Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia

Ohm, Daniel T.; Kım, Garam; Gefen, Tamar; Rademaker, Alfred; Weıntraub, Sandra; Bigio, Eileen H.; Mesulam, Marek-Marsel; Rogalskı, Emily; Geula, Changiz

doi:10.1111/nan.12494

Cited by 15 publications

(22 citation statements)

References 59 publications

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“…There have been few previous comparisons of microglia between grey and white matter in FTLD-tau and FTLD-TDP, and none in FTLD-FUS. In other studies, FTLD-tau [39] and FTLD-TDP [39,43,44] cases had more phagocytic microglia in frontotemporal white matter compared with grey matter, but microglia were also more activated in white matter.…”

Section: Discussionmentioning

confidence: 69%

“…This suggested that there are more numerous and/or more activated microglia in FTLD than controls, particularly in frontal white matter, although this varied by pathological subtype. Several histological studies have examined microglia in specific subtypes of FTLD, particularly FTLD-TDP [23,[40][41][42][43][44]. These suggest that microglia are altered in FTLD-TDP in a regionally selective manner, particularly in white matter [40,41,43], but whether microglia vary across all FTLD pathological subtypes has not been explored.…”

Section: Introductionmentioning

confidence: 99%

“…Several histological studies have examined microglia in specific subtypes of FTLD, particularly FTLD-TDP [23,[40][41][42][43][44]. These suggest that microglia are altered in FTLD-TDP in a regionally selective manner, particularly in white matter [40,41,43], but whether microglia vary across all FTLD pathological subtypes has not been explored. As regional pathology [1,45,46] and grey and white matter neuroimaging abnormalities [47][48][49][50][51][52] vary across the spectrum of genetic FTD, microglia may also differ regionally between genetic FTLD subtypes due to different mutations.…”

Section: Introductionmentioning

confidence: 99%

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Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

Woollacott

Toomey

Strand

et al. 2020

J Neuroinflammation

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Background: Microglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer's disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burden, activation and dystrophy in sporadic and genetic FTLD, sporadic AD and controls. Methods: Immunohistochemistry was performed in frontal and temporal grey and white matter from 50 pathologically confirmed FTLD cases (31 sporadic, 19 genetic: 20 FTLD-tau, 26 FTLD-TDP, four FTLD-FUS), five AD cases and five controls, using markers to detect phagocytic (CD68-positive) and antigen-presenting (CR3/43positive) microglia, and microglia in general (Iba1-positive). Microglial burden and activation (morphology) were assessed quantitatively for each microglial phenotype. Iba1-positive microglia were assessed semi-quantitatively for dystrophy severity and qualitatively for rod-shaped and hypertrophic morphology. Microglia were compared in each region between FTLD, AD and controls, and between different pathological subtypes of FTLD, including its main subtypes (FTLD-tau, FTLD-TDP, FTLD-FUS), and subtypes of FTLD-tau, FTLD-TDP and genetic FTLD. Microglia were also compared between grey and white matter within each lobe for each group. Results: There was a higher burden of phagocytic and antigen-presenting microglia in FTLD and AD cases than controls, but activation was often not increased. Burden was generally higher in white matter than grey matter, but activation was greater in grey matter. However, microglia varied regionally according to FTLD subtype and disease mechanism. Dystrophy was more severe in FTLD and AD than controls, and more severe in white than grey matter, but this also varied regionally and was particularly extensive in FTLD due to progranulin (GRN) mutations. Presence of rod-shaped and hypertrophic microglia also varied by FTLD subtype.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

Woollacott

Toomey

Strand

et al. 2020

J Neuroinflammation

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“…Concomitant factors may have influenced the relationship between AD neuropathology and cortical atrophy. We have recently shown that the same PPA‐AD cohort included in this study had significant microglial activation in the white matter that was associated with gray matter atrophy . In addition to glial‐mediated inflammation, upstream intermediates of NFTs and APs may have caused, at least in part, the neurodegenerative patterns.…”

Section: Discussionmentioning

confidence: 70%

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

et al. 2019

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The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language‐based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid‐ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA‐AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA‐AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense‐core APs visualized with the Thioflavin‐S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non‐language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non‐language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA‐AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD.

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“…Neuroinflammation and immunity have previously been reported in the context of FTLD, and the idea that immune dysfunction may contribute to FTLD risk is not new. Microglial activation is a pathological hallmark of patients with FTLD [43,66,82] and a key feature of genetic FTLD mouse models [40,52,79,99] and both GRN and C9orf72 have been extensively linked to neuroinflammation and microglial activation [41,55,65,99]. Genetic overlap between immune-mediated diseases and clinical FTLD was recently reported [8] and independent studies found an increased prevalence of autoimmune conditions in patients with GRN and C9orf72 mutations, and in clinical FTLD patients predicted to have an underlying FTLD-TDP pathology (svPPA and FTLD-MND) [58,59].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

et al. 2019

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Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

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Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia

Cited by 15 publications

References 59 publications

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

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