Primary Age-Related Tauopathy in Human Subcortical Nuclei.

Keqing Zhu,Chong Liu,Bing Sun,Huazheng Liang,Juanli Wu,Hui Lu,Dandan Zhang,Xiaoling Zhang,Xin Wang

doi:10.3389/fnins.2019.00529

Abstract

The present study aimed to determine the spatial distribution patterns of hyperphosphorylated tau-immunoreactive cells in subcortical nuclei of post-mortem human brain with primary age-related tauopathy (PART). Subcortical tauopathy has important pathological and clinical implications. Expression of tau was examined in different subcortical regions of definite PART cases with a Braak neurofibrillary tangle stage >0 and ≤IV, and with a Thal phase 0 (no beta-amyloid present). Post-mortem brain tissue of PART was studied using immunohistochemistry and subsequent semi-quantitative assessment with Braak NFT stage -matched pre-Alzheimer’s disease (AD) and AD cases as a control. Expression of tau was frequently found in subcortical nuclei including the substantia nigra, inferior colliculus, locus coeruleus, medulla oblongata in the brainstem, the caudate, putamen, nucleus globus pallidus in the striatum, the hypothalamus, thalamus, subthalamus in the diencephalon, and the cervical spinal cord in both PART and AD, but not in the dentate nucleus of the cerebellum. A positive correlation was found between the Braak NFT stage and the tau distribution (qualitative)/tau density (quantitative) in PART and AD. Brainstem nuclei were commonly involved in early PART with NFT Braak stage I/II, there was no preference among the substantia nigra, inferior colliculus, locus caeruleus and medulla oblongata. The prevalence and severity of tau pathology in subcortical nuclei of PART and AD were positively correlated with NFT Braak stage, suggesting that these nuclei were increasingly involved as PART and AD progressed. Subcortical nuclei were likely the sites initially affected by aging associated tau pathology, especially the brainstem nuclei including the substantia nigra, inferior colliculus, locus caeruleus and medulla oblongata.

Highlights

The stepwise progression of tau pathology in Alzheimer’s disease (AD) is reflected by NFT Braak stages and this pathology is generally assumed to begin from the trans-entorhinal region (Braak et al, 2006)
Recent studies indicated that tau pathology in AD did not initially manifest in the cerebral cortex but in selected subcortical nuclei, including the thalamus, striatum and brainstem, in particular locus caeruleus (LC) (Elobeid et al, 2012)
The thalamus and striatum were found to be atrophied in symptomatic patients, with an altered caudate volume implicated in early stage AD (Leh et al, 2016)

Summary

INTRODUCTION

The stepwise progression of tau pathology in Alzheimer’s disease (AD) is reflected by NFT Braak stages and this pathology is generally assumed to begin from the trans-entorhinal region (Braak et al, 2006). Tauopathy was reported in the aging brain (Wharton et al, 2016), but this phenomenon has not been comprehensively described in PART To address this issue, we examined tau pathology in the subcortical nuclei of definite PART cases that met the pathological criteria, Braak NFT stage-matched preAD, and AD cases. The severity (distribution and density) of tau pathology in these subcortical nuclei was significantly correlated with Braak stages and tauopathy in nuclei of the brainstem, striatum and diencephalon has important pathological and clinical consequences (Theofilas et al, 2015)

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT