Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.

Frontotemporal lobar degeneration (FTLD)–associated syndromes are progressive neurodegenerative disorders characterized by marked pathological and clinical heterogeneity. Diagnostic criteria are based primarily on presenting clinical features, including the behavioral variant of frontotemporal dementia (bvFTD), which is associated with early behavioral and executive dysfunction; the primary progressive aphasias (PPAs), characterized by progressive language impairment; and motor presentations, such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), or FTD associated with amyotrophic lateral sclerosis (FTD‐ALS)., , FTLD‐related syndromes are associated with atrophy of the frontal and temporal lobes, with the insular cortex proposed as a key epicenter or driving the spread of pathology., , Concomitantly, white matter hyperintensities (WMHs) have been variably described in both genetic and sporadic forms of the disease and have been associated with cognitive performance., , , FTLD‐related syndromes lack well‐established disease‐specific biological markers. Nevertheless, markers of neurodegeneration, such as plasma neurofilament light chain (NfL), and markers of astrogliosis, including plasma glial fibrillary acidic protein (GFAP), have been consistently shown to be increased., , Clinical, imaging, and biological alterations are readily detectable during symptomatic stages of FTLD‐related syndromes; however, abnormalities associated with prodromal disease phases, referred to as mild cognitive, behavioral, and/or motor impairment (MCBMI),, , remain incompletely characterized.