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NEUR0010 > Frontotemporal Dementia > Flashcards

Frontotemporal Dementia Flashcards

1
Q

Name the 3 types of FTD

A

Behavioural variant FTD
Progressive non-fluent aphasia
Semantic dementia

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2
Q

What are the main symptomatic differences between FTD and AD?

A

Episodic memory, navigation, general intellect preserved

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3
Q

What are the symptoms of behavioural variant FTD?

A 
Decline in interpersonal and executive skills
Lack of empathy
Abnormal behaviours (e.g. obsessions, stereotypies)
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4
Q

What are the symptoms of progressive non-fluent aphasia?

A

Effortful non-fluent speech

Apraxia of other orofacial movements

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5
Q

What are the symptoms of semantic dementia?

A

Decline of semantic memory

Initially affects knowledge of word meanings

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6
Q

How can CSF protein markers be used to molecularly distinguish AD from FTD?

A

In AD increased ratio of tau:AB42

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7
Q

What is the pathological name for FTD?

A

Frontotemporal lobar degeneration (FTLD)

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8
Q

What are the 3 macroscopic features of FTD brains?

A

Frontal and temporal lobe atrophy
Enlarged lateral ventricles
Hippocampal atrophy

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9
Q

What is the effect of hippocampal atrophy?

A

Spatial navigation difficulties - later in disease

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10
Q

Name the 4 molecular subtypes of FTLD and their relative rarities

A

FTLD-TDP - most common
FTLD-tau - common
FTLD-FET - rare
FTLD-UPS - very rare

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11
Q

What is the physiological role of tau and why is this important?

A

Promotes microtubule stability

Key for neuronal integrity and axonal transport

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12
Q

Which gene encodes tau?

A

MAPT

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13
Q

How many tau isoforms can be formed by alternative splicing?

A

6

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14
Q

What are the microscopic features of FTLD-tau?

A

Pick bodies in temporal lobe

Tufted astrocytes - tau deposition within

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15
Q

What is the physiological role of TDP-43 and why is this important?

A

Binds multiple RNAs

Key for RNA processing

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16
Q

What is the main microscopic feature of most FTLD-TDP cases?

A

Cytoplasmic inclusion bodies - TDP43+, ubiquitin+, tau-

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17
Q

Where is TDP-43 normally localised to?

A

Nucleus

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18
Q

Which abnormal modifications are found on pathological TDP-43?

A

Hyperphosphorylation
Ubiquitination
N-terminal truncation

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19
Q

How do the 4 FTLD-TDP subtypes vary?

A

Different inclusion morphology

Different inclusion cortical layer distribution

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20
Q

What is the physiological role of FET and why is this important?

A

Binds RNA/DNA

Key for DNA and RNA processing

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21
Q

Which markers label inclusions in FTLD-UPS and what does this suggest?

A

UPS markers

Problem with protein degradation systems

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22
Q

Mutations in which gene cause FTLD-UPS?

A

CHMP2B

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23
Q

What are the inclusions in FTLD-UPS composed of?

A

Ubiquitin

p62

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24
Q

Which gene is linked to both ALS and FTD?

A

C9orf72

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25
Q

Which mutation type in C9orf72 causes FTD and ALS?

A

Hexanucleotide repeat expansions

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26
Q

Give the main component of inclusions in ALS and their frequency

A

TDP-43 - 97%

SOD-1 - 2%

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27
Q

Give the main component of inclusions in FTD and their frequency

A

Tau - 45%
TDP-43 - 45%
FUS - 9%

28
Q

Name 3 major autosomal dominant causes of FTD

A

MAPT
GRN
C9orf72

29
Q

What is seen in neurons from MAPT mutant FTD patient-derived iPSCs and what does this suggest?

A

Endosome accumulation, decreased lysosomes

Impaired endocytic trafficking

30
Q

Where is GRN expressed?

A

Mature neurons

Microglia

31
Q

What does GRN encode?

A

Progranulin

32
Q

What is the disease mechanism of FTD due to a GRN mutation?

A

GRN haploinsufficiency - loss-of-function

33
Q

What is the effect of an absence of progranulin in neurons?

A

Decreased neurite outgrowth

34
Q

Which condition does a homozygous-null GRN mutation result in and what does this involve?

A

Neuronal ceroid lipofuscinosis (NCL)

Storage of abnormal lipopigment in lysosomes

35
Q

What is the sequence of a hexanucleotide repeat in C9orf72?

A

GGGGCC

36
Q

Are the hexanuclotide repeats in C9orf72 intronic or exonic?

A

Intronic

37
Q

How many hexanucleotide repeats are usually in C9orf72?

A

2-24

38
Q

How many hexanucleotide repeats are in C9orf72 in FTD-ALS?

A

100s/1000s

39
Q

What are the 3 possible disease mechanisms for C9orf72 in FTD/ALS?

A

Decreased C9orf72 levels
Bidirectional transcription of repeats - forms sense and antisense RNA foci - sequester RNA-binding proteins
Dipeptide repeat proteins (DPRs) - toxic - from sense and antisense RNA RAN translation

40
Q

What the physiological role of C9orf72?

A

Associated with autophagosomes - role in autophagy

41
Q

Where do the C9orf72 repeat RNA foci form?

A

Nucleus

Cytoplasm

42
Q

How do C9orf72 repeat RNAs sequester RNA-binding proteins?

A

G bases in repeat RNAs bind - via atypical pairing
Form square planar structures
Stack - form G-quadruplex
Traps RNA-binding proteins

43
Q

Where are C9orf72 dipeptide repeat proteins (DPRs) found?

A

Cytoplasm

Nucleus

44
Q

How does RAN translation differ from normal translation?

A

Non-canonical - no AUG start codon

45
Q

How many dipeptide repeat proteins (DPRs) are generated from C9orf72 hexanucleotide expanded repeats?

A

5

46
Q

What enables the formation of so many dipeptide repeat proteins (DPRs) from the C9orf72 hexanucleotide repeat expansion?

A

Bidirectional transcription - sense and antisense mRNA

Translation in 3 reading frames

47
Q

Name 3 minor genetic FTD causes

A

CHMP2B
VCP
TARDBP

48
Q

What is the physiological role of CHMP2B?

A

Part of endosomal sorting complex

Sorts proteins to late endosome and lysosome - for degradation

49
Q

Where in CHMP2B does the FTD-causing mutation occur and how does affect the protein?

A

In splice site

C-terminal truncation

50
Q

What can be seen in the neurons of FTD patients caused by CHMP2B mutation and what does this suggest?

A

Abnormally high lipoprotein deposition in neurons

Suggests lysosomal storage pathology

51
Q

Which diseases does VCP mutation cause?

A

FTD and inclusion body myopathy - IBMFTD

52
Q

What is the inheritance pattern of IBMFTD?

A

Autosomal dominant

53
Q

What is the physiological role of VCP?

A

Protein homeostasis

54
Q

What does TARDBP encode?

A

TDP-43

55
Q

Name a gene with an FTD risk variant

A

TMEM106B

56
Q

What is the effect of the TMEM106B FTD risk variant?

A

Increases TMEM106B levels

57
Q

What is the physiological role of TMEM106B?

A

Lysosome size, acidification, function, transport

58
Q

What are the advantages of Drosophila as neurodegenerative disease models?

A 
Cheap
Short lifespan
Complex behaviour - e.g. learning, memory
Fewer genes than humans
Widely-available molecular genetic tools
59
Q

What are the disadvantages of Drosophila as neurodegenerative disease models?

A

Not as complex as humans - may lack relevant pathology

Lack some genes

60
Q

What are the advantages of cell lines as neurodegenerative disease models?

A

Immortal
Cheap
No ethical issues

61
Q

What are the disadvantages of cell lines as neurodegenerative disease models?

A

Not neuronal

Altered morphology to tissue origin

62
Q

What are the advantages of mice as neurodegenerative disease models?

A

Genetically malleable

Fairly short lifespan

63
Q

What are the disadvantages of mice as neurodegenerative disease models?

A

Lack complex neuron circuits
Lack full complement of glia
Lack vascular and immunologic components

64
Q

What are the advantages of iPSCs as neurodegenerative disease models?

A

Contain mutation from patient derived from
Can be differentiated into multiple cell types
No ethical issues

65
Q

What are the disadvantages of iPSCs as neurodegenerative disease models?

A

In dish - lack supporting glia

Demanding - require daily attention

NEUR0010 (9 decks)

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