| 1. |
- Fenstermacher, M.E., et al.
(författare)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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| 2. |
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| 3. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Wang, Li-San, et al.
(författare)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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| 8. |
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| 9. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 10. |
- 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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| 11. |
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| 12. |
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| 13. |
- Arboleda-Velasquez, Joseph F, et al.
(författare)
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Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.
- 2019
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 25:11, s. 1680-1683
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Tidskriftsartikel (refereegranskat)abstract
- We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.
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| 14. |
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| 15. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 16. |
- Kloske, C. M., et al.
(författare)
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APOE and immunity: Research highlights
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2677-2696
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Forskningsöversikt (refereegranskat)abstract
- INTRODUCTIONAt the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODSThe meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTSDuring the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor alpha [TNF alpha]). DISCUSSIONThis manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
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| 17. |
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| 18. |
- Palumbo, A., et al.
(författare)
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International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation
- 2009
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 23:10, s. 1716-1730
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Forskningsöversikt (refereegranskat)abstract
- In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM. Leukemia (2009) 23, 1716-1730; doi: 10.1038/leu.2009.122; published online 4 June 2009
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| 19. |
- Quiroz, Y. T., et al.
(författare)
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Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study
- 2020
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Ingår i: Lancet Neurology. - 1474-4422. ; 19:6, s. 513-521
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Tidskriftsartikel (refereegranskat)abstract
- Background Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (G1u280A1a) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred. Methods In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8-75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellin, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers. Findings We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0 . 0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset. Interpretation Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies. (C) 2020 Elsevier Ltd. All rights reserved.
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| 20. |
- Treusch, Sebastian, et al.
(författare)
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Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast
- 2011
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Ingår i: Science. - Washington : American association of advancement in science. - 0036-8075 .- 1095-9203. ; 334:6060, s. 1241-1245
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Tidskriftsartikel (refereegranskat)abstract
- Aβ (beta amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained using yeast as a model system.
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| 21. |
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| 22. |
- Ocio, E. M., et al.
(författare)
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New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG)
- 2014
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 28:3, s. 525-542
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Forskningsöversikt (refereegranskat)abstract
- Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.
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| 23. |
- Aguillon, David, et al.
(författare)
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Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2585-2594
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD. Methods: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members. Results: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. Discussion: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials. Highlights: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance.
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| 24. |
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| 25. |
- van Amerongen, Suzan, et al.
(författare)
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Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project
- 2024
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Ingår i: JOURNAL OF NEUROINFLAMMATION. - 1742-2094. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1 beta, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. Methods Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, >= 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. Results CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. Conclusion Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.
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| 26. |
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| 27. |
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| 28. |
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| 29. |
- Guzmán-Vélez, Edmarie, et al.
(författare)
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Associations between plasma neurofilament light, in vivo brain pathology, and cognition in non-demented individuals with autosomal-dominant Alzheimer's disease.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:5, s. 813-821
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Tidskriftsartikel (refereegranskat)abstract
- Neurofilament light (NfL) is a promising biomarker of early neurodegeneration in Alzheimer's disease (AD). We examined whether plasma NfL was associated with in vivo amyloid beta and tau, and cognitive performance in non-demented presenilin-1 (PSEN1) E280A mutation carriers.Twenty-five mutation carriers and 19 non-carriers (age range: 28 to 49 years) were included in this study. Participants underwent 11C Pittsburgh compound B (PiB)-PET (positron emission tomography), flortaucipir-PET, blood sampling, and cognitive testing.Mutation carriers exhibited higher plasma NfL levels than non-carriers. In carriers, higher NfL levels were related to greater regional tau burden and worse cognition, but not amyloid beta load. When we adjusted for age, a proxy of disease progression, elevated plasma NfL levels were only correlated with worse memory recall.Findings support an association between plasma NfL, cognition, and tau pathology in non-demented individuals at genetic risk for developing AD dementia. Plasma NfL may be useful for selecting individuals at increased risk and tracking disease progression in AD.
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| 30. |
- Hey, John A., et al.
(författare)
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Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease
- 2024
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Ingår i: DRUGS. - 0012-6667 .- 1179-1950. ; 84, s. 811-823
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Tidskriftsartikel (refereegranskat)abstract
- Introduction ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (A beta) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments.Methods The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) >= 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau181, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma A beta 42 and A beta 40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau181 at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test.Results The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau181 reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks.Conclusions The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-A beta oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD.Trial Registration https://clinicaltrials.gov/study/NCT04693520.
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| 31. |
- Impellizzeri, Franco M., et al.
(författare)
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Patient-reported outcome measures for hip-related pain : A review of the available evidence and a consensus statement from the International Hip-related Pain Research Network, Zurich 2018
- 2020
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:14, s. 848-857
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Forskningsöversikt (refereegranskat)abstract
- Hip-related pain is a well-recognised complaint among active young and middle-aged active adults. People experiencing hip-related disorders commonly report pain and reduced functional capacity, including difficulties in executing activities of daily living. Patient-reported outcome measures (PROMs) are essential to accurately examine and compare the effects of different treatments on disability in those with hip pain. In November 2018, 38 researchers and clinicians working in the field of hip-related pain met in Zurich, Switzerland for the first International Hip-related Pain Research Network meeting. Prior to the meeting, evidence summaries were developed relating to four prioritised themes. This paper discusses the available evidence and consensus process from which recommendations were made regarding the appropriate use of PROMs to assess disability in young and middle-aged active adults with hip-related pain. Our process to gain consensus had five steps: (1) systematic review of systematic reviews; (2) preliminary discussion within the working group; (3) update of the more recent high-quality systematic review and examination of the psychometric properties of PROMs according to established guidelines; (4) formulation of the recommendations considering the limitations of the PROMs derived from the examination of their quality; and (5) voting and consensus. Out of 102 articles retrieved, 6 systematic reviews were selected and assessed for quality according to AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews). Two showed moderate quality. We then updated the most recent review. The updated literature search resulted in 10 additional studies that were included in the qualitative synthesis. The recommendations based on evidence summary and PROMs limitations were presented at the consensus meeting. The group makes the following recommendations: (1) the Hip and Groin Outcome Score (HAGOS) and the International Hip Outcome Tool (iHOT) instruments (long and reduced versions) are the most appropriate PROMs to use in young and middle-aged active adults with hip-related pain; (2) more research is needed into the utility of the HAGOS and the iHOT instruments in a non-surgical treatment context; and (3) generic quality of life measures such as the EuroQoL-5 Dimension Questionnaire and the Short Form Health Survey-36 may add value for researchers and clinicians in this field. We conclude that as none of the instruments shows acceptable quality across various psychometric properties, more methods studies are needed to further evaluate the validity of these PROMS-the HAGOS and iHOT-as well as the other (currently not recommended) PROMS.
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| 32. |
- Kemp, Joanne L., et al.
(författare)
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Physiotherapist-led treatment for young to middle-aged active adults with hip-related pain : Consensus recommendations from the International Hip-related Pain Research Network, Zurich 2018
- 2020
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:9, s. 504-511
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Tidskriftsartikel (refereegranskat)abstract
- The 1st International Hip-related Pain Research Network meeting discussed four prioritised themes concerning hip-related pain in young to middle-aged adults: (1) diagnosis and classification of hip-related pain; (2) patient-reported outcome measures for hip-related pain; (3) measurement of physical capacity for hip-related pain; (4) physiotherapist-led treatment for hip-related pain. Thirty-eight expert researchers and clinicians working in the field of hip-related pain attended the meeting. This manuscript relates to the theme of physiotherapist-led treatments for hip-related pain. A systematic review on the efficacy of physiotherapist-led interventions for hip-related pain (published separately) was conducted and found that strong evidence for physiotherapist-led treatments was lacking. Prior to the meeting, draft consensus recommendations for consideration in the meeting were also developed based on the systematic review. The draft consensus recommendations were presented to all of the meeting participants via email, at least 1 week prior to the meeting. At the meeting, these recommendations were discussed, revised and voted on. Six recommendations for clinical practice and five recommendations for research were included and all gained consensus. Recommendations for clinical practice were that (i) Exercise-based treatments are recommended for people with hip-related pain. (ii) Exercise-based treatment should be at least 3 months duration. (iii) Physiotherapist-led rehabilitation after hip surgery should be undertaken. (iv) Patient-reported outcome measures, measures of physical impairment and measures of psychosocial factors should be used to monitor response to treatment. (v) Physical activity (that may include sport) is recommended for people with hip-related pain. (vi) Clinicians should discuss patient expectations, use shared-decision making and provide education. Recommendations for research were (i) Reporting of exercise programmes: Exercise descriptors such as load magnitude, number of repetitions and sets, duration of whole programme, duration of contractile element of exercise, duration of one repetition, time under tension, rest between repetitions, range of motion through which the exercise is performed, and rest between exercise sessions should be reported. (ii) Research should investigate the optimal frequency, intensity, time, type, volume and progression of exercise therapy. (iii) Research should examine the effect of patient education in people with hip-related pain. (iv) Research should investigate the effect of other treatments used in people with hip-related pain (for example: manual therapy, medications, injections). (v) Research should examine the impact of comorbidities and social determinants on treatment effectiveness in people with hip-related pain. Clinicians and researchers working with young to middle-aged active adults with hip-related pain may use these consensus recommendations to guide, develop, test and implement individualised, evidence-based physiotherapist-led rehabilitation programmes.
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| 33. |
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| 34. |
- Ly, Monica T, et al.
(författare)
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Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players.
- 2024
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Ingår i: Neurology. - 1526-632X. ; 102:2
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Tidskriftsartikel (refereegranskat)abstract
- Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health.Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid β1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI.In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men.Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.
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| 35. |
- Mosler, Andrea Britt, et al.
(författare)
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Standardised measurement of physical capacity in young and middle-aged active adults with hip-related pain : Recommendations from the first International Hip-related Pain Research Network (IHiPRN) meeting, Zurich, 2018
- 2020
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:12, s. 702-710
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Tidskriftsartikel (refereegranskat)abstract
- Hip-related pain can significantly impact quality of life, function, work capacity, physical activity and family life. Standardised measurement methods of physical capacity of relevance to young and middle-aged active adults with hip-related pain are currently not established. The aim of this consensus paper was to provide recommendations for clinical practice and research on standardised measurement methods of physical capacity in young and middle-aged active adults with hip-related pain. Four areas of importance were identified: (1) clinical measures (range of motion, muscle strength, functional impairments), (2) laboratory-based measures (biomechanics and muscle function (muscle activity, size and adiposity)), (3) physical activity, and (4) return to sport/performance. The literature was reviewed, and a summary circulated to the working group to inform discussion at the consensus meeting. The working group developed clinical and research recommendations from the literature review, which were further discussed and modified within the working group at the consensus meeting. These recommendations were then presented to all 38 International Hip-related Pain Research Network (IHiPRN) participants for further discussion, refinement and consensus voting. Therefore, the recommendations voted on were based on a combination of current evidence and expert opinion. The consensus meeting voted on 13 recommendations, six of which were clinically orientated, and seven more research specific. We recommended that clinicians working with young and middle-aged active adults with hip-related pain assess strength using objective methods of measurement, and clinically assess performance of functional tasks, including walking and running. Physical activity should be quantified using both self-reported and objective measures, and patient expectations of recovery should be quantified prior to treatment. It was recommended that return to physical activity (including sport and occupation) be quantified, and sport-specific activities should be assessed prior to return to sport. The IHiPRN participants were uncertain regarding recommendations for range of motion assessment. Research recommendations were that the measurement properties of range of motion, strength and functional performance tests be investigated, reported and improved in both clinical and research settings. Reporting of movement-related parameters (biomechanics and muscle function) should be standardised and the relationship among movement-related parameters, symptoms, function, quality of life, and intra-articular and imaging findings should be investigated. Quantification of return to physical activity (including sport and occupational demands) is required in future research, and the return to sport continuum should be used. Future research is required to determine the best criteria for rehabilitation progression and return to physical activity following hip-related pain management.
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| 36. |
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| 37. |
- Palmqvist, Sebastian, et al.
(författare)
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Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders
- 2020
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Ingår i: Jama-Journal of the American Medical Association. - : American Medical Association (AMA). - 0098-7484. ; 324:8, s. 772-781
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Tidskriftsartikel (refereegranskat)abstract
- Key PointsQuestionWhat is the discriminative accuracy of plasma phospho-tau217 (P-tau217) for differentiating Alzheimer disease from other neurodegenerative disorders? FindingsIn this cross-sectional study that included 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated Alzheimer disease from other neurodegenerative diseases (area under the receiver operating characteristic curve of 0.89 in a neuropathologically defined cohort and 0.96 in a clinically defined cohort), with performance that was significantly better than established Alzheimer disease plasma- and MRI-based biomarkers but not significantly different from key CSF- or PET-based biomarkers. MeaningAlthough plasma P-tau217 was able to discriminate Alzheimer disease from other neurodegenerative diseases, further research is needed to validate the findings in unselected and diverse populations, optimize the assay, and determine its potential role in clinical care. ImportanceThere are limitations in current diagnostic testing approaches for Alzheimer disease (AD). ObjectiveTo examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and ParticipantsThree cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n=301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n=178), AD dementia (n=121), and other neurodegenerative diseases (n=99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). ExposuresPlasma P-tau217. Main Outcomes and MeasuresPrimary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). ResultsMean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P<.05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P<.001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P>.15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman rho =0.64; P<.001), but not without (Spearman =0.15; P=.33), beta -amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF A beta 42:A beta 40 ratio, and MRI measures (AUC range, 0.67-0.90; P<.05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P=.22). Conclusions and RelevanceAmong 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care. This cross-sectional study compares the accuracy of plasma tau phosphorylated at threonine 217 (P-tau217) levels vs other plasma-, MRI-, CSF-, and PET-based markers for distinguishing Alzheimer from other neurodegenerative diseases in 3 cohorts in Arizona, Sweden, and Columbia with or at risk for dementia.
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| 38. |
- Reiman, Michael P., et al.
(författare)
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Consensus recommendations on the classification, definition and diagnostic criteria of hip-related pain in young and middle-aged active adults from the International Hip-related Pain Research Network, Zurich 2018
- 2020
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:11, s. 631-641
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Forskningsöversikt (refereegranskat)abstract
- There is no agreement on how to classify, define or diagnose hip-related pain-a common cause of hip and groin pain in young and middle-aged active adults. This complicates the work of clinicians and researchers. The International Hip-related Pain Research Network consensus group met in November 2018 in Zurich aiming to make recommendations on how to classify, define and diagnose hip disease in young and middle-aged active adults with hip-related pain as the main symptom. Prior to the meeting we performed a scoping review of electronic databases in June 2018 to determine the definition, epidemiology and diagnosis of hip conditions in young and middle-aged active adults presenting with hip-related pain. We developed and presented evidence-based statements for these to a panel of 37 experts for discussion and consensus agreement. Both non-musculoskeletal and serious hip pathological conditions (eg, tumours, infections, stress fractures, slipped capital femoral epiphysis), as well as competing musculoskeletal conditions (eg, lumbar spine) should be excluded when diagnosing hip-related pain in young and middle-aged active adults. The most common hip conditions in young and middle-aged active adults presenting with hip-related pain are: (1) femoroacetabular impingement (FAI) syndrome, (2) acetabular dysplasia and/or hip instability and (3) other conditions without a distinct osseous morphology (labral, chondral and/or ligamentum teres conditions), and that these terms are used in research and clinical practice. Clinical examination and diagnostic imaging have limited diagnostic utility; a comprehensive approach is therefore essential. A negative flexion-adduction-internal rotation test helps rule out hip-related pain although its clinical utility is limited. Anteroposterior pelvis and lateral femoral head-neck radiographs are the initial diagnostic imaging of choice-advanced imaging should be performed only when requiring additional detail of bony or soft-tissue morphology (eg, for definitive diagnosis, research setting or when planning surgery). We recommend clear, detailed and consistent methodology of bony morphology outcome measures (definition, measurement and statistical reporting) in research. Future research on conditions with hip-related pain as the main symptom should include high-quality prospective studies on aetiology and prognosis. The most common hip conditions in active adults presenting with hip-related pain are: (1) FAI syndrome, (2) acetabular dysplasia and/or hip instability and (3) other conditions without distinct osseous morphology including labral, chondral and/or ligamentum teres conditions. The last category should not be confused with the incidental imaging findings of labral, chondral and/or ligamentum teres pathology in asymptomatic people. Future research should refine our current recommendations by determining the clinical utility of clinical examination and diagnostic imaging in prospective studies.
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| 39. |
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| 40. |
- Terpos, Evangelos, et al.
(författare)
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International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma-Related Bone Disease.
- 2013
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 31:18, s. 179-2347
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSEThe aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease.MethodologyAn interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members.RecommendationsBisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.
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| 41. |
- Vila-Castelar, C., et al.
(författare)
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Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer's disease
- 2023
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Ingår i: Alzheimers & Dementia. - 1552-5260. ; 19:9, s. 4127-4138
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONPlasma tau phosphorylated at threonine 217 (P-tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer's disease (AD) pathology. Few studies have examined the role of sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD. METHODSWe examined the effects of sex and age on plasma P-tau217 and NfL, and their association with cognitive performance in a cross-sectional study of 621 Presenilin-1 E280A mutation carriers (PSEN1) and non-carriers. RESULTSAs plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non-carriers. DISCUSSIONOur findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance. HIGHLIGHTSWe examined sex differences in plasma P-tau217 and NfL in Presenilin-1 E280A (PSEN1) mutation carriers and non-carriers.Female carriers had a greater plasma NfL increase, but not P-tau217, than male carriers.As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers.The interaction effect of sex by plasma NfL levels did not predict cognition among carriers.
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