Uruk, Gӧkhan

Background/Objectives: The role of iron in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) has been debated. However, the effects of iron on protein burden in these diseases remain poorly elucidated. We hypothesized that there is an association between iron deposition and tau and beta-amyloid deposition in deep grey matter (GM) regions in FTLD. Methods: Neuropathological samples were collected from two control subjects and 10 disease subjects. This included 12 subjects, with several pathological subgroups represented by only one or two cases. Of the 10 disease subjects, one had low-level AD neuropathology (L-AD), and one had high-level AD neuropathology (H-AD), whereas the remaining eight subjects had FTLD-tau pathology, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), globular glial tauopathy (GGT), and Pick’s disease (PiD). Neuropathological samples were stained for iron with Prussian blue (PB) and ferritin, tau, and beta-amyloid in the basal ganglia (BG). All 12 subjects had also undergone diffusion MRI, amyloid-PET (PiB-PET), and Tau-PET (flortaucipir) before death. Diffusion tensor imaging mean diffusivity (MD) from BG was examined in each subject. Spearman’s rank correlations between imaging and histology were calculated. Results: Increased BG iron was observed in PSP subjects. Prussian blue and ferritin measures were associated with higher tau- and β-amyloid pathological burden. Tau-PET uptake correlated with iron in the BG. Conclusions: The results of this exploratory study suggest associations between iron burden and tau- and β-amyloid-related measures within basal ganglia regions that may help to explain increased PET signals in AD and FTLD-Tau. Our findings should be considered to be hypothesis-generating and require validation. These preliminary findings require validation in larger cohorts.

ABSTRACT TAR DNA‐binding protein 43 (TDP‐43) inclusions are defining pathological features of frontotemporal lobar degeneration (FTLD) but are also often observed in Alzheimer's disease ( AD ) and primary age‐related tauopathy (PART). TDP‐43 in AD is either associated with cognitive impairment or a protective‐life prolonging impact, and yet the localization, cellular and fragment characteristics of TDP‐43 need to be determined. We investigated the relationships between TDP‐43 volumetric inclusion burden in low likelihood AD (lAD) and definite PART by immunostaining against phosphorylated TDP‐43 (pTDP‐43), TDP‐43 C terminal (TDP‐C) and TDP‐43 N‐terminal (TDP‐N) fragments combined with 3D confocal imaging taken from eight regions: amygdala (basolateral [amygdala‐BL] and centromedial amygdala [amygdala‐CM]), the hippocampus (Cornu Ammonis [CA]‐1, CA2/3, CA4, dentate gyrus [DG] and subiculum [SUB]) and entorhinal cortex (ERC) and artificial intelligence (AI)–based segmentation via object recognition, reconstruction and quantification. We found amygdala‐CM in lAD and PART to have the overall greatest burden of pTDP‐43 whereas TDP‐N burden in amygdala‐BL of PART cases was greater than other TDP‐43 fragments. There was no difference in TDP‐43 burden in hippocampal subfields in PART. However, CA2/3 region showed greater pTDP‐43 burden while TDP‐N stood out in DG and SUB. Multiple comparisons among the groups revealed that TDP‐C was the only fragment showing differences among PART and lAD in CA2/3, DG and SUB regions. Overall, unbiased AI‐based volumetric burden analysis pipeline demonstrated unique fragment aggregation patterns in the neurodegenerative processes of PART and AD .

Abstract TAR DNA‐binding protein 43 (TDP‐43) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age‐related tauopathy (PART). TDP‐43 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP‐43 are yet to be elucidated. We investigate relationships between TDP‐43 inclusions and the tangle maturation continuum in AD, PART, and co‐pathologies by multiplex immunostaining combined with artificial intelligence (AI)–based segmentation via object recognition, reconstruction, and quantification. We performed anti‐phosphorylated TDP‐43 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP‐43 (PART‐TDP), five cases with high likelihood AD and TDP‐43 (AD‐TDP), and four cases of high likelihood AD with TDP‐43 and Lewy Body disease (AD‐TDP‐LBD). Confocal imaging was taken from eight regions: amygdala (amygdala‐BL and amygdala‐CM) and hippocampus (Cornu Ammonis (CA)‐1, CA2/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP‐43 (TAT) inclusions. TATs, which were either identified by pTDP‐43 and AT8 or pTDP‐43 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre‐TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre‐TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI‐based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP‐43, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region‐specific dynamics in the neurodegenerative processes of PART and AD.

Abstract INTRODUCTION Globular glial tauopathy (GGT) is a rare type of frontotemporal lobar degeneration (FTLD) characterized by deposition of 4‐repeat tau. Detecting GGT with tau positron emission tomography (tau‐PET) is challenging. We aim to determine the associations between tau‐PET, autoradiography, and neuropathology methods in GGT. METHODS We identified three patients with GGT who had completed antemortem tau‐PET. Healthy control and two patients with Alzheimer's disease (AD) were also included for comparison. We analyzed gray matter (GM) and white matter (WM) from the superior/middle frontal gyrus (S/M‐FG) and the superior/middle temporal gyrus (S/M‐TG). Immunohistochemical staining was performed with antibodies against phospho‐tau (AT8, PHF‐1, RD4), glial fibrillary acidic protein (GFAP), and resting microglia (ionized calcium‐binding adaptor molecule 1; Iba1). Immunofluorescence with a fluorescent tau‐PET analog (T726) was performed. Regional tau‐PET standardized uptake value ratios (SUVRs) were calculated for comparative GM and WM regions. Autoradiographic studies with 18F‐AV1451 were also conducted. RESULTS Tau‐PET showed increased uptake in the WM regions of the S/M‐FG and S/M‐TG in GGT, and the GM regions in AD. Co‐localization was observed between T726 and PHF‐1, RD4, and GFAP in the WM in the patients with GGT, whereas co‐localization was observed with PHF‐1 predominantly in the GM in AD. Little co‐localization was observed with Iba1. In vitro 18F‐AV1451 autoradiography studies demonstrated minimal binding in GGT. Tau‐PET differentiated underlying GGT from AD based on the relative involvement of the WM and GM. CONCLUSION Histopathologic findings suggest that some flortaucipir uptake in GGT may represent underlying 4R tau, whereas autoradiographic analysis suggests that uptake is likely due to off‐target binding. Further studies with larger cohorts are needed to determine the pathological basis of flortaucipir uptake in GGT.

Transactive response DNA-binding protein of 43 kDa (TDP-43) and tau proteins play critical roles in neurodegenerative diseases, particularly frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). The co-occurrence of TDP-43 and tau pathologies raises questions about their role in disease progression. This review explores the simultaneous presence of tau and TDP-43 co-pathologies, emphasizing their molecular interactions and the resultant neuropathological implications. Additionally, we provide representative examples of their clinical presentations, neuroimaging, and neuropathological findings associated with FTLD-TDP and FTLD-tau, emphasizing the need for a comprehensive understanding of these intertwined pathologies. We analyze various clinical scenarios, including argyrophilic grain disease (AGD), primary age-related tauopathy (PART), and limbic predominant age-related TDP-43 encephalopathy (LATE), to elucidate the complex relationship between these proteinopathies. From the literature, the co-occurrence of tau and TDP-43 is linked to more severe and poorer clinical outcomes compared to isolated pathologies. This review underscores the necessity of considering co-pathologies in the context of FTLD, as they may act as accelerators of cognitive decline. This highlights the importance of integrated approaches in diagnosing and treating neurodegenerative conditions characterized by tau and TDP-43 misfolding. Understanding the interplay between these molecular markers is vital for advancing therapeutic strategies for such disorders.