FTLDtaunegative

FTLDtaunegative refers to forms of frontotemporal lobar degeneration in which tau protein pathology is not present. It is used to distinguish these non-tauopathies from FTLD conditions that involve abnormal tau deposits, such as some tauopathies. The term commonly encompasses FTLD with TDP-43 proteinopathy and FTLD with FET proteinopathies, which together account for a substantial portion of FTLD cases.

Pathology in FTLDtaunegative conditions is defined by neuronal and glial inclusions of non-tau proteins. In FTLD-TDP, aggregates of TAR DNA-binding protein 43 (TDP-43) are found in neurons and glia, with several histopathological subtypes described by inclusion patterns. In FTLD-FET, inclusions involve FET family proteins, such as FUS, or related protein partners, and typically lack tau pathology. These diseases show distinct morphological signatures under neuropathological examination, helping to differentiate them from tau-positive FTLD forms.

Clinically, FTLDtaunegative syndromes commonly present with behavioral variant frontotemporal dementia or primary progressive aphasia. Onset is typically in mid to late adulthood, with progressive changes in behavior, language, and executive function. The clinical course is variable and often more rapid than in some other neurodegenerative diseases. Distinguishing FTLDtaunegative from tauopathies is important for prognosis and potential future therapies.

Genetically, several FTLDtaunegative cases are linked to mutations or risk variants in genes such as GRN and expansions in C9orf72. MAPT mutations, which cause tau-related disease, are usually not the primary drivers of FTLDtaunegative pathology. Diagnosis relies on clinical assessment, neuroimaging showing frontal and/or temporal atrophy, biomarker studies, and ultimately neuropathological confirmation. Currently, management is supportive, with research ongoing into targeted therapies and biomarkers.