Relative Meaningfulness and Impacts of Symptoms in People with Early-Stage Parkinson's Disease.

BACKGROUND: Patient perspectives on meaningful symptoms and impacts in early Parkinson's disease (PD) are lacking and are urgently needed to clarify priority areas for monitoring, management, and new therapies. OBJECTIVE: To examine experiences of people with early-stage PD, systematically describe meaningful symptoms and impacts, and determine which are most bothersome or important. METHODS: Forty adults with early PD who participated in a study evaluating smartwatch and smartphone digital measures (WATCH-PD study) completed online interviews with symptom mapping to hierarchically delineate symptoms and impacts of disease from "Most bothersome" to "Not present," and to identify which of these were viewed as most important and why. Individual symptom maps were coded for types, frequencies, and bothersomeness of symptoms and their impacts, with thematic analysis of narratives to explore perceptions. RESULTS: The three most bothersome and important symptoms were tremor, fine motor difficulties, and slow movements. Symptoms had the greatest impact on sleep, job functioning, exercise, communication, relationships, and self-concept- commonly expressed as a sense of being limited by PD. Thematically, most bothersome symptoms were those that were personally limiting with broadest negative impact on well-being and activities. However, symptoms could be important to patients even when not present or limiting (e.g., speech, cognition). CONCLUSION: Meaningful symptoms of early PD can include symptoms that are present or anticipated future symptoms that are important to the individual. Systematic assessment of meaningful symptoms should aim to assess the extent to which symptoms are personally important, present, bothersome, and limiting.

Mapping Relevance of Digital Measures to Meaningful Symptoms and Impacts in Early Parkinson's Disease.

BACKGROUND: Adoption of new digital measures for clinical trials and practice has been hindered by lack of actionable qualitative data demonstrating relevance of these metrics to people with Parkinson's disease. OBJECTIVE: This study evaluated of relevance of WATCH-PD digital measures to monitoring meaningful symptoms and impacts of early Parkinson's disease from the patient perspective. METHODS: Participants with early Parkinson's disease (N = 40) completed surveys and 1:1 online-interviews. Interviews combined: 1) symptom mapping to delineate meaningful symptoms/impacts of disease, 2) cognitive interviewing to assess content validity of digital measures, and 3) mapping of digital measures back to personal symptoms to assess relevance from the patient perspective. Content analysis and descriptive techniques were used to analyze data. RESULTS: Participants perceived mapping as deeply engaging, with 39/40 reporting improved ability to communicate important symptoms and relevance of measures. Most measures (9/10) were rated relevant by both cognitive interviewing (70-92.5%) and mapping (80-100%). Two measures related to actively bothersome symptoms for more than 80% of participants (Tremor, Shape rotation). Tasks were generally deemed relevant if they met three participant context criteria: 1) understanding what the task measured, 2) believing it targeted an important symptom of PD (past, present, or future), and 3) believing the task was a good test of that important symptom. Participants did not require that a task relate to active symptoms or "real" life to be relevant. CONCLUSION: Digital measures of tremor and hand dexterity were rated most relevant in early PD. Use of mapping enabled precise quantification of qualitative data for more rigorous evaluation of new measures.

High risk of developing dementia in Parkinson's disease: a Swedish registry-based study.

Dementia have substantial negative impact on the affected individual, their care partners and society. Persons living with Parkinson's disease (PwP) are also to a large extent living with dementia. The aim of this study is to estimate time to dementia in PD using data from a large quality register with access to baseline clinical and patient reported data merged with Swedish national health registries. Persons with Parkinson's disease in the Swedish Neuro Registries/Parkinson's Disease Swedish PD Registry (PARKreg) in Sweden were included and linked to national health registries and matched by sex and age to controls without PD. Time to dementia was analysed with Cox regression models assuming proportional hazards, with time since diagnosis as the underlying time variable. In this large prospective cohort study, PwP had approximately four times higher risk of developing dementia as compared to age and sex-matched controls, a finding which remained after adjusting for potential confounders. The present results underline the high risk of dementia in PD and further emphasize the importance of developing symptomatic and ultimately disease modifying strategies to counteract this part of the non-motor symptomatology in PD.

Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania.

BACKGROUND: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). AIMS: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). METHODS: ST studies were three-week randomized, double-blind, flexible dose (2-4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2-4 mg/day) study for patients completing the ST studies. RESULTS: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (-1.74, 2.03), p = 0.8797; study 081: -1.62 (-3.56, 0.32), p = 0.1011. OL study patients (n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). CONCLUSIONS: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

New Drug and Biologics Approvals in 2019: A Systematic Analysis of Patient Experience Data in FDA Drug Approval Packages and Product Labels.

BACKGROUND: The FDA Patient-Focused Drug Development Initiative was launched to ensure the incorporation of the patient voice into drug development and evaluation. Since 2017, the FDA must publish a statement outlining patient experience data (PED) considered in the approval of new drugs. This study investigated the presence and role of PED in drug approval and translation into product label claims. METHODS: PED reported in approval packages of the 48 drugs approved by FDA's Center for Drug Evaluation and Research in 2019 was identified and categorized. PED in the form of clinical outcome assessments (COAs) was characterized by endpoint positioning and outcome. The product labels were analyzed for PED-related claims. RESULTS: PED was reported as relevant for 39 of 48 (81.3%) drugs approved in 2019. COAs were the predominant PED type; other PED was identified for only 9 (18.8%) drugs, and none included qualitative or patient preference studies. COAs were the only type of PED for which associated claims were identified in the product labels. 27 out of 48 (56.3%) labels contained one or more efficacy claims based on COAs; of these, patient-reported outcomes were the most prevalent with claims identified in 19 labels (39.6%). CONCLUSION: There are ample opportunities for incorporating PED beyond COAs to inform drug development and facilitate availability of medicines tailored to patient needs. A higher level of transparency on the role of PED in regulatory decision-making and a clear path to PED-based label claims could incentivize sponsors and enable patient empowerment in treatment decisions.

Environmental enrichment, exercise and corticosterone affect endothelial cell proliferation in adult rat hippocampus and prefrontal cortex.

Stress and environmental enrichment have opposing effects on cerebral cellular plasticity. Stress-induced disturbances in neuronal and glial plasticity have been implicated in the pathophysiology of affective disorders. Patients with depression often show volume reductions in specific brain regions. The mechanisms behind these changes are not well understood, but animal studies have indicated that increased levels of glucocorticoids and stress have negative impact on the neuronal and glial cell populations. On the contrary, enriched environment and physical activity have positive effects. In this study we have examined the effect of corticosterone (CORT), environmental enrichment (EE) and running on angiogenesis in hippocampus and prefrontal cortex (PFC). We demonstrate a dramatic inhibition in endothelial cell proliferation in these brain regions in CORT-treated rats. Environmental enrichment had the opposite effect and stimulated endothelial cell proliferation both in the hippocampus and in the PFC. Running had a stimulatory effect in hippocampus, but not in the PFC. We suggest that the angiostatic effect of CORT demonstrated in this study might be paralleled in human subjects exposed to high levels of stress hormones for prolonged periods of time. Raised cortisol levels in depressed or old patients could, by reducing endothelial cell formation/turnover, lead to rarefaction and aging of the vascular bed, and as a result, neuronal function could be impaired. It is tempting to speculate that a physically and intellectually active life may protect against stress-induced vascular changes. Therapeutic agents also targeting the cerebral vasculature could consequently constitute a new tool in the combat of stress-related disorders.

Differential inhibition of neurogenesis and angiogenesis by corticosterone in rats stimulated with electroconvulsive seizures.

Antidepressant drugs and electroconvulsive seizure (ECS)-treatment, an animal model of electroconvulsive therapy, induce neurogenesis in adult rats. Stress and high levels of corticosterone (CORT) on the contrary inhibit neurogenesis. Hippocampal neurogenesis has been described to occur in an angiogenic niche where proliferation of neural progenitors takes place in an environment with active vascular growth. Here we investigate the effect of ECS-treatment on the proliferation of endothelial cells and neuronal precursors in hippocampus of CORT-treated rats. Bromodeoxyuridine (BrdU) was used to identify dividing cells. The number of newborn neuronal precursors and endothelial cells was quantified in the subgranular zone (SGZ) and the molecular layer (ML) of the dentate gyrus. The increase in neuronal precursor proliferation in the SGZ following ECS-treatment was not inhibited by elevated levels of CORT despite CORT strongly inhibiting ECS-induced endothelial cell proliferation. Also in the ML CORT-treatment inhibited the ECS-induced angiogenic response. We conclude that despite common factors regulating neurogenesis and angiogenesis, ECS-induced proliferation of neuronal precursors can take place even if the angiogenic response is blunted. Whether inhibition of angiogenesis affects other steps in the chain of events leading to the formation of fully integrated granule neurons remains to be elucidated.

Region specific hypothalamic neuronal activation and endothelial cell proliferation in response to electroconvulsive seizures.

BACKGROUND: Major depression is often associated with disturbances in basal biological functions regulated by the hypothalamus. Electroconvulsive therapy (ECT), an efficient anti-depressant treatment, alters the activity of hypothalamic neurons. We have previously shown an increased proliferation of endothelial cells in specific areas of the rat hippocampus in response to electroconvulsive seizure (ECS) treatment, an animal model for ECT. Here we examine the effect of ECS treatment on neuronal activation and endothelial cell proliferation in mid-hypothalamus. METHODS: Rats received one daily ECS treatment for 5 days and cell proliferation was detected by bromodeoxyuridine (BrdU). The number of cells double-labeled for BrdU and the endothelial cell marker rat endothelial cell antigen-1 was determined. Neuronal activation in response to acute ECS treatment was detected as c-Fos immunoreactivity in an additional experiment. RESULTS: We demonstrate a correlating pattern of increases in neuronal activation and increased endothelial cell proliferation in the paraventricular nucleus, the supraoptic nucleus, and the ventromedial nucleus of the hypothalamus after ECS treatment. CONCLUSIONS: Hypothalamic areas with the largest increase in neuronal activation after ECS treatment exhibit increased endothelial cell proliferation. We suggest that similar angiogenic responses to ECT might counteract hypothalamic dysfunction in depressive disorder.

Corticosterone-induced inhibition of gliogenesis in rat hippocampus is counteracted by electroconvulsive seizures.

BACKGROUND: Volumetric changes and glial pathology have been reported in the central nervous system (CNS) of patients with depressive disorder, an illness often associated with elevated glucocorticoid levels. Glucocorticoids reduce gliogenesis in the adult rat CNS. Electroconvulsive seizure (ECS)-treatment, an animal model for the antidepressant treatment electroconvulsive therapy, can enhance proliferation of glial cells. This study examined glial cell proliferation in response to ECS in rats whose glucocorticoid levels were elevated to mimic the conditions seen in depression. METHODS: Rats were injected daily for seven days with either corticosterone or vehicle. ECS- or sham- treatment was given once daily during the first five days. Proliferating cells in the hippocampus were labeled with bromodeoxyuridine and analyzed for co-labeling with the glial cell markers NG2, Ox42, S-100beta and Rip. RESULTS: ECS counteracted the glucocorticoid-induced inhibition of NG2+, Ox42+ and Rip+ cell proliferation, and the gliogenesis rate was restored to baseline levels. Volumetric changes in rats treated with ECS were detected. CONCLUSIONS: Our results show that ECS-treatment affects the proliferation of glial cells even in the presence of elevated levels of glucocorticoids. This result adds to an increasing number of studies suggesting that antidepressant treatment can counteract degenerative processes associated with major depression.

Electroconvulsive seizures induce angiogenesis in adult rat hippocampus.

BACKGROUND: Electroconvulsive seizure (ECS)-treatment, a model for electroconvulsive therapy (ECT) has been shown to induce proliferation of endothelial cells in the dentate gyrus (DG) of adult rats. Here we quantified the net angiogenic response after chronic ECS-treatment in the molecular layer (ML) of the dentate gyrus. Patients undergoing ECT are routinely oxygenated to prevent hypoxia, a known inducer of angiogenesis. Therefore we also examined the effect of oxygenation on ECS-induced proliferation of endothelial cells. METHODS: Total endothelial cell numbers and vessel length were estimated utilizing design based stereological analysis methods. Endothelial cell proliferation in the DG after ECS with or without oxygenation was assessed using bromodeoxyuridine. RESULTS: The total number of endothelial cells and total vessel length was increased. Oxygenation did not abolish the ECS-induced proliferation of endothelial cells in the DG. CONCLUSIONS: ECS-treatment induces a dramatic increase in endothelial cell proliferation leading to a 30% increase in the total number of endothelial cells. The increase in cell number resulted in a 16% increase in vessel length. These findings raise the possibility that similar vascular growth is induced by clinically administered ECT.

Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in adult rat amygdala.

BACKGROUND: Volumetric changes and glial pathology have been reported in the amygdala in patients with major depressive disorder. Here we report an analysis of glial cell proliferation in response to electroconvulsive seizures (ECS), clinically used for the treatment of severe depression. METHODS: Male Wistar rats were subjected to five ECS-treatments and then injected with bromodeoxyuridine (BrdU) to detect cell proliferation in the amygdala. The animals were transcardially perfused either 12 hours or 3 weeks after the last BrdU injection. Tissue sections were double-stained for BrdU and the cell-type markers NG2, OX-42, RIP, S-100beta, Doublecortin, or NeuN. RESULTS: Electroconvulsive seizures dramatically increased the proliferation of amygdala cells expressing the oligodendrocyte progenitor marker NG2. Bromodeoxyuridine-labeled NG2-expressing cells were still present after 3 weeks of survival, and a small proportion of the proliferating cells had differentiated into mature oligodendrocytes. CONCLUSIONS: Major depression has been associated with a reduction of glial cells. Our results show that ECS, an antidepressant treatment, significantly increases the number of NG2+ glial cells and mature oligodendrocytes in the adult rat amygdala.

Electroconvulsive seizures induce endothelial cell proliferation in adult rat hippocampus.

BACKGROUND: Electroconvulsive seizures, an animal model for electroconvulsive treatment, induce a strong increase in neurogenesis in the dentate gyrus of adult rats. Hippocampal neurogenesis has previously been described as occurring in an angiogenic niche. This study examines the effect of electroconvulsive seizures on proliferation of vascular cells in rat hippocampus. METHODS: Rats were injected with bromodeoxyuridine to label proliferating cells in the dentate gyrus after single/multiple electroconvulsive seizures in a dose-response study and at various time points after single electroconvulsive seizures in a time-course study. RESULTS: A dose-response effect on the number of bromodeoxyuridine-labeled endothelial cells located in the granule cell layer, hilus, and molecular layer was noted, as was the case with the number of neural precursors in the subgranular zone. The time-course study revealed that endothelial cell and neural precursor proliferation occurred in concert in response to a single electroconvulsive seizure. CONCLUSIONS: Our data suggest that in response to electroconvulsive seizures, endothelial cell and neural proliferation is coregulated. The increase in endothelial cell proliferation may act to support the increased neural proliferation and neuronal activity or vice versa, possibly leading to structural changes within the hippocampus of importance for the antidepressant effect of electroconvulsive seizures.

Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in adult rat hippocampus.

BACKGROUND: Analysis of postmortem tissue from patients with major depression and bipolar disorder has revealed structural changes in several brain regions. We have shown that electroconvulsive seizure (ECS), used for the treatment of severe depression, induces proliferation of both neuronal and nonneuronal cells in the adult rat hippocampus. METHODS: Male Wistar rats were subjected to one or several ECS treatments, then injected with bromodeoxyuridine (BrdU) to detect cell proliferation. Animals were perfused either 1 day or 3 weeks following the last BrdU injection. Cells were double stained for BrdU and the cell type markers chondroitin sulfate proteoglycan (NG2), complement 3-receptor OX-42, 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), Ca(+) binding protein S100-beta, or neuron-specific nuclear protein (NeuN). RESULTS: We identified NG2-expressing cells as a major cell type proliferating in the rat dentate gyrus in response to ECS. A sharp increase in NG2-positive cell proliferation was seen 2 days after ECS, and a large number of NG2-expressing cells persisted at 3 weeks. CONCLUSIONS: Our results show that antidepressant treatment can induce a strong proliferation of glial progenitor cells in the adult rat hippocampus. We propose that this may counteract degenerative changes found in depression and be an important neurobiological event underlying the clinical effect of electroconvulsive seizures.

Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment.

Major depression is often associated with elevated glucocorticoid levels. High levels of glucocorticoids reduce neurogenesis in the adult rat hippocampus. Electroconvulsive seizures (ECS) can enhance neurogenesis, and we investigated the effects of ECS in rats where glucocorticoid levels were elevated in order to mimic conditions seen in depression. Rats given injections of corticosterone or vehicle for 21 days were at the end of this period treated with either a single or five daily ECSs. Proliferating cells were labelled with bromodeoxyuridine (BrdU). After 3 weeks, BrdU-positive cells in the dentate gyrus were quantified and analyzed for co-labelling with the neuronal marker neuron-specific nuclear protein (NeuN). In corticosterone-treated rats, neurogenesis was decreased by 75%. This was counteracted by a single ECS. Multiple ECS further increased neurogenesis and no significant differences in BrdU/NeuN positive cells were detected between corticosterone- and vehicle-treated rats given five ECS. Approximately 80% of the cells within the granule cell layer and 10% of the hilar cells were double-labelled with BrdU and NeuN. We therefore conclude that electroconvulsive seizures can increase hippocampal neurogenesis even in the presence of elevated levels of glucocorticoids. This further supports the hypothesis that induction of neurogenesis is an important event in the action of antidepressant treatment.