Neurodegenerative Disorders

Question 1

What does cortial degeneration lead to?

Answer 1

Dementia

Question 2

What does basal ganglia degeneration lead to?

Answer 2

Movement disorders

Question 3

What does spinocerebellar degernation lead to?

Answer 3

Ataxia

Question 4

What does moto neuron degeneration lead to?

Answer 4

Upper and lower motor neuron weakness

Question 5

What are 3 mechanisms in which protein aggregates can cause neurodegernative disease?

Answer 5

Sequester proteins from their normal function; Obstruction of axons by aggregates; Ubiquitin sinks sequestering ubiquitin that cannot be recycled

Question 6

What is the most common dementia in elderly?

Answer 6

Alzheimer Disease

Question 7

A brain shows cortical atrophy and Alzheimer Disease is Dx. What changes in the ventricles are seen? What histologic findings can be ssen?

Answer 7

Hydrocephalus ex vacuo; Senile plaques and neurofibrillary tangles

Question 8

What are the most conspicuous histologic lesions in an Alzheimer brain? Where within the cell are these plaques located?

Answer 8

Neuritic plaques of Beta-amyloid; They’re extracellular!

Question 9

What are the two major lesions found in Alzheimer Disease?

Answer 9

Neurofibrillary tangles and neuritic plaques

Question 10

What are neurofibrillary tangles made of? Where are they located in Alzheimer Disease?

Answer 10

Tau protein; Intracellularly

Question 11

A histological section of an Alzheimer brain shows the following morphology. What is this structure? What is the relationship betwixt this structure and Alzheimer Disease?

Answer 11

Intracytoplasmic Neurofibrillary Tangle; The sites and degrees of distribution of NFTs correlates with clinical Syx;

Question 12

What chromosomal abnormality is associated with Alzheimer Disease?

Answer 12

Trisomy 21

Question 13

What larger protein is cleaved to form ABeta?

Answer 13

APP

Question 14

Mutations in what three genes result in increased risk of Alzheimer disease?

Answer 14

APP, Apoliporpotein E, and Presenilin (PS1 and PS2)

Question 15

Given the chromosome, name the gene and the Alzheimer disease associated

1. 21
2. 14
3. 1
4. 19

Answer 15

1. Amyloid Precursor Protein (Early-Onset Familial Alzheimer Disease)
2. Presenilin 1 (Early-onset familial Alzheimer Disease
3. Presenilin 2 (Volga German Familial Azheimer Disease)
4. Apolipoprotein E (epsilon4 allele increased risk of both inherited and sporadic forms of late-onset Alzheimer Disease)

Question 16

A previously intelligent and reserved man has become disruptive and inappropriate over the past 3 years. He expires. What type of degeneration did he likely experience? What are typical lesions of a brain with this disorder?

Answer 16

Pick Disease Complex; Knife-Edge Atrophy of the frontotemporal regions.

Question 17

A patient expires. Below is a histological section of the patient. The patient had Pick Disease Complex. What are the histological findings?

Answer 17

Pick bodies; Intracytoplasmic intraneuronal aggregates of tau protein.

Question 18

A patient is found to have intracytoplasmic Alpha-synuclein. What disease does he have? What is his clinical presentation? What part of the brain is primarily affected?

Answer 18

Lewy Body Dementia; Fluctuating daily cognitive function; Cingulate Cortex

Question 19

What is the triad that is commonly seen in Parkinson Disease?

Answer 19

Difficulty initiating and sustaining voluntary movement, resting tremor and postural instability

Question 20

What are the prototypical bradykinetic and hyperkinetic basal ganglia degeneration diseases?

Answer 20

Parkinson and Huntington, respectively

Question 21

Describe the typical presentation of a person with Huntington Disease

Answer 21

Involuntary rapid twitching movements (chorea) and writhing dance-like movements (athetosis)

Question 22

Where is there loss of pigmentation in a Parkinson brain?

Answer 22

In the substantia nigra and locus coeruleus

Question 23

Below is a histologic section of a Parkinson brain. What is the artifact shown below? What is within it?

Answer 23

Lewy Body; Alpha-synuclein

Question 24

What is MPTP? What can it cause?

Answer 24

It is a contaminant of illicit meperidine synthesis which is metabolized by the brain’s MAO creating a free radical that damages the brain; It causes parkinsonism

Question 25

What is Multiple System Atrophy?

Answer 25

Filamentous Alpha-synuclein inclusions (glial cytoplasmic inclusions) accumulate in oligodendroglia

Question 26

What are the hallmarks of Progressive Supranuclear Palsy (PSP)? What are the inclusions?

Answer 26

Atrophy of the midbrain tegmentum leading to exaggerated contribution of the cerebral peduncles to the profile of the midbrain in axial sections resulting in parkinsonism and verticle gaze dysfunction; Tau-rich NFTs!

Question 27

A patient expires and the brain autopsy is shown below. The caudate nuclei show atrophy and the lateral ventricles are enlarged. What is your Dx? At what age were Syx likely seen? What age did this patient likely die?

Answer 27

Huntington Disease; 40 yo; 55 yo (life expectancy following onset of Syx is 15 y)

Question 28

What gene is mutated in Huntington Disease? What type of mutation? What determines severity of the disease?

Answer 28

Huntingtin; CAG repeat toxic gain of function mutation; Inherited from father causes greater severity of diease, the greater the number of repeats, the worse the phenotype

Question 29

What is the most common cause of mental rtardation in boys? What is the most common adult onset muscular dystrophy? What is the most common hereditary spinocerebellar ataxia? What do they all have in common?

Answer 29

FXS; Myotonic Dystrophy; Friedreich Ataxia; They are all nucleotide expansion syndromes

Question 30

A 25 yo patient presents with ataxia of both the upper and lower limbs, dysarthria, lower limb areflexia, extensor plantar reflex and sensory loss. Below is what his spinal cord looks like! What is the Dx? What is demyelinated in this disease? What type of ataxia is this?

Answer 30

Friedreich ataxia; Dorsal columns, lateral corticospinal tract, spinocerebellar tract; Inflow ataxia

Question 31

What type of inheritance is Friedreich Ataxia? What gene is mutated? What type of mutation? What determines disease severity?

Answer 31

Autosomal recessive; Frataxin; Unstable Expansion of trinucleotide GAA; The number of trinucleotidee repeats

Question 32

A patient presents claiming that they had left hand weakness and muscle wasting. He also stated that he had muscle twitches. Although his speech becomes unintelligible and breathing becomes difficult, his intellectual capacity remains the same. Shown in the image is his spine. What is your Dx?

Answer 32

Amyotrophic Lateral Sclerosis;

Question 33

What mutation occurs in ALS? What neurons are affected in ALS? What is the defining histologic change in ALS?

Answer 33

Missense mutation in the gene that codes for cytosolic Superoxide Dismutase; Lower Motor Neurons, Anterior Horn Cells of Spinal Cord, Motor Nuclei of Brainstem, UMN of cerebral cortex; Loss of large motor neurons and mild gliosis

Question 34

What disease is caused by a loss-of-function mutation of a neuronal apoptosis inhibitor protein resulting in neurons having an extremely low threshold for initiating programmed cell death?

Answer 34

Spinal muscular atrophy (Werdnig-Hoffman Disease)