Diffuse argyrophilic grain disease with TDP-43 proteinopathy and neuronal intermediate filament inclusion disease: FTLD with mixed tau, TDP-43 and FUS pathologies

Abstract

Abstract Frontotemporal lobar degeneration (FTLD) is a group of disorders characterized by degeneration of the frontal and temporal lobes, leading to progressive decline in language, behavior, and motor function. FTLD can be further subdivided into three main subtypes, FTLD-tau, FTLD-TDP and FTLD-FUS based which of the three major proteins – tau, TDP-43 or FUS – forms pathological inclusions in neurons and glia. In this report, we describe an 87-year-old woman with a 7-year history of cognitive decline, hand tremor and gait problems, who was thought to have Alzheimer’s disease. At autopsy, histopathological analysis revealed severe neuronal loss, gliosis and spongiosis in the medial temporal lobe, orbitofrontal cortex, cingulate gyrus, amygdala, basal forebrain, nucleus accumbens, caudate nucleus and anteromedial thalamus. Tau immunohistochemistry showed numerous argyrophilic grains, pretangles, thorn-shaped astrocytes, and ballooned neurons in the amygdala, hippocampus, parahippocampal gyrus, anteromedial thalamus, insular cortex, superior temporal gyrus and cingulate gyrus, consistent with diffuse argyrophilic grain disease (AGD). TDP-43 pathology in the form of small, dense, rounded neuronal cytoplasmic inclusion with few short dystrophic neurites was observed in the limbic regions, superior temporal gyrus, striatum and midbrain. No neuronal intranuclear inclusion was observed. Additionally, FUS-positive inclusions were observed in the dentate gyrus. Compact, eosinophilic intranuclear inclusions, so-called “cherry spots,” that were visible on histologic stains were immunopositive for α-internexin. Taken together, the patient had a mixed neurodegenerative disease with features of diffuse AGD, TDP-43 proteinopathy and neuronal intermediate filament inclusion disease. She met criteria for three subtypes of FTLD: FTLD-tau, FTLD-TDP and FTLD-FUS. Her amnestic symptoms that were suggestive of Alzheimer’s type dementia are best explained by diffuse AGD and medial temporal TDP-43 proteinopathy, and her motor symptoms were likely explained by neuronal loss and gliosis due to tau pathology in the substantia nigra. This case underscores the importance of considering multiple proteinopathies in the diagnosis of neurodegenerative diseases.

Keywords

• NIFID
• FUS
• TDP-43
• Argyrophilic grain disease
• Frontotemporal lobar degeneration
• Parkinsonism