Neuropathological criteria of anti-IgLON5-related tauopathy

Abstract

We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define "definite", "probable" and "possible" diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A "definite" diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a "probable" diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A "possible" diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.

Keywords: Brainstem; IgLON5; NREM; Parasomnia; Tauopathy.

Fig. 1

Distribution of tau related pathology in case 3. Coronal sections through the substantia innominata and hypothalamus (a), thalamus with nucleus ruber and substantia nigra (b), cerebellum with pons (c), higher magnification of hippocampus (d, e), pons (f), medulla oblongata at the level of olivary nucleus (g, h), cerebellar cortex (i), and cervical spinal cord (j, k). The tau pathology predominantly affects the hypothalamus, substantia innominata (a), zona incerta, hippocampus (b), and the tegmentum of the brain stem (c); Tangles and threads are abundantly present in the pyramidal layer with the highest density in the CA2 sector (d). Pretangles are also present in the dentate gyrus (rectangle in d enlarged in e). High densities of tangles and threads are present in the tegmentum of pons (f) and medulla oblongata (g). Bush-like delicate processes accumulating around neurons are visible in the olivary nucleus (rectangle in g enlarged in h). Grain-like processes are mainly found in the vermis of the cerebellar cortex, occasionally, a few Purkinje cells show a cytoplasmic tau immunoreactivity (rectangle in c enlarged in i). Moderate tau pathology is apparent mainly in the dorsal horn of the spinal cord (j, enlarged in k)

Fig. 2

Morphology of tau related pathology in case 3. pTau related pathologies include NFT and pretangles (a CA2 sector of the hippocampus; b substantia innominata), diffuse fine granular cytoplasmic immunoreactivity (c gigantocellular nucleus of reticular formation), and numerous somato-synaptic immunoreactivity in the brain stem nuclei (d hypoglossal nucleus), bush-like delicate processes accumulating around neurons (e olivary nucleus), fine granular synaptic-like-deposits (f cerebellar cortex) and long coarse and fine threads (g substantia innominata). These immunomorphologies stain positive for three-repeat- (h) and four-repeat (i) tau isoforms. a–g: AT8 ×400; h: 3RT ×400; i: 4RT ×400

Fig. 3

Schematic distribution of tau pathology in anti-IgLON5 related tauopathy. Coronal sections through the amygdala and the lateral geniculate body (a), midbrain (b), pons (c), medulla oblongata [level of olivary nucleus (d) and decussation of pyramids (e)], and cervical spinal cord (f). Scoring of the frequency of tau pathology in sections stained with tau AT8 is based on the number of tangles and threads: red many; orange moderate; orange dots moderate/few; green dots few; and blue dots isolated. A nucleus ambiguus, AC anterior commissure, Amy amygdala, CA anterior horn, CC crus cerebri, CI inferior colliculus, CN cuneate nucleus, CP posterior horn, ER entorhinal cortex, F fornix, GP pallidum, GN gracile nucleus, HC hippocampus, Hyp hypothalamus, LC locus coeruleus, LTN laterodorsal tegmental nucleus, NPB parabrachial nuclei, NS solitary nucleus, ON olivary nucleus, P putamen, PAG periaquaeductal gray, PI pars intermedia, PPN pedunculopontine nucleus, RU nucleus ruber, R raphe nucleus, RF reticular formation, RF(Gi) gigantocellular reticular nucleus, SG substantia gelatinosa, SI substantia innominata, SN substantia nigra, SNT nucleus of spinal tract of trigeminal nerve, STN subthalamic nucleus, TS solitary tract, V trigeminal nucleus, VIII inf inferior vestibularis nucleus, VIII med medial vestibularis nucleus, X dorsal nucleus vagal nerve, XI spinalis spinal accessory nucleus, XII hypoglossal nucleus, ZI zona incerta