Neurodegenerative disorders associated with Tau, Progranulin or TDP-43 pathology — pathology, presentation, course, prognosis and treatment

These three molecules define the frontotemporal lobar degeneration (FTLD) spectrum and its close relatives. FTLD is neuropathologically, genetically and clinically heterogeneous, and the term FTLD is preferred to “dementia” because patients may have progressive neurological dysfunction for substantial periods before meeting criteria for a dementia syndrome.

Histopathological dichotomy: FTLD divides broadly into FTLD-tauopathy and FTLD-U/TDP-43 types on immunohistochemistry. More than 95% of FTLD cases are either TDP-43 proteinopathies (50–60%) or tauopathies (35–45%), with dementia lacking distinctive histopathology (DLDH) and TDP-43-negative ubiquitinated inclusions making up the remaining 5%.

Historical evolution: FTLD was originally split into tau-positive pathology with or without Pick’s bodies and dementia lacking distinctive histopathology (DLDH). Improved immunohistochemistry showed that most “DLDH” cases actually contain ubiquitin-positive, tau-negative intraneuronal inclusions — some with motor neurone disease (FTLD-MND) and some without (FTLD-U).

TDP-43 (TAR DNA-binding protein 43) was then identified as the major pathogenic protein underlying sporadic and familial FTLD-U and FTLD-MND, and also amyotrophic lateral sclerosis — the discovery that unified the FTD–ALS spectrum.

Family history of dementia is present in about 40% of first-degree relatives. About 10% of familial and 0–3% of sporadic cases are linked to specific mutations.

Tau route: many mutations occur in the microtubule-associated protein tau (MAPT) gene on chromosome 17, collectively termed FTD with parkinsonism linked to chromosome 17 (FTDP-17) in familial cases with parkinsonism.

Progranulin route: mutations in the progranulin (GRN/PRGN) gene on chromosome 17 cause TDP-43 proteinopathy. Progranulin mutations are loss-of-function, reducing progranulin in plasma and CSF with over 90% penetrance — the basis for progranulin-elevating therapeutic strategies.

The valosin-containing protein (VCP) gene also produces TDP-43 pathology, causing the rare autosomal dominant inclusion body myopathy with Paget’s disease of bone and FTD (IBMPFD). C9orf72 hexanucleotide repeat expansion is the third major gene, linking FTD and ALS.

Although overlap prevents reliable prediction, the clinical presentation suggests the likely pathology: semantic dementia and FTLD-MND are usually TDP-43 proteinopathies; progressive non-fluent aphasia (and CBD/PSP) is nearly always FTLD-tauopathy; and behavioural-variant FTD is evenly split between tauopathy and TDP-43. This tau–TDP-43 dichotomy underpins strategies for pathology-targeted disease-modifying therapy.

Behavioural-variant FTD (bvFTD, ≥70%) — atrophy of frontal and/or anterior temporal cortex with subsequent basal ganglia involvement. The salient feature is early and profound alteration in personality and social conduct with relative preservation of memory, spatial skills and praxis: disinhibition, apathy, social withdrawal, loss of empathy, hyperorality and dietary change, diminished insight, neglect of personal hygiene, mental rigidity, perseveration, stereotypic and repetitive motor behaviours. Loss of sympathy and empathy often causes family members to resent the patient.

Semantic dementia (SD, ~15%) — temporal-variant FTD with loss of word and object meaning; a right temporal variant with asymmetric right temporal atrophy is the rare hemispheric counterpart. Prosopagnosia is characteristic of the right temporal form.

Progressive non-fluent aphasia (PNFA, ~10%) — atrophy of left inferior frontal lobe, anterior insula and basal ganglia, with progressively worsening non-fluent spontaneous speech, shortened phrase length, agrammatism, phonological paraphasia and anomia, plus stuttering, speech apraxia, impaired repetition, alexia and agraphia. Single-word comprehension and object knowledge are preserved early but syntactic relationships are impaired. Executive function and working memory are often impaired; patients may be impulsive, apathetic or depressed but are generally appropriate and many retain insight.

FTD phenocopy meets bvFTD criteria but runs a very slow course over decades with slow cognitive progression and often normal MRI and PET.

Progressive supranuclear palsy (PSP) — a tauopathy with marked midbrain atrophy, neurofibrillary tangles or neuropil threads in basal ganglia and brainstem, and tau-positive astrocytes. The hallmark is vertical supranuclear gaze palsy with disproportionate limitation of downward gaze (contrast with the upgaze limitation of normal ageing and PD), occurring with intact oculocephalic reflexes. The earliest sign is slowing of voluntary downward saccades. MRI shows the “hummingbird sign” (dorsal midbrain atrophy) or “eye of the tiger” sign; PET/SPECT shows frontal hypoactivity.

Corticobasal degeneration (CBD) — a tauopathy overlapping FTD and PSP, with asymmetric frontoparietal cortical degeneration, severe substantia nigra neuronal loss, ballooned achromatic cells, tau-positive astrocytic plaques, neurofibrillary tangles and neuropil threads. Presents in the sixth or seventh decade with (i) unilateral levodopa-unresponsive parkinsonism; (ii) asymmetrical rigidity, dystonia or focal myoclonus; (iii) cortical signs — asymmetric apraxia, cortical sensory loss, hemineglect, alien limb phenomenon; and (iv) late-onset cognitive impairment. Diagnostic sensitivity is only 30%, and the corticobasal syndrome commonly proves at autopsy to be AD, Pick’s disease, PSP or prion disease.

FTLD onset is most commonly between 45 and 65, though it may present before 30 or in old age; incidence rises with age (2.2 per 100,000 at 40–49, 3.3 at 50–59, 8.9 at 60–69) with equal gender distribution. It is the second commonest dementia under 65 after AD and widely regarded as the third commonest neurodegenerative dementia overall.

Disease duration is about nine years in FTLD-U and tau-positive groups, but significantly shorter — under three years — in FTLD-MND. Age- and education-adjusted autopsy-confirmed studies show FTLD carries shorter survival and faster cognitive and functional decline than AD. Over time the three variants converge into global cognitive impairment with motor deficits including parkinsonism and motor neurone disease.

PSP prognosis is poor: progression to a chairbound state at a median of five years and death at a median of seven years, usually from the sequelae of falls or dysphagia.

Management is multifaceted with no disease-modifying therapy. Caregiver education and support and optimisation of non-pharmacological measures are paramount. Pharmacotherapy is symptomatic, aimed at difficult behaviours and cognitive impairment.

Drug choices: consistent with the selective vulnerability of serotonergic neurons in FTLD, systematic review supports SSRIs and trazodone for modest improvement in behavioural symptoms of bvFTD — impulsivity, disinhibition, repetitive stereotyped behaviour and obsessive-compulsive behaviour; trazodone’s use is limited by sedation. Depression is rare in bvFTD but commoner in SD and PNFA and responds to SSRIs. Apathy is generally recalcitrant to pharmacotherapy, though bupropion (with dopaminergic agonist properties) may be considered where apathy coexists with parkinsonism. Low-dose atypical antipsychotics may be used cautiously for delusions, severe agitation and aggression, given enhanced sensitivity to extrapyramidal side effects, somnolence, weight gain and exacerbation of apathy. Cholinesterase inhibitors have not been shown useful in PSP, and memantine failed in the randomised FTLD trial (Boxer et al.). Emerging targets include tau antibodies, inhibition of tau aggregation with methylene blue derivatives, microtubule-stabilising drugs and tau vaccines. PSP and CBD treatment remains supportive, centred on falls prevention and aggressive surveillance and management of dysphagia.