Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology

Baayla D C Boon; Irene Frigerio; Danae de Gooijer; Tjado H J Morrema; John Bol; Yvon Galis-de Graaf; Martijn Heymans; Melissa E Murray; Sven J van der Lee; Henne Holstege; Wilma D J van de Berg; Laura E Jonkman; Annemieke J M Rozemuller; Femke H Bouwman; Jeroen J M Hoozemans

doi:10.1111/nan.13009

Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology

Baayla D C Boon, Irene Frigerio, Danae de Gooijer, Tjado H J Morrema, John Bol, Yvon Galis-de Graaf, Martijn Heymans, , Melissa E Murray, Sven J van der Lee, Henne Holstege, Wilma D J van de Berg, Laura E Jonkman, Annemieke J M Rozemuller, Femke H Bouwman, Jeroen J M Hoozemans

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AIMS: Although the neuroanatomical distribution of tau and amyloid-β is well studied in Alzheimer's disease (AD) (non)-amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid-β and phosphorylated tau in a clinically well-defined prospectively collected AD cohort.

METHODS: Clinical variants were diagnosed antemortem, and brain tissue was collected post-mortem. Typical AD (n = 10), behavioural/dysexecutive AD (n = 6), posterior cortical atrophy (PCA) AD (n = 3), and controls (n = 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid-β, CD68, MHC-II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology.

RESULTS: Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid-β was neocortical-dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE-NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC-II were hippocampal-dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC-II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants.

CONCLUSIONS: Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation-based biomarkers and future therapeutics.

Originele taal-2	Engels
Pagina's (van-tot)	e13009
Tijdschrift	Neuropathology and Applied Neurobiology
Volume	50
Nummer van het tijdschrift	5
DOI's	https://doi.org/10.1111/nan.13009
Status	Gepubliceerd - okt. 2024

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10.1111/nan.13009

Boon2024Final published version, 17,9 MB

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Boon, B. D. C., Frigerio, I., de Gooijer, D., Morrema, T. H. J., Bol, J., Galis-de Graaf, Y., Heymans, M., Murray, M. E., van der Lee, S. J., Holstege, H., van de Berg, W. D. J., Jonkman, L. E., Rozemuller, A. J. M., & Bouwman, F. H., & Hoozemans, J. J. M. (2024). Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology. Neuropathology and Applied Neurobiology, 50(5), e13009. https://doi.org/10.1111/nan.13009

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title = "Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology",

abstract = "AIMS: Although the neuroanatomical distribution of tau and amyloid-β is well studied in Alzheimer's disease (AD) (non)-amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid-β and phosphorylated tau in a clinically well-defined prospectively collected AD cohort.METHODS: Clinical variants were diagnosed antemortem, and brain tissue was collected post-mortem. Typical AD (n = 10), behavioural/dysexecutive AD (n = 6), posterior cortical atrophy (PCA) AD (n = 3), and controls (n = 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid-β, CD68, MHC-II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology.RESULTS: Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid-β was neocortical-dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE-NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC-II were hippocampal-dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC-II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants.CONCLUSIONS: Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation-based biomarkers and future therapeutics.",

keywords = "Humans, Alzheimer Disease/pathology, Female, Male, Aged, Neuroinflammatory Diseases/pathology, Aged, 80 and over, Brain/pathology, tau Proteins/metabolism, Amyloid beta-Peptides/metabolism, Middle Aged",

author = "Boon, {Baayla D C} and Irene Frigerio and {de Gooijer}, Danae and Morrema, {Tjado H J} and John Bol and {Galis-de Graaf}, Yvon and Martijn Heymans and Murray, {Melissa E} and {van der Lee}, {Sven J} and Henne Holstege and {van de Berg}, {Wilma D J} and Jonkman, {Laura E} and Rozemuller, {Annemieke J M} and Bouwman, {Femke H} and Hoozemans, {Jeroen J M}",

note = "{\textcopyright} 2024 The Author(s). Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.",

year = "2024",

month = oct,

doi = "10.1111/nan.13009",

language = "English",

volume = "50",

pages = "e13009",

journal = "Neuropathology and Applied Neurobiology",

issn = "0305-1846",

publisher = "Wiley-Blackwell",

number = "5",

}

Boon, BDC, Frigerio, I, de Gooijer, D, Morrema, THJ, Bol, J, Galis-de Graaf, Y, Heymans, M, Murray, ME, van der Lee, SJ, Holstege, H, van de Berg, WDJ, Jonkman, LE, Rozemuller, AJM & Bouwman, FH & Hoozemans, JJM 2024, 'Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology', Neuropathology and Applied Neurobiology, vol. 50, nr. 5, blz. e13009. https://doi.org/10.1111/nan.13009

Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology. / Boon, Baayla D C; Frigerio, Irene; de Gooijer, Danae et al.
In: Neuropathology and Applied Neurobiology, Vol. 50, Nr. 5, 10.2024, blz. e13009.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

TY - JOUR

T1 - Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology

AU - Boon, Baayla D C

AU - Frigerio, Irene

AU - de Gooijer, Danae

AU - Morrema, Tjado H J

AU - Bol, John

AU - Galis-de Graaf, Yvon

AU - Heymans, Martijn

AU - Murray, Melissa E

AU - van der Lee, Sven J

AU - Holstege, Henne

AU - van de Berg, Wilma D J

AU - Jonkman, Laura E

AU - Rozemuller, Annemieke J M

AU - Bouwman, Femke H

AU - Hoozemans, Jeroen J M

PY - 2024/10

Y1 - 2024/10

N2 - AIMS: Although the neuroanatomical distribution of tau and amyloid-β is well studied in Alzheimer's disease (AD) (non)-amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid-β and phosphorylated tau in a clinically well-defined prospectively collected AD cohort.METHODS: Clinical variants were diagnosed antemortem, and brain tissue was collected post-mortem. Typical AD (n = 10), behavioural/dysexecutive AD (n = 6), posterior cortical atrophy (PCA) AD (n = 3), and controls (n = 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid-β, CD68, MHC-II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology.RESULTS: Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid-β was neocortical-dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE-NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC-II were hippocampal-dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC-II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants.CONCLUSIONS: Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation-based biomarkers and future therapeutics.

AB - AIMS: Although the neuroanatomical distribution of tau and amyloid-β is well studied in Alzheimer's disease (AD) (non)-amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid-β and phosphorylated tau in a clinically well-defined prospectively collected AD cohort.METHODS: Clinical variants were diagnosed antemortem, and brain tissue was collected post-mortem. Typical AD (n = 10), behavioural/dysexecutive AD (n = 6), posterior cortical atrophy (PCA) AD (n = 3), and controls (n = 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid-β, CD68, MHC-II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology.RESULTS: Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid-β was neocortical-dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE-NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC-II were hippocampal-dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC-II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants.CONCLUSIONS: Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation-based biomarkers and future therapeutics.

KW - Humans

KW - Alzheimer Disease/pathology

KW - Female

KW - Male

KW - Aged

KW - Neuroinflammatory Diseases/pathology

KW - Aged, 80 and over

KW - Brain/pathology

KW - tau Proteins/metabolism

KW - Amyloid beta-Peptides/metabolism

KW - Middle Aged

U2 - 10.1111/nan.13009

DO - 10.1111/nan.13009

M3 - Article

C2 - 39400356

SN - 0305-1846

VL - 50

SP - e13009

JO - Neuropathology and Applied Neurobiology

JF - Neuropathology and Applied Neurobiology

IS - 5

ER -