Biomarkers and psychological stress in amyotrophic lateral sclerosis

Författare: Ulf Kläppe; Karolinska Institutet; Karolinska Institutet; []

Nyckelord: ;

Sammanfattning: 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.

  Denna avhandling är EVENTUELLT nedladdningsbar som PDF. Kolla denna länk för att se om den går att ladda ner.