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- Behzadi, Arvin, 1994-
(författare)
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Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to paresis, muscle atrophy, and respiratory failure. ALS can be difficult to diagnose and prognosticate early.Aim: To investigate the diagnostic and prognostic characteristics of biomarkers in cerebrospinal fluid (CSF), plasma, and skeletal muscle tissue in patients with ALS.Paper I: Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were analyzed in CSF using enzyme-linked immunosorbent assay (ELISA), and NFL in plasma was analyzed using single-molecule array (SIMOA). CSF NFL, CSF pNFH, and plasma NFL concentrations can differentiate ALS patients from ALS mimics, and were significantly negatively correlated with the disease duration in ALS patients.Paper II: Myosin heavy chain (MyHC) isoforms in extraocular muscles were investigated using immunofluorescence. Control donors had significantly higher proportion of myofibers containing MyHCIIa and significantly lower proportion of myofibers containing MyHCeom in the global layer compared to spinal-onset ALS and bulbar-onset ALS donors. Disease duration in the spinal-onset ALS donors was significantly correlated with the proportion of myofibers containing MyHCIIa in the global layer and MyHCeom in the orbital layer.Paper III: The study combined the neurofilament concentrations from Paper I, with cytokines previously analyzed in CSF and plasma using SIMOA, to investigate distinct molecular phenotypes in ALS. Patients with bulbar-onset ALS had significantly higher concentrations of CSF tumor necrosis factor α (TNF-α) compared to ALS mimics. TNF-α and NFL were significantly correlated with each other in both CSF and plasma in ALS patients. Combined analysis of NFL and IL-6 in plasma identified molecular prognostic subgroups in ALS patients.Paper IV: Creatine kinase (CK), high-sensitivity cardiac troponin T (hs-cTnT), hs-cTnI, and cystatin C (CysC) were analyzed in plasma in a fully accredited laboratory. CK and hs-cTnT concentrations were significantly elevated in limb-onset ALS compared to controls and bulbar-onset ALS. hs-cTnT concentrations were significantly elevated in truncal-onset ALS compared to controls and bulbar-onset ALS. Multivariable Cox proportional hazards models indicated elevated concentrations of CysC as a significant marker for worse prognosis in ALS.Conclusions: The papers report diagnostic and prognostic characteristics of biomarkers in CSF, plasma, and muscle tissue in ALS patients. The significant findings for biomarkers in plasma could be of value since plasma sampling does not involve a lumbar puncture.
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| 4. |
- Puschmann, Andreas
(författare)
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Heredity in Parkinson's disease. From rare mutations to common genetic risk factors.
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study investigated genetic causes of Parkinson's disease (PD) and parkinsonism in southern Sweden. The extensive Lister Family with parkinsonism caused by duplications and triplications of the gene for alpha-synuclein (SNCA) was studied. Clinical, genetic and genealogical data were compiled and evaluated. Thirty-five family members with parkinsonism were identified. They share a characteristic clinical subtype of parkinsonism with marked dysfunction of the autonomic nervous system, behavioral changes and cognitive decline. The clinical phenotype, heredity and genetic background of 132 probands from Southern Sweden with PD or parkinsonism was examined. The SNCA, LRRK2, EIF4G1, VPS35, PINK1, ATXN2 and ATXN3 genes were analyzed in all probands; the PARKIN, PINK1 and DJ1 genes were tested in a subgroup of 23 patients with young onset or marked heredity. DNA from the brain tissue of 7 patients with parkinsonism was also analyzed. Common genetic risk factors in DNA samples collected within this study were analyzed in collaboration with other research groups. Gene screening identified two rare causative mutations, SNCA A53T and LRRK2 N1437H. An additional patient was compound heterozygous for PARKIN R275W and R275Q mutations. Detailed information on their clinical picture is presented. We present the first neuropathological description of a patient with PD and LRRK2 N1437H mutation, showing pronounced ubiquitin and moderate alpha-synuclein pathology. A heterozygous PINK1 G411S mutation was present in two PD patients but showed no clear co-segregation with the disease in their families. Screening of 1,107 patients and controls as well as meta-analysis of published reports from 7,800 individuals revealed that the PINK1 G411S mutation is a rare risk variant with a relatively large effect size (odds ratios 4.06-8.42). One multicenter study confirmed that common variants in the SNCA and MAPT genes modify PD risk, and was large enough to refute gene-gene interaction between the MAPT and SNCA variants. These results suggest that specific mutations in PD-genes cause characteristic disease subtypes. Despite extensive screening and a high proportion of familial cases, known pathogenic mutations could only explain a small proportion of parkinsonism in this cohort. This may indicate that mutations causing parkinsonism in the Scandinavian population remain to be discovered. Alternatively, familial clustering and sporadic occurrence of PD may be explained by combinations of rare variants with relatively large effect size, such as PINK1 G411S.
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- Wictorin, Klas, et al.
(författare)
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Myoclonus-dystonia (DYT11, DYT-SGCE) - a channelopathy?
- 2020
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Ingår i: Neurologia i neurochirurgia polska. - 0028-3843. ; 54:1, s. 3-5
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Kaczyńska et al. reported a family with myoclonus-dystonia (M-D) caused by a truncating SGCE mutation, in which two members had epilepsy. Further, patients had mild psychiatric and developmental deficits. CLINICAL REFLECTIONS: Characteristic motor features of M-D include myoclonus, dystonia and tremor. A wide range of additional disease manifestations are known. A few patients with M-D have seizures. CLINICAL IMPLICATIONS: Altered neuronal excitability has been found in the pathogenesis of M-D. This may explain the partial effectiveness of antiepileptics and a lower seizure threshold, and could encourage trials of other membrane stabilisers. Careful clinical observations of seemingly well-known diseases remain important.
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