The
            <i>TMEM106B</i>
            locus and TDP-43 pathology in older persons without FTLD

Dickson, Dennis W.; Schneider, Julie A.; Rademakers, Rosa; Nicholson, Alexandra M.; Yu, Lei; Bennett, David A.

doi:10.1212/01.wnl.0000472918.79256.a9

Cited by 15 publications

(9 citation statements)

References 5 publications

(7 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aoki and colleagues reported that the frequency of the C-allele of TMEM106B rs1990622 in hippocampal sclerosis was lower than that in non-hippocampal sclerosis controls (Aoki et al , 2015). Following the initial studies, the findings were replicated of increased risk for hippocampal sclerosis associated with each copy of the T-allele of TMEM106B rs1990622 (Nelson et al , 2014, 2015 b ; Dickson et al , 2015; Yu et al , 2015).…”

Section: Introductionmentioning

confidence: 89%

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Nelson

Dickson

Trojanowski

et al. 2019

Brain

Self Cite

1,004

1,035

View full text Add to dashboard Cite

Nelson et al. describe a recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: L imbic-predominant A ge-related T DP-43 E ncephalopathy (LATE). They review the literature and present consensus-based recommendations of an international, multidisciplinary working group, providing guidelines for diagnosis and staging of LATE neuropathological changes.

show abstract

Section: Introductionmentioning

confidence: 89%

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Nelson

Dickson

Trojanowski

et al. 2019

Brain

Self Cite

1,004

1,035

View full text Add to dashboard Cite

show abstract

“…Furthermore, neurodegenerative disease hallmarks, such as TDP-43 aggregates, are seen even in apparently healthy individuals, albeit to a limited extent (Beecham et al, 2014;Crary et al, 2014;Yu et al, 2015). Indeed, TMEM106B risk variants have been associated with increased TDP-43 aggregates in neuropathology-based association studies of apparently healthy older individuals (Dickson et al, 2015;Yu et al, 2015). We hypothesize that the selective role of TMEM106B in the aging frontal cortex may reflect unique stressors present in this tissue late in life, such as the accumulation of inflammatory cell debris or protein aggregates.…”

Section: Discussionmentioning

confidence: 99%

“…A broader analysis of 70 neurodegenerative disease-associated genetic variants (Jun et al, 2016;Lambert et al, 2013;McMillan et al, 2014;Nalls et al, 2014;Rollinson et al, 2011;van Es et al, 2009) did not reveal any significant additional associations with D-aging, beyond TMEM106B and GRN (Table S6). TMEM106B and GRN share a number of common attributes: both have previously been associated with risk of FTD (Cruchaga et al, 2011;Finch et al, 2011;Van Deerlin et al, 2010), with primary hippocampal sclerosis (Aoki et al, 2015), and with TDP-43 neuropathology in the absence of a clinical neurological diagnosis (Dickson et al, 2015;Yu et al, 2015). Furthermore, both genes have been implicated together in the regulation of lysosomal function (Schwenk et al, 2014;Stagi et al, 2014), and TMEM106B has been reported to regulate progranulin protein accumulation (Chen-Plotkin et al, 2012).…”

Section: Tmem106b Inflammaging and Neurodegenerative Disordersmentioning

confidence: 99%

Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes

2017

View full text Add to dashboard Cite

Human age-associated traits, such as cognitive decline, can be highly variable across the population, with some individuals exhibiting traits that are not expected at a given chronological age. Here we present differential aging (Δ-aging), an unbiased method that quantifies individual variability in age-associated phenotypes within a tissue of interest, and apply this approach to the analysis of existing transcriptome-wide cerebral cortex gene expression data from several cohorts totaling 1,904 autopsied human brain samples. We subsequently performed a genome-wide association study and identified the TMEM106B and GRN gene loci, previously associated with frontotemporal dementia, as determinants of Δ-aging in the cerebral cortex with genome-wide significance. TMEM106B risk variants are associated with inflammation, neuronal loss, and cognitive deficits, even in the absence of known brain disease, and their impact is highly selective for the frontal cerebral cortex of older individuals (>65 years). The methodological framework we describe can be broadly applied to the analysis of quantitative traits associated with aging or with other parameters.

show abstract

“…TDP-43 pathology frequently associates with other disorders, including AD, DLB, and frequently with a hippocampal sclerosis (HS; a disorder affecting about 10% of individuals over the age of 85 years [ 203 ]) of ageing (in around 90% of cases), but also chronic traumatic encephalopathy; some of these associate with genetic risk factors [ 19 , 203 , 204 , 205 , 206 , 207 ]. The cellular distribution may resemble that observed in FTLD-TDP with only rare neuronal nuclear inclusions.…”

Section: Molecular Pathological Subtypingmentioning

confidence: 99%

Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine

Kovács

2016

IJMS

250

194

View full text Add to dashboard Cite

Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.

show abstract

The TMEM106B locus and TDP-43 pathology in older persons without FTLD

Cited by 15 publications

References 5 publications

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes

Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine

Contact Info

Product

Resources

About