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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

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×)
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Fig2: 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×)

Mentions: We further investigated the brain for neuropathology to explain his dementia. We hypothesized that the prominent subependymal amyloidosis (Fig. 1e,f) might damage hippocampal efferent tracts that line the ventricles, including the alveus, fimbria and fornix. Special stains for myelin, including LFB/PAS and myelin basic protein immunohistochemistry, demonstrated severe myelin pallor in the alveus and fimbria compared to 2 age-matched autopsy brains with no significant neuropathology (Fig. 2a-h). There was no histologic evidence of subcortical leukoencephalopathy and only a single, minute, remote cortical infarct was seen in a section of the right postcentral gyrus (Additional file 1: Figure S5f). The lack of ischemic pathology is consistent with pre-mortem 3 T magnetic resonance FLAIR images showing no obvious white matter changes or microinfarcts (Additional file 1: Figure S3a). We observed brisk gliosis in the upper neocortical layers subjacent to the subpial amyloid deposits (Fig. 2i,j). These findings suggest that subependymal and subpial TTR amyloid deposits are associated with injury to the subjacent brain parenchyma, including hippocampal efferent tracts and superficial layers of the neocortex. Iron deposits were observed histologically in the superficial neocortex, especially in sections of the frontal and temporal lobes (Fig. 2k), and in the Bergmann glia of the atrophied Purkinje cell layer of the vermis (Fig. 2l). Pre-mortem GRE images also demonstrate the superficial siderosis (Additional file 1: Figure S3b). Recent or remote microvascular hemorrhages were not seen.Fig. 2


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)

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×)
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Related In: Results  -  Collection

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Fig2: 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×)
Mentions: We further investigated the brain for neuropathology to explain his dementia. We hypothesized that the prominent subependymal amyloidosis (Fig. 1e,f) might damage hippocampal efferent tracts that line the ventricles, including the alveus, fimbria and fornix. Special stains for myelin, including LFB/PAS and myelin basic protein immunohistochemistry, demonstrated severe myelin pallor in the alveus and fimbria compared to 2 age-matched autopsy brains with no significant neuropathology (Fig. 2a-h). There was no histologic evidence of subcortical leukoencephalopathy and only a single, minute, remote cortical infarct was seen in a section of the right postcentral gyrus (Additional file 1: Figure S5f). The lack of ischemic pathology is consistent with pre-mortem 3 T magnetic resonance FLAIR images showing no obvious white matter changes or microinfarcts (Additional file 1: Figure S3a). We observed brisk gliosis in the upper neocortical layers subjacent to the subpial amyloid deposits (Fig. 2i,j). These findings suggest that subependymal and subpial TTR amyloid deposits are associated with injury to the subjacent brain parenchyma, including hippocampal efferent tracts and superficial layers of the neocortex. Iron deposits were observed histologically in the superficial neocortex, especially in sections of the frontal and temporal lobes (Fig. 2k), and in the Bergmann glia of the atrophied Purkinje cell layer of the vermis (Fig. 2l). Pre-mortem GRE images also demonstrate the superficial siderosis (Additional file 1: Figure S3b). Recent or remote microvascular hemorrhages were not seen.Fig. 2

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