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3 - Pathology > Dementia > Flashcards

Dementia Flashcards

1
Q

What is dementia?

A

Progressive decline in previously acquired cognitive abilities; that impairs the performance of daily activities

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2
Q

What is the most affected cognitive function?

A

Memory

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3
Q

What other abilities may be impaired with dementia?

A

Calculation, language, judgement, problem solving, visuospatial ability

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4
Q

What neuropsychiatric effects may be present?

A

Agitation, apathy, delusions, depression, hallucinations, insomnia, disinhibition

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5
Q

What does disease of the frontal lobe produce?

A

Abnormalities in Impaired judgement, abstract reasoning, strategic planning, emotional restraint, control of appetite and continence

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6
Q

What does disease of the parietal lobe lead to?

A

Impairment of visuospatial skills, integration of sensory inputs
= leads to sensory agnosias and apraxias

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7
Q

What does disease of the occipital lobe lead to?

A

Failure of visual sensory systems

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8
Q

What does disease of the temporal neocortex lead to?

A

Receptive dysphasia and automatisms

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9
Q

What does disease of the medial temporal lobe lead to?

A

Disorders of memory and hallucinations

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10
Q

List some causes of dementia.

A

Neurodegenerative diseases (Alzheimer disease, Huntington Disease)
Prion diseases
Vascular dementia (cerebrovascular disease)
Chronic Traumatic Encephalopathy (CTE) from repeated head injury
Hydrocephalus
Immune-mediated syndromes
Demyelinating diseases (MS)
Infective disorders (HIV)
Neoplasia (primary and secondary brain tumours)

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11
Q

What are neurodegenerative diseases?

A

Diseases of grey matter characterized by progressive loss of cortical and/or subcortical neurons with secondary white matter changes

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12
Q

What do neurodegenerative diseases have in common?

A

Development of different abnormal protein aggregates that are resistant to degradation by normal cellular mechanisms
Protein aggregates can accumulate within neurons (inclusions) or extracellularly (in neuropil)
These protein aggregates are toxic to neurons

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13
Q

What is the most common cause of dementia?

A

AD

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14
Q

What are the main symptoms of AD?

A

Defects in frontal, temporal and parietal lobes:
- short term memory loss
- impairment of visuospatial skills
- disorientation, word-finding difficulty
- changes in mood and behaviour
Over 5 to 10 years there is continuous decline with ultimate loss of mobility and speech

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15
Q

What do patients usually die of with AD?

A

Pneumonia

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16
Q

List the 5 main subgroups of AD.

A

1 - Sporadic, late onset AD (most common)
2 - Familial, late onset AD (uncommon)
3 - Familial. early onset AD (rare)
4 - Associated with Downsyndrome (Trisomy 21)
5 - Associated with other neurodegenerative diseases

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17
Q

What gene is a genetic risk factor and how?

A

Influenced by Apolipoprotein E (ApoE) gene - 3 alleles.

E4 allele increases risk of AD and decreases age of onset - promotes deposition through an unknown mechanism

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18
Q

Point mutations occur in which gene in families with early onset autosomal dominant familial AD?

A

APP gene

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19
Q

What other genes are implicated in FAD?

A

PSEN1 (presenilin 1) and PSEN 2 (presenilin 2)

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20
Q

Why are patients with downsyndrome strongly predisposed to develop AD at age 40?

A

APP gene is on chromosome 21

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21
Q

What is the amyloid cascade hypothesis?

A

Extracellular deposition of Amyloid Beta peptide.
Derived from enzymatic cleavage of Amyloid Precursor Protein (APP)
APP is a surface membrane protein of uncertain function

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22
Q

How does the enzymatic cleavage of the trans-membrane component of APP occur?

A

Non-amyloidogenic (normal)

Amyloidogenic (AB-producing)

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23
Q

What is an amyloid?

A

Extracellular deposit of an insoluble (misfolded) fibrillar protein that leads to tissue damage and functional compromise
Heterogenous group

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24
Q

What is amyloidosis?

A

Condition where these proteins are deposited in several organs leading to disease

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25
Q

Where do the AB peptides go and what do they do?

A

Go into the extracellular space
May aggregate forming amyloid fibrils (neurotoxic) - causing neuronal injury, neuronal synaptic dysfunction and eventually neuronal death
Also stimulate an inflammatory response from microglia and astrocytes = release mediators that cause neuronal damage - this may alter phosphorylation of “tau” protein leading to its aggregation

26
Q

Describe the key process of AD.

A

2 protein aggregates (tau and AB)
Neuronal toxicity and loss
Cortical gray matter atrophy (especially in frontal, temporal and parietal lobes)
Subsequent white matter changes
Global brain atrophy with compensatory ventricular dilation

27
Q

Describe the gross morphology of AD.

A

Narrowed gyri
Increased slyvian fissure
Global shrinkage - diffuse cerebral atrophy
Widened sulci margins
Ventricular enlargement (hydrocephalus ex vacuo)
Severe atrophy often develops in medial temporal lobe structures (hippocampus, amygdala)

28
Q

Name the two histological hallmarks of AD.

A 
Neurofibrillary Tangles (NFTs)
Neuritic Plaques
29
Q

What are tangles?

A

Aggregates of the protein tau - from intracellularly within neurons

30
Q

What are plaques?

A

Deposits of aggregated AB in the neuropil (extracellularly)

Neuritic when surrounded and traversed by dystrophic (degenerating) neurites (axons and dendrites)

31
Q

What do plaques look like?

A

Extracellular, roughly spherical AB deposits
Separated into central core and a peripheral halo = neuritic plaques
Diffuse/primitive plaques are early stages of plaque formation (little or no neuritic processes)

32
Q

What do neurofibrillary tangles look like?

A

Aggregates of filaments inside affected neurons
Hyperphosphorylated Tau protein
Flame shaped
In electron microscopy = paired filaments in a helical arrangement

33
Q

Where else does amyloid deposition occur?

A

Cerebral blood vessels

34
Q

What is found in preclinical AD?

A

Plaques and tangles

these greatly increase in number by the time dementia sets in

35
Q

Where else can NFTs (Tau inclusions) be found?

A

In brains of cognitively normal individuals unaffected by AD

Dementias caused by other neurodegenerative diseases

36
Q

What is the main feature in diagnosing AD?

A 
AB deposits (plaques) are specific to AD 
Can be seen in brain biopsy or PET scan of brain 
= considered AD neuropathologic change even if patient is not presenting with dementia = preclinical AD
37
Q

How do we diagnose dementia due to AD?

A

Number of plaques and tangles has to exceed a defined threshold
Best done using scoring system at postmortem examination of the whole brain

38
Q

What happens if a patient dies with dementia, yet there are few plaques?

A

Unlikely their dementia was caused by AD

39
Q

What is HD?

A

Fatal autosomal dominant disease characterized clinically by a progressive movement disorder and dementia

40
Q

What is the movement disorder of HD?

A

Involuntary, purposeless, jerky, hyperkinetic or writhing

= hunting chorea

41
Q

When is the disease onset of HD?

A

Between ages of 25-45 years

42
Q

Which gene causes HD?

A 
HD gene (short arm of chromosome 4) which encodes for a protein called huntingtin 
Normal number of CAG repeats in HD gene is about 6-35 
In HD = increase in polyglutamine trinucleotide repeats 
Disease occurs when the number of repeats is around 40 or more with formation of intraneuronal inclusions of huntingtin protein
43
Q

What information is given in the molecular genetics of HD?

A

Greater the number of repeats = earlier onset
Increase in number of repeats can occur during spermatogenesis = if disease is transmitted by father, offspring may develop earlier disease
Anticipation - increase in the number of repeats from one generation to the next results in earlier or more severe disease in the offspring

44
Q

What is the gross morphology of HD?

A

Atrophy of caudate (and putamen later on)
Atrophy of Globus Pallidus
Over time - diffuse cortical atrophy
Compensatory dilation of ventricles

45
Q

What is the microscopic morphology of HD?

A

Intranuclear inclusions of huntingtin protein

Neuronal loss especially in the striatum and gliosis

46
Q

What are prion diseases? (Transmissible Spongiform Encephalopathies)

A

A group of conditions in which dementia develops due to neurodegeneration caused by abnormal conformations of a normal cellular protein called Prion Protein
Abnormal conformations = prions

47
Q

How do prions arise?

A

Spontaneous conformational change or through mutations (familial cases in gene PRNP)

48
Q

List the prion diseases in humans vs animals.

A

Creutzfeldt-Jakob disease (CJD), Kuru - humans

Bovine Spongiform Encephalopathy (Mad Cow Disease), Scrapie in sheep and goats - animals

49
Q

What is the pathogenesis behind prions?

A

Prions are able to bind to normal PrPc and induce a conformational change = gives rise to a new prion
Prions reproduced & progressively accumulate over time forming aggregates which lead to dementia
Unknown how prions introduce conformational change in normal prion protein

50
Q

NB: prions are transmitted from one infected individual to another = infectious!!

A
51
Q

List some ways CJD has been passed on.

A

Contaminated corneal transplants
Dura mater grafts (lyophilized cadaveric dura)
Human growth hormones

52
Q

How is variant CJD thought to have resulted?

A

Exposure to beef from cattle with bovine spongiform encephalopathy

53
Q

Where does Kuru come from?

A

New Guinea - consumption of brain tissue during cannabilism

54
Q

What is the most common prion disease?

A

Creutzfeldt Jakob Disease
(50-75 years age group)
Rare disease - often sporadic, few familial cases
Rapidly progressive Dementia with myoclonus (quick, involuntary muscle jerks)
Most patients die within a year

55
Q

What is the gross morphology of CJD?

A

No/some atrophy

56
Q

What is the microscopic morphology of CJD?

A

Spongiform transformation of cortex and deep nuclei - many small empty appearing vacuoles within the neuropil and cytoplasm of neurones
Disease Progression:
- Neuronal loss
- Gliosis
- Coalescence of vacuolar spaces into larger cystic spaces

57
Q

What is vascular dementia?

A

Patients typically suffer TIAs and several mini strokes and develop cognitive impairment
Usually 6th decade onwards
Strokes often cause multiple lacunar or microinfarcts involving different brain regions
Dementia is caused by accumulation of deficits through multiple, bilateral infarcts & depends on the volume and location of infarcted cortex

58
Q

What do patients with vascular dementia present with?

A

History of discrete episodes of sudden neurologic deterioration with stepwise cognitive decline over time
History of HTN, diabetes and atherosclerotic CVS disease

59
Q

What does the microscopic and histologic examnination of vascualr dementia show?

A

Areas of ischaemic necrosis (infarcts) of varying age

60
Q

What are potentially treatable causes of dementia?

A 
Depression
Drug effects
Metabolic causes (hypothyroidism, vitamin B1 or B12 deficiency, hepatic encephalopathy) 
HIV associated neurocognitive disorder 
Wilson disease
SOL - neoplasm
Alcohol related dementia

3 - Pathology (7 decks)

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