An update on genetic frontotemporal dementia

Greaves, Caroline; Rohrer, Jonathan D.

doi:10.1007/s00415-019-09363-4

Cited by 295 publications

(350 citation statements)

References 87 publications

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“…Frontotemporal dementia (FTD) is the clinical manifestation of FTLD neuropathology and major clinical symptoms can be divided into either progressive deficits in executive function and behavior or language [26]. Importantly, ~ 30% of FTD patients have a familial history of FTD or related neurodegenerative disease, highlighting the important role of genetics in disease pathogenesis [26,39,43]. Taken together autosomal dominant mutations in three genes, progranulin (GRN), chromosome 9 open reading frame 72 (C9orf72), and microtubule associated protein tau (MAPT), account for the majority of FTD heritability [43].…”

Section: Introductionmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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Heterozygous, loss-of-function mutations in the granulin gene (GRN) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type (Grn+/+) and Grn knockout (Grn−/−) mice at 3- and 19-months of age. At 3-months lysosomal proteins (i.e. Gns, Scarb2, Hexb) are selectively increased indicating lysosomal dysfunction is an early consequence of PGRN deficiency. Additionally, proteins involved in lipid metabolism (Acly, Apoc3, Asah1, Gpld1, Ppt1, and Naaa) are decreased; suggesting lysosomal degradation of lipids may be impaired in the Grn−/− brain. Systems biology using weighted correlation network analysis (WGCNA) of the Grn−/− brain proteome identified 26 modules of highly co-expressed proteins. Three modules strongly correlated to Grn deficiency and were enriched with lysosomal proteins (Gpnmb, CtsD, CtsZ, and Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44, S100a, and C1qa). We find that lysosomal dysregulation is exacerbated with age in the Grn−/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons. In particular, GPNMB and LGALS3 (galectin-3) were upregulated by microglia and elevated in FTD-GRN brain samples, indicating common pathogenic pathways are dysregulated in human FTD cases and Grn−/− mice. GPNMB levels were significantly increased in the cerebrospinal fluid of FTD-GRN patients, but not in MAPT or C9orf72 carriers, suggesting GPNMB could be a biomarker specific to FTD-GRN to monitor disease onset, progression, and drug response. Our findings support the idea that insufficiency of PGRN and granulins in humans causes neurodegeneration through lysosomal dysfunction, defects in autophagy, and neuroinflammation, which could be targeted to develop effective therapies.

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Section: Introductionmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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“…In 2011, diagnostic criteria for bvFTD and PPA were revised which improved diagnostic accuracy . Mutations in genes, such as chromosome 9 open reading frame 72 ( C9orf72 ), progranulin ( GRN ), and microtubule associated protein tau ( MAPT ) have been identified in about 25% of patients with FTD . More recently, neuropsychiatric symptoms, such as psychosis and depressed mood, have been recognized to be part of the early clinical presentation of FTD, both in C9orf72 repeat expansion carriers and noncarriers .…”

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confidence: 99%

Frontotemporal Dementia: Correlations Between Psychiatric Symptoms and Pathology

Scarioni

Gami‐Patel

Timar

et al. 2020

Annals of Neurology

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Objective: The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP-43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features. Methods: The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features, such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors. Results: Our cohort consisted of 68.6% FTLD donors (35.3% TDP-43, 28% tau, and 5.3% FUS) and 31.3% non-FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate, such as Alzheimer's disease (23%). The presence of hyperorality points to FTLD rather than non-FTLD pathology (p < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP-43 pathology (p = 0.02), including but not limited to chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP-B and TDP-C histotypes (p = 0.002). Interpretation: Our findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms.

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“…Frontotemporal dementia is a subtype of neurodegenera tive dementia, characterised by progressive changes in behaviour and personality or language diffi culties. Frontotemporal dementia has a strong genetic compo nent, 1 and microtubuleassociated protein tau (MAPT), pro granulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) are the most common mutated genes. Patients with this condition show heterogeneity in clinic al presentation and a wide variability in age at symp tom onset, age at death, and disease duration.…”

Section: International View On Genetic Frontotemporal Dementiamentioning

confidence: 99%