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- Van Deerlin, Vivian M, et al.
(författare)
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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| 4. |
- Nilsson, Johanna, 1993, et al.
(författare)
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Cerebrospinal fluid biomarker panel of synaptic dysfunction in Alzheimer's disease and other neurodegenerative disorders
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:5, s. 1775-1784
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Tidskriftsartikel (refereegranskat)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.
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| 6. |
- Chen-Plotkin, A. S., et al.
(författare)
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Updating our definitions of Parkinson's disease for a molecular age
- 2018
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Ingår i: Journal of Parkinson's Disease. - 1877-7171. ; 8:s1
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Tidskriftsartikel (refereegranskat)abstract
- Clinical definitions of Parkinson's disease (PD) are over 200 years old, while neuropathological definitions-which are still the basis of how we define the disease now-are over 100 years old. We argue that for both clinical care and therapeutic development, these definitions need updating for the molecular age in which we live. We highlight specific instances in which genetic or biochemical biomarkers are increasingly used for clinical trial enrollment in the neurodegenerative diseases, suggesting that molecular definition(s) of PD are already emerging. We review candidate biomarkers for PD-related pathologies and highlight the need for further validation. © 2018 IOS Press and the authors. All rights reserved.
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| 7. |
- Gallagher, Michael D., et al.
(författare)
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TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
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Tidskriftsartikel (refereegranskat)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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| 8. |
- Portelius, Erik, 1977, et al.
(författare)
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Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology.
- 2018
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 136:3, s. 363-376
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Tidskriftsartikel (refereegranskat)abstract
- Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD),and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson's disease (p<0.0001), frontotemporal dementia (p<0.0001), and amyotrophic lateral sclerosis (p=0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p=0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p=0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p=0.0006 and p<0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.
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| 9. |
- Quilico Cousins, Katheryn Alexandra, et al.
(författare)
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CSF Biomarkers of Alzheimer Disease in Patients With Concomitant alpha-Synuclein Pathology
- 2022
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:20
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives CSF biomarkers beta-amyloid 1-42 (A beta(42)) phosphorylated tau 181 (p-tau(181)), total tau (t-tau), and neurogranin (Ng) can diagnose Alzheimer disease (AD) in life. However, it is unknown whether CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as alpha-synuclein (alpha Syn). Our primary goal was to test whether biomarkers in patients with AD are altered by concomitant alpha Syn. We compared CSF A beta(42), p-tau(181), t-tau, and Ng levels across autopsy-confirmed AD and concomitant AD and alpha Syn (AD + alpha Syn). Antemortem CSF levels were related to postmortem accumulations of alpha Syn. Finally, we tested how concommitant AD + alpha Syn affected the diagnostic accuracy of 2 CSF-based strategies: the amyloid/tau/neurodegeneration (ATN) framework and the t-tau/A beta(42) ratio. Methods Inclusion criteria were neuropathologic diagnoses of AD, mixed AD + alpha Syn, and alpha Syn. A convenience sample of nonimpaired controls was selected with available CSF and a Mini-Mental State Examination (MMSE) >= 27. alpha Syn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF A beta(42), t-tau, and Ng differences across AD and AD + alpha Syn. Linear models tested how biomarkers were altered by alpha Syn accumulation in AD, accounting for pathologic beta-amyloid and tau. Receiver operating characteristic and area under the curve (AUC), including 95% CI, evaluated diagnostic accuracy. Results Participants were 61 patients with AD, 39 patients with mixed AD + alpha Syn, 20 patients with alpha Syn, and 61 controls. AD had similar median age (73 [interquartile range {IQR} = 12] years), MMSE (23 [IQR = 9]), and sex distribution (male = 49%) compared with AD + alpha Syn age (70 [IQR = 13] years; p = 0.3), MMSE (25 [IQR = 9.5]; p = 0.19), and sex distribution (male = 69%; p = 0.077). ANCOVAs showed that AD + alpha Syn had lower p-tau(181) (F(1,94) = 17, p < 2.6e-16), t-tau (F(1,93) = 11, p = 0.0004), and Ng levels (F(1,50) = 12, p = 0.0004) than AD; there was no difference in A beta(42) = 0.44). Models showed increasing alpha Syn related to lower (beta = -0.26, SE = 0.092, p = 0.0065), t-tau (beta = -0.19, SE = 0.092, p = 0.041), and Ng levels (beta = -0.2, SE = 0.066, p = 0.0046); alpha Syn was not a significant factor for A beta(42) (p = 1). T-tau/A beta(42) had the highest accuracy when detecting AD, including mixed AD + alpha Syn cases (AUC = 0.95; CI 0.92-0.98). Discussion Findings demonstrate that concomitant alpha Syn pathology in AD is associated with lower CSF p-tau(181), t-tau, and Ng levels and can affect diagnostic accuracy in patients with AD.
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| 10. |
- Sandelius, Åsa P, et al.
(författare)
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Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology.
- 2019
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 15:1, s. 55-64
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Tidskriftsartikel (refereegranskat)abstract
- The level of the presynaptic protein growth-associated protein 43 (GAP-43) in cerebrospinal fluid (CSF) has previously been shown to be increased in Alzheimer's disease (AD) and thus may serve as an outcome measure in clinical trials and facilitate earlier disease detection.We developed an enzyme-linked immunosorbent assay for CSF GAP-43 and measured healthy controls (n=43), patients with AD (n=275), or patients with other neurodegenerative diseases (n=344). In a subpopulation (n=93), CSF GAP-43 concentrations from neuropathologically confirmed cases were related to Aβ plaques, tau, α-synuclein, and TDP-43 pathologies.GAP-43 was significantly increased in AD compared to controls and most neurodegenerative diseases and correlated with the magnitude of neurofibrillary tangles and Aβ plaques in the hippocampus, amygdala, and cortex. GAP-43 was not associated to α-synuclein or TDP-43 pathology.The presynaptic marker GAP-43 is associated with both diagnosis and neuropathology of AD and thus may be useful as a sensitive and specific biomarker for clinical research.
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