| 1. |
- van Rheenen, Wouter, et al.
(författare)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 2. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 3. |
- Carroll, Antonia S., et al.
(författare)
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Serum neurofilament light chain in hereditary transthyretin amyloidosis: validation in real-life practice
- 2024
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Ingår i: AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS. - 1350-6129 .- 1744-2818.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neurofilament light chain (NfL) has emerged as a sensitive biomarker in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN). We hypothesise that NfL can identify conversion of gene carriers to symptomatic disease, and guide treatment approaches. Methods: Serum NfL concentration was measured longitudinally (2015-2022) in 59 presymptomatic and symptomatic ATTR variant carriers. Correlations between NfL and demographics, biochemistry and staging scores were performed as well as longitudinal changes pre- and post-treatment, and in asymptomatic and symptomatic cohorts. Receiver-operating analyses were performed to determine cut-off values. Results: NfL levels correlated with examination scores (CMTNS, NIS and MRC; all p < .01) and increased with disease severity (PND and FAP; all p < .05). NfL was higher in symptomatic and sensorimotor converters, than asymptomatic or sensory converters irrespective of time (all p < .001). Symptomatic or sensorimotor converters were discriminated from asymptomatic patients by NfL concentrations >64.5 pg/ml (sensitivity= 91.9%, specificity = 88.5%), whereas asymptomatic patients could only be discriminated from sensory or sensorimotor converters or symptomatic individuals by a NfL concentration >88.9 pg/ml (sensitivity = 62.9%, specificity = 96.2%) However, an NfL increment of 17% over 6 months could discriminate asymptomatic from sensory or sensorimotor converters (sensitivity = 88.9%, specificity = 80.0%). NfL reduced with treatment by 36%/year and correlated with TTR suppression (r = 0.64, p = .008). Conclusions: This data validates the use of serum NfL to identify conversion to symptomatic disease in ATTRv-PN. NfL levels can guide assessment of disease progression and response to therapies.
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| 4. |
- Gabery, Sanaz, et al.
(författare)
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Loss of the metabolism and sleep regulating neuronal populations expressing orexin and oxytocin in the hypothalamus in amyotrophic lateral sclerosis
- 2021
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 47:7, s. 979-989
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease. Methods: The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression. Results: Tar DNA-binding protein 43 (TDP-43) inclusions were present in the hypothalamus of all patients with amyotrophic lateral sclerosis. When compared to controls, there was atrophy of the hypothalamus (average 21% atrophy, p = 0.004), PVN (average 30% atrophy p = 0.014) and a loss of paraventricular oxytocin-producing neurons (average 49% loss p = 0.02) and lateral hypothalamic orexin-producing neurons (average 37% loss, significance p = 0.02). Factor analysis identified strong relationships between abnormal eating behaviour, hypothalamic atrophy and loss of orexin-producing neurons. With increasing disease progression, abnormal sleep behaviour and cognition associated with atrophy of the fornix. Conclusions: Substantial loss of hypothalamic oxytocin-producing neurons occurs in ALS, with regional atrophy and the loss of orexin neurons relating to abnormal eating behaviour in ALS. Oxytocin- and orexin neurons display TDP43 inclusions. Our study points to significant pathology in the hypothalamus that may play a key role in metabolic and pathogenic changes in ALS.
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| 5. |
- Lin, Cindy Shin-Yi, et al.
(författare)
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Axonal changes in spinal cord injured patients distal to the site of injury.
- 2007
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 130:Pt 4, s. 985-94
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Tidskriftsartikel (refereegranskat)abstract
- It is generally assumed that the peripheral nervous system remains intact following a spinal injury. Accordingly, the electrical thresholds of motor axons in a peripheral nerve below the lesion should be similar to those in intact subjects. Yet in attempts to enter the common peroneal nerve with microelectrodes in 24 quadriplegic or paraplegic individuals it was often found that electrical stimulation over or within the nerve failed to elicit contractions in the pre-tibial flexors. To investigate whether consistent changes in axonal physiology occurred distal to the site of injury in patients with spinal cord injury (SCI), motor nerve excitability was formally tested in 15 of these patients. Threshold tracking techniques were used to measure axonal excitability parameters (stimulus-response curves, strength-duration properties, threshold electrotonus, a current-threshold relationship and the recovery cycle) of motor axons in the median and common peroneal nerves. In these patients motor axons were uniformly of high threshold and consequently, stimulus-response curves were shifted to the right. In some SCI patients, axons were completely inexcitable. Amplitudes of compound motor action potentials were reduced, consistent with axonal loss and strength-duration time constant was significantly reduced in SCI patients (SCI 0.13 +/- 0.02 ms, controls 0.43 +/- 0.02 ms, mean +/- SE, P < 0.0001). Excitability changes were more prominent the more clinically severe the injury, with progressive deterioration over time since the original injury. While compression and traction sustained during the original injury or subsequent hospital rehabilitation may contribute in part to some of these changes, it is difficult to attribute these findings solely to such processes. Changes in axonal structure and ion channel function, but perhaps more critically decentralization and consequent inactivity, are likely to underlie the complex changes observed in axonal excitability in SCI patients.
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| 6. |
- Salmon, Kristiana, et al.
(författare)
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The importance of offering early genetic testing in everyone with amyotrophic lateral sclerosis
- 2022
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 145:4, s. 1207-1210
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Tidskriftsartikel (refereegranskat)abstract
- Several genetically-targeted therapies are being developed for ALS. Research is increasingly supportive of a greater incidence of clinically actionable variants in sporadic ALS than previously reported. Salmon et al. outline the need to improve access, and offer genetic testing to all people diagnosed with ALS.
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