Behavioral variant frontotemporal dementia

General

bvFTD involves a progressive disturbance in personality, emotion, and behavior (Ljubenkov and Miller, 2016)

• reflects decline in function / connectivity among several paralimbic brain regions, including medial frontal, orbitofrontal, ACC, and frontal insular cortices (Ljubenkov and Miller, 2016)
• symptoms driven by severity of dysfunction in nondominant frontotemporal regions (generally right-sided)
• apathy is most common first symptom (passivity, indecisiveness, loss of interest (in hygiene, hobbies, social interaction, work responsibilities, domestic responsibilities) (Ljubenkov and Miller, 2016)
• social disinhibition or loss of tact is typically experienced by a profound and obvious loss of insight. (Ljubenkov and Miller, 2016)
• though not a core criteria, psychotic phenomenon such as hallucinations and bizarre or somatic delusions early in the dementia course can be associated with C9ORF72 mutation (Finger 2016)

Diagnosis

Clinical criteria for bvFTD (Rascovsky et al, 2011)

1) Shows progressive deterioration of behavior and/or cognition by observation or history

2) For possible diagnosis, three of the following must be present to meet criteria

a. Early behavioral disinhibition (1+ of the following):

i. Socially inappropriate behavior

ii. Loss of manners or decorum

iii. Impulsive, rash, or careless actions (including inappropriate disclosure of information to strangers, like medical information or finances)

b. Early apathy or inertia (1+ of the following):

i. Apathy (may spend hours sitting on the couch staring at wall or television)

ii. Inertia

c. Early loss of sympathy or empathy (1+ of the following):

i. Diminished response to other people’s needs and feelings

ii. Diminished social interest, interrelatedness, or personal warmth

d. Early perseverative, stereotyped, or compulsive/ritualistic behavior (1+ of the following):

i. Simple repetitive movements

ii. Complex, compulsive, or ritualistic behaviors

iii. Stereotypy of speech

e. Hyperorality and dietary changes (1+ of the following):

i. Altered food preferences (typically sweets)

ii. Binge eating, increased consumption of alcohol or cigarettes

iii. Oral exploration or consumption of inedible objects

f. On neuropsychological testing, all the following symptoms:

i. Deficits in executive tasks

ii. Relative sparing of episodic memory (presence of impaired episodic memory does not rule out bvFTD)

iii. Relative sparing of visuospatial skills

3) For probable diagnosis, all the following symptoms must be present:

a. Meets criteria for possible bvFTD

b. Exhibits significant functional decline (by caregiver report, CDRS, or FAQ)

c. Imaging results consistent with bvFTD (1+ of the following):

i. Frontal and/or anterior temporal atrophy on MRI or CT

ii. Frontal and/or anterior temporal hypoperfusion or hypometabolism on SPECT or PET

4) For bvFTD with definite FTLD pathology:

a. Must meet criteria for possible or probable bvFTD

b. Must have either of the following:

i. Histopathological evidence of FTLD on biopsy or at post-mortem

ii. Presence of a known pathogenic mutation

5) Exclusionary criteria for bvFTD, criteria A and B must be answered negative for any bvFTD diagnosis, criterion C can be positive for possible but not 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

Examination

- Neurological examination includes observation of above behavioral symptoms. They may show evidence of poor grooming and hygiene. Affect may be flat or conversely childish. Frontal release signs such as snout or grasp reflex may be present but this is neither sensitive or specific for bvFTD. (Finger 2016)

- Neuropsychological examination typically shows dysexecutive pattern with preservation of memory storage and visuospatial abilities, though early in the disease course executive functioning may be relatively normal. (Finger 2016)

Imaging

(Ljubenkov and Miller 2016)

- Axial view shows right greater than left atrophy of the frontal lobe, including the insular cortex (A1), lateral prefrontal cortex (A2), and anterior cingulate along with adjacent medial prefrontal cortex (A3).

- Coronal view shows asymmetric atrophy of the orbitofrontal cortex (B1), insular cortex (B2), lateral prefrontal cortex (B3), and anterior cingulate along with adjacent medial prefrontal cortex (B4).

- Sagittal view of the mesial right hemisphere shows frontal atrophy including medial prefrontal cortex (C1), pregenual cingulate (C2), orbitofrontal cortex (C3), and subgenual cingulate (C4).

- Mutation specific atrophy patterns (Finger 2016)

• C9ORF72: predominantly frontal atrophy

• MAPT: Predominantly anteromedial temporal atrophy

• GRN: Predominantly temporal, insular, and parietal lobe atrophy

Pathology

- bvFTD underlying pathology, generally Tau (3R > 4R) ≈ TDP-43 (type A ≥ type B > type D) > (Alzheimer’s pathology) > FUS (Ljubenkov and Miller 2016)

Treatment

1) Nonpharmacologic (Ljubenkov and Miller 2016)

a. Caregiver education / environmental intervention (encouraging caregivers to strategize with distraction, redirection, and simplification of complex decisions rather than confrontation and rational debate)

b. Social engagement is important, but avoid overstimulation in favor of ordered / structured environment

c. Restriction of access to items that may incite unwanted behaviors (car keys, excess food)

d. Caregiver support early in management, high risk of caregiver burnout

2) Pharmacologic (Ljubenkov and Miller 2016)

a. No FDA-approved therapies for treatment of bvFTD

b. SSRIs – early case reports and case series studies with various SSRIs (fluoxetine, sertraline, paroxetine) have some efficacy in treating compulsions, hyperorality, depression, inappropriate sexual behavior, disinhibition

c. Trazodone – some improvement in agitation, irritability, eating disorders

d. Stimulants – some limited benefit in risk-taking behavior or apathy, but overall due to risk of delirium and paucity of good data stimulants are generally discouraged.

e. Acetylcholinesterase inhibitors and memantine have not been shown to be helpful, and may paradoxically worsen agitation

f. Antipsychotics (risperidone, olanzapine) and mood stabilizers (valproate) are occasionally used to treat psychosis and agitation, but there’s inherent risk and paucity of evidence associated with their use

References

Finger, E. C. Frontotemporal Dementias. Contin. Minneap. Minn 22, 464–489 (2016). PubMed link

Ljubenkov, P. A. & Miller, B. L. A Clinical Guide to Frontotemporal Dementias. FOCUS 14, 448–464 (2016). PubMed link

Rascovsky, K. et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477 (2011). PubMed link