Pick’s disease — pathology and treatment

Pick’s disease is a tau-positive frontotemporal lobar degeneration characterised pathologically by Pick bodies, and is one of the classical non-reversible degenerative dementias of the central nervous system, listed alongside Alzheimer’s disease, Lewy body dementia, Parkinson’s disease, Huntington’s disease and progressive supranuclear palsy.

Historically, FTLD was divided into tau-positive pathology with or without Pick’s bodies and dementia lacking distinctive histopathology (DLDH). Pick’s disease is therefore the prototype of the tau-positive limb of the FTLD dichotomy, and today is best regarded as a pathological diagnosis within FTLD-tauopathy (35–45% of all FTLD), most often presenting clinically as behavioural-variant FTD.

Macroscopic: circumscribed, often asymmetric atrophy of the frontal and anterior temporal lobes — the classic “knife-edge” gyral atrophy — with relative sparing of the posterior two-thirds of the superior temporal gyrus, the parietal and occipital lobes.

Microscopic hallmark: Pick bodies — round, well-circumscribed, argyrophilic, tau-positive intraneuronal cytoplasmic inclusions, most abundant in the dentate gyrus of the hippocampus and in frontotemporal cortical neurons.

Pick cells (ballooned achromatic neurons) — swollen, pale-staining neurons — are also seen; identical ballooned achromatic cells occur in corticobasal degeneration, an important point of overlap.

Accompanying features are severe neuronal loss, superficial laminar (layer II/III) spongiosis and gliosis in the affected cortex, with subsequent basal ganglia involvement as the disease advances.

Molecular pathology: Pick’s disease is a 3-repeat (3R) tauopathy, in contrast to the 4-repeat (4R) tauopathies PSP and CBD and the mixed 3R/4R tau of Alzheimer’s disease — the single most discriminating molecular fact.

Genetics: Pick’s disease is usually sporadic, but tau-positive FTLD is linked to MAPT mutations on chromosome 17 (FTDP-17). A family history of dementia is present in about 40% of first-degree relatives across FTLD as a whole.

Presentation is usually that of behavioural-variant FTD: early and profound alteration in personality and social conduct with relative preservation of memory, spatial skills and praxis. Typical behaviours are disinhibition, apathy, social withdrawal, loss of empathy, hyperorality and dietary change, diminished insight, neglect of personal hygiene, mental rigidity, perseveration, stereotypic behaviour and repetitive motor behaviours.

Loss of sympathy and empathy toward family and friends, with decreased social interest and responsiveness to the needs of others, is characteristic and often leads to family members resenting the patient — a distinctive social consequence not seen in AD.

Some patients present instead with progressive non-fluent aphasia, which is nearly always an FTLD-tauopathy; the corticobasal syndrome may also prove at autopsy to be Pick’s disease.

Onset is most commonly between 45 and 65, with equal gender distribution; it is a leading cause of young-onset dementia.

Diagnosis in life is clinical and radiological; definitive diagnosis is neuropathological. MRI or CT shows focal, asymmetric frontal and anterior temporal atrophy, and HMPAO-SPECT shows diminished anterior perfusion, in contrast to the temporoparietal reduction of AD. FDG-PET shows characteristic frontotemporal hypometabolism.

Exclude the treatable and the mimics: complete blood count, glucose, electrolytes, calcium and phosphorus (mg/dL), liver function tests, TSH (µIU/mL), vitamin B12 (pg/mL), syphilis and HIV serology where suspected, plus structural imaging. Psychiatric illness, late-onset mania, AD with frontal presentation and the FTD phenocopy syndrome are the principal differentials.

Prognosis is poor and worse than AD. Disease duration is about nine years in tau-positive FTLD groups, and FTLD is associated with shorter survival and faster cognitive and functional decline than AD in age- and education-adjusted autopsy-confirmed studies. Over time patients develop global cognitive impairment and motor deficits including parkinsonism, and death is commonly from aspiration pneumonia, dysphagia complications or falls.

There is no disease-modifying or curative therapy. Management is multifaceted, with caregiver education and support and optimisation of non-pharmacological measures paramount; pharmacotherapy is aimed at difficult behaviours and cognitive impairment.

SSRIs and trazodone offer modest benefit for the behavioural symptoms of bvFTD, consistent with the selective vulnerability of serotonergic neurons in FTLD. Symptoms that respond include impulsivity, disinhibition, repetitive stereotyped behaviour and obsessive-compulsive behaviour. Trazodone’s use may be limited by sedation.

Depression is rare in bvFTD but commoner in semantic dementia and PNFA and is amenable to SSRI treatment. Apathy is generally recalcitrant to pharmacotherapy and may even be a relief for caregivers of a severely behaviourally disturbed patient; bupropion, with additional dopaminergic agonist properties, can be considered where apathy coexists with parkinsonism.

Low doses of atypical antipsychotics may be considered for delusions, severe agitation and aggression, but must be used cautiously owing to enhanced sensitivity to extrapyramidal side effects, somnolence, weight gain and exacerbation of apathy. Cholinesterase inhibitors and memantine are not indicated — memantine failed in the randomised FTLD trial and ChEIs may worsen behaviour in FTD.

Supportive care is the mainstay: structured routine and environmental simplification, safety measures (driving cessation, financial safeguarding, supervision for hyperorality and impulsivity), speech and language therapy for the aphasic variants, dysphagia surveillance and nutritional support, and early advance care planning. Emerging disease-modifying targets are tau antibodies, inhibition of tau aggregation with methylene blue derivatives, microtubule-stabilising drugs and tau vaccines.