Neurolysosomal pathology in human prosaposin deficiency suggests essential neurotrophic function of prosaposin

A neuropathologic study of three cases of prosaposin (pSap) deficiency (ages at death 27, 89 and 119 days), carried out in the standard autopsy tissues, revealed a neurolysosomal pathology different from that in the non-neuronal cells. Non-neuronal storage is represented by massive lysosomal accumulation of glycosphingolipids (glucosyl-, galactosyl-, lactosyl-, globotriaosylceramides, sulphatide, and ceramide). The lysosomes in the central and peripheral neurons were distended by pleomorphic non-lipid aggregates lacking specific staining and autofluorescence. Lipid storage was borderline in case 1, and at a low level in the other cases. Neurolysosomal storage was associated with massive ubiquitination, which was absent in the non-neuronal cells and which did not display any immunohistochemical aggresomal properties. Confocal microscopy and cross-correlation function analyses revealed a positive correlation between the ubiquitin signal and the late endosomal/lysosomal markers. We suppose that the neuropathology most probably reflects excessive influx of non-lipid material (either in bulk or as individual molecules) into the neurolysosomes. The cortical neurons appeared to be uniquely vulnerable to pSap deficiency. Whereas in case 1 they populated the cortex, in cases 2 and 3 they had been replaced by dense populations of both phagocytic microglia and astrocytes. We suggest that this massive neuronal loss reflects a cortical neuronal survival crisis precipitated by the lack of pSap. The results of our study may extend the knowledge of the neurotrophic function of pSap, which should be considered essential for the survival and maintenance of human cortical neurons

B-positive: a randomized controlled trial of a multicomponent positive psychology intervention for euthymic patients with bipolar disorder - study protocol and intervention development

Abstract Background Bipolar disorder (BD) is characterized by recurrent (hypo)manic and depressive episodes, alternating with euthymic states in which patients are relatively symptom free. Besides clinical recovery, it is important to also strive for improvement of mental well-being and personal recovery. One prominent field focussing on the improvement of well-being is positive psychology. However, studies assessing the effects of positive psychology or personal recovery interventions for people with BD are scarce and have used weak methodological designs. The study described in this protocol article aims to assess the effectiveness of a multicomponent positive psychology intervention (“Living well with bipolar disorder”) adjusted for people with BD in the euthymic phase to improve well-being and personal recovery. Method The study concerns a pragmatic randomized multicenter trial. The principle objective of the study is to assess whether the positive psychology intervention offered to BD patients in remission in addition to usual care (CAU) is more effective than CAU. The study will include 112 participants randomized to either the experimental condition receiving the intervention in addition to CAU or the control condition receiving CAU. The study population are patients with BD I or II in the euthymic phase. The inclusion criteria are 1) diagnosis of BD I or BD II, 2) between the ages of 18–65, 3) four or more supportive sessions in the last year, and 4) only residual depressive or manic symptoms. Patients are excluded if they are in a depressive or manic episode, have current addiction problems or have optimal levels of well-being. Measurements take place at baseline, post-intervention and follow-up 6 and 12 months from baseline. Outcomes of measures include positive well-being, personal recovery, psychopathology, self-compassion, positive relationships, dampening of positive affect and relapse. Discussion The outlined study will be the first RCT examining the effects of a multicomponent positive psychology intervention for patients with bipolar disorder. Several limitations, including generalizability of the results and possible attrition issues, are discussed in advance. Trial registration This study has been registered in the Netherlands Trial Register (NTR6729) on 12 October 2017