Neurodegenerative Diseases of the CNS

Question 1

Neurodegenerative disorders are (curable or incurable?) and debilitating conditions which result in ______________ of nerve cells

Answer 1

incurable

progressive degeneration

Question 2

Neurodegenerative disorders

Many are associated with the _____________ which serve as histologic hallmarks of certain disorders

Answer 2

accumulation of abnormal proteins

Question 3

Neurodegenerative disorders

The clinical manifestation is usually dictated by the area of the brain affected:
○Cortical neurons - ________
○Basal ganglia - _______
○Cerebellum - ________________

Answer 3

○Cortical neurons - dementia
○Basal ganglia - movement
○Cerebellum - ataxia

Question 4

Neurodegenerative disorders

Protein Diseases with inclusions

Aβ

TPD-43

α-synuclein

Polyglutamine aggregates

Answer 4

Alzheimer disease

Frontotemporal lobar degeneration; Amyotrophic lateral sclerosis

Parkinsons disease

Huntington disease

Question 5

Neurodegenerative disorders

Protein Diseases with inclusions

Tau

Answer 5

Alzheimer disease

Frontotemporal lobar degeneration

Parkinsons disease (LRRK2 mutation)

Progressive supranuclear palsy

Question 6

Neurodegenerative disorders

Protein Diseases with inclusions

______ Alzheimer disease

_____ Frontotemporal lobar degeneration

______ Amyotrophic lateral sclerosis

_______ Parkinsons disease

_______ Huntington disease

Answer 6

Aβ

TPD-43

α-synuclein

Polyglutamine aggregates

Question 7

Neurodegenerative diseases

_________ disease
_________ disease
_____________________
___________ disease

Answer 7

Parkinson disease
Alzheimer disease
Amyotrophic lateral sclerosis
Huntington’s disease

Question 8

Most common cause of dementia (senility) is ????

Answer 8

Alzheimer disease

Question 9

Alzheimer disease

Dementia refers to the effect of a group of brain diseases that result in (short or long?) term and (abrupt or gradual?) decrease in the ability to ______ and _______

Answer 9

Long; gradual

think and remember

Question 10

Alzheimer disease

Named after ________ who first described it on 1906b

Answer 10

Alois Alzheimer

Question 11

Alzheimer disease

The incidence when considered by age group:

○___% (65 to 74 years)
○____% (75 to 84 years)
○____% (85 years and above)

Answer 11

3

19

47

Question 12

Alzheimer disease

Most cases are _______, about 5 - 10% are ______ (may experience early onset of symptoms)

Answer 12

sporadic

familial

Question 13

Alzheimer disease : Pathogenesis

Accumulation of a peptide ( _______ or ________) in the brain

This peptide is derived from the cleavage of _________________________

Answer 13

Aβ protein

β amyloid

Amyloid Precursor Protein(APP).

Question 14

Alzheimer disease: Pathogenesis

The APP can be processed in two ways:
○Cleavage by ———- and _______ in a process that ________

○Cleavage by _________ cleaving enzyme and ________ to form Aβ

Answer 14

𝛼 -secretase and γ -secretase

prevents the formation of Aβ .

β site APP

β site APP

γ - secretase

Question 15

Alzheimer disease

Sporadic: Generation and accumulation of Aβ is said to occur (slowly or rapidly?) with ___________

Answer 15

Slowly

advancing age.

Question 16

Alzheimer disease

Risk Factors:
Increasing age

Genetic: ______ of apolipoprotein E
The e4 allele is (more or less?) effective.

Answer 16

e4 allele

Question 17

Apolipoprotein helps breakdown Beta amyloid

T/F

Answer 17

T

Question 18

Alzheimer’s disease

Familial

Mutations in _____,_______

Answer 18

APP

Gamma secretase

Question 19

Alzheimer’s disease

Familial: Mutations in ____ or in components of γ - secretase ( ___________ ) is seen in early onset familial cases with increased accumulation of Aβ

Answer 19

APP

presenilin(PS) 1 or 2

Question 20

Alzheimer’s Disease

AD occurs in almost all cases of Trisomy ——- ( _______ ) who survive beyond ____ years.

This is because the gene encoding_____ is located on chromosome (gene dosage effects).

Answer 20

21

Down’s syndrome

45

APP; 21

Question 21

Accumulation of Aβ :

○Alter ________

○Toxic to ——————- endings.

○Larger deposits (______) can also lead to neuronal death, ellicit a local inflammatory response, alteration of region-region communication through their mechanical effects on axons and dendrites

Answer 21

neuronal transmission

neurons and synaptic

plaques

Question 22

The presence of Aβ also leads the neurons to hyperphosphorylate the ————— protein called ——-.

○ With hyperphosphorylation, ____ redistributes from ———- into _______ and _______ and aggregates into ______.

○ This process results in neuronal dysfunction and cell death The anatomic distribution of the _____ and ________ account for the clinical manifestations seen and occur well ahead of the onset of clinical signs and symptoms.

Answer 22

microtubule binding; tau

tau; inside the axon

dendrites and cell bodies

tangles

plaques and tangles

Question 23

Alzheimer’s disease

The presence of Aβ also leads the neurons to _________ the _______ protein called tau.

○ With ______________, tau redistributes from ___________ into _________ and aggregates into ______ .

○ This process results in neuronal dysfunction and cell death

Answer 23

hyperphosphorylate

microtubule binding; tau.

hyperphosphorylation

inside the axon into dendrites and cell bodies

tangles

Question 24

Alzheimer’s disease

The __________________________ account for the clinical manifestations seen and occur _________ of the onset of clinical signs and symptoms.

Answer 24

anatomic distribution of the plaques and tangles

well ahead

Question 25

Gross findings of Alzheimer’s disease ○Cortical ______ with (narrowing or widening?) of the sulci more pronounced in the ______________________ lobes ○Compensatory _______ and ventricular ————- (Hydrocephalus- _______)

Answer 25

atrophy; Widening frontal, parietal and temporal increase in CSF enlargement; ex-vacuo

Question 26

Microscopic findings of Alzheimer’s disease ○______ (extracellular) ○_____________ (intracellular) ○Cerebral ______________

Answer 26

Plaques Neurofibrillary tangles amyloid angiopathy

Question 27

these changes seen in a demented patient may also be seen in the brain of elderly nondemented individuals. T/F

Answer 27

T Note that these changes may also be seen in the brain of elderly nondemented individuals. Therefore clinical signs and symptoms must be part of the diagnostic work-up

Question 28

Alzheimer’s disease Diagnosis _____ deposition in the brain can be detected through _____ methods that rely on ____-labeled _________compounds. Can also be used in ________ patients at ____ risk for developing AD

Answer 28

Aβ; imaging 18F; amyloid binding asymptomatic; high

Question 29

Alzheimer’s disease Diagnosis CSF analysis for the presence of _________________

Answer 29

increased phosphorylated tau

Question 30

Alzheimer’s disease Management Current approaches focus on helping people maintain ________, manage _______ symptoms and ______ the symptoms of the disease Assisted living facilities

Answer 30

mental function; behavioural slow down

Question 31

Parkinson’s disease Prevalence ranges from 42/100,000 in the ____ decade of life to >1900/100,000 among those who are ____ years and older

Answer 31

4th 80

Question 32

Parkinson’s disease More in males or females?

Answer 32

Males M>F

Question 33

Parkinson’s disease Named after __________ who published the first detailed description in 1817

Answer 33

James Parkinson

Question 34

Parkinson’s disease Mostly _______ however genetic analysis has identified certain causal mutations e.g. ________ mutations cause __________ Parkinson’s disease.

Answer 34

sporadic α-synuclein Autosomal dominant

Question 35

Parkinson’s disease The diagnostic feature of the disease is an inclusion containing ________ (______ body)

Answer 35

α-synuclein Lewy

Question 36

α-synuclein is a widely expressed _______ protein that is involved in __________ and other cellular processes

Answer 36

neuronal synaptic transmission

Question 37

Mechanism of Parkinson’s disease is generally unknown T/F

Answer 37

T

Question 38

Parkinson’s disease: Pathogenesis However the presence of ______ in Lewy bodies has suggested that _________ of the protein may be culpable. This is supported by the identification of two other genetic loci for Parkinson’s disease: ○Genes encoding ______ ○ genes encoding ————

Answer 38

α-synuclein defective degradation parkin UCHL-1

Question 39

Parkinson’s disease parkin (an _______________________) UCHL-1 (an enzyme involved in the recovery of ________ from proteins targeted to the _______________)

Answer 39

E3 ubiquitin ligase ubiquitin proteasome

Question 40

The α-synuclein which accumulates in the neuron is _______ resulting in the _______ of the cell. Up to 70% of __________ secreting neurons in the ________ are affected resulting in _____ depletion

Answer 40

cytotoxic; death dopamine substantia nigra dopamine

Question 41

Symptoms of Parkinsonism: _______kinesia ________ forms. ___mimia _____tremor Gait _______

Answer 41

Brady Rigidity Hypo Pill rolling Shuffling

Question 42

Symptoms of Parkinsonism: Bradykinesia ( ____ movement) Rigidity: “________” & “__________” forms. Hypomimia (_________ face) Pill rolling tremor ( _____ and _______ finger) Gait – shuffling

Answer 42

slow Lead pipe; Cog-wheel expressionless thumb and index

Question 43

Parkinsonism” can be induced by: ○Drugs that affect these neurons _ particularly __________ and toxins ○________________ parkinsonism ( __________ pandemic) ○ __________ hydrocephalus ○Head trauma, stroke

Answer 43

dopamine antagonists Post-encephalitic; post-influenza Normal pressure

Question 44

Other symptoms seen in Parkinson disease Autonomic disturbance e.g. ________,______ __________ impairment

Answer 44

hypersalivation, incontinence Cognitive

Question 45

Morphology (Autopsy) of Parkinson’s disease Gross: ______ of __________

Answer 45

Pallor of substantia nigra

Question 46

Morphology (Autopsy) of Parkinson’s disease Microscopic Loss of the ______ neurons in these regions _____ bodies (intracytoplasmic, ______ inclusions). These filaments are composed of ________

Answer 46

pigmented Lewy; eosinophilic eosinophilic α-synuclein

Question 47

Diagnosis of Parkinson’s disease Clinical response to L-DOPA treatment. ○L-DOPA ________________ of the disease ○Over time, _______________

Answer 47

does not halt the progression L-DOPA becomes less effective