Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Patients with Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis with the &lt;b&gt;&lt;i&gt;C9ORF72 &lt;/i&gt;&lt;/b&gt;Repeat Expansion

Kämäläinen, Anna; Herukka, Sanna‐Kaisa; Hartikainen, Päivi; Helisalmi, Seppo; Moilanen, Virpi; Knuuttila, Anna; Jansson, Lilja; Tienari, Pentti J.; Remes, Anne M.

doi:10.1159/000371704

Cited by 17 publications

(19 citation statements)

References 33 publications

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“…; Kämäläinen et al . ). Some studies showed specific changes in C9orf72 mutation carriers with ALS including increased CSF concentrations of poly(GP) expression as a result of the hexanucleotide repeat extension (Su et al .…”

Section: Genetic Ftld Casesmentioning

confidence: 97%

Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update

Oeckl

Steinacker

Feneberg

et al. 2016

Journal of Neurochemistry

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Frontotemporal lobar degeneration (FTLD) is a spectrum of rare neurodegenerative diseases with overlapping symptoms and neuropathology. It includes the behavioral variant of frontotemporal dementia (bvFTD), the semantic and non-fluent variant of primary progressive aphasia (svPPA and nfvPPA), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy, and corticobasal syndrome. The diagnosis of the FTLD spectrum of diseases is based on clinical symptoms which hampers the differentiation of the diseases among each other and with other disorders that show a similar clinical appearance resulting in a high rate of misdiagnoses.This highlights the need for objective and selective measures in the diagnostic criteria and there is extensive research on neurochemical biomarkers in FTLD as one option to address this unmet clinical need. Here, we review the advances in CSF biomarker research in FTLD in the last 2 years with regard to the validation of previously suggested and identification of new biomarker candidates for the differential diagnosis of FTLD. Keywords: biomarker, cerebrospinal fluid, corticobasal syndrome, frontotemporal dementia, frontotemporal lobar degeneration, progressive supranuclear palsy.This article is part of the Frontotemporal Dementia special issue.Frontotemporal lobar degeneration (FTLD) describes a group of neurodegenerative disorders with overlapping symptomatology and neuropathology. The common feature is the degeneration of the frontal and anterior temporal lobe, and at present, the following syndromes are assigned to the FTLD spectrum (Seltman and Matthews 2012): the three types of frontotemporal dementia (FTD) including the behavioral variant of frontotemporal dementia (bvFTD) and the semantic and non-fluent variant of primary progressive aphasia (svPPA and nfvPPA), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). These syndromes can further be classified as behavioral variant (bvFTD), language variant (svPPA and nfvPPA), and motor variant (FTD-MND, PSP and CBS) of FTLD.FTD is the third most common subtype of neurodegenerative dementia after Alzheimer 0 s disease (AD) and dementia with Lewy bodies (DLB) with an estimated prevalence of 1-26 cases per 100 000 persons and bvFTD accounts for most cases (50-70%) (Bang et al. 2015). The prevalence of PSP is estimated to 4-9 cases per 100 000 persons in the age-group > 60 years (Savica et al. 2013).

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Section: Genetic Ftld Casesmentioning

confidence: 97%

Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update

Oeckl

Steinacker

Feneberg

et al. 2016

Journal of Neurochemistry

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“…The patients with such altered biomarker status fulfilled the clinical criteria of the behavioral variant FTD with no clinical signs of AD. In this study, neuropathological confirmation was available only for one patient, showing TAR DNA-binding protein 43 (TDP-43) pathology, but no A or tau pathology [19]. Albeit the reason for the decrease in the CSF 1-42 levels remains thus far unknown, these results suggest that decreased CSF A 1-42 5 levels may not exclude C9orf72 repeat expansion-carrying FTD patients in clinical diagnostics [19].…”

Section: Introductionmentioning

confidence: 78%

“…Increased levels of total and phosphorylated tau and decreased levels of A 42 peptides in the cerebrospinal fluid (CSF) are used as diagnostic biomarkers for AD [17,18]. We have previously reported that 25% of Finnish C9orf72 repeat expansion-carrying FTD patients show decreased CSF A 1-42 levels [19]. The patients with such altered biomarker status fulfilled the clinical criteria of the behavioral variant FTD with no clinical signs of AD.…”

Section: Introductionmentioning

confidence: 99%

Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples

Leskelä

Takalo

Marttinen

et al. 2018

JAD

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A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

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“…It has been previously reported that AD-associated neuropathology is occasionally linked to the C9ORF72 -associated FTLD [27]. In addition, similarly to the AD patients, abnormally low CSF Aβ 1–42 levels have been identified in over 20% of the FTLD patients with the C9ORF72 expansion [28]. As AD and vascular dementia are the most frequent cognitive disorders showing comorbidity with iNPH, the pathological features perceived in iNPH most commonly represent both vascular and AD-related changes [29].…”

Section: Discussionmentioning

confidence: 99%

Prevalence of <b><i>C9ORF72</i></b> Expansion in a Large Series of Patients with Idiopathic Normal-Pressure Hydrocephalus

Korhonen

Remes

Helisalmi

et al. 2019

Dement Geriatr Cogn Disord

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Background/Aims: The C9ORF72 expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH). Methods: We analysed the C9ORF72 expansion in a large cohort of patients with possible iNPH (n = 487) and cognitively intact elderly controls (n = 432; age > 65 years). Results: While the C9ORF72 expansion was detected in 1.6% (n = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range: 52–67 years), 11 years less than non-carriers (p = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted C9ORF72 expansion carriers. Conclusion: This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.

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

Cited by 17 publications

References 33 publications

Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update

Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update

Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples

Prevalence of <b><i>C9ORF72</i></b> Expansion in a Large Series of Patients with Idiopathic Normal-Pressure Hydrocephalus

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