Frontotemporal dementia (frontotemporal lobar degeneration)

Frontotemporal dementia is a condition in which the frontal and temporal lobes are affected, causing cognitive and behavioral changes. It is one of the most common causes of midlife dementia.

Pathological features include atrophy of the frontal and temporal lobes, inclusions, microvacuolation, swollen neurons, neuronal loss and gliosis. Different substances may be present in different types of frontotemporal lobar degeneration, such as hyper phosphorylated tau protein, 43 kD transactive response (TAR) DNA binding protein (TDP-43) protein or fused in sarcoma (FUS) protein. Pick bodies (round, silver-staining inclusions) may be present.

CLINICAL PRESENTATIONS:

Behavioral Variant FTD (bvFTD) (~50% of the cases): Presents with disinhibition (improper social or sexual behavior), loss of empathy, hyperorality and compulsive behavior.

Nonfluent/Agrammatic Primary Progressive Aphasia: Progressive motor speech deficit characterized by effortful production of the linguistic units of sound (phonemes).

Semantic Primary Progressive Aphasia: Progressive impaired single-word comprehension and object naming in the setting of preserved fluency, repetition, and grammar.

FTD may present with motor symptoms, although that is not common. When motor symptoms appear, it is usually one of the syndromes below:

Motor neuron disease: Affects both upper motor neurons (resulting in pyramidal signs such as spasticity and hyperreflexia) and lower motor neurons (resulting in weakness, atrophy, and fasciculations). It also may have bulbar involvement resulting in facial weakness, tongue weakness or dysphagia).

Corticobasal syndrome: Progressive asymmetric movement disorder characterized by various combinations of akinesia, rigidity, dystonia, focal myoclonus, ideomotor apraxia, and alien-limb phenomena

Progressive supranuclear palsy: Progressive supranuclear ophthalmoplegia (vertical gaze palsy), gait disorder and postural instability (axial dystonia with hypererect posture), dysarthria, dysphagia, rigidity, and falls.

In patients with prominent psychosis or hallucinations, dementia with Lewy bodies should be considered.

DIAGNOSIS:

Diagnosis is made by detailed history and neurologic examination.

Additional tests such as blood tests (CBC, autoimmune tests, B12, TSH), brain imaging, EEG and CSF analysis may be useful to exclude differential diagnosis.

Criteria for 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 Clinical Dementia Rating Scale or Functional Activities Questionnaire 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 and/or anterior temporal hypoperfusion or hypometabolism on PET or SPECT

Behavioural variant FTD 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 post-mortem

C. Presence of a known pathogenic mutation

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. Behavioural disturbance is better accounted for by a psychiatric diagnosis

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

*As a general guideline ‘early’ refers to symptom presentation within the first 3 years (for further discussion see Supplementary material, Appendix 1).

Criteria for PPA (general):

Inclusion: criteria 1–3 must be answered positively

Most prominent clinical feature is difficulty with language
These deficits are the principal cause of impaired daily living activities
Aphasia should be the most prominent deficit at symptom onset and for the initial phases of the disease

Exclusion: criteria 1–4 must be answered negatively for a PPA diagnosis

Pattern of deficits is better accounted for by other nondegenerative nervous system or medical disorders
Cognitive disturbance is better accounted for by a psychiatric diagnosis
Prominent initial episodic memory, visual memory, and visuoperceptual impairments
Prominent, initial behavioral disturbance

TREATMENT:

Due to extreme behavioral changes, discussions regarding financial decision making, early retirement, and driving safety should be a part of the initial treatment. Other nonpharmacological treatments (exercise, speech therapy) should be encouraged.

Patients with sudden change of the basal status should be investigated for delirium and its causes (environment change, medications, drugs, dehydration, infection, metabolic abnormalities).

SSRIs (paroxetine 10mg qDay or BID) may be useful for behavioral symptoms. Other medications, including antipsychotics, should be used only as a last resort if necessary. Dopamine agonists and cholinesterase inhibitors do not produce good results in these patients.

SOURCES & FURTHER READING: