Decreasing prevalence of centers meeting the Society for Vascular Surgery abdominal aortic aneurysm guidelines in the United States.

OBJECTIVE: Based on data supporting a volume-outcome relationship in elective aortic aneurysm repair, the Society of Vascular Surgery (SVS) guidelines recommend that endovascular aortic repair (EVAR) be localized to centers that perform ≥10 operations annually and have a perioperative mortality and conversion-to-open rate of ≤2% and that open aortic repair (OAR) be localized to centers that perform ≥10 open aortic operations annually and have a perioperative mortality ≤5%. However, the number and distribution of centers meeting the SVS criteria remains unclear. This study aimed to estimate the temporal trends and geographic distribution of Centers Meeting the SVS Aortic Guidelines (CMAG) in the United States. METHODS: The SVS Vascular Quality Initiative was queried for all OAR, aortic bypasses, and EVAR from 2011 to 2019. Annual OAR and EVAR volume, 30-day elective operative mortality for OAR or EVAR, and EVAR conversion-to-open rate for all centers were calculated. The SVS guidelines for OAR and EVAR, individually and combined, were applied to each institution leading to a CMAG designation. The proportion of CMAGs by region (West, Midwest, South, and Northeast) were compared by year using a χ2 test. Temporal trends were estimated using a multivariable logistic regression for CMAG, adjusting by region. RESULTS: Overall, 67,865 patients (49,264 EVAR; 11,010 OAR; 7591 aortic bypasses) at 336 institutions were examined. The proportion of EVAR CMAGs increased nationally by 1.7% annually from 51.6% (n = 33/64) in 2011 to 67.1% (n = 190/283) in 2019 (ß = .05; 95% confidence interval [CI], 0.01-0.09; P = .02). The proportion of EVAR CMAGs across regions ranged from 27.3% to 66.7% in 2011 to 63.9% to 72.9% in 2019. In contrast, the proportion of OAR CMAGs has decreased nationally by 1.8% annually from 32.8% (n = 21/64) in 2011 to 16.3% (n = 46/283) in 2019 (ß = -.14; 95% CI, -0.19 to -0.10; P < .01). Combined EVAR and OAR CMAGs were even less frequent and decreased by 1.5% annually from 26.6% (n = 17/64) in 2011 to 13.1% (n = 37/283) in 2019 (ß = -.12; 95% CI, -0.17 to -0.07; P < .01). In 2019, there was no significant difference in regional variation of the proportion of combined EVAR and OAR CMAGs (P = .82). CONCLUSIONS: Although an increasing proportion of institutions nationally meet the SVS guidelines for EVAR, a smaller proportion meet them for OAR, with a concerning downward trend. These data question whether we can safely offer OAR at most institutions, have important implications about sufficient OAR exposure for trainees, and support regionalization of OAR.

Vascular Burden Moderates the Relationship Between ADHD and Cognition in Older Adults.

OBJECTIVES: Recent evidence suggests attention-deficit/hyperactivity disorder (ADHD) is a risk factor for cognitive impairment in later life. Here, we investigated cerebrovascular burden, quantified using white matter hyperintensity (WMH) volumes, as a potential mediator of this relationship. DESIGN: This was a cross-sectional observational study. SETTING: Participants were recruited from a cognitive neurology clinic where they had been referred for cognitive assessment, or from the community. PARTICIPANTS: Thirty-nine older adults with clinical ADHD and 50 age- and gender-matched older adults without ADHD. MEASUREMENTS: A semiautomated structural MRI pipeline was used to quantify periventricular (pWMH) and deep WMH (dWMH) volumes. Cognition was measured using standardized tests of memory, processing speed, visuo-construction, language, and executive functioning. Mediation models, adjusted for sex, were built to test the hypothesis that ADHD status exerts a deleterious impact on cognitive performance via WMH burden. RESULTS: Results did not support a mediated effect of ADHD on cognition. Post hoc inspection of the data rather suggested a moderated effect, which was investigated as an a posteriori hypothesis. These results revealed a significant moderating effect of WMH on the relationship between ADHD memory, speed, and executive functioning, wherein ADHD was negatively associated with cognition at high and medium levels of WMH, but not when WMH volumes were low. CONCLUSIONS: ADHD increases older adults' susceptibility to the deleterious cognitive effects of WMH in the brain. Older adults with ADHD may be at risk for cognitive impairment if they have deep WMH volumes above 61 mm3 and periventricular WMH above 260 mm3.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

Development and Validation of a Novel Preoperative Risk Score to Identify Patients at Risk for Nonhome Discharge after Elective Endovascular Aortic Aneurysm Repair (EVAR).

BACKGROUND: Nonhome discharge (NHD) to a rehabilitation or skilled nursing facility after elective endovascular aortic repair (EVAR) is uncommon. However, NHD after surgery has an important impact on patient quality of life and postdischarge outcomes. Understanding factors that put patients undergoing EVAR at high risk for NHD is essential to providing adequate preoperative counseling and shared decision making. This study aimed to identify independent predictors of NHD following elective EVAR and to create a clinically useful preoperative risk score. METHODS: Elective EVAR cases were queried from the Society for Vascular Surgery Vascular Quality Initiative 2014-2018. A risk score was created by splitting the data set into two-thirds for development and one-third for validation. A parsimonious stepwise hierarchical multivariable logistic regression controlling for hospital level variation was performed in the development dataset, and the beta-coefficients were used to assign points for a risk score. The score was then validated, and model performance assessed. RESULTS: Overall, 24,426 patients were included and 932 (3.8%) required NHD. Multivariable analysis in the development group identified independent predictors of NHD, which were used to create a 20-point risk score. Patients were stratified into 3 groups based upon their risk score: low risk (0-7 points; n = 16,699) with an NHD rate of 1.8%, moderate risk (8-13 points; n = 7,315) with an NHD rate of 7.3%, and high risk (≥14 points; n = 412) with an NHD rate of 21.8%. The risk score had good predictive ability with c-statistic = 0.75 for model development and c-statistic = 0.73 in the validation dataset. CONCLUSIONS: This novel risk score can predict NHD following EVAR using characteristics that can be identified preoperatively. Utilization of this score may allow for improved risk assessment, preoperative counseling, and shared decision making.

Readability of Spanish-Language Online Patient Educational Materials for Peripheral Artery Disease Do Not Meet Recommended Standards and Represent a Literacy Barrier to Care.

BACKGROUND: Online resources are a valuable source of information for patients and have been reported to improve engagement and adherence to medical care. However, readability of online patient educational materials (OPEMs) is crucial for them to serve their intended purpose. The American Medical Association (AMA) recommends that OPEM be written at or below the sixth grade reading level. To avoid disparities in access to comprehensible health information on peripheral artery disease (PAD), it is imperative that the readability of PAD OPEM is appropriate for both English-speaking and Spanish-speaking patients. The aim of this study is to evaluate the readability of PAD OPEM in Spanish and compare to English-language OPEM. METHODS: We conducted a Google search in English and Spanish using "peripheral arterial disease" and "enfermedad arterial periferica", respectively, and the top 25 patient-accessible articles were collected for each. Articles were categorized by source type: hospital, professional society, or other. Readability of English-language OPEM was measured using the Flesch Reading Ease Readability Formula, Automated Readability Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Gunning Fog, Linsear Write Formula, and the Simple Measure of Gobbledygook Index. Readability of Spanish OPEM was measured using the Fernández-Huerta Index and Índice Flesch-Szigriszt Scale. Readability of the articles was compared to the AMA recommendation, between English- and Spanish-language, and across sources using statistical tests appropriate to the data. RESULTS: OPEM from professional societies represented the fewest number of English- (n = 7, 28%) and Spanish-language (n = 6, 24%) articles. Most English-speaking (n = 18, 72%) and Spanish-language (n = 20, 80%) OPEM were considered difficult as measured by the Flesch Reading Ease Readability Formula and Fernández-Huerta Index, respectively, but did not significantly differ between languages (P = 0.59). There were no significant differences in the average readability of all readability measurements across sources (hospital, professional society, or other). All the average readability grade levels for English-speaking and Spanish-language OPEM was significantly higher than the sixth grade reading level (P < 0.01). Only 3 (6%) OPEM met the AMA recommended reading level and there was no significant difference between English-language and Spanish-language OPEM (P = 1.0). CONCLUSIONS: Nearly all Spanish-language and English-language PAD OPEM assessed were written at a reading grade level higher than recommended by the AMA. There was no significant difference in the readability of materials from hospitals or professional societies. To prevent further widening of health disparities related to literacy, health content creators, particularly hospitals and professional societies, should prioritize, develop, and ensure that English-language and Spanish-language patient education materials are written at a level appropriate for the public.

Investigating the impact of hypertension with and without diabetes on Alzheimer's disease risk: A clinico-pathological study.

INTRODUCTION: Hypertension and diabetes are common cardiovascular risk factors that increase Alzheimer's disease (AD) risk. However, it is unclear whether AD risk differs in hypertensive individuals with and without diabetes. METHODS: Cognitively normal individuals (N = 11,074) from the National Alzheimer's Coordinating Center (NACC) were categorized as having (1) hypertension with diabetes (HTN+/DM+), (2) hypertension without diabetes (HTN+/DM-), or (3) neither (HTN-/DM-). AD risk in HTN+/DM+ and HTN+/DM- was compared to HTN-/DM-. This risk was then investigated in those with AD neuropathology (ADNP), cerebral amyloid angiopathy (CAA), cerebrovascular neuropathology (CVNP), arteriolosclerosis, and atherosclerosis. Finally, AD risk in HTN-/DM+ was compared to HTN-/DM-. RESULTS: Seven percent (N = 830) of individuals developed AD. HTN+/DM+ (hazard ratio [HR] = 1.31 [1.19-1.44]) and HTN+/DM- (HR = 1.24 [1.17-1.32]) increased AD risk compared to HTN-/DM-. AD risk was greater in HTN+/DM+ with ADNP (HR = 2.10 [1.16-3.79]) and CAA (HR = 1.52 [1.09-2.12]), and in HTN+/DM- with CVNP (HR = 1.54 [1.17-2.03]). HTN-/DM+ also increased AD risk (HR = 1.88 [1.30-2.72]) compared to HTN-/DM-. DISCUSSION: HTN+/DM+ and HTN+/DM- increased AD risk compared to HTN-/DM-, but pathological differences between groups suggest targeted therapies may be warranted based on cardiovascular risk profiles. HIGHLIGHTS: AD risk was studied in hypertensive (HTN+) individuals with/without diabetes (DM+/-). HTN+/DM+ and HTN+/DM- both had an increased risk of AD compared to HTN-/DM-. Post mortem analysis identified neuropathological differences between HTN+/DM+ and HTN+/DM-. In HTN+/DM+, AD risk was greater in those with AD neuropathology and CAA. In HTN+/DM-, AD risk was greater in those with cerebrovascular neuropathology.

Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology.

INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.

Link among apolipoprotein E E4, gait, and cognition in neurodegenerative diseases: ONDRI study.

INTRODUCTION: Apolipoprotein E E4 allele (APOE E4) and slow gait are independently associated with cognitive impairment and dementia. However, it is unknown whether their coexistence is associated with poorer cognitive performance and its underlying mechanism in neurodegenerative diseases. METHODS: Gait speed, APOE E4, cognition, and neuroimaging were assessed in 480 older adults with neurodegeneration. Participants were grouped by APOE E4 presence and slow gait. Mediation analyses were conducted to determine if brain structures could explain the link between these factors and cognitive performance. RESULTS: APOE E4 carriers with slow gait had the lowest global cognitive performance and smaller gray matter volumes compared to non-APOE E4 carriers with normal gait. Coexistence of APOE E4 and slow gait best predicted global and domain-specific poorer cognitive performances, mediated by smaller gray matter volume. DISCUSSION: Gait slowness in APOE E4 carriers with neurodegenerative diseases may indicate extensive gray matter changes associated with poor cognition. HIGHLIGHTS: APOE E4 and slow gait are risk factors for cognitive decline in neurodegenerative diseases. Slow gait and smaller gray matter volumes are associated, independently of APOE E4. Worse cognition in APOE E4 carriers with slow gait is explained by smaller GM volume. Gait slowness in APOE E4 carriers indicates poorer cognition-related brain changes.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

ROOD-MRI: Benchmarking the robustness of deep learning segmentation models to out-of-distribution and corrupted data in MRI.

Deep artificial neural networks (DNNs) have moved to the forefront of medical image analysis due to their success in classification, segmentation, and detection challenges. A principal challenge in large-scale deployment of DNNs in neuroimage analysis is the potential for shifts in signal-to-noise ratio, contrast, resolution, and presence of artifacts from site to site due to variances in scanners and acquisition protocols. DNNs are famously susceptible to these distribution shifts in computer vision. Currently, there are no benchmarking platforms or frameworks to assess the robustness of new and existing models to specific distribution shifts in MRI, and accessible multi-site benchmarking datasets are still scarce or task-specific. To address these limitations, we propose ROOD-MRI: a novel platform for benchmarking the Robustness of DNNs to Out-Of-Distribution (OOD) data, corruptions, and artifacts in MRI. This flexible platform provides modules for generating benchmarking datasets using transforms that model distribution shifts in MRI, implementations of newly derived benchmarking metrics for image segmentation, and examples for using the methodology with new models and tasks. We apply our methodology to hippocampus, ventricle, and white matter hyperintensity segmentation in several large studies, providing the hippocampus dataset as a publicly available benchmark. By evaluating modern DNNs on these datasets, we demonstrate that they are highly susceptible to distribution shifts and corruptions in MRI. We show that while data augmentation strategies can substantially improve robustness to OOD data for anatomical segmentation tasks, modern DNNs using augmentation still lack robustness in more challenging lesion-based segmentation tasks. We finally benchmark U-Nets and vision transformers, finding robustness susceptibility to particular classes of transforms across architectures. The presented open-source platform enables generating new benchmarking datasets and comparing across models to study model design that results in improved robustness to OOD data and corruptions in MRI.

Venous Collagenosis as Pathogenesis of White Matter Hyperintensity.

OBJECTIVE: Periventricular white matter hyperintensities (pvWMHs) are commonly observed on MRI in older individuals and are associated with cognitive and motor decline. The etiology of pvWMH remains unknown. Venous collagenosis has been implicated, which may also interfere with perivascular fluid flow leading to dilation of perivascular spaces (PVS). Here, we examine relationships between in vivo pvWMH volume and ex vivo morphological quantification of collagenosis and the PVS in veins and arteries. METHODS: Brain tissue from 25 Oregon Alzheimer's Disease Research Center subjects was selected to cover the full range of WMH burden. Tissue from white matter abutting the ventricle was stained with Masson's trichrome and smooth muscle actin. An automated hue based algorithm identified and segmented vessel into collagenized vessel walls, lumen, and PVS. Multiple linear regressions with pvWMH volume as the dependent variable and either collagen thickness or PVS width were performed with covariates of vessel diameter, age at death, sex, and interval between MRI and death. RESULTS: PVS width and collagen thickness were significantly correlated in both arteries (r = 0.21, p = 0.001) and veins (r = 0.23, p = 0.001). Increased venous collagen (p = 0.017) was a significant predictor of higher pvWMH burden while arterial collagen was not (p = 0.128). Neither PVS width in arteries (p = 0.937) nor veins (p = 0.133) predicted pvWMH burden. INTERPRETATION: These findings are consistent with a model in which venous collagenosis mediates the relationship between vascular risk factors and pvWMH. This study confirms the importance of changes to the venous system in contributing to MRI white matter lesions commonly observed with advanced age. ANN NEUROL 2022;92:992-1000.

Anemia is associated with higher mortality and morbidity after thoracic endovascular aortic repair.

BACKGROUND: It is uncertain whether preoperative anemia is independently associated with thoracic endovascular aortic repair (TEVAR) outcomes. Using a national vascular surgery database, we evaluated the associations between preoperative anemia and 30-day mortality, postoperative complications, and 1-year survival for patients undergoing TEVAR. METHODS: We retrospectively analyzed all patients in the Vascular Quality Initiative who had undergone TEVAR for aortic dissection, aortic aneurysm, penetrating aortic ulcer, hematoma, or thrombus between January 2011 and December 2019. We excluded patients with a ruptured aneurysm, traumatic dissection, emergent repair, treated aorta distal to zone 5, polycythemia, transfusion of >4 U of packed red blood cells intraoperatively or postoperatively, and missing data on hemoglobin level or surgical indications. The final study cohort was dichotomized into two groups: normal/mild anemia (women, ≥10 g/dL; men, ≥12 g/dL) and moderate/severe anemia (women, <10 g/dL; male, <12 g/dL). Propensity scores by stratification were used to control for confounding in the analysis of the association between the outcomes of 30-day mortality, postoperative complications, and 1-year survival and a binary indicator variable of moderate/severe anemia vs normal/mild anemia. Kaplan-Meier analysis and log-rank tests were used to compare the 1-year survival between the two groups. A Cox regression model was fitted to assess the associations between anemia and survival outcomes. RESULTS: A total of 3391 patients were analyzed, 958 (28.3%) of whom had had moderate/severe anemia. After adjustment for multiple clinical factors using propensity score stratification, moderate/severe anemia was associated with a 141% increased odds of 30-day mortality (adjusted odds ratio [aOR], 2.41; 95% confidence interval [CI], 1.15-5.05; P = .019), 58% increased odds of any in-hospital complication (aOR, 1.58; 95% CI, 1.17-2.13; P = .003), 281% increased odds of intraoperative transfusion (aOR, 3.81; 95% CI, 2.68-5.53; P < .001). In addition, moderate/severe anemia was associated with significantly worse survival within the first year after TEVAR (log-rank P < .001; 1-year survival rate using Kaplan-Meier estimates, 86.4% ± 1.3% standard error vs 92.5% ± 0.6% standard error) and with an increased risk of mortality in the first postoperative year (adjusted hazard ratio, 1.81; 95% CI, 1.16-2.82; P = .009). CONCLUSIONS: We found that moderate or severe anemia is associated with significantly increased odds of mortality, postoperative complications, and worse 1-year survival after TEVAR. Future studies are needed to evaluate the effect of anemia correction on the outcomes of TEVAR.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

BACKGROUND AND PURPOSE: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. METHODS: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. RESULTS: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. CONCLUSION: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.

Sex differences in risk factors that predict progression from mild cognitive impairment to Alzheimer's dementia.

OBJECTIVES: To evaluate whether cerebrospinal fluid biomarkers, apolipoprotein e4, neuroimaging abnormalities, and neuropsychological data differentially predict progression from mild cognitive impairment (MCI) to dementia for men and women. METHODS: Participants who were diagnosed with MCI at baseline (n = 449) were classified as either progressing to Alzheimer's dementia at follow-up or as not progressing. Men and women were first compared using bivariate analyses. Sex-stratified Cox proportional hazard regressions were performed examining the relationship between baseline data and the likelihood of progressing to dementia. Sex interactions were subsequently examined. RESULTS: Cox proportional hazard regression controlling for age and education indicated that all variables significantly predicted subsequent progression to dementia for men and women. Sex interactions indicated that only Rey Auditory Verbal Learning Test (RAVLT) delayed recall and Functional Activities Questionnaire (FAQ) were significantly stronger risk factors for women. When all variables were entered into a fully adjusted model, significant risk factors for women were Aß42, hippocampal volume, RAVLT delayed recall, Boston Naming Test, and FAQ. In contrast, for men, Aß42, p-tau181, p-tau181/Aß42, hippocampal volume, category fluency and FAQ were significant risk factors. Interactions with sex were only significant for p-tau181/Aß42 and RAVLT delayed recall for the fully adjusted model. CONCLUSIONS: Men and women with MCI may to differ for which factors predict subsequent dementia although future analyses with greater power are needed to evaluate sex differences. We hypothesize that brain and cognitive reserve theories may partially explain these findings.

Spanish-speaking caregivers' use of referential labels with toddlers is a better predictor of later vocabulary than their use of referential gestures.

Variation in how frequently caregivers engage with their children is associated with variation in children's later language outcomes. One explanation for this link is that caregivers use both verbal behaviors, such as labels, and non-verbal behaviors, such as gestures, to help children establish reference to objects or events in the world. However, few studies have directly explored whether language outcomes are more strongly associated with referential behaviors that are expressed verbally, such as labels, or non-verbally, such as gestures, or whether both are equally predictive. Here, we observed caregivers from 42 Spanish-speaking families in the US engage with their 18-month-old children during 5-min lab-based, play sessions. Children's language processing speed and vocabulary size were assessed when children were 25 months. Bayesian model comparisons assessed the extent to which the frequencies of caregivers' referential labels, referential gestures, or labels and gestures together, were more strongly associated with children's language outcomes than a model with caregiver total words, or overall talkativeness. The best-fitting models showed that children who heard more referential labels at 18 months were faster in language processing and had larger vocabularies at 25 months. Models including gestures, or labels and gestures together, showed weaker fits to the data. Caregivers' total words predicted children's language processing speed, but predicted vocabulary size less well. These results suggest that the frequency with which caregivers of 18-month-old children use referential labels, more so than referential gestures, is a critical feature of caregiver verbal engagement that contributes to language processing development and vocabulary growth. RESEARCH HIGHLIGHTS: We examined the frequency of referential communicative behaviors, via labels and/or gestures, produced by caregivers during a 5-min play interaction with their 18-month-old children. We assessed predictive relations between labels, gestures, their combination, as well as total words spoken, and children's processing speed and vocabulary growth at 25 months. Bayesian model comparisons showed that caregivers' referential labels at 18 months best predicted both 25-month vocabulary measures, although total words also predicted later processing speed. Frequent use of referential labels by caregivers, more so than referential gestures, is a critical feature of communicative behavior that supports children's later vocabulary learning.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Rare neurovascular genetic and imaging markers across neurodegenerative diseases.

INTRODUCTION: Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status. METHODS: The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1). RESULTS: NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood. DISCUSSION: Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

Secondary thalamic atrophy related to brain infarction may contribute to post-stroke cognitive impairment.

BACKGROUND AND PURPOSE: The thalamus is a key brain hub that is globally connected to many cortical regions. Previous work highlights thalamic contributions to multiple cognitive functions, but few studies have measured thalamic volume changes or cognitive correlates. This study investigates associations between thalamic volumes and post-stroke cognitive function. METHODS: Participants with non-thalamic brain infarcts (3-42 months) underwent MRI and cognitive testing. Focal infarcts and thalami were traced manually. In cases with bilateral infarcts, the side of the primary infarct volume defined the hemisphere involved. Brain parcellation and volumetrics were extracted using a standardized and previously validated neuroimaging pipeline. Age and gender-matched healthy controls provided normal comparative thalamic volumes. Thalamic atrophy was considered when the volume exceeded 2 standard deviations greater than the controls. RESULTS: Thalamic volumes ipsilateral to the infarct in stroke patients (n=55) were smaller than left (4.4 ± 1.4 vs. 5.4 ± 0.5 cc, p < 0.001) and right (4.4 ± 1.4 vs. 5.5 ± 0.6 cc, p < 0.001) thalamic volumes in the controls. After controlling for head-size and global brain atrophy, infarct volume independently correlated with ipsilateral thalamic volume (ß= -0.069, p=0.024). Left thalamic atrophy correlated significantly with poorer cognitive performance (ß = 4.177, p = 0.008), after controlling for demographics and infarct volumes. CONCLUSIONS: Our results suggest that the remote effect of infarction on ipsilateral thalamic volume is associated with global post-stroke cognitive impairment.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases.

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.