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

Plasma biomarker profiles in autosomal dominant Alzheimer's disease

© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease. Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF. Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF. Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.Peer reviewe

Genes modificadores en enfermedades poliglutamínicas.

Las enfermedades poliglutamínicas constituyen un grupo creciente de enfermedades neurodegenerativas humanas, causadas por la expansión de secuencias repetitivas de CAG que son traducidas para dar lugar a proteínas con dominios poliglutamínicos expandidos. La edad de inicio es un marcador fenotípico para estas enfermedades, y muestra una gran variación en  las familias afectadas. El número de repeticiones de CAG contenido en los genes causales, explica entre el 47 y 80% de la variabilidad observada en la edad de inicio. Para explicar la varianza restante ha sido propuesta la hipótesis de la existencia de genes modificadores. Aquí realizamos una revisión actualizada acerca de esta temática, abordando las estrategias más usadas para su identificación, los principales hallazgos obtenidos y sus implicaciones. La identificación de estos genes contribuye al esclarecimiento de los mecanismo patológicos involucrados en estas enfermedades, y puede conducir a la proposición y diseño de estrategias terapéuticas potenciales

Gen Ataxin-2 en la población cubana:mecanismo mutagénico de la expansión trinucleotídica y metilación epigenética modificadora del fenotipo

Las expansiones de CAG en el gen ATXN2 causan SCA2, y se asocian con Esclerosis Lateral Amiotr&amp;oacute;fica, Par&amp;aacute;lisis Supra nuclear Progresiva y Enfermedad de Parkinson. No se conocen mecanismos moleculares explicativos del origen de estas alteraciones gen&amp;eacute;ticas. El efecto fenot&amp;iacute;pico de esta mutaci&amp;oacute;n es pleiotr&amp;oacute;pico existiendo un conocimiento limitado de los fen&amp;oacute;menos moleculares asociados a esta variabilidad. Se presenta la m&amp;aacute;s amplia caracterizaci&amp;oacute;n de los polimorfismos gen&amp;eacute;ticos asociados con la expansi&amp;oacute;n de CAG de ATXN2, no afectada por SCA2. Se determina la relaci&amp;oacute;n existente entre la frecuencia de alelos largos normales y la de SCA2 (r2=0.841, p&amp;lt;0.000). Los alelos largos mostraron inestabilidad i) som&amp;aacute;tica y ii) intergeneracional (&amp;chi;2=159.80, p&amp;lt;0.0000). Se defini&amp;oacute; el rango premutacional desde expansiones de 25-31CAG. Se identifican factores gen&amp;eacute;ticos que determinan el origen de mutaciones nuevas desde expansiones no patog&amp;eacute;nicas. Se comprob&amp;oacute; que a partir de estas expansiones se originaron expansiones patog&amp;eacute;nicas causales de ELA y SCA2. Se identific&amp;oacute; metilaci&amp;oacute;n la cual modific&amp;oacute; el debut de la SCA2 (&amp;chi;2=11.59, p&amp;lt;0.0007). Se aplica esta informaci&amp;oacute;n al asesoramiento gen&amp;eacute;tico. Se demuestra el origen de las mutaciones y la metilaci&amp;oacute;n de ATXN2, siendo importante para atender y tratar las enfermedades con estas mutaciones en ATXN2

Gen Ataxin-2 en la población cubana:mecanismo mutagénico de la expansión trinucleotídica y metilación epigenética modificadora del fenotipo

Las expansiones de CAG en el gen ATXN2 causan SCA2, y se asocian con Esclerosis Lateral Amiotr&amp;oacute;fica, Par&amp;aacute;lisis Supra nuclear Progresiva y Enfermedad de Parkinson. No se conocen mecanismos moleculares explicativos del origen de estas alteraciones gen&amp;eacute;ticas. El efecto fenot&amp;iacute;pico de esta mutaci&amp;oacute;n es pleiotr&amp;oacute;pico existiendo un conocimiento limitado de los fen&amp;oacute;menos moleculares asociados a esta variabilidad. Se presenta la m&amp;aacute;s amplia caracterizaci&amp;oacute;n de los polimorfismos gen&amp;eacute;ticos asociados con la expansi&amp;oacute;n de CAG de ATXN2, no afectada por SCA2. Se determina la relaci&amp;oacute;n existente entre la frecuencia de alelos largos normales y la de SCA2 (r2=0.841, p&amp;lt;0.000). Los alelos largos mostraron inestabilidad i) som&amp;aacute;tica y ii) intergeneracional (&amp;chi;2=159.80, p&amp;lt;0.0000). Se defini&amp;oacute; el rango premutacional desde expansiones de 25-31CAG. Se identifican factores gen&amp;eacute;ticos que determinan el origen de mutaciones nuevas desde expansiones no patog&amp;eacute;nicas. Se comprob&amp;oacute; que a partir de estas expansiones se originaron expansiones patog&amp;eacute;nicas causales de ELA y SCA2. Se identific&amp;oacute; metilaci&amp;oacute;n la cual modific&amp;oacute; el debut de la SCA2 (&amp;chi;2=11.59, p&amp;lt;0.0007). Se aplica esta informaci&amp;oacute;n al asesoramiento gen&amp;eacute;tico. Se demuestra el origen de las mutaciones y la metilaci&amp;oacute;n de ATXN2, siendo importante para atender y tratar las enfermedades con estas mutaciones en ATXN2

GENES MODIFICADORES EN ENFERMEDADES POLIGLUTAMÍNICAS Modifying genes in poliglutaminic diseases

Las enfermedades poliglutamínicas constituyen un grupo creciente de enfermedades neurodegenerativas humanas, causadas por la expansión de secuencias repetitivas de CAG que son traducidas para dar lugar a proteínas con dominios poliglutamínicos expandidos. La edad de inicio es un marcador fenotípico para estas enfermedades, y muestra una gran variación en las familias afectadas. El número de repeticiones de CAG contenido en los genes causales, explica entre el 47 y 80% de la variabilidad observada en la edad de inicio. Para explicar la varianza restante ha sido propuesta la hipótesis de la existencia de genes modificadores. Aquí realizamos una revisión actualizada acerca de esta temática, abordando las estrategias más usadas para su identificación, los principales hallazgos obtenidos y sus implicaciones. La identificación de estos genes contribuye al esclarecimiento de los mecanismo patológicos involucrados en estas enfermedades, y puede conducir a la proposición y diseño de estrategias terapéuticas potenciales.<br>Poliglutaminic diseases are an increasing group of human neurodegenerative diseases caused by the expansion of repetitive sequences of CAG which give way to expanded poliglutaminic domains proteins. Ages of onset are a phenotypic marker for these diseases and show a great variation in the affected families. The number of CAG content repetitions in the causal genes, explains a 47 to 80 % of the variability of the age of onset. To explain the remaining variability, the hypothesis of modifying genes has been proposed. We have performed an updated revision of the the subject approaching the more utilized techniques to its identification, the principal findings and its implications. The identification of these genes contribute to clarify the involved pathological mechanisms in these diseases and might conduct to the proposition of potential therapeutic strategies

Single-cell multimodal analysis in a case with reduced penetrance of Progranulin-Frontotemporal Dementia

We identified an autosomal dominant progranulin mutation carrier without symptoms of dementia in her lifetime (Reduced Penetrance Mutation Carrier, RedPenMC). This resistance to develop expected pathology presents a unique opportunity to interrogate neurodegenerative mechanisms. We performed multimodal single-nuclei analyses of post-mortem frontal cortex from RedPenMC, including transcriptomics and global levels of chromatin marks. RedPenMC had an increased ratio of GRN-expressing microglia, higher levels of activating histone mark H3k4me3 in microglia and lower levels of the repressive chromatin marks H3k9me1 and H3k9me3 in the frontal cortex than her affected mutation carrier son and evidence of higher protein levels of progranulin in both plasma and brain homogenates. Although the study is limited to one case, the results support that restoring brain progranulin levels may be sufficient to escape neurodegeneration and FTD. In addition to previously identified modifier genes, it is possible that epigenetic marks may contribute to the increased progranulin expression in cases of reduced penetrance. These findings may stimulate similar follow-up studies and new therapeutic approaches