Background Alzheimer's Disease (AD) is a complex and multifactorial disease and novel approaches are needed to illuminate the underlying pathology. Metabolites comprise the end-product of genes, transcripts, and protein regulations and might reflect disease pathogenesis. Blood is a common biofluid used in metabolomics; however, since extracellular vesicles (EVs) hold cell-specific biological material and can cross the blood-brain barrier, their utilization as biological material warrants further investigation. We aimed to investigate blood- and EV-derived metabolites to add insigts to the pathological mechanisms of AD. Methods Blood samples were collected from 10 AD and 10 Mild Cognitive Impairment (MCI) patients, and 10 healthy controls. EVs were enriched from plasma using 100,000× g , 1 h, 4 °C with a wash. Metabolites from serum and EVs were measured using liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy. Multivariate and univariate analyses were employed to identify altered metabolites in cognitively impaired individuals. Results While no significant EV-derived metabolites were found differentiating patients from healthy individuals, six serum metabolites were found important; valine ( p = 0.001, fold change, FC = 0.8), histidine ( p = 0.001, FC = 0.9), allopurinol riboside ( p = 0.002, FC = 0.2), inosine ( p = 0.002, FC = 0.3), 4-pyridoxic acid ( p = 0.006, FC = 1.6), and guanosine ( p = 0.004, FC = 0.3). Pathway analysis revealed branched-chain amino acids, purine and histidine metabolisms to be downregulated, and vitamin B6 metabolism upregulated in patients compared to controls. Conclusion Using a combination of LC-MS and NMR methodologies we identified several altered mechanisms possibly related to AD pathology. EVs require additional optimization prior to their possible utilization as a biological material for AD-related metabolomics studies.
Alzheimer’s disease (AD) is the most common form of dementia and without readily available clinical biomarkers. Blood-derived proteins are routinely used for diagnostics; however, comprehensive plasma profiling is challenging due to the dynamic range in protein concentrations. Extracellular vesicles (EVs) can cross the blood–brain barrier and may provide a source for AD biomarkers. We investigated plasma-derived EV proteins for AD biomarkers from 10 AD patients, 10 Mild Cognitive Impairment (MCI) patients, and 9 healthy controls (Con) using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The ultracentrifuged EVs were washed and confirmed according to the MISEV2018 guidelines. Some AD patients presented with highly elevated FXIIIA1 (log2 FC: 4.6, p-value: 0.005) and FXIIIB (log2 FC: 4.9, p-value: 0.018). A panel of proteins was identified discriminating Con from AD (AUC: 0.91, CI: 0.67–1.00) with ORM2 (AUC: 1.00, CI: 1.00–1.00), RBP4 (AUC: 0.99, CI: 0.95–1.00), and HYDIN (AUC: 0.89, CI: 0.72–1.00) were found especially relevant for AD. This indicates that EVs provide an easily accessible matrix for possible AD biomarkers. Some of the MCI patients, with similar protein profiles as the AD group, progressed to AD within a 2-year timespan.
Cholinergic changes play a fundamental role in the natural history of Dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: First, to examine the integrity of cholinergic terminals in newly diagnosed Dementia with Lewy bodies. Second, to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia. Third, to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease. Fourth, to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed Dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male), and 15 Parkinson’s disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent [18F]fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical [18F]fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus, and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. By contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without dementia. Interhemispheric asymmetry of cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function. In conclusion, this study provides robust evidence for severe cholinergic terminal loss in newly diagnosed Dementia with Lewy bodies, which correlates with structural imaging measures of cholinergic basal forebrain degeneration. In patients without dementia, our findings suggest that loss of cholinergic terminal function occurs before neuronal cell degeneration. Moreover, the study supports that degeneration of the cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism, and disease progression patterns.
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