Figure 1.

Pedigree of families 1–3 with radiological and pathological features. Upper panel: three families were found to have a common ancestor following genealogical research. These families include 8 FTD patients and 3 ALS patients with a confirmed I383V variant in TARDBP (numbered A–K; fully coloured). Half coloured symbols represent patients with a clinical diagnosis without genetic testing. Red: clinical diagnosis of FTD or PPA. Black: clinical diagnosis of ALS or PSMA. Grey: relatives of index patients affected by other forms of dementia or psychiatric disorders. Numbers inside symbols represent additional family members without further clinical information. Numbers below the symbols indicate age at death or current age. Clinical diagnoses: bvFTD, behavioural variant of frontotemporal dementia; svPPA, semantic variant of primary progressive aphasia; ALS, amyotrophiclateral sclerosis; PSMA, progressive spinal muscular atrophy; UD, unspecified dementia; Psych, psychiatric disorder; NA, not affected based on family history; unk, disease status unknown. *Neuropathological examination (patient 1F). Lower left panel: neuroimaging of three FTD patients with the I383V variant showing predominant bitemporal atrophy. MRI scans were obtained 7 years (1C), 6 years (1E) and 9 years (2H) after symptom onset. Quantitative analysis of volumetric loss per brain region is shown in online supplemental figure 2. Lower right panel: immunohistochemistry of patient 1F revealed several pTDP-43 positive neuronalcytoplasmic inclusions (NCI) of various morphologies in the frontal cortex (A) and nucleus caudate (B). Compared to other FTD-TDP cases, the amount of inclusions is low and intranuclear inclusions were not found. Therefore, this patient could not be readily classified into one of the FTLD-TDP subtypes. Staining with AT8 antibody revealed NCI in the hippocampus (C) and tufted astrocytes in nucleus caudate (D). Although this patient was 81 years at death, the observed tau pathology is not compatible with normal aging.