-
Chemical & Pharmaceutical Bulletin 2024Alzheimer's disease (AD) is the leading cause of senile dementia, and the rapid increase in the frequency of AD cases has been attributed to population aging. However,... (Review)
Review
Alzheimer's disease (AD) is the leading cause of senile dementia, and the rapid increase in the frequency of AD cases has been attributed to population aging. However, current drugs have difficulty adequately suppressing symptoms and there is still a medical need for symptomatic agents. On the other hand, it has recently become clear that epigenetic dysfunctions are deeply involved in the development of cognitive impairments. Therefore, epigenetics-related proteins have attracted much attention as drug targets for AD. Early-developed epigenetic inhibitors were inappropriate for AD treatment because of their limited potential for oral administration, blood-brain barrier penetration, high target selectivity, and sufficient dose-limiting toxicity which are essential properties for small molecule drugs targeting chronic neurodegenerative diseases such as AD. In recent years, drug discovery studies have been actively performed to overcome such problems and several novel inhibitors targeting the epigenetics-related proteins are of interest as promising AD therapeutic agents. Here, we review the small molecule inhibitors of histone deacetylase (HDAC), lysine-specific demethylase 1 (LSD1) or bromodomains and extra-terminal domain (BET) protein, that enable memory function improvement in AD model mice.
Topics: Alzheimer Disease; Humans; Animals; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Demethylases; Histone Deacetylases
PubMed: 38945939
DOI: 10.1248/cpb.c23-00027 -
Chemical & Pharmaceutical Bulletin 2024Alzheimer's disease (AD) is a common form of dementia. Although the causal mechanisms of AD are not fully understood, intracerebral accumulation of amyloid beta (Aβ)... (Review)
Review
Alzheimer's disease (AD) is a common form of dementia. Although the causal mechanisms of AD are not fully understood, intracerebral accumulation of amyloid beta (Aβ) and tau aggregates seems to play an important role in disease development. Therefore, numerous experimental and clinical studies targeting the Aβ and tau proteins have been performed. However, these treatments have not achieved good clinical results. Additionally, recent findings have indicated that immune abnormalities contribute to the pathogenesis of AD. Several immune- and microglia-related genes have been identified as putative causative genes for the disease. Microglia, which are resident immune cells in the central nervous system (CNS), are key players that maintain brain homeostasis by communicating with other cells, such as astrocytes and immune cells, in or around the CNS. Furthermore, dysfunction of microglia and the immune system of the CNS could lead to chronic neuroinflammation and impairment of protective neuroimmune responses, which have been associated with the pathogenesis of AD and other forms of dementia. In this review, we assemble information regarding genetic evidence, imaging and biofluid biomarkers, and the pathophysiology of AD, especially highlighting bilateral (protective or detrimental) microglial functions, thus connecting neuroimmune dysfunction and AD. We also introduce candidate drugs to target neuroimmune dysfunction in AD. Finally, we discuss future therapeutic precision medicine approaches for AD, which could be achieved by identifying and targeting signals critical for AD pathogenesis through analyses of interactions between genetic risk factors, as well as identifying and modulating disease-relevant immune cell populations.
Topics: Humans; Alzheimer Disease; Microglia; Animals; Dementia; Amyloid beta-Peptides
PubMed: 38945938
DOI: 10.1248/cpb.c23-00464 -
Chemical & Pharmaceutical Bulletin 2024Agitation and psychosis are key behavioral and psychological symptoms of Alzheimer's disease (AD). For family and caregivers of patients, such symptoms are critical... (Review)
Review
Agitation and psychosis are key behavioral and psychological symptoms of Alzheimer's disease (AD). For family and caregivers of patients, such symptoms are critical factors of distress and increased burden, but medication to treat them is limited. In most cases, drugs for other neuropsychiatric diseases have been used to manage these symptoms in an off-label manner. Due to the complex pathological background of AD and limited clinical data, obtaining proof of concept for the treatment of these symptoms is challenging. However, in 2023, the U.S. Food and Drug Administration approved brexpiprazole as the first and only drug to treat agitation in AD. Several other compounds have been evaluated in clinical situations. This review highlights recent pipelines being developed for agitation and psychosis for patients living with AD.
Topics: Alzheimer Disease; Humans; Psychotic Disorders; Psychomotor Agitation; Antipsychotic Agents
PubMed: 38945937
DOI: 10.1248/cpb.c23-00416 -
Chemical & Pharmaceutical Bulletin 2024Amyloid-β (Aβ) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to... (Review)
Review
Amyloid-β (Aβ) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to target Aβ and tau have been the primary focus for several decades. Recently, substantial breakthroughs have been achieved in the clinical development of Aβ antibodies; aducanumab was approved under conditional accelerated pathway by Food and Drug Administration (FDA) in the U.S. as the first disease-modifying agent for treating AD, and lecanemab has been granted traditional full approved in the U.S. and Japan. In addition, donanemab met the primary endpoint in a phase 3 study. On the other hand, tau-targeting therapies have failed to show clinical benefit although that increased tau levels show a strong correlation with cognitive impairment relative to Aβ depositions. Currently, tau immunotherapies, such as anti-tau antibodies and tau vaccines, have shown functional benefits in clinical trials. Also, clinical trials for combination therapy of Aβ and tau antibodies to see their potential are being investigated. In this review, we provide updates on the results of clinical trials of anti-Aβ antibodies and anti-tau therapeutics and suggest future directions for these therapeutics.
Topics: Alzheimer Disease; Humans; tau Proteins; Amyloid beta-Peptides; Immunotherapy; Animals
PubMed: 38945936
DOI: 10.1248/cpb.c24-00069 -
Heart & Lung : the Journal of Critical... Jun 2024Factors associated with cardiovascular complications of COVID-19 remain understudied.
Cardiovascular complications in the course of COVID-19 - lessons learned and implications for the future care of patients with viral respiratory diseases: Data from a single center retrospective observational study.
BACKGROUND
Factors associated with cardiovascular complications of COVID-19 remain understudied.
OBJECTIVES
Here we investigate the occurrence and risk factors of arrythmias, myocardial infarction and/or stroke, and thromboembolism in the course of COVID-19.
METHODS
We have performed an observational study with prospectively designed data collection. Data of patients diagnosed with COVID-19 who were admitted from March 6th 2020 to November 30th 2021 in our Hospital were analyzed. Logistic regression was used to identify variables associated with the odds of early hospital death due to COVID-19.
RESULTS
Fourteen-point three percent of 1964 patients had cardiovascular complications, 6.36 % arrhythmias, 5.5 % thromboembolic events and 2.39 % myocardial infarction and/or stroke. Factors independently increasing the odds of arrhythmia were older age (OR=1.49 [95 % CI: 1.17-1.92], p = 0.02), longer time between admission and the first onset of symptoms (1.02 [0.99-1.05], p = 0.049), concomitant atrial fibrillation/flutter (2.84 [1.37-5.70], p = 0.004), nicotinism (2.49 [1.37-4.49], p = 0.002), and eGFR<60 ml/min/1.73m (2.44 [1.08-5.59], p = 0.033). Factors independently increasing the odds of myocardial infarction and/or stroke were dementia (4.55 [0.97-19.3], p = 0.044), hemiplegia (12.67 [3.12-46.1], p < 0.001), nicotinism (3.36 [1.30-10.4], p = 0.013) and higher C-reactive protein concentration (1.01 [1.00-1.01], p = 0.040). Factors independently increasing the odds of thromboembolic events were longer hospitalization (1.08 [1.05-1.10], p < 0.001) and higher d-dimers (1.04 [1.02-1.05], <0.001).
CONCLUSIONS
The risk of cardiovascular complications was especially pronounced in patients with older age, pre-existing cardiovascular disease and more sever pneumonia at presentation to care. This underlines the importance of close and careful clinical follow-up in the course of COVID-19 for specific patients' populations, including a pro-active approach in diagnosis.
PubMed: 38944910
DOI: 10.1016/j.hrtlng.2024.06.009 -
Seizure Jun 2024The unique patho-clinical entity of late-onset epilepsy (LOE), distinguished by its distinct natural history, from its onset to the prognosis it portends, necessitates... (Review)
Review
The unique patho-clinical entity of late-onset epilepsy (LOE), distinguished by its distinct natural history, from its onset to the prognosis it portends, necessitates specialized care. We lack a universally accepted definition, but LOE is typically identified as epilepsy onset after the age of 60 or 65. Unlike epilepsy in younger individuals, LOE is almost by default focal in origin, secondary to acquired etiologies, and presents unique diagnostic and management challenges due to its atypical semiology, higher comorbidity burden, frailty, and increased risks of subsequent stroke and dementia. LOE clinics have been established to address these challenges, providing a multidisciplinary approach to optimize outcomes in patients with new-onset seizures beyond the fifth decade of life. LOE clinics are essential for comprehensive care, offering not only seizure management but also monitoring and addressing associated comorbidities. The care model involves collaboration among neurologists, primary care providers, cardiologists, mental health professionals, and social workers to manage LOE patients' complex needs effectively. The prevalence of cognitive dysfunction in LOE patients underscores the need for regular cognitive assessments and interventions. Biomarker research, particularly involving amyloid beta, offers promising avenues for early diagnosis and a better understanding of the interplay between LOE and Alzheimer's disease. Establishing LOE clinics in major referral centers can enhance provider expertise, improve patient outcomes, and facilitate research to advance diagnostic and therapeutic strategies. In conclusion, LOE clinics play a critical role in addressing the multifaceted needs of older adults with epilepsy, tailored to local resources and challenges, thus enhancing epilepsy care in an aging global population.
PubMed: 38944548
DOI: 10.1016/j.seizure.2024.06.026 -
Journal of Ethnopharmacology Jun 2024Cistanche deserticola is a kind of parasitic plant living in the roots of desert trees. It is a rare Chinese medicine, which has the effect of tonifying kidney Yang,...
ETHNOPHARMACOLOGICAL RELEVANCE
Cistanche deserticola is a kind of parasitic plant living in the roots of desert trees. It is a rare Chinese medicine, which has the effect of tonifying kidney Yang, benefiting essence and blood and moistening the intestinal tract. Cistache deserticola phenylethanoid glycoside (PGS), an active component found in Cistanche deserticola Ma, have potential kidney tonifying, intellectual enhancing, and neuroprotective effects. Cistanche total glycoside capsule has been marketed to treat vascular dementia disease.
AIM OF THE STUDY
To identify the potential renal, intellectual enhancing and neuroprotective effects of PGS and explore the exact targets and mechanisms of PGS.
MATERIALS AND METHODS
This study systematically investigated the four types of pathways leading to ferroptosis through transcriptome, metabolome, ultrastructure and molecular biology techniques and explored the molecular mechanism by which multiple PGS targets and pathways synergistically exert neuroprotective effects on hypoxia.
RESULTS
PGS alleviated learning and memory dysfunction and pathological injury in mice exposed to hypobaric hypoxia by attenuating hypobaric hypoxia-induced hippocampal histopathological damage, impairing blood‒brain barrier integrity, increasing oxidative stress levels, and increasing the expression of cognitive proteins. PGS reduced the formation of lipid peroxides and improved ferroptosis by upregulating the GPX-4/SCL7A311 axis and downregulating the ACSL4/LPCAT3/LOX axis. PGS also reduced ferroptosis by facilitating cellular Fe efflux and regulating mitochondrial Fe transport and effectively antagonized cell ferroptosis induced by erastin (a ferroptosis inducer).
CONCLUSIONS
This study demonstrated the mechanism by which PGS prevents hypobaric hypoxic nerve injury through four types of ferroptosis pathways, achieved neuroprotective effects and alleviated learning and memory dysfunction in hypobaric hypoxia mice. This study provides a theoretical basis for the development and application of PGS.
PubMed: 38944360
DOI: 10.1016/j.jep.2024.118465 -
Neuroscience and Biobehavioral Reviews Jun 2024Cognitive challenges and brain structure variations are common in autism spectrum disorder (ASD) but are rarely explored in middle-to-old aged autistic adults. Cognitive... (Review)
Review
Cognitive challenges and brain structure variations are common in autism spectrum disorder (ASD) but are rarely explored in middle-to-old aged autistic adults. Cognitive deficits that overlap between young autistic individuals and elderlies with dementia raise an important question: does compromised cognitive ability and brain structure during early development drive autistic adults to be more vulnerable to pathological aging conditions, or does it protect them from further decline? To answer this question, we have synthesized current theoretical models of aging in ASD and conducted a systematic literature review (Jan 1, 1980 - Feb 29, 2024) and meta-analysis to summarize empirical studies on cognitive and brain deviations in middle-to-old aged autistic adults. We explored findings that support different aging theories in ASD and addressed study limitations and future directions. This review sheds light on the poorly understood consequences of aging question raised by the autism community to pave the way for future studies to identify sensitive and reliable measures that best predict the onset, progression, and prognosis of pathological aging in ASD.
PubMed: 38944227
DOI: 10.1016/j.neubiorev.2024.105782 -
Current Biology : CB Jun 2024Rapid eye movement (REM) sleep has been hypothesized to promote emotional resilience, but any neuronal circuits mediating this have not been identified. We find that in...
Rapid eye movement (REM) sleep has been hypothesized to promote emotional resilience, but any neuronal circuits mediating this have not been identified. We find that in mice, somatostatin (Som) neurons in the entopeduncular nucleus (EP)/internal globus pallidus are predominantly active during REM sleep. This unique REM activity is both necessary and sufficient for maintaining normal REM sleep. Inhibiting or exciting EP neurons reduced or increased REM sleep duration, respectively. Activation of the sole downstream target of EP neurons, Vglut2 cells in the lateral habenula (LHb), increased sleep via the ventral tegmental area (VTA). A simple chemogenetic scheme to periodically inhibit the LHb over 4 days selectively removed a significant amount of cumulative REM sleep. Chronic, but not acute, REM reduction correlated with mice becoming anxious and more sensitive to aversive stimuli. Therefore, we suggest that cumulative REM sleep, in part generated by the EP → LHb → VTA circuit identified here, could contribute to stabilizing reactions to habitual aversive stimuli.
PubMed: 38944034
DOI: 10.1016/j.cub.2024.06.010 -
Maturitas Jun 2024A helpful method to understand cognitive decline in older people is to consider this entity as increasing cognitive frailty caused by a number of interacting... (Review)
Review
A helpful method to understand cognitive decline in older people is to consider this entity as increasing cognitive frailty caused by a number of interacting pathological processes. Over the last 20 years, multiple lifestyle, environmental and constitutional factors have been linked to the development of cognitive decline. For two interventions based on these factors, increasing physical activity and the control of hypertension, there is class 1 evidence for benefit. Other interventions based on these factors do not have the support of high-level evidence for the alteration of cognitive decline, but their other benefits would argue for their implementation. These interventions include increasing education, smoking cessation, avoiding head injuries, decreasing exposure to air pollution and increased social connections. As cognitive decline is experienced almost universally with ageing, and serious cognitive decline is experienced by substantial numbers of low-risk individuals, whole-of-population intervention strategies are the most effective and efficient. For other interventions to help prevent cognitive decline there is not sufficient evidence for their implementation to be recommended. These include alteration of alcohol ingestion, correction of hearing loss, treatment of depression, dietary interventions, menopausal hormone treatment and monoclonal antibodies directed against amyloid-β.
PubMed: 38943792
DOI: 10.1016/j.maturitas.2024.108062