| 721. |
- Rostgaard, Nina, et al.
(författare)
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CSF neurofilament light concentration is increased in presymptomatic CHMP2B mutation carriers
- 2018
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Ingår i: Neurology. - 0028-3878. ; 90:2, s. e157-e163
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Tidskriftsartikel (refereegranskat)abstract
- A rare cause of familial frontotemporal dementia (FTD) is a mutation in theCHMP2Bgene on chromosome 3 (FTD-3), described in a Danish family. Here we examine whether CSF biomarkers change in the preclinical phase of the disease.In this cross-sectional explorative study, we analyzed CSF samples from 16 mutation carriers and 14 noncarriers from the Danish FTD-3 family. CSF biomarkers included total tau (t-tau) and neurofilament light chain (NfL) as a marker for neurodegeneration, phosphorylated tau (p-tau) as a marker for tau pathology, β-amyloid (Aβ) 38, 40, and 42 (Aβ38, Aβ40, and Aβ42) to monitor Aβ metabolism, and YKL-40 as a marker of neuroinflammation. Aβ isoform concentrations were measured using a multiplexed immunoassay; t-tau, p-tau, NfL, and YKL-40 concentrations were measured using sandwich ELISAs.CSF NfL concentration was significantly increased in mutation carriers vs noncarriers. Further, CSF NfL concentration was significantly higher in symptomatic mutation carriers compared to presymptomatic carriers, and also significantly higher in presymptomatic carriers compared to noncarriers. No differences in t-tau and p-tau and YKL-40 concentrations between controls and mutation carriers were observed. CSF concentrations of the Aβ peptides Aβ38and Aβ40but not Aβ42were significantly lower in mutation carriers compared to noncarriers.Increased NfL levels in presymptomatic individuals and in symptomatic patients with FTD-3 indicate a continuous process of neurodegeneration from the presymptomatic to symptomatic state. Although not specific for FTD-3 pathology, our data suggest that CSF NfL could serve as a valuable biomarker to detect onset of neurodegeneration in FTD-3 mutation carriers.
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| 722. |
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| 723. |
- Sacuicu, S, et al.
(författare)
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Prodromal cognitive signs of dementia in 85-year-olds using four sources of information
- 2005
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Ingår i: Neurology. - 0028-3878. ; 65:12, s. 1894-1900
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Tidskriftsartikel (refereegranskat)abstract
- The objective was to evaluate the utility of assessing four cognitive domains ob-tained from four information sources to identify individuals at risk for developing dementia, Alzheimer disease (AD), and vascular dementia (VaD). METHODS: A representative population sample of nondemented 85-year-olds (n = 313) from Gothenburg, Sweden, was examined regarding memory, language, and visuospa-tial and executive functions, using self- and key informant reports and neuropsy-chiatric and psychometric examinations. The sample was followed 3 years for in-cident dementia, AD, or possible VaD. RESULTS: All cases of dementia, AD, and VaD were preceded by low performance in most domains irrespective of informa-tion source. Isolated low memory performance or low cognitive performance with unimpaired memory did not predict dementia. Positive predictive values in-creased with number of domains affected. Self- and key informant reports were less useful for predicting dementia than neuropsychiatric and psychometric ex-aminations. The best positive predictive value (88%) was for low cognitive per-formance in all domains using neuropsychiatric and psychometric examinations; however, sensitivity was only 18%. CONCLUSIONS: Although memory impair-ment was necessary to predict dementia, it was not sufficient. Other cognitive domains needed to be affected. Relying on self-reports or key informants for early detection of dementia excluded a large group at risk. In addition, vascular de-mentia appeared to have a prodromal stage.
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| 724. |
- Sacuiu, Simona, 1971, et al.
(författare)
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Secular changes in cognitive predictors of dementia and mortality in 70-year-olds.
- 2010
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Ingår i: Neurology. - 1526-632X. ; 75:9, s. 779-85
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Successive elderly birth cohorts improved in cognitive performance during the 20th century. It is not clear whether this influences cognitive predictors of dementia and mortality. OBJECTIVE: In 2 longitudinal population studies, representing 2 cohorts of 70-year-olds examined 30 years apart, we investigated the relation between baseline cognitive function and 5-year occurrence of dementia and mortality. METHODS: Two representative cohorts of 70-year-olds initially free from dementia born in 1901-1902 (cohort 1901-1902: n = 381) and 1930 (cohort 1930: n = 551) from Gothenburg, Sweden, were examined in 1971-1972 and 2000-2001 and after 5 years for the outcome of dementia and death. Recent memory was evaluated during psychiatric examinations, and nonmemory domains using psychometric tests. RESULTS: At age 70, cohort 1930 performed better on psychometric tests, and had fewer recent memory problems compared to cohort 1901-1902. During 5-year follow-up, 5.0% in cohort 1901-1902 and 4.4% in cohort 1930 (p = 0.742) developed dementia, and 15.7% in cohort 1901-1902 and 4.4% in cohort 1930 died (p < 0.001). Recent memory was associated with incident dementia in both cohorts. Low scores in nonmemory tests were associated with incident dementia in cohort 1901-1902, but not in cohort 1930. Recent memory problems and lower scores in nonmemory tests were associated with 5-year mortality in cohort 1901-1902, but not in cohort 1930. CONCLUSIONS: Secular changes in cognitive performance may influence cognitive predictors of dementia and mortality, despite similar incidence of dementia. The findings should be taken cautiously due to differences between cohorts in refusal rates, quality of education, and dementia recognition in medical records.
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| 725. |
- Sailer, Anna, et al.
(författare)
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A genome-wide association study in multiple system atrophy
- 2016
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Ingår i: Neurology. - 0028-3878. ; 87:15, s. 1591-1598
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.
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| 726. |
- Salloway, S, et al.
(författare)
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A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease.
- 2009
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Ingår i: Neurology. - 1526-632X. ; 73:24, s. 2061-70
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD. METHODS: The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline. RESULTS: No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms. CONCLUSIONS: Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status. Classification of evidence: Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.
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| 727. |
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| 728. |
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| 729. |
- Salzer, J., et al.
(författare)
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Rituximab in multiple sclerosis
- 2016
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Ingår i: Neurology. - 0028-3878. ; 87:20, s. 2074-2081
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded. Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective. © 2016 American Academy of Neurology.
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| 730. |
- Sandelius, Åsa P, et al.
(författare)
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Plasma neurofilament light chain concentration in the inherited peripheral neuropathies.
- 2018
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Ingår i: Neurology. - 1526-632X. ; 90:6, s. e518-e524
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Tidskriftsartikel (refereegranskat)abstract
- To perform a cross-sectional study to determine whether plasma neurofilament light chain (NfL) concentration is elevated in patients with Charcot-Marie-Tooth disease (CMT) and if it correlates with disease severity.Blood samples were collected from 75 patients with CMT and 67 age-matched healthy controls over a 1-year period. Disease severity was measured using the Rasch modified CMT Examination and neuropathy scores. Plasma NfL concentration was measured using an in-house-developed Simoa assay.Plasma NfL concentration was significantly higher in patients with CMT (median 26.0 pg/mL) compared to healthy controls (median 14.6 pg/mL,p< 0.0001) and correlated with disease severity as measured using the Rasch modified CMT examination (r= 0.43,p< 0.0001) and neuropathy (r= 0.37,p= 0.044) scores. Concentrations were also significantly higher when subdividing patients by genetic subtype (CMT1A,SPTLC1, andGJB1) or into demyelinating or axonal forms compared to healthy controls.There are currently no validated blood biomarkers for peripheral neuropathy. The significantly raised plasma NfL concentration in patients with CMT and its correlation with disease severity suggest that plasma NfL holds promise as a biomarker of disease activity, not only for inherited neuropathies but for peripheral neuropathy in general.
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