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- Bloniecki Kallio, Victor
(author)
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Using CSF biomarkers to understand mechanisms of behavioral changes and effects of drug treatment in dementia
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Dementia is affecting millions of people around the world, and the global prevalence will continuously rise. Neuropsychiatric symptoms (NPS) in dementia are frequent and constitute a key driving force in the disease burden for both patients, families, caregivers and society. The clinical presentation includes symptoms such as agitation, depression, anxiety, apathy and irritability, which are highly frequent in patients with dementia. NPS have a significant negative impact on a patient’s ability to perform activities of daily living and also contribute largely to the disease-associated health care costs. Current knowledge of the pathophysiological mechanisms causing NPS is lacking, and improved understanding of these processes is of great importance in order to improve treatment of NPS. The main purpose of this thesis was to examine the pathophysiological mechanisms underlying NPS by investigating their associations to cerebrospinal fluid (CSF) biomarkers reflecting core Alzheimer’s dementia (AD) pathology (phosphorylatedtau [P-tau], total-Tau [T-tau], β-amyloid 1-42 [Aβ-1-42]), synaptic degeneration (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal degeneration (neurofilament light protein [NFL]) in patients with dementia. Secondary aims included investigation of how treatment with an acetylcholinesterase inhibitor (AChEI) (Galantamine) or antipsychotic (Risperidone) impacts both the clinical symptoms and CSF biomarker patterns. In the first study, we showed that agitation correlated with increased levels of P-tau and T-tau in CSF, but not with Aβ-1-42. Thus, suggesting an association between agitation and tau-mediated pathology. The second study was an open randomized clinical trial comparing the efficacy of Galantamine and Risperidone for the treatment of agitation in patients with dementia. Both drugs were effective in reducing levels of agitation. However, Risperidone was more efficient at decreasing NPS, although at the cost of lower tolerability and increased rate of adverse events. In the third study, we showed that treatment with Risperidone, but not Galantamine, was associated with a decrease of CSF Aβ-1-42. Indicating a potential association between Risperidone and progression of amyloid pathology. In the fourth study, we investigated the association between NPS and biomarkers for synaptic degeneration (Ng, GAP-43) and axonal degeneration (NFL). Levels of Ng, GAP-43 and NFL did not differ between AD patients with high vs low levels of NPS. We also found associations between CSF markers for synaptic (Ng, GAP-43) and axonal degeneration (NFL) with NPS, especially of the psychotic spectrum, in patients with vascular dementia (VaD). In conclusion, our results implicate tau-mediated pathology and synaptic dysfunction as contributing components to the presence of NPS in AD and VaD. In contrast, no clear evidence supporting the role of amyloid pathology in NPS was observed. Interestingly, treatment with Risperidone affected CSF Aβ-1-42 levels, providing a possible pathway for the previously observed association between use of antipsychotics and accelerated rate of cognitively decline seen in patients with dementia.
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| 2. |
- Bloniecki, Victor, et al.
(author)
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Agitation in dementia : relation to core cerebrospinal fluid biomarker levels
- 2014
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In: Dementia and Geriatric Cognitive Disorders Extra. - : S. Karger. - 1664-5464. ; 4:2, s. 335-43
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Journal article (peer-reviewed)abstract
- BACKGROUND: The objective of this study was to examine the associations of agitation with the cerebrospinal fluid dementia biomarkers total-tau (T-tau), phosphorylated-tau (P-tau) and Aβ1-42.METHODS: One hundred patients (mean age ± SD, 78.6 ± 7.5 years) with dementia and neuropsychiatric symptoms, of whom 67% were female, were included. Agitation was measured using the Cohen-Mansfield Agitation Inventory (CMAI; 46.5 ± 11.8 points).RESULTS: Total CMAI correlated with T-tau [rs (31) = 0.36, p = 0.04] and P-tau [rs (31) = 0.35, p = 0.05] in patients with Alzheimer's disease (AD; n = 33) but not in the total dementia population (n = 95).CONCLUSIONS: Our results suggest that tau-mediated pathology including neurofibrillary tangles and the intensity of the disease process might be associated with agitation in AD.
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| 3. |
- Bloniecki, Victor, et al.
(author)
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Are neuropsychiatric symptoms in dementia linked to CSF biomarkers of synaptic and axonal degeneration?
- 2020
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In: Alzheimer's Research & Therapy. - : BioMed Central. - 1758-9193. ; 12:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: The underlying disease mechanism of neuropsychiatric symptoms (NPS) in dementia remains unclear. Cerebrospinal fluid (CSF) biomarkers for synaptic and axonal degeneration may provide novel neuropathological information for their occurrence. The aim was to investigate the relationship between NPS and CSF biomarkers for synaptic (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal (neurofilament light [NFL]) injury in patients with dementia.METHODS: A total of 151 patients (mean age ± SD, 73.5 ± 11.0, females n = 92 [61%]) were included, of which 64 had Alzheimer's disease (AD) (34 with high NPS, i.e., Neuropsychiatric Inventory (NPI) score > 10 and 30 with low levels of NPS) and 18 were diagnosed with vascular dementia (VaD), 27 with mixed dementia (MIX), 12 with mild cognitive impairment (MCI), and 30 with subjective cognitive impairment (SCI). NPS were primarily assessed using the NPI. CSF samples were analyzed using enzyme-linked immunosorbent assays (ELISAs) for T-tau, P-tau, Aβ1-42, Ng, NFL, and GAP-43.RESULTS: No significant differences were seen in the CSF levels of Ng, GAP-43, and NFL between AD patients with high vs low levels of NPS (but almost significantly decreased for Ng in AD patients < 70 years with high NPS, p = 0.06). No significant associations between NPS and CSF biomarkers were seen in AD patients. In VaD (n = 17), negative correlations were found between GAP-43, Ng, NFL, and NPS.CONCLUSION: Our results could suggest that low levels of Ng may be associated with higher severity of NPS early in the AD continuum (age < 70). Furthermore, our data may indicate a potential relationship between the presence of NPS and synaptic as well as axonal degeneration in the setting of VaD pathology.
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| 4. |
- Bloniecki, Victor, et al.
(author)
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Effects of Risperidone and Galantamine Treatment on Alzheimer's Disease Biomarker Levels in Cerebrospinal Fluid
- 2017
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 57:2, s. 387-393
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Journal article (peer-reviewed)abstract
- BACKGROUND: Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF).OBJECTIVE: This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aβ1-42, and Aβ42/40-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS.METHODS: 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n = 44) or risperidone (n = 39) treatment. CSF samples were collected at baseline and after 12 weeks.RESULTS: Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1 - 42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1-42, Aβ42/40, and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p = 0.03).CONCLUSIONS: Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.
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| 5. |
- Bloniecki, Victor, et al.
(author)
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The Geras Solutions Cognitive Test for Assessing Cognitive Impairment : Normative Data from a Population-Based Cohort
- 2023
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In: The Journal of Prevention of Alzheimer's Disease. - : Springer. - 2274-5807 .- 2426-0266. ; 2:10, s. 207-211
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Journal article (peer-reviewed)abstract
- Background: There is a need for the development of accurate, accessible and efficient screening instruments, focused on early-stage detection of neurocognitive disorders. The Geras Solutions cognitive test (GSCT) has showed potential as a digital screening tool for cognitive impairment but normative data are needed.Objective: The aim of this study was to obtain normative data for the GSCT in cognitively healthy patients, investigate the effects of gender and education on test scores as well as examine test-retest reliability.Methods: The population in this study consisted of 144 cognitively healthy subjects (MMSE>26) all at the age of 70 who were earlier included in the Healthy Aging Initiative Study conducted in Umea, Sweden. All patients conducted the GSCT and a subset of patients (n=32) completed the test twice in order to establish test-retest reliability.Results: The mean GSCT score was 46.0 (+/- 4.5) points. High level of education (>12 years) was associated with a high GSCT score (p = 0.02) while gender was not associated with GSCT outcomes (p = 0.5). GSCT displayed a high correlation between test and retest (r(30) = 0.8, p <0.01).Conclusion: This study provides valuable information regarding normative test-scores on the GSCT for cognitively healthy individuals and indicates education level as the most important predictor of test outcome. Additionally, the GSCT appears to display a good test-retest reliability further strengthening the validity of the test.
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| 6. |
- Freund-Levi, Yvonne, 1956-, et al.
(author)
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Galantamine versus risperidone for agitation in people with dementia : a randomized, twelve-week, single-center study
- 2014
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In: Dementia and Geriatric Cognitive Disorders. - : S. Karger. - 1420-8008 .- 1421-9824. ; 38:3-4, s. 234-244
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Journal article (peer-reviewed)abstract
- AIMS: To examine the effects of galantamine and risperidone on agitation in patients with dementia.METHODS: A total of 100 patients with dementia and neuropsychiatric symptoms (mean age ± SD: 78.6 ± 7.5 years; 67% female) were included in this 12-week, randomized, parallel-group, controlled, single-center trial. The participants received galantamine (n = 50; target dose: 24 mg) or risperidone (n = 50; target dose: 1.5 mg) for 12 weeks.RESULTS: Both galantamine and risperidone treatment resulted in reduced agitation. However, risperidone showed a significant advantage over galantamine both at week 3 (mean difference in total Cohen-Mansfield Agitation Inventory score: 3.7 points; p = 0.03) and at week 12 (4.3 points; p = 0.01).CONCLUSIONS: Agitation improved in both groups, even if the treatment effects were more pronounced in the risperidone group; however, the effects on cognition and other aspects of tolerability were stronger with galantamine.
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