Neurodegenerative Disorders

Question 1

Dementia

Answer 1

Acquired global impairment of intellect, reason and personality without impairment of consciousness. Abnormalities of executive function.

Emotional lability and memory dysfunction are prominent manifestations = implies involvement of cerebral cortex and limbic system

Question 2

Causes of dementia

Answer 2

Primary neurodegenerative disorders : Alzheimer’s disease, diffuse levy body disease , frontotemporal lobar degeneration , Huntington’s disease

Secondary causes : Cerebrovascular disease ( multi-infarct dementia ) , infection ( CJD/HIV) , drugs/toxins , metabolic disorders , vitamin deficiency ( Wernicke’s Korsakoff syndrome ) , paraneoplastic syndromes ( limbic encephalitis )

Question 3

Explain Alzheimer’s disease

Answer 3

• Associated with age
• most cases sporadic but genetic predisposition is important because early onset is inheritable recognized with autosomal dominant forms
• Genes identified ; amyloid precursor
  protein on chromosome 21, the PS 1 gene on
  chromosome 14 and the PS2 gene on chromosome 1.
• primary role for Aβ
  protein amyloid accumulation, derived from abnormal cleavage of the
  normal protein APP, encoded by the APP gene on
  chromosome 21 as part of the amyloid cascade pathway.

Question 4

Where is there predisposition to early onset Alzheimers

Answer 4

e4e4 in the Apo E gene on chromosome

19.

Question 5

What does the brain show in Alzheimer’s

Answer 5

severe cortical atrophy with narrowing of the gyri and widening of the sulci.
White matter loss is accompanied by
dilatation of the ventricular
system (compensatory hydrocephalus).

Question 6

What is amyloid

Answer 6

proteins/ glycoproteins that may be deposited in tissues in EC locations

• associated with B pleated sheet conformation
• systemic forms associated with significant medical complications
• localized forms may be incidental or cause significant problems eg accumulation of amyloid in the myocardium and heart failure

Question 7

What can Amyloid accumulation cause

Answer 7

Heart failure , nephrotic syndrome , organ enlargement ( ex: hepatospenomegaly )

Question 8

Which amyloid is associated with Alzheimer’s

Answer 8

A-beta amyloid derived from amyloid precursor protein

Question 9

How does amyloid stain on Congo red staining

Answer 9

salmon pink colour on congo red staining which exhibits apple green birefringence under polarised light

Question 10

Where else other than Alzheimer’s can amyloid appear

Answer 10

predisposing to spontaneous intracerebral hemorrhage

Question 11

What is Parkinsonism

Answer 11

Impaired function of dopaminergic neurons projecting from substantia nigra to corpus striatum

Question 12

What can CO poisoning cause

Answer 12

Parkinsonism

Question 13

What mutations cause autosomal dominant Parkinson’s disease

Answer 13

Alpha synuclein gene mutations or duplications

Question 14

What eugenic forms could cause PD

Answer 14

Parkin gene or UCHL1 , genetic changes in LLRK2 kinase or PARK 7 or PINK1

Question 15

Substantia nigra is shown how in PD

Answer 15

Depigmentation of substantia nigra

Question 16

Histological findings in PD

Answer 16

Found in the brain stem: 
substantia nigra
- Lewy bodies
- Single or multiple rounded 
cytoplasmic inclusions with 
dense core and pale halo
- Contain aggregates of α 
synuclein with neurofilaments 
and ubiqutin

Question 17

PD vs Lewy body dementia

Answer 17

PD
- Lewy bodies found lower in the brain stem in advance of nigro-striatal involvement, autonomic dysfunction and behavioural disturbances can precede the onset of motor symptoms
• Dementia can develop in idiopathic Parkinson’s disease, attributable to involvement of the cerebral cortex

Lewy body dementia

• Onset of dementia within a year of the onset of motor symptoms or if dementia preceeds the onset of motor symptoms may be termed Lewy body dementia
• Lewy bodies seen in a more widespread distribution including the cerebral cortex and limbic system
• associated with visual hallucinations, problems with confusion/sleepiness that can fluctuate, disturbed sleep, fainting spells, unsteadiness and falls

Question 18

What is Huntington’s Disease and what is it associated with

Answer 18

Autosomal dominant condition 
associated with degeneration of corpus the striatum
- Associated with movement 
disorder (choreiform 
movements) and behavioural
changes progressing to 
dementia and associated with 
increased risk of suicide in early stages

Question 19

Severe Lewy body dementia features

Answer 19

• A progressive dementia with prominent deficits in attention, executive function, and visuospatial abilities
• Parkinson-like features (bradykinesia, rigidity, posture, and balance)
• Visual hallucinations
• Spontaneous fluctuations in concentration and attention
• Disturbances in sleep known as REM sleep behavior disorder (i.e., acting out one’s dreams)

Question 20

Causes of HD and progression

Answer 20

Expansion of CAG trinucleotide repeats that encode hinting tin protein

• causes alleles to have increased number of repeats
• number of repeats associated with earlier onset of disease
• intranucleaur inclusions in neurons will lead to cell death, atrophy of the caudate nucleus and the putamen within the striatum

Question 21

Where in the Brian does HD affect

Answer 21

Caudate and Putamen in the corpus striatum

Question 22

What is Chronic Traumatic encephalopathy and what is it associated with

Answer 22

Degenerative brain disease associated with a history of repetitive head impacts ( ex: boxing , football )

• ” punch drunk” syndrome
• associated with cognitive impairment or specific neurological syndromes eg parkinsonism,
• neurobehavioural dysregulation egimpulsivity rage, violent outbursts, emotional lability may also be associated

Question 23

Finding in brain with CTE ( chronic traumatic encephalopathy )

Answer 23

structural abnormalities of the septum pellucidum

• thinning of the corpus callosum
• degeneration of the substantia nigra
• cerebral cortical neurofibrillary tangles.

Question 24

What are Prion diseases

Answer 24

Group of
neurodegenerative disease including Creutzfeldt
Jakob disease (CJD) , scrapie in sheep and mad
cow disease

• can be inherited or infected with ( via being exposed to infectious prion agent )
• Agent is an abnormal form of a cellular protein; there is no nucleic acid

Question 25

Explain physiology of prion disease

Answer 25

abnormal form PrPsc is resistant to proteolysis

and can induce conformational change in the native protein in process of propagation and aggregation

Question 26

What is CJD ( NEW VARIANT )

Answer 26

Type of Prion disease

• primarily affects young adults
• associated with behavioural changes and slower onset of neurological signs
• new CJD variant linked with exposure to prion disease of cattle ( bovine spongiform encephalopathy ) - eating beef
• spongiform change in cerebral cortex and deep grey matter due to accumulation of abnormal proteinase resistant PrPsc and amyloid plaques