Frontotemporal lobar degeneration: current perspectives

Figures & data

Table 1 International consensus criteria for bvFTD

I. Neurodegenerative disease

The following symptom must be present to meet criteria for bvFTD

A. Shows progressive deterioration of behavior and/or cognition by observation or history (as provided by a knowledgable informant)

II. Possible bvFTD

Three of the following behavioral/cognitive symptoms [A–F] must be present to meet criteria. Ascertainment requires that symptoms be persistent or recurrent, rather than single or rare events

A. Early* behavioral disinhibition (one of the following symptoms [A.1–A.3] must be present):

A.1. Socially inappropriate behavior

A.2. Loss of manners or decorum

A.3. Impulsive, rash, or careless actions

B. Early apathy or inertia (one of the following symptoms [B.1–B.2] must be present):

B.1. Apathy

B.2. Inertia

C. Early loss of sympathy or empathy (one of the following symptoms [C.1–C.2] must be present):

C.1. Diminished response to other people’s needs and feelings

C.2. Diminished social interest, interrelatedness, or personal warmth

D. Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following symptoms [D.1–D.3] must be present):

D.1. Simple repetitive movements

D.2. Complex, compulsive, or ritualistic behaviors

D.3. Stereotypy of speech

E. Hyperorality and dietary changes (one of the following symptoms [E.1–E.3] must be present):

E.1. Altered food preferences

E.2. Binge eating, increased consumption of alcohol or cigarettes

E.3. Oral exploration or consumption of inedible objects

F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (all of the following symptoms [F.1–F.3] must be present):

F.1. Deficits in executive tasks

F.2. Relative sparing of episodic memory

F.3. Relative sparing of visuospatial skills

III. Probable bvFTD

All of the following symptoms [A–C] must be present to meet criteria

A. Meets criteria for possible bvFTD

B. Exhibits significant functional decline (by caregiver report or as evidenced by CDR or FAQ scores)

C. Imaging results consistent with bvFTD (one of the following [C.1–C.2] must be present):

C.1. Frontal and/or anterior temporal atrophy on MRI or CT

C.2. Frontal hypoperfusion or hypometabolism on PET or SPECT

IV. bvFTD with definite FTLD pathology

Criterion A and either Criterion B or C must be present to meet criteria

A. Meets criteria for possible or probable bvFTD

B. Histopathological evidence of FTLD on biopsy or at postmortem

C. Presence of a known pathogenic mutation

V. Exclusionary criteria for bvFTD

Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be positive for possible bvFTD but must be negative for probable bvFTD

A. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders

B. Behavioral disturbance is better accounted for by a psychiatric diagnosis

C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process

Notes:

* As a general guideline, “early” refers to symptom presentation within the first 3 years. Reproduced from Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456–2477, by permission of Oxford University Press.⁷

Abbreviations: bvFTD, behavioral-variant frontotemporal dementia; CDR, clinical dementia rating scale; FAQ, functional activities questionnaire scores; CT, computed tomography; FTLD, frontotemporal lobar degeneration; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

Table 2 Molecular classification of FTLD with genetic and clinical correlations

Molecular class	Pathological subtype*	Associated genes	Clinical phenotypes
			bvFTD	nfvPPA	svPPA	Park	MND
FTLD-tau		• MAPT	+	(+)	(+)	+	ALS, PLS
	• PiD		+	+	(+)
	• CBD		+	+		+	PLS
	• PSP		+	+		+	PLS
	• AGD		+
	• NFT-dementia		+
	• MSTD		+			+	PLS
FTLD-TDP		• (TARDBP)	(+)			+	ALS
	• Type A	• GRN	+	+		+
	• Type B	• C9orf72	+	+	(+)	+	ALS
	• Type C		+		+
	• Type D	• VCP	+			(+)	ALS
FTLD-FUS		• (FUS)	(+)				ALS
	• aFTLD-U		+
	• NIFID		+			+	PLS
	• BIBD		+			+	ALS
FTLD-UPS	• FTD-3	• CHMP2B	+			(+)	(ALS)

Notes:

* Indicates the characteristic pattern of pathology, not the clinical syndrome. (+) Rare cause or unusual phenotype.

Abbreviations: aFTLD-U, atypical frontotemporal lobar degeneration with ubiquitinated inclusions; AGD, argyrophilic grain disease; ALS, amyotrophic lateral sclerosis; BIBD, basophilic inclusion body disease; bvFTD, behavioral-variant FTD; C9orf72, chromosome 9 open reading frame 72; CBD, corticobasal degeneration; CHMP2B, charged multivesicular body protein 2B; FTD, frontotemporal dementia; FTD-3, FTD linked to chromosome 3; FTLD, frontotemporal lobar degeneration; FUS, fused in sarcoma; GRN, progranulin gene; MAPT, microtubule-associated protein tau; MND, motor neuron disease; MSTD, multiple system tauopathy with dementia; NFT-dementia, neurofibrillary tangle predominant dementia; nfvPPA, nonfluent variant primary progressive aphasia; NIFID, neuronal intermediate filament inclusion disease; Park, parkinsonism; PiD, Pick’s disease; PLS, primary lateral sclerosis; PSP, progressive supranuclear palsy; svPPA, semantic variant primary progressive aphasia; TARDBP, transactive response DNA-binding protein; TDP, transactive response DNA-binding protein with molecular weight 43 kDa; UPS, ubiquitin proteasome system; VCP, valosin-containing protein.

Table 3 FTLD – genes

Gene symbol	Chromosomal location	Gene name	Mutation frequency
C9orf72	9p21.2	Chromosome 9 open reading frame 21	14%–48%
GRN	17q21.32	Progranulin	3%–26%
MAPT	17q21.1	Microtubule-associated protein tau	0%–50%
CHMP2B	3p11.2	Charged multivesicular body protein 2B	<1%
VCP	9p13.3	Valosin-containing protein	<1%

Note: Data from Sieben et al.⁵⁷

Abbreviation: FTLD, frontotemporal lobar degeneration.

Table 4 Clinical drug trials in FTLD

Drug	Author	Method	n	Duration	Behavior	Cognition/function
Rivastigmine (3–9 mg/d)	Moretti et al^Citation115	Open-label, controlled	20	12 months	Improved (NPI)	Executive function: unchanged; MMSE: deterioration
Donepezil (5–10 mg/d)	Mendez et al^Citation116	Randomized, open-label, controlled	24	6 months	Worsened (FTD inventory)	Global cognitive performance: unchanged; dementia severity: unchanged
Donepezil (10 mg/d) or rivasigmine (6–12 mg/d)	Lampl et al^Citation117	Randomized comparison trial	9	6 months	Not evaluated	Improved (MMSE, clock drawing)
Galantamine (16 or 24 mg/d)	Kertesz et al^Citation118	Open-label followed by randomized, double-blind, placebo-controlled	36	18 weeks open-label and 8 weeks randomized	No treatment effects (FBI)	Trend of efficacy in language subscores of PPA subgroup; no treatment effect on Clinical Global Impression of Severity and Improvement
Memantine (20 mg/d)	Diehl-Schmid et al^Citation119	Open-label, uncontrolled	16	6 months	Unchanged (NPI, FBI)	Worsened (ADAScog)
Memantine (20 mg/d)	Vercelletto et al^Citation120	Double-blind, placebo-controlled	49	52 weeks	Treatment group slightly better compared to placebo group (FBI)	No treatment effects (CIBIC, MMSE, DAD, MDRS)
Memantine (20 mg/d)	Chow et al^Citation121	Open-label, uncontrolled	16	7–8 weeks	Unchanged (FAB, FBI, SRI)	Unchanged (CDR)
Memantine (20 mg/d)	Boxer et al^Citation122	Multicenter, randomized, double-blind, placebo-controlled	76	26 weeks	No treatment effect (NPI)	No treatment effect (CGIC)

Abbreviations: FTLD, frontotemporal lobar degeneration; NPI, Neuropsychiatric Inventory; FTD, frontotemporal dementia; FBI, Frontal Behavioral Inventory; FAB, Frontal Assessment Battery; SRI, Stereotypy Rating Inventory; MMSE, Mini-Mental State Examination; PPA, primary progressive aphasia; ADAScog, Alzheimer’s Disease Assessment Scale-cognitive subscale; CIBIC, Clinician Interview Based Impression of Change; DAD, Disability Assessment for Dementia; MDRS, Mattis Dementia Rating Scale; CDR, Clinical Dementia Rating; CGIC, Clinical Global Impression of Change; d, day.

Table 5 Serotonergic antidepressants

Drug	Author	Method	n	Duration	Behavior	Cognition/function
Paroxetine (20 mg/d) versus piracetam (1,200 mg/d)	Moretti et al^Citation85	Randomized, controlled	16	14 months	Improved in paroxetine group	Stable in paroxetine group
Paroxetine (40 mg/d)	Deakin et al^Citation123	Randomized, double-blind, placebo-controlled	10	6 weeks	No treatment effect (NPI, CBI)	Cognition (neuropsychological battery): unchanged/worsened
Sertraline (50–100 mg/d)	Mendez et al^Citation124	Open-label	8	6 months	Decreased stereotypical movements	Not evaluated
Trazodone (300 mg/d)	Lebert et al^Citation125	Randomized, double-blind, placebo-controlled, crossover	26	12 weeks	Improved (NPI)	No treatment effect (MMSE)
Fluvoxamine (50–150 mg/d)	Ikeda et al^Citation126	Open-label	15	12 weeks	Improved (NPI, SRI)	Unchanged (MMSE)
Citalopram (40 mg)	Herrmann et al^Citation127	Open-label	15	6 weeks	Improved (NPI, FBI)	Not evaluated
Moclobemide (300–600 mg/d)	Adler et al^Citation128	Open-label	6	4 weeks	Minor improvement of some BPSD (symptom list) in a few patients	Unchanged

Abbreviations: NPI, Neuropsychiatric Inventory; CBI, Cambridge Behavioral Inventory; SRI, Stereotypy Rating Inventory; FBI, Frontal Behavioral Inventory; BPSD, Behavioral and Psychological Symptoms in Dementia; d, day; MMSE, Mini-Mental State Examination.

Table 6 Dopaminergic drugs

Drug	Author	Method	n	Duration	Behavior	Cognition/function
Dextroamphetamine (20 mg/d) versus quetiapine (150 mg/d)	Huey et al^Citation129	Randomized, double-blind, crossover design	8	Two arms of 3 weeks	Improved with dextroamphetamine (NPI)	No treatment effect (RBANS)
Bromocriptine (22.5 mg/d)	Reed et al^Citation130	Double-blind, placebo-controlled, crossover	6, only PPA	Two arms of 7 weeks	Not evaluated	Slight slowing of language deterioration
Methylphenidate (40 mg/d; single dose)	Rahman et al^Citation131	Randomized, double-blind, placebo controlled, crossover	8	Two test sessions, single dose	Decreased risk taking behavior on gambling task	Unchanged (cognitive test battery)

Abbreviations: NPI, Neuropsychiatric Inventory; PPA, primary progressive aphasia; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status.

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