Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability

Proudfoot, Malcolm J.; Gutowski, N. J.; Edbauer, Dieter; Hilton, David A.; Stephens, M. A.; Rankin, Julia; Mackenzie, Ian R.

doi:10.1007/s00401-014-1245-7

Cited by 73 publications

(85 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Such observations are reminiscent of a recent report [24] in which a family bearing expansion in C9ORF72 and demonstrating intellectual disability as a preceding feature to dementia at an early age is described. In this family, the proband presented with psychiatric features progressing into typical FTD and at autopsy showed extensive DPR, but only minimal TDP, pathology.…”

Section: Discussionsupporting

confidence: 59%

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Baborie

Griffiths

Jaros

et al. 2015

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

AimsFrontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP‐43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non‐ATG RAN translation of the expanded region of the gene.MethodsTwenty‐two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP‐43, p62 and DPR. The extent of TDP‐43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease.ResultsThree Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP‐43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP‐43 pathology was significantly less.ConclusionWidespread accumulation of DPR within nerve cells may occur much earlier than that of TDP‐43 in patients with FTLD bearing expansion in C9ORF72.

show abstract

Section: Discussionsupporting

confidence: 59%

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Baborie

Griffiths

Jaros

et al. 2015

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

show abstract

“…This notion is supported by in vitro experiments that show that DPR proteins are secreted from cultured cells 11, 29. Reports of autopsy studies in C9orf72‐ patients have also described widespread DPR protein pathology prior to the formation of TDP‐43 inclusions and neuronal loss 30, 31, 32. These studies provide converging evidence that poly(GP) expression arises early in the lifespan of C9orf72 expansion carriers.…”

Section: Discussionmentioning

confidence: 78%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

show abstract

“…It remains an open question to what extent symptoms of ALS are preceded by temporally remote cellular abnormalities [Eisen et al, 2014]. Although animal models of ALS demonstrate abnormal neural architecture and function during embryonic stages [Martin et al, 2013; Vinsant et al, 2013], human epidemiological [Byrne et al, 2013; Schoder et al, 2010] and pathological [Proudfoot et al, 2014a] links to neurodevelopmental disorders remain sparse. Suggestions that ALS (or FTD) pathology might manifest in a behavioural prodrome long before diagnostic symptoms remain speculative [Eisen et al, 2014; Lule et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

“…The cortical neuronal dynamics underlying motor performance can be ascertained with particularly high sensitivity using magnetoencephalography (MEG) [Proudfoot et al, 2014a, 2014b]. Movement preparation and execution are consistently associated with modulations to motor and premotor neuronal oscillation power, particularly within the beta‐band (15–30 Hz) [Pfurtscheller and Lopes Da Silva, 1999].…”

Section: Introductionmentioning

confidence: 99%

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Proudfoot

Rohenkohl

Quinn

et al. 2016

Human Brain Mapping

Self Cite

View full text Add to dashboard Cite

Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15–30 Hz) power. Cortical beta‐band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven “classical” ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS‐associated gene mutations were compared with age‐similar healthy control groups. Augmented beta desynchronization was observed in both contra‐ and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237–254, 2017. © 2016 Wiley Periodicals, Inc.

show abstract

Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability

Cited by 73 publications

References 55 publications

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Contact Info

Product

Resources

About