Severe Alzheimer Research Articles

RESOLUTION OF INAPPROPRIATE SEXUAL BEHAVIOR IN AN ELDERLY MALE WITH MAJOR NEUROCOGNITIVE DISORDER AND DEVELOPMENTAL DELAY WITH MEMANTINE

RESOLUTION OF INAPPROPRIATE SEXUAL BEHAVIOR IN AN ELDERLY MALE WITH MAJOR NEUROCOGNITIVE DISORDER AND DEVELOPMENTAL DELAY WITH MEMANTINE

Body Mass Index and Age Effects on Brain 11β-Hydroxysteroid Dehydrogenase Type 1: a Positron Emission Tomography Study.

Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11β-HSD1 in the brain has not been quantified directly in vivo. We analyzed positron emission tomography (PET) scans with an 11β-HSD1 inhibitor radioligand in twenty-eight individuals (23M/5F): 10 lean, 13 overweight, and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of 11C-AS2471907 (n= 17) or 18F-AS2471907 (n= 11). Injected activity and mass doses were 246 ± 130MBq and 0.036 ± 0.039μg, respectively, for 11C-AS2471907, and 92 ± 15MBq and 0.001 ± 0.001μg for 18F-AS2471907. Correlations of mean whole brain and regional distribution volume (VT) with body mass index (BMI) and age were performed with a linear regression model. Significant correlations of whole brain mean VT with BMI and age (VT = 15.23-0.63 × BMI + 0.27 × Age, p = 0.001) were revealed. Age-adjusted mean whole brain VT values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean VT values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lower VT value in obese vs. lean individuals. A significant age-associated increase of 2.7mL/cm3 per decade was seen in BMI-corrected mean whole brain VT values. In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11β-HSD1 in the brain and correlation of increased 11β-HSD1 levels in the brain with advancing age.

Effect of Extended Nursing on the Behavioral and Psychological Symptoms and Cognitive Dysfunction of Patients with Moderate and Severe Alzheimer's Disease

The purpose of this investigation is to study the effect of extended nursing on the behavioral and psychological symptoms and cognitive dysfunction of patients with moderate and severe Alzheimer's disease. A total of 102 patients with moderate and severe Alzheimer's disease admitted to the People’s Hospital of Nanjing Medical University from February 2016 to March 2018 were randomly divided into the observation group and the control group. The control group received routine health education and nursing guidance after discharge, while the observation group received additional extended nursing scheme for 1 y, including daily living ability training, body function training, language training, memory training, music therapy, psychological nursing support and offline collective activities of patients. The scores of behavioral pathology assessment scale of Alzheimer's disease, Montreal cognitive assessment, and Barthel activities of daily living were compared between the two groups. There was no significant difference in the scores of behavioral pathology assessment scale of Alzheimer's, Montreal cognitive assessment and Barthel activities of daily living between the two groups on admission. One year later, the behavioral pathology assessment scale of Alzheimer's disease scores of the observation group were significantly lower than that of the control group (p<0.05), the Montreal cognitive assessment scores and Barthel activities of daily living scores of the observation group were significantly higher than that of the control group (p<0.05). The extended nursing scheme of this study improved the behavioral and psychological symptoms of Alzheimer's disease patients significantly, including anxiety, fear, hallucination, delusion, emotional disorder, aggressive behavior, behavioral disorder and circadian rhythm disorder. It could also improve the cognitive ability of Alzheimer's disease patients significantly, and improve their ability to handle daily life activities.

Chinese Version of the Baylor Profound Mental Status Examination: A Brief Staging Measure for Patients with Severe Alzheimer's Disease.

A specialized instrument for assessing the cognition of patients with severe Alzheimer's disease (AD) is needed in China. To validate the Chinese version of the Baylor Profound Mental Status Examination (BPMSE-Ch). The BPMSE is a simplified scale which has proved to be a reliable and valid tool for evaluating patients with moderate to severe AD, it is worthwhile to extend the use of it to Chinese patients with AD. Patients were assessed from the Memory Clinic Outpatient. All participants were diagnosed as having probable AD by assessment. The BPMSE was translated into Chinese and back translated. The BPMSE-Ch was administered to 102 AD patients with a Mini-Mental State Examination (MMSE) score below 17. We assessed the internal consistency, reliability, and construct validity between the BPMSE-Ch and MMSE, Severe Impairment Battery (SIB), Global Deterioration Scale (GDS-1), Geriatric Depression Scale(GDS-2), Instrumental Activities of Daily Living (IADL), Physical Self-Maintenance Scale (PSMS), Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). The BPMSE-Ch showed good internal consistency (α = 0.87); inter-rater and test-retest reliability were both excellent, ranging from 0.91 to 0.99. The construct validity of the measure was also supported by significant correlations with MMSE, SIB. Moreover, as expected, the BMPSE-Ch had a lower floor effect than the MMSE, but a ceiling effect existed for patients with MMSE scores above 11. The BPMSE-Ch is a reliable and valid tool for evaluating cognitive function in Chinese patients with severe AD.

A Phase III Multi Regional Clinical Trial (MRCT) of Tricaprilin in Mild to Moderately Severe Probable Alzheimer's Disease

A Phase III Multi Regional Clinical Trial (MRCT) of Tricaprilin in Mild to Moderately Severe Probable Alzheimer's Disease

How does memantine compare with placebo for treating adults with moderate to severe Alzheimer's disease?

How does memantine compare with placebo for treating adults with moderate to severe Alzheimer's disease?

Recognition-based memory through familiarity assessment in severe Alzheimer’s disease

Recognition-based memory through familiarity assessment in severe Alzheimer’s disease

Effect of Suvorexant on Nocturnal Delirium in Elderly Patients with Alzheimer's Disease: A Case-series Study.

Suvorexant, an orexin receptor antagonist used for insomnia, has been shown to have a preventive effect on delirium in a randomized placebo-controlled trial. However, its effectiveness in the management of nocturnal delirium has not yet been determined. Here we report four cases in which elderly patients with moderate to severe Alzheimer’s disease who developed nocturnal delirium were treated with suvorexant. In case 1, 15 mg suvorexant was initiated to manage nocturnal delirium refractory to antipsychotics, antidepressants, and a Japanese herbal medicine, resulting in immediate sleep improvement. However, treatment discontinuation led to recurrence of symptoms, which were reversed by recommencing suvorexant. In case 2, as antipsychotics used for the treatment of nocturnal delirium were ineffective, 15 mg suvorexant was administered. The patient achieved rapid improvement in sleep. In case 3, the use of atypical antipsychotics for the treatment of nocturnal delirium was contraindicated, as the patient had diabetes. Therefore, 15 mg suvorexant was administered following good outcomes in cases 1 and 2, resulting in immediate sleep improvement. Finally, in case 4, 15 mg suvorexant was used as an initial medication for nocturnal delirium, and the patient showed sleep improvement immediately. Elevated orexin levels in the cerebrospinal fluid are reportedly linked to sleep deterioration in patients with moderate to severe Alzheimer’s disease. The immediate and reproducible action and effectiveness of suvorexant observed in our patients suggest that enhanced cerebral orexin activity might be associated with sleep-wake cycle disturbances due to delirium in elderly patients with Alzheimer’s disease.

Validation Prognostic of the Baylor Profound Mental Status Examination

Background: There are no validated prognostic instruments to evaluate severe Alzheimer’s disease (AD) patients. Objective: To validate the prognostic value of the Baylor Profound Mental Status Examination (BPMSE). Methods: We selected 200 patients with severe AD. The following prognostic variables were collected: hospitalization, use of the emergency room, death, and prescription of drugs. ROC curve analysis was performed to see the overall behavior of the test when predicting the adverse event. We analyzed the AUC ROC and the best cut point was determined, and by using contingency tables, the risk was calculated. Results: For a BPMSE ≥16 points, there was a risk of 1.8 (95% CI 0.9–3.4) of prescription of psychotropic drugs in 12 months. For memantine in 12 months, for a BPMSE ≥16 points, there was a risk of 2.9 (95% CI 1.1–7.2). Emergency room visits, for a BMPSE ≤15 points, showed a risk of 1.7 (95% CI 1–3.2). The risk of hospitalization at 12 months, for a BPMSE ≤15, was 1.4 (95% CI 0.8–2.6). When comparing medians, patients with a higher BPMSE were prescribed more drugs at 12 months. Conclusions: BPMSE has a limited predictive value for the variables studied.

Computational analysis of Alzheimer-causing mutations in amyloid precursor protein and presenilin 1

Single-point mutations in the genes coding for amyloid precursor protein (APP) and presenilin 1 (PS1), the active subunit of γ-secretase that cleaves APP to produce Aβ, are the main causes of rare but severe familial Alzheimer's disease (fAD). Recent structures of the transmembrane parts of APP and γ-secretase with a fragment of APP bound enable us to study the origins of the pathogenicity of the single amino acid changes in the context of the actual enzyme-substrate complex, which has not previously been possible. We used the new structures as input for several state-of-the-art computational methods that predict the folding stability effect of mutations. We find that pathogenic mutations almost exclusively reduce the stability of the proteins. Since most “random” mutations of an evolutionarily optimized protein tend to destabilize, we also show that the APP mutations destabilize the complex-bound substrate more than the free substrate, indicating reduced affinity of APP to γ-secretase. We confirmed this using two other methods, BEATMUSIC and mCSM PPI, specifically developed for calculating binding affinities of mutants. Although pathogenic PS1 mutations destabilize the complex and substrate-free form to the same extent, they significantly destabilize the protein more than the control set of random mutations. We conclude that fAD mutations most likely reduce the stability of the protein-substrate complex and thus retention time of APP-C99, leading to premature release of longer toxic Aβ42 in accordance with the FIST model of Aβ production, whereas the observed general destabilization of the protein may reduce activity towards other substrates.

Initial programming of deep brain stimulation of hypothalamic/fornix for severe Alzheimer′s disease

Objective To explore the initial start-up programming and efficacy of deep brain electrical stimulation (DBS) of the hypothalamic fornix (HF) in the treatment of severe Alzheimer′s disease (AD). Methods A retrospective study was conducted on 9 patients with severe AD who underwent DBS-HF at Department of Neurosurgery, the First Medical Center of Chinese PLA General Hospital from June 2015 to September 2018. Postoperative cranial MRI was performed to determine the electrode position. Four weeks after operation, DBS device was turned on with initial programming set as unipolar stimulation with a frequency of 130 Hz, pulse width 90 μs and voltage of 3 V. The emotion, memory, calculation, language or communication and orientation of the patients were observed based on corresponding function of the brain area where the electrode contacts were located in order to determine the optimal contact and stimulating mode was thus maintained. Outpatient follow-up was conducted for all patients 3 months after the start-up. The follow-up included assessment of the patient′s emotion, memory, calculation, language, communication and orientation evaluated at initial programming. In addition, the patient′s sleep conditions and social skills were documented through consultation with the patient′s families. Results Nine patients were successfully operated. No perioperative complications such as intracerebral hemorrhage, abnormal electrode connection or wound infection occurred after operation. The electrodes of 9 patients were accurately implanted into the preset target position. At initial programming, there were no adverse effects reported including psychiatric and behavioral disorders, cardiovascular events and intolerance of stimulation. Among the 9 patients, memory was improved in 2 and mood was improved in 1. No symptom worsening was observed in the patient with severe psychiatric disorder who underwent bipolar stimulation through optimal contacts. Nine patients were followed up for 3 months. Among them, 7 had improved mood, 5 had improved memory, 7 had improved sleep, 6 had improved language ability, 3 had changed social intercourse, and 4 had changed orientation. However, there was no significant change in calculating power of 9 patients. Conclusions The preliminary results have suggest that the program-controlled startup scheme with functions of test, calculation, memory, emotion and physiology could be a way to ensure the efficacy of HF-DBS in the treatment of severe AD patients. Key words: Alzheimer′s disease; Deep brain stimulation; Fornix, brain; Treatment outcome; Programming

Reduced systemic exposure and brain uptake of donepezil in rats with scopolamine-induced cognitive impairment

1. Donepezil (DPZ) is an acetylcholinesterase (AchE) inhibitor used in the mild to moderately severe Alzheimer’s disease. Among its major metabolites, 6-O-desmethyl DPZ (6-DDPZ), 5-O-desmethyl DPZ (5-DDPZ) and DPZ N-oxide, the anti-AchE activities of 5-DDPZ and DPZ N-oxide have never been clearly identified before. Besides, there is no report on simultaneous determination of DPZ and its three metabolites in the brain, thus their uptake in hippocampus and cortex are unknown. Therefore, the current studies are proposed aiming to: (1) investigate the anti-AchE activities and brain uptake of DPZ and its three metabolites and (2) compare their pharmacokinetics and brain uptake between normal and scopolamine-induced rats.2. DPZ and its three metabolites demonstrated anti-AchE activities with the IC50 in the order of DPZ (7.20 × 10−2 μM), 6-DDPZ (1.14 × 10−1 μM), 5-DDPZ (4.03 × 10−1 μM) and DPZ N-oxide (1.61 μM). They were also evenly distributed in the brain and retained much longer in the brain than that in plasma in normal rats.3. Compared to normal rats, Cmax, AUC0→24h and AUC0→∞ of DPZ were reduced by 52.0%, 31.2% and 30.1%, respectively; Tmax of DPZ and its three metabolites were prolonged and their brain uptake were decreased in scopolamine-induced rats, suggesting the potential reduced absorption of DPZ.

Acetylcholinesterase inhibitors combined with memantine for moderate to severe Alzheimer's disease: a meta-analysis.

The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer&rsquo;s disease is inconclusive. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer&#39;s disease (Mini-Mental State Examination score is &lt;20). We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD &minus;0.15, 95% CI &minus;0.28 to &minus;0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI &minus;0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference &minus;3.07, 95% CI &minus;6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (&ge; 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy. Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed. &nbsp.

Evaluation of Activities of Daily Living/Instrumental Activities of Daily Living to Accurately Determine Severity of Moderate and Severe Alzheimer’s Disease: Comparison of Assessments by Receiver Operating Characteristic Curve and Discriminant Analyses

Aim: The aim of this study was to determine Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) evaluations that will enable better understanding of the severity of Alzheimer’s disease (AD). Methods: AD patients were evaluated by Functional Independence Measure (FIM), Hyogo Activities of Daily Living Scale (HADLS), and Assessment of Motor and Process Skills (AMPS) to identify the assessments that will enable highly precise discrimination of AD Clinical Dementia Rating (CDR) 2 (moderate) and CDR3 (severe) using receiver operating characteristic (ROC) curve and discriminant analyses. Results: The participants were 75 AD patients (CDR2 = 50, mean age = 80.3 ± 5.9 years; CDR3 = 25, mean age = 78.3 ± 9.0 years). The evaluation methods consisted of FIM, HADLS, and AMPS. The results were divided into FIM-M, FIM-C, HADLS-ADL, HADLS-IADL, AMPS-motor skills, and AMPS-process skills. The values for the area under the curve (AUC) were compared by ROC curve and discriminant analyses. AUC values for FIM-C and AMPS-process skills were 0.956 and 0.947, respectively. With these two evaluations only, values ≥0.9 were shown. Moreover, the AUC of the discrimination score (combination of the FIM-C and AMPS-process skills) was significantly higher than those for FIM-M, FIM-C, HADLS-ADL, HADLS-IADL, and AMPS-motor skills. Conclusions: The results demonstrated that evaluation by FIM-C and AMPS-process skills methods was useful for discriminating between CDR2 (moderate) and CDR3 (severe) AD. Moreover, the results indicated that these two evaluation methods enabled more accurate determination of severity and the spared capabilities of AD patients.

Investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe Alzheimer's disease: Study protocol for a cross-over randomized controlled trial.

Agitation is a prevalent and difficult-to-treat symptom in patients with moderate-to-severe Alzheimer's disease (AD). Though there are nonpharmacological and pharmacological interventions recommended for the treatment of agitation, the efficacy of these are modest and not always consistent. Furthermore, the safety profiles of currently prescribed medications are questionable. Nabilone, a synthetic cannabinoid, has a distinct pharmacological profile that may provide a safer and more effective treatment for agitation, while potentially having benefits for weight and pain. Additionally, emerging evidence suggests nabilone may have neuroprotective effects. We describe a clinical trial investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe AD. This will be a double-blind, randomized cross-over study comparing 6 weeks of nabilone (0.5–2 mg) and placebo, with a 1-week washout preceding each phase. Study outcomes will be measured at baseline and end of treatment for each treatment phase. The primary outcome measure will be agitation as assessed by the Cohen-Mansfield Agitation Inventory. The secondary outcomes include safety, behaviour (Neuropsychiatric Inventory), cognition (standardized Mini Mental Status Exam and either Severe Impairment Battery or Alzheimer's disease Assessment Scale-Cognitive subscale) and global impression (Clinician's Global Impression of Change). Exploratory outcomes include pain (Pain Assessment in Advanced AD), nutritional status (Mini-Nutritional Assessment-Short Form), caregiver distress (NPI caregiver distress), and blood-based biomarkers. A safe and efficacious pharmacological intervention for agitation, with effects on pain and weight loss in patients with moderate-to-severe AD could increase quality-of-life, reduce caregiver stress and avoid unnecessary institutionalization and related increases in health care costs.Clinical trials numberNCT02351882

The Role of N-Methyl-D-Aspartate Receptor Neurotransmission and Precision Medicine in Behavioral and Psychological Symptoms of Dementia.

While the world’s population is aging, the prevalence of dementia and the associated behavioral and psychological symptoms of dementia (BPSD) rises rapidly. BPSD are associated with worsening of cognitive function and poorer prognosis. No pharmacological treatment has been approved to be beneficial for BPSD to date. Dysfunction of the N-methyl-D-aspartate receptor (NMDAR)-related neurotransmission leads to cognitive impairment and behavioral changes, both of which are core symptoms of BPSD. Memantine, an NMDAR partial antagonist, is used to treat moderate to severe Alzheimer’s disease (AD). On the other hand, a D-amino acid oxidase inhibitor improved early-phase AD. Whether to enhance or to attenuate the NMDAR may depend on the phases of dementia. It will be valuable to develop biomarkers indicating the activity of NMDAR, particularly in BPSD. In addition, recent reports suggest that gender difference exists in the treatment of dementia. Selecting subpopulations of patients with BPSD who are prone to improvement with treatment would be important. We reviewed literatures regarding the treatment of BPSD, focusing on the NMDAR-related modulation and precision medicine. Future studies examining the NMDAR modulators with the aid of potential biomarkers to tailor the treatment for individualized patients with BPSD are warranted.

Meta-Analysis of Randomized Controlled Trials on the Efficacy and Safety of Donepezil, Galantamine, Rivastigmine, and Memantine for the Treatment of Alzheimer's Disease.

To study the impact of donepezil, rivastigmine, galantamine, and memantine on cognitive, functional, behavioral, global changes and adverse effects in patients with mild, moderate and severe Alzheimer’s disease (AD), we screened the literature published before September 2017 in the Pubmed, Embase, Cochrane library and Web of Science Electronic databases according to the inclusion criteria. Thirty-six studies were finally determined from 1560 preliminary screened articles. The AD Assessment Scale-cognitive Subscale (ADAS-cog), AD Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Clinician’s Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+) were used as valid endpoints. Of the 36 trials included, meta-analyses of these placebo-control trials showed that there were significant differences between the donepezil, rivastigmine and placebo groups using ADAS-cog, ADCS-ADL, and CIBIC+. Meta-analyses of these placebo-controlled trials showed that there were significant differences between the galantamine and placebo groups using ADAS-cog, ADCS-ADL, NPI, and CIBIC+. These observations suggest that memantine is beneficial for stabilizing or slowing the decline in ADAS-cog and ADCS-ADL19 changes in AD patients. However, there was no significant effect according to the ADCS-ADL23, NPI, and CIBIC+ tests, which indicated that memantine treatment has no significant effect on these cognitive aspects of AD patients. Different effects of donepezil, rivastigmine, galantamine, or memantine on AD were found in this study. According to the results, we conclude that galantamine is effective in treating all aspects of AD and is the first choice for the treatment of AD. However, due to limited data, we should consider additional data to obtain more stable results.

Determinants of self- and carer-rated quality of life and caregiver burden in Alzheimer disease.

We aimed to investigate factors associated with self- and carer-rated quality of life (QoL) and caregiver burden related to very mild to severe clinical Alzheimer disease (AD). One hundred patient-carer dyads were recruited, and assessments of relevant outcomes were performed, including sociodemographic characteristics, QoL, activities of daily living (ADL), cognitive performance, behavioural and psychological symptoms of dementia (BPSD), caregiver burden, and health resource utilisation. There was a strong correlation between carer- and self-rated QoL, with patients consistently rating their QoL higher than caregivers. Duration of illness did not affect the QoL ratings. There was an inverse association between both self- and carer-rated QoL with age, age at symptom onset, impairment of ADL, time spent on assisting the patient, and depression. Both self- and carer-rated QoL ratings were higher if the caregiver was a spouse vs a child. Carer-rated QoL was inversely associated with severity of dementia, BPSD, caregiver burden, and requirement to supervise the patient. The variables age at symptom onset, ADL, and living together with the primary caregiver explained 34.50% of the variance in self-rated QoL, whereas age at symptom onset, ADL, and BPSD explained 48.20% of the variance in carer-rated QoL. For caregiver burden, 26% of the variance was explained by the variables ADL, living together with the primary caregiver, and agitation. Our study highlights the need for a stronger focus on QoL in clinical AD research by providing further pieces of evidence on the key determinants, including the important aspect of caregiver burden.

Nanoparticle Assisted Regulation of Nucleation Pathway of Amyloid Tetramer and Inhibition of Their Fibrillation Kinetics.

Low molecular weight (LMW) soluble amyloid oligomers have been established as primary neurotoxic species that play a key role in Alzheimer's disease etiology. However, detection and separation of such energetically unfavored, metastable species are extremely challenging due to their short lifetime and dynamic nature. In this work, the aggregation of amyloid beta has been precisely regulated to produce their tetramer, the most toxic species among the pool of LMW amyloid oligomer since this tetramer is of key scientific importance and its inhibition could offer insights into developing early phase therapeutics for amyloidosis. The in-depth structural characterization as well as the regulation of these isolated tetramers has also been achieved for the first time in an in vitro model using nontoxic novel N-methyl d-aspartic acid (NMDA) functionalized gold nanoparticle (GNP-NMDA) that interacts specifically through electrostatic interactions to form stable GNP-amyloid coaggregates and directing the nucleation toward secondary nucleation pathway rapidly unlike in control experiment where nucleation proceeds mainly via primary nucleation pathway. NMDA receptor modulators are approved by the Food and Drug Administration (FDA) as an existing treatment for moderate to severe stage Alzheimer's Disease (AD); hence, GNP decorated with NMDA offers a promising strategy toward AD. This remarkable strategy for the inhibition of the most neurotoxic LMW tetramer form of the soluble amyloid oligomers toward a nontoxic aggregation path by GNP-NMDA presents a rationale target for drug designing and to develop early stage therapeutics against several neurodegenerative diseases.

A case of Fournier’s gangrene diagnosed with POCUS

An 87-year-old man with a history of type 2 diabetes and severe Alzheimer disease was admitted to the emergency department with a lesion of the perineum for two days. The patient appeared agitated and not collaborating on the visit. His vital signs were normal. Physical examination revealed an edematous, suppurative, and foul-smelling perineal-scrotal lesion, with possible subcutaneous emphysema.