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Cattaneo A.,Biological Psychiatry Laboratory | Cattaneo A.,King's College London | Cattane N.,Biological Psychiatry Laboratory | Galluzzi S.,Irccs Centro San Giovanni Of Dio Fatebenefratelli | And 27 more authors.
Neurobiology of Aging | Year: 2017

The pathway leading from amyloid-β deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimer's disease (AD). However, what drives amyloid buildup in sporadic nongenetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (1) GMB taxa with pro- and anti-inflammatory activity; and (2) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa (Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, interleukin [IL]-1β, IL-6, IL-18, IL-8, inflammasome complex (NLRP3), tumor necrosis factor-alpha [TNF-α]; anti-inflammatory cytokines: IL-4, IL-10, IL-13) in cognitively impaired patients with (n = 40, Amy+) and with no brain amyloidosis (n = 33, Amy−) and also in a group of controls (n = 10, no brain amyloidosis and no cognitive impairment). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3, and IL-1β) compared with both controls and with Amy− patients. A reduction of the anti-inflammatory cytokine IL-10 was observed in Amy+ versus Amy−. Amy+ showed lower abundance of E. rectale and higher abundance of Escherichia/Shigella compared with both healthy controls (fold change, FC = −9.6, p < 0.001 and FC = +12.8, p < 0.001, respectively) and to Amy− (FC = −7.7, p < 0.001 and FC = +7.4, p = 0.003). A positive correlation was observed between pro-inflammatory cytokines IL-1β, NLRP3, and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho = 0.60, p < 0.001; rho = 0.57, p < 0.001; and rho = 0.30, p = 0.007, respectively) and a negative correlation with the anti-inflammatory E. rectale (rho = −0.48, p < 0.001; rho = −0.25, p = 0.024; rho = −0.49, p < 0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundance of an anti-inflammatory taxon, E. rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation. © 2016


Halpern J.H.,Laboratory for Integrative Psychiatry | Sherwood A.R.,McLean Hospital | Sherwood A.R.,Harvard University | Sherwood A.R.,University of New Mexico | And 4 more authors.
Addiction | Year: 2011

Aims In field studies assessing cognitive function in illicit ecstasy users, there are several frequent confounding factors that might plausibly bias the findings toward an overestimate of ecstasy-induced neurocognitive toxicity. We designed an investigation seeking to minimize these possible sources of bias. Design We compared illicit ecstasy users and non-users while (1) excluding individuals with significant life-time exposure to other illicit drugs or alcohol; (2) requiring that all participants be members of the 'rave' subculture; and (3) testing all participants with breath, urine and hair samples at the time of evaluation to exclude possible surreptitious substance use. We compared groups with adjustment for age, gender, race/ethnicity, family-of-origin variables and childhood history of conduct disorder and attention deficit hyperactivity disorder. We provide significance levels without correction for multiple comparisons. Setting Field study. Participants Fifty-two illicit ecstasy users and 59 non-users, aged 18-45 years. Measurements Battery of 15 neuropsychological tests tapping a range of cognitive functions. Findings We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic self-regulation, possibly reflecting increased impulsivity. However, this finding might have reflected a pre-morbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug. Conclusions In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings-including our own-and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.


PubMed | University of Zürich, Biological Psychiatry Laboratory, University of Milan, ETH Zurich and King's College London
Type: | Journal: Cerebral cortex (New York, N.Y. : 1991) | Year: 2016

Prenatal exposure to maternal infection increases the risk of neurodevelopmental disorders, including schizophrenia and autism. The molecular processes underlying this pathological association, however, are only partially understood. Here, we combined unbiased genome-wide transcriptional profiling with follow-up epigenetic analyses and structural magnetic resonance imaging to explore convergent molecular and neuromorphological alterations in corticostriatal areas of adult offspring exposed to prenatal immune activation. Genome-wide transcriptional profiling revealed that prenatal immune activation caused a differential expression of 116 and 251 genes in the medial prefrontal cortex and nucleus accumbens, respectively. A large part of genes that were commonly affected in both brain areas were related to myelin functionality and stability. Subsequent epigenetic analyses indicated that altered DNA methylation of promoter regions might contribute to the differential expression of myelin-related genes. Quantitative relaxometry comparing T


PubMed | Ecole Polytechnique Federale de Lausanne, Neurology Unit, European Foundation Biomedical Research FERB, Biological Psychiatry Laboratory and 11 more.
Type: | Journal: Neurobiology of aging | Year: 2016

The pathway leading from amyloid- deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimers disease (AD). However, what drives amyloid buildup in sporadic nongenetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (1) GMB taxa with pro- and anti-inflammatory activity; and (2) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa (Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, interleukin [IL]-1, IL-6, IL-18, IL-8, inflammasome complex (NLRP3), tumor necrosis factor-alpha [TNF-]; anti-inflammatory cytokines: IL-4, IL-10, IL-13) in cognitively impaired patients with (n= 40, Amy+) and with no brain amyloidosis (n= 33, Amy-) and also in a group of controls (n= 10, no brain amyloidosis and no cognitive impairment). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3, and IL-1) compared with both controls and with Amy- patients. A reduction of the anti-inflammatory cytokine IL-10 was observed in Amy+ versus Amy-. Amy+ showed lower abundance of E.rectale and higher abundance of Escherichia/Shigella compared with both healthy controls (fold change, FC=-9.6, p < 0.001 and FC=+12.8, p < 0.001, respectively) and to Amy- (FC=-7.7, p < 0.001 and FC=+7.4, p= 0.003). A positive correlation was observed between pro-inflammatory cytokines IL-1, NLRP3, and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho= 0.60, p < 0.001; rho= 0.57, p < 0.001; and rho= 0.30, p= 0.007, respectively) and a negative correlation with the anti-inflammatory E.rectale (rho=-0.48, p < 0.001; rho=-0.25, p= 0.024; rho=-0.49, p < 0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundance of an anti-inflammatory taxon, E.rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation.


Eitan R.,Biological Psychiatry Laboratory | Landshut G.,Biological Psychiatry Laboratory | Lifschytz T.,Biological Psychiatry Laboratory | Einstein O.,Hebrew University of Jerusalem | And 2 more authors.
International Journal of Neuropsychopharmacology | Year: 2010

The thyroid hormone triiodothyronine (T3) may accelerate and augment the action of antidepressants. Antidepressants up-regulate neurogenesis in adult rodent hippocampus. We studied the effect of T3 and T3+fluoxetine in enhancement of hippocampal neurogenesis beyond that induced by fluoxetine alone and the correlation with antidepressant behaviour in the novelty suppressed feeding test (NSFT). Rats were administered fluoxetine (5 mg/kg.d), T3 (50 g/kg.d), fluoxetine (5 mg/kg.d)+T3 (50 g/kg.d) or saline, for 21 d. Neurogenesis was studied by doublecortin (DCX) immunohistochemistry in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). In the NSFT, latency to feeding in animals deprived of food was measured. Fluoxetine and fluoxetine+T3 increased the number of doublecortin-positive (DCX+) cells in the SGZ compared to saline (p=0.00005, p=0.008, respectively). There was a trend towards an increased number of DCX+ cells by T3 compared to saline (p=0.06). Combined treatment with fluoxetine+T3 further increased the number of DCX+ cells compared to T3 or fluoxetine alone (p=0.001, p=0.014, respectively). There was no effect of any of the treatments on number of DCX+ cells in the SVZ. In the NSFT, all treatments (T3, fluoxetine+T3 and fluoxetine) reduced latency to feeding compared to saline (p=0.0004, p=0.00001, p=0.00009, respectively). Fluoxetine+T3 further reduced latency to feeding compared to T3 alone (p=0.05). The results suggest that enhancement of antidepressant action by T3 may be related to its effect of increasing hippocampal neurogenesis and that the antidepressant effect of these treatments is specific to the hippocampus and does not represent a general effect on cell proliferation. © 2010 CINP.

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