Editorial

3 pages, 177 KiB

Open AccessEditorial

The Role of Cerebrospinal Fluid Biomarkers in Dementia and Other Related Neurodegenerative Disorders

by George P. Paraskevas

Brain Sci. 2022, 12(5), 627; https://doi.org/10.3390/brainsci12050627 - 11 May 2022

Cited by 2 | Viewed by 1377

Over the course of the last 20 years, cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD), including amyloid beta peptide with 42 amino acids (Aβ₄₂), total tau protein (τ_T), and tau protein phosphorylated at a threonine residue at position [...] Read more.

Over the course of the last 20 years, cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD), including amyloid beta peptide with 42 amino acids (Aβ₄₂), total tau protein (τ_T), and tau protein phosphorylated at a threonine residue at position 181 (τ_P-181), have become a useful tool for the recognition and diagnosis of AD, even in early or atypical clinical presentations and in the presymptomatic stage of the disease [...] Full article

(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers in Dementia Disorders)

Research

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19 pages, 1903 KiB

Open AccessArticle

Genotyping and Plasma/Cerebrospinal Fluid Profiling of a Cohort of Frontotemporal Dementia–Amyotrophic Lateral Sclerosis Patients

by Mara Bourbouli, George P. Paraskevas, Mihail Rentzos, Lambros Mathioudakis, Vasiliki Zouvelou, Anastasia Bougea, Athanasios Tychalas, Vasilios K. Kimiskidis, Vasilios Constantinides, Spiros Zafeiris, Minas Tzagournissakis, Georgios Papadimas, Georgia Karadima, Georgios Koutsis, Christos Kroupis, Chrisoula Kartanou, Elisabeth Kapaki and Ioannis Zaganas

Brain Sci. 2021, 11(9), 1239; https://doi.org/10.3390/brainsci11091239 - 19 Sep 2021

Cited by 5 | Viewed by 2629

Abstract

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of the same pathophysiological spectrum and have common genetic and cerebrospinal fluid (CSF) biomarkers. Our aim here was to identify causative gene variants in a cohort of Greek patients with FTD, ALS and [...] Read more.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of the same pathophysiological spectrum and have common genetic and cerebrospinal fluid (CSF) biomarkers. Our aim here was to identify causative gene variants in a cohort of Greek patients with FTD, ALS and FTD-ALS, to measure levels of CSF biomarkers and to investigate genotype-phenotype/CSF biomarker associations. In this cohort of 130 patients (56 FTD, 58 ALS and 16 FTD-ALS), we performed C9orf72 hexanucleotide repeat expansion analysis, whole exome sequencing and measurement of “classical” (Aβ₄₂, total tau and phospho-tau) and novel (TDP-43) CSF biomarkers and plasma progranulin. Through these analyses, we identified 14 patients with C9orf72 repeat expansion and 11 patients with causative variants in other genes (three in TARDBP, three in GRN, three in VCP, one in FUS, one in SOD1). In ALS patients, we found that levels of phospho-tau were lower in C9orf72 repeat expansion and MAPT c.855C>T (p.Asp285Asp) carriers compared to non-carriers. Additionally, carriers of rare C9orf72 and APP variants had lower levels of total tau and Aβ₄₂, respectively. Plasma progranulin levels were decreased in patients carrying GRN pathogenic variants. This study expands the genotypic and phenotypic spectrum of FTD/ALS and offers insights in possible genotypic/CSF biomarker associations. Full article

(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers in Dementia Disorders)

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12 pages, 788 KiB

Open AccessArticle

Cerebrospinal Fluid α-Synuclein Species in Cognitive and Movements Disorders

by Vasilios C. Constantinides, Nour K. Majbour, George P. Paraskevas, Ilham Abdi, Bared Safieh-Garabedian, Leonidas Stefanis, Omar M. El-Agnaf and Elisabeth Kapaki

Brain Sci. 2021, 11(1), 119; https://doi.org/10.3390/brainsci11010119 - 17 Jan 2021

Cited by 15 | Viewed by 2962

Abstract

Total CSF α-synuclein (t-α-syn), phosphorylated α-syn (pS129-α-syn) and α-syn oligomers (o-α-syn) have been studied as candidate biomarkers for synucleinopathies, with suboptimal specificity and sensitivity in the differentiation from healthy controls. Studies of α-syn species in patients with other underlying pathologies are lacking. The [...] Read more.

Total CSF α-synuclein (t-α-syn), phosphorylated α-syn (pS129-α-syn) and α-syn oligomers (o-α-syn) have been studied as candidate biomarkers for synucleinopathies, with suboptimal specificity and sensitivity in the differentiation from healthy controls. Studies of α-syn species in patients with other underlying pathologies are lacking. The aim of this study was to investigate possible alterations in CSF α-syn species in a cohort of patients with diverse underlying pathologies. A total of 135 patients were included, comprising Parkinson’s disease (PD; n = 13), multiple system atrophy (MSA; n = 9), progressive supranuclear palsy (PSP; n = 13), corticobasal degeneration (CBD; n = 9), Alzheimer’s disease (AD; n = 51), frontotemporal degeneration (FTD; n = 26) and vascular dementia patients (VD; n = 14). PD patients exhibited higher pS129-α-syn/α-syn ratios compared to FTD (p = 0.045), after exclusion of samples with CSF blood contamination. When comparing movement disorders (i.e., MSA vs. PD vs. PSP vs. CBD), MSA patients had lower α-syn levels compared to CBD (p = 0.024). Patients with a synucleinopathy (PD and MSA) exhibited lower t-α-syn levels (p = 0.002; cut-off value: ≤865 pg/mL; sensitivity: 95%, specificity: 69%) and higher pS129-/t-α-syn ratios (p = 0.020; cut-off value: ≥0.122; sensitivity: 71%, specificity: 77%) compared to patients with tauopathies (PSP and CBD). There are no significant α-syn species alterations in non-synucleinopathies. Full article

(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers in Dementia Disorders)

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Review

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56 pages, 2200 KiB

Open AccessReview

Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

by Donovan A. McGrowder, Fabian Miller, Kurt Vaz, Chukwuemeka Nwokocha, Cameil Wilson-Clarke, Melisa Anderson-Cross, Jabari Brown, Lennox Anderson-Jackson, Lowen Williams, Lyndon Latore, Rory Thompson and Ruby Alexander-Lindo

Brain Sci. 2021, 11(2), 215; https://doi.org/10.3390/brainsci11020215 - 10 Feb 2021

Cited by 56 | Viewed by 8232

Abstract

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current [...] Read more.

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ₄₂), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented. Full article

(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers in Dementia Disorders)

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Other

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9 pages, 751 KiB

Open AccessOpinion

Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments

by George P. Paraskevas and Elisabeth Kapaki

Brain Sci. 2021, 11(10), 1258; https://doi.org/10.3390/brainsci11101258 - 23 Sep 2021

Cited by 4 | Viewed by 2127

Abstract

Correct in vivo diagnosis of Alzheimer’s disease (AD) helps to avoid administration of disease-modifying treatments in non-AD patients, and allows the possible use of such treatments in clinically atypical AD patients. Cerebrospinal fluid (CSF) biomarkers offer a tool for AD diagnosis. A reduction [...] Read more.

Correct in vivo diagnosis of Alzheimer’s disease (AD) helps to avoid administration of disease-modifying treatments in non-AD patients, and allows the possible use of such treatments in clinically atypical AD patients. Cerebrospinal fluid (CSF) biomarkers offer a tool for AD diagnosis. A reduction in CSF β-amyloid (marker of amyloid plaque burden), although compatible with Alzheimer’s pathological change, may also be observed in other dementing disorders, including vascular cognitive disorders due to subcortical small-vessel disease, dementia with Lewy bodies and normal-pressure hydrocephalus. Thus, for the diagnosis of AD, an abnormal result of CSF β-amyloid may not be sufficient, and an increase in phospho-tau (marker of tangle pathology) is also required in order to confirm AD diagnosis in patients with a typical amnestic presentation and reveal underlying AD in patients with atypical or mixed and diagnostically confusing clinical presentations. Full article

(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers in Dementia Disorders)

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14 pages, 1741 KiB

Open AccessSystematic Review

Blood Biomarkers in Frontotemporal Dementia: Review and Meta-Analysis

by Sofia Ntymenou, Ioanna Tsantzali, Theodosis Kalamatianos, Konstantinos I. Voumvourakis, Elisabeth Kapaki, Georgios Tsivgoulis, George Stranjalis and George P. Paraskevas

Brain Sci. 2021, 11(2), 244; https://doi.org/10.3390/brainsci11020244 - 15 Feb 2021

Cited by 14 | Viewed by 3099

Abstract

Biomarkers in cerebrospinal fluid (CSF) are useful in the differential diagnosis between frontotemporal dementia (FTD) and Alzheimer’s dementia (AD), but require lumbar puncture, which is a moderately invasive procedure that can cause anxiety to patients. Gradually, the measurement of blood biomarkers has been [...] Read more.

Biomarkers in cerebrospinal fluid (CSF) are useful in the differential diagnosis between frontotemporal dementia (FTD) and Alzheimer’s dementia (AD), but require lumbar puncture, which is a moderately invasive procedure that can cause anxiety to patients. Gradually, the measurement of blood biomarkers has been attracting great interest. Testing blood instead of CSF, in order to measure biomarkers, offers numerous advantages because it negates the need for lumbar puncture, it is widely available, and can be repeated, allowing the prediction of disease course. In this study, a systematic review of the existing literature was conducted, as well as meta-analysis with greater emphasis on the most studied biomarkers, p-tau and progranulin. The goal was to give prominence to evidence regarding the use of plasma biomarkers in clinical practice. Full article

(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers in Dementia Disorders)

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14 pages, 476 KiB

Open AccessOpinion

Cerebrospinal Fluid Biomarkers in Parkinson’s Disease: A Critical Overview of the Literature and Meta-Analyses

by Takayuki Katayama, Jun Sawada, Kae Takahashi and Osamu Yahara

Brain Sci. 2020, 10(7), 466; https://doi.org/10.3390/brainsci10070466 - 20 Jul 2020

Cited by 24 | Viewed by 3677

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder; however, well-established biochemical markers have not yet been identified. This review article covers several candidate cerebrospinal fluid (CSF) biomarkers for PD based on the recent literature and meta-analysis data. The decrease of α-synuclein in PD [...] Read more.

Parkinson’s disease (PD) is a common neurodegenerative disorder; however, well-established biochemical markers have not yet been identified. This review article covers several candidate cerebrospinal fluid (CSF) biomarkers for PD based on the recent literature and meta-analysis data. The decrease of α-synuclein in PD is supported by meta-analyses with modest reproducibility, and a decrease of amyloid β42 is seen as a prognostic marker for cognitive decline. Tau, phosphorylated tau (p-tau), and neurofilament light chains have been used to discriminate PD from other neurodegenerative disorders. This article also describes more hopeful biochemical markers, such as neurotransmitters, oxidative stress markers, and other candidate biomarkers. Full article

(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers in Dementia Disorders)

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12 pages, 4608 KiB

Open AccessCase Report

Parkinsonian Syndrome with Frontal Lobe Involvement and Anti-Glycine Receptor Antibodies

by Dominique Endres, Harald Prüss, Michel Rijntjes, Tina Schweizer, Rita Werden, Kathrin Nickel, Sophie Meixensberger, Kimon Runge, Horst Urbach, Katharina Domschke, Philipp T. Meyer and Ludger Tebartz van Elst

Brain Sci. 2020, 10(6), 399; https://doi.org/10.3390/brainsci10060399 - 23 Jun 2020

Cited by 7 | Viewed by 3079

Abstract

Background: Atypical Parkinsonian syndromes with prominent frontal lobe involvement can occur in the 4R-taupathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Secondary forms of movement disorders may occur in the context of autoimmune encephalitis with antineuronal antibodies, such as anti-glycine receptor (anti-GlyR) [...] Read more.

Background: Atypical Parkinsonian syndromes with prominent frontal lobe involvement can occur in the 4R-taupathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Secondary forms of movement disorders may occur in the context of autoimmune encephalitis with antineuronal antibodies, such as anti-glycine receptor (anti-GlyR) antibodies, which are typically associated with Stiff-Person spectrum syndrome, or progressive encephalomyelitis with rigidity and myoclonus. Overlaps between neurodegenerative and immunological mechanisms have been recently suggested in anti-IgLON5 disease. In this case study, the authors describe a patient with a Parkinsonian syndrome with frontal lobe involvement and anti-GlyR antibodies. Case presentation: The patient presented was a 63-year-old female. Her symptoms had begun with insomnia at the age of 60, after which, since the age of 61, increasing personality changes developed, leading to a diagnosis of depression with delusional symptoms. Severe cognitive deficits emerged, along with a left-side accentuated Parkinsonian syndrome with postural instability. The personality changes involved frontal systems. Magnetic resonance imaging (MRI) showed low-grade mesencephalon atrophy. [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG PET) depicted a moderate hypometabolism bilateral frontal and of the midbrain, while [¹²³I]FPCIT single-photon emission computed tomography (SPECT) revealed severely reduced dopamine transporter availability in both striata, indicating pronounced nigrostriatal degeneration. In addition, anti-GlyR antibodies were repeatedly found in the serum of the patient (max. titer of 1:640, reference: <1:20). Therefore, an anti-inflammatory treatment with steroids and azathioprine was administered; this resulted in a decrease of antibody titers (to 1:80) but no detectable clinical improvement. The cerebrospinal fluid (CSF) and electroencephalography diagnostics showed inconspicuous findings, and negative CSF anti-GlyR antibody results. Conclusion: The patient presented here was suffering from a complex Parkinsonian syndrome with frontal lobe involvement. Because of the high anti-GlyR antibody titers, the presence of an autoimmune cause of the disorder was discussed. However, since no typical signs of autoimmune anti-GlyR antibody syndrome (e.g., hyperexcitability, anti-GlyR antibodies in CSF, or other inflammatory CSF changes) were detected, the possibility that the anti-GlyR antibodies might have been an unrelated bystander should be considered. Alternatively, the anti-GlyR antibodies might have developed secondarily to neurodegeneration (most likely a 4-repeat tauopathy, PSP or CBD) without exerting overt clinical effects, as in cases of anti-IgLON5 encephalopathy. In this case, such antibodies might also potentially modify the clinical course of classical movement disorders. Further research on the role of antineuronal antibodies in Parkinsonian syndromes is needed. Full article

(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers in Dementia Disorders)

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