The molecular basis of frontotemporal dementia

Neumann, Manuela; Tolnay, Markus; Mackenzie, Ian R.

doi:10.1017/s1462399409001136

Cited by 69 publications

(61 citation statements)

References 189 publications

(272 reference statements)

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“…In FTLD-related tauopathies and associated FTLD subtypes tau accumulation is prominent in striatal regions (Macedo et al, 2009, Neumann et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Differential putaminal morphology in Huntington’s disease, frontotemporal dementia and Alzheimer’s disease

Looi

Rajagopalan

Walterfang

et al. 2012

Aust N Z J Psychiatry

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Objective Direct neuronal loss or deafferentation of the putamen, a critical hub in corticostriatal circuits, may result in diverse and distinct cognitive and motoric dysfunction in neurodegenerative disease. Differential putaminal morphology, as a quantitative measure of corticostriatal integrity, may thus be evident in Huntington disease (HD), Alzheimer Disease (AD) and Frontotemporal Dementia (FTD), diseases with differential clinical dysfunction. Method HD (n=17), FTD (n=33) and AD (n=13) patients were diagnosed according to international consensus criteria, and with healthy controls (n=17), were scanned on the same MRI scanner. Patients underwent brief cognitive testing using the Neuropsychiatry unit cognitive assessment tool (NUCOG). Ten MRI scans from this dataset were manually segmented as a training set for the Adaboost algorithm, which automatically segmented all remaining scans for the putamen, yielding the following subset of the data: 9 left and 12 right putamen segmentations for AD; 25 left and 26 right putamina for FTD; 16 left and 15 right putamina for HD; 12 left and 12 right putamina for controls. Shape analysis was performed at each point on the surface of each structure using a multiple regression controlling for age and sex to compare radial distance across diagnostic groups. Results Age, but not sex and ICV, were significantly different in the segmentation subgroups by diagnosis. The AD group showed significantly poorer performance on cognitive testing than FTD. Mean putaminal volumes were HD

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“…In FTLD-related tauopathies and associated FTLD subtypes tau accumulation is prominent in striatal regions (Macedo et al, 2009, Neumann et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Differential putaminal morphology in Huntington’s disease, frontotemporal dementia and Alzheimer’s disease

Looi

Rajagopalan

Walterfang

et al. 2012

Aust N Z J Psychiatry

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“…Frontotemporal dementia (FTD) is a clinically, genetically, and neuropathologically heterogeneous disorder, accounting for 20% of early-onset dementia [1, 2]. FTD is characterized by behavioral and language dysfunction, without amnesia, and consensus clinical and pathological diagnostic criteria have been proposed [1,3–5].…”

Section: Introductionmentioning

confidence: 99%

Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

Gabryelewicz

Masellis

Berdyński

et al. 2011

JAD

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Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1-13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g. 2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation

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“…These are the insoluble, aggregation prone building blocks of neurofibrillary tangles which form within the cytoplasm of neuronal cells (Goedert et al 1995). Tau is also implicated in a number of other neurodegenerative disorders, such as frontal temporal dementia (Neumann et al 2009). This can be caused by mutations within the gene encoding tau, microtubule associated protein tau (MAPT) (Goedert and Jakes 2005), which leads to neuronal cell loss and consequent cognitive decline.…”

Section: Neurofibrillary Tanglesmentioning

confidence: 99%

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

Lord

Turton

Braae

et al. 2014

Alzheimer's & Dementia

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In 2009, two large genome wide association studies (GWAS) found associations between common single nucleotide polymorphisms (SNPs) at three loci (CLU, PICALM and CR1) and Alzheimer's disease (AD) risk. The causal variants underlying these associations and how these impact on AD susceptibility remain unclear. Target enrichment and next generation sequencing (NGS) were used to completely resequence the three associated loci in 96 AD patients in an attempt to uncover potentially causative and rare variants that may explain the observed association signals. A pipeline was developed for the handling of pooled NGS data following a comparison of several different combinations of programs. 33 exonic SNPs were found within the three genes, along with over 1000 non-coding variants. To identify the variants most likely to be affecting AD risk, a two pronged approach was adopted. The variants were imputed in a large case-control cohort (2067 cases, 7376 controls) to test for association with AD, and the likely functional consequences of the variants were assessed using in silico resources. Several of the analysed variants showed suggestive or significant association with AD in the imputed data, and/or were predicted to have consequences on the function or regulation of the genes, suggesting avenues for future research in AD genetics. The whole method of pooled, targeted NGS and prioritisation using imputed data for association testing and in silico resources for functional analysis represents a new strategy for tracking down the illusive causation of GWAS signals. PublicationsNext generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions. Lord J,

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The molecular basis of frontotemporal dementia

Cited by 69 publications

References 189 publications

Differential putaminal morphology in Huntington’s disease, frontotemporal dementia and Alzheimer’s disease

Differential putaminal morphology in Huntington’s disease, frontotemporal dementia and Alzheimer’s disease

Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

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