| 1. |
- Adori, Csaba, et al.
(author)
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Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons
- 2015
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In: Frontiers in Neuroanatomy. - : Frontiers Media SA. - 1662-5129. ; 9
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Journal article (peer-reviewed)abstract
- Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal promoting effects of NPS make the NPS NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 +/- 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kolliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions.
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| 2. |
- Alafuzoff, Irina, et al.
(author)
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Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions : an inter-laboratory study by the BrainNet Europe consortium
- 2015
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In: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 122:7, s. 957-972
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Journal article (peer-reviewed)abstract
- The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.
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| 3. |
- Idland, Ane Victoria, et al.
(author)
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Preclinical amyloid-β and axonal degeneration pathology in delirium
- 2016
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 55:1, s. 371-379
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Journal article (peer-reviewed)abstract
- Background: The clinical relevance of brain β-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues. Objective: To determine whether the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia. Methods: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aβ42, T-tau, and P-tau were analyzed. Results: In patients without dementia, we found lower CSF Aβ42 levels (median, 310ng/L versus 489ng/L, p=0.006), higher T-tau levels (median, 505ng/L versus 351ng/L, p=0.02), but no change in P-tau in patients who developed delirium (n=16) compared to those who remained lucid (n=49). Delirious patients also had lower ratios of Aβ42 to T-tau (p<0.001) and P-tau (p=0.001) relative to those without delirium. CSF Aβ42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (n=54) and without delirium (n=10). Conclusion: The reduction in CSF Aβ42, indicating β-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology.
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| 4. |
- Johansson, Yvonne A., 1956-, et al.
(author)
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Assessment of cognitive function and delirium - Lack of clinical routines
- 2018
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Conference paper (peer-reviewed)abstract
- Introduction: Cognitive impairment and delirium are often unidentified in hospitalized patients. Despite the fact that 40 % of all cases of delirium might be prevented, national guidelines are missing in Sweden. Study aim was to examine the routines about assessing cognitive function and delirium in a university hospital and a county hospital in Sweden.Methods: A web based questionnaire was developed and distributed to 58 managers. The questionnaire addressed routines for identifying cognitive impairment and delirium in clinical practice, for instance which assessment tools, and which terms were used.Results: The response rate was 43 % (25/58) equally distributed for nurses and physicians managers (43 and 44 %). Study findings showed that structured assessment of cognitive function and delirium were missing. Twelve managers (48 %) had established routines for assessment of cognitive function and seven (28 %) for assessment of delirium. It was unclear how the assessments were performed. Most common was free descriptions based on varying questions. Assessment tools and the term delirium were rarely used. Conclusion: Established routines of assessing cognitive function and delirium are missing. Validated rapid clinical assessment tools for cognitive function and delirium are needed as well as consensus to use the term “delirium”.
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| 5. |
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| 6. |
- Leuzy, Antoine, et al.
(author)
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Clinical impact of [18F]flutemetamol PET among memory clinic patients with an unclear diagnosis.
- 2019
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 46:6, s. 1276-1286
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Journal article (peer-reviewed)abstract
- PURPOSE: To investigate the impact of amyloid PET with [18F]flutemetamol on diagnosis and treatment management in a cohort of patients attending a tertiary memory clinic in whom, despite extensive cognitive assessment including neuropsychological testing, structural imaging, CSF biomarker analysis and in some cases [18F]FDG PET, the diagnosis remained unclear.METHODS: The study population consisted of 207 patients with a clinical diagnosis prior to [18F]flutemetamol PET including mild cognitive impairment (MCI; n = 131), Alzheimer's disease (AD; n = 41), non-AD (n = 10), dementia not otherwise specified (dementia NOS; n = 20) and subjective cognitive decline (SCD; n = 5).RESULTS: Amyloid positivity was found in 53% of MCI, 68% of AD, 20% of non-AD, 20% of dementia NOS, and 60% of SCD patients. [18F]Flutemetamol PET led, overall, to a change in diagnosis in 92 of the 207 patients (44%). A high percentage of patients with a change in diagnosis was observed in the MCI group (n = 67, 51%) and in the dementia NOS group (n = 11; 55%), followed by the non-AD and AD (30% and 20%, respectively). A significant increase in cholinesterase inhibitor treatment was observed after [18F]flutemetamol PET (+218%, 34 patients before and 108 patients after).CONCLUSION: The present study lends support to the clinical value of amyloid PET in patients with an uncertain diagnosis in the tertiary memory clinic setting.
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| 7. |
- Ni, Ruiqing, et al.
(author)
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Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer's disease
- 2017
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 13:4, s. 419-430
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Journal article (peer-reviewed)abstract
- Introduction: Amyloid imaging has been integrated into diagnostic criteria for Alzheimer's disease (AD). How amyloid tracers binding differ for different tracer structures and amyloid-beta aggregates in autosomal dominant AD (ADAD) and sporadic AD is unclear. Methods: Binding properties of different amyloid tracers were examined in brain homogenates from six ADAD with APPswe, PS1 M146V, and PS1 E Delta 9 mutations, 13 sporadic AD, and 14 control cases. Results: H-3-PIB, H-3-florbetaben, H-3-AZD2184, and BTA-1 shared a high-and a varying low-affinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The H-3-AZD2184 and H-3-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on H-3-AZD84 binding followed by H-3-florbetaben and minimal on H-3-PIB. Discussion: This study implies amyloid tracers of different structures detect different sites on amyloid-beta fibrils or conformations.
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| 8. |
- Tiiman, Ann, et al.
(author)
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Amyloidogenic Nanoplaques in Blood Serum of Patients with Alzheimer's Disease Revealed by Time-Resolved Thioflavin T Fluorescence Intensity Fluctuation Analysis
- 2019
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In: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 68:2, s. 571-582
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Journal article (peer-reviewed)abstract
- Background: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer's disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies. Objective: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size. Methods: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size. Results: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects. Conclusion: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids.
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