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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
Where do the AB peptides go and what do they do?
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
Describe the key process of AD.
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
Describe the gross morphology of AD.
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
Name the two histological hallmarks of AD.
``` Neurofibrillary Tangles (NFTs) Neuritic Plaques ```
29
What are tangles?
Aggregates of the protein tau - from intracellularly within neurons
30
What are plaques?
Deposits of aggregated AB in the neuropil (extracellularly) | Neuritic when surrounded and traversed by dystrophic (degenerating) neurites (axons and dendrites)
31
What do plaques look like?
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
What do neurofibrillary tangles look like?
Aggregates of filaments inside affected neurons Hyperphosphorylated Tau protein Flame shaped In electron microscopy = paired filaments in a helical arrangement
33
Where else does amyloid deposition occur?
Cerebral blood vessels
34
What is found in preclinical AD?
Plaques and tangles | these greatly increase in number by the time dementia sets in
35
Where else can NFTs (Tau inclusions) be found?
In brains of cognitively normal individuals unaffected by AD | Dementias caused by other neurodegenerative diseases
36
What is the main feature in diagnosing AD?
``` 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
How do we diagnose dementia due to AD?
Number of plaques and tangles has to exceed a defined threshold Best done using scoring system at postmortem examination of the whole brain
38
What happens if a patient dies with dementia, yet there are few plaques?
Unlikely their dementia was caused by AD
39
What is HD?
Fatal autosomal dominant disease characterized clinically by a progressive movement disorder and dementia
40
What is the movement disorder of HD?
Involuntary, purposeless, jerky, hyperkinetic or writhing | = hunting chorea
41
When is the disease onset of HD?
Between ages of 25-45 years
42
Which gene causes HD?
``` 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
What information is given in the molecular genetics of HD?
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
What is the gross morphology of HD?
Atrophy of caudate (and putamen later on) Atrophy of Globus Pallidus Over time - diffuse cortical atrophy Compensatory dilation of ventricles
45
What is the microscopic morphology of HD?
Intranuclear inclusions of huntingtin protein | Neuronal loss especially in the striatum and gliosis
46
What are prion diseases? (Transmissible Spongiform Encephalopathies)
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
How do prions arise?
Spontaneous conformational change or through mutations (familial cases in gene PRNP)
48
List the prion diseases in humans vs animals.
Creutzfeldt-Jakob disease (CJD), Kuru - humans | Bovine Spongiform Encephalopathy (Mad Cow Disease), Scrapie in sheep and goats - animals
49
What is the pathogenesis behind prions?
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
NB: prions are transmitted from one infected individual to another = infectious!!
51
List some ways CJD has been passed on.
Contaminated corneal transplants Dura mater grafts (lyophilized cadaveric dura) Human growth hormones
52
How is variant CJD thought to have resulted?
Exposure to beef from cattle with bovine spongiform encephalopathy
53
Where does Kuru come from?
New Guinea - consumption of brain tissue during cannabilism
54
What is the most common prion disease?
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
What is the gross morphology of CJD?
No/some atrophy
56
What is the microscopic morphology of CJD?
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
What is vascular dementia?
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
What do patients with vascular dementia present with?
History of discrete episodes of sudden neurologic deterioration with stepwise cognitive decline over time History of HTN, diabetes and atherosclerotic CVS disease
59
What does the microscopic and histologic examnination of vascualr dementia show?
Areas of ischaemic necrosis (infarcts) of varying age
60
What are potentially treatable causes of dementia?
``` 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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