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Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

ABSTRACT: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year. One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis. The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint. Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials. NCT01676077.

SUBMITTER: Moore U

PROVIDER: S-EPMC6369904 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

Moore Ursula U Jacobs Marni M James Meredith K MK Mayhew Anna G AG Fernandez-Torron Roberto R Feng Jia J Cnaan Avital A Eagle Michelle M Bettinson Karen K Rufibach Laura E LE Lofra Robert Muni RM Blamire Andrew M AM Carlier Pierre G PG Mittal Plavi P Lowes Linda Pax LP Alfano Lindsay L Rose Kristy K Duong Tina T Berry Katherine M KM Montiel-Morillo Elena E Pedrosa-Hernández Irene I Holsten Scott S Sanjak Mohammed M Ashida Ai A Sakamoto Chikako C Tateishi Takayuki T Yajima Hiroyuki H Canal Aurélie A Ollivier Gwenn G Decostre Valerie V Mendez Juan Bosco JB Sánchez-Aguilera Praxedes Nieves N Thiele Simone S Siener Catherine C Shierbecker Jeanine J Florence Julaine M JM Vandevelde Bruno B DeWolf Brittney B Hutchence Meghan M Gee Richard R Prügel Juliana J Maron Elke E Hilsden Heather H Lochmüller Hanns H Grieben Ulrike U Spuler Simone S Tesi Rocha Carolina C Day John W JW Jones Kristi J KJ Bharucha-Goebel Diana X DX Salort-Campana Emmanuelle E Harms Matthew M Pestronk Alan A Krause Sabine S Schreiber-Katz Olivia O Walter Maggie C MC Paradas Carmen C Hogrel Jean-Yves JY Stojkovic Tanya T Takeda Shin'ichi S Mori-Yoshimura Madoka M Bravver Elena E Sparks Susan S Díaz-Manera Jordi J Bello Luca L Semplicini Claudio C Pegoraro Elena E Mendell Jerry R JR Bushby Kate K Straub Volker V

Neurology 20190128 5

<h4>Objective</h4>To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.<h4>Methods</h4>One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke sca ...[more]

PMID: 30626655

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Project description:BackgroundA substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range.MethodsWe did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11.2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes-fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)-were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group.FindingsBetween Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1.2%, 95% CI 0.5-1.9, p=0.002) but not thigh level (0.2%, -0.2 to 0.6, p=0.38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2.6%, 1.3-4.0, p=0.002) and thigh level (3.3%, 1.8-4.9, p=0.0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (ρ=-0.64, p=0.002) and the Charcot-Marie-Tooth examination score (ρ=0.63, p=0.003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4.0 ms [SE 0.5], calf 3.5 ms [0.6]; Charcot-Marie-Tooth 1A thigh 1.0 ms [0.3], calf 2.0 ms [0.3]) and MTR reduced compared with controls (inclusion body myositis thigh -1.5 percentage units [pu; 0.2], calf -1.1 pu [0.2]; Charcot-Marie-Tooth 1A thigh -0.3 pu [0.1], calf -0.7 pu [0.1]).InterpretationMRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials.FundingMedical Research Council UK.

Project description:BACKGROUND:The prevalence of diabetes, heart disease, and stroke multimorbidity (co-occurrence of two or three of these conditions) has increased rapidly. Little is known about how the three conditions progress from one to another sequentially through the life course. We aimed to delineate this progression in middle-aged women and to determine the roles of common risk factors in the accumulation of diabetes, heart disease, and stroke multimorbidity. METHODS AND FINDINGS:We used data from 13,714 women aged 45-50 years without a history of any of the three conditions. They were participants in the Australian Longitudinal Study on Women's Health (ALSWH), enrolled in 1996, and surveyed approximately every 3 years to 2016. We characterized the longitudinal progression of the three conditions and multimorbidity. We estimated the accumulation of multimorbidity over 20 years of follow-up and investigated their association with both baseline and time-varying predictors (sociodemographic factors, lifestyle factors, and other chronic conditions). Over 20 years, 2,511 (18.3%) of the women progressed to at least one condition, of whom 1,420 (56.6%) had diabetes, 1,277 (50.9%) had heart disease, and 308 (12.3%) had stroke; 423 (16.8%) had two or three of these conditions. Over a 3-year period, the age-adjusted odds of two or more conditions was approximately twice that of developing one new condition compared to women who did not develop any new conditions. For example, the odds for developing one new condition between Surveys 7 and 8 were 2.29 (95% confidence interval [CI], 1.93-2.72), whereas the odds for developing two or more conditions was 6.51 (95% CI, 3.95-10.75). The onset of stroke was more strongly associated with the progression to the other conditions (i.e., 23.4% [95% CI, 16.3%-32.2%] of women after first onset of stroke progressed to other conditions, whereas the percentages for diabetes and heart disease were 9.9% [95% CI, 7.9%-12.4%] and 11.4% [95% CI, 9.1%-14.4%], respectively). Being separated, divorced, or widowed; being born outside Australia; having difficulty managing on their available income; being overweight or obese; having hypertension; being physically inactive; being a current smoker; and having prior chronic conditions (i.e., mental disorders, asthma, cancer, osteoporosis, and arthritis) were significantly associated with increased odds of accumulation of diabetes, heart disease, and stroke multimorbidity. The main limitations of this study were the use of self-reported data and the low number of events. CONCLUSIONS:Stroke was associated with increased risk of progression to diabetes or heart disease. Social inequality, obesity, hypertension, physical inactivity, smoking, or having other chronic conditions were also significantly associated with increased odds of accumulating multimorbidity. Our findings highlight the importance of awareness of the role of diabetes, heart disease, and stroke multimorbidity among middle-aged women for clinicians and health-promotion agencies.

Project description:ImportanceThe incidence of age-related macular degeneration (AMD) is unknown in Africa.ObjectiveTo estimate the 6-year cumulative incidence and progression of AMD in older adults (≥50 years old) in Nakuru, Kenya.Design, setting, and participantsThis study assessed a population-based cohort with 6-year follow-up of 4414 participants who had a complete assessment. Random cluster sampling with probability proportionate to size procedures was used to select a representative, cross-sectional sample of adults 50 years and older from January 26, 2007, through November 11, 2008. A 6-year follow-up was undertaken from January 7, 2013, through March 12, 2014. On both occasions, a comprehensive ophthalmic examination was performed that included logMAR visual acuity, digital retinal photography, and grading of images at Moorfields Eye Hospital Reading Centre. Data were collected on general health and risk factors.Main outcomes and measuresIncident AMD in participants with no AMD at baseline and progression from early to late AMD.ResultsA total of 1453 of the 2900 individuals (50.1%) at risk for AMD were followed up after 6 years (mean [SD] age, 60.7 [8.2] years; 635 female [49.5%]; 799 Kikuyu [62.3%], 324 Kalenjin [25.3%], and 159 other [12.4%]); 1282 had data on AMD status at follow-up. Of these, 202 developed early AMD, and no participants developed late AMD. The 6-year weighted (for loss to follow-up) cumulative incidence of early AMD was 164.2 per 1000 persons (95% CI, 136.7-195.9 per 1000 persons). Two individuals with baseline early AMD from the 142 at risk had developed late AMD at follow-up, with a 6-year cumulative incidence of progression from early to late AMD of 24.5 per 1000 persons (95% CI, 5.0-111.7 per 1000 persons). Cumulative incidence of AMD increased with age (≥80 years old vs 50-59 years old: 1.8; 95% CI, 0.9-3.5) and was higher in women (female vs male: 1.6; 95% CI, 1.2-2.1) and persons with diabetes (diabetes vs no diabetes: 1.7; 95% CI, 1.0-2.8).Conclusions and relevanceIn Kenya, more than 100 000 estimated new cases of AMD, mainly early AMD, will develop every year in individuals 50 years or older, although a 50% loss to follow-up and wide CIs for progression to late AMD limit definitive conclusions from these findings.

Project description:ObjectiveDental caries is one of the most prevalent chronic non-communicable diseases worldwide. There is a lack of evidence, especially in adult populations, documenting caries disease progression considering lesion severity, activity and tooth surface-level characteristics. The study aimed to investigate the extent to which primary active caries lesions in adults affect caries lesions progression compared with inactive caries lesions over a 2-year follow-up period, considering their severity, surface and tooth type.MethodsA prospective study data set from a cohort of workers in a factory in Belarus were used. Participants aged 18-64 years with 20 or more natural teeth were included in the study. The participants were clinically examined twice within an interval of 2 years and completed a self-reported questionnaire. One calibrated examiner evaluated caries lesions using the International Caries Detection and Assessment System (ICDAS) and the Nyvad system. The primary outcome was caries lesions' progression. The lesion was classified as 'progressed' if it turned to a more advanced severity stage, was restored or missing/extracted due to caries. A multilevel Poisson regression was used to estimate the association between baseline caries lesions' characteristics and caries lesion progression.ResultsOut of 495 participants, 322 people completed clinical examinations at baseline and 2 years later, with an attrition rate of 35%. The prevalence of active DS1-6 and DS5-6 lesions at the baseline was 83.8% and 64.8%, respectively. In 2 years, 24% of active non-cavitated and 31% of active micro-cavitated/shadowed caries lesions progressed, while 15% of inactive caries lesions, non- or micro-cavitated/shadowed, progressed. The adjusted rate ratio (RR) for ICDAS3 + 4 caries lesions progression was 1.41 (CI 95% 1.16, 1.70) than ICDAS1 + 2 lesions. The RR for ICDAS1 + 2, active and ICDAS3 + 4, active lesions was 1.78 (CI 95%, 1.40, 2.27) and 1.97 (CI 95%, 1.53, 2.55), respectively than ICDAS1 + 2, inactive lesions. The RR for caries lesions progression on proximal surfaces and on pits and fissures was 1.57 (CI 95%, 1.30, 1.89) and 1.37 (CI 95%, 1.11, 1.67), respectively than smooth surface lesions.ConclusionIn caries active adults over 2 years, most non- and micro-cavitated/shadowed active and inactive caries lesions did not progress. Among caries lesions that showed progression, more severe lesions were more likely to progress than less severe lesions; active lesions were more likely to progress than inactive lesions. Pit and fissure caries lesions and proximal lesions were more likely to progress than smooth surface lesions.

Dataset Information

Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

Publications

Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

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