| 1. |
- Bergström, Sofia, et al.
(författare)
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Multi-cohort profiling reveals elevated CSF levels of brain-enriched proteins in Alzheimer's disease
- 2021
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:7, s. 1456-1470
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Decreased amyloid beta (A beta) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer's disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages. Methods: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification. Results: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of A beta 42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations. Interpretation: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.
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| 2. |
- Goldberg, Yehuda, et al.
(författare)
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Continuous and interval training attenuate encephalomyelitis by separate immunomodulatory mechanisms.
- 2021
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley-Blackwell. - 2328-9503. ; 8:1, s. 190-200
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies have reported beneficial effects of exercise training on autoimmunity, and specifically on multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, it is unknown whether different training paradigms affect disease course via shared or separate mechanisms.OBJECTIVE: To compare the effects and mechanism of immune modulation of high intensity continuous training (HICT) versus high intensity interval training (HIIT) on systemic autoimmunity in EAE.METHODS: We used the proteolipid protein (PLP)-induced transfer EAE model to examine training effects on the systemic autoimmune response. Healthy mice performed HICT or HIIT by running on a treadmill. Lymph-node (LN)-T cells from PLP-immunized trained- versus sedentary donor mice were transferred to naïve recipients and EAE clinical and pathological severity were assessed. LN cells derived from donor trained and sedentary PLP-immunized mice were analyzed in vitro for T-cell activation and proliferation, immune cell profiling, and cytokine mRNA levels and cytokine secretion measurements.RESULTS: Both HICT and HIIT attenuated the encephalitogenicity of PLP-reactive T cells, as indicated by reduced EAE clinical severity and inflammation and tissue pathology in the central nervous system, following their transfer into recipient mice. HICT caused a marked inhibition of PLP-induced T-cell proliferation without affecting the T-cell profile. In contrast, HIIT did not alter T-cell proliferation, but rather inhibited polarization of T cells into T-helper 1 and T-helper 17 autoreactive populations.INTERPRETATION: HICT and HIIT attenuate systemic autoimmunity and T cell encephalitogenicity by distinct immunomodulatory mechanisms.
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| 3. |
- Hansson, Oskar, et al.
(författare)
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Plasma phosphorylated tau181 and neurodegeneration in Alzheimer’s disease
- 2021
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:1, s. 259-265
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Tidskriftsartikel (refereegranskat)abstract
- We examined if plasma phosphorylated tau is associated with neurodegeneration in Alzheimer’s disease. We investigated 372 cognitively unimpaired participants, 554 mild cognitive impairment patients, and 141 Alzheimer’s disease dementia patients. Tau phosphorylated at threonine 181, regional cortical thickness (using magnetic resonance imaging) and hypometabolism (using fluorodeoxyglucose positron emission tomography) were measured longitudinally. High plasma tau was associated with hypometabolism and cortical atrophy at baseline and over time, and longitudinally increased tau was associated with accelerated atrophy, but these associations were only observed in Aβ-positive participants. Plasma phosphorylated tau may identify and track processes linked to neurodegeneration in Alzheimer’s disease.
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| 4. |
- Hikmat, O., et al.
(författare)
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Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease
- 2021
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:11, s. 2155-2165
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To delineate the full phenotypic spectrum of BCS1L-related disease, provide better understanding of the genotype-phenotype correlations and identify reliable prognostic disease markers. Methods: We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed. Patients were stratified into different groups based on the age of disease onset, whether homozygous or compound heterozygous for the c.232A>G (p.Ser78Gly) variant, and those with other pathogenic BCS1L variants. Results: Thirty-three patients were included. We found that growth failure, lactic acidosis, tubulopathy, hepatopathy and early death were more frequent in those with disease onset within the first month of life. In those with onset after 1 month, neurological features including movement disorders and seizures were more frequent. Novel phenotypes, particularly involving movement disorder, were identified in this group. The presence of the c.232A>G (p.Ser78Gly) variant was associated with significantly worse survival and exclusively found in those with disease onset within the first month of life, whilst other pathogenic BCS1L variants were more frequent in those with later symptom onset. Interpretation: The phenotypic spectrum of BCS1L-related disease comprises a continuum of clinical features rather than a set of separate syndromic clinical identities. Age of onset defines BCS1L-related disease clinically and early presentation is associated with poor prognosis. Genotype correlates with phenotype in the presence of the c.232A>G (p.Ser78Gly) variant.
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| 5. |
- James, Sarah-Naomi, et al.
(författare)
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A population-based study of head injury, cognitive function and pathological markers.
- 2021
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Ingår i: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 8:4, s. 842-856
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Tidskriftsartikel (refereegranskat)abstract
- To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals.Participants (n=502, age=69-71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18 F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer's disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15years prior to the scan (ii) anytime up to age 71.Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15years prior (16%, n=80) performed worse on cognitive tests at age 69-71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p>0.01).Having a LOC HI aged 50's and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).
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| 6. |
- Natarajan, Karthick, et al.
(författare)
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Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: a pilot study.
- 2021
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Ingår i: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 8:3, s. 579-591
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Tidskriftsartikel (refereegranskat)abstract
- PSEN1-H163Y carriers, at the presymptomatic stage, have reduced 18 FDG-PET binding in the cerebrum of the brain (Scholl et al., Neurobiol Aging 32:1388-1399, 2011). This could imply dysfunctional energy metabolism in the brain. In this study, plasma of presymptomatic PSEN1 mutation carriers was analyzed to understand associated metabolic changes.We analyzed plasma from noncarriers (NC, n=8) and presymptomatic PSEN1-H163Y mutation carriers (MC, n=6) via untargeted metabolomics using gas and liquid chromatography coupled with mass spectrometry, which identified 1199 metabolites. All the metabolites were compared between MC and NC using univariate analysis, as well as correlated with the ratio of Aβ1-42/Aβ1-40 , using Spearman's correlation. Altered metabolites were subjected to Ingenuity Pathway Analysis (IPA).Based on principal component analysis the plasma metabolite profiles were divided into dataset A and dataset B. In dataset A, when comparing between presymptomatic MC and NC, the levels of 79 different metabolites were altered. Out of 79, only 14 were annotated metabolites. In dataset B, 37 metabolites were significantly altered between presymptomatic MC and NC and nine metabolites were annotated. In both datasets, annotated metabolites represent amino acids, fatty acyls, bile acids, hexoses, purine nucleosides, carboxylic acids, and glycerophosphatidylcholine species. 1-docosapentaenoyl-GPC was positively correlated, uric acid and glucose were negatively correlated with the ratio of plasma Aβ1-42 /Aβ1-40 (P<0.05).This study finds dysregulated metabolite classes, which are changed before the disease symptom onset. Also, it provides an opportunity to compare with sporadic Alzheimer's Disease. Observed findings in this study need to be validated in a larger and independent Familial Alzheimer's Disease (FAD) cohort.
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