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Case Reports
. 2015 Jul 10:3:43.
doi: 10.1186/s40478-015-0216-0.

Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia

Jennifer L Ziskin  1 , Michael D Greicius  2 , Wan Zhu  1 , Anna N Okumu  3 , Christopher M Adams  3 , Edward D Plowey  4
Affiliations
Case Reports

Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia

Jennifer L Ziskin et al. Acta Neuropathol Commun. .

Abstract

Transthyretin/TTR gene mutations usually cause systemic amyloidotic diseases. Few TTR variants preferentially affect the central nervous system, manifesting as oculoleptomeningeal amyloidosis. Patients with TTR meningovascular amyloidosis often show dementia, however the neuropathologic features of dementia in these cases have not been elucidated. We report the neuropathologic findings from a brain autopsy of a 72-year-old man with the rare Tyr69His (Y69H) TTR gene variant, dementia and ataxia. Severe amyloid deposits were observed in the leptomeninges and in a subpial and subependymal distribution. Mass spectrometry analysis demonstrated that the amyloid deposits were comprised of over 80 % of the variant TTR. TTR was undetectable by mass spectrometry in the neocortex subjacent to the subpial amyloid deposits. Subpial TTR amyloid deposits were associated with brisk superficial reactive gliosis and siderosis in the neocortex and cerebellar cortex. Subependymal TTR amyloid deposits were associated with subjacent myelin pallor in the hippocampal outflow tract structures including the alveus, fimbria and fornix. Phospho-tau immunostains demonstrated transentorhinal-stage neurofibrillary degeneration (Braak stage II) which, in the absence of neocortical amyloid-beta and neuritic plaques, was indicative of primary age-related tauopathy (PART). However, distinctive phospho-tau aggregates were observed subjacent to the subpial TTR amyloid deposits in all regions of the neocortex, including the primary motor and striate cortices, suggesting a potential link between TTR amyloid and neocortical tauopathy. Our report reveals novel insights into the potential neuropathologic substrates of dementia in variant TTR amyloidosis that need to be investigated in larger autopsy series.

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Figures

Fig. 1
Fig. 1
Meningovascular and ventricular amyloidosis associated with Tyr69His substitution in TTR. a Gross images demonstrating golden-brown discoloration of the leptomeninges of the cerebral hemispheres and the cisterns at the base of the brain. A coronal section of the brain demonstrates diffuse cortical atrophy, but very little hippocampal atrophy or ventricular dilatation. b A Congo red stain performed on the cerebral leptomeninges highlights the vascular and extravascular amyloid deposits (inset, Congo red under epifluorescence microscopy with Texas red filter; original magnifications of 40×). c Visualization of the Congophilic meningovascular amyloid under polarized light reveals the diagnostic apple-green birefringence (Congo red; original magnification of 40×). d Subpial amyloid deposits in the insular cortex (H&E; original magnification of 40×). e, f Subependymal amyloid deposits in the alveus (e; H&E; original magnification of 100×) and fornix (f; H&E; original magnification of 40×)
Fig. 2
Fig. 2
Evidence of subependymal and subpial injury. Sections of hippocampal efferent tracts from our patient (a-d) were compared to age-matched control cases (e-h). Luxol fast blue (LFB) stains demonstrate myelin pallor in Ammon’s horn (a, e; LFB; original magnification of 10×), the alveus (b, f; LFB; original magnification of 100×) and fimbria (c, g; LFB; original magnification of 100×) in TTR amyloidosis compared to the age matched hippocampus. Myelin basic protein (MBP) immunostains demonstrated similar myelin pallor in the fimbria (d, h; MBP; original magnification of 100×). i. The superficial insular cortex demonstrated gliosis with eosinophilic bodies (arrows; H&E; original magnification of 100×), similar to those reported in Herrick et al. [14], that were variably GFAP immunoreactive (j; GFAP; original magnification of 100×). Iron stains demonstrated siderosis in the upper cortical layers of the superior temporal gyrus (k; iron stain; original magnification of 200×) and in the Bergmann glia of the atrophied cerebellar vermis (l; iron stain; original magnification of 200×)
Fig. 3
Fig. 3
Cortical tauopathy in TTR meningovascular amyloidosis. Phospho-MAPT (AT8) immunostains were performed to determine if TTR meningovascular amyloidosis and dementia were associated with tauopathy. a, b Intense granular, threadlike and globular AT8 immunoreactivity was observed in the molecular layer of the entorhinal cortex (a; AT8; original magnification of 100×) and frontal neocortex (b; AT8; original magnification of 100×) subjacent to subpial amyloid deposits (asterisk). c AT8ir threads and neurons were observed in deep layers of the frontal neocortex (AT8; original magnification of 200×). d Rare neocortical neurofibrillary tangles were also seen (AT8; original magnification of 200×)
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