Cortical cholinergic denervation in primary progressive aphasia with Alzheimer pathology

Marek-Marsel Mesulam, Nava Lalehzari, Farzan Rahmani, Daniel Ohm, Ryan Shahidehpour, Garam Kim, Tamar Devora Gefen, Sandra Weintraub, Eileen H Bigio, Changiz Geula

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To investigate the status of the basal forebrain cholinergic system in primary progressive aphasia (PPA) as justification for cholinergic therapy. METHODS: A cohort of 36 brains from PPA participants with the neuropathology of Alzheimer disease (PPA-AD, n = 14) or frontotemporal lobar degeneration (PPA-tau, n = 12; PPA-TDP, n = 10) were used for semiquantitative rating of degeneration and gliosis of basal forebrain cholinergic neurons (BFCN). A subpopulation of 5 PPA-AD and 7 control brains underwent detailed analysis of BFCN pathology and cortical cholinergic axonal loss employing immunohistochemical and histochemical methods and stereologic analysis. RESULTS: Semiquantitatively, 11 (∼80%) PPA-AD participants were rated as having moderate/severe BFCN loss and gliosis, whereas none of the PPA-tau and only 1 (10%) PPA-TDP participant received such a rating. Detailed analysis in the subpopulation of PPA-AD participants revealed substantial tangle formation, loss of BFCN, and degeneration of cortical cholinergic axons. Compared to controls, loss of p75 low affinity neurotrophin receptor-positive BFCN was detected in the PPA-AD participants (p < 0.01). Acetylcholinesterase-positive cholinergic axons in all cortical areas studied displayed loss in PPA-AD (p < 0.005-0.0001). The loss was more severe in the language-dominant left hemisphere and, within the left hemisphere, in language-affiliated cortical areas. CONCLUSIONS: Our results demonstrate prominent depletion of BFCN and cortical cholinergic axons in PPA-AD when compared with normal control or other neuropathologic variants of PPA. The demonstration of cholinergic denervation with an anatomy that fits the clinical picture suggests that cholinergic treatment is justified in patients with PPA who have positive AD biomarkers.

Original languageEnglish (US)
Pages (from-to)e1580-e1588
JournalNeurology
Volume92
Issue number14
DOIs
StatePublished - Apr 2 2019

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Primary Progressive Aphasia
Denervation
Cholinergic Agents
Pathology
Cholinergic Neurons
Axons
Gliosis
Language
Frontotemporal Lobar Degeneration
Nerve Growth Factor Receptors
Nerve Degeneration

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Mesulam, Marek-Marsel ; Lalehzari, Nava ; Rahmani, Farzan ; Ohm, Daniel ; Shahidehpour, Ryan ; Kim, Garam ; Gefen, Tamar Devora ; Weintraub, Sandra ; Bigio, Eileen H ; Geula, Changiz. / Cortical cholinergic denervation in primary progressive aphasia with Alzheimer pathology. In: Neurology. 2019 ; Vol. 92, No. 14. pp. e1580-e1588.
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title = "Cortical cholinergic denervation in primary progressive aphasia with Alzheimer pathology",
abstract = "OBJECTIVE: To investigate the status of the basal forebrain cholinergic system in primary progressive aphasia (PPA) as justification for cholinergic therapy. METHODS: A cohort of 36 brains from PPA participants with the neuropathology of Alzheimer disease (PPA-AD, n = 14) or frontotemporal lobar degeneration (PPA-tau, n = 12; PPA-TDP, n = 10) were used for semiquantitative rating of degeneration and gliosis of basal forebrain cholinergic neurons (BFCN). A subpopulation of 5 PPA-AD and 7 control brains underwent detailed analysis of BFCN pathology and cortical cholinergic axonal loss employing immunohistochemical and histochemical methods and stereologic analysis. RESULTS: Semiquantitatively, 11 (∼80{\%}) PPA-AD participants were rated as having moderate/severe BFCN loss and gliosis, whereas none of the PPA-tau and only 1 (10{\%}) PPA-TDP participant received such a rating. Detailed analysis in the subpopulation of PPA-AD participants revealed substantial tangle formation, loss of BFCN, and degeneration of cortical cholinergic axons. Compared to controls, loss of p75 low affinity neurotrophin receptor-positive BFCN was detected in the PPA-AD participants (p < 0.01). Acetylcholinesterase-positive cholinergic axons in all cortical areas studied displayed loss in PPA-AD (p < 0.005-0.0001). The loss was more severe in the language-dominant left hemisphere and, within the left hemisphere, in language-affiliated cortical areas. CONCLUSIONS: Our results demonstrate prominent depletion of BFCN and cortical cholinergic axons in PPA-AD when compared with normal control or other neuropathologic variants of PPA. The demonstration of cholinergic denervation with an anatomy that fits the clinical picture suggests that cholinergic treatment is justified in patients with PPA who have positive AD biomarkers.",
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Cortical cholinergic denervation in primary progressive aphasia with Alzheimer pathology. / Mesulam, Marek-Marsel; Lalehzari, Nava; Rahmani, Farzan; Ohm, Daniel; Shahidehpour, Ryan; Kim, Garam; Gefen, Tamar Devora; Weintraub, Sandra; Bigio, Eileen H; Geula, Changiz.

In: Neurology, Vol. 92, No. 14, 02.04.2019, p. e1580-e1588.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cortical cholinergic denervation in primary progressive aphasia with Alzheimer pathology

AU - Mesulam, Marek-Marsel

AU - Lalehzari, Nava

AU - Rahmani, Farzan

AU - Ohm, Daniel

AU - Shahidehpour, Ryan

AU - Kim, Garam

AU - Gefen, Tamar Devora

AU - Weintraub, Sandra

AU - Bigio, Eileen H

AU - Geula, Changiz

PY - 2019/4/2

Y1 - 2019/4/2

N2 - OBJECTIVE: To investigate the status of the basal forebrain cholinergic system in primary progressive aphasia (PPA) as justification for cholinergic therapy. METHODS: A cohort of 36 brains from PPA participants with the neuropathology of Alzheimer disease (PPA-AD, n = 14) or frontotemporal lobar degeneration (PPA-tau, n = 12; PPA-TDP, n = 10) were used for semiquantitative rating of degeneration and gliosis of basal forebrain cholinergic neurons (BFCN). A subpopulation of 5 PPA-AD and 7 control brains underwent detailed analysis of BFCN pathology and cortical cholinergic axonal loss employing immunohistochemical and histochemical methods and stereologic analysis. RESULTS: Semiquantitatively, 11 (∼80%) PPA-AD participants were rated as having moderate/severe BFCN loss and gliosis, whereas none of the PPA-tau and only 1 (10%) PPA-TDP participant received such a rating. Detailed analysis in the subpopulation of PPA-AD participants revealed substantial tangle formation, loss of BFCN, and degeneration of cortical cholinergic axons. Compared to controls, loss of p75 low affinity neurotrophin receptor-positive BFCN was detected in the PPA-AD participants (p < 0.01). Acetylcholinesterase-positive cholinergic axons in all cortical areas studied displayed loss in PPA-AD (p < 0.005-0.0001). The loss was more severe in the language-dominant left hemisphere and, within the left hemisphere, in language-affiliated cortical areas. CONCLUSIONS: Our results demonstrate prominent depletion of BFCN and cortical cholinergic axons in PPA-AD when compared with normal control or other neuropathologic variants of PPA. The demonstration of cholinergic denervation with an anatomy that fits the clinical picture suggests that cholinergic treatment is justified in patients with PPA who have positive AD biomarkers.

AB - OBJECTIVE: To investigate the status of the basal forebrain cholinergic system in primary progressive aphasia (PPA) as justification for cholinergic therapy. METHODS: A cohort of 36 brains from PPA participants with the neuropathology of Alzheimer disease (PPA-AD, n = 14) or frontotemporal lobar degeneration (PPA-tau, n = 12; PPA-TDP, n = 10) were used for semiquantitative rating of degeneration and gliosis of basal forebrain cholinergic neurons (BFCN). A subpopulation of 5 PPA-AD and 7 control brains underwent detailed analysis of BFCN pathology and cortical cholinergic axonal loss employing immunohistochemical and histochemical methods and stereologic analysis. RESULTS: Semiquantitatively, 11 (∼80%) PPA-AD participants were rated as having moderate/severe BFCN loss and gliosis, whereas none of the PPA-tau and only 1 (10%) PPA-TDP participant received such a rating. Detailed analysis in the subpopulation of PPA-AD participants revealed substantial tangle formation, loss of BFCN, and degeneration of cortical cholinergic axons. Compared to controls, loss of p75 low affinity neurotrophin receptor-positive BFCN was detected in the PPA-AD participants (p < 0.01). Acetylcholinesterase-positive cholinergic axons in all cortical areas studied displayed loss in PPA-AD (p < 0.005-0.0001). The loss was more severe in the language-dominant left hemisphere and, within the left hemisphere, in language-affiliated cortical areas. CONCLUSIONS: Our results demonstrate prominent depletion of BFCN and cortical cholinergic axons in PPA-AD when compared with normal control or other neuropathologic variants of PPA. The demonstration of cholinergic denervation with an anatomy that fits the clinical picture suggests that cholinergic treatment is justified in patients with PPA who have positive AD biomarkers.

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