Cognitive Defects Research Articles

Factors associated with delay in breast biopsy in a vulnerable population.

e13526 Background: Prompt diagnosis and treatment of breast cancer can improve outcomes and reduce stress and anxiety in patients. Race, socioeconomic status, and education level are associated with delays in diagnosis in breast cancer patients. 63% of Louisiana’s parishes are classified as rural, and 18.8% of the population is below the poverty line (the second highest in the country). The above factors make access to care challenging. Our study aimed to identify factors associated with delay in breast biopsy after abnormal diagnostic imaging in our patient population. Methods: A retrospective cohort study including female patients >18 years undergoing breast biopsy for abnormal diagnostic imaging findings from 1/1/2022 to 12/31/2022 at LSU Health, Shreveport, was done. Patients with a prior history of breast cancer, pregnant females, and patients with cognitive defects were excluded. Patients were followed from abnormal diagnostic imaging to biopsy. Descriptive analysis was done for baseline cohort characteristics. Univariate and multivariate logistic regression models were used to find 95% Confidence Interval and Odds ratio (ORs) for independent factors associated with time to biopsy (TTB). The study was approved by IRB. Results: 148 women (mean age [SD]: 54 [12] years) were included in the analysis. 67.5% were African American, and 25.6% lived in rural areas. The mean distance from the patient’s home to our center was 26.7 miles (Range: 3-219). The mean TTB from abnormal diagnostic imaging was 13.79 days (Range: 0-84), and 67.5% of patients had TTB of =<14 days. A TTB of more than 14 days was considered a delay in biopsy. After adjusting for age, multivariate logistic regression showed rural residence was associated with TTB of >14 days. (OR: 2.5, 95% CI: 1.15-5.67, p=0.02) (Table). A distance more than 40 miles from the hospital was associated with a higher likelihood of TTB of >14 days on a multivariate model adjusted for age and race revealed (OR: 2.2, 95% CI: 1.004-5.10, p= 0.04). Conclusions: Patients residing in rural parishes and at a distance more than 40 miles from our center have a higher likelihood of delay in time to biopsy from the diagnostic imaging. Same-day breast biopsy should be prioritized in such patients to ensure timely diagnosis and treatment. Cancer Centers serving the safety net population can conduct similar studies and implement changes to ensure equitable access to care. [Table: see text]

Role of defective mirror neurons in causing autism spectrum disorder and the effectiveness of current treatment strategies for autism

The presence of mirror neurons (MN) in the premotor cortex, and parietal regions of the brain, has always been an area of interest to neurophysiologists, because unlike most neurons, they are activated, not only while an individual is performing an action, but also when one witnesses another experiencing a sentiment, and hence, is compelled to do the same. This phenomenon, helps develop empathy, as well as an individual's social behavior. Autism spectrum disorder (ASD) is defined as a socially isolating disease, and has been hypothesised to be caused by defective MNs. According to the World Health Organization (WHO), about 1 out of every 100 children suffer from ASD. Although many studies have proven that the impaired MN system is the underlying cause of the cognitive function defects seen in these individuals, the exact role it plays in causing the disease is still unclear.

Clinical features of COVID-19-related encephalitis: comparison with the features of herpes virus encephalitis and autoimmune encephalitis

IntroductionIdentifying coronavirus disease 2019 (COVID-19)-related encephalitis without clear etiological evidence is clinically challenging. The distinctions between this condition and other prevalent encephalitis types remain unknown. Therefore, we aimed to explore the similarities and differences in the clinical characteristics of COVID-19-related encephalitis and other encephalitis types.MethodsAdult patients with encephalitis admitted to the neurology department at Xuanwu Hospital were enrolled and categorized into the following six groups based on the results of metagenomic next-generation sequencing and autoimmune antibody detection in cerebrospinal fluid (CSF): COVID-19-related encephalitis (n = 36), herpes simplex virus type 1 encephalitis (HSV-1 encephalitis; n = 28), human herpesvirus 3 encephalitis (HHV-3 encephalitis; n = 10), NMDAR-antibody encephalitis (n = 18), LGI1-antibody encephalitis (n = 12), and GABAB-antibody encephalitis (n = 8).ResultsThe predominant characteristics of COVID-19-related encephalitis include a low incidence of seizures (38.9%), cognitive defects (30.6%), and meningeal irritation signs (8.3%). Compared with HSV-1 and HHV-3 encephalitis, COVID-19-related encephalitis exhibited lower white blood cell count (2.5 count/mm3), protein (32.2 mg/dL), and immunoglobulin M, G, and A levels (0.09, 3.2, and 0.46 mg/dL, respectively) in the CSF tests. Abnormal imaging findings were present in only 36.1% of COVID-19-related encephalitis cases, mostly showing diffuse inflammation scattered in various parts, which differed from HSV-1 encephalitis. Additionally, COVID-19-related encephalitis exhibited significant differences in clinical symptoms and CSF white blood cell counts compared with NMDAR-antibody encephalitis; however, it showed limited differences compared with LGI1-antibody and GABAB-antibody encephalitis.DiscussionCOVID-19-related encephalitis and herpes virus or autoimmune encephalitis differ clinically. Symptoms and auxiliary examinations can be used as distinguishing tools.

Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington's disease model.

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.

Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy

Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.

SIK1 Downregulates Synaptic AMPA Receptors and Contributes to Cognitive Defects in Alzheimer's Disease.

A reduction in AMPA receptor (AMPAR) expression and weakened synaptic activity is early cellular phenotypes in Alzheimer's disease (AD). However, the molecular processes leading to AMPAR downregulation are complex and remain less clear. Here, we report that the salt inducible kinase SIK1 interacts with AMPARs, leading to a reduced accumulation of AMPARs at synapses. SIK1 protein level is sensitive to amyloid beta (Aβ) and shows a marked increase in the presence of Aβ and in AD brains. In neurons, Aβ incubation causes redistribution of SIK1 to synaptic sites and enhances SIK1-GluA1 association. SIK1 function is required for Aβ-induced AMPAR reduction. Importantly, in 3xTG AD mice, knockdown of SIK1 in the brain leads to restoration of AMPAR expression and a rescue of the cognitive deficits. These findings indicate an important role for SIK1 in meditating the cellular and functional pathology in AD.

Amygdala neuronal dyshomeostasis via 5-HT receptors mediates mood and cognitive defects in Alzheimer's disease.

Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre- to post-onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5-HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5-HT levels, in which both restrained inhibitory inputs by excessive 5-HT1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5-HT2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5-HT receptors simultaneously enables neurons to resist β-amyloid peptides (Aβ) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5-HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline.

Activating transcription factor 6 alleviates secondary brain injury by increasing cystathionine γ-lyase expression in a rat model of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) comprises primary and secondary injuries, the latter of which induces increased inflammation and apoptosis and is more severe. Activating transcription factor 6 (ATF6) is a type-II transmembrane protein in the endoplasmic reticulum (ER). ATF6 target genes could improve ER homeostasis, which contributes to cryoprotection. Hence, we predict that ATF6 will have a protective effect on brain tissue after ICH. The ICH rat model was generated through autologous blood injection into the right basal ganglia, the expression of ATF6 after ICH was determined by WB and IF. The expression of ATF6 was effectively controlled by means of intervention, and a series of measures was used to detect cell death, neuroinflammation, brain edema, blood-brain barrier and other indicators after ICH. Finally, the effects on long-term neural function of rats were measured by behavioral means. ATF6 was significantly increased in the ICH-induced brain tissues. Further, ATF6 was found to modulate the expression of cystathionine γ-lyase (CTH) after ICH. Upregulation of ATF6 attenuated neuronal apoptosis and inflammation in ICH rats, along with mitigation of ICH-induced brain edema, blood-brain barrier deterioration, and cognitive behavior defects. Conversely, ATF6 genetic knockdown induced effects counter to those aforementioned. This study thereby emphasizes the crucial role of ATF6 in secondary brain injury in response to ICH, indicating that ATF6 upregulation may potentially ameliorate ICH-induced secondary brain injury. Consequently, ATF6 could serve as a promising therapeutic target to alleviate clinical ICH-induced secondary brain injuries.

Novel insights into minipuberty and GnRH: Implications on neurodevelopment, cognition, and COVID-19 therapeutics.

In humans, the first 1000 days of life are pivotal for brain and organism development. Shortly after birth, gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus are activated, a phenomenon known as minipuberty. This phenomenon, observed in all mammals studied, influences the postnatal development of the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. This review will put into perspective the results of recent studies showing that the impact of minipuberty extends beyond reproductive function, influencing sensory and cognitive maturation. Studies in mice have revealed the role of nitric oxide (NO) in regulating minipuberty amplitude, with NO deficiency linked to cognitive and olfactory deficits. Additionally, findings indicate that cognitive and sensory defects in adulthood in a mouse model of Down syndrome are associated with an age-dependent decline of GnRH production, whose origin can be traced back to minipuberty, and point to the potential therapeutic role of pulsatile GnRH administration in cognitive disorders. Furthermore, this review delves into the repercussions of COVID-19 on GnRH production, emphasizing potential consequences for neurodevelopment and cognitive function in infected individuals. Notably, GnRH neurons appear susceptible to SARS-CoV-2 infection, raising concerns about potential long-term effects on brain development and function. In conclusion, the intricate interplay between GnRH neurons, GnRH release, and the activity of various extrahypothalamic brain circuits reveals an unexpected role for these neuroendocrine neurons in the development and maintenance of sensory and cognitive functions, supplementing their established function in reproduction. Therapeutic interventions targeting the HPG axis, such as inhaled NO therapy in infancy and pulsatile GnRH administration in adults, emerge as promising approaches for addressing neurodevelopmental cognitive disorders and pathological aging.

Complementary and alternative medicine on cognitive defects and neuroinflammation after sepsis.

Sepsis-associated encephalopathy (SAE) is a common manifestation of sepsis, ranging from mild confusion and delirium to severe cognitive impairment and deep coma. SAE is associated with higher mortality and long-term outcomes, particularly substantial declines in cognitive function. The mechanisms of SAE probably include neuroinflammation that is mediated by systemic inflammation and ischemic lesions in the brain, a disrupted blood-brain barrier, oxidative stress, neurotransmitter dysfunction, and severe microglial activation. Increasing evidence suggests that complementary and alternative medicine, especially Traditional Chinese Medicine (TCM), is favorable in alleviating cognitive decline after sepsis. Here, we summarized the studies of traditional herbal remedies, TCM formulas and acupuncture therapy in animal models of neurological dysfunctions after sepsis in recent decades and reviewed their potential mechanisms.

Structural interhemispheric connectivity defects in mouse models of BBSOAS: Insights from high spatial resolution 3D white matter tractography

White matter (WM) tract formation and axonal pathfinding are major processes in brain development allowing to establish precise connections between targeted structures. Disruptions in axon pathfinding and connectivity impairments will lead to neural circuitry abnormalities, often associated with various neurodevelopmental disorders (NDDs). Among several neuroimaging methodologies, Diffusion Tensor Imaging (DTI) is a magnetic resonance imaging (MRI) technique that has the advantage of visualizing in 3D the WM tractography of the whole brain non-invasively. DTI is particularly valuable in unpinning structural tract connectivity defects of neural networks in NDDs. In this study, we used 3D DTI to unveil brain-specific tract defects in two mouse models lacking the Nr2f1 gene, which mutations in patients have been proven to cause an emerging NDD, called Bosch-Boonstra-Schaaf Optic Atrophy (BBSOAS). We aimed to investigate the impact of the lack of cortical Nr2f1 function on WM morphometry and tract microstructure quantifications. We found in both mutant mice partial loss of fibers and severe misrouting of the two major cortical commissural tracts, the corpus callosum, and the anterior commissure, as well as the two major hippocampal efferent tracts, the post-commissural fornix, and the ventral hippocampal commissure. DTI tract malformations were supported by 2D histology, 3D fluorescent imaging, and behavioral analyses. We propose that these interhemispheric connectivity impairments are consistent in explaining some cognitive defects described in BBSOAS patients, particularly altered information processing between the two brain hemispheres. Finally, our results highlight 3DDTI as a relevant neuroimaging modality that can provide appropriate morphometric biomarkers for further diagnosis of BBSOAS patients.

Transient demyelination causes long-term cognitive impairment, myelin alteration and network synchrony defects.

In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination. However, reformed myelin, although functional, may not exhibit the same morphological characteristics as developmental myelin, which can have an impact on the activity of neural networks. In this context, we used the cuprizone-treated mouse model to analyze the structural, functional, and cognitive long-term effects of transient demyelination. Our results show that an episode of demyelination induces despite remyelination long-term cognitive impairment, such as deficits in spatial working memory, social memory, cognitive flexibility, and hyperactivity. These deficits were associated with a reduction in myelin content in the medial prefrontal cortex (mPFC) and hippocampus (HPC), as well as structural myelin modifications, suggesting that the remyelination process may be imperfect in these structures. In vivo electrophysiological recordings showed that the demyelination episode altered the synchronization of HPC-mPFC activity, which is crucial for memory processes. Altogether, our data indicate that the myelin repair process following transient demyelination does not allow the complete recovery of the initial myelin properties in cortical structures. These subtle modifications alter network features, leading to prolonged cognitive deficits in mice.

Nelumbo nucifera leaves extract ameliorated scopolamine-induced cognition impairment via enhanced adult hippocampus neurogenesis.

In this presentation, we explored the molecular mechanisms of N. nucifera leaf water extracts (NLWEs) and polyphenol extract (NLPE) on scopolamine-induced cell apoptosis and cognition defects. The administration of NLWE and NLPE did not alter the body weight and serum biomarker rs and significantly ameliorated scopolamine-induced cognition impairment according to Y-maze test analysis. In mice, treatment with scopolamine disrupted normal histoarchitecture in the hippocampus, whereas the administration of NLWE and NLPE reversed the phenomenon. Western blot analysis revealed that scopolamine mitigated the expression of doublecortin (DCX), nestin, and NeuN, and cotreatment with NLWE or NLPE significantly recovered the expression of these proteins. NLWE and NLPE upregulated DCX and NeuN expression in the hippocampus region, as evidenced by immunohistochemical staining analysis of scopolamine-treated mice. NLWE and NLPE obviously elevated brain-derived neurotrophic factor (BDNF) and enhanced its downstream proteins activity. NLWE and NLPE attenuated scopolamine-induced apoptosis by reducing Bax and increased Bcl-2 expression. In addition, scopolamine also triggered apoptosis in human neuroblastoma SH-SY5Y cells whereas co-treatment with NLWE or quercetin-3-glucuronide (Q3G) reversed the phenomenon. NLWE or Q3G enhanced Bcl-2 and reduced Bax expression in the presence of scopolamine in SH-SY5Y cells. NLWE or Q3G recovered the inhibitory effects of scopolamine on neurogenesis and BDNF signals in SH-SY5Y cells. Overall, our results revealed that N. nucifera leaf extracts and Q3G promoted adult hippocampus neurogenesis and prevented apoptosis to mitigate scopolamine-induced cognition dysfunction through the regulation of BDNF signaling pathway.

Nose-to-Brain Targeted Delivery of Donepezil Hydrochloride via Novel Hyaluronic Acid-Doped Nanotransfersomes for Alzheimer's Disease Mitigation

Alzheimer's disease is the most serious neurodegenerative disorder characterized by cognitive and memorial defects alongside deterioration in behavioral, thinking and social skills. Donepezil hydrochloride (DPZ) is one of the current two FDA-approved cholinesterase inhibitors used for the management of Alzheimer's disease. The current study aimed to formulate hyaluronic acid-coated transfersomes containing DPZ (DPZ-HA-TFS) for brain delivery through the intranasal pathway to surpass its oral-correlated GIT side effects. DPZ-HA-TFS were produced using a thin film hydration method and optimized with a 24 factorial design. The influence of formulation parameters on vesicle diameter, entrapment, cumulative release after 8 h, and ex vivo nasal diffusion after 24 h was studied. The optimal formulation was then evaluated for morphology, stability, histopathology and in vivo biodistribution studies. The optimized DPZ-HA-TFS formulation elicited an acceptable vesicle size (227.5 nm) with 75.83% entrapment efficiency, 37.94% cumulative release after 8 h, 547.49 µg/cm2 permeated through nasal mucosa after 24 h and adequate stability. Histopathological analysis revealed that the formulated DPZ-HA-TFS was nontoxic and tolerable for intranasal delivery. Intranasally administered DPZ-HA-TFS manifested significantly superior values for drug targeting index (5.08), drug targeting efficiency (508.25%) and direct nose-to-brain transport percentage (80.32%). DPZ-HA-TFS might be deemed as a promising intranasal nano-cargo for DPZ cerebral delivery to tackle Alzheimer's disease safely, steadily and in a non-invasive long-term pattern.

Systemic lupus erythematosus and Down syndrome: a case report and literature review

Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve any organ system, and may lead to significant morbidity and even mortality. Down syndrome (DS) is the most frequent genetic cause of intellectual disabilities, typically caused by the presence of an extra chromosome 21. Case presentation: A 47-year-old Syrian female of DS who complained of low-grade fever, oral aphthae, fatigue, and arthralgia three months before presentation. Although the patient was diagnosed with phenotypically and gynogenically DS, a milder mosaic type was identified. She appeared fatigued with a blood pressure 110/70 mmHg, pulse 104/min, temp 100 F, having oral ulcers, tenderness of joints on palpation, haemoglobin 9.4 g/dl, white blood cells 10.9/mm3, platelets 87 000×109/cm with C-reactive protein of 2,3 mg/dl, and an erythrocyte sedimentation rate of 68. Urea 33 mg/dl with creatinine 0.9. The rest of the tests were unremarkable. Urine analysis was normal. Discussion: The prevalence of SLE in DS in the literature was found only in five cases, with different presentations, in the last 36 years. In our case the patient presented with mild lupus manifestations and responded well to steroids and hydroxychloroquine. Also, In our case, an onset of SLE in an old DS (DS female patient), whereas SLE is more frequent in childbirth-aged women, in addition to that DS patients had a short life expectancy. Conclusions: DS is associated with a predisposition to developing connective tissue disorders, especially in young females. unfortunately, patients were not diagnosed in all five cases until later with a flare because of the cognitive defect.

Developmental defects in cognition, metabolic and cardiac function following maternal exposures to low environmental levels of selective serotonin re-uptake inhibitors and tributyltin in Daphnia magna

Aquatic organisms are exposed to low concentrations of neuro-active chemicals, many of them acting also as neuroendocrine disruptors that can be hazardous during earlier embryonic stages. The present study aims to assess how exposure early in live to environmental low concentrations of two selective serotonin reuptake inhibitors (SSRIs), fluoxetine and sertraline, and tributyltin (TBT) affected cognitive, metabolic and cardiac responses in the model aquatic crustacean Daphnia magna. To that end, newly brooded females were exposed for an entire reproductive cycle (3–4 days) and the response of collected juveniles in the first, second and third consecutive broods, which were exposed, respectively, as embryos, provisioned and un-provisioned egg stages, was monitored. Pre-exposure to the selected SSRIs during embryonic and egg developmental stages altered the swimming behaviour of D. magna juveniles to light in a similar way reported elsewhere by serotonergic compounds while TBT altered cognition disrupting multiple neurological signalling routes. The studied compounds also altered body size, the amount of storage lipids in lipid droplets, heart rate, oxygen consumption rates and the transcription of related serotonergic, dopaminergic and lipid metabolic genes in new-born individuals, mostly pre-exposed during their embryonic and provisioning egg stages. The obtained cognitive, cardiac and metabolic defects in juveniles developed from exposed sensitive pre-natal stages align with the “Developmental Origins of Health and Disease (DoHAD)” paradigm.

Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

Biomimetic engineering of a neuroinflammation-targeted MOF nanozyme scaffolded with photo-trigger released CO for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most fatal and irreversible neurodegenerative diseases, which causes a huge emotional and financial burden on families and society. Despite the progress made with recent clinical use of inhibitors of acetylcholinesterase and amyloid-β (Aβ) antibodies, the curative effects of AD treatment remain unsatisfactory, which is probably due to the complexity of pathogenesis and the multiplicity of therapeutic targets. Thus, modulating complex pathological networks could be an alternative approach to treat AD. Here, a neutrophil membrane-coated MOF nanozyme (denoted as Neu-MOF/Fla) is biomimetically engineered to disturb the malignant Aβ deposition-inflammation cycle and ameliorate the pathological network for effective AD treatment. Neu-MOF/Fla could recognize the pathological inflammatory signals of AD, and deliver the photo-triggered anti-inflammatory CO and MOF based hydrolytic nanozymes to the lesion area of the brain in a spontaneous manner. Based on the in vitro and in vivo studies, Neu-MOF/Fla significantly suppresses neuroinflammation, mitigates the Aβ burden, beneficially modulates the pro-inflammatory microglial phenotypes and improves the cognitive defects of AD mice models. Our work presents a good example for developing biomimetic multifunctional nanotherapeutics against AD by means of amelioration of multiple symptoms and improvement of cognitive defects.

Prescribing Cascade Complicating a Geriatric Patient

Abstract Prescribing cascades entail misinterpreting drug-related adverse events as new medical problems, resulting in unnecessary prescriptions and potential harm, especially in the elderly, leading to adverse outcomes like falls, cognitive defects, and increased health-care costs. For geriatric patients with complex medical histories, the intricacies of symptom differentiation and polypharmacy poses further challenges. This report focuses on managing a geriatric patient with multiple conditions, highlighting the risks and complexities of prescribing cascades.

Pharmacological mTOR inhibitors in ameliorating Alzheimer's disease: current review and perspectives.

Traditionally, pharmacological mammalian/mechanistic targets of rapamycin (mTOR) kinase inhibitors have been used during transplantation and tumor treatment. Emerging pre-clinical evidence from the last decade displayed the surprising effectiveness of mTOR inhibitors in ameliorating Alzheimer's Disease (AD), a common neurodegenerative disorder characterized by progressive cognitive function decline and memory loss. Research shows mTOR activation as an early event in AD development, and inhibiting mTOR may promote the resolution of many hallmarks of Alzheimer's. Aberrant protein aggregation, including amyloid-beta (Aβ) deposition and tau filaments, and cognitive defects, are reversed upon mTOR inhibition. A closer inspection of the evidence highlighted a temporal dependence and a hallmark-specific nature of such beneficial effects. Time of administration relative to disease progression, and a maintenance of a functional lysosomal system, could modulate its effectiveness. Moreover, mTOR inhibition also exerts distinct effects between neurons, glial cells, and endothelial cells. Different pharmacological properties of the inhibitors also produce different effects based on different blood-brain barrier (BBB) entry capacities and mTOR inhibition sites. This questions the effectiveness of mTOR inhibition as a viable AD intervention strategy. In this review, we first summarize the different mTOR inhibitors available and their characteristics. We then comprehensively update and discuss the pre-clinical results of mTOR inhibition to resolve many of the hallmarks of AD. Key pathologies discussed include Aβ deposition, tauopathies, aberrant neuroinflammation, and neurovascular system breakdowns.