Co‐incidental C9orf72 expansion mutation‐related frontotemporal lobar degeneration pathology and sporadic Creutzfeldt−Jakob disease

Background: TDP-43 is the main protein component of ubiquitinated inclusions in a subgroup of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients. The C9ORF72 hexanucleotide expansion is one of the main mutations associated with TDP-43 pathology in FTLD and ALS. Our aim was to analyze cerebrospinal fluid (CSF) TDP-43 levels and Alzheimer's disease biomarkers in FTLD and ALS patients and to test whether the C9ORF72 expansion carrier status affects these variables. Methods: The patient cohort consisted of 90 clinically well-characterized FTLD (n = 69) and ALS (n = 21) patients. There were 30 patients with the C9ORF72 expansion and 60 patients without the expansion. CSF TDP-43, Aβ1-42, t-tau, and phospho-tau levels were measured using commercial ELISA kits. Results: There was no difference in CSF TDP-43 levels between the C9ORF72 expansion carriers and the noncarriers. CSF TDP-43 levels were higher in ALS patients than in FTLD patients, and this finding was independent of the C9ORF72 expansion carrier status. Males had significantly higher TDP-43 levels than females (p = 0.008 in the total cohort). Conclusion: CSF TDP-43 does not seem to distinguish the C9ORF72 expansion carriers from noncarriers. However, higher CSF TDP-43 levels were detected in ALS than in FTLD, which might be an indicator of a more rapid progression of TDP-43 pathology in ALS.

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Nuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies

Journal of Cell Science ◽

10.1242/jcs.224303 ◽

2019 ◽

Vol 132 (5) ◽

pp. jcs224303 ◽

Cited By ~ 5

Author(s):

Ana Bajc Česnik ◽

Simona Darovic ◽

Sonja Prpar Mihevc ◽

Maja Štalekar ◽

Mirjana Malnar ◽

...

Keyword(s):

C9orf72 Expansion ◽

Rna Foci ◽

Nuclear Rna ◽

Expansion Mutation

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Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Patients with Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis with the C9ORF72 Repeat Expansion

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000371704 ◽

2015 ◽

Vol 39 (5-6) ◽

pp. 287-293 ◽

Cited By ~ 8

Author(s):

Anna Kämäläinen ◽

Sanna-Kaisa Herukka ◽

Päivi Hartikainen ◽

Seppo Helisalmi ◽

Virpi Moilanen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Frontotemporal Lobar Degeneration ◽

Clinical Signs ◽

Clinical Diagnostics ◽

C9orf72 Expansion ◽

T Tau ◽

Lateral Sclerosis

Background: The C9ORF72 expansion is one of the most common causes of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The C9ORF72 expansion is associated with TDP-43 and p62 neuropathology, and amyloid plaques and neurofibrillary tangles are not common in patients with the C9ORF72 expansion. Therefore, we hypothesized that cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease [AD; Aβ1-42, total tau (T-tau) and phospho-tau] are normal in these patients. Methods: The CSF Aβ1-42, T-tau and phospho-tau levels were measured in 40 Finnish patients with the C9ORF72 expansion (29 FTLD, 10 ALS and 1 FTLD-ALS) using ELISA. Results: A decreased Aβ1-42 level was found in 25% of cases, while there were only single cases with changes in the t-Tau or phospho-tau level. The patients with abnormal biomarkers fulfilled the clinical criteria of the behavioral variant frontotemporal dementia and expressed no clinical signs of AD. Conclusions: In clinical diagnostics, a decreased CSF Aβ1-42 level does not exclude the C9ORF72 expansion associated with FTLD.

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C9orf72 Repeat Expansion Does Not Affect the Phenotype in Primary Progressive Aphasia

Journal of Alzheimer s Disease ◽

10.3233/jad-200795 ◽

2020 ◽

Vol 78 (3) ◽

pp. 919-925

Author(s):

Marjut Haapanen ◽

Kasper Katisko ◽

Tuomo Hänninen ◽

Johanna Krüger ◽

Päivi Hartikainen ◽

...

Keyword(s):

Retrospective Study ◽

Frontotemporal Lobar Degeneration ◽

Primary Progressive Aphasia ◽

Repeat Expansion ◽

Speech And Language ◽

C9orf72 Repeat Expansion ◽

Progressive Aphasia ◽

C9orf72 Expansion ◽

Primary Progressive ◽

C9orf72 Gene

Primary progressive aphasia (PPA) forms the spectrum of language variants of frontotemporal lobar degeneration (FTLD), including three subtypes each consisting of distinctive speech and language features. Repeat expansion in C9orf72 gene is the most common genetic cause of FTLD. However, thus far only little is known about the effects of the C9orf72 repeat expansion on the phenotype of PPA. This retrospective study aimed at determining the differences between the PPA phenotypes of the C9orf72 expansion carriers and non-carriers. Our results demonstrated no significant differences between these groups, indicating that the C9orf72 repeat expansion does not substantially affect the phenotype of PPA.

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