α-Synuclein Seed Amplification in CSF and Brain from Patients with Different Brain Distributions of Pathological α-Synuclein in the Context of Co-Pathology and Non-LBD Diagnoses.

OBJECTIVE: The purpose of this study was to determine the sensitivity and specificity of α-synuclein seed amplification assay (αSyn-SAA) in antemortem and postmortem cerebrospinal fluid (CSF) of autopsy-confirmed patients with different distributions of pathological αSyn, co-pathologies, and clinical diagnoses. METHODS: The αSyn-SAA was used to test antemortem CSF samples from 119 subjects with a variety of clinical syndromes and standardized neuropathological examinations from Oregon Health and Science University (OHSU) and University of California San Diego (UCSD; 56 additional postmortem CSF samples available). The αSyn-SAA was also applied to frontal cortex and amygdala homogenates. Sensitivity and specificity were compared across distributions of αSyn pathology. Clinical data and co-pathologies were compared across αSyn-SAA positive and negative groups. RESULTS: Fifty-three individuals without and 66 with αSyn-pathology (neocortical [n = 38], limbic [n = 7], and amygdala-predominant [n = 21]) were included. There was a sensitivity of 97.8% and specificity of 98.1% of the αSyn-SAA to identify patients with limbic/neocortical pathology from antemortem CSF. Sensitivity to detect amygdala-predominant pathology was only 14.3%. Postmortem CSF and brain tissue αSyn-SAA analyses also showed higher assay positivity in samples from limbic/neocortical cases. INTERPRETATION: CSF αSyn-SAA reliably identifies αSyn seeds in patients with diffuse αSyn pathology in the context of co-pathology and non-Lewy body disease (LBD) diagnoses. The analysis of brain homogenates suggests that pathological αSyn in the amygdala might differ from pathological αSyn in the frontal cortex. The αSyn-SAA might facilitate the differential diagnosis of dementias with mixed pathologies. ANN NEUROL 2022;92:650-662.

Remote Spectral Light Sensing in the Home Environment: Further Development of the TWLITE Study Concept.

Aging is a significant contributor to changes in sleep patterns, which has compounding consequences on cognitive health. A modifiable factor contributing to poor sleep is inadequate and/or mistimed light exposure. However, methods to reliably and continuously collect light levels long-term in the home, a necessity for informing clinical guidance, are not well established. We explored the feasibility and acceptability of remote deployment and the fidelity of long-term data collection for both light levels and sleep within participants' homes. The original TWLITE study utilized a whole-home tunable lighting system, while the current project is an observational study of the light environment already existing in the home. This was a longitudinal, observational, prospective pilot study involving light sensors remotely deployed in the homes of healthy adults (n = 16, mean age: 71.7 years, standard deviation: 5.0 years) who were co-enrolled in the existing Collaborative Aging (in Place) Research Using Technology (CART) sub-study within the Oregon Center for Aging and Technology (ORCATECH). For 12 weeks, light levels were recorded via light sensors (ActiWatch Spectrum), nightly sleep metrics were recorded via mattress-based sensors, and daily activity was recorded via wrist-based actigraphy. Feasibility and acceptability outcomes indicated that participants found the equipment easy to use and unobtrusive. This proof-of-concept, feasibility/acceptability study provides evidence that light sensors can be remotely deployed to assess relationships between light exposure and sleep among older adults, paving the way for measurement of light levels in future studies examining lighting interventions to improve sleep.

Age Predicts Older Adults' Driving Self-Regulation but Not Dangerous Driving Behaviors after Controlling for Executive Function.

OBJECTIVES: The aim of the study was to examine the unique contributions of age to objectively measure driving frequency and dangerous driving behaviors in healthy older adults after adjusting for executive function (EF). METHOD: A total of 28 community-dwelling older adults (mean age = 82.0 years, standard deviation [SD] = 7.5) without dementia who were in good physical health and enrolled in a longitudinal aging study completed several EF and clinical self-report measures at baseline. Participants subsequently had a sensor installed in their vehicle for a mean of 208 (SD = 38, range = 127-257) days. RESULTS: Participants drove for an average of 54 min per day. Mixed-effects models indicated that after controlling for EF, older age was associated with less time driving per day, decreased number of trips, and less nighttime driving. Age was not associated with hard brakes or hard accelerations. DISCUSSION: After accounting for EF, greater age is associated with higher driving self-regulation but not dangerous driving behaviors in healthy older adults. Future studies should recruit larger samples and collect sensor-measured driving data over a more extended time frame to better determine how and why these self-regulation changes take place.

Tunable White Light for Elders (TWLITE): A Protocol Demonstrating Feasibility and Acceptability for Deployment, Remote Data Collection, and Analysis of a Home-Based Lighting Intervention in Older Adults.

Sleep disturbances are common in older adults and may contribute to disease progression in certain populations (e.g., Alzheimer's disease). Light therapy is a simple and cost-effective intervention to improve sleep. Primary barriers to light therapy are: (1) poor acceptability of the use of devices, and (2) inflexibility of current devices to deliver beyond a fixed light spectrum and throughout the entirety of the day. However, dynamic, tunable lighting integrated into the native home lighting system can potentially overcome these limitations. Herein, we describe our protocol to implement a whole-home tunable lighting system installed throughout the homes of healthy older adults already enrolled in an existing study with embedded home assessment platforms (Oregon Center for Aging & Technology-ORCATECH). Within ORCATECH, continuous data on room location, activity, sleep, and general health parameters are collected at a minute-to-minute resolution over years of participation. This single-arm longitudinal protocol collected participants' light usage in addition to ORCATECH outcome measures over a several month period before and after light installation. The protocol was implemented with four subjects living in three ORCATECH homes. Technical/usability challenges and feasibility/acceptability outcomes were explored. The successful implementation of our protocol supports the feasibility of implementing and integrating tunable whole-home lighting systems into an automated home-based assessment platform for continuous data collection of outcome variables, including long-term sleep measures. Challenges and iterative approaches are discussed. This protocol will inform the implementation of future clinical intervention trials using light therapy in patients at risk for developing Alzheimer's disease and related conditions.

Subtle Changes in Medication-taking Are Associated With Incident Mild Cognitive Impairment.

INTRODUCTION: Medication-taking is a routine instrumental activity of daily living affected by mild cognitive impairment (MCI) but difficult to measure with clinical tools. This prospective longitudinal study examined in-home medication-taking and transition from normative aging to MCI. METHODS: Daily, weekly, and monthly medication-taking metrics derived from an instrumented pillbox were examined in 64 healthy cognitively intact older adults (Mage=85.5 y) followed for a mean of 2.3 years; 9 transitioned to MCI during study follow-up. RESULTS: In the time up to and after MCI diagnosis, incident MCI participants opened their pillbox later in the day (by 19 min/mo; ß=0.46, P<0.001) and had increased day-to-day variability in the first pillbox opening over time (by 4 min/mo) as compared with stable cognitively intact participants (ß=4.0, P=0.003). DISCUSSION: Individuals who transitioned to MCI opened their pillboxes later in the day and were more variable in their medication-taking habits. These differences increased in the time up to and after diagnosis of MCI. Unobtrusive medication-taking monitoring is an ecologically valid approach for identifying early activity of daily living changes that signal transition to MCI.

The Survey for Memory, Attention, and Reaction Time (SMART): Development and Validation of a Brief Web-Based Measure of Cognition for Older Adults.

INTRODUCTION: Brief, Web-based, and self-administered cognitive assessments hold promise for early detection of cognitive decline in individuals at risk for dementia. The current study describes the design, implementation, and convergent validity of a fWeb-based cognitive assessment tool, the Survey for Memory, Attention, and Reaction Time (SMART), for older adults. METHODS: A community-dwelling sample of older adults (n = 69) was included, classified as cognitively intact (n = 44) or diagnosed with mild cognitive impairment (MCI, n = 25). Participants completed the SMART at home using their computer, tablet, or other Internet-connected device. The SMART consists of 4 face-valid cognitive tasks available in the public domain assessing visual memory, attention/processing speed, and executive functioning. Participants also completed a battery of standardized neuropsychological tests, a cognitive screener, and a daily function questionnaire. Primary SMART outcome measures consisted of subtest completion time (CT); secondary meta-metrics included outcomes indirectly assessed or calculated within the SMART (e.g., click count, total CT, time to complete practice items, and time of day the test was completed). RESULTS: Regarding validity, total SMART CT, which includes time to complete test items, practice items, and directions, had the strongest relationship with global cognition (ß = -0.47, p < 0.01). Test item CT was significantly greater for the MCI group (F = 5.20, p = 0.026). Of the SMART tasks, the executive functioning subtests had the strongest relationship with cognitive status as compared to the attention/processing speed and visual memory subtests. The primary outcome measures demonstrated fair to excellent test-retest reliability (intraclass correlation coefficient = 0.50-0.76). CONCLUSIONS: This study provides preliminary evidence for the use of the SMART protocol as a feasible, reliable, and valid assessment method to monitor cognitive performance in cognitively intact and MCI older adults.

Type and frequency of social contacts associated with low mood before and during the COVID-19 pandemic in older adults: I-CONECT project.

BACKGROUND: Social isolation is a risk factor for dementia, but the underlying mechanism is not well understood. It is possible that lack of social contacts negatively affects emotional well-being, which leads to cognitive decline. To shed light on this potential mediation mechanism, we examined changes in type and frequency of social contacts and their effects on mood using data collected before and during the COVID-19 pandemic among socially isolated older adults aged 75 and older. METHOD: The data come from an ongoing randomized controlled trial, the Internet-Based Conversational Engagement Clinical Trial (I-CONECT, ClinicalTirals.gov: NCT02871921). One hundred forty-six participants (age=81.0±4.5, 71.9% women) who were in the trial both before and during the pandemic and whose data were available as of November of 2020 were included in the current analysis. Weekly health questionnaires administered on all participants regardless of treatment assignments were collected before and during the COVID-19 pandemic. Low mood ("Blueness") was self-reported as feeling downhearted or blue for three or more days in the past week (YES/NO). Social contacts were self-reported by amount of time they had interacted, with whom (family; friends; others), and via which modalities (in-person; phone/video call; text/email). RESULT: A total of 4,774 weeks of survey data were analyzed (3,047 before COVID 19). The weekly average time spent in-person, on phone/video call, and via text/email were 282, 113, and 44 minutes, respectively. During the COVID-19 pandemic, participants on average spent 82 minutes less in total social contact per week (in-person: reduced 123 minutes, video/call: increased 28 minutes, text/email: increased 13 minutes per week). Generalized estimating equation model revealed that in-person family contact was associated with less blueness regardless of the pandemic (OR=0.91, p=0.04). There was a COVID*text/email time with friends interaction (OR=0.68, p=0.03), suggesting that during the COVID-19 pandemic, an increase of 1 hour of texting/emailing with friends per week was associated with 32% decrease in experiencing blueness three or more days per week. CONCLUSION: In-person family time is beneficial for mental health. While in-person contacts become less frequent during the COVID-19 pandemic, increased text/email time with friends becomes an alternative to maintain mental health for socially isolated older adults.

Well-being in dementia: a cross-sectional dyadic study of the impact of multiple dimensions of strain on persons living with dementia and their family care partners.

ABSTRACTBackground and Purpose:The impact of dementia-related stressors and strains have been examined for their potential to threaten the well-being of either the person with dementia or the family care partner, but rarely have studies considered the dyadic nature of well-being in dementia. The purpose of this study was to examine the dyadic effects of multiple dimensions of strain on the well-being of dementia care dyads. METHODS: Using multilevel modeling to account for the inter-relatedness of individual well-being within dementia care dyads, we examined cross-sectional responses collected from 42 dyads comprised of a hospitalized patient diagnosed with a primary progressive dementia (PWD) and their family care partner (CP). Both PWDs and CPs self-reported on their own well-being using measures of quality of life (QOL-Alzheimer's Disease scale) and depressive symptoms (Center for Epidemiological Studies Depression Scale). RESULTS: In adjusted models, the PWD's well-being (higher QOL and lower depressive symptoms) was associated with significantly less strain in the dyad's relationship. The CP's well-being was associated with significantly less care-related strain and (for QOL scale) less relationship strain. CONCLUSIONS: Understanding the impact of dementia on the well-being of PWDs or CPs may require an assessment of both members of the dementia care dyad in order to gain a complete picture of how dementia-related stressors and strains impact individual well-being. These results underscore the need to assess and manage dementia-related strain as a multi-dimensional construct that may include strain related to the progression of the disease, strain from providing care, and strain on the dyad's relationship quality.

MR Imaging-based Multimodal Autoidentification of Perivascular Spaces (mMAPS): Automated Morphologic Segmentation of Enlarged Perivascular Spaces at Clinical Field Strength.

Purpose To describe a fully automated segmentation method that yields object-based morphologic estimates of enlarged perivascular spaces (ePVSs) in clinical-field-strength (3.0-T) magnetic resonance (MR) imaging data. Materials and Methods In this HIPAA-compliant study, MR imaging data were obtained with a 3.0-T MR imager in research participants without dementia (mean age, 85.3 years; range, 70.4-101.2 years) who had given written informed consent. This method is built on (a) relative normalized white matter, ventricular and cortical signal intensities within T1-weighted, fluid-attenuated inversion recovery, T2-weighted, and proton density data and (b) morphologic (width, volume, linearity) characterization of each resultant cluster. Visual rating was performed by three raters, including one neuroradiologist, after established single-section guidelines. Correlations between visual counts and automated counts, as well session-to-session correlation of counts within each participant, were assessed with the Pearson correlation coefficient r. Results There was a significant correlation between counts by visual raters and automated detection of ePVSs in the same section (r = 0.65, P < .001; r = 0.69, P < .001; and r = 0.54, P < .01 for raters 1, 2, and 3, respectively). With regard to visual ratings and whole-brain count consistency, average visual rating scores were highly correlated with automated detection of total burden volume (r = 0.58, P < .01) and total ePVS number (r = 0.76, P < .01). Morphology of clusters across 28 data sets was consistent with published radiographic estimates of ePVS; mean width of clusters segmented was 3.12 mm (range, 1.7-13.5 mm). Conclusion This MR imaging-based method for multimodal autoidentification of perivascular spaces yields individual whole-brain morphologic characterization of ePVS in clinical MR imaging data and is an important tool in the detailed assessment of these features. © RSNA, 2017 Online supplemental material is available for this article.

APOE DNA methylation is altered in Lewy body dementia.

INTRODUCTION: Inheritance of the ε4 allele of apolipoprotein E (APOE) increases a person's risk of developing both Alzheimer's disease (AD) and Lewy body dementia (LBD), yet the underlying mechanisms behind this risk are incompletely understood. The recent identification of reduced APOE DNA methylation in AD postmortem brains prompted this study to investigate APOE methylation in LBD. METHODS: Genomic DNA from postmortem brain tissues (frontal lobe and cerebellum) of neuropathological pure (np) controls and npAD, LBD + AD, and npLBD subjects were bisulfite pyrosequenced. DNA methylation levels of two APOE subregions were then compared for these groups. RESULTS: APOE DNA methylation was significantly reduced in npLBD compared with np controls, and methylation levels were lowest in the LBD + AD group. DISCUSSION: Given that npLBD and npAD postmortem brains shared a similar reduction in APOE methylation, it is possible that an aberrant epigenetic change in APOE is linked to risk for both diseases.

The ageing systemic milieu negatively regulates neurogenesis and cognitive function.

In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease.

INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD). METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with lacunes and/or large infarcts). RESULTS: The coexistence of lacunes and large infarcts results in higher likelihood of clinical diagnosis of AD only when AD pathology burden is low. DISCUSSION: Our results reinforce the diagnostic importance of AD pathology in clinical AD. Further harmonization of assessment approaches for vascular pathologies is required.

Embedded Online Questionnaire Measures Are Sensitive to Identifying Mild Cognitive Impairment.

BACKGROUND/AIMS: Early changes in cognitively demanding daily activities occur between normal cognition and the development of mild cognitive impairment (MCI). These real-world functional changes as early signals of cognitive change form a prime target for meaningful early detection of dementia. We examined whether passive aspects of responding to a remotely monitored weekly online questionnaire discriminated between older adults with and without MCI. METHODS: Participants were 83 independent, community-dwelling older adults enrolled in a longitudinal study of in-home monitoring technologies, which included completion of a short weekly online questionnaire of health and life events. RESULTS: In longitudinal analyses, time to complete the online questionnaire decreased over 1 year in both MCI and cognitively intact participants (P<0.01). MCI and intact participants did not differ in the time of day they submitted their questionnaires initially; however, over the course of 1 year MCI participants began to submit their questionnaires progressively later in the day and they needed greater assistance from staff as compared with intact participants (P<0.05). The online questionnaire performance measures were significantly correlated to conventional cognitive test scores (P<0.05) across the spectrum of normal cognition to MCI. CONCLUSIONS: Ambiently assessed, passive performance measures embedded within an online questionnaire are able to discriminate between normal cognition and MCI. Remote monitoring of cognitively demanding routine daily activities is a promising approach for ecologically valid real-world cognitive assessment.

Surgery is associated with ventricular enlargement as well as cognitive and functional decline.

INTRODUCTION: In preclinical studies, surgery/anesthesia contribute to cognitive decline and enhance neuropathologic changes underlying Alzheimer's disease (AD). Nevertheless, the link between surgery, anesthesia, apolipoprotein E ε4 (APOE ε4), and AD remains unclear. METHODS: We performed a retrospective cohort analysis of two prospective longitudinal aging studies. Mixed-effects statistical models were used to assess the relationship between surgical/anesthetic exposure, the APOE genotype, and rate of change in measures of cognition, function, and brain volumes. RESULTS: The surgical group (n = 182) experienced a more rapid rate of deterioration compared with the nonsurgical group (n = 345) in several cognitive, functional, and brain magnetic resonance imaging measures. Furthermore, there was a significant synergistic effect of anesthesia/surgery exposure and presence of the APOE ε4 allele in the decline of multiple cognitive and functional measures. DISCUSSION: These data provide insight into the role of surgical exposure as a risk factor for cognitive and functional decline in older adults.

Non-targeted lipidomics of CSF and frontal cortex grey and white matter in control, mild cognitive impairment, and Alzheimer's disease subjects.

OBJECTIVE: We undertook a non-targeted lipidomics analysis of post-mortem cerebrospinal fluid (CSF), frontal cortex grey matter, and subjacent white matter to define potential biomarkers that distinguish cognitively intact subjects from those with incipient or established dementia. Our objective was to increase our understanding of the role of brain lipids in pathophysiology of aging and age-related cognitive impairment. METHODS: Levels of 650 individual lipids, across 26 lipid subclasses, were measured utilising a high-resolution mass spectrometric analysis platform. RESULTS: Monoacylglycerols (MAG), diacylglycerols (DAG), and the very-long-chain fatty acid 26:0 were elevated in the grey matter of the mild cognitive impairment (MCI) and old dementia (OD) cohorts. Ethanolamine plasmalogens (PlsEtn) were decreased in the grey matter of the young dementia (YD) and OD cohorts while and phosphatidylethanolamines (PtdEth) were lower in the MCI, YD and OD cohorts. In the white matter, decrements in sulphatide levels were detected in the YD group, DAG levels were elevated in the MCI group, and MAG levels were increased in the YD and OD groups. CONCLUSION: The parallel changes in grey matter MAGs and DAGs in the MCI and OD groups suggest that these two cohorts may have a similar underlying pathophysiology; consistent with this, MCI subjects were more similar in age to OD than to YD subjects. While PlsEtn and phosphatidylethanolamine were decreased in the YD and OD groups they were unaltered in the MCI group indicating that alterations in plasmalogen synthesis are unlikely to represent an initiating event in the transition from MCI to dementia.

Sleep habits in mild cognitive impairment.

We explored the relationship between sleep disturbances and mild cognitive impairment (MCI) in community-dwelling seniors. Recent evidence suggests that sleep habits are differentially compromised in different subtypes of MCI, but the relationship between sleep disruption and MCI remains poorly understood. We gathered daily objective measures of sleep disturbance from 45 seniors, including 16 with MCI (mean age, 86.9±4.3 y), over a 6-month period. We also collected self-report measures of sleep disturbance. Although there were no differences between groups in any of our self-report measures, we found that amnestic MCI (aMCI) volunteers had less disturbed sleep than both nonamnestic MCI (naMCI) and cognitively intact volunteers, as measured objectively by movement in bed at night (F2,1078=4.30, P=0.05), wake after sleep onset (F2,1078=41.6, P<0.001), and number of times up at night (F2,1078=26.7, P<0.001). The groups did not differ in total sleep time. In addition, the aMCI group had less day-to-day variability in these measures than the intact and naMCI volunteers. In general, the naMCI volunteers showed a level of disturbed sleep that was intermediate to that of aMCI and intact volunteers. These differences in sleep disruption between aMCI and naMCI may be related to differences in the pathology underlying these MCI subtypes.

Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins.

A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

Biomarker progressions explain higher variability in stage-specific cognitive decline than baseline values in Alzheimer disease.

BACKGROUND: It is unknown which commonly used Alzheimer disease (AD) biomarker values-baseline or progression-best predict longitudinal cognitive decline. METHODS: 526 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI composite memory and executive scores were the primary outcomes. Individual-specific slope of the longitudinal trajectory of each biomarker was first estimated. These estimates and observed baseline biomarker values were used as predictors of cognitive declines. Variability in cognitive declines explained by baseline biomarker values was compared with variability explained by biomarker progression values. RESULTS: About 40% of variability in memory and executive function declines was explained by ventricular volume progression among mild cognitive impairment patients. A total of 84% of memory and 65% of executive function declines were explained by fluorodeoxyglucose positron emission tomography (FDG-PET) score progression and ventricular volume progression, respectively, among AD patients. CONCLUSIONS: For most biomarkers, biomarker progressions explained higher variability in cognitive decline than biomarker baseline values. This has important implications for clinical trials targeted to modify AD biomarkers.

Internet-Based Conversational Engagement Randomized Controlled Clinical Trial (I-CONECT) Among Socially Isolated Adults 75+ Years Old With Normal Cognition or Mild Cognitive Impairment: Topline Results.

BACKGROUND AND OBJECTIVES: Social isolation is a risk factor for cognitive decline and dementia. We conducted a randomized controlled clinical trial (RCT) of enhanced social interactions, hypothesizing that conversational interactions can stimulate brain functions among socially isolated older adults without dementia. We report topline results of this multisite RCT (Internet-based conversational engagement clinical trial [I-CONECT]; NCT02871921). RESEARCH DESIGN AND METHODS: The experimental group received cognitively stimulating semistructured conversations with trained interviewers via internet/webcam 4 times per week for 6 months (induction) and twice per week for an additional 6 months (maintenance). The experimental and control groups both received weekly 10 minutes telephone check-ins. Protocol modifications were required due to the coronavirus disease 2019 pandemic. RESULTS: A total of 186 participants were randomized. After the induction period, the experimental group had higher global cognitive test scores (Montreal Cognitive Assessment [primary outcome]; 1.75 points [p = .03]) compared with the control group. After induction, experimental group participants with normal cognition had higher language-based executive function (semantic fluency test [secondary outcome]; 2.56 points [p = .03]). At the end of the maintenance period, the experimental group of mild cognitive impairment subjects had higher encoding function (Craft Story immediate recall test [secondary outcome]; 2.19 points [p = .04]). Measure of emotional well-being improved in both control and experimental groups. Resting-state functional magnetic resonance imaging showed that the experimental group had increased connectivity within the dorsal attention network relative to the control group (p = .02), but the sample size was limited. DISCUSSION AND IMPLICATIONS: Providing frequent stimulating conversational interactions via the internet could be an effective home-based dementia risk-reduction strategy against social isolation and cognitive decline. CLINICAL TRIALS REGISTRATION NUMBER: NCT02871921.

Modeling of pathological traits in Alzheimer's disease based on systemic extracellular signaling proteome.

The study of chronic brain diseases including Alzheimer's disease in patients is typically limited to brain imaging or psychometric testing. Given the epidemic rise and insufficient knowledge about pathological pathways in sporadic Alzheimer's disease, new tools are required to identify the molecular changes underlying this disease. We hypothesize that levels of specific secreted cellular signaling proteins in cerebrospinal fluid or plasma correlate with pathological changes in the Alzheimer's disease brain and can thus be used to discover signaling pathways altered in the disease. Here we measured 91 proteins of this subset of the cellular communication proteome in plasma or cerebrospinal fluid in patients with Alzheimer's disease and cognitively normal controls to mathematically model disease-specific molecular traits. We found small numbers of signaling proteins that were able to model key pathological markers of Alzheimer's disease, including levels of cerebrospinal fluid ß-amyloid and tau, and classify disease in independent samples. Several of these factors had previously been implicated in Alzheimer's disease supporting the validity of our approach. Our study also points to proteins which were previously unknown to be associated with Alzheimer's disease thereby implicating novel signaling pathways in this disorder.