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Many physicians report that Internet health information can affect their clinical decisions. Much of Internet geriatric health information (IGHI) is not controlled for quality, and there is no available process to assess the quality of IGHI used in clinical practice or in medical education. The objective of this project was to describe the development of an assessment process of IGHI and to report on the quality of existing IGHI through the GeriatricWeb project. The assessment was a trilevel process: identification, screening, and peer review. Medical librarians completed the identification of resources, and geriatric specialists conducted the screening and peer review. The peer-review process was accomplished using a developed tool (4 domains: credibility, accuracy, design, educational features; score 0-100, favorable assessment score > or = 75). More than 5,000 IGHI resources were identified, and 1,142 (22%) were advanced for screening. Of those, 246 (21%) were already peer reviewed, and 354 (31%) were advanced for peer review. Of those, 181 (51% or 20% of all those advanced for screening excluding those already peer reviewed) had a favorable assessment. Poor credibility and educational features contributed to this low quality. IGHI authored by national, federal, or academic organizations and targeted to higher academic levels was more likely to have a favorable assessment (P=0.01). Much publicly available IGHI is of suboptimal quality, particularly with regard to credibility and educational domains. Healthcare professionals need to be aware of how to locate high-quality IGHI and how to assess the quality of available IGHI. [ABSTRACT FROM AUTHOR]

With age our ability to maintain haemodynamic homeostasis during position changes becomes less effective. This predisposes elderly patients to significant changes in blood pressure upon standing and orthostatic hypotension (OH). The prevalence of OH varies according to the population being studied. A range of between 5% and 60% has been reported with the lower rate in elderly individuals living in the community and higher rates in those living in an institution or in the acute-care setting. Multiple factors have been linked to OH including age, bed rest, low body mass index and medications. Although antihypertensive medications can theoretically, as a group, worsen OH, the majority of cross-sectional studies have found no association. In addition, prospective randomised trials have demonstrated an improvement in postural blood pressure (PBP) changes with antihypertensive medications. When considering the individual classes, peripheral vasodilators, specifically alpha-adrenoceptor antagonists and nondihydropyridine calcium channel antagonists, can exacerbate PBP changes and lead to OH. ACE inhibitors, angiotensin-receptor antagonists and beta-adrenoceptor antagonists with intrinsic sympathomimetic activity are less likely to worsen OH. Careful management of electrolyte disturbance can decrease the risk of developing OH with diuretic use. With the aging population, this problem will be encountered by the clinicians at a much higher rate. A detailed patient history, an accurate orthostatic blood pressure measurement and careful evaluation of the autonomic nervous system can provide clinical guidance for management of OH. In hypertensive individuals with no pre-treatment OH, the use of antihypertensive medication can be safe and lead to a low risk of developing OH. In individuals with pre-treatment OH or who develop OH while on antihypertensive medications avoidance of the classes that may exacerbate OH and a judicious use of antihypertensive classes that may improve PBP changes may be safe and adequate treatment. [ABSTRACT FROM AUTHOR]

Despite the growth in the elderly population, physicians with special geriatric training and certification number only 9,000 out of 650,000 doctors in the United States. The flexibility and increasing availability of the Internet makes it an ideal avenue for addressing the educational needs of health care providers to improve the health and care of older adults. We performed an Internet search using popular search engines. This yielded between 321 and 358,000 websites about geriatrics and 164 to 175,000 about geriatric education. This paper reviews popular health and medical Web sites to determine geriatric educational content and proposes a structure for an 'ideal' geriatric Web site that would provide resources and enhance training for allied health professionals, physicians in training and community doctors in practice. We also propose a framework addressing the design and content for developing a geriatric specific website. We use this framework to propose a prototype resource on falls and gait instability. [ABSTRACT FROM AUTHOR]

Background: Although Amyloid-beta and Tau are the hallmarks of Alzheimer's Disease (AD), other protein pathways such as endothelial dysfunction may be involved and may precede cognitive symptoms. Our objective was to characterize the cerebrospinal fluid (CSF) proteomic profiles focusing on cardiometabolic-related protein pathways in individuals on the AD spectrum., Methods: We performed CSF and plasma-targeted proteomics (276 proteins) from 354 participants of the Brain Stress Hypertension and Aging Program (BSHARP), of which 8% had preclinical AD, and 24% had MCI due to AD. We instituted a bioinformatic pipeline to generate data-driven protein modules, used "Hub" and "Critical" proteins within each module to describe protein signatures for each AD stage and then assessed their associations with clinical and biological AD traits. Finally, we completed pathway enrichment analysis to get insight into pathways that might be implicated in AD pathogenesis., Results: The 276 measured proteins clustered into five modules that were associated with CSF Amyloid-β42, Tau, and pTau. (all p -value <0.05). A CSF protein AD signature was characterized by elevated levels of CSF Hepatocyte Growth Factor ( HGF ), Intercellular and Vascular Cell Adhesion Molecule 1 (ICAM-1, VCAM-1 ), Neuropilin 1 and 2 ( NRP-1 , NRP-2 ), Scavenger Receptor Class B Member 2( SCARB2 ), Plasminogen Activator, Urokinase ( PLAU ). (all <0.05) We also found a significant difference in the CSF/Plasma ratio for the proteins associated with Cognitive Status and the Tau/Aβ42 ratio (TAR) in the CSF. Pathway enrichment analysis revealed that cell adhesion and endothelial dysfunction (all p -value <0.05) were key mechanisms involved in AD pathogenesis, especially in the preclinical stage., Conclusion: Our results suggest a proteomic signature in the CSF of individuals with preclinical AD that is driven by adhesion molecules and might be implicated in the pathogenesis of AD. Future studies investigating these pathways may provide insights into novel AD biomarkers and therapeutic targets., Competing Interests: CONFLICT OF INTEREST STATEMENT: All authors reported no conflicts.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are both widely used neuroimaging techniques to study brain functional and molecular connectivity. Although whole brain resting functional MRI (fMRI) connectomes (a matrix describing the inter-regional connectivity patterns) are widely used, the integration or association of whole brain molecular connectomes with PET data are rarely done. This likely stems from the fact that PET data is typically analyzed by using a region of interest approach, while whole brain spatial networks and their connectivity (covariation) receive much less attention. As a result, to date, there have been little focus on directly comparing whole brain PET and fMRI connectomes. In this study, we present a method that uses spatially constrained independent component analysis (scICA) (utilizing fMRI components as spatial priors) to estimate corresponding (Amyloid) PET and fMRI connectomes and examine the relationship between them using datasets that include individuals with mild cognitive impairment (MCI). Our results demonstrate highly modularized PET connectome patterns that complement those identified from resting fMRI. In particular, fMRI showed strong intra-domain connectivity with interdomain anticorrelation in sensorimotor and visual domains as well as default mode network. PET amyloid data showed similar strong intra-domain effects, but showed much higher correlations within cognitive control and default mode domains, as well as anticorrelation between cerebellum and other domains. The estimated fMRI informed PET networks have similar, but not identical, network spatial patterns to the resting fMRI networks, with the fMRI informed PET networks being slightly smoother and, in some cases, showing variations in subnodes. To further compare the two modalities, we also analyzed the differences between individuals with MCI receiving medication versus a placebo. Results show both common and modality specific treatment effects on fMRI and PET connectomes. From our fMRI analysis, we observed higher connectivity differences in various regions, such as the connection between the thalamus and middle occipital gyrus, as well as the insula and right middle occipital gyrus. Meanwhile, the PET analysis revealed increased activation between the anterior cingulate cortex and the left inferior parietal lobe, along with other regions, in individuals who received medication versus placebo. In sum, our novel approach identifies corresponding whole-brain fMRI informed PET and fMRI networks and connectomes. While we observed common patterns of network connectivity, our analysis of the MCI treatment and placebo groups revealed that each modality captures modality and group specific information about brain networks, highlighting differences between the two groups in both network expression and network connectivity.

Introduction: Essential tremor (ET) is a highly prevalent neurological disease. At present, there are no clinical biomarkers. Neurofilament light (NfL) has been studied as a measure of neuronal damage in a considerable number of neurological disorders. There have been three studies of ET, and results are inconsistent., Methods: Forty ET cases were enrolled in a research study between February and November 2023 and compared to two control groups from study 1 (n = 41) and study 2 (n = 185). Total tremor score was a measure of the severity of action tremor. Blood samples were analyzed for serum NfL level on the Simoa® platform using an NF-Light™ kit as a marker of axonal injury., Results: Serum log NfL levels were higher in ET cases than controls in study 1 (p < 0.001) and study 2 (p < 0.001). In a multivariate linear regression model, ET cases (p = 0.03) and individuals of older age (p < 0.001) had higher serum log NfL levels than controls (combined in studies 1 and 2). There was no association in ET cases between serum log NfL level and total tremor score (Pearson's r = 0.08, p = 0.63)., Conclusion: This new study further validates the elevation in serum NfL levels in ET, now representing the third study to do so. In combination, the converging data suggest that there is an overall increase in serum NfL levels in ET. The demonstration of elevated serum levels of NfL in ET adds an additional piece of evidence that there is neuronal damage in ET., (© 2024 S. Karger AG, Basel.)

Background: The SARS-CoV-2 pandemic accelerated development of innovative methods for conducting research remotely via digital technologies. However, few studies have examined participant technological literacy skills or access as key social determinants of brain health in aging populations at risk of Alzheimer's disease and other dementias., Objective: To identify associations of sociodemographic and clinical characteristics, cognitive status and geolocation with digital technology access and skill within dementia research cohorts., Methods: A self-administered questionnaire surveyed digital access and literacy skills in persons enrolled across various studies conducted at Emory Goizueta Alzheimer's Disease Research Center. We investigated cognitive and sociodemographic characteristics, and neighborhood disadvantage related to these digital attributes., Results: Of 1860 participants (mean age: 65.3 years (SD:11.4)) surveyed, 71.6% were women, 87.1% Whites, 10.4% African Americans, and 46.9% had postgraduate-level education. Most participants had access to digital devices: desktop (53.7%), laptop (81.6%), tablet (71.6%), smartphone (94.6%), internet (82.0%), or videoconferencing (95.5%). Cognitively unimpaired participants had higher odds of digital access (OR:3.75; 95% CI:2.45-5.73) and skill (OR:1.22; 95% CI:1.14-1.30). Although Whites were likelier to have access (OR:1.36; 95% CI:1.01-1.82) than African Americans, no differences were found in skill between the two groups. Living in more disadvantaged neighborhoods was significantly associated with lower technology skills (OR:0.86; 95% CI:0.82-0.91)., Conclusions: Cognitive impairment, race, and neighborhood socioeconomic disadvantage are significant barriers which limit digital access and skill. Improving digital knowledge, skill-building, and geographic access may encourage research participation especially in geographically remote or disadvantaged areas and help narrow sociodemographic and racial disparities existing in dementia research., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: High-density lipoprotein cholesterol efflux function may prevent brain amyloid beta deposition and neurodegeneration. However, the relevance of this finding has not been established in the diverse middle-aged population. Methods: We examined 1826 adults (47% Black adults) who participated in the Dallas Heart Study to determine associations between high-density lipoprotein (HDL) measures and brain structure and function. White matter hyperintensities (WMH) and whole-brain grey matter volume (GMV) were measured using brain MRI, and the Montreal Cognitive Assessment (MoCA) was used to measure neurocognitive function. HDL cholesterol efflux capacity (HDL-CEC) was assessed using fluorescence-labeled cholesterol efflux from J774 macrophages, and HDL particle size measures were assessed using nuclear magnetic resonance (NMR) spectroscopy (LipoScience). Multivariable linear regressions were performed to elucidate associations between HDL-CEC and brain and cognitive phenotypes after adjustment for traditional risk factors such as age, smoking status, time spent in daily physical activity, and education level. Results: Higher HDL-CEC and small HDL particle (HDL-P) concentration were positively associated with higher GMV normalized to total cranial volume (TCV) (GMV/TCV) after adjustment for relevant risk factors (β = 0.078 [95% CI: 0.029, 0.126], p = 0.002, and β = 0.063 [95% CI: 0.014, 0.111], p = 0.012, respectively). Conversely, there were no associations between HDL measures and WMH or MoCA (all p > 0.05). Associations of HDL-CEC and small HDL-P with GMV/TCV were not modified by ApoE-ε4 status or race/ethnicity. Interpretation: Higher HDL cholesterol efflux and higher plasma concentration of small HDL-P were associated with higher GMV/TCV. Additional studies are needed to explore the potential neuroprotective functions of HDL.

Background: Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets., Methods: In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories., Results: Over a median follow-up of 5.1 years, 830 of 8111 participants (10.2%) developed MCI or PD. Participants in the highest biomarker category were at higher risk of MCI or PD compared with those in the lowest category (hazard ratio, 1.34 [95% CI, 1.00-1.56]). The effect of intensive treatment on reducing the risk of MCI or PD was greater among participants in the lowest biomarker category (hazard ratio, 0.64 [95% CI, 0.50-0.81]) than those in the intermediate (hazard ratio, 1.01 [95% CI, 0.80-1.28]) or highest categories (hazard ratio, 0.90 [95% CI, 0.72-1.13]; P interaction =0.02). The 5-year absolute risk differences in MCI or PD with intensive treatment were -2.9% (-4.4%, -1.3%), -0.2% (-3.0%, 2.6%), and -1.9% (-6.2%, 2.4%) in the lowest, intermediate, and highest biomarker categories, respectively., Conclusions: In SPRINT, the relative effect of intensive systolic blood pressure lowering on preventing cognitive impairment appears to be stronger among participants with lower compared with higher cardiac biomarker levels, though the absolute risk reductions were similar., Competing Interests: J.A. de Lemos reports grant support from Roche Diagnostics and Abbott Diagnostics, consulting fees from Ortho Clinical Diagnostics, Quidel Cardiovascular Inc, and Siemen’s Health Care Diagnostics. He has been named a co-owner on a patent awarded to the University of Maryland (US Patent Application Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.” C.M. Ballantyne reports consulting and research support from Abbott and Roche Diagnostics. J.D. Berry reports grant support from the National Institutes of Health, Roche Diagnostics, and Abbott Diagnostics, consulting fees from Roche Diagnostics, and the Cooper Institute. The other authors report no conflicts.

Competing Interests: Declaration of competing interest The authors have no competing interests to declare.

Introduction: Recent Alzheimer's disease (AD) clinical trials have used cerebrospinal fluid (CSF) biomarker levels for screening and enrollment. Preliminary evidence suggests that AD risk is related to impaired renal function. The impact of kidney function on commonly used AD biomarkers remains unknown., Methods: Participants in studies conducted at the Goizueta Alzheimer's Disease Research Center ( N  = 973) had measurements of serum creatinine and CSF AD biomarkers. General linear models and individual data were used to assess the relationships between biomarkers and eGFR., Results: Lower estimated glomerular filtration rate (eGFR) was associated with lower amyloid beta (Aβ)42/tau ratio ( p  < 0.0001) and Aβ42 ( p  = 0.002) and higher tau ( p  < 0.0001) and p-tau ( p  = 0.0002). The impact of eGFR on AD biomarker levels was more robust in individuals with cognitive impairment (all p -values were < 0.005)., Discussion: The association between eGFR and CSF AD biomarkers has a significant impact that varies by cognitive status. Future studies exploring this impact on the pathogenesis of AD and related biomarkers are needed., Highlights: There is a significant association between Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers and both estimated glomerular filtration rate (eGFR) and mild cognitive impairment (MCI).Kidney function influences CSF biomarker levels in individuals with normal cognitive function and those with MCI.The impact of kidney function on AD biomarker levels is more pronounced in individuals with cognitive impairment.The variation in CSF tau levels is independent of cardiovascular factors and is likely directly related to kidney function.Tau may have a possible role in both kidney and cognitive function., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The biology of individual lipid species and their relevance in Alzheimer's disease (AD) remains incompletely understood. We utilized non-targeted mass spectrometry to examine brain lipids variations across 316 post-mortem brains from participants in the Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) cohorts classified as either control, asymptomatic AD (AAD), or symptomatic AD (SAD) and integrated the lipidomics data with untargeted proteomic characterization on the same individuals. Lipid enrichment analysis and analysis of variance identified significantly lower abundance of lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) species in SAD than controls or AAD. Lipid-protein co-expression network analyses revealed that lipid modules consisting of LPE and LPC exhibited a significant association to protein modules associated with MAPK/metabolism, post-synaptic density, and Cell-ECM interaction pathways and were associated with better antemortem cognition and with neuropathological changes seen in AD. Particularly, LPE 22:6 [sn-1] levels are significantly decreased across AD cases (SAD) and show the most influence on protein changes compared to other lysophospholipid species. LPE 22:6 may be a lipid signature for AD and could be leveraged as potential therapeutic or dietary targets for AD., Competing Interests: Conflicts of Interest The authors declare no competing interests.

Background: Previous studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between cardiac function, brain structure, and cognitive function and even less have included diverse middle-aged populations., Objectives: The objective of this study was to determine associations between cardiac and brain structure and function in a multiethnic cohort of middle-aged adults., Methods: A cross-sectional study was conducted in participants of the Dallas Heart Study phase 2 (N = 1,919; 46% Black participants). Left ventricular (LV) mass, LV ejection fraction, LV concentricity, and peak systolic strain (LV E cc ) were assessed by cardiac magnetic resonance imaging. White matter hyperintensities (WMH) volume was measured by fluid attenuated inversion recovery magnetic resonance imaging. The Montreal Cognitive Assessment was used to measure cognitive functioning. Associations between cardiac and brain measures were determined using multivariable linear regression after adjusting for cardiovascular risk factors, education level, and physical activity., Results: LV ejection fraction was associated with total Montreal Cognitive Assessment score (β = 0.06 [95% CI: 0.003-0.12], P  = 0.042) and LV E cc was associated with WMH volume (β = 0.08 [95% CI: 0.01-0.14], P  = 0.025) in the overall cohort without significant interaction by race/ethnicity. Higher LV mass and concentricity were associated with larger WMH volume in the overall cohort (β = 0.13 [95% CI: 0.03-0.23], P  = 0.008 and 0.10 [95% CI: 0.03-0.17], P  = 0.005). These associations were more predominant in Black than White participants (β = 0.17 [95% CI: 0.04-0.30] vs β = -0.009 [95% CI: -0.16 to 0.14], P  = 0.036 and β = 0.22 [95% CI: 0.13-0.32] vs β = -0.11 [95% CI: -0.21 to -0.01], P  < 0.0001, for LV mass and concentricity, respectively)., Conclusions: Subclinical cardiac dysfunction indicated by LVEF was associated with lower cognitive function. Moreover, LV mass and concentric remodeling were associated with higher WMH burden, particularly among Black individuals., Competing Interests: The Dallas Heart Study was funded by the Donald W. Reynolds Foundation and was partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award Number UL1TR001105. Dr Vongpatanasin is supported by the 10.13039/100007914UT Southwestern O’Brien Kidney Center, the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research: R01 AG057571. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE: Subclinical cardiac dysfunction was associated with lower cognitive function. Additionally, subclinical cardiac remodeling was associated with subclinical brain injury. These findings highlight the importance of maintaining optimal cardiovascular health to aid in maintaining brain health. TRANSLATIONAL OUTLOOK: Further studies are needed to determine if strategies to maintain normal cardiac structure and function during midlife offers protection against cognitive decline in late life., (© 2024 The Authors.)

Anti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer's disease (AD). AATs target amyloid β plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals seen on magnetic resonance imaging (MRI) of the brain in patients with AD, may occur spontaneously but occur more frequently as side effects of AATs. Cerebral amyloid angiopathy (CAA) is a major risk factor for ARIA. Amyloid β plays a key role in the pathogenesis of AD and of CAA. Amyloid β accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid β accumulation in cerebral vessels leads to CAA. A better understanding of the pathophysiology of ARIA is necessary for early detection of those at highest risk. This could lead to improved risk stratification and the ultimate reduction of symptomatic ARIA. Histopathological confirmation of CAA by brain biopsy or autopsy is the gold standard but is not clinically feasible. MRI is an available in vivo tool for detecting CAA. Cerebrospinal fluid amyloid β level testing and amyloid PET imaging are available but do not offer specificity for CAA vs amyloid plaques in AD. Thus, developing and testing biomarkers as reliable and sensitive screening tools for the presence and severity of CAA is a priority to minimize ARIA complications.

Background: Subjective cognitive complaints are frequent following COVID-19 infection, but assessment of whether these complaints map onto objective cognitive findings may not be routine in busy clinical settings. Consequently, opportunities to confirm these complaints and to provide follow-up referrals and appropriate care may be missed, thereby impacting patients' functional independence and quality of life. African Americans are vulnerable to poor outcomes from COVID-19, and thus represent a minority group in whom subjective concerns are especially important to investigate. Towards this end, we examined the frequency and correlates of subjective complaints and objective screening results of African American patients referred to the Post-Acute Sequelae of SARS-CoV-2 (PASC) Clinic at Grady Memorial Hospital, a large county teaching hospital in Atlanta, Georgia., Methods: Eighty seven African American patients (mean age = 52.5, SD = 10.5, range = 30-73) were evaluated between January 28, 2021-October 14, 2021 in the Grady PASC clinic. They ranged from 1 to 17 months post positive SARS-COV-2 antigen testing. Patients were administered a subjective cognitive complaint questionnaire (PROMIS Cognitive Function Scale Short Form 8a) as well as cognitive screening measures including the Mini-Cog (3 item recall, clock) and the Digit Symbol Substitution Test (timed visuomotor sequencing). Mood was assessed via the Patient Health Questionnaire-9, and anxiety via the Generalized Anxiety Disorders Scale. Published norms were used to identify clinically elevated scores., Results: Sixty six (76%) patients denied experiencing meaningful cognitive concerns, and of these, 25 (38%) had positive cognitive screens indicating impaired performance on objective testing. Of 21 patients with subjectively elevated cognitive concerns, 17 (81%) also had positive cognitive screens. There were no significant differences in sociodemographic factors (p values = .07-.71), days post-acute positive SARS-COV-2 Antigen Test (p = .99), disease severity (p values = .67-.75), or COVID-19 comorbidity indices (medical conditions (p values = .20-.77), substance abuse (p = .79), psychiatric history (p values = .11-.99) in those with or without subjective complaints and objective cognitive findings. However, patients with subjective complaints and objective cognitive findings reported more post-COVID-19 anxiety (p = .02) and depression (p = .001)., Conclusions: Findings indicate a high concordance between subjective complaints on the PROMIS Cognitive Scale and objectively confirmed cognitive impairments in African Americans. Further, almost 40% who reported no cognitive complaints screened positive for cognitive impairment. Although depression and anxiety are associated with subjective complaints, they do not account for positive cognitive screening results, as those patients without depressive complaints also had similar rates of positive objective screens. The findings suggest that cognitive screening using assessment tools should be routinely performed in African Americans, especially those reporting cognitive symptoms on outcome scales. While future studies are needed to assess long-term outcomes, we highly recommend follow-ups in those with positive screens to characterize the specific domains that are impacted and that could affect activities of daily living and quality of life., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

Subjective cognitive complaints (SCC) in cognitively intact older adults have been investigated as a clinically important symptom that may portend the onset of a neurodegenerative disorder such as Alzheimer's disease. Few studies have concurrently incorporated demographic features, depressive symptoms, neuropsychological status, and neuroimaging correlates of SCC and evaluated whether these differ in White and African American older adults. In the current study, 131 (77 White, 54 African American) healthy participants ≥50 years old completed the Cognitive Function Instrument (CFI) to assess SCC, and they underwent objective cognitive testing, assessment of mood, and brain magnetic resonance imaging. Pearson Product Moment correlations were performed to evaluate associations of the CFI self-ratings with the above measures for the combined group and separately for White and African American participants. SCC were associated with greater depressive symptoms in both White and African American participants in adjusted models controlling for overall cognitive status, education, and hypertension. Greater white matter hyperintensities, lower cortical thickness, older age, and slower set shifting speed were associated with increased SCC in White participants. Although the correlations were not significant for African Americans, the strength of the associations were comparable to White participants. Hippocampal volume was not associated with either total SCC or items specific to memory functioning in the entire group. Longitudinal studies are needed to further evaluate the clinical significance of these associations with risk of conversion to mild cognitive impairment and dementia.

Background: The impact of COVID-19 severity on development of long-term sequelae remains unclear, and symptom courses are not well defined., Methods: This ambidirectional cohort study recruited adults with new or worsening symptoms lasting ≥3 weeks from confirmed SARS-CoV-2 infection between August 2020-December 2021. COVID-19 severity was defined as severe for those requiring hospitalization and mild for those not. Symptoms were collected using standardized questionnaires. Multivariable logistical regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between clinical variables and symptoms., Results: Of 332 participants enrolled, median age was 52 years (IQR 42-62), 233 (70%) were female, and 172 (52%) were African American. Antecedent COVID-19 was mild in 171 (52%) and severe in 161 (48%). In adjusted models relative to severe cases, mild COVID-19 was associated with greater odds of fatigue (OR:1.83, CI:1.01-3.31), subjective cognitive impairment (OR:2.76, CI:1.53-5.00), headaches (OR:2.15, CI:1.05-4.44), and dizziness (OR:2.41, CI:1.18-4.92). Remdesivir treatment was associated with less fatigue (OR:0.47, CI:0.26-0.86) and fewer participants scoring >1.5 SD on PROMIS Cognitive scales (OR:0.43, CI:0.20-0.92). Fatigue and subjective cognitive impairment prevalence was higher 3-6 months after COVID-19 and persisted (fatigue OR:3.29, CI:2.08-5.20; cognitive OR:2.62, CI:1.67-4.11). Headache was highest at 9-12 months (OR:5.80, CI:1.94-17.3)., Conclusions: Mild antecedent COVID-19 was associated with highly prevalent symptoms, and those treated with remdesivir developed less fatigue and cognitive impairment. Sequelae had a delayed peak, ranging 3-12 months post infection, and many did not improve over time, underscoring the importance of targeted preventative measures., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. F. Eun-Hyung Lee reports grants from Genetech and the Gates Foundation. She has received royalties for BLI, Inc and consulting fees from Be Bio Pharma. She received honoraria from Gerontological Advanced Practice Nurses Association and has patents for plasma cell survival media and MENSA. She is the founder of the MicroB-plex, Inc. Dr. Ignacio Sanz reports grants from GlaxoSmithKline, Bristol Myers Squibb, Exagen, and consulting fees from Pfizer, Octagon, and Bristol Myers Squibb. He serves on the DSMB for and has stock options in Kyverna. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Walker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cerebral microvascular dysfunction is commonly seen in Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Cerebrovascular reactivity (CVR) to CO 2 reflects cerebral microvascular health and may be modulated by the renin-angiotensin system (RAS). This study aimed to investigate the effects of RAS modulation on CVR in individuals with mild cognitive impairment (MCI) due to underlying vascular or AD etiologies., Methods: This study presents findings of candesartan's effects on the secondary outcomes of two double-blind randomized clinical trials of 12-month therapy of candesartan versus lisinopril in VCI (CALIBREX (Candesartan vs Lisinopril Effects on the Brain and Endothelial Function in Executive MCI)) and candesartan versus placebo in prodromal AD (Candesartan's Effects on Alzheimer's Disease and Related Biomarkers (CEDAR)). Primary outcome results of these trials have been reported in previous publications. Participants underwent identical brain blood oxygenation level dependent (BOLD)-CVR in response to a 2-min CO 2 challenge at baseline and 12 months. Regions of interest and voxel-wise CVR maps were derived from BOLD signal changes during CO 2 challenge. CVR effects were compared between candesartan and lisinopril (CALIBREX) and candesartan and placebo (CEDAR) using mixed-model repeated measures., Results: Data from 102 participants in the CALIBREX study (mean age = 65 years, 45% female, 63% African American) and 59 in the CEDAR study (mean age = 67 years, 32% female, 20% African American) were analyzed. Candesartan was associated with improved whole brain CVR compared to placebo in the CEDAR study (adjusted within-group mean difference for candesartan = 0.27 (95% confidence interval (CI) = 0.006, 0.53) vs placebo = -0.17 (95% CI = 0.42, 0.08), p-value = 0.018), and compared to lisinopril in the CALIBREX study (adjusted within-group mean difference for candesartan = 0.28 (95% CI = 0.10, 0.46) vs lisinopril = -0.08 (95% CI = -0.31, 0.14), p-value = 0.012), independent of blood pressure. In an exploratory meta-analysis of the two trials, improved CVR in the hippocampus was linked to improved attention and working memory (p = 0.044) and a trend for improved executive function (p = 0.087) with candesartan therapy., Conclusion: This study suggests that candesartan is associated with improved microvascular function in MCI, and these findings are independent of its blood pressure effect in these VCI and prodromal AD populations.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are two commonly used imaging techniques to visualize brain function. The use of inter-network covariation (a functional connectome) is a widely used approach to infer links among different brain networks. While whole brain resting fMRI connectomes are widely used, PET data has mostly been analyzed using a few regions of interest. There has been much less work estimating PET spatial networks and almost no work on their connectivity (covariation) in the context of a whole brain data-driven connectome, nor have there been direct comparisons between whole brain PET and fMRI connectomes. Here we present an approach to leverage spatially constrained ICA to compute an estimate of the PET connectome. Results reveal highly modularized connectome patterns that are complementary to that identified from resting fMRI. Similarly, we were able to identify comparable resting networks from a PiB PET scan that can be directly compared to networks in rest fMRI data and results reveal similar, but not identical, network spatial patterns, with the PET networks being slightly smoother and, in some cases, showing variations in subnodes. The resulting networks, decomposed into spatial maps and subject expressions (loading parameters) linked to resting fMRI provide a new way to evaluate the complementary information in PET and fMRI and open up new possibilities for biomarker development.Clinical Relevance-This study analyzes the whole-brain PET and fMRI connectomes, capturing the complementary information from both imaging modalities, thereby introducing a new scope for biomarker development.

Importance: Perceived stress can have long-term physiological and psychological consequences and has shown to be a modifiable risk factor for Alzheimer disease and related dementias., Objective: To investigate the association between perceived stress and cognitive impairment in a large cohort study of Black and White participants aged 45 years or older., Design, Setting, and Participants: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study is a national population-based cohort of 30 239 Black and White participants aged 45 years or older, sampled from the US population. Participants were recruited from 2003 to 2007, with ongoing annual follow-up. Data were collected by telephone, self-administered questionnaires, and an in-home examination. Statistical analysis was performed from May 2021 to March 2022., Exposures: Perceived stress was measured using the 4-item version of the Cohen Perceived Stress Scale. It was assessed at the baseline visit and during 1 follow-up visit., Main Outcomes and Measures: Cognitive function was assessed with the Six-Item Screener (SIS); participants with a score below 5 were considered to have cognitive impairment. Incident cognitive impairment was defined as a shift from intact cognition (SIS score >4) at the first assessment to impaired cognition (SIS score ≤4) at the latest available assessment., Results: The final analytical sample included 24 448 participants (14 646 women [59.9%]; median age, 64 years [range, 45-98 years]; 10 177 Black participants [41.6%] and 14 271 White participants [58.4%]). A total of 5589 participants (22.9%) reported elevated levels of stress. Elevated levels of perceived stress (dichotomized as low stress vs elevated stress) were associated with 1.37 times higher odds of poor cognition after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (adjusted odds ratio [AOR], 1.37; 95% CI, 1.22-1.53). The association of the change in the Perceived Stress Scale score with incident cognitive impairment was significant in both the unadjusted model (OR, 1.62; 95% CI, 1.46-1.80) and after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (AOR, 1.39; 95% CI, 1.22-1.58). There was no interaction with age, race, and sex., Conclusions and Relevance: This study suggests that there is an independent association between perceived stress and both prevalent and incident cognitive impairment. The findings suggest the need for regular screening and targeted interventions for stress among older adults.

Introduction: Advances in natural language processing (NLP), speech recognition, and machine learning (ML) allow the exploration of linguistic and acoustic changes previously difficult to measure. We developed processes for deriving lexical-semantic and acoustic measures as Alzheimer's disease (AD) digital voice biomarkers., Methods: We collected connected speech, neuropsychological, neuroimaging, and cerebrospinal fluid (CSF) AD biomarker data from 92 cognitively unimpaired (40 Aβ+) and 114 impaired (63 Aβ+) participants. Acoustic and lexical-semantic features were derived from audio recordings using ML approaches., Results: Lexical-semantic (area under the curve [AUC] = 0.80) and acoustic (AUC = 0.77) scores demonstrated higher diagnostic performance for detecting MCI compared to Boston Naming Test (AUC = 0.66). Only lexical-semantic scores detected amyloid-β status ( p = 0.0003). Acoustic scores associated with hippocampal volume ( p = 0.017) while lexical-semantic scores associated with CSF amyloid-β ( p = 0.007). Both measures were significantly associated with 2-year disease progression., Discussion: These preliminary findings suggest that derived digital biomarkers may identify cognitive impairment in preclinical and prodromal AD, and may predict disease progression., Highlights: This study derived lexical-semantic and acoustics features as Alzheimer's disease (AD) digital biomarkers.These features were derived from audio recordings using machine learning approaches.Voice biomarkers detected cognitive impairment and amyloid-β status in early stages of AD.Voice biomarkers may predict Alzheimer's disease progression.These markers significantly mapped to functional connectivity in AD-susceptible brain regions., Competing Interests: Ihab Hajjar, Maureen Okafor, Jinho D. Choi, Elliot Moore II, Anees Abrol, Vince Calhoun, and Felicia C. Goldstein report no conflicts. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Functional decline in Alzheimer's disease (AD) is impacted by impaired ability to integrate and modulate complex cognitive and motor abilities, commonly known as motor-cognitive integration. Impaired motor-cognitive integration occurs in the early stages of AD, prodromal AD (pAD), and may precede other symptoms. Combined motor and cognitive training have been recommended for people with pAD and need to be better researched. Our data suggest that partnered rhythmic rehabilitation (PRR) improves motor-cognitive integration in older adults with cognitive impairment. PRR is an ideal intervention to simultaneously target cardiovascular, social, and motor-cognitive domains important to AD., Objective/methods: We propose to conduct a 1-year Phase II, single-blind randomized controlled trial using PRR in 66 patients with pAD. Participants will be assigned to three months of biweekly sessions, followed by nine months of weekly sessions of PRR or group walking (WALK) with 1 : 1 allocation. Group walking in the control group will allow us to compare physical exercise alone versus the added benefit of the cognitively engaging elements of PRR., Results/conclusion: Using an intent-to-treat approach, this innovative pilot study will 1) Determine acceptability, safety, tolerability, and satisfaction with PRR; 2) Compare efficacy of PRR versus WALK for improving motor-cognitive integration and identify the most sensitive endpoint for a Phase III trial from a set of motor-cognitive, volumetric MRI, and cognitive measures. The study will additionally explore potential neural, vascular, and inflammatory mechanisms by which PRR affects pAD to derive effect size of these intermediary measures and aid us in estimating sample size for a future trial.

APOE4 is the strongest genetic risk factor for Alzheimer's disease 1-3 . However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease 4-8 . Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE 2-6 , APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Observational studies suggest that angiotensin receptor blockers in hypertensive adults are associated with lower post-mortem indicators of Alzheimer's disease pathology. Candesartan, an angiotensin receptor blocker, has a positive cognitive effect in mild cognitive impairment with hypertension. However, its safety and effects in non-hypertensive individuals with Alzheimer's disease are unclear. This is the first double-blind randomized placebo-controlled trial aimed to assess safety and effects of 1-year therapy of candesartan on biomarkers and clinical indicators of Alzheimer's disease in non-hypertensive individuals with biomarker-confirmed prodromal Alzheimer's disease. Seventy-seven non-hypertensive participants 50 years or older (mean age: 68.1 years; 62% women; 20% African American) with mild cognitive impairment and biomarker confirmed Alzheimer's disease were randomized to escalating doses of once daily oral candesartan (up to 32 mg) or matched placebo. Main outcomes included safety and tolerability of candesartan, cerebrospinal fluid biomarkers (amyloid-β42, amyloid-β40, total tau and phospho-tau). Additional exploratory outcomes included PET imaging (Pittsburgh Compound-B ( 11 C-PiB) and 18 F-flortaucipir), brain MRI (structural and connectivity measures) and cognitive functioning. Analyses used intention-to-treat approach with group comparisons of safety measures using Chi-square test, and repeated measures mixed effects models were used to assess candesartan effects on main and exploratory outcomes (ClinicalTrials.gov, NCT02646982). Candesartan was found to be safe with no significant difference in safety measures: symptoms of hypotension, renal failure or hyperkalemia. Candesartan was also found to be associated with increases in cerebrospinal fluid Aβ40 (between-group mean difference: 1211.95 pg/ml, 95% confidence interval: 313.27, 2110.63) and Aβ42 (49.51 pg/ml, 95% confidence interval: -98.05, -0.98) reflecting lower brain amyloid accumulation. Candesartan was associated with decreased 11 C-PiB in the parahippocampal region (-0.1104, 95% confidence interval: -0.19, -0.029) which remained significant after false discovery rate correction, and with an increase in functional network connectivity in the subcortical networks. Candesartan was further associated with improved executive function (Trail Making Test Part B) performance (-11.41 s, 95% confidence interval: -11.94, -10.89) and trended for an improved global cognitive functioning reflected by a composite cognitive score (0.002, 95% confidence interval: -0.0002, 0.005). We did not observe significant effects on tau levels, hippocampal volume or other cognitive measures (memory or clinical dementia rating scale-sum of boxes). In conclusion, among non-hypertensive prodromal Alzheimer's disease, candesartan is safe and likely decreases brain amyloid biomarkers, enhances subcortical brain connectivity and has favourable cognitive effects. These findings suggest that candesartan may have an important therapeutic role in Alzheimer's disease, and warrant further investigation given the lack of clear treatment options for this devastating illness., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: Differences in cerebrospinal fluid (CSF) tau Alzheimer dementia (AD) biomarkers by self-identified race have been observed in prior studies. More recently, plasma biomarkers have been gaining recognition, but whether they exhibit similar differences is unclear. Furthermore, the underlying explanation for these differences in AD biomarkers is still unexplored., Objectives: To investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences., Design, Setting, and Participants: This cross-sectional study used participant data from the Brain, Stress, Hypertension, and Aging Research Program (B-SHARP), an observational study conducted in the greater Atlanta metropolitan area. Participants were enrolled from March 1, 2016, to January 1, 2020., Main Outcomes and Measures: Main outcomes were plasma and CSF amyloid-β (Aβ) 42, Aβ40, phosphorylated tau181 (p-tau181), and neurofilament light. General linear models were used for key comparisons., Exposures: Main independent variables were self-identified race and genetic ancestry. Additional variables were cardiovascular factors, APOE4, educational attainment, Area Deprivation Index, and C-reactive protein (reflecting systemic inflammation state)., Results: This analysis included 617 participants (mean [SD] age, 66 [7.9] years; 300 [49%] African American and 317 [51%] White; 429 [70%] with mild cognitive impairment). On the basis of self-reported race, plasma levels of Aβ42 (adjusted mean difference, -1.20 pg/mL; 95% CI, -2.33 to -0.07 pg/mL), Aβ40 (adjusted mean difference, -37.78 pg/mL; 95% CI, -60.16 to -15.39 pg/mL), p-tau181 (adjusted mean difference, -4.66 pg/mL; 95% CI, -7.05 to -1.90 pg/mL), and neurofilament light (adjusted mean difference, -1.58; 95% CI, -2.83 to -0.19 pg/mL) were consistently lower in African American individuals after adjusting for demographic characteristics, educational attainment, cognition, APOE4, and cardiovascular factors. A similar pattern was observed in the CSF biomarkers except for Aβ42 and Aβ40. Although unadjusted analyses revealed an association between these biomarkers and African ancestry, these associations were not significant after adjusting for the same covariates. Differences by self-reported race were not explained by varied cardiovascular risk factors, C-reactive protein, educational attainment, or Area Deprivation Index., Conclusions and Relevance: In this cross-sectional study of plasma biomarkers by race and genetic ancestry, the results indicated that plasma p-tau181, Aβ40, and NFL were lower in African American individuals based on self-reported race but not genetic ancestry. These differences were not explained by cardiovascular risks or clinical stage differences. These racial differences should be considered in clinical interpretations and clinical trial screenings to avoid an additional increase in underrepresentation of African American individuals in AD trials.

Background: Increased arterial stiffness is associated with adverse cardiovascular outcomes. We studied the sex-specific impact of angiotensin antagonists on vascular function in hypertension with the hypothesis that their effects on arterial stiffness may be variable in men and women., Methods: In 141 hypertensive participants with mild cognitive impairment (age 65.9±7.7, 57% female), candesartan (up to 32 mg, n=77) or lisinopril (up to 40 mg, n=64) were administered to achieve blood pressure <140/90 mm Hg. Pulse wave velocity, central pulse pressure, and central augmentation index were measured using applanation tonometry (SphygmoCor, Australia). Multivariate linear regression and mixed model analyses were performed using intention-to-treat and per protocol analyses for those completing the study., Results: Blood pressure reduction was similar among candesartan and lisinopril groups. Compared with candesartan, lisinopril therapy resulted in lower pulse wave velocity (0.5±0.8 versus -0.7±0.4 m/s, respectively; P =0.003) and central pulse pressure (-1±3 versus -7±4 mm Hg; P =0.03) after 1 year. There was a significant interaction by sex whereby the improvements in pulse wave velocity and central pulse pressure with lisinopril compared with candesartan were only observed in women. In contrast, there was greater improvement in augmentation index with candesartan compared with lisinopril (-4±7% versus -1.5±8%; P =0.05), with no sex differences., Conclusions: Despite equipotent antihypertensive effects, lisinopril was more effective than candesartan at lowering arterial stiffness in women. In contrast, candesartan was more effective than lisinopril in improving pulse wave reflections in both sexes. These findings demonstrate differential sex-specific effects of renin-angiotensin system antagonists on arterial function in hypertension that may contribute to long-term cardiovascular and neurocognitive outcomes in this population.