FTLD-TDP with motor neuron disease, visuospatial impairment and a progressive supranuclear palsy-like syndrome: broadening the clinical phenotype of TDP-43 proteinopathies. A report of three cases

We present three cases with similar clinical symptoms, including Parkinsonism, supranuclear gaze palsy, visuospatial impairment and a behavioral variant of frontotemporal dementia, associated with either clinically possible or definite MND. Neuropathological examination revealed hallmarks of FTLD-TDP with major involvement of subcortical and, in particular, mesencephalic structures. These cases differed in onset and progression of clinical manifestations as well as distribution of histopathological changes in the brain and spinal cord. Two cases were sporadic, whereas the third case had a pathological variation in the progranulin gene 102 delC.Association of a "progressive supranuclear palsy-like" syndrome with marked visuospatial impairment, motor neuron disease and early behavioral disturbances may represent a clinically distinct phenotype of FTLD-TDP. Our observations further support the concept that TDP-43 proteinopathies represent a spectrum of disorders, where preferential localization of pathogenetic inclusions and neuronal cell loss defines clinical phenotypes ranging from frontotemporal dementia with or without motor neuron disease, to corticobasal syndrome and to a progressive supranuclear palsy-like syndrome.Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by frontotemporal lobar degeneration with ubiquitin and transactive response DNA binding protein 43 (TDP-43) positive inclusions (FTLD-TDP) represent two different manifestations of the same neurodegenerative disease [1]. Distribution of TDP-43 related neuropathological changes include various anatomical regions with differences in the predominance of lesions, suggesting that TDP-43 proteinopathies reflect the spectrum of a multisystem disorder [2-4]. Mutations in the progranulin (PGRN) gene, located on chromosome 17, have been linked to inherited forms associated with neuropathologically detectable TDP-43 proteinopathy and with different clinical symptomatology [5-7]. Moreov