Combined Transcriptomics and Proteomics in Frontal Cortex Area 8 in Frontotemporal Lobar Degeneration Linked to C9ORF72 Expansion

Abstract Sporadic amyotrophic lateral sclerosis (sALS) and FTLD-TDP are neurodegenerative diseases within the spectrum of TDP-43 proteinopathies. Since abnormal blood vessels and altered blood-brain barrier have been described in sALS, we wanted to know whether TDP-43 pathology also occurs in blood vessels in sALS/FTLD-TDP. TDP-43 deposits were identified in association with small blood vessels of the spinal cord in 7 of 14 cases of sALS and in small blood vessels of frontal cortex area 8 in 6 of 11 FTLD-TDP and sALS cases, one of them carrying a GRN mutation. This was achieved using single and double-labeling immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy. In the sALS spinal cord, P-TDP43 Ser403-404 deposits were elongated and parallel to the lumen, whereas others were granular, seldom forming clusters. In the frontal cortex, the inclusions were granular, or elongated and parallel to the lumen, or forming small globules within or in the external surface of the blood vessel wall. Other deposits were localized in the perivascular space. The present findings are in line with previous observations of TDP-43 vasculopathy in a subset of FTLD-TDP cases and identify this pathology in the spinal cord and frontal cortex in a subset of cases within the sALS/FTLD-TDP spectrum.

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Complex Inflammation mRNA-Related Response in ALS Is Region Dependent

Neural Plasticity ◽

10.1155/2015/573784 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 11

Author(s):

Sara Berjaoui ◽

Mónica Povedano ◽

Paula Garcia-Esparcia ◽

Margarita Carmona ◽

Ester Aso ◽

...

Keyword(s):

Spinal Cord ◽

Frontal Cortex ◽

Motor Neurons ◽

Unknown Origin ◽

Lumbar Spinal Cord ◽

Pyramidal Tracts ◽

Abnormal Distribution ◽

Cortex Area ◽

Lumbar Spinal ◽

Inflammatory Changes

Inflammatory changes are analyzed in the anterior spinal cord and frontal cortex area 8 in typical spinal-predominant ALS cases. Increased numbers of astrocytes and activated microglia are found in the anterior horn of the spinal cord and pyramidal tracts. Significant increased expression ofTLR7,CTSS, andCTSCmRNA and a trend to increased expression ofIL10RA,TGFB1, andTGFB2are found in the anterior lumbar spinal cord in ALS cases compared to control cases, whereasC1QTNF7andTNFRSF1AmRNA expression levels are significantly decreased.IL6is significantly upregulated andIL1Bshows a nonsignificant increased expression in frontal cortex area 8 in ALS cases. IL-6 immunoreactivity is found in scattered monocyte-derived macrophages/microglia and TNF-αin a few cells of unknown origin in ALS cases. Increased expression and abnormal distribution of IL-1βoccurred in motor neurons of the lumbar spinal cord in ALS. Strong IL-10 immunoreactivity colocalizes with TDP-43-positive inclusions in motor neurons in ALS cases. The present observations show a complex participation of cytokines and mediators of the inflammatory response in ALS consistent with increased proinflammatory cytokines and sequestration of anti-inflammatory IL-10 in affected neurons.

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Mitochondrial activity in the frontal cortex area 8 and angular gyrus in Parkinson's disease and Parkinson's disease with dementia

Brain Pathology ◽

10.1111/bpa.12474 ◽

2017 ◽

Vol 28 (1) ◽

pp. 43-57 ◽

Cited By ~ 11

Author(s):

Paula Garcia-Esparcia ◽

Anusha Koneti ◽

M. Cruz Rodríguez-Oroz ◽

Belen Gago ◽

José Antonio del Rio ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Frontal Cortex ◽

Angular Gyrus ◽

Mitochondrial Activity ◽

Cortex Area ◽

Parkinson’S Disease With Dementia

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Cerebrospinal Fluid TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis Patients with and without the C9ORF72 Hexanucleotide Expansion

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000444788 ◽

2016 ◽

Vol 6 (1) ◽

pp. 142-149 ◽

Cited By ~ 20

Author(s):

Anna Junttila ◽

Mari Kuvaja ◽

Päivi Hartikainen ◽

Maritta Siloaho ◽

Seppo Helisalmi ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Frontotemporal Lobar Degeneration ◽

Rapid Progression ◽

Carrier Status ◽

C9orf72 Expansion ◽

Main Protein ◽

Als Patients ◽

T Tau ◽

Lateral Sclerosis

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

European Journal of Neurology ◽

10.1111/ene.14621 ◽

2020 ◽

Author(s):

Sigrid Klotz ◽

Theresa König ◽

Marcus Erdler ◽

Andreas Ulram ◽

Anita Nguyen ◽

...

Keyword(s):

Frontotemporal Lobar Degeneration ◽

C9orf72 Expansion ◽

Jakob Disease ◽

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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