Author Correction:Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates (Scientific Reports DOI: 10.1038/s41598-017-01678-4)

2 p.- Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-01678-4, published online 10 May 2017Peer reviewe

La dépression du sujet de plus de cinquante ans est-elle une maladie neurodégénérative ? (résultats préliminaires d'un suivi de cohorte)

La dépression survenant après l'age de 50 ans, pose des problèmes diagnostiques et physiopathologiques. Parallèlement, la démence frontotemporale se manifeste fréquemment par une symptomatologie psychiatrique, dont la dépression. De nombreuses similitudes semblent exister entre ces deux pathologies. L'objectif principal de cette étude était d'utiliser une approche évaluative similaire afin de comparer le profil neurologique, neuropsychiatrique et psychiatrique de patients présentant une dépression débutant après 50 ans et de patients présentant une démence frontotemporale, pour tenter de déterminer s'il s'agit ou non de la même affection. Quinze patients ont été inclus dans létude (8 patients DFT et 7 patients dépressifs). Seule la présence d'une symptomatologie dépressive significative différencie les deux groupes de patients. Des altérations frontales spécifiques existent dans les deux groupes, selon des modalités très proches. Sous réserve de l'étude d'un plus large échantillon de patients et du suivi évolutif à plus long terme de la cohorte ainsi formée, il semblerait que certaines dépressions survenant après l'âge de 50 ans soient d'authentiques maladies neurodégénératives, variantes symptomatologiques de DFT.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Corrélation entre profils cognitifs dans la sclérose en plaques et biomarqueurs du LCS (b amyloïde, tau totale et phospho tau)

La Sclérose En Plaques (SEP) est une maladie inflammatoire et dégénérative du système nerveux central. Les troubles cognitifs sont fréquents dans la SEP, et de type sous corticaux. Cependant, des troubles cognitifs d allure corticale, avec des troubles de la mémoire épisodique de type hippocampique ont été décrits. Dans les maladies neurodégénératives et notamment dans la maladie d'Alzheimer (MA), trois biomarqueurs du liquide cérébrospinal (LCS) sont dosés à visée diagnostic: le peptide b amyloïde, les protéines tau totale et phospho tau. Nous avons dosé ces biomarqueurs chez des patients SEP présentant des troubles cognitifs d'allure corticale, chez des patients SEP présentant des troubles cognitifs de type sous cortical et chez de patients présentant un premier évènement démyélinisant. L'objectif de l'étude était de mettre en évidence un pattern de biomarqueur spécifique à un profil cognitif, ce que nous n avons pas montré. Néanmoins, les valeurs de tau totale sont comparables aux données de la littérature, qui pour la plupart montraient une augmentation de ce biomarqueur chez les patients SEP comparativement aux témoins. Il existe une corrélation entre les valeurs de tau totale et de phospho tau, en faveur d'une participation spécifique de tau dans le processus neurodégénératif de la SEP. Le peptide b amyloïde est quant à lui retrouvé dans les limites basses des valeurs normatives. Concernant le profil cognitif des patients, notre étude a permis de confirmer l'existence chez certains patients SEP d'une atteinte cognitive d'allure corticale.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

[In Press] The discounted future : relationship between temporal discounting and future thinking in Alzheimer's disease

Temporal discounting refers to the tendency to prefer smaller sooner rewards over larger later rewards. Prior research has reported temporal discounting in Alzheimer’s disease (AD). We thus investigated, in this study, the relationship between temporal discounting and future thinking in AD. The study included 40 patients with AD and 42 control participants. We invited participants, on a temporal discounting task, to choose between an immediate but smaller or a delayed but larger amount of money (e.g. “would you prefer 10 dollars today or 50 dollars after one month?”). We also invited the participants to imagine events that may happen in the future, a task known as future thinking. Analysis demonstrated a bias toward immediate rewards (i.e. temporal discounting) as well as difficulties to imagine specific future events in patients with AD. Critically, temporal discounting and future thinking in AD were significantly correlated. Generally speaking, a lack of thinking about the future may lead to impulsive behavior. More specifically, decline in future thinking in AD may limit the ability of patients to project themselves in time to consider outcomes of their decisions, resulting in a tendency to devaluate future rewards in favor of more imminent ones (i.e. temporal discounting)

Different Trajectories of Apathy and Depression Among Subjective Cognitive Impairment Individuals with or without Conversion to Dementia: Results from the Memento Cohort in France

International audienceBackground: Apathy and depression are two early behavioral symptoms in Alzheimer’s disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology. Objective: The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion. Methods: Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort. Results: Among individuals with SCD (n = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time. Conclusion: Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely—compared to depression—to be associated with conversion to dementia

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

International audienceBackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012–2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers—total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42—in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants

Previously unreported French families with AD-EOAD and sporadic cases carrying a <i>PSEN1</i> mutation.

<p>Novel mutations appear in bold.</p

Previously unreported French families with AD-EOAD carrying an <i>APP</i> mutation.

<p>Previously unreported French families with AD-EOAD carrying an <i>APP</i> mutation.</p

CSF biomarkers levels in mutation carriers (pg/mL).

<p>CSF biomarkers levels in mutation carriers (pg/mL).</p

Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression

International audienceGRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases. We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography. Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers. This study evidences an age-dependent increase of β-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases