1. |
- Alping, P, et al.
(author)
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Reply
- 2016
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In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 80:5, s. 791-792
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Journal article (other academic/artistic)
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2. |
- Alping, P., et al.
(author)
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Rituximab versus Fingolimod after Natalizumab in Multiple Sclerosis Patients
- 2016
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In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 79:6, s. 950-958
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Journal article (peer-reviewed)abstract
- Objective: Many JC virus antibody-positive relapsing-remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy. Methods: We compared outcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swedish multiple sclerosis centers with different preferential use of rituximab and fingolimod (Stockholm, n = 156, fingolimod 51%; Gothenburg, n = 64, fingolimod 88%; Umea, n = 36, fingolimod 19%), yielding a total cohort of N = 256 (fingolimod 55%). Results: Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab = 0.10, 95% confidence interval [CI] = 0.02-0.43). The hazard ratio (favoring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI = 0.10-0.59) and 0.07 (95% CI = 0.02-0.30), respectively. Furthermore, contrast-enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio = 0.05, 95% CI = 0.00-0.22). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center). Interpretation: Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in 2 of the centers mitigates these concerns.
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3. |
- Anderson, Christopher D., et al.
(author)
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Genetic variants in CETP increase risk of intracerebral hemorrhage
- 2016
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In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 80:5, s. 730-740
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Journal article (peer-reviewed)abstract
- OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10(-4) ) with no heterogeneity across studies (I(2) = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10(-6) ).INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.
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4. |
- Benatar, Michael, et al.
(author)
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Neurofilament light : a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion
- 2018
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In: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 84:1, s. 130-139
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Journal article (peer-reviewed)abstract
- Objective: To evaluate neurofilament light (NfL) as a biomarker of the presymptomatic phase of amyotrophic lateral sclerosis (ALS).Methods: The study population includes 84 individuals at risk for developing ALS, 34 controls, 17 ALS patients, and 10 phenoconverters (at-risk individuals observed both before and after the emergence of clinically manifest disease). At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation (in SOD1, C9orf72, TARDBP, FUS, VCP, etc), but who, at the time of enrollment, demonstrated no clinical symptoms or signs (including electromyographic evidence) of manifest disease. NfL in serum and cerebrospinal fluid (CSF) were quantified using an electrochemiluminescence immunoassay.Results: Serum and CSF NfL are substantially higher in ALS patients compared to controls and at-risk individuals and remain relatively stable over time. Among phenoconverters, however, NfL levels were elevated (ie, above the range observed in controls) as far back as approximate to 12 months preceding the emergence of the earliest clinical symptoms or signs of disease.Interpretation: Serum (and CSF) NfL are informative biomarkers of presymptomatic ALS, providing a new tool to quantify presymptomatic disease progression and to potentially predict the timing of clinical phenoconversion. As such, quantification of NfL may aid the design and implementation of early therapeutic intervention for affected individuals and/or disease prevention trials for individuals at short-term risk of developing ALS.
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5. |
- Bergeron, David, et al.
(author)
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Prevalence of amyloid-β pathology in distinct variants of primary progressive aphasia
- 2018
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In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 84:5, s. 729-740
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p
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7. |
- Chelban, V., et al.
(author)
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PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation
- 2019
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In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 86:2, s. 225-240
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Journal article (peer-reviewed)abstract
- Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240. © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
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8. |
- Curtze, Sami, et al.
(author)
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Cerebral white matter lesions and post-thrombolytic remote parenchymal hemorrhage.
- 2016
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In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 80:4, s. 593-9
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Journal article (peer-reviewed)abstract
- Parenchymal hematoma (PH) following intravenous thrombolysis (IVT) in ischemic stroke can occur either within the ischemic area (iPH) or as a remote PH (rPH). The latter could be, at least partly, related to cerebral amyloid angiopathy, which belongs to the continuum of cerebral small vessel disease. We hypothesized that cerebral white matter lesions (WMLs)-an imaging surrogate of small vessel disease-are associated with a higher rate of rPH.We analyzed 2,485 consecutive patients treated with IVT at the Helsinki University Hospital. Blennow rating scale of 5 to 6 points on baseline computed tomographic head scans was considered as severe WMLs. An rPH was defined as hemorrhage that-contrary to iPH-appears in brain regions without visible ischemic damage and is clinically not related to the symptomatic acute lesion site. The associations between severe WMLs and pure rPH versus no PH, pure iPH versus no PH, and pure rPH versus pure iPH were studied in multivariate logistic regression models.rPHs were mostly (74%) located in lobar regions. After adjustments, the presence of severe WMLs was associated with pure rPH (odds ratio [OR]=6.79, 95% confidence interval [CI]=2.57-17.94) but not with pure iPH (OR=1.45, 95% CI=0.83-2.53) when compared to patients with no PH. In direct comparison of pure rPH with pure iPH, severe cerebral WMLs were further associated with higher iPH rates (OR=3.60, 95% CI=1.06-12.19).Severe cerebral WMLs were associated with post-thrombolytic rPH but not with iPH within the ischemic area. Ann Neurol 2016;80:593-599.
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9. |
- Dekhtyar, Serhiy, et al.
(author)
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Genetic risk of dementia mitigated by cognitive reserve : A cohort study
- 2019
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In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 86:1, s. 68-78
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Journal article (peer-reviewed)abstract
- Objective We investigated whether cognitive reserve modifies the risk of dementia attributable to apolipoprotein epsilon 4 (APOE-epsilon 4), a well-known genetic risk factor for dementia. Methods We followed 2,556 cognitively intact participants aged >= 60 years from the ongoing prospective community-based Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Dementia was ascertained through clinical and neuropsychological assessments and diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. Structural equation modeling was used to generate a cognitive reserve indicator from 4 previously validated contributors: early life education, midlife substantive work complexity, late life leisure activities, and late life social networks. Cox proportional hazard models estimated dementia risk in relation to cognitive reserve indicator. The interaction between the cognitive reserve indicator and APOE-epsilon 4 was assessed on multiplicative and additive scales. Results After an average of 6.3 years (range = 2.1-10.7) of follow-up, 232 dementia cases were ascertained. Relative to individuals in the lowest tertile of cognitive reserve indicator, those with moderate and high reserve were at a reduced risk of dementia. There was no multiplicative interaction between APOE-epsilon 4 status and cognitive reserve indicator (p = 0.113). Additive interaction was statistically significant. Relative to APOE-epsilon 4 carriers with low cognitive reserve, epsilon 4 carriers with high reserve had a reduced risk of dementia (hazard ratio [HR] = 0.28, 95% confidence interval [CI] = 0.13-0.59). The magnitude of risk reduction was similar in epsilon 4 noncarriers with a high cognitive reserve indicator (HR = 0.24, 95% CI = 0.15-0.40). Interpretation Lifelong engagement in reserve-enhancing activities attenuates the risk of dementia attributable to APOE-epsilon 4. Promoting cognitive reserve might be especially effective in subpopulations with high genetic risk of dementia. ANN NEUROL 2019
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10. |
- Eklund, Anders, et al.
(author)
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The Pressure Difference between Eye and Brain Changes with Posture
- 2016
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In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 80:2, s. 269-276
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Journal article (peer-reviewed)abstract
- Objective: The discovery of a posture-dependent effect on the difference between intraocular pressure (IOP) and intracranial pressure (ICP) at the level of lamina cribrosa could have important implications for understanding glaucoma and idiopathic intracranial hypertension and could help explain visual impairments in astronauts exposed to microgravity. The aim of this study was to determine the postural influence on the difference between simultaneously measured ICP and IOP.Methods: Eleven healthy adult volunteers (age = 46 ± 10 years) were investigated with simultaneous ICP, assessed through lumbar puncture, and IOP measurements when supine, sitting, and in 9° head-down tilt (HDT). The trans–lamina cribrosa pressure difference (TLCPD) was calculated as the difference between the IOP and ICP. To estimate the pressures at the lamina cribrosa, geometrical distances were estimated from magnetic resonance imaging and used to adjust for hydrostatic effects.Results: The TLCPD (in millimeters of mercury) between IOP and ICP was 12.3 ± 2.2 for supine, 19.8 ± 4.6 for sitting, and 6.6 ± 2.5 for HDT. The expected 24-hour average TLCPD on earth—assuming 8 hours supine and 16 hours upright—was estimated to be 17.3mmHg. By removing the hydrostatic effects on pressure, a corresponding 24-hour average TLCPD in microgravity environment was simulated to be 6.7mmHg.Interpretation: We provide a possible physiological explanation for how microgravity can cause symptoms similar to those seen in patients with elevated ICP. The observed posture dependency of TLCPD also implies that assessment of the difference between IOP and ICP in upright position may offer new understanding of the pathophysiology of idiopathic intracranial hypertension and glaucoma.
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