Special Issue "Commemorative Issue Celebrating the 20th Anniversary of the Alzheimer's Foundation of America: Understanding and Treating Alzheimer's Disease".

Alzheimer's disease (AD) is the most common form of dementia in older persons [...].

Drawing the Line Between Postacute Sequelae of COVID-19 and Functional Neurologic Disorders: A Daunting Clinical Overlap or Irrelevant Conundrum?

ABSTRACT: Coronavirus disease 2019 (COVID-19) is an acute infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in its multiple variants that classically presents with cough, fatigue, fever, headache, myalgias, and diarrhea. As vaccination becomes widely available and infection rates facilitate herd immunity across the globe, more attention has been given to long-term symptoms that may persist after the index infection, which include impairments in concentration, executive dysfunction, sensory disturbances, depression, anxiety, fatigue, and cough, among other symptoms classified under the umbrella term of postacute sequelae of SARS-CoV-2 infection (PASC).Functional neurologic disorder (FND), also known as conversion disorder and functional neurologic symptom disorder, refers to the presence of one or more symptoms of altered voluntary motor or sensory function that are incompatible with and not better explained by a known neurological or medical condition that causes significant distress and functional impairment. Although the diagnosis of FND may not require the identification of an underlying psychological stressor, being diagnosed with an FND can worsen stigma and shift attention and resources away from other medical concerns that should be concomitantly addressed.This review summarizes the literature on the overlapping nature and discrimination of PASC from FND in COVID-19 survivors. Based on this, we develop a treatment framework that targets unique domains of these complex overlapping presentations, following a multidisciplinary approach with an individualized treatment plan inclusive of physical and psychological interventions focused on functional rehabilitation.

Alzheimer's Disease Treatment: The Search for a Breakthrough.

As the search for modalities to cure Alzheimer's disease (AD) has made slow progress, research has now turned to innovative pathways involving neural and peripheral inflammation and neuro-regeneration. Widely used AD treatments provide only symptomatic relief without changing the disease course. The recently FDA-approved anti-amyloid drugs, aducanumab and lecanemab, have demonstrated unclear real-world efficacy with a substantial side effect profile. Interest is growing in targeting the early stages of AD before irreversible pathologic changes so that cognitive function and neuronal viability can be preserved. Neuroinflammation is a fundamental feature of AD that involves complex relationships among cerebral immune cells and pro-inflammatory cytokines, which could be altered pharmacologically by AD therapy. Here, we provide an overview of the manipulations attempted in pre-clinical experiments. These include inhibition of microglial receptors, attenuation of inflammation and enhancement of toxin-clearing autophagy. In addition, modulation of the microbiome-brain-gut axis, dietary changes, and increased mental and physical exercise are under evaluation as ways to optimize brain health. As the scientific and medical communities work together, new solutions may be on the horizon to slow or halt AD progression.

Androgen Deprivation Therapy for Prostate Cancer: Focus on Cognitive Function and Mood.

Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer's disease. ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs. A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology. The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer's disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.

Plants, Plants, and More Plants: Plant-Derived Nutrients and Their Protective Roles in Cognitive Function, Alzheimer's Disease, and Other Dementias.

Background and Objectives: Alzheimer's disease (AD) is the most common form of dementia, with the risk of developing it attributed to non-modifiable and modifiable factors. Currently, there is no cure for AD. A plant-based diet may protect against cognitive decline, due to the effects of plant-based nutrients such as vitamins, antioxidants, and fiber. The aim of the review is to summarize current literature on plant-based nutrients and their impact on cognition. Materials and Methods: A search was conducted on PubMed for clinical and murine studies, using combinations of the following words: "Alzheimer's disease", "dementia", "cognition", "plant-based diet", "mild cognitive impairment", "vitamin B", "vitamin C", "vitamin E, "beta carotene", "antioxidants", "fiber", "vitamin K", "Mediterranean diet", "vitamin D", and "mushrooms". Results and Conclusions: A diet rich in vitamin B and antioxidants can benefit the cognitive functions of individuals as shown in randomized clinical trials. Vitamin K is associated with improved cognition, although large randomized controlled trials need to be done. Fiber has been shown to prevent cognitive decline in animal studies. Vitamin D may contribute to cognitive health via anti-inflammatory processes. Several medical organizations have recommended a plant-based diet for optimizing cognitive health and potentially helping to prevent dementia.

Effect of oxytocin on lipid accumulation under inflammatory conditions in human macrophages.

INTRODUCTION AND AIMS: Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS: THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while oxLDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS: RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of oxLDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION: We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.

Cycloid Psychosis Comorbid with Prader-Willi Syndrome: A Case Series.

Psychosis is a relatively common psychiatric phenomenon seen in patients with Prader-Willi Syndrome (PWS). However, the presentation is atypical and difficult to classify within currently defined affective or psychotic disorders. This distinct presentation may be better understood as a phenomenon called "cycloid psychosis," described as an episodic psychosis with rapid full recovery between episodes. This study retrospectively analyzed the cases of 12 patients with genetically confirmed PWS who presented to an ambulatory psychiatric center for a change in behavior consistent with psychosis. Each case was then assessed for symptoms of cycloid psychosis, bipolar disorder, depression with psychotic features, schizophrenia, and schizoaffective disorder. Out of the 12 patients, 11 (91.7%) met the currently described diagnostic criteria for cycloid psychosis. Of the 12 patients, 7 (58.3%) also met the diagnostic criteria for bipolar disorder, and 1 (8.3%) also met the diagnostic criteria for schizoaffective disorder. None of the patients met the criteria for schizophrenia or depression with psychotic features. The findings in this study suggest that cycloid psychosis and bipolar disorder may both be comorbid with PWS. Psychiatric comorbidities in patients with PWS are atypical and clinicians should be aware of conditions such as cycloid psychosis when managing this vulnerable population.

The ALPIM (Anxiety, Laxity, Pain, Immune, and Mood) Syndrome in Adolescents and Young Adults: A Cohort Study.

OBJECTIVE: ALPIM (anxiety, laxity, pain, immune, and mood) syndrome has been previously described in adults. The authors aimed to identify its occurrence in adolescents and confirm its existence in adults. Given the association of the disorder with somatic symptoms, separation anxiety disorder (SAD) was explored as an ALPIM comorbidity. METHODS: Medical records of patients aged 11-34 with a diagnosis of depression or anxiety (panic disorder, SAD, social anxiety or generalized anxiety disorder) seen during a 1-year period were reviewed. Data were collected on the presence of ALPIM comorbidities. Analyses were conducted to detect their co-occurrence and evaluate possible predictors of the ALPIM syndrome. RESULTS: Inclusion criteria were met by 185 patient charts. A significant association was observed between the ALPIM comorbidities with 20 study subjects (10.8%) meeting criteria for ALPIM syndrome (patients with one or more diagnoses from each ALPIM domain). Patients with SAD had increased odds of being diagnosed with ALPIM (odds ratio=7.14, 95% CI=2.48-20.54, p<0.001). Neither major depression nor generalized anxiety disorder was found to be predictive of ALPIM syndrome. There was no difference in the prevalence of ALPIM-related comorbidities between study subjects <18 years old compared with those ≥18 years old. CONCLUSIONS: These findings reestablish the association of distinct psychiatric and nonpsychiatric conditions described as the ALPIM syndrome. Furthermore, the syndrome may present during adolescence. SAD may be an independent predictive factor for the occurrence of ALPIM syndrome. Patients with individual ALPIM comorbidities should be assessed for the syndrome, especially if they have a history of SAD.

The Impact of Designated Behavioral Health Services on Resource Utilization and Quality of Care in Patients Requiring Constant Observation in a General Hospital Setting: A Quality Improvement Project.

Constant observation (CO) is a common economic burden on general hospitals. A quality improvement (QI) project focusing on behavioral health (BH) management of this population was piloted using a novel BH protocol for the proactive assessment and management of all patients requiring CO. The impact on CO-cost and length of stay (LOS) was assessed. Data on demographics, diagnoses, psychopharmacologic treatment, complications and clinical setting were collected and analyzed for all CO-patients over a 6-month period. Cost and LOS data were compared with a similar sequential group prior to project implementation. Out of the 533 patients requiring CO during the study period, 491 underwent the protocol. This QI-project resulted in a significant reduction in the average monthly CO-cost by 33.06% and a 15% reduction in LOS without any increase in complications.

Pudendal nerve entrapment leading to avoidant/restrictive food intake disorder (ARFID): A case report.

Avoidant/restrictive food intake disorder (ARFID) is a diagnosis in diagnostic and statistical manual of mental disorders-5 (DSM-5) manifested by persistent failure to meet nutritional and/or energy needs. Pudendal nerve entrapment (PNE) often causes pelvic discomfort in addition to constipation and painful bowel movements. Current literature on ARFID is sparse and focuses on the pediatric and adolescent population. No association between PNE and ARFID has been described. We present a case of ARFID in an adult male with PNE resulting from subsequent scarring from testicular cancer surgery. The patient's gastrointestinal symptoms due to PNE caused significant food avoidance and restriction subsequently leading to severe malnourishment. Clinicians should be aware that distressing gastrointestinal symptoms arising from a secondary disease process such as PNE might lead to dietary restriction and food aversion. More research is needed for proper screening, detection, and treatment of ARFID. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2017; 50:84-87).

Protocol for Psychopharmacologic Management of Behavioral Health Comorbidity in Adult Patients with Diabetes and Soft Tissue Infections in a Tertiary Care Hospital Setting.

GENERAL PURPOSE: To provide information about the effect of psychiatric comorbidities on wound healing in patients with diabetes mellitus (DM). TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Discuss the connection between DM and the development of psychiatric comorbidities.2. Identify the drugs recommended in the treatment of these psychiatric comorbidities.3. List cautions and contraindications related to the drugs discussed. ABSTRACT: In patients with diabetes mellitus type 2, psychiatric comorbidities such as depressive and anxiety disorders are 60% or more prevalent than in the general population. The severity of mental illness and the duration of diabetes have been shown to correlate with worsening glycemic control, thus impeding wound healing. A retrospective chart review was conducted in all patients with diabetes mellitus admitted to the wound service with prior or current psychiatric symptoms of anxiety, depression, or cognitive impairment. A psychopharmacologic protocol was developed based on the clinical data collected and treatment parameters used by the behavioral health consultation liaison service.

Mitochondria in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-ß and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.

Cholesterol deficiency as a mechanism for autism: A valproic acid model.

Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.

Maximizing the Clinical Value of Blood-Based Biomarkers for Mild Traumatic Brain Injury.

Mild traumatic brain injury (TBI) and concussion can have serious consequences that develop over time with unpredictable levels of recovery. Millions of concussions occur yearly, and a substantial number result in lingering symptoms, loss of productivity, and lower quality of life. The diagnosis may not be made for multiple reasons, including due to patient hesitancy to undergo neuroimaging and inability of imaging to detect minimal damage. Biomarkers could fill this gap, but the time needed to send blood to a laboratory for analysis made this impractical until point-of-care measurement became available. A handheld blood test is now on the market for diagnosis of concussion based on the specific blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl terminal hydrolase L1 (UCH-L1). This paper discusses rapid blood biomarker assessment for mild TBI and its implications in improving prediction of TBI course, avoiding repeated head trauma, and its potential role in assessing new therapeutic options. Although we focus on the Abbott i-STAT TBI plasma test because it is the first to be FDA-cleared, our discussion applies to any comparable test systems that may become available in the future. The difficulties in changing emergency department protocols to include new technology are addressed.

Long COVID, the Brain, Nerves, and Cognitive Function.

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms. Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies. This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored.

Traumatic brain injury: Mechanisms, manifestations, and visual sequelae.

Traumatic brain injury (TBI) results when external physical forces impact the head with sufficient intensity to cause damage to the brain. TBI can be mild, moderate, or severe and may have long-term consequences including visual difficulties, cognitive deficits, headache, pain, sleep disturbances, and post-traumatic epilepsy. Disruption of the normal functioning of the brain leads to a cascade of effects with molecular and anatomical changes, persistent neuronal hyperexcitation, neuroinflammation, and neuronal loss. Destructive processes that occur at the cellular and molecular level lead to inflammation, oxidative stress, calcium dysregulation, and apoptosis. Vascular damage, ischemia and loss of blood brain barrier integrity contribute to destruction of brain tissue. This review focuses on the cellular damage incited during TBI and the frequently life-altering lasting effects of this destruction on vision, cognition, balance, and sleep. The wide range of visual complaints associated with TBI are addressed and repair processes where there is potential for intervention and neuronal preservation are highlighted.

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer's Disease.

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer's disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-ß accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-ß generation and improving neuronal health by maintaining mitochondrial function in neurons.

Mild-to-Moderate Traumatic Brain Injury: A Review with Focus on the Visual System.

Traumatic Brain Injury (TBI) is a major global public health problem. Neurological damage from TBI may be mild, moderate, or severe and occurs both immediately at the time of impact (primary injury) and continues to evolve afterwards (secondary injury). In mild (m)TBI, common symptoms are headaches, dizziness and fatigue. Visual impairment is especially prevalent. Insomnia, attentional deficits and memory problems often occur. Neuroimaging methods for the management of TBI include computed tomography and magnetic resonance imaging. The location and the extent of injuries determine the motor and/or sensory deficits that result. Parietal lobe damage can lead to deficits in sensorimotor function, memory, and attention span. The processing of visual information may be disrupted, with consequences such as poor hand-eye coordination and balance. TBI may cause lesions in the occipital or parietal lobe that leave the TBI patient with incomplete homonymous hemianopia. Overall, TBI can interfere with everyday life by compromising the ability to work, sleep, drive, read, communicate and perform numerous activities previously taken for granted. Treatment and rehabilitation options available to TBI sufferers are inadequate and there is a pressing need for new ways to help these patients to optimize their functioning and maintain productivity and participation in life activities, family and community.

The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. METHODS: Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. RESULTS: This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. CONCLUSIONS: There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.

The Effect of Abuse and Mistreatment on Healthcare Providers (TEAM): A Survey Assessing the Prevalence of Aggression From Patients and Their Families and Its Impact.

OBJECTIVE: Aggression from patients and families on health care providers (HCP) is common yet understudied. We measured its prevalence and impact on HCPs in inpatient and outpatient settings. METHODS: Four thousand six hundred seven HCPs employed by a community teaching hospital received an anonymous survey with results analyzed. RESULTS: Of 1609 HCPs (35%) completing the survey, 88% of inpatient staff reported experiencing different types of aggression compared to 82% in outpatient setting. Almost half did not report it to their supervisor. Younger staff were more likely to report abuse. Negative impacts on productivity and patient care were reported. A third of all responders' indicated negative effects on mental health. CONCLUSIONS: Despite negative impacts on staff wellbeing and productivity, patient/family aggression toward HCPs is highly prevalent and underreported. Our healthcare system needs measures to address staff security and wellness.