FRONTOTEMPORAL

DEMENTIA
What is frontotemporal dementia (FTD)?
• Neurodegenerative disorder

• Degeneration of frontal and/or temporal lobes

Overview
• Epidemiology

• Pathogenesis & Pathology

• Presentation & Diagnosis

• Types of FTD

• Management
Overview
• Epidemiology

• Pathogenesis & Pathology

• Presentation & Diagnosis

• Types of FTD

• Management
Who gets FTD?
• Early onset
• Mean age of onset = 58
• Similar frequency as Alzheimer’s Disease < age 65
• 3.5 vs. 4.2/100 000 person-years
• 15/100 000 person-years

• M >= F
Overview
• Epidemiology

• Pathogenesis & Pathology

• Presentation & Diagnosis

• Types of FTD

• Management
Genetics
• 40% FHx of dementia or psychiatric condition
• 10-25% autosomal dominant inheritance

• Mutations:
• C9ORF72: hexanucleotide expansion
• Most common (12%)
• MAPT: microtubule-associated protein tau
• Increase tendency tau -> neurotoxic aggregates
• GRN: progranulin
• Other rare mutations
Pathology
• Frontotemporal lobar degeneration (FTLD)

• FTLD-tau (50%): hyperphosphorylated tau protein

• FTLD-TDP: TAR DNA-binding protein (ubiquitinated
protein)
• 4 types based on types of inclusions
• FTLD-FUS: FUS protein (ubiquitinated protein)

• Inconsistent clinical-pathological correlation

“Pick Disease”
Overview
• Epidemiology

• Pathogenesis & Pathology

• Presentation & Diagnosis

• Types of FTD

• Management
What does FTD look like?
Frontotemporal
Dementia (FTD)

Behavioural Primary
Variant FTD Progressive
(bvFTD) Aphasia (PPA)

Semantic Nonfluent (Logopenic

Variant PPA Variant PPA Variant PPA)
bvFTD
• Historically “frontal-variant”

• Most common (50%)

Diagnostic Criteria
• Possible bvFTD
• 3 of:
• Behavioural disinhibition
• Apathy/inertia
• Loss of sympathy/empathy
• Perseverative/compulsive behaviour
• Hyperorality
• Executive function deficit + relative sparing of STM and visuospatial

• Probable bvFTD
• Possible bvFTD
• plus
• Supportive neuroimaging
• bvFTD with definite FTLD pathology
• Possible or probably bvFTD
• plus
• Histopathological evidence
• or
• Known pathogenic mutation

• Using confirmed FTLD as gold standard

• Possible bvFTD sensitivity = 85%
• Probable bvFTD sensitivity = 75%
PPA
• Historically “temporal-variant”
Semantic Variant PPA
Neuroimaging

• L > R temporopolar atrophy

Nonfluent Variant
Neuroimaging

• L posterior frontoinsular atrophy

Logopenic Variant
Neuroimaging

• L posterior perisylvian atrophy

Association with Motor Syndromes
• FTD-motor neuron disease: similar to classic ALS
• UMN + LMN, bulbar involvement, pseudobulbar affect

• Corticobasal syndrome (CBS)

• Asymmetric Parkinsonism, apraxia, alien limb syndrome

• Progressive supranuclear palsy

• Parkinsonism, supranuclear vertical gaze palsy, postural instability,
falls
Overview
• Epidemiology

• Pathogenesis & Pathology

• Presentation & Diagnosis

• Types of FTD

• Management
Management
• Nonpharmacologic
• Behavioural modification
• Speech therapy
• Physiotherapy to maintain mobility

• Pharmacologic
• No current FDA approved disease-modifying treatment
• Symptomatic relief
Neurotransmitters in FTD
• Cholinergic system relatively preserved

• Serotonergic dysfunction

• Dopaminergic dysfunction
Medications used in Alzheimer’s Disease
• Donepezil
• Mendez MF et al. Am J Geriatr Psychiatry. 2007;15(1):84. 
• n = 24. Donepezil x 6 months vs. control. All patients on sertraline.
• No changes in MMSE (t = 0.46, p = 0.65). Worsening on FTD Inventory
(t = 2.18, p < 0.05). 4 patients increased disinhibition with improvement
on discontinuation.

• Rivastigmine
• Moretti R et al. Drugs Aging. 2004;21(14):931. 
• n = 40. Rivastigmine x 12 months vs. control (antipsychotics + benzos +
selegiline). Manually divided.
• Reduction in NPI (p < 0.001), BEHAVE-AD (p < 0.001), CSDD (p <
0.001), RSS (p < 0.001). No improvement on MMSE vs. controls.
• Galantamine
• Kertesz A et al. Dement Geriatr Cogn Disord. 2008;25(2):178.
Epub 2008 Jan 14. 
• n = 36. Galantamine open-label x 18 weeks, then randomized, placebo-
controlled x 8 weeks.
• No significant differences in behaviour or language in total group.
Language scores for PPA group remained stable compared to placebo.

• Memantine
• Boxer AL et al. Lancet Neurol. 2013 Feb;12(2):149-56. Epub 2013
Jan 2. 
• n = 81. Memantine x 26 weeks (n = 39) vs. placebo. 5 patients
discontinued.
• No effect on NPI (mean difference 2.2, 95% CI -3.9 to 8.3, p = 0.47),
CGIC (mean difference 0·0, -0.4 to 0.4, p = 0.90). 6 patients had
cognitive adverse events vs. 1 in placebo group.
Serotonergic Medications
• SSRIs
• Swartz JR et al. J Clin Psychiatry. 1997;58(5):212. 
• n = 11. SSRIs x 3 months, no control.
• Improvement in disinhibition (6/9), depressive symptoms (4/6),
carbohydrate craving (5/9), compulsions (4/7) as measured by modified
version of CGI. No improvement on MMSE (p = 0.07, 0.47, 0.46, 0.18
for each subgroup). 

• Moretti R et al. Eur Neurol. 2003;49(1):13. 

• n = 16. Randomized to receive paroxetine vs. piracetam x 20 months.
• Significant improvement in NPI (p < 0.05, p < 0.01), BEHAVE-AD (p <
0.01), CSDD (p < 0.01), RSS (p < 0.05, p < 0.01).
 • Deakin JB et al. Psychopharmacology (Berl). 2004;172(4):400.
Epub 2003 Dec 10. 
• n = 10. Randomized, double-blind, placebo-controlled crossover trial,
assessed at 6 weeks.
• No significant differences on NPI (f = 0.119, p = 0.740) or CBI (f = 2.25,
p = 0.177).

• Trazodone
• Lebert F et al. 2004;17(4):355. 
• n = 26. Randomized, double-blind, placebo-controlled cross-over trial,
assessed at 6 weeks.
• Decrease in NPI (p = 0.028), no change in MMSE (p = 0.1).
Dopaminergic Medications
• Moretti R et al. Am J Alzheimers Dis Other Demen. 2003;18(4):205. 
• 68 patients with AD, vascular dementia, FTD (n = 17), Parkinson’s, DLB.
Neuroleptics started as indicated. Followed x 24 months.
• Decrease in delusions, lability, general social misconduct as measured by NPI (p
< 0.01) and BEHAVE (p < 0.05). Reduced caregiver stress (p < 0.01).

• Fellgiebel A et al. World J Biol Psychiatry. 2007;8(2):123. 

• One 73 year-old male with FTD x 13 months. Clinical status deteriorated over 1
year, then aripiprazole started.
• Improvement in apathy after 5-7 days. MMSE increased from 22 to 24 points. PET
showed increased in glucose metabolism in bilateral prefrontal, premotor, anterior
temporal cortices.

• Pijnenburg YA et al. Int J Geriatr Psychiatry. 2003;18(1):67. 

• n = 100, case notes reviewed.
• 24 prescribed neuroleptics, 8 reported significant extrapyramidal side effects, 5
severe enough to cause mobility problems, 1 resulted in impaired consciousness.
Treatment for Parkinsonism in FTD
• Limited response
• Chow TW et al. Am J Alzheimers Dis Other Demen.
2002;17(5):267. 
• Levodopa/Carbidopa (n = 3): 2 responded with relief of rigidity and
bradykinesia
• Amantadine (n = 9): Improved alertness in one patient, no effect in 2
other patients, increased confusion in one patient. Improved speech
transiently (not detectable on objective testing) for all nonfluent PPA
patients.
Up and coming
• Tau-modifying compounds

• Progranulin boosting medications

Take Home Messages
• Early onset
• Tauopathy, otherwise not fully clear
• bvFTD, semantic variant PPA, nonfluent variant PPA
• Symptom control
• Some evidence for
• SSRIs
• Trazodone,
• Antipsychotics (vulnerable to extrapyramidal side effects)
• Parkinsonism in FTD has limited response to dopamine
agonists
References
• Chapter 424. Frontotemporal Dementia: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of
Internal Medicine, 20e New York, NY: McGraw-Hill.
• Suzee E Lee, MDBruce L Miller, MD. Frontotemporal dementia: Epidemiology, pathology, and pathogenesis. Post TW, ed. UpToDate. Waltham,
MA: UpToDate Inc. http://www.uptodate.com
• Suzee E Lee, MDBruce L Miller, MD. Frontotemporal dementia: Clinical features and diagnosis. Post TW, ed. UpToDate. Waltham, MA:
UpToDate Inc. http://www.uptodate.com
• Suzee E Lee, MDBruce L Miller, MD. Frontotemporal dementia: Treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc.
http://www.uptodate.com
• Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal
dementia. Am J Geriatr Psychiatry. 2007;15(1):84. 
• Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A. Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging.
2004;21(14):931. 
• Kertesz A, Morlog D, Light M, Blair M, Davidson W, Jesso S, Brashear R. Galantamine in frontotemporal dementia and primary progressive
aphasia. Dement Geriatr Cogn Disord. 2008;25(2):178. Epub 2008 Jan 14. 
• Boxer AL, Knopman DS, Kaufer DI, Grossman M, Onyike C, Graf-Radford N, Mendez M, Kerwin D, Lerner A, Wu CK, Koestler M, Shapira J,
Sullivan K, Klepac K, Lipowski K, Ullah J, Fields S, Kramer JH, Merrilees J, Neuhaus J, Mesulam MM, Miller BL. Memantine in patients with
frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2013 Feb;12(2):149-56.
Epub 2013 Jan 2. 
• Swartz JR, Miller BL, Lesser IM, Darby AL. Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. J Clin
Psychiatry. 1997;58(5):212. 
• Moretti R, Torre P, Antonello RM, Cazzato G, Bava A. Frontotemporal dementia: paroxetine as a possible treatment of behavior symptoms. A
randomized, controlled, open 14-month study. Eur Neurol. 2003;49(1):13. 
• Deakin JB, Rahman S, Nestor PJ, Hodges JR, Sahakian BJ. Paroxetine does not improve symptoms and impairs cognition in frontotemporal
dementia: a double-blind randomized controlled trial. Psychopharmacology (Berl). 2004;172(4):400. Epub 2003 Dec 10. 
• Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn
Disord. 2004;17(4):355. 
• Moretti R, Torre P, Antonello RM, Cazzato G, Griggio S, Bava A. Olanzapine as a treatment of neuropsychiatric disorders of Alzheimer's disease
and other dementias: a 24-month follow-up of 68 patients. Am J Alzheimers Dis Other Demen. 2003;18(4):205. 
• Fellgiebel A, Müller MJ, Hiemke C, Bartenstein P, Schreckenberger M. Clinical improvement in a case of frontotemporal dementia under
aripiprazole treatment corresponds to partial recovery of disturbed frontal glucose metabolism. World J Biol Psychiatry. 2007;8(2):123. 
• Pijnenburg YA, Sampson EL, Harvey RJ, Fox NC, Rossor MN. Vulnerability to neuroleptic side effects in frontotemporal lobar degeneration. Int
J Geriatr Psychiatry. 2003;18(1):67. 
• Chow TW, Mendez MF. Goals in symptomatic pharmacologic management of frontotemporal lobar degeneration. Am J Alzheimers Dis Other
Demen. 2002;17(5):267.