17 research outputs found
Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: a pilot study
Background and Objective: PSEN1-H163Y carriers, at the presymptomatic
stage, have reduced 18FDG-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. Methods: 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 Ab1–42/Ab1–40, using Spearman’s correlation. Altered metabolites were
subjected to Ingenuity Pathway Analysis (IPA). Results: 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 Ab1–42/Ab1–40
(P < 0.05). Interpretation: 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
Genetic and epigenetic studies of amyotrophic lateral sclerosis
The identification of genetic and epigenetic factors that are associated with an increased risk of developing amyotrophic lateral sclerosis (ALS), or that modify the age of onset or rate of progression, requires a multimodal research strategy, facilitated through international collaboration. The discovery of several ALS genes strongly linked to RNA biology, the proteasome pathway, and axonal transport suggest they have an important role in pathogenesis, but the immense complexity of these processes is also apparent. The increasing rate of genetic discoveries brings the hope of designing more targeted and efficacious therapies