Elderly Controls Research Articles

Plasma transcript profiling identifies significant differentially expressed genes and expression of quantitative trait loci in African Americans

AbstractBackgroundAfrican Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being ∼2X higher in this population compared to non‐Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing primarily on the identification of genetic risk factors and novel plasma biomarkers.MethodUtilizing plasma samples from FCA3DS AD cases (n=158) and cognitively unimpaired elderly controls (n=272), we have performed differential gene expression (DEG) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom NanoString® panel that we have designed to measure transcript levels in plasma of genes relevant to AD. Transcript counts were determined using the NanoString® nCounter system, following manufacturer’s protocols. Transcript counts from 43 of the 50 customs assays passed pre‐established quality control thresholds and were utilized for the DEG and eQTL analyses. Our published FCA3DS whole exome sequence (WES) data was utilized for the eQTL analyses. Linear mixed models adjusted for relevant biological and technical covariates were implemented with the lme4 package in R software (v3.6.2) for the DEG and eQTL analyses.ResultAn association with higher plasma CLU in controls compared to AD remained significant after Bonferroni correction for the 43 transcripts tested. The eQTL analysis revealed significant association (FDR q‐value<0.05) with 105 WES variants in cis with 22 of 43 genes tested, including variants in genes previously associated with AD risk in AA. ConclusionThe results from this AA plasma eQTL analysis revealed ABCA7 variants that are significantly associated with lower plasma ABCA7 transcript levels. One of the significant plasma ABCA7 eQTLs was previously shown by our group to be associated with increased AD risk in AA, suggesting that this may be a functional eQTL underlying the risk of AD in AA. The association of higher levels of CLU transcript in plasma from controls compared to AD is in line with results published by others which showed that higher baseline concentration of clusterin protein in plasma was associated with slower rates of brain atrophy. These results support plasma transcripts as novel endophenotypes in AD biomarker studies.

Elevated CSF inflammatory markers in patients with idiopathic normal pressure hydrocephalus do not promote NKCC1 hyperactivity in rat choroid plexus

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological condition of unresolved etiology characterized by a clinical triad of symptoms; gait disturbances, urinary incontinence, and cognitive deterioration. In the present study, we aimed to elucidate the molecular coupling between inflammatory markers and development of iNPH and determine whether inflammation-induced hyperactivity of the choroidal Na+/K+/2Cl− cotransporter (NKCC1) that is involved in cerebrospinal fluid (CSF) secretion could contribute to the iNPH pathogenesis.MethodsLumbar CSF samples from 20 iNPH patients (10 with clinical improvement upon CSF shunting, 10 without clinical improvement) and 20 elderly control subjects were analyzed with the novel proximity extension assay technique for presence of 92 different inflammatory markers. RNA-sequencing was employed to delineate choroidal abundance of the receptors for the inflammatory markers found elevated in the CSF from iNPH patients. The ability of the elevated inflammatory markers to modulate choroidal NKCC1 activity was determined by addition of combinations of rat version of these in ex vivo experiments on rat choroid plexus.Results11 inflammatory markers were significantly elevated in the CSF from iNPH patients compared to elderly control subjects: CCL28, CCL23, CCL3, OPG, CXCL1, IL-18, IL-8, OSM, 4E-BP1, CXCL6, and Flt3L. One inflammatory marker, CDCP1, was significantly decreased in iNPH patients compared to control subjects. None of the inflammatory markers differed significantly when comparing iNPH patients with and without clinical improvement upon CSF shunting. All receptors for the elevated inflammatory markers were expressed in the rat and human choroid plexus, except CCR4 and CXCR1, which were absent from the rat choroid plexus. None of the elevated inflammatory markers found in the CSF from iNPH patients modulated the choroidal NKCC1 activity in ex vivo experiments on rat choroid plexus.ConclusionThe CSF from iNPH patients contains elevated levels of a subset of inflammatory markers. Although the corresponding inflammatory receptors are, in general, expressed in the choroid plexus of rats and humans, their activation did not modulate the NKCC1-mediated fraction of choroidal CSF secretion ex vivo. The molecular mechanisms underlying ventriculomegaly in iNPH, and the possible connection to inflammation, therefore remains to be elucidated.

Decrease of event related theta power is more profound in patients with Parkinson's disease dementia in comparison to Alzheimer's disease dementia

AbstractBackgroundAlzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD) are the most common types of dementia. ADD and PDD have different pathophysiology and clinical profile. It is important to understand mechanisms underlying pathophysiology, clinical symptoms, and the electrophysiological differences between these two types of dementia. Event‐related theta responses during cognitive paradimgs are one of the essential biomarkers that could succfesully show cognitive decline in dementia patients (Yener et al.,2007;Güntekin et al.,2020). The aim of the present study was to investigate the Event‐related theta responses during the visual cognitive task in patients with PDD and ADD in order to find the differentiation between these two types of dementia.MethodEEG recordings of 15 patients with ADD, 15 patients with PDD, and matched 15 healthy elderly controls (HC) were performed during the visual oddball paradigm. Event‐related phase‐locking and power analysis were performed for theta frequency band (4‐7 Hz). Repeated measures of ANOVA was used for statistical analysis (p<0.05).ResultThere were significant differences among groups for both event‐related theta phase‐locking (p=0.004) and theta power (p<0.0001). ADD (p<0.005) and PDD (p<0.005) groups had reduced theta phase‐locking in comparison to the HC group (Figure 1). Especially, this reduction was more pronounced in the PDD group. In addition, the PDD group had decreased theta power as compared to the HC (p<0.0001) and ADD (p<0.005) group (Figure 1). Figure 1 shows the grand average of event‐related theta power (upper part) and phase‐locking (lower part) and in HC, ADD and PDD groups.ConclusionThe present study showed decreased event‐related theta responses during the visual oddball paradigm in patients with dementia. Especially, PDD patients had the worst event‐related theta responses. These findings could be interpreted as the visual cognitive processes are more impaired in PDD patients compared to ADD patients.

Vividness of visual imagery questionnaire scores and their relationship to visual short-term memory performance

Mechanisms underlying visual imagery, the ability to create vivid mental representations of a scene in the absence of sensory input, remain to be fully understood. Some previous studies have proposed that visual imagery might be related to visual short-term memory (STM), with a common mechanism involving retention of visual information over short periods of time. Other observations have shown a strong relationship between visual imagery and functional activity in the hippocampus and primary visual cortex, both regions also associated with visual STM. Here we examined the relationship of visual imagery to STM and hippocampal and primary visual cortex volumes, first in a large sample of healthy people across a large age range (N = 229 behavioural data; N = 56 MRI data in older participants) and then in patients with Alzheimer's disease and Parkinson's disease (N = 19 in each group compared to 19 age-matched healthy controls).We used a variant of the “What was where?” visual object-location binding task to assess the quality of remembered information over short delays. In healthy people, no evidence of a relationship between the vividness of visual imagery and any visual STM performance parameter was found. However, there was a significant positive correlation between visual imagery and the volumes of the hippocampus and primary visual cortex. Although visual STM performance was significantly impaired in patients with Alzheimer's disease, their vividness of visual imagery scores were comparable to those of age-matched elderly controls and patients with Parkinson's disease. Despite hippocampal volumes also being reduced in Alzheimer's patients, there appeared to be no impact on their self-reported visual imagery. In conclusion, visual imagery was not significantly related to visual STM performance, either in healthy controls or Alzheimer's or Parkinson's disease but it was related to hippocampal and visual cortex volume in healthy people.

Abstract 11949: Disease-Specific and Comorbidity-Related Polygenic Risk in Spontaneous Coronary Artery Dissection

Introduction: Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute coronary syndrome that typically affects younger women (24-52 years). Several comorbidities have now been reported, including migraine, fibromuscular dysplasia (FMD), connective tissue disorders, anxiety, and depression. Associations between SCAD and other conditions, such as autoimmune disorders, have been reported but remain contentious. SCAD is known to have a genetic element: both common and rare variants have been associated with the disease and familial clustering has been identified. However, the genetic etiology is not well resolved although common variants have been identified between SCAD, FMD, and migraine. Aims: We sought to determine if there is a polygenic disease burden of common genetic variation in a cohort of sporadic SCAD cases, and shared genetics between SCAD and reported comorbidities via the application of polygenic risk scores (PRSs) for these comorbidities. Methods: A cohort of 173 sporadic European SCAD cases and 1314 European controls were genotyped (88 cases, 1127 healthy elderly controls and 76 non-SCAD cardiomyopathy-diseased patients by whole genome sequencing; 85 cases and 111 controls by Axiom UK Biobank and PMDA array, respectively). Differences in genetic risk was assessed for cases and controls using established PRS, specific to either SCAD or conditions reported to be comorbid. Results: SCAD cases showed significantly higher SCAD-PRS than did controls (WGS p = 1.372e-09; array p = 5.264e-05). In contrast, there were no differences in SCAD-PRS between non-SCAD patients and controls (WGS only: p-value = 0.291) and non-SCAD patients also had lower risk than SCAD cases (WGS only: p-value = 2.08e-07). Multiple PRS derived from comorbid disorders are currently being investigated in this cohort. Conclusions: We have shown that there is a common genetic risk element to SCAD, while genetic risk for, and, therefore, genetic overlap with, reported comorbidities in SCAD will be further discussed. These findings illustrate the role of common variants in SCAD etiology and may further contribute to our understanding of the mechanisms leading to SCAD formation.

Exploring the Serum Level of RE1 Silencing Transcription Factor in Alzheimer's Disease

Objectives The aim of this study was to evaluate the serum RE1 silencing transcription factor (REST) level in Alzheimer's disease (AD), mild cognitive impairment (MCI), and elderly controls by using surface plasmon resonance (SPR) technology. Materials and Methods In this case–control study of 133 subjects, 49 patients with AD, 49 patients with MCI, and 35 elderly controls were recruited. The REST protein concentrations were evaluated by SPR. The resonance unit for each sample was recorded and the concentration of serum REST of study group was derived from the standard curve. All the experiments were done in triplicates. Statistical analysis was done and p-value of < 0.05 was considered as statistically significant. Results A significant difference was observed in the Montreal Cognitive Assessment score, Hindi Mental State Examination scale (HMSE) score education, disease duration, and gender among the groups. A significant (p>0.0001) difference in the duration of disease between AD and MCI was observed. It was observed that the mean concentration of serum REST was not significantly (p = 0.266) different among the groups. Conclusion This study first time evaluated the serum levels of REST in AD, MCI and age-matched elderly controls. The rest levels were similar in all groups; however, it can provide a new direction to future blood-based biomarker studies of REST.

Impaired Sensorimotor Adaption in Schizophrenia in Comparison to Age-Matched and Elderly Controls

Background: The “cognitive dysmetria hypothesis” of schizophrenia proposes a disrupted communication between the cerebellum and cerebral cortex, resulting in sensorimotor and cognitive symptoms. Sensorimotor adaptation relies strongly on the function of the cerebellum. Objectives: This study investigated whether sensorimotor adaptation is reduced in schizophrenia compared with age-matched and elderly healthy controls. Methods: Twenty-nine stably treated patients with schizophrenia, 30 age-matched, and 30 elderly controls were tested in three motor adaptation tasks in which visual movement feedback was unexpectedly altered. In the “rotation adaptation task” the perturbation consisted of a rotation (30° clockwise), in the “gain adaptation task” the extent of the movement feedback was reduced (by a factor of 0.7) and in the “vertical reversal task,” up- and downward pen movements were reversed by 180°. Results: Patients with schizophrenia adapted to the perturbations, but their movement times and errors were substantially larger than controls. Unexpectedly, the magnitude of adaptation was significantly smaller in schizophrenia than elderly participants. The impairment already occurred during the first adaptation trials, pointing to a decline in explicit strategy use. Additionally, post-adaptation aftereffects provided strong evidence for impaired implicit adaptation learning. Both negative and positive schizophrenia symptom severities were correlated with indices of the amount of adaptation and its aftereffects. Conclusions: Both explicit and implicit components of sensorimotor adaptation learning were reduced in patients with schizophrenia, adding to the evidence for a role of the cerebellum in the pathophysiology of schizophrenia. Elderly individuals outperformed schizophrenia patients in the adaptation learning tasks.

A Review of Methods of Diagnosis and Complexity Analysis of Alzheimer's Disease Using EEG Signals.

This study will concentrate on recent research on EEG signals for Alzheimer's diagnosis, identifying and comparing key steps of EEG-based Alzheimer's disease (AD) detection, such as EEG signal acquisition, preprocessing function extraction, and classification methods. Furthermore, highlighting general approaches, variations, and agreement in the use of EEG identified shortcomings and guidelines for multiple experimental stages ranging from demographic characteristics to outcomes monitoring for future research. Two main targets have been defined based on the article's purpose: (1) discriminative (or detection), i.e., look for differences in EEG-based features across groups, such as MCI, moderate Alzheimer's disease, extreme Alzheimer's disease, other forms of dementia, and stable normal elderly controls; and (2) progression determination, i.e., look for correlations between EEG-based features and clinical markers linked to MCI-to-AD conversion and Alzheimer's disease intensity progression. Limitations mentioned in the reviewed papers were also gathered and explored in this study, with the goal of gaining a better understanding of the problems that need to be addressed in order to advance the use of EEG in Alzheimer's disease science.

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer’s disease patients

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition.This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25–59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively.The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).

Transcript Levels in Plasma Contribute Substantial Predictive Value as Potential Alzheimer's Disease Biomarkers in African Americans

Background: African Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. Method: Utilizing FCA 3 DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. Findings: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. ROC analysis of age, sex APOE-e4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% AUC to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-e4 dosage. Interpretation: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. Funding: National Institute on Aging, Florida Health Ed and Ethel Moore Alzheimer’s Disease grants. Declaration of Interest: None to declare. Ethical Approval: Informed consent and approval by the Mayo Clinic Institutional Review Board was obtained.

Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer's disease.

The roles of APOEε4 and APOEε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that APOE alleles differentially impact glial responses by investigating their effects on the glial transcriptome from elderly control brains with no neuritic amyloid plaques. We identified a cluster of microglial genes that are upregulated in APOEε4 and downregulated in APOEε2 carriers relative to APOEε3 homozygotes. This microglia-APOE cluster is enriched in phagocytosis-including TREM2 and TYROBP-and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in APOE knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human APOE-linked expression patterns. Thus, the APOEε4 allele might prime microglia towards a phagocytic and proinflammatory state through an APOE-TREM2-TYROBP axis in normal aging as well as in Alzheimer's disease.

Salivary Lactoferrin Expression in a Mouse Model of Alzheimer's Disease.

In the last few years, microbial infection and innate immune theories have been proposed as an alternative approach explaining the etiopathogenesis and origin of Alzheimer’s disease (AD). Lactoferrin, one of the main antimicrobial proteins in saliva, is an important modulator of immune response and inflammation, and represents an important defensive element by inducing a broad spectrum of antimicrobial effects against microbial infections. We demonstrated that lactoferrin levels in saliva are decreased in prodromal and dementia stages of AD compared with healthy subjects. That finding seems to be specific to cerebral amyloid-β (Aβ) load as such observation was not observed in healthy elderly controls or those subjects with frontotemporal dementia. In the present study, we analysed salivary lactoferrin levels in a mouse model of AD. We observed robust and early reduction of lactoferrin levels in saliva from 6- and 12-month-old APP/PS1 mice. Because saliva is secreted by salivary glands, we presume that deregulation in salivary glands resulting in reduced salivary lactoferrin levels may occur in AD. To test this hypothesis, we collected submandibular glands from APP/PS1 mice, as well as submandibular gland tissue from AD patients and we analysed the expression levels of key components of the salivary protein signalling pathway. A significant reduction in M3 receptor levels was found along with decreased acetylcholine (Ach) levels in submandibular glands from APP/PS1 mice. Similarly, a reduction in M3 receptor levels was observed in human submandibular glands from AD patients but in that case, the Ach levels were found increased. Our data suggest that the ACh-mediated M3 signalling pathway is impaired in salivary glands in AD, resulting in salivary gland dysfunction and reduced salivary lactoferrin secretion.

Multiparametric MRI for the improved diagnostic accuracy of Alzheimer's disease and mild cognitive impairment: Research protocol of a case-control study design.

BackgroundAlzheimer’s disease (AD) is a major neurocognitive disorder identified by memory loss and a significant cognitive decline based on previous level of performance in one or more cognitive domains that interferes in the independence of everyday activities. The accuracy of imaging helps to identify the neuropathological features that differentiate AD from its common precursor, mild cognitive impairment (MCI). Identification of early signs will aid in risk stratification of disease and ensures proper management is instituted to reduce the morbidity and mortality associated with AD. Magnetic resonance imaging (MRI) using structural MRI (sMRI), functional MRI (fMRI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (1H-MRS) performed alone is inadequate. Thus, the combination of multiparametric MRI is proposed to increase the accuracy of diagnosing MCI and AD when compared to elderly healthy controls.MethodsThis protocol describes a non-interventional case control study. The AD and MCI patients and the healthy elderly controls will undergo multi-parametric MRI. The protocol consists of sMRI, fMRI, DTI, and single-voxel proton MRS sequences. An eco-planar imaging (EPI) will be used to perform resting-state fMRI sequence. The structural images will be analysed using Computational Anatomy Toolbox-12, functional images will be analysed using Statistical Parametric Mapping-12, DPABI (Data Processing & Analysis for Brain Imaging), and Conn software, while DTI and 1H-MRS will be analysed using the FSL (FMRIB’s Software Library) and Tarquin respectively. Correlation of the MRI results and the data acquired from the APOE genotyping, neuropsychological evaluations (i.e. Montreal Cognitive Assessment [MoCA], and Mini–Mental State Examination [MMSE] scores) will be performed. The imaging results will also be correlated with the sociodemographic factors. The diagnosis of AD and MCI will be standardized and based on the DSM-5 criteria and the neuropsychological scores.DiscussionThe combination of sMRI, fMRI, DTI, and MRS sequences can provide information on the anatomical and functional changes in the brain such as regional grey matter volume atrophy, impaired functional connectivity among brain regions, and decreased metabolite levels specifically at the posterior cingulate cortex/precuneus. The combination of multiparametric MRI sequences can be used to stratify the management of MCI and AD patients. Accurate imaging can decide on the frequency of follow-up at memory clinics and select classifiers for machine learning that may aid in the disease identification and prognostication. Reliable and consistent quantification, using standardised protocols, are crucial to establish an optimal diagnostic capability in the early detection of Alzheimer’s disease.

Semantic Recollection in Parkinson's Disease: Functional Reconfiguration and MAPT Variants.

Decline in semantic cognition in early stages of Parkinson’s disease (PD) is a leading risk factor for future dementia, yet the underlying neural mechanisms are not understood. The present study addressed this gap by investigating the functional connectivity of regions involved in semantic recollection. We further examined whether microtubule-associated protein tau (MAPT) risk variants, which may accelerate cognitive decline, altered the strength of regional functional connections. Cognitively normal PD and healthy elder controls underwent fMRI while performing a fame-discrimination task, which activates the semantic network. Analyses focused on disturbances in fame-modulated functional connectivity in PD for regions that govern semantic recollection and interrelated processes. Group differences were found in multiple connectivity features, which were reduced into principal components that reflected the strength of fame-modulated regional couplings with other brain areas. Despite the absence of group differences in semantic cognition, two aberrant connectivity patterns were uncovered in PD. One pattern was related to a loss in frontal, parietal, and temporal connection topologies that governed semantic recollection in older controls. Another pattern was characterized by functional reconfiguration, wherein frontal, parietal, temporal and caudate couplings were strengthened with areas that were not recruited by controls. Correlations between principal component scores and cognitive measures suggested that reconfigured frontal coupling topologies in PD supported compensatory routes for accessing semantic content, whereas reconfigured parietal, temporal, and caudate connection topologies were detrimental or unrelated to cognition. Increased tau transcription diminished recruitment of compensatory frontal topologies but amplified recruitment of parietal topologies that were unfavorable for cognition. Collectively, the findings provide a new understanding of early vulnerabilities in the functional architecture of regional connectivity during semantic recollection in cognitively normal PD. The findings also have implications for tracking cognitive progression and selecting patients who stand to benefit from therapeutic interventions.

CYP3A Activity in End-of-Life Cancer Patients Measured by 4β-Hydroxycholesterol/cholesterol Ratio, in Men and Women.

Simple SummaryThe elimination of drugs by enzymes in the liver may be impaired in cancer patients that are close to death (end-of-life). This could cause unwanted side effects or lack of effect of drugs and compromise the quality of life in patients. Blood samples collected in 137 deceased end-of-life cancer patients were analyzed for the marker 4β-hydroxycholesterol/cholesterol (4β-OHC/C), representing the activity of the most important drug eliminating enzyme, CYP3A. In addition, samples from young (n = 280) and elderly (n = 30) controls were analyzed for 4β-OHC/C. The average 4β-OHC/C was higher in male and female end-of-life cancer patients than in young and elderly controls without cancer. This finding may suggest that the ability to eliminate drugs by CYP3A is maintained until end of life and that drugs metabolized by CYP3 may not need dose adjustment or discontinuation in cancer patients close to death.More than 50% of all drugs are metabolized by the cytochrome P450 3A enzyme (CYP3A). The aim of this study was to investigate if the CYP3A activity, measured by the endogenous marker 4β-hydroxycholesterol/cholesterol ratio (4β-OHC/C), is changed during the last weeks and days of life in men and women. To this end, serum samples from 137 deceased patients (median age 70 years) collected at a single time point 1–60 days before death, were analyzed and compared to 280 young (median 27 years), and 30 elderly (median age 70 years) non-cancer controls. There were no significant differences in the 4β-OHC/C ratio between men and women in end-of-life patients (p < 0.25). The median 4β-OHC/C was significantly higher in end-of-life male patients compared to both young (p < 0.0001) and elderly (p < 0.05) male controls. In a similar manner, 4β-OHC/C in end-of-life female patients was significantly higher compared to young and elderly female controls, p < 0.0001 and p < 0.001, respectively. There was no significant correlation between 4β-OHC/C and survival time. The results from this study suggest maintained CYP3A activity to the very last days of life and even a capacity of induction of the enzyme in end-of-life cancer patients.

Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer's Disease by Splicing-Based Aggregation.

TREM2 is among the most well-known Alzheimer’s disease (AD) risk genes; however, the functional roles of its AD-associated variants remain to be elucidated, and most known risk alleles are low-frequency variants whose investigation is challenging. Here, we utilized a splicing-guided aggregation method in which multiple low-frequency TREM2 variants were bundled together to investigate the functional impact of those variants on alternative splicing in AD. We analyzed whole genome sequencing (WGS) and RNA-seq data generated from cognitively normal elderly controls (CN) and AD patients in two independent cohorts, representing three regions in the frontal lobe of the human brain: the dorsolateral prefrontal cortex (CN = 213 and AD = 376), frontal pole (CN = 72 and AD = 175), and inferior frontal (CN = 63 and AD = 157). We observed an exon skipping event in the second exon of TREM2, with that exon tending to be more frequently skipped (p = 0.0012) in individuals having at least one low-frequency variant that caused loss-of-function for a splicing regulatory element. In addition, genes differentially expressed between AD patients with high vs. low skipping of the second exon (i.e., loss of a TREM2 functional domain) were significantly enriched in immune-related pathways. Our splicing-guided aggregation method thus provides new insight into the regulation of alternative splicing of the second exon of TREM2 by low-frequency variants and could be a useful tool for further exploring the potential molecular mechanisms of multiple, disease-associated, low-frequency variants.

Vibration of the Whole Foot Soles Surface Using an Inexpensive Portable Device to Investigate Age-Related Alterations of Postural Control.

Background: Standing on a foam surface is used to investigate how aging affect the ability to keep balance when somatosensory inputs from feet soles become unreliable. However, since standing on foam also affects the efficacy of postural adjustments, the respective contributions of sensory and motor components are impossible to separate. This study tested the hypothesis that these components can be untangled by comparing changes of center of pressure (CoP) parameters induced by standing on a foam pad vs. a novel vibration (VIB) platform developed by our team and targeting feet soles’ mechanoreceptors.Methods: Bipedal postural control of young (n = 20) and healthy elders (n = 20) was assessed while standing barefoot on a force platform through 3 randomized conditions: (1) Baseline (BL); (2) VIB; and (3) Foam. CoP Amplitude and Velocity in the antero-posterior/medio-lateral (AP/ML) directions and COP Surface were compared between conditions and groups.Findings: Both VIB and Foam increased CoP parameters compared to BL, but Foam had a significantly greater impact than VIB for both groups. Young and Old participants significantly differed for all three Conditions. However, when correcting for BL levels of postural performance, VIB-related increase of COP parameters was no longer different between groups, conversely to Foam.Interpretation: Although both VIB and Foam highlighted age-related differences of postural control, their combined use revealed that “motor” and “sensory” components are differently affected by aging, the latter being relatively unaltered, at least in healthy/active elders. The combined used of these methods could provide relevant knowledge to better understand and manage postural impairments in the aging population.

Gray matter asymmetry in asymptomatic carotid stenosis.

Even clinically “asymptomatic” carotid stenosis is associated with multidomain cognitive impairment, gray matter (GM) atrophy, and silent lesion. However, the links between them remain unclear. Using structural MRI data, we examined GM asymmetry index (AI) and white matter hyperintensity (WMH) in 24 patients with severe asymptomatic carotid stenosis (SACS), 24 comorbidity‐matched controls, and independent samples of 84 elderly controls and 22 young adults. As compared to controls, SACS patients showed worse verbal memories, higher WMH burden, and right‐lateralized GM in posterior middle temporal and mouth‐somatomotor regions. These clusters extended to pars triangularis, lateral temporal, and cerebellar regions, when compared with young adults. Further, a full‐path of WMH burden (X), GM volume (atrophy, M1), AI (asymmetry, M2), and neuropsychological variables (Y) through a serial mediation model was analyzed. This analysis identified that left‐dominated GM atrophy and right‐lateralized asymmetry in the posterior middle temporal cortex mediated the relationship between WMH burden and recall memory in SACS patients. These results suggest that the unbalanced hemispheric atrophy in the posterior middle temporal cortex is crucial to mediating relationship between WMH burden and verbal recall memories, which may underlie accelerated aging and cognitive deterioration in patients with SACS and other vascular cognitive impairment.

Dorsolateral prefrontal cortex excitability abnormalities in Alzheimer's Dementia: Findings from transcranial magnetic stimulation and electroencephalography study

There is some evidence of cortical hyper-excitability in Alzheimer's Dementia (AD) but its relationship with cognition is not clear. In this study, we assessed dorsolateral prefrontal cortex (DLPFC) excitability and its relationship with cognition in AD. Twenty-four participants with AD (mean [SD] age = 74.1 [7.2] years) and eleven elderly healthy controls (HC) (mean [SD] age = 68.8 [7.3] years) were recruited. Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) was used to assess cortical excitability. Cortical evoked activity (CEA) between 25 and 80 ms post-TMS stimulus was calculated as the primary measure of cortical excitability. TMS-evoked potential peak (TEP) amplitudes (P30, N45 and P60) were also calculated. Cognition was assessed using Montreal Cognitive Assessment (MoCA), Executive Interview (EXIT) and Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge (SOC). There was no difference in TMS stimulus intensity between the groups. DLPFC-CEA was higher in the AD (mean [SD] = 134.64 [90.22] μV) than the HC group (mean [SD] = 82.65 [40.28] μV; t33 = 2.357, p = 0.025). There were no differences in TEP peak amplitudes between the groups. Further, DLPFC-CEA was inversely associated with MoCA and SOC, and positively associated with EXIT scores in AD. These results suggest increased DLPFC excitability in AD, and its inverse associations with global cognition and executive function. Future studies should examine these findings in larger samples and longitudinally, and could also assess these markers of cortical excitability in relation to other established markers of AD and in response to interventions.

Abnormal microglial reactivity in gray matter of the prefrontal cortex in schizophrenia.

Microglial activation has been proposed to contribute to the pathogenesis of schizophrenia. The present study addressed the questions of whether microglial reactivity is involved in the course of schizophrenia and is associated with aging. Transmission electron microscopy and morphometry were applied to estimate microglial density and ultrastructural parameters in layer 5 of the prefrontal cortex (BA10) in postmortem 21 chronic schizophrenia and 20 healthy control cases. A significant increase in microglial density was found in the schizophrenia group (+20 %), in young group (≤50 y.o.), in shorter duration of disease (≤26 yrs.) group, in early age at onset of disease (≤ 21 y.o.) group as compared to controls (p < 0.05) and in young schizophrenia group as compared to both young and elderly (>50 y.o.) controls (p < 0.05). Volume fraction (Vv) of mitochondria was significantly lower and area of lipofuscin granules was significantly higher in young and elderly schizophrenia groups as compared to young and elderly controls. Vv of lipofuscin granules strongly positively correlated with age and duration of disease in the schizophrenia group. Vv and the number (N) of lipofuscin granules were higher in longer duration (>26 yrs.) group as compared to shorter duration group (p < 0.01). Vv and N of vacuoles were increased in longer duration group as compared to controls (p < 0.01). The study provides evidence for microgliosis associated with age, duration of disease and age at onset of disease, progressive dystrophy and accelerated aging of microglia in gray matter of the prefrontal cortex in schizophrenia.