Lecture 9: Frontotemporal dementia

Question 1

frontotemporal dementia

• first known case (1892):
• autopsy:

Answer 1

Arnold Pick (1892)- german neurologist

• 71-year old man: progressive decline speech, paraphasias (characterized by the production of unintended syllables, words, or phrases during the effort to speak), difficulties recognizing objects
• Autopsy: atrophy frontal and temporal lobes
• in the same patient:
  
  • Neuropathology (Pick’s bodies, Pick cells), described by Alois Alzheimer (1911)
  • Pick’s disease (sort of forerunner for frontotemporal dementia)

Question 2

Pick cells:

Answer 2

• its presence used to be a requirement for diagnosis of frontotemporal dementia

Question 3

Pick’s bodies:

Answer 3

• its presence used to be a requirement for diagnosis of frontotemporal dementia

Question 4

Frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD)

• Epidemiology
• ¨Genetic factor

Answer 4

• Epidemiology
  
  • FTD ± 5% of all dementia cases
  • (early onset) FTD as common as (early onset) AD
  • under 60 FTD more common AD
• Genetic factor
  • 30-50% patients FTD family history
  • Relatives patients with FTD – 3.5 x risk FTD than general population

Question 5

FTD - variations with different symptoms and underlying neuropathology

• Several classifications proposed:
• Neary et al. (1998):

Answer 5

Neary et al. (1998):

• Behavioural variant: behavioural changes prominent symptom
• Language variant (primary progressive aphasia): language disturbances prominent symptoms
  
  • semantic dementia – word comprehension
  • progressive nonfluent aphasia – word production difficulties

Question 6

¨frontotemporal dementia

• most recent classification: Rascovsky et al. (2011):

Answer 6

• Behavioural variant
• Language variants - primary progressive aphasia (PPA):
  • semantic variant (comparable SD)
  • agrammatic variant (overlap progressive nonfluent aphasia)
  • logopenic variant - word findings difficulties, no impairments comprehension

Question 7

¨frontotemporal dementia

• Etiology

Answer 7

• Typical neuropathology FTD - focal damage frontal and anterior temporal lobes
• Damage caused by abnormal aggregation of proteins:
  
  • Tau, TARDNA binding protein (TDP), fused in sarcoma (FUS) protein
  • Also associated other CNS diseases (e.g. amyotrophic lateral sclerosis)

From: LaForce (2013)

Question 8

FTD - variations with different symptoms and underlying neuropathology

• “the” neuropsychology of FTD difficult to define (there is not one underlying neuropathology but many different)

Answer 8

• “the” neuropsychology of FTD difficult to define
  
  • variations lumped together
  • variant-specific neuropsychology

Question 9

frontotemporal dementia​

• Hutchinson & Mathias (2007) – meta-analysis 94 studies comparing FTD (n=1748) and AD (n=2936)
  
  • All subtypes FTD

Answer 9

• Best discrimination FTD and AD:
  
  • Memory (e.g. AVLT, Rey): FTD > AD
  • Language/verbal ability (e.g. naming, fluency): FTD < AD
• Visual spatial/construction (e.g. Beery): FTD > AD
• EF tasks did not distinguish between FTD and AD

Question 10

frontotemporal dementia:

• Behavioural variant (bvFTD)
  
  • 6 major symptoms (consensus 2011)

Answer 10

• Most common (50-70% FTD cases)
• More common in men
• Insidious beginning, slow progression symptoms
• Earliest signs subtle personality, behavioural changes
• 6 major symptoms (consensus 2011):
  
  • Behavioural disinhibition
  • Apathy
  • Loss empathy
  • Compulsive behaviour
  • Hyperorality (could be an unusual preference for food e.g. ice cream, babyfood, objects that are not eadable)
  • Deficits EF with relatively preserved memory and visuospatial functions
    
    • at least three symptoms need to be present
• With progression disease, more functions affected

Question 11

Accurate Assessment of Behavioural Variant of FTD:

• criteria for Neurodegenerative disease (BvFTD) vs possible BvFTD

Answer 11

Question 12

frontotemporal dementia: behavioural variant

• Neuropathology (typical location)

Answer 12

• ¨Initially degeneration in anterior temporal and frontal areas – anterior cingulate gyrus, dorsal anterior insula, lateral orbitofrontal cortex.
• With progression disease - widespread damage in frontal and temporal areas

*

Question 13

Cognitive impairments (bvFTD):

• 204 bvFTD, 674 AD, 126 age-matched HC (Ranasinghe et al., 2016)
  
  • Memory:
  • Visuospatial:
  • Language:
  • Working memory:
  • Executive functions:

Answer 13

• Memory: AD < bvFTD < HC
• Visuospatial: AD < bvFTD < HC
• Language: bvFTD < HC naming, syntax comprehensio
• Working memory: CDR=0.5: bvFTD = HC

CDR = 1: bvFTD < HC

* CDR is a severity score * Executive functions: bvFTD \< HC

Question 14

¨frontotemporal dementia: behavioural variant

• Neuropsychiatric symptoms

204 bvFTD, 674 AD, 126 age-matched HC (Ranasinghe et al., 2016)

Answer 14

Neuropsychiatric symptoms

204 bvFTD, 674 AD, 126 age-matched HC (Ranasinghe et al., 2016)

• NPI scales
• High levels disturbances and caregiver stress from CDR 0.5. (compared with AD)
• apathy, disinhibition, abnormal eating, motor symptoms

Question 15

frontotemporal dementia:

• primary progressive aphasia

Answer 15

Language main impairment (in early stage disease)

• E.g. word finding difficulties, paraphasias, effortful speech, grammatical or comprehension difficulties
• (non-language) cognitive impairments and behavioural changes in later stages
• 3 variants: nonfluent/agrammatic variant (naPPA), semantic variant (svPPA), logopenic variant (lvPPA).

Question 16

frontotemporal dementia: primary progressive aphasia (PPA)

• 3 criteria diagnosis
• difference between PPA and other languague disorders?

Answer 16

1. Insidious onset , gradual progression
2. Only language difficulties impact daily functioning
3. Explained by neurodegerative process, not other medical condition

Difference language impairments?

• PPA - dementia because characterised by gradual cognitive decline that affects activities of daily living.

Question 17

¨Semantic variant (svPPA) - “semantic dementia”

• characteristics

Answer 17

• fluent speech, circumlocutions, word findings difficulties, anomia, progressive loss of semantic knowledge
  
  • Obvious in naming tasks, especially of low frequency words.
• Impairments word comprehension
• Semantic impairment can extend to other modalities (e.g. faces, objects)
  
  • Gradual deterioration object naming (Hodges & Patterson, 2007)
    • objects are referred to in more and more general ways (ostrich -> bird ->animal but also mistakes (cat))
• Informants may report behavioural changes:
  
  • Apathy, social withdrawal, irritability, bizarre food choices.
• Episodic memory for day-to-day events relatively intact
• 20% FTD cases

Question 18

Semantic variant (svPPA) - “semantic dementia”

• Neuropathology

Answer 18

• Early stage: atrophy anterior temporal lobes
• With progression: degeneration posterior temporal lobe, posterior inferior frontal lobe or both
• Overlap degeneration bvFTD – overlap behavioural changes

Question 19

¨Nonfluent/agrammatic variant (naPPA)

Answer 19

Nonfluent/agrammatic variant (naPPA)

• 25% FTD cases
• Impairment speech production: effortful, non-fluent speech, pauses between and within utterances, agrammatism, comprehension intact
  
  • “ trees … children … run “
  • “ go shop, buy ice cream”

Question 20

¨Nonfluent/agrammatic variant (naPPA)

• Neuropathology

Answer 20

• atrophy left posterior and frontal lobe and insular cortex
  
  • slightly more frontal than the semantic variant
    *

Question 21

¨Logopenic variant (lvPPA)

• characteristics
• progression
• neuropathology

Answer 21

• Intermittent word findings difficulties, long word finding pauses
• Spontaneous speech slow, no agrammatism
• Phonological paraphasias
  
  • “papple” for apple or “lelephone” for telephone
• Impaired repetition of sentences
• No/mild impairments comprehension
• No articulation difficulties
• With progression, more language functions affected
• Atrophy posterior temporal and parietal regions, mainly left

Question 22

Relative location of the primary progressive aphasia variants:

Answer 22

Question 23

frontotemporal dementia: primary progressive aphasia

Cognitive impairments (other than language)

• Episodic memory
• Working memory

Answer 23

• Episodic memory
  
  • All variants < HC (Eikelboom et al., 2018)
  • lvFTD < nfvFTD, svFTD < HC only verbal memory tests
• Working memory
  
  • All variants < HC
  • lvFTD < nfvFTD, svFTD impairment less severe

Question 24

frontotemporal dementia: behavioural variant

• Assessment bvFTD

Answer 24

Interview relatives/close others

• Patients may lack insight (according to them there is often nothing wrong but relatives can give more accurate information)
• Cover
  
  • Onset and progression of symptoms:
  • Changes behaviour and personality
    
    • Abrupt, sudden changes unlikely typical of bvFTD

Cognitive testing: EF, memory, language, visuospatial ability

• episodic memory relatively spared - key difference FTD and AD
• EF mostly impaired, overlap EF performance in FTD and AD

bvFTD frequently misdiagnosed as AD

• Overlap symptoms and location lesions (e.g. medial temporal)

bvFTD frequently misdiagnosed as psychiatric disorder (depression, late onset schizophrenia) - behavioural disturbances

Question 25

Assessment PPA

Answer 25

• Different language functions
  
  • Language batteries
• Demonstrate (early) language impairment and different subtypes.
• Other cognitive tests - minimize language requirements.
• Neuroimaging - atrophy mainly frontal – temporal areas.
  
  • Other pathologies, e.g. tumor or ischemia, rule out PPA.
• With progression - more symptoms emerge, more difficult to distinguish FTD variants.

Question 26

Overview/summary of Diagnosis criteria for the different ariants of PPA:

Answer 26

Question 27

¨Frontotemporal dementia

• Treatment

Answer 27

• No cure
• Symptomatic treatment, cognition and behaviour:
  • Pharmacological (no effect cognition)
  • Non-pharmacological