scholarly journals Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease

2020 ◽  
Vol 21 (17) ◽  
pp. 6298
Author(s):  
Petar Podlesniy ◽  
Franc Llorens ◽  
Margalida Puigròs ◽  
Nuria Serra ◽  
Diego Sepúlveda-Falla ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Mitochondrial Dna ◽  
Clinical Diagnosis ◽  
Neuronal Damage ◽  
Clinical Signs ◽  
Amyloid Peptide ◽  
Slow Progression ◽  
Csf Levels ◽  
T Tau ◽  
The Relationship

Alzheimer’s type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf-mtDNA) precedes clinical signs of AD. We have now investigated the relationship between cf-mtDNA and other biomarkers of AD to determine whether a particular biomarker profile underlies the different rates of AD progression. We measured the content of cf-mtDNA, beta-amyloid peptide 1–42 (Aβ), total tau protein (t-tau) and phosphorylated tau (p-tau) in the CSF from a cohort of 95 subjects consisting of 49 controls with a neurologic disorder without dementia, 30 patients with a clinical diagnosis of spAD and 16 patients with rpAD. We found that 37% of controls met at least one AD biomarker criteria, while 53% and 44% of subjects with spAD and rpAD, respectively, did not fulfill the two core AD biomarker criteria: high t-tau and low Aβ in CSF. In the whole cohort, patients with spAD, but not with rpAD, showed a statistically significant 44% decrease of cf-mtDNA in CSF compared to control. When the cohort included only subjects selected by Aβ and t-tau biomarker criteria, the spAD group showed a larger decrease of cf-mtDNA (69%), whereas in the rpAD group cf-mtDNA levels remained unaltered. In the whole cohort, the CSF levels of cf-mtDNA correlated positively with Aβ and negatively with p-tau. Moreover, the ratio between cf-mtDNA and p-tau increased the sensitivity and specificity of spAD diagnosis up to 93% and 94%, respectively, in the biomarker-selected cohort. These results show that the content of cf-mtDNA in CSF correlates with the earliest pathological markers of the disease, Aβ and p-tau, but not with the marker of neuronal damage t-tau. Moreover, these findings confirm that low CSF content of cf-mtDNA is a biomarker for the early detection of AD and support the hypothesis that low cf-mtDNA, together with low Aβ and high p-tau, constitute a distinctive CSF biomarker profile that differentiates spAD from other neurological disorders.

scholarly journals Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Sarinnapha M. Vasunilashorn ◽  
◽  
Long H. Ngo ◽  
Simon T. Dillon ◽  
Tamara G. Fong ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Plasma Levels ◽  
Inflammatory Markers ◽  
Brain Barrier ◽  
Markers Of Inflammation ◽  
Blood Brain ◽  
Csf Levels ◽  
The Relationship

Abstract Background Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation. Methods We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). The integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine the correlation between biofluids. Results Mean Qalb did not change between baseline and PO1MO. Mean plasma and CSF levels of CRP and plasma levels of YKL-40 and IL-6 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CRP CSF levels relative to plasma levels (CRP tripled in CSF vs. increased 10% in plasma). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline. Conclusions In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, plasma-CSF correlations were observed for CRP and IL-6, plasma levels of all three markers (CRP, IL-6, and YKL-40) increased from PREOP to PO1MO, and CSF levels of only CRP increased between the two time points. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

scholarly journals Are neuropsychiatric symptoms in dementia linked to CSF biomarkers of synaptic and axonal degeneration?

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Victor Bloniecki ◽  
Henrik Zetterberg ◽  
Dag Aarsland ◽  
Patrizia Vannini ◽  
Hlin Kvartsberg ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Axonal Degeneration ◽  
Neuropsychiatric Symptoms ◽  
Underlying Disease ◽  
Csf Biomarkers ◽  
Neurofilament Light ◽  
Csf Levels ◽  
Low Levels ◽  
T Tau ◽  
The Relationship

Abstract Background The underlying disease mechanism of neuropsychiatric symptoms (NPS) in dementia remains unclear. Cerebrospinal fluid (CSF) biomarkers for synaptic and axonal degeneration may provide novel neuropathological information for their occurrence. The aim was to investigate the relationship between NPS and CSF biomarkers for synaptic (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal (neurofilament light [NFL]) injury in patients with dementia. Methods A total of 151 patients (mean age ± SD, 73.5 ± 11.0, females n = 92 [61%]) were included, of which 64 had Alzheimer’s disease (AD) (34 with high NPS, i.e., Neuropsychiatric Inventory (NPI) score > 10 and 30 with low levels of NPS) and 18 were diagnosed with vascular dementia (VaD), 27 with mixed dementia (MIX), 12 with mild cognitive impairment (MCI), and 30 with subjective cognitive impairment (SCI). NPS were primarily assessed using the NPI. CSF samples were analyzed using enzyme-linked immunosorbent assays (ELISAs) for T-tau, P-tau, Aβ1–42, Ng, NFL, and GAP-43. Results No significant differences were seen in the CSF levels of Ng, GAP-43, and NFL between AD patients with high vs low levels of NPS (but almost significantly decreased for Ng in AD patients < 70 years with high NPS, p = 0.06). No significant associations between NPS and CSF biomarkers were seen in AD patients. In VaD (n = 17), negative correlations were found between GAP-43, Ng, NFL, and NPS. Conclusion Our results could suggest that low levels of Ng may be associated with higher severity of NPS early in the AD continuum (age < 70). Furthermore, our data may indicate a potential relationship between the presence of NPS and synaptic as well as axonal degeneration in the setting of VaD pathology.

scholarly journals Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis

2015 ◽  
Vol 21 (5) ◽  
pp. 550-561 ◽  
Author(s):  
M Alba Mañé Martínez ◽  
Bob Olsson ◽  
Laura Bau ◽  
Elisabet Matas ◽  
Álvaro Cobo Calvo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disability Progression ◽  
Neurofilament Light ◽  
Monocyte Chemoattractant Protein 1 ◽  
Neuronal Markers ◽  
Independent Prognostic Marker ◽  
Csf Levels ◽  
In Cis ◽  
T Tau

Objective: To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing–remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS. Methods: CSF levels of neurofilament light protein (NFL), t-tau, p-tau, glial fibrillary acidic protein (GFAP), S-100B, human chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), α-sAPP and β-sAPP; and Aβ38, Aβ40 and Aβ42, were analyzed in 109 CIS patients and 192 RRMS patients. The mean follow-up time of these 301 patients was 11.7 ± 6.4 years. Results: High levels of NFL were associated with early conversion from CIS to CDMS (hazard ratio (HR) with 95% confidence interval (CI): 2.69 (1.75 – 4.15); p < 0.0001). High levels of YKL-40 and GFAP were associated with earlier progression in the Expanded Disability Status Scale (EDSS), score 3: YKL-40 (HR (95% CI): 2.78 (1.48 – 5.23); p = 0.001) and GFAP (HR (95% CI): 1.83 (1.01 – 3.35); p = 0.04). High levels of YKL-40 were associated with earlier progression to EDSS 6 (HR (95% CI): 4.57 (1.01 – 20.83); p = 0.05). Conclusions: CSF levels of NFL in CIS patients are an independent prognostic marker for conversion to CDMS. Whereas, CSF levels of YKL-40 and GFAP are independent prognostic markers for disability progression in MS.

scholarly journals Plasma and Cerebrospinal Fluid Inflammation and the Blood Brain Barrier in Older Surgical Patients: The Role of Inflammation after Surgery for Elders Study

2020 ◽  
Author(s):  
Sarinnapha Vasunilashorn ◽  
Long H. Ngo ◽  
Simon T. Dillon ◽  
Tamara G Fong ◽  
Becky C Carlyle ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Inflammatory Markers ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Markers Of Inflammation ◽  
Blood Brain ◽  
Csf Levels ◽  
The Relationship

Abstract Background Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to: examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation. Methods We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). Integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine correlation between biofluids. For the plasma-CSF biofluids with significant correlations, we determined whether the markers were associated by using linear regression models. Results Mean Qalb did not change between baseline and PO1MO. Plasma and CSF levels of IL-6, CRP, and YKL-40 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CSF levels relative to plasma levels (IL-6 doubled and CRP tripled in CSF). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline. Conclusions In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, inflammation levels were higher PO1MO than baseline, and plasma-CSF correlations were observed for CRP and IL-6. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

IL-1β, IL-6, IL-10, and TNFα single nucleotide polymorphisms are associated with cerebrospinal fluid levels of biomarkers of Alzheimer’s disease

2019 ◽  
Author(s):  
Mirjana Babić Leko ◽  
Matea Nikolac Perković ◽  
Nataša Klepac ◽  
Dubravka Švob Štrac ◽  
Fran Borovečki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Inflammatory Cytokines ◽  
Nucleotide Polymorphisms ◽  
Neuron Damage ◽  
Csf Levels ◽  
Factor Α ◽  
Fluid Levels ◽  
T Tau

Abstract Background Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α (TNFα) that participate in neuron damage. However, anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response, are also released. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β -1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896) and TNFα -308A/G (rs1800629) polymorphisms with AD.Methods In this study, we assessed whether people carrying certain genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid β1–42 (Aβ1–42), total tau (t‐tau), tau phosphorylated at Thr 181 (p‐tau181), Ser 199 (p‐tau199), and Thr 231 (p‐tau231), and visinin‐like protein 1 (VILIP‐1). The study included 115 AD patients, 53 patients with mild cognitive impairment (MCI), 11 healthy controls, and 54 patients with other causes of dementia.Results A significant increase in p-tau CSF levels was found in patients with the AA IL-10 -1082G/A and GG TNFα -308A/G genotypes, and in carriers of a G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. T-tau levels were increased while Aβ1-42 levels were decreased in carriers of a G allele in IL-1β -1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G and GG TNFα -308A/G genotype.Conclusions These results suggest that persons carrying certain genotypes in IL10 (-1082G/A), IL1β (1473C/G), IL6 (-174C/G) and TNFα (-308A/G) could be more vulnerable to development of neuroinglammation, and consequently of AD.

scholarly journals Role of cerebrospinal fluid biomarkers to predict conversion to dementia in patients with mild cognitive impairment: a clinical cohort study

2015 ◽  
Vol 53 (3) ◽  
Author(s):  
Manuela Tondelli ◽  
Roberta Bedin ◽  
Annalisa Chiari ◽  
Maria Angela Molinari ◽  
Guendalina Bonifacio ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Csf Biomarkers ◽  
Neuropsychological Evaluation ◽  
Neurological Assessment ◽  
Blood Tests ◽  
Clinical Cohort ◽  
Cerebrospinal Fluid Biomarkers ◽  
Csf Levels ◽  
T Tau

AbstractCerebrospinal fluid (CSF) levels assessment of AβA group of 71 MCI patients underwent neurological assessment, extended neuropsychological evaluation, routine blood tests, ApoE determination, and lumbar puncture to dose t-tau, p-tauBaseline AβOur results confirm the key role of CSF biomarkers in predicting patient conversion from MCI to dementia. The study suggests that CSF biomarkers may also be reliable in a real world clinical setting.

scholarly journals Cerebral Microbleeds, Cerebrospinal Fluid, and Neuroimaging Markers in Clinical Subtypes of Alzheimer's Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Masaki Ikeda ◽  
Sayaka Kodaira ◽  
Hiroo Kasahara ◽  
Eriko Takai ◽  
Kazuaki Nagashima ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cerebral Microbleeds ◽  
The Other ◽  
Cortical Atrophy ◽  
Amyloid Angiopathy ◽  
Temporal Area ◽  
Csf Levels ◽  
T Tau

Lobar cerebral microbleeds (CMBs) in Alzheimer's disease (AD) are associated with cerebral amyloid angiopathy (CAA) due to vascular amyloid beta (Aβ) deposits. However, the relationship between lobar CMBs and clinical subtypes of AD remains unknown. Here, we enrolled patients with early- and late-onset amnestic dominant AD, logopenic variant of primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA) who were compatible with the AD criteria. We then examined the levels of cerebrospinal fluid (CSF) biomarkers [Aβ1-42, Aβ1-40, Aβ1-38, phosphorylated tau 181 (P-Tau), total tau (T-Tau), neurofilament light chain (NFL), and chitinase 3-like 1 protein (YKL-40)], analyzed the number and localization of CMBs, and measured the cerebral blood flow (CBF) volume by 99mTc-ethyl cysteinate dimer single photon emission computerized tomography (99mTc ECD-SPECT), as well as the mean cortical standard uptake value ratio by 11C-labeled Pittsburgh Compound B-positron emission tomography (11C PiB-PET). Lobar CMBs in lvPPA were distributed in the temporal, frontal, and parietal lobes with the left side predominance, while the CBF volume in lvPPA significantly decreased in the left temporal area, where the number of lobar CMBs and the CBF volumes showed a significant inversely correlation. The CSF levels of NFL in lvPPA were significantly higher compared to the other AD subtypes and non-demented subjects. The numbers of lobar CMBs significantly increased the CSF levels of NFL in the total AD patients, additionally, among AD subtypes, the CSF levels of NFL in lvPPA predominantly were higher by increasing number of lobar CMBs. On the other hand, the CSF levels of Aβ1-38, Aβ1-40, Aβ1-42, P-Tau, and T-Tau were lower by increasing number of lobar CMBs in the total AD patients. These findings may suggest that aberrant brain hypoperfusion in lvPPA was derived from the brain atrophy due to neurodegeneration, and possibly may involve the aberrant microcirculation causing by lobar CMBs and cerebrovascular injuries, with the left side dominance, consequently leading to a clinical phenotype of logopenic variant.

scholarly journals Cognitive Dispersion Is Not Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Results from the European Prevention of Alzheimer’s Dementia (EPAD) v500.0 Cohort

2020 ◽  
Vol 78 (1) ◽  
pp. 185-194
Author(s):  
Tam Watermeyer ◽  
Alejandra Marroig ◽  
Craig W. Ritchie ◽  
Karen Ritchie ◽  
Kaj Blennow ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Aging ◽  
Amyloid Β ◽  
Cost Effective ◽  
Csf Levels ◽  
T Tau

Background: Cognitive dispersion, variation in performance across cognitive domains, is posited as a non-invasive and cost-effective marker of early neurodegeneration. Little work has explored associations between cognitive dispersion and Alzheimer’s disease (AD) biomarkers in healthy older adults. Even less is known about the influence or interaction of biomarkers reflecting brain pathophysiology or other risk factors on cognitive dispersion scores. Objective: The main aim of this study was to examine whether higher cognitive dispersion was associated with cerebrospinal fluid (CSF) levels of amyloid-β (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), and amyloid positivity in a cohort of older adults at various severities of AD. A secondary aim was to explore which AD risk factors were associated with cognitive dispersion scores. Methods: Linear and logistic regression analyses explored the associations between dispersion and CSF levels of Aβ42, t-tau, and p-tau and amyloid positivity (Aβ42 < 1000 pg/ml). Relationships between sociodemographics, APOE ɛ4 status, family history of dementia, and levels of depression and dispersion were also assessed. Results: Dispersion did not emerge as associated with any of the analytes nor amyloid positivity. Older (β= –0.007, SE = 0.002, p = 0.001) and less educated (β= –0.009, SE = 0.003, p = 0.009) individuals showed greater dispersion. Conclusion: Dispersion was not associated with AD pathology, but was associated with age and years of education, highlighting individual differences in cognitive aging. The use of this metric as a screening tool for existing AD pathology is not supported by our analyses. Follow-up work will determine if dispersion scores can predict changes in biomarker levels and/or positivity status longitudinally.

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

2015 ◽  
Vol 39 (5-6) ◽  
pp. 287-293 ◽  
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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