-
The Journal of Nutritional Biochemistry Jun 2024The developing brain is sensitive to the impacts of early-life nutritional intake. This study investigates whether maternal high fat diet (HFD) causes glucose metabolism...
The developing brain is sensitive to the impacts of early-life nutritional intake. This study investigates whether maternal high fat diet (HFD) causes glucose metabolism impairment, neuroinflammation, and memory impairment in immature and adult offspring, and whether it may be affected by postweaning diets in a sex-dependent manner in adult offspring. After weaning, female rats were fed HFD (55.9% fat) or normal chow diet (NCD; 10% fat) for 8 weeks before mating, during pregnancy, and lactation. On postnatal day 21 (PND21), the male and female offspring of both groups were split into two new groups, and NCD or HFD feeding was maintained until PND180. On PND21 and PND180, brain glucose metabolism-, inflammation-, and Alzheimer's pathology-related markers were by qPCR. In adult offspring, peripheral insulin resistance parameters, spatial memory performance, and brain glucose metabolism (18F-FDG-PET scan and protein levels of IDE and GLUT3) were assessed. Histological analysis was also performed on PND21 and adult offspring. On PND21, we found that maternal HFD affected transcript levels of glucose metabolism markers in both sexes. In adult offspring, more profoundly in males, postweaning HFD in combination with maternal HFD induced peripheral and brain metabolic disturbances, impaired memory performance and elevated inflammation, dementia risk markers, and neuronal loss. Our results suggest that maternal HFD affects brain glucose metabolism in the early ages of both sexes. Postweaning HFD sex-dependently causes brain metabolic dysfunction and memory impairment in later-life offspring; effects that can be worsened in combination with maternal HFD.
PubMed: 38945454
DOI: 10.1016/j.jnutbio.2024.109675 -
Gene Jun 2024Endosomal acid base balance functions as a master orchestrator within the cell, engaging with many cellular pathways to maintain homeostasis. Mutations in the endosomal...
Endosomal acid base balance functions as a master orchestrator within the cell, engaging with many cellular pathways to maintain homeostasis. Mutations in the endosomal pH regulator Na/H exchanger NHE6 may disrupt this delicate balancing act and cause monogenic Parkinsonism. Here, gene expression studies in post-mortem substantia nigra of Parkinson's disease (PD) patients and normal controls were performed to investigate whether NHE6 represents a pathophysiological link between monogenic and sporadic PD. The substantia nigra in PD displayed down-regulation of NHE6, coincident with a loss of expression of several SNARE signalling pathway members, suggesting impaired membrane fusion and vesicle-recycling. Increased abundance of related NHE9 was also identified in the parkinsonian nigra that could reflect compensatory changes or be a consequence of neuronal dysfunction. The current model suggests the possibility that neurons expressing low levels of NHE6 are more susceptible to injury in PD, potentially directly contributing to the loss of nigral dopaminergic neurons and the genesis of the disease. These results have important implications for disease-modifying therapies as they suggest that endosomal pH correctors, including epigenetic modifiers that regulate NHE6 expression, may be beneficial for PD. Thus, aberrant endosomal acidification in the nigrostriatal pathway is a possible unifying pathomechanism in both monogenic and sporadic PD, with implications for understanding and treating this disorder. Replication of these observations in the post-mortem brains of Alzheimer's disease and frontotemporal dementia patients supports a model of conserved mechanisms underlying injury and death of neurons.
PubMed: 38945311
DOI: 10.1016/j.gene.2024.148737 -
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 -
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 -
International Journal of Geriatric... Jul 2024Rates of dementia are increasing in migrant populations, however, there is evidence that they remain underrepresented in older adult healthcare services. Barriers and... (Review)
Review
BACKGROUND
Rates of dementia are increasing in migrant populations, however, there is evidence that they remain underrepresented in older adult healthcare services. Barriers and facilitators to accessing dementia care have been explored from the viewpoint of migrants and caregivers, however, no review has synthesised the literature pertaining to clinicians' viewpoints. This review aimed to explore clinician perspectives as to the barriers and facilitators in assessing and diagnosing dementia in migrant populations.
METHODS
A systematic review of the literature was conducted. Databases included EMBASE, CINAHL, PsycINFO, MEDLINE and ProQuest. Qualitative studies from the perspective of European clinicians were included. The methodological quality of each study was assessed using the Critical Appraisals Programme Tool (CASP). The analysis adopted a thematic synthesis approach.
RESULTS
The review included 11 qualitative studies relating to the diagnosis of dementia in migrants. The quality of the studies was generally high, although few studies reported on the relationship between the researcher and the participants. The data related more to the barriers in diagnosing dementia, and few facilitators were found. Four themes were constructed: (1) service access (2) perceptions of migrant beliefs (3) relationships and (4) quality of the diagnostic process.
CONCLUSIONS
The review is limited by the small number of studies available. The findings highlight significant clinical concerns in the diagnosis of migrants, in particular the underrepresentation of migrants within services and the barriers to access they may face. The quality of the diagnostic process was often thought to be undermined by a lack of culturally sensitive assessment tools. Further research on the use of an interpreter in diagnosing dementia is needed.
Topics: Humans; Dementia; Health Services Accessibility; Transients and Migrants; Attitude of Health Personnel; Europe; Qualitative Research; Health Personnel
PubMed: 38944812
DOI: 10.1002/gps.6118 -
Advances in Gerontology = Uspekhi... 2024Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive cognitive decline. This review discusses current therapeutic... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive cognitive decline. This review discusses current therapeutic strategies for the treatment of Alzheimer's disease, their limitations, and potential prospects. The feasibility of comprehensive approach for AD therapy is considered in contrast to the classical method in the development of therapeutic strategy. Leu-Ile, Glu-Trp, Lys-Glu, Gly-Pro, Glu-Asp-Arg, Lys-Glu-Asp, Met-Glu-His-Phe-Pro-Gly-Pro short peptides are described as multitarget agents with a wide range of activity.
Topics: Alzheimer Disease; Humans; Oligopeptides
PubMed: 38944767
DOI: No ID Found -
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