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Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia.

Ziskin JL, Greicius MD, Zhu W, Okumu AN, Adams CM, Plowey ED - Acta Neuropathol Commun (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Stanford University School of Medicine, Edwards Building, Room R-241, 300 Pasteur Drive, Stanford, CA, 94305, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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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Fig3: 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×)

Mentions: Phospho-MAPT immunostains (clone AT8) revealed neurofibrillary tangles in Pre α cells of the entorhinal cortex and focally moderate neurofibrillary tangles in the pyramidal cells of the hippocampal CA1 sector, indicative of Braak stage II or B1 transentorhinal stage of neurofibrillary degeneration (Additional file 1: Figure S4). Although there were conspicuous AT8 immunoreactive (AT8ir) threads surrounding the vestigial hippocampal sulcus (Additional file 1: Figure S4c), we saw no tangles in CA2 or the fascia dentata. Curiously, we also observed neocortical tauopathy characterized by AT8ir threads and neuronal somata. Most distinctive were subpial AT8ir granules, globules and threads subjacent to the subpial TTR amyloid deposits throughout the neocortex (Fig. 3a,b). AT8ir threads and neurons and rare neurofibrillary tangles were also found in the deeper levels of the neocortex (Fig. 3c,d). Subpial and neocortical tauopathy was most prominent in a section of the middle frontal gyrus (Fig. 3), but was present throughout the neocortex including primary motor and striate cortices (Additional file 1: Table S2). The parenchymal threads and most of the AT8ir neurons were not argyrophilic (Gallyas stains, not shown). Scattered axons in the subcortical white matter also demonstrated AT8 immunoreactivity, but there was no apparent tauopathy in glial somata.Fig. 3


Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia.

Ziskin JL, Greicius MD, Zhu W, Okumu AN, Adams CM, Plowey ED - Acta Neuropathol Commun (2015)

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×)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4496870&req=5

Fig3: 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×)
Mentions: Phospho-MAPT immunostains (clone AT8) revealed neurofibrillary tangles in Pre α cells of the entorhinal cortex and focally moderate neurofibrillary tangles in the pyramidal cells of the hippocampal CA1 sector, indicative of Braak stage II or B1 transentorhinal stage of neurofibrillary degeneration (Additional file 1: Figure S4). Although there were conspicuous AT8 immunoreactive (AT8ir) threads surrounding the vestigial hippocampal sulcus (Additional file 1: Figure S4c), we saw no tangles in CA2 or the fascia dentata. Curiously, we also observed neocortical tauopathy characterized by AT8ir threads and neuronal somata. Most distinctive were subpial AT8ir granules, globules and threads subjacent to the subpial TTR amyloid deposits throughout the neocortex (Fig. 3a,b). AT8ir threads and neurons and rare neurofibrillary tangles were also found in the deeper levels of the neocortex (Fig. 3c,d). Subpial and neocortical tauopathy was most prominent in a section of the middle frontal gyrus (Fig. 3), but was present throughout the neocortex including primary motor and striate cortices (Additional file 1: Table S2). The parenchymal threads and most of the AT8ir neurons were not argyrophilic (Gallyas stains, not shown). Scattered axons in the subcortical white matter also demonstrated AT8 immunoreactivity, but there was no apparent tauopathy in glial somata.Fig. 3

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Stanford University School of Medicine, Edwards Building, Room R-241, 300 Pasteur Drive, Stanford, CA, 94305, USA.

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.

No MeSH data available.


Related in: MedlinePlus