Diffuse Lewy Body Disease and Alzheimer Disease

Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation

Dibson D. Gondim, Adrian Oblak, Jill R. Murrell, Rose Richardson, Francine Epperson, Owen A. Ross, Bernardino Ghetti

Research output: Contribution to journalArticle

Abstract

In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.

Original languageEnglish (US)
Pages (from-to)585-594
Number of pages10
JournalJournal of neuropathology and experimental neurology
Volume78
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

Synucleins
Lewy Body Disease
Alzheimer Disease
Phenotype
Mutation
Neurons
Clinical Pathology
Brain
Amyloid
Immunohistochemistry

Keywords

  • Alzheimer disease
  • Amyloid-β
  • Lewy body
  • PSEN
  • Tau
  • α-Synuclein

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Diffuse Lewy Body Disease and Alzheimer Disease : Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation. / Gondim, Dibson D.; Oblak, Adrian; Murrell, Jill R.; Richardson, Rose; Epperson, Francine; Ross, Owen A.; Ghetti, Bernardino.

In: Journal of neuropathology and experimental neurology, Vol. 78, No. 7, 01.07.2019, p. 585-594.

Research output: Contribution to journalArticle

Gondim, Dibson D. ; Oblak, Adrian ; Murrell, Jill R. ; Richardson, Rose ; Epperson, Francine ; Ross, Owen A. ; Ghetti, Bernardino. / Diffuse Lewy Body Disease and Alzheimer Disease : Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation. In: Journal of neuropathology and experimental neurology. 2019 ; Vol. 78, No. 7. pp. 585-594.
@article{f83b769cf1e54984bd657fde8d8b2d80,
title = "Diffuse Lewy Body Disease and Alzheimer Disease: Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation",
abstract = "In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.",
keywords = "Alzheimer disease, Amyloid-β, Lewy body, PSEN, Tau, α-Synuclein",
author = "Gondim, {Dibson D.} and Adrian Oblak and Murrell, {Jill R.} and Rose Richardson and Francine Epperson and Ross, {Owen A.} and Bernardino Ghetti",
year = "2019",
month = "7",
day = "1",
doi = "10.1093/jnen/nlz039",
language = "English (US)",
volume = "78",
pages = "585--594",
journal = "American Journal of Psychotherapy",
issn = "0002-9564",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Diffuse Lewy Body Disease and Alzheimer Disease

T2 - Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation

AU - Gondim, Dibson D.

AU - Oblak, Adrian

AU - Murrell, Jill R.

AU - Richardson, Rose

AU - Epperson, Francine

AU - Ross, Owen A.

AU - Ghetti, Bernardino

PY - 2019/7/1

Y1 - 2019/7/1

N2 - In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.

AB - In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.

KW - Alzheimer disease

KW - Amyloid-β

KW - Lewy body

KW - PSEN

KW - Tau

KW - α-Synuclein

UR - http://www.scopus.com/inward/record.url?scp=85068488713&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068488713&partnerID=8YFLogxK

U2 - 10.1093/jnen/nlz039

DO - 10.1093/jnen/nlz039

M3 - Article

VL - 78

SP - 585

EP - 594

JO - American Journal of Psychotherapy

JF - American Journal of Psychotherapy

SN - 0002-9564

IS - 7

ER -