Search

The hippocampal complex is affected early in Alzheimer's disease (AD). Increasingly, altered functional connectivity of the hippocampus is recognized as an important feature of preclinical AD. Carriers of the APOEeɛ4 allele are at an increased risk for AD, which could lead to altered hippocampal connectivity even in healthy older adults. To test this hypothesis, we used a paired-associates memory task to examine differences in task-dependent functional connectivity of the anterior and posterior hippocampus in nondemented APOEeɛ4 carriers (n = 34, 18F) and noncarriers (n = 46, 31F). We examined anterior and posterior portions of the hippocampus separately to test the theory that APOEeɛ4-mediated differences would be more pronounced in the anterior region, which is affected earlier in the AD course. This study is the first to use a psychophysiological interaction approach to query the context-dependent connectivity of subregions of the hippocampus during a memory task in adults at increased genetic risk for AD. During encoding, APOEeɛ4 carriers had lower functional connectivity change compared to baseline between the anterior hippocampus and right precuneus, anterior insula and cingulate cortex. During retrieval, bilateral supramarginal gyrus and right precuneus showed lower functional connectivity change with anterior hippocampus in carriers. Also during retrieval, carriers showed lower connectivity change in the posterior hippocampus with auditory cortex. In each case, APOEeɛ4 carriers showed strong negative connectivity changes compared to noncarriers where positive connectivity change was measured. These differences may represent prodromal functional changes mediated in part by APOEeɛ4 and are consistent with the anterior-to-posterior theory of AD progression in the hippocampus. © 2015 Wiley Periodicals, Inc.

A field experiment examined whether increasing opportunities for face-to-face interaction while eliminating the use of screen-based media and communication tools improved nonverbal emotion-cue recognition in preteens. Fifty-one preteens spent five days at an overnight nature camp where television, computers and mobile phones were not allowed; this group was compared with school-based matched controls (n = 54) that retained usual media practices. Both groups took pre- and post-tests that required participants to infer emotional states from photographs of facial expressions and videotaped scenes with verbal cues removed. Change scores for the two groups were compared using gender, ethnicity, media use, and age as covariates. After five days interacting face-to-face without the use of any screen-based media, preteens' recognition of nonverbal emotion cues improved significantly more than that of the control group for both facial expressions and videotaped scenes. Implications are that the short-term effects of increased opportunities for social interaction, combined with time away from screen-based media and digital communication tools, improves a preteen's understanding of nonverbal emotional cues. © 2014 The Authors. Published by Elsevier Ltd.

Identifying subjects with mild cognitive impairment (MCI) most likely to decline in cognition over time is a major focus in Alzheimer's disease (AD) research. Neuroimaging biomarkers that predict decline would have great potential for increasing the efficacy of early intervention. In this study, we used high-resolution MRI, combined with a cortical unfolding technique to increase visibility of the convoluted medial temporal lobe (MTL), to assess whether gray matter thickness in subjects with MCI correlated to decline in cognition over two years. We found that thickness in the entorhinal (ERC) and subicular (Sub) cortices of MCI subjects at initial assessment correlated to change in memory encoding over two years (ERC: r = 0.34; P = .003) and Sub (r = 0.26; P = .011) but not delayed recall performance. Our findings suggest that aspects of memory performance may be differentially affected in the early stages of AD. Given the MTL's involvement in early stages of neurodegeneration in AD, clarifying the relationship of these brain regions and the link to resultant cognitive decline is critical in understanding disease progression.

Diagnosis of Alzheimer's disease is often missed or delayed in clinical practice; thus, methods to improve early detection would provide opportunities for early intervention, symptomatic treatment, and improved patient function. Emerging data suggest that the disease process begins years before clinical diagnostic confirmation. This paper reviews current research focusing on methods for more specific and sensitive early detection using measures of genetic risk for Alzheimer's disease and functional brain imaging. This approach aims to identify patients in a presymptomatic stage for early treatment to delay progressive cognitive decline and disease onset.

Objectives: Amyloid senile plaques and tau neurofibrillary tangles are neuropathologic hallmarks of Alzheimer disease, which may be associated with mild cognitive impairment (MCI) or mood and anxiety symptoms years before the dementia diagnosis. To address this issue, the authors obtained positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to amyloid plaques and neurofibrillary tangles, to determine whether symptoms of depression and anxiety in nondemented subjects were associated with increased FDDNP-PET binding values.Methods: Forty-three middle-aged and elderly volunteers received clinical and FDDNP-PET assessments. Subjects were nondemented--23 of them were diagnosed with MCI and 20 were cognitively normal. Subjects with a diagnosis of major depression or an anxiety disorder were excluded. Correlations between standardized measures of depressive and anxiety symptoms and regional FDDNP binding values were calculated.Results: The MCI and comparison subjects did not differ by the depression and anxiety scores. In the MCI group, depression scores correlated with lateral temporal and trait anxiety scores correlated with posterior cingulate FDDNP binding. In the comparison group, depression scores correlated with medial temporal, and trait anxiety scores correlated with medial temporal and frontal FDDNP binding.Discussion: This is the first report to demonstrate a relationship between the severity of depression and anxiety symptoms and FDDNP binding values in nondemented middle age and older individuals. The results suggest a relationship between relatively mild mood symptoms and biomarkers of cerebral amyloid and tau deposition and vary according to degree of cognitive impairment. The presence of MCI may signify different pathophysiological mechanisms underlying mood and anxiety symptoms. [ABSTRACT FROM AUTHOR]

Background: Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease that accumulate in the cortical regions of the brain in persons with mild cognitive impairment who are at risk for Alzheimer's disease. Noninvasive methods to detect these abnormal proteins are potentially useful in developing surrogate markers for drug discovery and diagnostics.Methods: We enrolled 83 volunteers with self-reported memory problems who had undergone neurologic and psychiatric evaluation and positron-emission tomography (PET). On the basis of cognitive testing, 25 volunteers were classified as having Alzheimer's disease, 28 as having mild cognitive impairment, and 30 as having no cognitive impairment (healthy controls). PET was performed after injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro. All subjects also underwent 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET, and 72 underwent magnetic resonance imaging (MRI).Results: Global values for FDDNP-PET binding (average of the values for the temporal, parietal, posterior cingulate, and frontal regions) were lower in the control group than in the group with mild cognitive impairment (P<0.001), and the values for binding in the group with mild cognitive impairment were lower than in the group with Alzheimer's disease (P<0.001). FDDNP-PET binding differentiated among the diagnostic groups better than did metabolism on FDG-PET or volume on MRI.Conclusions: FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alzheimer's disease (AD) patients experiencing more rapid symptom progression are likely to have a poorer prognosis than those experiencing slow symptom progression. In a recent retrospective analysis, treatment effects of rivastigmine were more pronounced in AD patients with rapid cognitive decline than in those with slow cognitive decline. This warranted further investigation. METHODS: Rapidly and slowly progressing patients were identified by rates of cognitive decline [>/=4 points and <4 points, respectively, on the Alzheimer's Disease Assessment Scale -- cognitive subscale (ADAS-cog)] during 26 weeks of placebo treatment in four randomized controlled trials (weeks 0--26). This meta-analysis evaluated rates of cognitive decline in both subgroups during subsequent open-label rivastigmine 26-week extension studies (weeks 26--52). A longitudinal mixed effects model compared cognitive decline in rapidly and slowly progressing patients, including correction for possible regression to the mean. RESULTS: 180 (75%) rapidly and 337 (78%) slowly progressing patients provided ADAS-cog data after 26 weeks of open-label rivastigmine treatment. Improvements in cognitive symptoms were observed during the first 12 weeks, which were more pronounced in patients with rapid progression than in those with slow progression. Rapidly progressing patients experienced significantly greater cognitive benefits than slowly progressing patients (p=0.029), who experienced a modest decline in cognitive symptoms at the end of the study. COMMENT: Patients experiencing rapid symptom progression may receive greater benefit from rivastigmine than those with slow progression. In this study, cholinesterase inhibition appeared to be of particular utility in the management of AD patients whose symptoms were rapidly worsening. [ABSTRACT FROM AUTHOR]

Context: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD.Objective: To identify genetic risk factors for idiopathic PD.Design, Setting, and Participants: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status.Main Outcome Measures: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis.Results: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients.Conclusions: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD. [ABSTRACT FROM AUTHOR]

Context: Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined.Objective: To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia.Design, Setting, and Patients: Positron emission tomography (PET) studies of [(18)F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000.Main Outcome Measures: Regional distribution of [(18)F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses.Results: Progressive dementia was detected by PET with a sensitivity of 93% (191/206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P<.001).Conclusion: In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur. [ABSTRACT FROM AUTHOR]

Objective: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research?Participants: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy.Evidence: The expert presenters summarized data from the world scientific literature on the questions posed to the panel.Consensus Process: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached.Conclusions: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness. [ABSTRACT FROM AUTHOR]

Pieces of the Alzheimer's puzzle are falling into place as new genes are identified and markers detected. But the clinical reality of Alzheimer's disease is still tragedy and hardship for all involved. Your therapeutic role is central--and your help is vital. [ABSTRACT FROM AUTHOR]

Depression in the elderly too often goes unrecognized and untreated. Look for it in your older patients, and know that treatment can be as effective and life-enhancing for them as it is for the young. [ABSTRACT FROM AUTHOR]

The onset of Alzheimer's disease (AD) is accompanied by a complex and distributed pattern of neuroanatomic change, difficult to distinguish clinically from dynamic alterations in normal aging. Extreme variations in the sulcal patterns of the human cortex have made it difficult to identify diffuse and focal variations in cortical structure in neurodegenerative disease. We report the first comprehensive 3D statistical analysis of deep sulcal structure in vivo, in both normal aging and dementia. High-resolution 3D T[sub 1]-weighted fast SPGR (spoiled GRASS) MRI volumes were acquired from 10 patients diagnosed with AD (NINCDS-ARDRA criteria; age: 71.9 ± 10.7 years) and 10 normal subjects matched for age (72.9 ± 5.6 years), gender, educational level and handedness. Scans were digitally transformed into Talairach stereotaxic space. To determine specific patterns of cortical variation in dementia patients, 3D average and probabilistic maps of primary deep sulci were developed for both normal and AD groups. Major sulci (including supracallosal, cingulate, marginal, parieto-occipital, anterior and posterior calcarine sulci, and Sylvian fissures) were modeled as complex systems of 3D surfaces using a multi-resolution parametric mesh approach. Variations and asymmetries in their extents, curvature, area and surface complexity were evaluated. Three-dimensional maps of anatomic variability, structural asymmetry and local atrophy indicated severe regionally selective fiber loss in AD. A midsagittal area loss of 24.5% at the corpus callosums's posterior midbody (P < 0.025) matched increases in structural variability in corresponding temporo-parietal projection areas. Confidence limits on 3D cortical variation, visualized in 3D, exhibited severe increases in AD from 2 to 4 mm at the callosum to a peak SD of 19.6 mm at the posterior left Sylvian fissure. Normal Sylvian fissure asymmetries (right higher than left; P < 0.0005), mapped for the first time in thre... [ABSTRACT FROM AUTHOR]

BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) are the most common types of dementia worldwide. Galantamine, an acetylcholinesterase inhibitor and allosteric nicotinic modulator, has shown broad clinical benefits in patients with mild to moderate dementia due to AD, probable VaD, or AD with cerebrovascular disease (CVD)-so-called mixed dementia. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profiles of galantamine 24 mg/d in patients with VaD or AD with CVD over the longer term (>6 months). METHODS: This was an open-label extension of a 6-month double-blind study of galantamine. Patients who had been randomized to receive galantamine 24 mg/d or placebo in the double-blind phase were eligible to continue open-label treatment with galantamine 24 mg/d for 6 months. The primary efficacy end point was change in cognition, based on scores on the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11). Secondary measures included changes in functional ability (as measured on the Disability Assessment for Dementia [DAD]) and behavior (as measured on the Neuropsychiatric Inventory [NPI]). Safety and tolerability were also monitored. RESULTS: Four hundred fifty-nine patients (240 men, 219 women; mean [SE] age, 75.2 [0.33] years) entered the open-label phase. Of these patients, 195 (42.5%) had a diagnosis of probable VaD, and 238 (51.9%) had a diagnosis of AD with CVD; the remainder had an inconclusive diagnosis. At month 12 of the study, improvements from baseline (the start of the double-blind phase) in ADAS-cog/11 scores were observed in both the group that received placebo during the double-blind phase (placebo/galantamine group: -0.3 point; 95% CI, -1.64 to 1.06) and the group that received galantamine during the double-blind phase (galantamine/galantamine group: -0.9 point; 95% CI, -1.73 to 0.03). Improvement in functional ability was demonstrated by statistically significant mean (SE) changes from baseline in DAD score in both the placebo/galantamine group (-7.4 [1.68]; P < or = 0.001) and the galantamine/galantamine group (-3.6 [1.33]; P < or = 0.01). There was no significant change in mean (SE) NPI scores in either group (0.2 [0.98] and 0.1 [0.70], respectively). Galantamine treatment was well tolerated. CONCLUSIONS: In these patients with VaD and AD with CVD, galantamine treatment produced similar sustained benefits in terms of maintenance of or improvement in cognition (ADAS-cog/11), functional ability (DAD), and behavior (NPI) after 12 months. [ABSTRACT FROM AUTHOR]

Background: The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition.Methods: We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon4 allele and 14 were homozygous for the APOE epsilon3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later.Results: Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer's disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon4 allele than among the carriers of the APOE epsilon3 allele. During periods of recall, the carriers of the APOE epsilon4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P=0.005) than did carriers of the APOE epsilon3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory.Conclusions: Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer's disease and may predict a subsequent decline in memory. [ABSTRACT FROM AUTHOR]

As a potent and convenient genome-editing tool, Cas9 has been widely used in biomedical research and evaluated in treating human diseases. Numerous engineered variants of Cas9, dCas9 and other related prokaryotic endonucleases have been identified. However, as these bacterial enzymes are not naturally present in mammalian cells, whether and how bacterial Cas9 proteins are recognized and regulated by mammalian hosts remain poorly understood. Here, we identify Keap1 as a mammalian endogenous E3 ligase that targets Cas9/dCas9/Fanzor for ubiquitination and degradation in an 'ETGE'-like degron-dependent manner. Cas9-'ETGE'-like degron mutants evading Keap1 recognition display enhanced gene editing ability in cells. dCas9-'ETGE'-like degron mutants exert extended protein half-life and protein retention on chromatin, leading to improved CRISPRa and CRISPRi efficacy. Moreover, Cas9 binding to Keap1 also impairs Keap1 function by competing with Keap1 substrates or binding partners for Keap1 binding, while engineered Cas9 mutants show less perturbation of Keap1 biology. Thus, our study reveals a mammalian specific Cas9 regulation and provides new Cas9 designs not only with enhanced gene regulatory capacity but also with minimal effects on disrupting endogenous Keap1 signaling., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Automated detection of volatile organic compounds in the atmosphere can be achieved by applying pattern recognition analysis to passive infrared (IR) multispectral remote sensing data. However, obtaining analyte-active training data through field experiments is time-consuming and expensive. To address this issue, methodology has been developed for simulating radiance profiles acquired using a multispectral IR line-scanner mounted in a downward-looking position on a fixed-wing aircraft. The simulation strategy used Planck's radiation law and a radiometric model along with the laboratory spectrum of the target compound to compute the upwelling IR background radiance with the presence of the analyte within the instrumental field-of-view. By combining the simulated analyte-active radiances and field-collected analyte-inactive radiances, a synthetic training dataset was constructed. A backpropagation neural network was employed to build classifiers with the synthetic training dataset. Employing methanol as the target compound, the performance of the classifiers was evaluated with field-collected data from airborne surveys at two test fields., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Primary care clinicians (PCCs) are typically the first practitioners to detect cognitive impairment in their patients, including those with Alzheimer's disease or related dementias (ADRD). However, conversations around cognitive changes can be challenging for patients, family members, and clinicians to initiate, with all groups reporting barriers to open dialogue. With the expanding array of evidence-based interventions for ADRD, from multidomain care management to novel biotherapeutics for early-stage AD, incorporating conversations about brain health into routine healthcare should become a standard of care. We conducted a systematic review to identify barriers to and facilitators of brain health conversations in primary care settings., Methods: We systematically searched PubMed, Scopus, Web of Science, and the Cochrane Library for qualitative or quantitative studies conducted in the US between January 2000 and October 2022 that evaluated perceptions of cognition and provider-patient brain health conversations prior to formal screening for, or diagnosis of, mild cognitive impairment or ADRD. We assessed the quality of the included studies using the Mixed Methods Appraisal Tool., Results: In total, 5547 unique abstracts were screened and 22 articles describing 19 studies were included. The studies explored perceptions of cognition among laypersons or clinicians, or provider-patient interactions in the context of a patient's cognitive concerns. We identified 4 main themes: (1) PCCs are hesitant to discuss brain health and cognitive concerns; (2) patients are hesitant to raise cognitive concerns; (3) evidence to guide clinicians in developing treatment plans that address cognitive decline is often poorly communicated; and (4) social and cultural context influence perceptions of brain health and cognition, and therefore affect clinical engagement., Conclusions: Early conversations about brain health between PCCs and their patients are rare, and effective tools, processes, and strategies are needed to make these vital conversations routine., (© 2023. The Author(s).)

Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene MKL1 displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of MKL1 by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated TGFB1I1 as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG + cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the MKL1 gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy.

Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene MKX-AS1 and partnered sense gene MKX could impact the response of genetically varied cell lines to OXAL treatment. This study found that the expression levels of MKX-AS1 and MKX in lymphocytes (LCLs) and CRC cell lines differed between the rs11006706 genotypes, indicating that this gene pair could play a role in OXAL response. Further analysis of patient survival data from the Cancer Genome Atlas (TCGA) and other sources showed that patients with high MKX-AS1 expression status had significantly worse overall survival (HR = 3.2; 95%CI = (1.17-9); p = 0.024) compared to cases with low MKX-AS1 expression status. Alternatively, high MKX expression status had significantly better overall survival (HR = 0.22; 95%CI = (0.07-0.7); p = 0.01) compared to cases with low MKX expression status. These results suggest an association between MKX-AS1 and MKX expression status that could be useful as a prognostic marker of response to OXAL and potential patient outcomes in CRC.

Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the RYK (receptor-like kinase) gene with TMZ drug response. Functional validation of RYK using lymphocytes and glioma cell lines resulted in gene expression analysis indicating differences in expression status between genotypes of the cell lines and TMZ dose response. We conducted univariate and multivariate Cox regression analyses using publicly available TCGA and GEO datasets to investigate the impact of RYK gene expression status on glioma patient overall (OS) and progression-free survival (PFS). Our results indicated that in IDH mutant gliomas, RYK expression and tumor grade were significant predictors of survival. In IDH wildtype glioblastomas (GBM), MGMT status was the only significant predictor. Despite this result, we revealed a potential benefit of RYK expression in IDH wildtype GBM patients. We found that a combination of RYK expression and MGMT status could serve as an additional biomarker for improved survival. Overall, our findings suggest that RYK expression may serve as an important prognostic or predictor of TMZ response and survival for glioma patients.

Dementia due to Parkinson's disease and Alzheimer's disease are associated with behavioural and psychological symptoms, including psychosis. Long-term management presents a challenge for health care providers and caregivers. Symptoms of psychosis include hallucinations and delusions; if untreated, these can lead to institutionalisation, decreased quality of life, and significant patient and caregiver distress. A critical step in the effective management of dementia-related psychosis (DRP) is the identification and diagnosis of affected patients. The lack of a standardised diagnostic approach presents a barrier to treatment and there are no consensus guidelines for DRP. Furthermore, there are no approved therapies for the treatment of DRP. Antipsychotic medications are often prescribed off-label, even though some are associated with an increased risk of adverse events or mortality. We present currently available screening tools and guidelines for the diagnosis and treatment of Parkinson's disease psychosis and DRP in the context of what is needed for effective management of psychosis.KEY POINTSWe present currently available screening tools and guidelines for Parkinson's disease psychosis and dementia-related psychosis, and discuss the unmet need for simple clinical diagnostic tools and treatment guidelines.The identification of psychosis is variable across different settings and specialties, without a unified approach to screening, definition, or diagnosis.Currently used tools for defining and assessing psychosis in a research setting are usually too cumbersome for everyday clinical practice.The development of a standardised set of diagnostic criteria would provide clinicians the opportunity to improve the detection, treatment, and quality of life of patients and their caregivers.

Machine learning methods were used to develop an automated classification model for detecting gamma-ray spectra with anomalous (i.e., non-background) signatures collected during airborne surveys. Spectra were preprocessed with an altitude-based normalization procedure, followed by application of a digital filter to remove baseline and noise effects. Segments of the preprocessed spectra were then used as input patterns to piecewise linear discriminant analysis (PLDA). For use in building the classification model, a training set was constructed based on two data classes: (1) spectra containing various radioisotope signatures and (2) background spectra. Through the use of a piecewise linear discriminant based on seven separating boundaries, a general-purpose spectral anomaly detector was developed for use in the automated screening of large spectral datasets collected during airborne surveys. The intended application of the methodology is to aid first responders in locating lost or stolen radioactive sources or in managing other incidents in which radioactive material is released into the environment. In developing and testing the methodology, laboratory spectra, spectra collected during airborne surveys, and mathematically synthesized spectra were used. When applied to 17 airborne surveys in which known radioisotope sources were present, the anomaly detector was able to locate each source with high confidence. While false detections were observed at a rate of 3.7%, many of these were in the vicinity of the known source location but the radioisotope signature could not be visually observed in the spectrum. For false detections away from the source locations, elevated signatures from naturally occurring background components were typically observed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gary W. Small reports financial support was provided by Kalman & Co., Inc., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Hypothesis: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action., Key Predictions: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints)., Strategy and Key Results: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments., Interpretation: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials., (© 2022 Longeveron Inc. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Wiley Periodicals LLC.)

Introduction: Hallucinations and delusions present with psychosis are debilitating non-motor symptoms of Parkinson's disease, with a prevalence of up to 50-70% at some point during the course of the disease. Often patients and caregivers do not report the presence of hallucinations or delusions unless specifically questioned. A panel of experts in neurology and geriatric psychiatry convened to develop a simple screening tool and guidance on diagnosis and treatment of Parkinson's disease psychosis (PDP)., Methods: The working group reviewed literature for existing PDP guidelines on diagnosis and management and identified gaps in recommendations. The group discussed and developed a screening tool and treatment guidance that addressed the gaps in existing methodology based on their clinical experience., Results: The proposed screening tool consists of two parts: (1) a brief pre-visit screening portion to be completed by the patient and caregiver, and (2) a clinician portion to be completed via clinical interview of the patient and caregiver. If psychotic symptoms are present, an appropriate treatment plan is developed for PDP based on evaluation., Conclusions: This simple screening tool and treatment guidance offers a practical clinical approach for clinicians in the diagnosis and management of PDP., (© 2022. The Author(s).)

Pattern recognition methodology was developed for the automated detection of marine oil spills in passive infrared multispectral remote sensing images. The images employed in this work were collected from the Deepwater Horizon oil spill accident in 2010. The imaging instrument for data collection was a downward-looking infrared line scanner equipped with eight optical bandpass filters in the spectral range of 8-12 μm on a fixed-wing aircraft. Oil slicks may show either positive or negative thermal contrast against the surrounding sea water, depending on the sun glint conditions or the oil thickness. Classifiers were developed separately to detect oil with different contrasts by the application of backpropagation neural networks to the preprocessed radiances. Preprocessing strategies included: (1) assembly of training data through k -means clustering analysis; (2) elimination of variation in radiance magnitudes by a customized temperature correction method; (3) removal of sun glint artifacts in images by polynomial correction; and (4) extraction of the most representative features as inputs for the neural networks by a subset selection approach. The classifiers designed to detect oil with positive and negative thermal contrast relative to water achieved overall classification accuracies of 88.7 and 92.2%, respectively. Composite classification images were generated by integrating classification scores produced by the two classifiers. The prediction performance of the classification system was demonstrated through its application to images not involved during the training of the networks.

Learning Objectives: At the end of the activity, participants will be able to:Implement evidence-based methods for cognitive impairment screening in primary care. Identify correct diagnostic criteria for mild cognitive impairment (MCI) and Alzheimer disease (AD) based on current guideline recommendations. Design appropriate and effective treatment plans for patients with MCI and AD and refer to a specialist when necessary. Describe advances in testing and treatment for AD that may impact dementia care.