Frontotemporal Lobar degeneration with TDP-43 presenting as progressive supranuclear palsy syndrome

Abstract

Objective: Frontotemporal lobar degeneration with TDP-43 pathology (FTLD) usually presents with frontotemporal dementia, semantic aphasia or progressive nonfluent aphasia. Corticobasal syndrome and atypical parkinsonism have been occasionally reported, but progressive supranuclear palsy (PSP) syndrome (also known as Richardson syndrome (RS)) has not been reported in patients with FTLD-TDP. In this study we report clinical and pathologic characteristics of FTLD-TDP, clinically diagnosed as PSP syndrome (FTLD-TDP-PSP).

Methods: We reviewed clinical information of 270 patients with FTLD-TDP from the Mayo Clinic brain bank and identified 5 patients with FTLD-TDP-PSP. As a control group, we selected ten consecutive patients of pathologically confirmed PSP with clinical presentations of PSP syndrome (PSP-RS). We compared the clinical and pathological features of FTLD-TDP-PSP and PSP-RS.

Results: The most common clinical symptoms in FTLD-TDP-PSP were memory loss (100%) followed by parkinsonism (80%), early falls (60%), and behavioral variant FTD (60%). All patients with PSP-RS met the Movement Disorder Society's criteria for probable PSP, while only one FTLD-TDP-PSP met the probable PSP. Two of the five patients with FTLD-TDP-PSP had moderate or severe neuronal loss in the substantia nigra and one had moderate or severe neuronal loss in the putamen and globus pallidus.

Conclusion: A small subset of patients with FTLD-TDP can, in rare instances, present with symptoms associated with PSP. Therefore, FTLD-TDP may be considered in differential diagnosis, especially in patients who do not meet the diagnostic criteria. Our findings emphasize the need for further clinical and biomarker studies of FTLD-TDP.

Keywords: Frontotemporal Lobar degeneration; Progressive supranuclear palsy; TDP-43.

Fig. 1

Flow chart of study design. FTLD-TDP = frontotemporal lobar degeneration with TDP-43; FTLD-TDP-PSP = frontotemporal lobar degeneration with TDP-43, clinically diagnosed as progressive supranuclear palsy syndrome; PSP-RS = progressive supranuclear palsy with PSP syndrome; PSP = progressive supranuclear palsy; RS = Richardson syndrome

Fig. 2

Heatmap based on neuronal loss and neuronal cytoplasmic inclusions in 5 cases of FTLD-TDP-PSP. The heatmap reflects the severity of neuronal loss and density of neuronal cytoplasmic inclusions in each brain region. The color scale is on the right. According to the Movement Disorder Society progressive supranuclear palsy (PSP) diagnostic criteria, Case 1 fulfilled the criteria for probable PSP, Cases 2 and 3 for suggestive PSP, and Cases 4 and 5 did not meet the diagnostic criteria. NCI = TDP-43-positive neuronal cytoplasmic inclusions

Fig. 3

Representative macroscopic and histopathologic images. (A) The brain shows frontotemporal atrophy. (B) The substantia nigra has reduced pigment (arrow). (C) The H&E staining of the substantia nigra shows a moderate neuronal loss. Free melanin is observed (arrow). (D-K) pTDP43-positive NCIs and glial cytoplasmic inclusions are observed in the substantia nigra (D), globus pallidus (E), putamen (F), subthalamic nucleus (G), middle frontal gyrus (H), superior temporal gyrus (I), subiculum (J), and amygdala (K). B: H&E staining; D-K: pTDP43 immunostaining. Scale bars: A = 3 cm; B = 1 cm; C-K = 50 μm