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To investigate feasibility and target engagement of high‐dose, add‐on pramipexole treatment in anhedonic depression. In this open‐label pilot study, we included 12 patients with unipolar or bipolar, moderate‐to‐severe depression and with significant anhedonia symptoms. All patients were on a stable dose of one or a combination of antidepressants and/or mood stabilizers and received 10 weeks of adjunctive pramipexole titrated to a maximum dose of 4.5 mg salt/day. All patients were rated with the Dimensional Anhedonia Rating Scale (DARS), the Montgomery Åsberg Depression Rating (MADRS) and the Snaith Hamilton Pleasure Scale (SHAPS). Serum high‐sensitivity C‐reactive protein (hs‐CRP) was analyzed pre‐ and post‐treatment. Eight patients underwent fMRI pre‐ and post‐treatment and a simplified version of the monetary incentive delay task was used to investigate the effect of treatment on striatal activity during reward anticipation. DARS, MADRS and SHAPS scores all improved significantly over 10 weeks of pramipexole treatment (p<0.01). Mean levels of hs‐CRP decreased significantly over the course of treatment from mean 3.8 mg/L at baseline to 2.6 mg/L at endpoint (p<0.01). There were significant treatment‐associated increases in reward related activity in several brain areas including the right lateral putamen, anterior left caudate, left posterior putamen, right dorsal caudate, left anterior putamen, and the right nucleus accumbens. This is the first study to suggest efficacy and target engagement of pramipexole in anhedonic depression. Larger randomized controlled trials are needed to confirm or refute these preliminary findings. In this open‐label pilot study, high dose, add‐on pramipexole was a feasible and well‐tolerated treatment for anhedonic depressionSerum high sensitivity C‐reactive protein decreased over the treatment courseAdd‐on pramipexole was associated with increased activity in the ventral striatum In this open‐label pilot study, high dose, add‐on pramipexole was a feasible and well‐tolerated treatment for anhedonic depression Serum high sensitivity C‐reactive protein decreased over the treatment course Add‐on pramipexole was associated with increased activity in the ventral striatum

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC?=?0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined.

DNA methylation patterns change with age and can be used to derive an estimate of “epigenetic age,” an indicator of biological age. Several studies have shown associations of posttraumatic stress disorder (PTSD) with worse somatic health and early mortality, raising the possibility of accelerated biological aging. This study examined associations between estimated epigenetic age and various variables in 160 male combat-exposed war veterans with (n= 79) and without PTSD (n= 81). DNA methylation was assessed in leukocyte genomic DNA using the Illumina 450K DNA methylation arrays. Epigenetic age was estimated using Horvath’s epigenetic clock algorithm and Δage (epigenetic age-chronological age) was calculated. In veterans with PTSD (Δage = 3.2), Δage was on average lower compared to those without PTSD (Δage = 5.0; p= 0.02; Cohen’s d = 0.42). This between-group difference was not explained by race/ethnicity, lifestyle factors or childhood trauma. Antidepressant use, however, explained part of the association. In the PTSD positive group, telomerase activity was negatively related to Δage (β = –0.35; p= 0.007). In conclusion, veterans with PTSD had significantly lower epigenetic age profiles than those without PTSD. Further, current antidepressant use and higher telomerase activity were related to relatively less epigenetic aging in veterans with PTSD, speculative of a mechanistic pathway that might attenuate biological aging-related processes in the context of PTSD.

Major depressive disorder (MDD) has been linked to mitochondrial defects, which could manifest in mitochondrial DNA (mtDNA) polymorphisms or mutations. Additionally, copy number of mtDNA (mtDNA-cn) can be quantified in peripheral blood mononuclear cells (PBMC)s, indirectly reflecting cellular energetics, or in the circulating cell-free mtDNA (ccf-mtDNA) levels, which may reflect a fraction of the mitochondrial genome released during cellular stress. Few studies have examined ccf-mtDNA in MDD, and no studies have tested its relationship with intracellular mtDNA-cn or with antidepressant treatment response. Here, mtDNA levels were quantified in parallel from: (i) PBMCs and (ii) cell-free plasma of 50 unmedicated MDD subjects and 55 controls, in parallel with PBMC telomere length (TL) and antioxidant enzyme glutathione peroxidase (GpX) activity. MtDNA measures were repeated in 19 MDD subjects after 8 weeks of open-label SSRI treatment. In analyses adjusted for age, sex, BMI, and smoking, MDD subjects had significantly elevated levels of ccf-mtDNA (F= 20.6, p= 0.00002). PBMC mtDNA-cn did not differ between groups (p> 0.4). In preliminary analyses, we found that changes in ccf-mtDNA with SSRI treatment differed between SSRI responders and non-responders (F= 6.47, p= 0.02), with the non-responders showing an increase in ccf-mtDNA and responders not changing. Baseline ccf-mtDNA was positively correlated with GpX (r= 0.32, p= 0.001), and PBMC mtDNA correlated positively with PBMC TL (r= 0.38, p= 0.0001). These data suggest that plasma ccf-mtDNA and PBMC mtDNA-cn reflect different cellular processes and that the former may be more reflective of certain aspects of MDD pathophysiology and of the response to SSRI antidepressants.

Background:Mitochondrial dysfunction has been implicated in the pathophysiology of Parkinson’s disease (PD)-related pathologies. Objective:To investigate the role of the Translocase of the Outer Mitochondrial Membrane 40 homolog (TOMM40)variants in PD without dementia (PDND), PD with dementia (PDD) and in Dementia with Lewy bodies (DLB). Methods:248 individuals, including 92 PDND, 55 PDD, and 101 DLB, were included. The rs10524523 locus in the TOMM40gene (TOMM40poly-T repeat) is characterized by a variable number of T residues that were classified into three groups based on length; short (S), long (L), and very long (VL). We tested log-additive genetic model of association with dementia and adjusted for age, sex, and APOEɛ4 carrier status. We analyzed cerebrospinal fluid (CSF) levels of Aβ42and Tau, biomarkers related to Alzheimer’s disease (AD). Results:PDD/DBL status and abnormal CSF AD biomarkers (Aβ42and Aβ42/Tau ratio) were both associated with the APOEɛ4 allele (p <  0.014) and the L allele of TOMM40poly-T repeat (p <  0.008). The VL allele was less frequently observed in the PDD/DLB group (p = 0.013). In APOE-ɛ4 adjusted analyses, the relationships between the L and VL alleles and dementia status as well as CSF AD biomarkers were not significant. When adjusting for APOE-ɛ4, however, there were associations between S carrier status and PDD/DLB (p = 0.019) and abnormal CSF levels of Aβ42/Tau ratio (p = 0.037) although these were not significant after adjustment for multiple comparisons. Conclusion:Our results do not support the notion that TOMM40poly-T repeat variants have independent effects on PDD and DLB pathology. This relationship seems to be driven by APOE-ɛ4.

Short leukocyte telomere length (LTL) may be associated with several psychiatric disorders, including major depressive disorder (MDD). Short LTL has previously been associated with poor response to psychiatric medications in bipolar disorder and schizophrenia, but no studies have prospectively assessed the relationship of LTL to selective serotonin reuptake inhibitor (SSRI) response in MDD. We assessed pre-treatment LTL, depression severity [using the Hamilton Depression Rating Scale (HDRS)], and self-reported positive and negative affect in 27 healthy, unmedicated adults with MDD. The subjects then underwent open-label treatment with an SSRI antidepressant for 8 weeks, after which clinical ratings were repeated. The analyses were corrected for age, sex, and body mass index. ‘Non-responders' to treatment (HDRS improvement <50%) had significantly shorter pre-treatment LTL than ‘responders' (p = 0.037). Further, shorter pre-treatment LTL was associated with less improvement in negative affect (p < 0.010) but not with changes in positive affect (p = 0.356). This preliminary study is the first to assess the relationship between LTL and response to SSRIs in MDD and among the first to prospectively assess its relationship to treatment outcome in any psychiatric illness. Our data suggest that short LTL may serve as a vulnerability index of poorer response to SSRI treatment, but this needs examination in larger samples.

To investigate whether certain CSF biomarkers at baseline can predict future progression of motor symptoms and cognitive decline in patients with Parkinson disease (PD).

Background:Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts caused by a combination of both impaired platelet production and increased peripheral platelet destruction. Current first-line ITP treatments include glucocorticoids and intravenous immunoglobulin (IVIG). However, these drugs have variable and transient efficacy, significant toxicities, and relapse is common upon discontinuation. Subsequent treatment options include the thrombopoietin receptor agonists (TPO-RAs). Avatrombopag (AVA) is an orally administered small molecule TPO-RA. It binds to the human TPO receptor (c-Mpl) at a site that is different from the endogenous TPO binding, stimulating signal transduction and mimicking the biological effects of endogenous TPO. In phase 2 and 3 studies in patients with ITP, AVA was administered to 128 patients for a median duration of 7 months (maximum duration >2 years; Birhiray R, et al. EHA 2020). In a phase 3 trial (NCT01438840), the primary efficacy endpoint of cumulative number of weeks with platelet count ≥50×10 9/L during 6 months of treatment in the absence of rescue therapy was statistically significant favoring AVA over placebo. The most common treatment-emergent adverse events (AEs) in these phase 2 and 3 trials were headache, fatigue, and contusion. AVA has no significant hepatotoxicity and is administered with food without restrictions on meal composition. AVA is approved by FDA and EMA for the treatment of primary chronic ITP in adult patients who are refractory to other treatments (e.g. corticosteroids, IVIG). However, there is a need to provide data to treaters and the ITP community on the real-world usage and effectiveness of AVA (including patients previously treated with TPO-RAs). Described here is the rationale and design of the ADOPT study (NCT04943042), evaluating the use and effectiveness of AVA in adult patients with ITP in routine clinical practice in Europe.

McDonald: Grifols: Research Funding; Bayer, Sobi, Novartis, Amgen, argenx: Honoraria. Matzdorff: Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Current holder of individual stocks in a privately-held company. Mellbring: Sobi: Current Employment. Nazir: Sobi: Current Employment. Lindqvist: Sobi: Current Employment. Santagostino: Sobi: Current Employment.

The human appendix is a reservoir for α-synuclein aggregates and its removal may reduce the risk of Parkinson’s disease.