APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

Retinal perfusion is linked to cognition and brain MRI biomarkers in Black Americans.

INTRODUCTION: We investigated whether retinal capillary perfusion is a biomarker of cerebral small vessel disease and impaired cognition among Black Americans, an understudied group at higher risk for dementia. METHODS: We enrolled 96 Black Americans without known cognitive impairment. Four retinal perfusion measures were derived using optical coherence tomography angiography. Neurocognitive assessment and brain magnetic resonance imaging (MRI) were performed. Multiple linear regression analyses were performed. RESULTS: Lower retinal capillary perfusion was correlated with worse Oral Symbol Digit Test (P < = 0.005) and Fluid Cognition Composite scores (P < = 0.02), but not with the Crystallized Cognition Composite score (P > = 0.41). Lower retinal perfusion was also correlated with higher free water and peak width of skeletonized mean diffusivity, and lower fractional anisotropy (all P < 0.05) on MRI (N = 35). DISCUSSION: Lower retinal capillary perfusion is associated with worse information processing, fluid cognition, and MRI biomarkers of cerebral small vessel disease, but is not related to crystallized cognition.

MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.

Mapping water exchange across the blood-brain barrier using 3D diffusion-prepared arterial spin labeled perfusion MRI.

PURPOSE: To present a novel MR pulse sequence and modeling algorithm to quantify the water exchange rate (kw ) across the blood-brain barrier (BBB) without contrast, and to evaluate its clinical utility in a cohort of elderly subjects at risk of cerebral small vessel disease (SVD). METHODS: A diffusion preparation module with spoiling of non-Carr-Purcell-Meiboom-Gill signals was integrated with pseudo-continuous arterial spin labeling (pCASL) and 3D gradient and spin echo (GRASE) readout. The tissue/capillary fraction of the arterial spin labeling (ASL) signal was separated by appropriate diffusion weighting (b = 50 s/mm2 ). kw was quantified using a single-pass approximation (SPA) model with total generalized variation (TGV) regularization. Nineteen elderly subjects were recruited and underwent 2 MRIs to evaluate the reproducibility of the proposed technique. Correlation analysis was performed between kw and vascular risk factors, Clinical Dementia Rating (CDR) scale, neurocognitive assessments, and white matter hyperintensity (WMH). RESULTS: The capillary/tissue fraction of ASL signal can be reliably differentiated with the diffusion weighting of b = 50 s/mm2 , given ~100-fold difference between the (pseudo-)diffusion coefficients of the 2 compartments. Good reproducibility of kw measurements (intraclass correlation coefficient = 0.75) was achieved. Average kw was 105.0 ± 20.6, 109.6 ± 18.9, and 94.1 ± 19.6 min-1 for whole brain, gray and white matter. kw was increased by 28.2%/19.5% in subjects with diabetes/hypercholesterolemia. Significant correlations between kw and vascular risk factors, CDR, executive/memory function, and the Fazekas scale of WMH were observed. CONCLUSION: A diffusion prepared 3D GRASE pCASL sequence with TGV regularized SPA modeling was proposed to measure BBB water permeability noninvasively with good reproducibility. kw may serve as an imaging marker of cerebral SVD and associated cognitive impairment.

Undetectable gadolinium brain retention in individuals with an age-dependent blood-brain barrier breakdown in the hippocampus and mild cognitive impairment.

INTRODUCTION: Blood-brain barrier (BBB) breakdown is an early independent biomarker of human cognitive dysfunction, as found using gadolinium (Gd) as a contrast agent. Whether Gd accumulates in brains of individuals with an age-dependent BBB breakdown and/or mild cognitive impairment remains unclear. METHODS: We analyzed T1-weighted magnetic resonance imaging (MRI) scans from 52 older participants with BBB breakdown in the hippocampus 19-28 months after either cyclic or linear Gd agent. RESULTS: There was no change in T1-weighted signal intensity between the baseline contrast MRI and unenhanced MRI on re-examination in any of the studied 10 brain regions with either Gd agent suggesting undetectable Gd brain retention. DISCUSSION: Gd does not accumulate in brains of older individuals with a BBB breakdown in the hippocampus. Thus, Gd agents can be used without risk of brain retention within a ∼2-year follow-up to study BBB in the aging human brain in relation to cognition and/or other pathologies.

Body image predicts quality of life in men with prostate cancer.

OBJECTIVE: Most men diagnosed with prostate cancer in the USA will survive. Of the many aspects of survivorship affected by prostate cancer, body image receives limited attention despite some indication that it may be important to men with the disease. The present study investigated how body image changes over time and the relations between changes in body image and quality of life (QOL) in men with prostate cancer. METHODS: In a longitudinal design, patients (N = 74) completed questionnaires before treatment (T1) and at 1 month (T2) and 2 years (T3) following treatment completion. RESULTS: Growth curve modeling indicated that there was no significant change over time in group-level body image scores. However, hormone treatment was associated with a negative trajectory of change over 2 years. Also, analysis of individual difference scores indicated that ≥50% of patients demonstrated change of at least 0.5 standard deviation between time points. Hierarchical regression indicated that change in body image between T1 and T2 was significantly associated with change in QOL between T1 and T3, while controlling for demographic variables, treatment, treatment-related functioning, and general and treatment-specific positive expectations. In predicting change in body image between T1 and T2, treatment-specific positive expectation was the only significant predictor. CONCLUSIONS: The present study demonstrates that body image is an important component of the prostate cancer experience. Findings suggest that body image has a meaningful association with QOL among prostate cancer survivors.

Emotion regulation expectancies and smoking cessation factors: A daily diary study of California adults who smoke cigarettes during a practice quit attempt.

SIGNIFICANCE: Cross-sectional studies have shown that greater cigarette smoking-related emotion regulation expectancies were associated with retrospectively reported withdrawal during prior quit attempts and greater barriers to cessation. Few studies have investigated the relationship of within-person daily emotion regulation expectancies to factors related to initiating and maintaining a brief quit attempt. METHODS: People living in California who smoked cigarettes daily (n = 220, 50 % female; 48.5 % white, 14.6 % Hispanic, 16.7 % Black or African American, 9.6 % Asian, 7.6 % Multi-race, 3.0 % other race; mean age=43.71 years old) completed a practice quit attempt and 28-days of daily diary surveys. In the morning, participants reported non-smoking and smoking emotion regulation expectancies based on the Affective Processing Questionnaire, daily abstinence plan, abstinence self-efficacy, and cigarettes smoked. Successful abstinence plans were calculated as days with an abstinence plan and no cigarettes smoked. Multilevel models investigated whether within-person emotion regulation expectancies were associated with abstinence plan, self-efficacy, and successful abstinence plan. RESULTS: Greater within-person non-smoking emotion regulation expectancies were associated with increased odds of having an abstinence plan, higher self-efficacy, and a successful abstinence plan on a given day (ps < .05). Greater within-person smoking emotion regulation expectancies were associated with lower odds of having an abstinence plan and lower self-efficacy (ps < .001) but did not significantly associate with a successful abstinence plan. CONCLUSIONS: These findings show that within-person levels of expectations in emotion regulation abilities may contribute to factors relevant to initiating and achieving daily abstinence during a practice attempt.

Use of the Spanish English Neuropsychological Assessment Scale in older adult Latines and those at risk for autosomal dominant Alzheimer's disease.

OBJECTIVE: The Spanish English Neuropsychological Assessment Scale (SENAS) is a cognitive battery with English and Spanish versions for use with persons for whom either language is predominant. Few studies have examined its utility outside the normative sample. The current study examined SENAS performance in samples of older adult Latines and Latines with or at risk for autosomal dominant Alzheimer's disease (ADAD) mutations. METHOD: The SENAS was administered to 202 older adults from the Los Angeles Latino Eye Study (LALES) and 29 adults with (carriers) or without (non-carriers) mutations causing ADAD. We examined associations between SENAS, age, education, and language (LALES) and between SENAS, estimated years from familial age of dementia diagnosis, education, language, and acculturation (ADAD). Partial correlations were used to examine differences in correlational strength between estimated years from familial age of dementia diagnosis and SENAS scores among ADAD carriers compared to chronological age and SENAS in the LALES sample. Exploratory t-tests were performed to examine SENAS performance differences between ADAD carriers and non-carriers. RESULTS: In an older adult sample (LALES), increased age correlated with worse verbal delayed recall; English fluency and higher education correlated with better naming and visuospatial subtest performance. Among ADAD carriers, verbal and nonverbal delayed recall and object naming subtest performance worsened as they approached their familial age of dementia diagnosis. English fluency and higher U.S.-acculturation were related to better SENAS performance among carriers and non-carriers. Tests of verbal delayed recall and object naming best distinguished ADAD carriers from their familial non-carrier counterparts. CONCLUSIONS: Verbal delayed recall and object naming measures appear to be most sensitive to age-related changes in older adult samples and mutation-related changes in distinguishing ADAD carriers from non-carriers. Future research should examine the sensitivity of SENAS in other samples, such as larger samples of symptomatic ADAD carriers and other AD subtypes.

Characterization of spastic paraplegia in a family with a novel PSEN1 mutation.

Spastic paraparesis has been described to occur in 13.7% of PSEN1 mutations and can be the presenting feature in 7.5%. In this paper, we describe a family with a particularly young onset of spastic paraparesis due to a novel mutation in PSEN1 (F388S). Three affected brothers underwent comprehensive imaging protocols, two underwent ophthalmological evaluations and one underwent neuropathological examination after his death at age 29. Age of onset was consistently at age 23 with spastic paraparesis, dysarthria and bradyphrenia. Pseudobulbar affect followed with progressive gait problems leading to loss of ambulation in the late 20s. Cerebrospinal fluid levels of amyloid-ß, tau and phosphorylated tau and florbetaben PET were consistent with Alzheimer's disease. Flortaucipir PET showed an uptake pattern atypical for Alzheimer's disease, with disproportionate signal in posterior brain areas. Diffusion tensor imaging showed decreased mean diffusivity in widespread areas of white matter but particularly in areas underlying the peri-Rolandic cortex and in the corticospinal tracts. These changes were more severe than those found in carriers of another PSEN1 mutation, which can cause spastic paraparesis at a later age (A431E), which were in turn more severe than among persons carrying autosomal dominant Alzheimer's disease mutations not causing spastic paraparesis. Neuropathological examination confirmed the presence of cotton wool plaques previously described in association with spastic parapresis and pallor and microgliosis in the corticospinal tract with severe amyloid-ß pathology in motor cortex but without unequivocal disproportionate neuronal loss or tau pathology. In vitro modelling of the effects of the mutation demonstrated increased production of longer length amyloid-ß peptides relative to shorter that predicted the young age of onset. In this paper, we provide imaging and neuropathological characterization of an extreme form of spastic paraparesis occurring in association with autosomal dominant Alzheimer's disease, demonstrating robust diffusion and pathological abnormalities in white matter. That the amyloid-ß profiles produced predicted the young age of onset suggests an amyloid-driven aetiology though the link between this and the white matter pathology remains undefined.

Affect and subjective cognitive functioning by depression symptom levels during naturalistic cigarette smoking in premenopausal females who smoke daily.

Objective: High negative affect, low positive affect, and low cognitive functioning are depression-related states that may be particularly relevant to females who smoke cigarettes and may be more prominent following overnight tobacco abstinence. This study aimed to assess relations between depression symptom levels and negative affect, positive affect, and subjective cognitive functioning in premenopausal females who smoke. Methods: Premenopausal females who smoke daily with low (n = 66) or elevated (n = 33) baseline depression symptoms completed subjective ratings of negative affect, positive affect, and cognitive functioning pre-first cigarette (i.e., after overnight tobacco abstinence) and at random prompts throughout the day via ecological momentary assessment (EMA) for 35 days. Results: Participants with elevated depression symptoms reported overall higher negative affect (p = .01). Positive affect was significantly lower prior to the first cigarette of the day (p < .001), but did not significantly differ between depression symptom groups. Subjective cognitive functioning was significantly lower pre-first cigarette of the day (p < .001). There was a significant Depression Symptom × Prompt Type interaction for subjective cognitive functioning (p = .01). Subjective cognitive functioning did not significantly differ by depression symptom group pre-first cigarette of the day but was significantly different at random prompts throughout the day. Conclusions: As participants smoked as usual, findings identify naturalistic factors which may influence smoking behavior among premenopausal females who smoke with elevated depression symptoms. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Association of depression symptom level with smoking urges, cigarette withdrawal, and smoking reinstatement: A preliminary laboratory study.

BACKGROUND: Cigarette smoking urges, withdrawal, and smoking reinstatement may be especially relevant to people with elevated depression symptoms who smoke. This laboratory study aimed to assess relations between depression symptom level and smoking urges for reward and relief, cigarette withdrawal, and smoking reinstatement in people who smoke cigarettes daily during acute abstinence and while smoking as usual. METHODS: Participants with low (n = 51) or elevated (n = 29) baseline depression symptoms underwent two counterbalanced laboratory sessions (i.e., abstinent, non-abstinent). At each session, they completed subjective measures of smoking urges for reward and relief, and withdrawal. They also completed a laboratory smoking reinstatement task measuring whether they would delay smoking and the number of cigarettes smoked. RESULTS: The elevated depression symptom group reported significantly higher withdrawal (p = .01) and smoked more cigarettes than the low depression symptoms group during the smoking reinstatement task self-administration period at the abstinent session (p = .04). Smoking urges for reward and relief were not significantly different by depression symptom group. There were no significant interactions of depression and abstinence with any outcomes. CONCLUSIONS: As outcomes were measured at both an abstinent and non-abstinent session, findings identify factors for people with elevated depression symptoms who smoke which may drive smoking behavior and impede smoking cessation efforts. This study provides evidence that people with elevated depression symptoms who smoke may need additional/more pharmacological or behavioral smoking cessation aids targeted at reducing withdrawal and number of cigarettes smoked.

Effects of cigarette abstinence on negative and positive affect by depression symptom levels: A lab study.

BACKGROUND: High negative affect and low positive affect are key depression-related states that may be greater following acute tobacco abstinence. This study aimed to test associations between depression symptom levels and acute tobacco abstinence with negative affect and positive affect. METHODS: Following a baseline session, participants attended two counterbalanced laboratory sessions (non-abstinent, abstinent) and completed measures of positive and negative affect at rest (i.e., when not completing a task) and during a film clip task. RESULTS: Individuals with elevated depression symptoms had higher negative affect and lower positive affect at rest and during the film clip task compared to individuals with low depression symptoms. There was no interaction of depression symptom levels and abstinence on negative and positive affect at rest. There was an interaction of depression symptom level and abstinence on negative and positive affect during the film clip task. Individuals with elevated depression showed significant differences in positive and negative affect between the abstinent and non-abstinent session, but no significant abstinence effects were noted in individuals with low depression symptoms. LIMITATIONS: The study included a non-treatment seeking sample and experimentally induced acute cigarette abstinence. We excluded for the use of smoking cessation medications that are also used to treat depression, classified depression levels using dichotomized CES-D scores, and used self-report measures of affect. CONCLUSIONS: Results of this study suggest individuals with elevated depression symptoms who smoke experience elevated negative affect and lower positive affect and cigarette abstinence may uniquely alter affective reactivity in individuals with elevated depression symptoms.

Psychosocial adjustment among low-income Latina cervical cancer patients.

Cancer-related coping strategies and social support, life stress, and optimism were tested in regression analyses as predictors of depression, affect, and quality of life among 54 low-income, immigrant Latina cervical cancer patients. Sixty-seven percent of the patients endorsed symptoms similar to diagnosable depression. Predictors significantly accounted for 35% to 54% of the variance in outcomes. Cancer-related coping strategies were found to mediate several of the relations between life stress, social support, and optimism and outcomes. Findings emphasize the need to consider the context within which patients live when assessing adjustment to cancer and developing culturally-sensitive interventions.

Cerebroarterial pulsatility and resistivity indices are associated with cognitive impairment and white matter hyperintensity in elderly subjects: A phase-contrast MRI study.

Increased cerebroarterial pulsations are thought to be contributing factors in microvascular damage and cognitive impairment. In this study, we assessed the utility of two-dimensional (2D) phase-contrast MRI (PC-MRI) in quantifying cerebroarterial pulsations and evaluated the associations of pulsatile and non-pulsatile hemodynamic measures with cognitive performance and white matter hyperintensities (WMH). Neurocognitive assessments on 50 elderly subjects were performed using clinical dementia rating (CDR) and Montreal cognitive assessment (MoCA). An electrocardiogram-gated 2D PC-MRI sequence was used to calculate mean flow rate, pulsatility index (PI), and resistivity index (RI) of the internal carotid artery. For each subject, whole brain global cerebral blood flow (gCBF) and relative WMH volume were also quantified. Elevated RI was significantly associated with reduced cognitive performance quantified using MoCA (p = 0.04) and global CDR (p = 0.02). PI and RI were both significantly associated with relative WMH volume (p = 0.01, p < 0.01, respectively). However, non-pulsatile hemodynamic measures were not associated with cognitive impairment or relative WMH volume. This study showed that the cerebroarterial pulsatile measures obtained using PC-MRI have stronger association with the measures of cognitive impairment compared to global blood flow measurement and as such, might be useful as potential biomarkers of cerebrovascular dysfunction in preclinical populations.

Anhedonia in tobacco withdrawal among African-American smokers.

Anhedonia-diminished interest and pleasure in response to rewards-may be a symptom of tobacco withdrawal that is understudied in priority populations. This experiment investigated the magnitude and correlates of various dimensions of anhedonia during tobacco withdrawal among African-American (AA) smokers-a population subject to health disparities. AA smokers (N = 607; ≥ 10 cigarettes/day, 37.8% female, M[SD] age = 50.0[10.6] years) completed self-report measures assessing expected pleasure from (i.e., consummatory anhedonia) and desire to engage in (i.e., anticipatory anhedonia) various types of hypothetically experienced rewards at counterbalanced 16-hr tobacco deprived and nondeprived lab visits. Other tobacco withdrawal symptom measures (e.g., craving, negative affect, hunger) were also assessed. Tobacco deprivation most robustly increased scores on a composite measure of consummatory anhedonia directed toward various reward domains (i.e., hobbies, sensory experiences, social activities; d = .32, p < .001). Deprivation modestly increased consummatory and anticipatory anhedonia directed toward sexual rewards (ds = .09-.12, ps < .02), did not significantly change anhedonia toward food rewards, and decreased anhedonia directed toward psychoactive drug rewards (i.e., increased desire for and pleasure from drugs; ds = -.21 to -.19, ps < .001). Deprivation-induced changes in anhedonia were modestly correlated with other withdrawal symptoms (average |r|s = .04-.23) and were amplified among participants with higher nicotine dependence and lower positive affect-related traits (|ß|s = .10-.12, ps < .01). Some dimensions of anhedonia may be genuine expressions of acute tobacco withdrawal in AA smokers. Applying multi-dimensional anhedonia conceptualizations might advance basic knowledge and treatment of tobacco use disorder, improve smoking cessation outcomes, and address tobacco-related health disparities facing AA smokers. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Evaluation of Cerebral Blood Flow Measured by 3D PCASL as Biomarker of Vascular Cognitive Impairment and Dementia (VCID) in a Cohort of Elderly Latinx Subjects at Risk of Small Vessel Disease.

Cerebral small vessel disease (cSVD) affects arterioles, capillaries, and venules and can lead to cognitive impairments and clinical symptomatology of vascular cognitive impairment and dementia (VCID). VCID symptoms are similar to Alzheimer's disease (AD) but the neurophysiologic alterations are less well studied, resulting in no established biomarkers. The purpose of this study was to evaluate cerebral blood flow (CBF) measured by 3D pseudo-continuous arterial spin labeling (pCASL) as a potential biomarker of VCID in a cohort of elderly Latinx subjects at risk of cSVD. Forty-five elderly Latinx subjects (12 males, 69 ± 7 years) underwent repeated MRI scans ∼6 weeks apart. CBF was measured using 3D pCASL in the whole brain, white matter and 4 main vascular territories (leptomeningeal anterior, middle, and posterior cerebral artery (leptoACA, leptoMCA, leptoPCA), as well as MCA perforator). The test-retest repeatability of CBF was assessed by intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Absolute and relative CBF was correlated with gross cognitive measures and domain specific assessment of executive and memory function, vascular risks, and Fazekas scores and volumes of white matter hyperintensity (WMH). Neurocognitive evaluations were performed using Montreal Cognitive Assessment (MoCA) and neuropsychological test battery in the Uniform Data Set v3 (UDS3). Good to excellent test-retest repeatability was achieved (ICC = 0.77-0.85, wsCV 3-9%) for CBF measurements in the whole brain, white matter, and 4 vascular territories. Relative CBF normalized by global mean CBF in the leptoMCA territory was positively correlated with the executive function composite score, while relative CBF in the leptoMCA and MCA perforator territory was positively correlated with MoCA scores, controlling for age, gender, years of education, and testing language. Relative CBF in WM was negatively correlated with WMH volume and MoCA scores, while relative leptoMCA CBF was positively correlated with WMH volume. Reliable 3D pCASL CBF measurements were achieved in the cohort of elderly Latinx subjects. Relative CBF in the leptomeningeal and perforator MCA territories were the most likely candidate biomarker of VCID. These findings need to be replicated in larger cohorts with greater variability of stages of cSVD.

Lower retinal capillary density in minimal cognitive impairment among older Latinx adults.

INTRODUCTION: We investigated the hypothesis that retinal capillary perfusion is a biomarker of early cognitive decline and cerebrovascular perfusion associated with small vessel disease in a pilot data set of Latinx adults at high risk for vascular cognitive impairment and dementia. METHODS: High-resolution optical coherence tomography angiography (OCTA) images were acquired from dilated eyes of Latinx subjects using a 3 × 3 mm2 scan pattern from a commercially available device. A previously validated method was used to quantify the density of perfused retinal capillaries as the retinal vessel skeleton density (VSD). The association of VSD with Clinical Dementia Rating Sum of Boxes, total Montreal Cognitive Assessment (MoCA) score, and individual MoCA test elements were analyzed using multivariate statistics that adjusted for confounders. VSD was also compared with magnetic resonance imaging (MRI) measures of cerebrovascular reactivity (CVR) and perfusion in the middle cerebral artery perforator (MCA-Perf) territory. RESULTS: The mean (± SD) age of the subjects was 68 (± 6) years. For every 0.01-unit lower VSD, the risk of having a CDR-SOB >0 was 20% higher (95%CI = 5%-90%; P = .031). Similarly, a lower VSD was associated with lower total MoCA score (r = 0.3; P = .038). The Visuospatial/Executive domain of the MoCA assessment showed the strongest association with VSD ( ß  = 0.02; P = .022). Lower retinal VSD was associated with worse MRI measure of CVR (r = 0.7, P = .04) and less perfusion in the MCA-Perf territory (r = 0.45, P = .02). DISCUSSION: Impaired retinal capillary perfusion is associated with cognitive impairment and abnormalities in cerebrovascular perfusion and function. OCTA-based retinal capillary assessment holds promise for identifying and quantifying retinal correlates of neurovascular abnormalities associated with vascular cognitive impairment.

Effectiveness of transdermal nicotine patch in premenopausal female smokers is moderated by within-subject severity of negative affect and physical symptoms.

RATIONALE: Nicotine patches may be less effective in female compared with male smokers. However, it is unknown if negative affect and physical symptoms influence transdermal nicotine patch-related effects on smoking behaviors. METHODS: Eighty-one acutely tobacco-abstinent premenopausal female smokers attended three counter-balanced experimental sessions across the menstrual cycle (early follicular, late follicular, and mid-luteal) and were randomized to patch condition (nicotine [21 mg] vs. placebo [0 mg] transdermal patch). Negative affect and physical symptoms were assessed prior to patch administration. The patch was removed 5 h post-administration, and participants completed a smoking reinstatement task. Multilevel linear models tested associations of patch condition, negative affect and physical symptoms, and their interaction on smoking behavior. RESULTS: There was a significant patch condition × Negative Affect and Pain symptoms interaction on the number of cigarettes smoked (p < 0.05). When Negative Affect and Pain were lower-than-usual, females administered a nicotine patch smoked significantly fewer cigarettes than females administered a placebo patch (p < .05), but there were no significant patch differences when Negative Affect and Pain were higher-than-usual. There was also a significant patch condition × Negative Affect interaction on time delay. The effects of patch condition on time delay to smoking were greater during sessions in which Negative Affect was higher-than-usual. CONCLUSIONS: Results suggest that among female smokers transdermal nicotine patch effectiveness may interact with negative affect and pain. Understanding and considering female-specific factors that may impact the efficacy of one of the most commonly used cessation medications is important for improving smoking cessation in female smokers.

Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial.

BACKGROUND: Past clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment. METHODS: 33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition. FINDINGS: A 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups. INTERPRETATION: Dementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers. TRIAL REGISTRATION: NCT02541929. FUNDING: HNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.

Vascular contributions to cognitive impairment are increasingly recognized1-5 as shown by neuropathological6,7, neuroimaging4,8-11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-ß (Aß)3,11,14, and more recently tau15. Animal studies suggest that Aß and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown14-16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8-10,12,13, how they relate to changes in the AD classical biomarkers Aß and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-ß8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8-10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer's Aß and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aß and tau.