| 1. |
- Montoliu-Gaya, Laia, et al.
(author)
-
Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study.
- 2024
-
In: Acta neuropathologica. - 1432-0533. ; 147:1
-
Journal article (peer-reviewed)abstract
- Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD=69, non-AD=54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC=89.8), p-tau231 (AUC=83.4), and p-tau205 (AUC=81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR<1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217=15.29, ORp-tau205=5.05 and ORp-tau231=3.86) and Braak staging (ORp-tau217=14.29, ORp-tau205=5.27 and ORp-tau231=4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.
|
|
| 2. |
- Bartl, Michael, et al.
(author)
-
Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid of de novo Parkinson's disease
- 2024
-
In: NPJ PARKINSONS DISEASE. - 2373-8057. ; 10:1
-
Journal article (peer-reviewed)abstract
- Lysosomal and synaptic dysfunctions are hallmarks in neurodegeneration and potentially relevant as biomarkers, but data on early Parkinson's disease (PD) is lacking. We performed targeted mass spectrometry with an established protein panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) of drug-na & iuml;ve de novo PD, and sex-/age-matched healthy controls (HC) cross-sectionally (88 PD, 46 HC) and longitudinally (104 PD, 58 HC) over 10 years. Multiple markers of autophagy, synaptic plasticity, and secretory pathways were reduced in PD. We added samples from prodromal subjects (9 cross-sectional, 12 longitudinal) with isolated REM sleep behavior disorder, revealing secretogranin-2 already decreased compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins in PD correlated with clinical progression, showing predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials.
|
|
| 3. |
- Camporesi, Elena, et al.
(author)
-
Fluid Biomarkers for Synaptic Dysfunction and Loss
- 2020
-
In: Biomarker Insights. - : SAGE Publications. - 1177-2719. ; 15
-
Journal article (peer-reviewed)abstract
- Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer's disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and alpha-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.
|
|
| 4. |
- Camporesi, Elena, et al.
(author)
-
Quantification of the trans-synaptic partners neurexin-neuroligin in CSF of neurodegenerative diseases by parallel reaction monitoring mass spectrometry
- 2022
-
In: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 75
-
Journal article (peer-reviewed)abstract
- Background: Synaptic proteins are increasingly studied as biomarkers for synaptic dysfunction and loss, which are early and central events in Alzheimer's disease (AD) and strongly correlate with the degree of cognitive decline. In this study, we specifically investigated the synaptic binding partners neurexin (NRXN) and neuroligin (Nlgn) proteins, to assess their biomarker's potential. Methods: we developed a parallel reaction monitoring mass spectrometric method for the simultaneous quantification of NRXNs and Nlgns in cerebrospinal fluid (CSF) of neurodegenerative diseases, focusing on AD. Specifically, NRXN-1α, NRXN-1β, NRXN-2α, NRXN-3α and Nlgn1, Nlgn2, Nlgn3 and Nlgn4 proteins were targeted. Findings: The proteins were investigated in a clinical cohort including CSF from controls (n=22), mild cognitive impairment (MCI) due to AD (n=44), MCI due to other conditions (n=46), AD (n=77) and a group of non-AD dementia (n=28). No difference in levels of NRXNs and Nlgns was found between AD (both at dementia and MCI stages) or controls or the non-AD dementia group for any of the targeted proteins. NRXN and Nlgn proteins correlated strongly with each other, but only a weak correlation with the AD core biomarkers and the synaptic biomarkers neurogranin and growth-associated protein 43, was found, possibly reflecting different pathogenic processing at the synapse. Interpretation: we conclude that NRXN and Nlgn proteins do not represent suitable biomarkers for synaptic pathology in AD. The panel developed here could aid in future investigations of the potential involvement of NRXNs and Nlgns in synaptic dysfunction in other disorders of the central nervous system. Funding: a full list of funding can be found under the acknowledgments section. © 2021 The Author(s)
|
|
| 5. |
- Gkanatsiou, Eleni, et al.
(author)
-
Amyloid pathology and synaptic loss in pathological aging
- 2021
-
In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 159:2, s. 258-272
-
Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Both AD and PA contain amyloid plaques dominated by amyloid beta (A beta) peptides. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and A beta peptide patterns between AD and PA. Two cohorts of post-mortem brain tissue were investigated. In the first, consisting of controls, PA, AD, and familial AD (FAD) individuals, synaptic proteins extracted with tris(hydroxymethyl)aminomethane-buffered saline (TBS) were analyzed. In the second, consisting of tissue from AD and PA patients from three different regions (occipital lobe, frontal lobe, and cerebellum), a two-step extraction was performed. Five synaptic proteins were extracted using TBS, and from the remaining portion A beta peptides were extracted using formic acid. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. The amyloid plaque load was increased in AD compared with PA, and the relative amount of A beta 40 was higher in AD while for A beta 42 it was higher in PA. In AD loss of synaptic function was associated with increased plaque load and increased amounts of A beta 40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of A beta.
|
|
| 6. |
- Gonzalez-Ortiz, Fernando, 1990, et al.
(author)
-
Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease.
- 2024
-
In: Nature communications. - 2041-1723. ; 15:1
-
Journal article (peer-reviewed)abstract
- Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n=1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.
|
|
| 7. |
- Gracias, J., et al.
(author)
-
Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
- 2022
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
-
Journal article (peer-reviewed)abstract
- Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia. Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
|
|
| 8. |
- Huber, Hanna, 1989, et al.
(author)
-
Biomarkers of Alzheimer's disease and neurodegeneration in dried blood spots-A new collection method for remote settings
- 2024
-
In: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279.
-
Journal article (peer-reviewed)abstract
- BACKGROUND: We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPSvenous) for the diagnosis and monitoring of neurodegenerative diseases in remote settings. METHODS: In a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (A beta) 40, A beta 42; and phosphorylated tau (p-tau181 and p-tau217) were measured in paired DPSvenous and ethylenediaminetetraacetic acid plasma samples with single-molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers. RESULTS: All DPSvenous and plasma analytes correlated significantly, except for A beta 42. In the validation cohort, DPSvenous GFAP, NfL, p-tau181, and p-tau217 differed between CSF A beta-positive and -negative individuals and were associated with worsening cognition. DISCUSSION: Our data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPSvenous extends the utility of blood-based biomarkers to remote settings with simplified sampling conditions, storage, and logistics.
|
|
| 9. |
- Kirsebom, B. E., et al.
(author)
-
Stable cerebrospinal fluid neurogranin and beta-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients
- 2022
-
In: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:5
-
Journal article (peer-reviewed)abstract
- Kirsebom & Richter et al. report that levels of the CSF synapse markers neurogranin and BACE1 remain stable in Alzheimer's disease A/T/N subgroups, even when progressing to dementia. Their results suggest that CSF levels may differentiate pathomechanistic Alzheimer's disease subtypes, putatively with different options for treatment. Cerebrospinal fluid (CSF) beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer's disease continuum and controlled with normal markers (A-/T-/N-, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n = 12), from A+/T-/N- to A+/T or N+ (n = 12), remained stable A+/T-/N- (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A-/T-/N- (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T-/N- (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = -0.29, P = 0.0006) than neurogranin (b = -0.20, P = 0.002) and BACE1 (b = -0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer's disease subgroups, putatively with different options for treatment.
|
|
| 10. |
|
|
| 11. |
- Knorr, Ulla, et al.
(author)
-
Cerebrospinal fluid synaptic biomarker changes in bipolar disorder - A longitudinal case-control study.
- 2024
-
In: Journal of affective disorders. - 1573-2517. ; 358, s. 250-259
-
Journal article (peer-reviewed)abstract
- This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections.Fifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14-3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes.The synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up.It is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect.This first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.
|
|
| 12. |
- Montoliu-Gaya, Laia, et al.
(author)
-
Mass spectrometric simultaneous quantification of tau species in plasma shows differential associations with amyloid and tau pathologies
- 2023
-
In: Nature Aging. - 2662-8465. ; 3:6, s. 661-669
-
Journal article (peer-reviewed)abstract
- Blood phosphorylated tau (p-tau) biomarkers, at differing sites, demonstrate high accuracy to detect Alzheimer & apos;s disease (AD). However, knowledge on the optimal marker for disease identification across the AD continuum and the link to pathology is limited. This is partly due to heterogeneity in analytical methods. In this study, we employed an immunoprecipitation mass spectrometry method to simultaneously quantify six phosphorylated (p-tau181, p-tau199, p-tau202, p-tau205, p-tau217 and p-tau231) and two non-phosphorylated plasma tau peptides in a total of 214 participants from the Paris Lariboisiere and Translational Biomarkers of Aging and Dementia cohorts. Our results indicate that p-tau217, p-tau231 and p-tau205 are the plasma tau forms that best reflect AD-related brain changes, although with distinct emergences along the disease course and correlations with AD features-amyloid and tau. These findings support the differential association of blood p-tau variants with AD pathology, and our method offers a potential tool for disease staging in clinical trials. A mass spectrometric analysis of plasma tau species identifies phosphorylated tau peptides p-tau217, p-tau231 and p-tau205 with distinct correlations with amyloid and tau pathologies and emergences along the AD continuum.
|
|
| 13. |
- Nilsson, Johanna, 1993, et al.
(author)
-
Cerebrospinal fluid biomarker panel for synaptic dysfunction in a broad spectrum of neurodegenerative diseases.
- 2024
-
In: Brain : a journal of neurology. - 1460-2156.
-
Journal article (peer-reviewed)abstract
- Synaptic dysfunction and degeneration is likely the key pathophysiology for the progression of cognitive decline in various dementia disorders. Synaptic status can be monitored by measurement of synaptic proteins in cerebrospinal fluid (CSF). In the current study, the aim was to investigate and compare both known and new synaptic proteins as potential biomarkers of synaptic dysfunction, especially in the context of Alzheimer's disease (AD). Seventeen synaptic proteins were quantified in CSF using two different targeted mass spectrometry assays in the prospective Swedish BioFINDER-2 study. The study included 958 individuals, characterized as having mild cognitive impairment (MCI, n=205), AD dementia (n=149), and a spectrum of other neurodegenerative diseases (n=171), as well as cognitively unimpaired (CU, n=443). Synaptic protein levels were compared between diagnostic groups and their associations with cognitive decline and key neuroimaging measures (Aβ-PET, tau-PET, and cortical thickness) were assessed. Among the 17 synaptic proteins examined, 14 were specifically elevated in the AD continuum. SNAP-25, 14-3-3 zeta/delta, beta-synuclein, and neurogranin exhibited the highest discriminatory accuracy to differentiate AD dementia from controls (AUCs=0.81-0.93). SNAP-25 and 14-3-3 zeta/delta also had the strongest associations with tau-PET, Aβ-PET, and cortical thickness at baseline, and were associated with longitudinal changes in these imaging biomarkers (β(SE)=-0.056(0.0006) to 0.058(0.005), p<0.0001). SNAP-25 was the strongest predictor of progression to AD dementia in non-demented individuals (Hazard ratio=2.11). In contrast, neuronal pentraxins were decreased in all neurodegenerative diseases (except for Parkinson's disease), and NPTX2 showed the strongest associations with subsequent cognitive decline (longitudinal MMSE; β(SE)=0.57(0.1), p≤0.0001 and mPACC; β(SE)=0.095(0.024), p≤0.001) across the AD continuum. Interestingly, utilizing a ratio of the proteins that displayed higher levels in AD, such as SNAP-25 or 14-3-3 zeta/delta, over NPTX2 improved the biomarkers' association with cognitive decline and brain atrophy. We found that especially 14-3-3 zeta/delta and SNAP-25 are promising synaptic biomarkers of pathophysiological changes in AD. Neuronal pentraxins were identified as general indicators of neurodegeneration and associated with cognitive decline across various neurodegenerative dementias. The ratios of SNAP-25/NPTX2 and 14-3-3 zeta/delta/NPTX2 were found to best predict cognitive decline and brain atrophy.
|
|
| 14. |
- Nilsson, Johanna, 1993, et al.
(author)
-
Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzheimer's disease
- 2021
-
In: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
-
Journal article (peer-reviewed)abstract
- Introduction Synaptic dysfunction and degeneration is one of the earliest events in Alzheimer's disease (AD) and the best correlate of cognitive decline. Thus, identification and validation of biomarkers reflecting synaptic degeneration to be used as prognostic biomarkers are greatly needed. Method Solid-phase extraction and parallel reaction monitoring mass spectrometry were used to quantify 17 synaptic proteins in CSF, in two cross-sectional studies including AD (n = 52) and controls (n = 37). Results Increased concentrations of beta-synuclein, gamma-synuclein, neurogranin, phosphatidylethanolamine-binding protein 1, and 14-3-3 proteins were observed in AD patients compared to controls, while neuronal pentraxin-2 and neuronal pentraxin receptor were decreased. Discussion We have established a method with a novel panel of synaptic proteins as biomarkers of synaptic dysfunction. The results indicate that several of the proteins included in the panel may serve as synaptic biomarkers for AD.
|
|
| 15. |
- Nilsson, Johanna, 1993, et al.
(author)
-
Cerebrospinal fluid biomarker panel of synaptic dysfunction in Alzheimer's disease and other neurodegenerative disorders
- 2023
-
In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:5, s. 1775-1784
-
Journal article (peer-reviewed)abstract
- Introduction Synaptic degeneration is a key part of the pathophysiology of neurodegenerative diseases, and biomarkers reflecting the pathological alterations are greatly needed. Method Seventeen synaptic proteins were quantified in a pathology-confirmed cerebrospinal fluid cohort of patients with Alzheimer's disease (AD; n = 63), frontotemporal lobar degeneration (FTLD; n = 53), and Lewy body spectrum of disorders (LBD; n = 21), as well as healthy controls (HC; n = 48). Results Comparisons revealed four distinct patterns: markers decreased across all neurodegenerative conditions compared to HC (the neuronal pentraxins), markers increased across all neurodegenerative conditions (14-3-3 zeta/delta), markers selectively increased in AD compared to other neurodegenerative conditions (neurogranin and beta-synuclein), and markers selectively decreased in LBD and FTLD compared to HC and AD (AP2B1 and syntaxin-1B). Discussion Several of the synaptic proteins may serve as biomarkers for synaptic dysfunction in AD, LBD, and FTLD. Additionally, differential patterns of synaptic protein alterations seem to be present across neurodegenerative diseases. Highlights A panel of synaptic proteins were quantified in the cerebrospinal fluid using mass spectrometry. We compared Alzheimer's disease, frontotemporal degeneration, and Lewy body spectrum of disorders. Pathology was confirmed by autopsy or familial mutations. We discovered synaptic biomarkers for synaptic degeneration and cognitive decline. We found differential patterns of synaptic proteins across neurodegenerative diseases.
|
|
| 16. |
- Nilsson, Johanna, 1993, et al.
(author)
-
Cerebrospinal fluid biomarkers of synaptic dysfunction are altered in Parkinson's disease and related disorders
- 2023
-
In: Movement Disorders. - : John Wiley & Sons. - 0885-3185 .- 1531-8257. ; 38:2, s. 267-277
-
Journal article (peer-reviewed)abstract
- Background: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects.Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders.Methods: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1 = 51, n2 = 101), corticobasal degeneration (CBD) (n1 = 11, n2 = 3), progressive supranuclear palsy (PSP) (n1 = 22, n2 = 21), multiple system atrophy (MSA) (n1 = 31, n2 = 26), and healthy control (HC) (n1 = 48, n2 = 30) participants, as well as Alzheimer's disease (AD) (n2 = 23) patients in the second cohort.Results: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25–0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate = −0.025 to −0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate = 0.32, P = 0.021).Conclusions: These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD.
|
|
| 17. |
- Nilsson, Johanna, 1993
(author)
-
CSF biomarker panels. Focus on synaptic pathology
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Fluid biomarkers of neuropathological features are important clinical tools in diagnostics and patient monitoring of neurodegenerative diseases. For the most prevalent cause of dementia, Alzheimer’s disease (AD), several biomarkers have been introduced in the clinic reflecting the underlying pathophysiology features of amyloid-β deposition, tau pathology with hyperphosphorylation, and neurodegeneration (ATN). Together the biomarkers have been demonstrated to have >90% sensitivity and specificity for the early stages of AD. However, in the field of biomarker research, one area which has gained recent attention is biomarkers reflective of synaptic pathology (degeneration and dysfunction of the synapse), which is an early and central part of the pathophysiology of many neurodegenerative diseases, including AD, and clinically relevant since synaptic function is the foundation of cognition. Synaptic biomarkers are thus of interest not only in the routine clinical assessment of neurodegenerative diseases to facilitate diagnosis, disease staging, and progression, but especially to monitor the efficacy and endpoints of treatments in drug trials which commonly aim to halt or reduce synaptic damage. The main goals of this thesis were to develop and optimize methods for quantifying biomarkers of synaptic pathology, to evaluate their potential in AD and across neurodegenerative diseases, and to examine concordance and discordance between biomarker results and other measures of synaptic dysfunction. The work focused on multiplexed mass spectrometric (MS) methods that enable quantification with high specificity and sensitivity of a range of potential biomarkers with different functions and localizations. These methods were then used not only to compare the biomarkers’ diagnostic and disease monitoring potential but also to reinforce the credibility of the results of proteins with similar outcomes, i.e., validating general and specific pathological patterns across and within neurodegenerative diseases. A synaptic panel assay was successfully established, quantifying 17 synaptic proteins, including several SNARE proteins, neurogranin, synucleins, neuronal pentraxins, and 14-3-3 proteins. Together with an in-house-established MS assay quantifying SNAP-25 and synaptotagmin-1, the panel method was used to study synaptic proteins across neurodegenerative diseases in several studies included in this thesis. One of the main findings is that out of the potential synaptic biomarkers, several of them showed specifically higher concentrations in the AD continuum in contrast to other neurodegenerative diseases. Indicating that higher levels of synaptic proteins are possibly generally a specific feature of AD and thus a marker of AD-specific synaptic dysfunction mechanisms compared with other neurodegenerative diseases. The possible exemption to this seems to be 14-3-3 ζ/δ, of which higher levels across neurodegenerative diseases might indicate that it is a general biomarker of synaptic degeneration mechanisms. Particularly, SNAP-25, neurogranin, and β-synuclein, as well as 14-3-3 ζ/δ, seem to be promising AD biomarkers able to both predict disease progression as well as cognitive decline. For SNAP-25, it was also shown that a newly developed Single molecule array (Simoa) assay for SNAP-25 quantification can be used interchangeably with other previously established methods. Furthermore, this thesis work demonstrated that the neuronal pentraxins are present at lower concentrations across neurodegenerative diseases, indicative of synaptic dysfunction and degeneration mechanisms equally affected across diseases. The neuronal pentraxins were also found to be associated with cognitive status in AD dementia and Parkinson’s disease, the latter in which they were also associated with cognitive decline and the progression of motor symptoms and might be useful to predict disease severity. This thesis establishes that the neuronal pentraxins are possible prognostic and monitoring biomarkers for synaptic dysfunction/degeneration that associate with cognitive and motor symptoms across neurodegenerative diseases. Additionally, novel differences in synaptic proteins were found in both parkinsonian disorders and genetic frontotemporal dementia (FTD), with differential synaptic impairment represented by different synaptic proteins. Interestingly, multiple abnormalities were shown in the symptomatic patients with MAPT mutations indicating specific synaptic dysfunction in regard to the underlying proteinopathy found in each genetic FTD mutation. The results demonstrate that differential patterns of synaptic protein alterations across neurodegenerative diseases exist, probably due to differences in synaptic pathology mechanisms. In conclusion, several of the studied synaptic proteins show promise as possible complements to other CSF and imaging markers as diagnostic, prognostic, stage, or monitoring biomarkers of cognitive decline and synaptic pathology. Furthermore, this thesis provided novel insight into synaptic pathology in neurodegenerative diseases. A better understanding of the mechanistic pathways of synaptic dysfunction across and between diseases may thus contribute to improving diagnostics and potentially also to the development of new therapeutic strategies targeting said pathways. The work included in this thesis demonstrates the importance of MS-based biomarker discovery, allowing for the simultaneous quantification and exploration of multiple biomarkers leading to knowledge that can drive the development of biomarkers as well as new, highly precise methods and increase the availability of biomarker quantification.
|
|
| 18. |
- Nilsson, Johanna, 1993, et al.
(author)
-
Quantification of SNAP-25 with mass spectrometry and Simoa: a method comparison in Alzheimer's disease
- 2022
-
In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
-
Journal article (peer-reviewed)abstract
- Background Synaptic dysfunction and degeneration are central to Alzheimer's disease (AD) and have been found to correlate strongly with cognitive decline. Thus, studying cerebrospinal fluid (CSF) biomarkers reflecting synaptic degeneration, such as the presynaptic protein synaptosomal-associated protein 25 (SNAP-25), is of importance to better understand the AD pathophysiology. Methods We compared a newly developed Single molecule array (Simoa) immunoassay for SNAP-25 with an in-house immunoprecipitation mass spectrometry (IP-MS) method in a well-characterized clinical cohort (n = 70) consisting of cognitively unimpaired (CU) and cognitively impaired (CI) individuals with and without A beta pathology (A beta+ and A beta-). Results A strong correlation (Spearman's rank correlation coefficient (r(s)) > 0.88; p < 0.0001) was found between the Simoa and IP-MS methods, and no statistically significant difference was found for their clinical performance to identify AD pathophysiology in the form of A beta pathology. Increased CSF SNAP-25 levels in CI A beta+ compared with CU A beta- (Simoa, p <= 0.01; IP-MS, p <= 0.05) and CI A beta- (Simoa, p <= 0.01; IP-MS, p <= 0.05) were observed. In independent blood samples (n = 32), the Simoa SNAP-25 assay was found to lack analytical sensitivity for quantification of SNAP-25 in plasma. Conclusions These results indicate that the Simoa SNAP-25 method can be used interchangeably with the IP-MS method for the quantification of SNAP-25 in CSF. Additionally, these results confirm that CSF SNAP-25 is increased in relation to amyloid pathology in the AD continuum.
|
|
| 19. |
- Saloner, R., et al.
(author)
-
Combined Effects of Synaptic and Axonal Integrity on Longitudinal Gray Matter Atrophy in Cognitively Unimpaired Adults
- 2022
-
In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:20
-
Journal article (peer-reviewed)abstract
- Background and Objectives Synaptic dysfunction and degeneration is a predominant feature of brain aging, and synaptic preservation buffers against Alzheimer disease (AD) protein-related brain atrophy. We tested whether CSF synaptic protein concentrations similarly moderate the effects of axonal injury, indexed by CSF neurofilament light [NfL]), on brain atrophy in clinically normal adults. Methods Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (mean scan [follow-up] = 2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 25 [SNAP-25], neurogranin, growth-associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau(181)/A beta(42) ratio; reflecting AD proteinopathy). Ten bilateral temporoparietal gray matter region of interest (ROIs) shown to be sensitive to clinical AD were summed to generate a composite temporoparietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporoparietal trajectories, controlling for ptau(181)/A beta(42) ratios. Results Forty-six clinically normal older adults (mean age = 70 years; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: 0.10-0.36). Higher baseline NfL, but not ptau(181)/A beta(42) ratios, predicted steeper temporoparietal atrophy (NfL x time: beta = -0.08, p < 0.001; ptau(181)/A beta(42) x time: beta = -0.02, p = 0.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07 <= beta's >= -0.06, p's < 0.05) such that NfL was associated with temporoparietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5-4.5 times weaker when synaptic protein concentrations were low (beta range: -0.21 to -0.07) than high (beta range: -0.33 to -0.30). Discussion The association between baseline CSF NfL and longitudinal temporoparietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.
|
|
| 20. |
- Sogorb-Esteve, Aitana, et al.
(author)
-
Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia.
- 2022
-
In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
-
Journal article (peer-reviewed)abstract
- Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for most of the inheritance: C9orf72, GRN, and MAPT. Impaired synaptic health is a common mechanism in all three genetic variants, so developing fluid biomarkers of this process could be useful as a readout of cellular dysfunction within therapeutic trials.A total of 193 cerebrospinal fluid (CSF) samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72, 23 GRN, 23 MAPT) and 55 symptomatic (26 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 61 mutation-negative controls were measured using a microflow LC PRM-MS set-up targeting 15 synaptic proteins: AP-2 complex subunit beta, complexin-2, beta-synuclein, gamma-synuclein, 14-3-3 proteins (eta, epsilon, zeta/delta), neurogranin, Rab GDP dissociation inhibitor alpha (Rab GDI alpha), syntaxin-1B, syntaxin-7, phosphatidylethanolamine-binding protein 1 (PEBP-1), neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), and neuronal pentraxin 2 (NPTX2). Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex.CSF levels of eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: beta-synuclein, gamma-synuclein, 14-3-3-eta, neurogranin, Rab GDI alpha, syntaxin-1B, syntaxin-7, and PEBP-1, with three other proteins increased in MAPT mutation carriers compared with the other genetic groups (AP-2 complex subunit beta, complexin-2, and 14-3-3 zeta/delta). In contrast, CSF NPTX1 and NPTX2 levels were affected in all three genetic groups (decreased compared with controls), with NPTXR concentrations being affected in C9orf72 and GRN mutation carriers only (decreased compared with controls). No changes were seen in the CSF levels of these proteins in presymptomatic mutation carriers. Concentrations of the neuronal pentraxins were correlated with brain volumes in the presymptomatic period for the C9orf72 and GRN groups, suggesting that they become abnormal in proximity to symptom onset.Differential synaptic impairment is seen in the genetic forms of FTD, with abnormalities in multiple measures in those with MAPT mutations, but only changes in neuronal pentraxins within the GRN and C9orf72 mutation groups. Such markers may be useful in future trials as measures of synaptic dysfunction, but further work is needed to understand how these markers change throughout the course of the disease.
|
|
| 21. |
- van den Berg, E., et al.
(author)
-
Cerebrospinal Fluid Panel of Synaptic Proteins in Cerebral Amyloid Angiopathy and Alzheimer's Disease
- 2023
-
In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 92:2, s. 467-475
-
Journal article (peer-reviewed)abstract
- Background: Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-beta deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. Objective: We therefore aimed to investigate synaptic dysfunction in CAA. Methods: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. Results: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (p = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p= 0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup ofCAApatients positive forADbiomarkers (CAA/ATN+; n = 6) were similar to AD patients, while levels in CAA/ATN- (n = 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). Conclusion: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.
|
|
