Physical Violence and Aggression in Parkinson's Disease: A Systematic Review.

BACKGROUND: Physical violence and aggression (PVA), defined as behaviors with the potential to cause bodily injury, are unfortunate risks in the management of all-cause neurodegenerative dementias. While dementia in Parkinson's disease (PD) may not be evident for many years after clinical onset, neuropsychiatric disturbances occur at all stages of the disease. At issue is whether PVA in PD is associated with clinical factors that can be targets for prevention and management in the absence of a prevailing dementia syndrome. OBJECTIVE: This systematic review examined the extent to which PVA in PD without dementia is a clinically significant concern and whether it is associated with factors that could warrant proactive management. METHODS: A systematic search of 9 electronic databases used MeSH headings and equivalent terms for PD, aggression, and violence. Eligible manuscripts were original articles that were published in peer-reviewed journals and reported on adults with PD in the awake state with PVA as possible outcomes. Extracted data included study design, PD ascertainment methods and characteristics, PVA assessment methods, subject demographics, psychiatric and medical comorbidities, and pertinent results. Inciting and confounding factors were extracted from case reports. Quality assessment tools were applied in accordance with the study design (e.g., observational, qualitative, or case report). RESULTS: The search identified 10 manuscripts: 2 observational quantitative studies (total n with PD = 545), 1 qualitative study (n with PD = 20), and 7 case reports (n = 7). The observational studies suggested that PVA is less common than other neuropsychiatric disturbances, but heterogeneous methods and quality concerns prevented further conclusions. In the case reports, all patients were male, and most were early onset. In 6 of the reports, PVA occurred in the context of bilateral subthalamic nucleus deep brain stimulation. CONCLUSIONS: PVA, while relatively rare in PD, can be a significant management issue that is associated with select premorbid characteristics and antiparkinsonian motor treatments. As PVA may be under-reported, further understanding of its frequency, causes, risk factors, and outcomes would benefit from its systematic assessment, ideally using self-report and informant-based questionnaires.

Hormonal changes in veterans with Gulf War Illness.

AIMS: Gulf War Illness (GWI) is a multi-system condition of complex etiology and pathophysiology without specific treatment. There is an overlap between the symptoms of GWI and endocrinopathies. This study aimed to identify hormonal alterations in 1990-91 Gulf War (GW) veterans and the relationship between GWI and hormonal dysregulation. MAIN METHODS: Data from 81 GW veterans (54 with GWI and 27 controls without GWI) was analyzed in a cross-sectional, case-control observational study. Participants completed multiple questionnaires, neuropsychiatric assessments, and a comprehensive set of hormone assays including a glucagon stimulation test (GST) for adult growth hormone deficiency (AGHD) and a high-dose adrenocorticotropic hormone (ACTH) stimulation test for adrenal insufficiency. KEY FINDINGS: The GWI group had lower quality of life and greater severity of all symptoms compared to controls. Pain intensity and pain-related interference with general activity were also higher in the GWI group. AGHD was observed in 18 of 51 veterans with GWI (35.3 %) and 2 of 26 veterans without GWI (7.7 %) (p = 0.012 for interaction). Veterans with GWI also exhibited reduced insulin-like growth factor 1 (IGF-1) levels and IGF-1 Z-scores compared to controls. One participant with GWI met the criteria for adrenal insufficiency. No significant changes were observed in other hormonal axes. SIGNIFICANCE: The frequency of AGHD was significantly higher in veterans with GWI compared to controls. Recombinant human growth hormone replacement therapy (GHRT) may become a breakthrough therapeutic option for this subgroup. A large clinical trial is needed to evaluate the efficacy of GHRT in patients with GWI and AGHD.

Post-Traumatic Stress Disorder and Risk of Degenerative Synucleinopathies: Systematic Review and Meta-Analysis.

OBJECTIVE: A systematic review was conducted to answer whether adult-onset post-traumatic stress disorder (PTSD) is associated with increased risk of Parkinson's disease (PD) and related synucleinopathies. DESIGN: A systematic search of Medline (Ovid), Embase (Elsevier), PsycInfo (Ovid), Cochrane Library (Wiley), and Web of Science (Clarivate) was performed using MeSH headings and equivalent terms for PTSD, PD, DLB, and related disorders. SETTING: No restrictions. PARTICIPANTS: Eligible articles were published in peer-reviewed journals, sampled adult human populations, and treated PTSD and degenerative synucleinopathies as exposures and outcomes, respectively. MEASUREMENTS: Extracted data included diagnostic methods, sample characteristics, matching procedures, covariates, and effect estimates. Bias assessment was performed with the Newcastle-Ottawa scale. Hazard ratios were pooled using the random effects model, and the Hartung-Knapp adjustment was applied due to the small number of studies. RESULTS: A total of six articles comprising seven unique samples (total n = 1,747,378) met eligibility criteria. The risk of PD was reported in three retrospective cohort studies and one case-control study. Risk of DLB was reported in one retrospective cohort, one case-control, and one prospective cohort study. No studies addressed potential relationships with multiple system atrophy or pure autonomic failure. Meta-analysis of hazard ratios from four retrospective cohort studies supported the hypothesis that incident PTSD was associated with PD and DLB risk (pooled HR 1.88, 95% C.I. 1.08-3.24; p = 0.035). CONCLUSIONS: The sparse literature to-date supports further investigations on the association of mid- to late-life PTSD with Parkinson's and related neurodegenerative disorders.

Effect of Vagus Nerve Stimulation on Attention and Working Memory in Neuropsychiatric Disorders: A Systematic Review.

BACKGROUND: It has been suggested that vagus nerve stimulation (VNS) may enhance attention and working memory. The neuromodulator effects of VNS are thought to activate the release of neurotransmitters involving cognition and to promote neuronal plasticity. Therefore, VNS has been studied for its effects on attention and working memory impairment in neuropsychiatric disorders. OBJECTIVES: This study aimed to assess the effects of VNS on attention and working memory among patients with neuropsychiatric disorders, examine stimulation parameters, provide mechanistic hypotheses, and propose future studies using VNS. MATERIALS AND METHODS: We conducted a systematic review using electronic databases MEDLINE (Ovid), Embase (Ovid), Cochrane library, and PsycINFO (Ovid). Narrative analysis was used to describe the therapeutic effects of VNS on attention and working memory, describe stimulation parameters, and propose explanatory mechanisms. RESULTS: We identified 20 studies reporting VNS effects on attention and working memory in patients with epilepsy or mood disorders. For epilepsy, there was one randomized controlled trial from all 18 studies. It demonstrated no statistically significant differences in the cognitive tasks between active and control VNS. From a within-subject experimental design, significant improvement of working memory after VNS was demonstrated. One of three nonrandomized controlled trials found significantly improved attentional performance after VNS. The cohort studies compared VNS and surgery and found attentional improvement in both groups. Nine of 12 pretest-posttest studies showed improvement of attention or working memory after VNS. For mood disorders, although one study showed significant improvement of attention following VNS, the other did not. CONCLUSIONS: This review suggests that, although we identified some positive results from eligible studies, there is insufficient good-quality evidence to establish VNS as an effective intervention to enhance attention and working memory in persons with neuropsychiatric disorders. Further studies assessing the efficacy of such intervention are needed.

The impact of early life stress and immune challenge on behavior and glia cells alteration in late adolescent rats.

Maternal deprivation (MD) is known to be related to long-term changes that could influence the onset of psychiatric disorders. Studies have demonstrated that early life stress makes the cells in the brain more susceptible to subsequent stressors. To test it, we used an animal model of MD conducted from postnatal day (PND) 1 to 10. Deprived and non-deprived rats (control) were randomized to receive or not lipopolysaccharide (LPS) at 5 mg/kg on PND 50. The behavior and glial cells activation were evaluated in all groups from 51 to 53 PND. There was an increase in the immobility time in the MD and MD+LPS groups. The spontaneous locomotor activity was not changed between groups. We found elevated ionized calcium-binding adapter molecule 1 (Iba-1)-positive cells levels in the control+LPS and MD+LPS groups. In the MD+LPS group, it was found an increase in Iba-positive cells compared to the MD+sal group. The glial fibrillary acidic protein (GFAP)-positive cells were also increased in the MD+LPS, compared to control+sal, control+LPS, and MD+sal groups. Immune challenge by LPS in late adolescence, which was subjected to MD, did not influence the depressive-like behavior but exerted a pronounced effect in the microglial activation and astrocyte atrophy.

Receptor for Advanced Glycation End Products (RAGE) Mediates Cognitive Impairment Triggered by Pneumococcal Meningitis.

Pneumococcal meningitis is a life-threatening infection of the central nervous system (CNS), and half of the survivors of meningitis suffer from neurological sequelae. We hypothesized that pneumococcal meningitis causes CNS inflammation via the disruption of the blood-brain barrier (BBB) and by increasing the receptor for advanced glycation end product (RAGE) expression in the brain, which causes glial cell activation, leading to cognitive impairment. To test our hypothesis, 60-day-old Wistar rats were subjected to meningitis by receiving an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid as a control group and were treated with a RAGE-specific inhibitor (FPS-ZM1) in saline. The rats also received ceftriaxone 100 mg/kg intraperitoneally, bid, and fluid replacements. Experimental pneumococcal meningitis triggered BBB disruption after meningitis induction, and FPS-ZM1 treatment significantly suppressed BBB disruption. Ten days after meningitis induction, surviving animals were free from infection, but they presented increased levels of TNF-α and IL-1ß in the prefrontal cortex (PFC); high expression levels of RAGE, amyloid-ß (Aß1-42), and microglial cell activation in the PFC and hippocampus; and memory impairment, as evaluated by the open-field, novel object recognition task and Morris water maze behavioral tasks. Targeted RAGE inhibition was able to reduce cytokine levels, decrease the expression of RAGE and Aß1-42, inhibit microglial cell activation, and improve cognitive deficits in meningitis survivor rats. The sequence of events generated by pneumococcal meningitis can persist long after recovery, triggering neurocognitive decline; however, RAGE blocker attenuated the development of brain inflammation and cognitive impairment in experimental meningitis.

Inflammation as a Mechanism of Bipolar Disorder Neuroprogression.

Bipolar disorder (BD) is a severe, debilitating psychiatric condition with onset in adolescence or young adulthood and often follows a relapsing and remitting course throughout life. The concept of neuroprogression in BD refers to the progressive path with an identifiable trajectory that takes place with recurrent mood episodes, which eventually leads to cognitive, functional, and clinical deterioration in the course of BD. Understanding the biological basis of neuroprogression helps to explain the subset of BD patients who experience worsening of their disorder over time. Additionally, the study of the neurobiological mechanisms underpinning neuroprogression will help BD staging based on systems biology. Replicated epidemiological studies have suggested inflammatory mechanisms as primary contributors to the neuroprogression of mood disorders. It is known that dysregulated inflammatory/immune pathways are often associated with BD pathophysiology. Hence, in this chapter, we focus on the evidence for the involvement of inflammation and immune regulated pathways in the neurobiological consequences of BD neuroprogression. Herein we put forth the evidence of immune markers from autoimmune disorders, chronic infections, and gut-brain axis that lead to BD neuroprogression. Further, we highlighted the peripheral and central inflammatory components measured along with BD progression.

The impact of the microbiota-gut-brain axis on Alzheimer's disease pathophysiology.

The gut microbiota is a complex ecosystem that comprises of more than 100 trillion symbiotic microbial cells. The microbiota, the gut, and the brain form an association, 'the microbiota-gut-brain axis,' and synchronize the gut with the central nervous system and modify the behavior and brain immune homeostasis. The bidirectional communication between gut and brain occurs via the immune system, the vagus nerve, the enteric nervous system, and microbial metabolites, including short-chain fatty acids (SCFAs), proteins, and tryptophan metabolites. Recent studies have implicated the gut microbiota in many neurodegenerative diseases, including Alzheimer's disease (AD). In this review, we present an overview of gut microbiota, including Firmicutes, Bacteroidetes, SCFA, tryptophan, bacterial composition, besides age-related changes in gut microbiota composition, the microbiota-gut-brain axis pathways, the role of gut metabolites in amyloid-beta clearance, and gut microbiota modulation from experimental and clinical AD models. Understanding the role of the microbiota may provide new targets for treatment to delay the onset, progression, or reverse AD, and may help in reducing the prevalence of AD.