Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias

Allegra Kawles; Rachel Keszycki; Grace Minogue; Antonia Zouridakis; Ivan Ayala; Nathan Pruneau Gill; Alyssa Macomber; Vivienne Lubbat; Christina Coventry; Emily Joy Rogalski Miller; Sandra Weintraub; Qinwen Mao; Margaret E. Flanagan; Hui Zhang; Rudolph Castellani; Eileen H Bigio; Marek Marsel Mesulam; Changiz Geula; Tamar Gefen

doi:10.1186/s40478-024-01738-7

Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias

Allegra Kawles, Rachel Keszycki, Grace Minogue, Antonia Zouridakis, Ivan Ayala, Nathan Pruneau Gill, Alyssa Macomber, Vivienne Lubbat, Christina Coventry, Emily Joy Rogalski Miller, Sandra Weintraub, Qinwen Mao, Margaret E. Flanagan, Hui Zhang, Rudolph Castellani, Eileen H Bigio, Marek Marsel Mesulam, Changiz Geula, Tamar Gefen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Pick’s disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer’s Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.

Original language	English (US)
Article number	31
Journal	Acta Neuropathologica Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1186/s40478-024-01738-7
State	Published - Dec 2024

Funding

This study was supported by grants from the National Institute on Aging (P30AG013854, P30 AG072977, R01 AG062566, R01 AG077444, R01 AG056258, K08 AG065463, F31 AG076318, T32 AG020506), National Institute on Deafness and Other Communication Disorders (R01 DC008552), National Institute of Neurological Disorders and Stroke (R01 NS085770, R01 NS075075, T32 NS047987), the National Alzheimer’s Coordinating Center New Investigator Grant (U01 AG016976), the Karen Toffler Charitable Trust, and the National Science Foundation’s Graduate Research Fellowship (DGE-1842165).

Keywords

Behavioral variant frontotemporal dementia
Frontotemporal lobar degeneration
Pick’s disease
Primary progressive aphasia
Stereology
Tau

ASJC Scopus subject areas

Clinical Neurology
Cellular and Molecular Neuroscience
Pathology and Forensic Medicine

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10.1186/s40478-024-01738-7

Cite this

Kawles, A., Keszycki, R., Minogue, G., Zouridakis, A., Ayala, I., Gill, N. P., Macomber, A., Lubbat, V., Coventry, C., Rogalski Miller, E. J., Weintraub, S., Mao, Q., Flanagan, M. E., Zhang, H., Castellani, R., Bigio, E. H., Mesulam, M. M., Geula, C., & Gefen, T. (2024). Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias. Acta Neuropathologica Communications, 12(1), Article 31. https://doi.org/10.1186/s40478-024-01738-7

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title = "Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias",

abstract = "Pick{\textquoteright}s disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer{\textquoteright}s Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.",

keywords = "Behavioral variant frontotemporal dementia, Frontotemporal lobar degeneration, Pick{\textquoteright}s disease, Primary progressive aphasia, Stereology, Tau",

author = "Allegra Kawles and Rachel Keszycki and Grace Minogue and Antonia Zouridakis and Ivan Ayala and Gill, {Nathan Pruneau} and Alyssa Macomber and Vivienne Lubbat and Christina Coventry and {Rogalski Miller}, {Emily Joy} and Sandra Weintraub and Qinwen Mao and Flanagan, {Margaret E.} and Hui Zhang and Rudolph Castellani and Bigio, {Eileen H} and Mesulam, {Marek Marsel} and Changiz Geula and Tamar Gefen",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1186/s40478-024-01738-7",

language = "English (US)",

volume = "12",

journal = "Acta Neuropathologica Communications",

issn = "2051-5960",

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Kawles, A, Keszycki, R, Minogue, G, Zouridakis, A, Ayala, I, Gill, NP, Macomber, A, Lubbat, V, Coventry, C, Rogalski Miller, EJ, Weintraub, S, Mao, Q, Flanagan, ME, Zhang, H, Castellani, R , Bigio, EH , Mesulam, MM , Geula, C & Gefen, T 2024, 'Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias', Acta Neuropathologica Communications, vol. 12, no. 1, 31. https://doi.org/10.1186/s40478-024-01738-7

TY - JOUR

T1 - Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias

AU - Kawles, Allegra

AU - Keszycki, Rachel

AU - Minogue, Grace

AU - Zouridakis, Antonia

AU - Ayala, Ivan

AU - Gill, Nathan Pruneau

AU - Macomber, Alyssa

AU - Lubbat, Vivienne

AU - Coventry, Christina

AU - Rogalski Miller, Emily Joy

AU - Weintraub, Sandra

AU - Mao, Qinwen

AU - Flanagan, Margaret E.

AU - Zhang, Hui

AU - Castellani, Rudolph

AU - Bigio, Eileen H

AU - Mesulam, Marek Marsel

AU - Geula, Changiz

AU - Gefen, Tamar

PY - 2024/12

Y1 - 2024/12

N2 - Pick’s disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer’s Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.

AB - Pick’s disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer’s Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.

KW - Behavioral variant frontotemporal dementia

KW - Frontotemporal lobar degeneration

KW - Pick’s disease

KW - Primary progressive aphasia

KW - Stereology

KW - Tau

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Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias

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