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- Kläppe, Ulf
(författare)
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Biomarkers and psychological stress in amyotrophic lateral sclerosis
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyotrophic lateral sclerosis (ALS) is a complex and progressive neurological disorder that causes a wide range of symptoms, including muscle weakness, mobility impairment, and marked functional decline. Unfortunately, there is currently no known cure for ALS, and median survival time is between two to four years, although this varies considerably between individuals. While no established biomarkers for ALS exist, potential candidates are being explored. Identifying biomarkers could aid in faster and more accurate diagnosis, predicting disease prognosis to prepare and guide patients and their families, and in drug development to recognise when there is indeed an effect. Given the rapid progression of ALS and the lack of effective treatments, it is crucial to prioritize symptom management, including alleviating patients’ psychological stress and improving their quality of life (QoL). Severe depression in ALS patients appears to be rare, and depression and QoL seem stable over time. However, measuring outcomes such as depression and QoL can be challenging, and data on these outcomes are commonly missing in research reports. To what extent and how such missingness is taken care of in the statistical analyses is not consistently, if at all, reported. To our knowledge, no study has yet comprehensively investigated the missingness of these so-called patient reported outcome measures (PROMs) in ALS. As ALS patients’ symptoms progress, their need for care increases. The informal care of ALS patients is often provided by their partners at home, and these caregivers experience a substantial burden, and show signs of elevated levels of depression and anxiety. There is some evidence to suggest that caregivers with high burden and/or high levels of stress have an increased mortality rate, although this had, to our knowledge, not been studied specifically in caregivers of ALS patients prior to our study IV. In study I, we assessed high-sensitivity cardiac Troponin T (hs-cTnT) in plasma, and neurofilament light (NfL) in cerebrospinal fluid (CSF) as diagnostic and prognostic biomarkers of ALS among 150 incident ALS patients, 28 ALS mimics and 108 healthy controls. We also analysed the temporal patterns of these potential biomarkers over time. We found that both hs-cTnT and CSF NfL were elevated in ALS patients compared with controls, and that hs-cTnT concentrations were higher in spinal compared with bulbar onset patients. While hs-cTnT could differentiate ALS patients from mimics, CSF NfL performed better as a diagnostic tool. Combining hs-cTnT and CSF NfL did not improve the diagnostic performance. CSF NfL was also better at predicting functional decline and survival. Longitudinally, hs-cTnT increased, whereas CSF NfL decreased over time since ALS diagnosis. In study II, we evaluated several biomarkers related to neurodegeneration (NfL in serum and CSF, and phosphorylated neurofilament heavy [pNfH] in CSF) and neuroinflammation (chitotriosidase-1 [CHIT1] and monocyte chemoattractant protein 1 [MCP-1] in CSF) as diagnostic and prognostic biomarkers among 192 incident ALS patients, 42 ALS mimics, 114 neurological controls and 117 healthy controls. We also assessed the temporal trends of these biomarkers in ALS patients. We found that neurofilaments (NFs) were better as diagnostic and prognostic biomarkers compared with CHIT1 and MCP-1, and that combining the biomarkers did not improve the diagnostic performance. In the longitudinal analysis, all biomarkers were stable over time. In some analyses, there were clear differences depending on site of onset: 1) biomarkers performed worse in predicting survival among bulbar onset patients than in spinal onset patients, and 2) NFs and CHIT1 increased over time among bulbar onset patients, but remained stable or decreased over time among spinal onset patients. In study III, we investigated factors associated with missing data (i.e. missingness) in the screening for anxiety and depression (using an adapted version of the Hospital Anxiety and Depression Scale [HADS]) at the time after ALS diagnosis. We included all incident patients who were diagnosed with ALS in Stockholm, Sweden, between 2016 and 2022 (n=438). We found that almost 50% of the patients did not fill in HADS shortly after diagnosis. Factors associated with such missingness were higher disease burden, faster disease progression rate, older age and not having a partner. However, during follow-up of the patients, the level of missingness was low, with only 7% of patients missing the repeated measurement. Missingness at follow-up was associated with cognitive impairment. Additionally, we found that high scores on HADS, indicating signs of anxiety and depression, were associated with factors related to missingness, such as higher disease burden and faster progression. We concluded that missing data is a common problem in ALS research utilizing PROMs, and that a detailed characterization of patients not included in research is necessary to better understand missing data and decrease the risk of bias. Finally, in study IV, we performed a nationwide, population-based study investigating the impact of ALS diagnosis on mortality among partners, biological parents, and full siblings of ALS patients, utilizing over 50 years of follow-up. We found an increased mortality in suicide and accidents among partners of ALS patients after ALS diagnosis, likely due to elevated psychological stress. Furthermore, parents and siblings had increased mortality in dementias, indicating the already known shared mechanisms between ALS and dementias. In conclusion, the care of family members of ALS patients probably needs improvement, particularly during the final stages of the disease and after the patient’s death. This may involve interventions that address psychological stress and support for families coping with the loss of a loved one.
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| 2. |
- Kläppe, Ulf, et al.
(författare)
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Mortality among family members of patients with amyotrophic lateral sclerosis : a Swedish register-based study
- 2022
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Informa Healthcare. - 2167-8421 .- 2167-9223. ; 23:3-4, s. 226-235
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To test two hypotheses: (1) partners of ALS patients have higher mortality due to outcomes related to psychological distress, and (2) parents and siblings of ALS patients have higher mortality due to diseases that co-occur with ALS.Methods: We performed a nationwide, register-based cohort study in Sweden. We included ALS-free partners, biological parents and full siblings (N = 11,704) of ALS patients, as well as ALS-free partners, biological parents and full siblings (N = 14,460,150) of ALS-free individuals, and followed them during 1961-2013. Hazard ratios (HRs) and 95% confidence intervals (CIs) of overall and cause-specific mortality were derived from Cox regression.Results: Partners of ALS patients, compared to partners of ALS-free individuals, displayed higher mortality due to external causes (HR 2.14; 95% CI 1.35-3.41), including suicide (HR 2.44; 95% CI 1.09-5.44) and accidents (HR 2.09; 95% CI 1.12-3.90), after diagnosis of the ALS patients. Parents of ALS patients had a slightly higher overall mortality (HR 1.03; 95% CI 1.00-1.07), compared with parents of ALS-free individuals. This was driven by mortality due to dementias and cardiovascular, respiratory, and skin diseases. Parents of ALS patients had, however, lower mortality than parents of ALS-free individuals due to neoplasms. Siblings of ALS patients had higher mortality due to dementias, and digestive and skin diseases.Conclusions: Increased mortality due to suicide and accidents among partners of ALS patients is likely attributable to severe psychological distress following the ALS diagnosis. Increased mortality due to dementias among parents and full siblings of ALS patients suggests shared mechanisms between neurodegenerative diseases.
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| 3. |
- Kläppe, Ulf, et al.
(författare)
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Neurodegenerative biomarkers outperform neuroinflammatory biomarkers in amyotrophic lateral sclerosis.
- 2023
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Ingår i: Amyotrophic lateral sclerosis & frontotemporal degeneration. - 2167-9223. ; 25:1-2, s. 150-61
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Tidskriftsartikel (refereegranskat)abstract
- To describe the diagnostic and prognostic performance, and longitudinal trajectories, of potential biomarkers of neuroaxonal degeneration and neuroinflammation in amyotrophic lateral sclerosis (ALS).This case-control study included 192 incident ALS patients, 42 ALS mimics, 114 neurological controls, and 117 healthy controls from Stockholm, Sweden. Forty-four ALS patients provided repeated measurements. We assessed biomarkers of (1)neuroaxonal degeneration: neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in cerebrospinal fluid (CSF) and NfL in serum, and (2)neuroinflammation: chitotriosidase-1 (CHIT1) and monocyte chemoattractant protein 1 (MCP-1) in CSF. To evaluate diagnostic performance, we calculated the area under the curve (AUC). To estimate prognostic performance, we applied quantile regression and Cox regression. We used linear regression models with robust standard errors to assess temporal changes over time.Neurofilaments performed better at differentiating ALS patients from mimics (AUC: pNfH 0.92, CSF NfL 0.86, serum NfL 0.91) than neuroinflammatory biomarkers (AUC: CHIT1 0.71, MCP-1 0.56). Combining biomarkers did not improve diagnostic performance. Similarly, neurofilaments performed better than neuroinflammatory biomarkers at predicting functional decline and survival. The stratified analysis revealed differences according to the site of onset: in bulbar patients, neurofilaments and CHIT1 performed worse at predicting survival and correlations were lower between biomarkers. Finally, in bulbar patients, neurofilaments and CHIT1 increased longitudinally but were stable in spinal patients.Biomarkers of neuroaxonal degeneration displayed better diagnostic and prognostic value compared with neuroinflammatory biomarkers. However, in contrast to spinal patients, in bulbar patients neurofilaments and CHIT1 performed worse at predicting survival and seemed to increase over time.
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| 4. |
- Månberg, Anna, 1985-, et al.
(författare)
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Altered perivascular fibroblast activity precedes ALS disease onset
- 2021
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Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 27:4, s. 640-646
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Tidskriftsartikel (refereegranskat)abstract
- Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.
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