Elevated Amyloid-ß PET Scan and Cognitive and Functional Decline in Mild Cognitive Impairment and Dementia of Uncertain Etiology.

BACKGROUND: Elevated amyloid-ß (Aß) on positron emission tomography (PET) scan is used to aid diagnosis of Alzheimer's disease (AD), but many prior studies have focused on patients with a typical AD phenotype such as amnestic mild cognitive impairment (MCI). Little is known about whether elevated Aß on PET scan predicts rate of cognitive and functional decline among those with MCI or dementia that is clinically less typical of early AD, thus leading to etiologic uncertainty. OBJECTIVE: We aimed to investigate whether elevated Aß on PET scan predicts cognitive and functional decline over an 18-month period in those with MCI or dementia of uncertain etiology. METHODS: In 1,028 individuals with MCI or dementia of uncertain etiology, we evaluated the association between elevated Aß on PET scan and change on a telephone cognitive status measure administered to the participant and change in everyday function as reported by their care partner. RESULTS: Individuals with either MCI or dementia and elevated Aß (66.6% of the sample) showed greater cognitive decline compared to those without elevated Aß on PET scan, whose cognition was relatively stable over 18 months. Those with either MCI or dementia and elevated Aß were also reported to have greater functional decline compared to those without elevated Aß, even though the latter group showed significant care partner-reported functional decline over time. CONCLUSIONS: Elevated Aß on PET scan can be helpful in predicting rates of both cognitive and functional decline, even among cognitively impaired individuals with atypical presentations of AD.

Association between results of an amyloid PET scan and healthcare utilization in individuals with cognitive impairment.

BACKGROUND: The Imaging Dementia Evidence for Amyloid Scanning (IDEAS) study reports that amyloid PET scans help providers diagnose and manage Alzheimer's disease and related dementias (ADRD). Using CARE-IDEAS, an IDEAS supplemental study, we examined the association between amyloid PET scan result (elevated or non-elevated amyloid), patient characteristics, and participant healthcare utilization. METHODS: We linked respondents in CARE-IDEAS study to their Medicare fee-for-service records (n = 1333). We examined participants' cognitive impairment-related, outpatient, emergency department (ED), and inpatient encounters in the year before compared with the 2 years after the amyloid PET scan. RESULTS: Individuals with a non-elevated amyloid scan had more healthcare encounters throughout the overall study period than those with an elevated amyloid scan. Regardless of the amyloid scan result, cognitive impairment-related and outpatient encounters overall decreased, but ED and inpatient encounters increased in the 2 years after the scan compared with the year prior. There was minimal evidence of differences in healthcare utilization between participants with an elevated and non-elevated amyloid scan. CONCLUSIONS: There is no difference in change in healthcare utilization between people with scans showing elevated and non-elevated beta-amyloid.

Structure-activity relationship study of central pyridine-derived TYK2 JH2 inhibitors: Optimization of the PK profile through C4' and C6 variations.

Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study.

Prevalence and incidence of depressive symptoms and diagnosis of depression as associated with elevated amyloid among Medicare beneficiaries with cognitive impairment.

BACKGROUND: Depression and cognitive impairment commonly co-occur, and it has been hypothesized that the two share pathological processes. Our objective for this study was to determine the relationship between elevated ß-amyloid level and the prevalence and incidence of depressive symptoms and diagnosed depression over two years among fee-for-service Medicare beneficiaries with cognitive impairment. METHODS: We utilized data from the CARE-IDEAS cohort study (N = 2078) including two measures of depressive symptoms (PHQ-2) and administrative claims data to identify pre-scan and incident depression diagnosis in subsample of fee-for-service Medicare beneficiaries (N = 1443). We used descriptive statistics and Poisson regression models with robust covariance. RESULTS: Beneficiaries whose scan results indicated not-elevated ß-amyloid were significantly more likely to have been diagnosed with depression pre-scan (46.4 % vs. 33.1 %). There was no significant association between elevated amyloid and the incidence of depressive symptoms or diagnosed depression. LIMITATIONS: The sample was limited to Medicare beneficiaries with cognitive impairment. Race/ethnic composition and education levels were not representative of the general population and there was substantial loss to follow-up. Mixed depressive / anxious episodes were captured as diagnoses of depression, potentially overestimating depression in this population. CONCLUSIONS: There was a high prevalence and incidence of diagnosed depression in this cohort of Medicare beneficiaries, but the incidence of depressive symptoms and diagnosed depression was not associated with elevated ß-amyloid.

The Preventing Alzheimer's with Cognitive Training (PACT) randomized clinical trial.

BACKGROUND: To address the rising prevalence of Alzheimer's disease and related dementias, effective interventions that can be widely disseminated are warranted. The Preventing Alzheimer's with Cognitive Training study (PACT) investigates a commercially available computerized cognitive training program targeting improved Useful Field of View Training (UFOVT) performance. The primary goal is to test the effectiveness of UFOVT to reduce incidence of clinically defined mild cognitive impairment (MCI) or dementia with a secondary objective to examine if effects are moderated by plasma ß-amyloid level or apolipoprotein E e4 (APOE e4) allele status. METHODS/DESIGN: This multisite study utilizes a randomized, controlled experimental design with blinded assessors and investigators. Individuals who are 65 years of age and older are recruited from the community. Eligible participants who demonstrate intact cognitive status (Montreal Cognitive Assessment score > 25) are randomized and asked to complete 45 sessions of either a commercially available computerized-cognitive training program (UFOVT) or computerized games across 2.5 years. After three years, participants are screened for cognitive decline. For those demonstrating decline or who are part of a random subsample, a comprehensive neuropsychological assessment is completed. Those who perform below a pre-specified level are asked to complete a clinical evaluation, including an MRI, to ascertain clinical diagnosis of normal cognition, MCI, or dementia. Participants are asked to provide blood samples for analyses of Alzheimer's disease related biomarkers. DISCUSSION: The PACT study addresses the rapidly increasing prevalence of dementia. Computerized cognitive training may provide a non-pharmaceutical option for reducing incidence of MCI or dementia to improve public health. REGISTRATION: The PACT study is registered at http://Clinicaltrials.govNCT03848312.

Amyloid-ß PET Scan Results Disclosure and Care-Partner Emotional Well-Being Over Time.

BACKGROUND: Diagnostic tests, such as amyloid-ß positron emission tomography (PET) scans, can increase appropriate therapeutic management for the underlying causes of cognitive decline. To evaluate the full utility of this diagnostic tool, information is needed on whether results from amyloid-ß PET scans influence care-partner outcomes. OBJECTIVE: This study examines the extent to which previous disclosure of elevated amyloid (suggestive of Alzheimer's disease (AD) etiology) versus not-elevated amyloid (not suggestive of AD etiology) is associated with changes in care-partner wellbeing. METHODS: The study used data derived from a national longitudinal survey of Medicare beneficiaries (n = 921) with mild cognitive impairment (MCI) or dementia and their care-partners. Care-partner wellbeing outcomes included depressive symptoms (PHQ-8), subjective burden (4-item Zarit burden score), and a 3-item measure of loneliness. Change was measured between 4 (Time 1) and 18 (Time 2) months after receiving the scan results. Adjusted linear regression models regressed change (Time 2-Time 1) in each outcome on scan result. RESULTS: Care-partners were primarily white, non-Hispanic, college-educated, and married to the care recipient. Elevated amyloid was not associated with statistically significant Time 1 differences in outcomes or with statistically significant changes in depressive symptoms 0.22 (-0.18, 0.61), subjective burden 0.36 (-0.01, 0.73), or loneliness 0.15 (-0.01, 0.32) for care-partners from one time point to another. CONCLUSION: Given advances in AD biomarker testing, future research in more diverse samples is needed to understand the influence of scan results on care-partner wellbeing across populations.

Convolutional neural network to identify symptomatic Alzheimer's disease using multimodal retinal imaging.

BACKGROUND/AIMS: To develop a convolutional neural network (CNN) to detect symptomatic Alzheimer's disease (AD) using a combination of multimodal retinal images and patient data. METHODS: Colour maps of ganglion cell-inner plexiform layer (GC-IPL) thickness, superficial capillary plexus (SCP) optical coherence tomography angiography (OCTA) images, and ultra-widefield (UWF) colour and fundus autofluorescence (FAF) scanning laser ophthalmoscopy images were captured in individuals with AD or healthy cognition. A CNN to predict AD diagnosis was developed using multimodal retinal images, OCT and OCTA quantitative data, and patient data. RESULTS: 284 eyes of 159 subjects (222 eyes from 123 cognitively healthy subjects and 62 eyes from 36 subjects with AD) were used to develop the model. Area under the receiving operating characteristic curve (AUC) values for predicted probability of AD for the independent test set varied by input used: UWF colour AUC 0.450 (95% CI 0.282, 0.592), OCTA SCP 0.582 (95% CI 0.440, 0.724), UWF FAF 0.618 (95% CI 0.462, 0.773), GC-IPL maps 0.809 (95% CI 0.700, 0.919). A model incorporating all images, quantitative data and patient data (AUC 0.836 (CI 0.729, 0.943)) performed similarly to models only incorporating all images (AUC 0.829 (95% CI 0.719, 0.939)). GC-IPL maps, quantitative data and patient data AUC 0.841 (95% CI 0.739, 0.943). CONCLUSION: Our CNN used multimodal retinal images to successfully predict diagnosis of symptomatic AD in an independent test set. GC-IPL maps were the most useful single inputs for prediction. Models including only images performed similarly to models also including quantitative data and patient data.

Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. FINDINGS: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85-12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45-1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. INTERPRETATION: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. FUNDING: Takeda and Zinfandel.

Assessing the Retinal Microvasculature in Individuals With Early and Late-Onset Alzheimer's Disease.

BACKGROUND AND OBJECTIVE: To evaluate retinal microvascular changes in early and late-onset Alzheimer's disease (AD). PATIENTS AND METHODS: Eighty-six eyes of 50 late-onset AD participants, 27 eyes of 15 early onset AD participants, and 111 eyes of 57 cognitively normal controls were included. Optical coherence tomography angiography (OCTA) vessel density (VD) and perfusion density (PD) in Early Treatment Diabetic Retinopathy Study 3-mm and 6-mm circles and rings were assessed. RESULTS: There was decreased PD in early onset AD 3-mm circle (P = .026) and ring (P = .026) versus controls as well as in late-onset AD 3-mm circle (P = .023) and ring (P = .023) versus controls. There was decreased VD in late-onset AD 3-mm circle (P = .012) and ring (P = .006). No parameters differed between early and late-onset AD (P > .05). CONCLUSIONS: AD eyes exhibited decreased retinal microvascular density compared to controls. Retinal parameters may not differ between early onset AD and late-onset AD after adjusting for age. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:336-344.].

Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2.

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.

Association of OCT Angiography Parameters With Age in Cognitively Healthy Older Adults.

BACKGROUND AND OBJECTIVE: To evaluate the association of changes in retinal anatomy and microvasculature with age and sex in cognitively healthy older adults. PATIENTS AND METHODS: Cross-sectional study of cognitively healthy subjects aged 50 years and older who underwent optical coherence tomography angiography (OCTA) to estimate the association between age and sex with ganglion cell layer-inner plexiform layer (GC-IPL); central subfield thickness (CST); subfoveal choroidal thickness (CT); foveal avascular zone (FAZ) size; and superficial (SCP), deep (DCP), and whole capillary plexus (WCP) vessel density (VD) and perfusion density (PD) measured in the ETDRS 3-mm and 6-mm circle and rings. RESULTS: Among 141 older adults (72.9% female; median age: 69 years), 282 eyes were imaged. Females had a greater CT, GC-IPL thickness, and FAZ size and a lower CST than males. After controlling for sex, both CT (P = .001) and GC-IPL thickness (P < .001) decreased with age, whereas FAZ size and CST did not. There was a reduction in VD and PD in SCP, DCP, and WCP with age in the 3-mm circle, 3-mm ring, and 6-mm circle (all P < .05). CONCLUSIONS: There is a significant reduction in both VD and PD, as well as decreased choroidal and GC-IPL thickness associated with aging, even beyond the fifth decade, in cognitively healthy adults. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:706-714.].

Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches.

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK.

Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

Metabolic and Neurocognitive Changes Following Lifestyle Modification: Examination of Biomarkers from the ENLIGHTEN Randomized Clinical Trial.

BACKGROUND: Previous studies have demonstrated that aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet can improve neurocognition. However, the mechanisms by which lifestyle improves neurocognition have not been widely studied. We examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants from the Exercise and Nutritional Interventions for Neurocognitive Health Enhancement (ENLIGHTEN) trial. OBJECTIVE: To examine the association between changes in metabolic function and neurocognition among older adults with cognitive impairment, but without dementia (CIND) participating in a comprehensive lifestyle intervention. METHODS: ENLIGHTEN participants were randomized using a 2×2 factorial design to receive AE, DASH, both AE+DASH, or a health education control condition (HE) for six months. Metabolic biomarkers included insulin resistance (homeostatic model assessment [HOMA-IR]), leptin, and insulin-like growth factor (IGF-1); neurotrophic biomarkers included brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF); and inflammatory biomarkers included interleukin-6 (IL-6) and C-Reactive Protein (CRP). RESULTS: Participants included 132 sedentary older adults (mean age = 65 [SD = 7]) with CIND. Results demonstrated that both AE (d = 0.48, p = 0.015) and DASH improved metabolic function (d = 0.37, p = 0.039), without comparable improvements in neurotrophic or inflammatory biomarkers. Greater improvements in metabolic function, including reduced HOMA-IR (B = -2.3 [-4.3, -0.2], p = 0.033) and increased IGF-1 (B = 3.4 [1.2, 5.7], p = 0.004), associated with increases in Executive Function. CONCLUSION: Changes in neurocognition after lifestyle modification are associated with improved metabolic function.

Measurement Properties of the CAPACITY Instrument to Assess Perceived Communication With the Health Care Team Among Care Partners of Patients With Cognitive Impairment.

BACKGROUND: The CAregiver Perceptions About CommunIcaTion with Clinical Team members (CAPACITY) instrument measures how care partners perceive themselves to be supported by the patient's health care team and their experiences communicating with the team. OBJECTIVES: The objective of this study was to assess the measurement properties (ie, structural validity of the construct and internal consistency) of the CAPACITY instrument in care partners of patients with cognitive impairment, and to examine whether care partner health literacy and patient cognitive impairment are associated with a higher or lower CAPACITY score. RESEARCH DESIGN: This was a retrospective cohort study. SUBJECTS: A total of 1746 dyads of community-dwelling care partners and older adults in the United States with cognitive impairment who obtained an amyloid positron emission tomography scan. MEASURES: The CAPACITY instrument comprises 12 items that can be combined as a total score or examined as subdomain scores about communication with the team and care partner capacity-assessment by the team. The 2 covariates of primary interest in the regression model are health literacy and level of cognitive impairment of the patient (Modified Telephone Interview Cognitive Status). RESULTS: Confirmatory factor analysis showed the CAPACITY items fit the expected 2-factor structure (communication and capacity). Higher cognitive functioning of patients and higher health literacy among care partners was associated with lower communication domain scores, lower capacity domain scores, and lower overall CAPACITY scores. CONCLUSIONS: The strong psychometric validity of the CAPACITY measure indicates it could have utility in other family caregivers or care partner studies assessing the quality of interactions with clinical teams. Knowing that CAPACITY differs by care partner health literacy and patient impairment level may help health care teams employ tailored strategies to achieve high-quality care partner interactions.

Racially diverse participant registries to facilitate the recruitment of African Americans into presymptomatic Alzheimer's disease studies.

INTRODUCTION: The Alzheimer's Disease Prevention Registry (ADPR) of the Joseph and Kathleen Bryan Alzheimer's Disease Research Center at Duke University has been successful in achieving a racially diverse and "research ready" cohort of cognitively healthy volunteers. METHODS: The ADPR is based on an infrastructure that includes: (1) an administrative leadership team; (2) a coordinating center; (3) an IT management team; (4) a community engagement team; and (5) collaborations with study partners across disciplines. RESULTS: The ADPR currently has more than 4677 members, 26% of whom are African American. The ADPR has supported 21 studies including 8 biomarker studies, 7 clinical trials, 4 cognitive neuroscience studies, and 2 studies assessing novel computerized measures. DISCUSSION: We describe our experiences establishing and maintaining a diverse ADPR as well as insights on recruitment strategies to increase the representation of African Americans in Alzheimer's disease studies.

How Accurately Do Patients and Their Care Partners Report Results of Amyloid-ß PET Scans for Alzheimer's Disease Assessment?

BACKGROUND: Amyloid-ß PET scans will likely become an integral part of the diagnostic evaluation for Alzheimer's disease if Medicare approves reimbursement for the scans. However, little is known about patients' and their care partners' interpretation of scan results. OBJECTIVE: This study seeks to understand how accurately patients with mild cognitive impairment (MCI) or dementia and their care partners report results of amyloid-ß PET scans and factors related to correct reporting. METHODS: A mixed-methods approach was used to analyze survey data from 1,845 patient-care partner dyads and responses to open-ended questions about interpretation of scan results from a sub-sample of 200 dyads. RESULTS: Eighty-three percent of patients and 85% of care partners correctly reported amyloid-ß PET scan results. Patients' higher cognitive function was associated with a small but significant decrease in the predicted probability of not only patients accurately reporting scan results (ME: -0.004, 95% CI: -0.007, -0.000), but also care partners accurately reporting scan results (ME: -0.006, 95% CI: -0.007, -0.001), as well as decreased concordance between patient and care partner reports (ME: -0.004, 95% CI: -0.007, -0.001). Content analysis of open-ended responses found that participants who reported the scan results incorrectly exhibited more confusion about diagnostic terminology than those who correctly reported the scan results. CONCLUSION: Overall, patients with MCI or dementia showed high rates of accurate reporting of amyloid-ß PET scan results. However, responses to questions about the meaning of the scan results highlight the need for improved provider communication, including providing written explanations and better prognostic information.

Longer Term Effects of Diet and Exercise on Neurocognition: 1-Year Follow-up of the ENLIGHTEN Trial.

OBJECTIVES: To evaluate the longer term changes in executive functioning among participants with cardiovascular disease (CVD) risk factors and cognitive impairments with no dementia (CIND) randomized to a diet and exercise intervention. DESIGN: A 2 (Exercise) × 2 (Dietary Approaches to Stop Hypertension [DASH] eating plan) factorial randomized clinical trial. SETTING: Academic tertiary care medical center. PARTICIPANTS: Volunteer sample of 160 older sedentary adults with CIND and at least one additional CVD risk factor enrolled in the ENLIGHTEN trial between December 2011 and March 2016. INTERVENTIONS: Six months of aerobic exercise (AE), DASH diet counseling, combined AE + DASH, or health education (HE) controls. MEASUREMENTS: Neurocognitive battery recommended by the Neuropsychological Working Group for Vascular Cognitive Disorders including measures of executive function, memory, and language/verbal fluency. Secondary outcomes included the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Six-Minute Walk Distance (6MWD), and CVD risk including blood pressure, body weight, and CVD medication burden. RESULTS: Despite discontinuation of lifestyle changes, participants in the exercise groups retained better executive function 1 year post-intervention (P = .041) compared with non-exercise groups, with a similar, albeit weaker, pattern in the DASH groups (P = .054), without variation over time (P's > .867). Participants in the exercise groups also achieved greater sustained improvements in 6MWD compared with non-Exercise participants (P < .001). Participants in the DASH groups exhibited lower CVD risk relative to non-DASH participants (P = .032); no differences in CVD risk were observed for participants in the Exercise groups compared with non-Exercise groups (P = .711). In post hoc analyses, the AE + DASH group had better performance on executive functioning (P < .001) and CDR-SB (P = .011) compared with HE controls. CONCLUSION: For participants with CIND and CVD risk factors, exercise for 6 months promoted better executive functioning compared with non-exercisers through 1-year post-intervention, although its clinical significance is uncertain. J Am Geriatr Soc 68:559-568, 2020.

Correlation of OCTA and Volumetric MRI in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUD AND OBJECTIVE: To evaluate the relationship between retinal microvascular parameters on optical coherence tomography angiography (OCTA) and neurodegenerative changes assessed by measurement of brain volume on volumetric magnetic resonance imaging (MRI) in Alzheimer's disease (AD) and mild cognitive impairment (MCI). PATIENTS AND METHODS: Sixteen subjects with AD and MCI underwent OCTA imaging (3 mm × 3 mm and 6 mm × 6 mm scans) and volumetric brain MRI imaging with automated volumetric segmentation and quantification. Spearman's correlation (ρ) was performed between forebrain parenchyma, cortical gray matter, inferolateral ventricle (ILV), lateral ventricle (LV), and hippocampus (HP) MRI volumes and vessel density (VD), along with perfusion density (PD) for the 6-mm circle, 6-mm ring, 3-mm circle, and 3-mm ring Early Treatment Diabetic Retinopathy Study regions of the superficial capillary plexus. RESULTS: Thirty eyes of 16 patients (seven MCI and nine AD) with good-quality OCTA images were analyzed. ILV volume inversely correlated with the VD in the 6-mm circle (ρ = -0 .565, P = .028) and 3-mm ring (ρ = -0.569, P = .027) and PD in the 3-mm ring (ρ = -0.605, P = .0169). Forebrain, cortical gray matter, LV, and HP volumes did not significantly correlate with either VD or PD (P > .05). CONCLUSIONS: In this pilot investigation, the authors found a significant correlation between reduction in the superficial capillary plexus VD and PD on OCTA and expansion of the ILV in MCI and AD. This relationship between the retinal microvasculature and cerebral volumetric changes deserves further investigation. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:709-718.].

Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.