Acta Neuropathologica

, Volume 122, Issue 2, pp 137-153

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Neuropathological background of phenotypical variability in frontotemporal dementia

  • Keith A. JosephsAffiliated withBehavioral Neurology and Movement Disorders, Department of Neurology, Mayo Clinic Email author 
  • , John R. HodgesAffiliated withNeuroscience Research Australia and University of New South Wales
  • , Julie S. SnowdenAffiliated withCerebral Function Unit, University of Manchester
  • , Ian R. MackenzieAffiliated withDepartment of Pathology, University of British Columbia
  • , Manuela NeumannAffiliated withInstitute of Neuropathology, University Hospital of Zurich
  • , David M. MannAffiliated withDepartment of Pathological Sciences, University of Manchester
  • , Dennis W. DicksonAffiliated withDepartment of Neuroscience (Neuropathology), Mayo Clinic


Frontotemporal lobar degeneration (FTLD) is the umbrella term encompassing a heterogeneous group of pathological disorders. With recent discoveries, the FTLDs have been show to classify nicely into three main groups based on the major protein deposited in the brain: FTLD-tau, FTLD-TDP and FTLD-FUS. These pathological groups, and their specific pathologies, underlie a number of well-defined clinical syndromes, including three frontotemporal dementia (FTD) variants [behavioral variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia, and semantic dementia (SD)], progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS). Understanding the neuropathological background of the phenotypic variability in FTD, PSPS and CBS requires large clinicopathological studies. We review current knowledge on the relationship between the FTLD pathologies and clinical syndromes, and pool data from a number of large clinicopathological studies that collectively provide data on 544 cases. Strong relationships were identified as follows: FTD with motor neuron disease and FTLD-TDP; SD and FTLD-TDP; PSPS and FTLD-tau; and CBS and FTLD-tau. However, the relationship between some of these clinical diagnoses and specific pathologies is not so clear cut. In addition, the clinical diagnosis of bvFTD does not have a strong relationship to any FTLD subtype or specific pathology and therefore remains a diagnostic challenge. Some evidence suggests improved clinicopathological association of bvFTD by further refining clinical characteristics. Unlike FTLD-tau and FTLD-TDP, FTLD-FUS has been less well characterized, with only 69 cases reported. However, there appears to be some associations between clinical phenotypes and FTLD-FUS pathologies. Clinical diagnosis is therefore promising in predicting molecular pathology.


Frontotemporal lobar degeneration Progressive supranuclear palsy Tau TDP-43 FUS