Tauopathy with Hippocampal 4‐Repeat Tau Immunoreactive Spherical Inclusions in a Patient with PSP

Dear editor,

We read with interest the manuscript by Kovacs et al entitled “Tauopathy with hippocampal 4‐repeat tau immunoreactive spherical inclusions: a report of three cases” 2. The authors described the clinical and neuropathologic features of three patients with a novel 4‐repeat tauopathy characterized by hippocampal spherical inclusions. Previously, Miki and colleagues, also reported another case with similar neuropathologic findings 3.

One of the cases reported by Kovacs et al was identified after screening 240 Alzheimer disease (AD) or primary age‐related tauopathy (PART) cases, while two of them were identified among 50 patients with subcortical tau pathology consistent with progressive supranuclear palsy (PSP). This prompted us to systematically assess hippocampal sections stained by AT8 immunohistochemistry of 70 PSP and 30 Cortico‐Basal Degeneration (CBD) archival cases with the aim to identify potential subjects with hippocampal spherical inclusions. We detected a single case among the PSP group with the same neuropathological features as described by Miki et al and Kovacs et al. The patient was a 69‐year‐old man who suffered from progressive memory dysfunction, depression, and apathy starting at age of 58. He scored 24/30 at the Mini mental state examination when he was 64. During disease evolution, he developed hallucinations and a rapidly progressive parkinsonism. No further clinical details were available. The clinical diagnosis was dementia with Lewy bodies. The patient died at the age of 69 years after total disease duration of 11 years. There was no family history of neurological disorders or dementia. No mutations in exons 1, 9, 10, 11, 12, and 13 of the MAPT gene were found.

Brain was removed after death for diagnostic and research purposes after obtaining written informed consent form the next of kin. Unfixed brain weight was 1115 g. Gross examination revealed mild global brain atrophy accentuated in the hippocampus. The subthalamic nucleus was atrophic and the substantia nigra showed severe pallor.

Histological examination confirmed a severe loss of pigmented neurons of the substantia nigra pars compacta, a mild neuronal loss in locus coeruleus and of the external and internal globus pallidus. There was also prominent neuronal loss of the subthalamic nucleus. All these areas were accompanied by astrogliosis and microglial activation. Residual neurons of the brainstem, subthalamic nucleus, and large cholinergic neurons of basal ganglia showed frequent globose tangles. The most striking feature was the severe involvement of the hippocampus. There was a nearly complete loss of pyramidal neurons of the CA4‐CA1 sectors and a prominent depletion of granular neurons of the dentate gyrus, consistent with hippocampal sclerosis (Figure 1A,B). Frequent basophilic spherical inclusions of the size of the nucleus reminiscent of Pick bodies were detected in granular neurons of the dentate gyrus and pyramidal neurons of CA1 sector (Figure 1C).

Figure 1.

A–C. HE stained section of the hippocampus showing prominent narrowing of the hippocampus and parahippocampal region. B. Marked neuronal loss is observed in dentate gyrus and CA1 sector. C. Residual neurons of the dentate gyrus reveal frequent large basophilic and fibrilar spherical cytoplasmic inclusions. D–J. Immunohistochemistry of the hippocampus shows an extensive tauopathy (D, RD4 tau isoforms), with severe involvement of granular neurons of the hippocampus (E, AT8). Spherical inclusions consist mainly of 4R tau isoforms (F, RD4); immunohistochemistry for 3R‐tau isoforms shows a granular cytoplasmic immunoreactivity of some neurons (F, lower right). G–J. Spherical inclusions are immunoreactive for phosphospecific tau antibodies to serine 422 (G), serine 396 (H), threonine 181 (I) residues, and are weakly stained by serine 262 (J). K–M. PSP type pathology: abundant tufted astrocytes in caudate nucleus (K and L: upper panel; RD4 immunohistochemistry) and coiled bodies in white matter tracts (L, lower panel; RD4 immunohistochemistry). M. Involvement of substantia nigra with abundant globose tangles, some pretangles and glial tau pathology (AT8 immunohistochemistry).

Immunohistochemistry showed extensive neuronal and glial p‐tau pathology. There were frequent tufted astrocytes in all cortical areas, basal ganglia, limbic system, and brainstem nuclei as well as frequent coiled bodies in white matter oligodendrocytes (Figure 1K,L). In addition, a moderate amount of neurofibrillary tangles of the globose type were observed in basal ganglia, subthalamic nucleus, nucleus basalis of Meynert, and brainstem nuclei (Figure 1M). There was also moderate involvement of the pontine nuclei and of the dentate nucleus of the cerebellum, as well as of the spinal cord. The hippocampus showed very frequent spherical inclusions in the dentate gyrus and also in the different sectors of the hippocampus, parahippocampal gyrus, and temporo‐occipital cortex together with Neurofibrillary Tangle (NFT) (Figure 1E). Spherical inclusions were also detected in cortical areas and basal ganglia. This pathology was predominantly immunoreactive for 4R tau isoforms and was negative for 3R tau isoforms, except for few NFT in the CA1 sector of the hippocampus (Figure 1F) and an unusual granular cytoplasmic immunoreactivity of some hippocampal neurons (Figure 1F lower right panel). Spherical inclusions were strongly stained by phospho‐specific tau antibodies to serine 396, serine 422, threonine 181, and to a lesser extent to serine 262 (all from Calbiochem, La Jolla, CA, USA) (Figure 1G–J). There were only mild B4 amyloid deposits in cortical areas and the limbic system with only few deposits in basal ganglia corresponding to Thal phase 3, and few neuritic plaques (CERAD plaques score A). No α‐synuclein or TDP‐43 proteins aggregates were detected.

These features were consistent with those of PSP with an atypical and severe involvement of the hippocampus, concordant with the observations made by Miki et al and Kovacs and colleagues. Our findings reinforce the notion that this morphological phenotype seems to be different from other established tauopathies. Indeed, our patient presented more prominent supratentorial pathology than in the brainstem in contrast to what is observed in typical PSP 1. The prominent hippocampal involvement is reminiscent of Pick's disease but instead of 3R tau pathology these cases are dominated by 4R tau isoforms. In accordance with the clinical features described by Kovacs, our patient also presented cognitive impairment that could be related to the severe degeneration of hippocampal structures. Cognitive impairment was not reported in the patient described by Miki et al. Our patient also presented psychiatric symptoms, specifically depression and hallucinations. Although no psychiatric symptoms were reported in the patients described by Kovacs, depression was the main symptom in the case reported by Miki and colleagues.

In conclusion, we report an additional case of this uncommon and newly described morphological phenotype that expands the spectrum of previously described tauopathies. This tauopathy with hippocampal 4‐repeat tau immunoreactive spherical inclusions and hippocampal sclerosis may be the substrate of cognitive, extrapyramidal and psychiatric symptoms. More studies are needed to identify the whole clinico‐pathologic spectrum of this novel tauopathy.