| 1. |
- 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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| 2. |
- 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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| 3. |
- Adams, D., et al.
(författare)
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Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
- 2018
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 379:1, s. 11-21
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters] x albumin level in grams per liter; lower values indicated worse nutritional status).RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (+/- SD) mNIS+7 at baseline was 80.9 +/- 41.5 in the patisiran group and 74.6 +/- 37.0 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.0 +/- 1.7 versus 28.0 +/- 2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (+/- SD) baseline Norfolk QOL-DN score was 59.6 +/- 28.2 in the patisiran group and 55.5 +/- 24.3 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.7 +/- 1.8 versus 14.4 +/- 2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08 +/- 0.02 m per second with patisiran versus -0.24 +/- 0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7 +/- 9.6 versus -119.4 +/- 14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups.CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis.
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| 4. |
- Pelttari, LM, et al.
(författare)
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RAD51B in Familial Breast Cancer
- 2016
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5, s. e0153788-
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Tidskriftsartikel (refereegranskat)
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| 5. |
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| 6. |
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| 7. |
- Berk, J.L., et al.
(författare)
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The diflunisal trial : update on study drug tolerance and disease progression
- 2011
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Ingår i: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis. - : Informa UK Limited. - 1744-2818. ; 18:Suppl. 1, s. 191-192
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Familial amyloidotic polyneuropathy (FAP) is a lethal genetic disorder that affects the peripheral and autonomic nervous systems, heart, gastro-intestinal (GI) tract, and soft tissues. Disease progression is increasingly reported following liver transplantation, the only proven treatment for FAP. Small molecule thyroxine mimetics stabilize transthyretin, inhibiting FAP amyloid fibril formation under stringent in vitro conditions. We report on the progress of an international, randomized placebo-controlled study designed to determine the effect of diflunisal, a thyroxine mimetic, on neurologic disease progression in patients with active FAP. Our experience to date indicates diflunisal is well tolerated by this study cohort and that neurologic disease advances more rapidly in FAP than it does in diabetes mellitus.Background: Transthyretin-related familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant genetic disorder that predominantly affects the peripheral nervous system. FAP amyloid fibrils result from the misfolding of transthyretin, a transport protein predominantly produced by the liver. Although liver transplantation effectively treats patients with certain FAP mutations and limited disease, reports increasingly document progressive amyloid deposition following transplantation [1,2]. Alternative treatments are needed. In vitro investigations and a phase I clinical trial have demonstrated that thyroxine and small molecule mimetics, e.g. diflunisal, inhibit tetrameric transthyretin dissociation and suppress amyloid fibril formation [3,4].Methods: To examine the effect of diflunisal on disease progression in FAP, we designed a randomized, placebo controlled, double blind, multicenter international study employing the validated diabetic (DM) polyneuropathy metric, Neurologic Impairment Score + 7 attributes (NIS+7®), as the primary endpoint. A two-point change in NIS+7 correlates with clinically detectable progression of peripheral neuropathy among diabetics [5]. Entry criteria include proven FAP genotype, biopsy-proven amyloid deposits, and peripheral or autonomic neuropathy. Patients with alternate causes of neuropathy, other NSAID use, severe heart or kidney dysfunction, or previous liver transplantion are excluded. Study evaluations occur at entry, 6, 12, and 24 months. Adverse are collected by monthly telephone interviews, diary entries, and study site visit interactions. Relatedness of adverse events to study drug is assigned according to documentation in the investigational brochure, the protocol, the informed consent form; or at the investigator's discretion.Results: To date, 90 subjects have enrolled – 62 men and 28 women with median age 63 years (range 27–76 years). Adverse events tabulated by affected organ systems predominantly involved gastrointestinal events, more often attributed to disease complications than study drug side effects (Table 1). Although rare events, congestive heart failure in two subjects and GI bleeding in another prompted study drug discontinuation. Two disease-related deaths have occurred, both off study drug. Aggregate data from all study subjects (placebo and active drug arms) followed for at least 12 months identified a 3.2 point increase in median NIS+7 summated scores. In contrast, Dyck et al. [6] reported an annual 0.85 point increase in NIS+7 median scores in a large cohort of diabetics with polyneuropathy. Taken together, NIS+7 detected neurologic disease progression in this FAP cohort after 12 months observation. Additionally, NIS+7 measured disease advanced 3.5 times faster in our aggregate FAP study population than previously reported in DM.Conclusions: Diflunisal is well tolerated in FAP patients participating in the study. NIS+7, a composite scoring system, appears to be an effective study instrument for ATTR neuropathy, detecting significant change over 12 months observation. Neurologic disease progresses more rapidly in FAP than DM cohorts. The exact rate of disease progression in untreated FAP subjects detected by NIS+7 awaits unblinding of the data. These data will provide basis for future study design in FAP patients.
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| 8. |
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| 9. |
- Budd Haeberlein, Samantha, et al.
(författare)
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Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease
- 2022
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Ingår i: Journal of Prevention of Alzheimer's Disease. - : SERDI. - 2274-5807. ; 9:2, s. 197-210
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. Objectives: We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease. Design: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease. Setting: These studies involved 348 sites in 20 countries. Participants: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. Intervention: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. Measurements: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. Results: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. Conclusions: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose-and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.
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| 10. |
- Coelho, Teresa, et al.
(författare)
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Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen
- 2023
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Ingår i: Neurology and Therapy. - : Springer Nature. - 2193-8253 .- 2193-6536. ; 12, s. 267-287
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study.Methods: Patients eligible for NEURO-TTRansform were 18–82 years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II.Results: The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8 years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0.Conclusion: The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice.
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