing inclusions in the cytoplasm of neurons

1. histology: only shows Tau (AD has both amyloid beta and Tau)
2. Under the broad category, a specific stereotypic lobar distribution and distinctive inclusions can be seen. What is this disease called? Pick Disease

Question 14

Pick Disease

1. definition
2. histologically:

Answer 14

Pick Disease

1. definition: brain invariable shows a pronounced, frequently asymmetric atrophy of the frontal and temporal lobes with sparing of the posterior 2/3 of the superior temporal gyrus and only rare involvement of either the parietal or occipital lobe.
2. histologically: surviving neurons are characteristically swollen (Pick Cells) and show cytoplasmic, round to oval filamentous inclusions athat stain strongly with silver stain

Question 15

What is this?

Answer 15

Asymmetric atrophy of the frontal and temporal lobes associated with FLTD

Question 16

What is this?

Answer 16

1. A- FTLD tau. a tangle is present with numberous tau containing neurites
2. B- Pick disease. The pick cells are round, homogenous neuronal cytoplasmic inclusions that stain intensely with silver stain
3. C- FTLD
4. D- FTLD

Question 17

Parkinson Disease

1. Clinical syndrome

Answer 17

Parkinson Disease

marked by a prominent hypokinetic movement disorder that is caused by loss of dopaminergic neurons fro the substantia nigra

1. Clinical syndrome:
   
   1. diminished facial expression
   2. stooped posture
   3. slowing of voluntary movements
   4. festinating gait
   5. rigidity
   6. pill-rolling tremor

Question 18

PD

1. What is the triad of symptoms upon which a diagnosis of PD can be based?
2. How is diagnosis of PD confirmed?
3. Severity of symptoms is proportional to the extent of_______

Answer 18

PD

1. A dx of PD can be presumed by tremor, rigidity, and bradykinesia
2. How is diagnosis of PD confirmed? symptomatic response to L-DOPA
3. Severity of symptoms is proportional to the extent of dopamine deficiency

Question 19

PD

1. Most forms are ______
2. where does neuronal loss occur?

Answer 19

PD

1. Most forms are sporadic
2. where does neuronal loss occur? Substantia nigra

Question 20

PD- AD form

1. what protien is mutated?
2. what type of mutation typically occurs
3. this protein is a major component of _________.

Answer 20

PD- AD form

1. what protien is mutated? alpha- synuclein
2. What type of mutation typically occurs: point mutation
3. this protein is a major component of lewy bodies.
   
   1. lewy bodies are a diagnostic hallmark of PD

Question 21

PD

1. Contributing factors:

Answer 21

PD

1. Contributing factors:
   
   1. Mitochondrial dysfunction
   2. mutations in the gene LRRK2
      
      1. more common cause of AD PD

Question 22

PD

1. Morphologic findings:

Answer 22

PD

1. Morphologic findings:
   
   1. pallor of the substantia nigra and locus ceruleus secondary to loss of pigmented catecholaminergic neurons
   2. Lewy Bodies my be found in remaining cells

Question 23

What is this?

what is normal?

Answer 23

Pallor of the SN

Question 24

what is this?

what is it characteristic of?

Answer 24

Lewey body!

characteristic finding of PD

Question 25

Dementia with Lewy Bodies

1. histologic correlate
2. What are lewy neurites?
3. Characteristic findings:

Answer 25

Dementia with Lewy Bodies

1. histologic correlate: widespread lewy bodies in neurons in the cortex and brainstem
2. What are lewy neurites? abnormal neurites (axon or dendrite) that contain alpha-synuclein
3. Characteristic findings of dementia:
   
   1. fluctuating course
   2. Hallucinations
   3. prominent frontal signs

Question 26

Atypical Parkinsonism Syndromes

1. How do we distinguis Atypical Parkinsonism Syndrome from PD?

Answer 26

Atypical Parkinsonism Syndromes

reflectes relative dysfunction in dopaminergic nigrostriatal projection

1. How do we distinguis Atypical Parkinsonism Syndrome from PD?
   
   1. minimally responsive to L-DOPA treatment
   2. additional signs andd symptoms:
      
      1. progressive supranuclear palsy
      2. corticobasal degeneration
      3. multiple system strophy

Question 27

Atypical PD

1. Progressive supranuclear palsy
   
   1. signs/symptoms
   2. histology

Answer 27

Atypical PD

1. Progressive supranuclear palsy
   
   1. signs/symptoms
      
      1. truncal rigidity, disequilibrium with frequent falls and difficulty with voluntary eye movements
      2. 2x more common in males
      3. often fatal w/in 5 yrs
2. Histology:
   
   1. presence of tau-containing inclusions in neurons and glia
   2. widespread neuronal loss in the globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqeductal grey matter, and dentate nucleus of the cerebellum

Question 28

Atypical PD- Corticobasal degeneration

1. Characteristics
2. histology:

Answer 28

Atypical PD- Corticobasal degeneration

1. Characteristics:
   
   1. progressive tauopathy
   2. extrapyramidial rigidity
   3. asymmetric motor distrurbances
   4. impaired higher cortical function
   5. cognitive decline in later disease state
2. histology:
   
   1. cortical atrophy, mainly of the motor, premotor and anteriaor parietal lobes
   2. severe loss of neurons, gliosis, and ballooned neurons
      3.

Question 29

Atypical PD- Multiple system atrophy

1. 3 tracts that are involved
2. histology

Answer 29

Atypical PD- Multiple system atrophy

1. 3 tracts that are involved
   
   1. striatonigral circuit (leads to parkinsonism)
   2. olivopontocerebellar circuit (leads to ataxia)
   3. autonomic nervous system (leading to autonomic dysfunction, ith orthostatic hypotension as a prominent component)
2. histology:
   
   1. typically observed in glial cells and is commonly associated with degeneration of white matter tracts
   2. alpha-synuclein