A United States-based patient-reported adult polyglucosan body disease registry: initial results.

Background: Adult Polyglucosan Body Disease (APBD) is an ultra-rare, genetic neurodegenerative disorder caused by autosomal recessive mutations in the glycogen branching enzyme gene. Knowledge of the demographic and clinical characteristics of APBD patients and the natural history of the disease is lacking. We report here initial results from a patient-reported registry of APBD patients. Objectives: (1) Maximize the quality of the APBD Registry survey data; (2) provide an initial report on APBD disease progression and natural history using these data; and (3) specify next steps in the process for testing potential new therapies. Design: Data are from members of the APBD Research Foundation (New York), surveyed from 2014 by the Columbia APBD Patient/Family (CAP) Registry. Inclusion criteria are: disease onset at age 18+ and progressive clinical triad of peripheral neuropathy, spasticity, and neurogenic bladder. Methods: Genetic testing results were used when available. Respondents found to not have APBD in clinical records were excluded. All changes and exclusions were recorded in a database edit log. Results are reported in frequency tables, bar graphs, time plots, and heat maps. Results: The 96 respondents meeting inclusion criteria were predominantly (96.8%) White, highly educated (89.3% at least some college education), and mostly (85.1%) of Ashkenazi Jewish descent. 57.1% had at least one parent born in the United States, with at least one grandparent from Europe (excluding Russia; 75.4%), the United States (42.1%), or Russia (33.3%). 37.2% reported a family history of APBD, and 33.3% had an affected sibling. Median APBD onset age was 51 [Interquartile range (IQR) 11], and median age of diagnosis 57 (IQR 10.5). The 75 reported prior misdiagnoses were mainly peripheral neuropathy (43, 60.6%) and spinal stenosis (11, 15.1%). Conclusion: Although from a demographically constricted survey, the results provide basic clinical information for future studies to develop treatments for APBD.

A United States based patient-reported adult polyglucosan body disease registry: initial results Adult Polyglucosan Body Disease, or APBD, is an ultra-rare neurological disorder caused by mutations of the GBE1 gene. While potential therapies exist, to establish if they work we need a "natural history" study that shows the normal path of the disease. Our goal was to provide the first patient-reported natural history study of APBD. We analyzed survey data from 96 patients recruited by the APBD Research Foundation (New York), aged 18 or older, who self-reported having APBD. We maximized data quality by using results from genetic testing when these were available, and by excluding respondents if we could not review clinical records confirming they had APBD. More than 95% of our 96 patients were white. They were highly educated: 89% had at least some college education. Most (85%) were of Ashkenazi Jewish descent. More than half (57.1%) had a parent born in the United States. Many had at least one grandparent from Europe (excluding Russia) (75.4%), the United States (42.1%), or Russia (33.3%). More than a third (37%) reported a family history of APBD, and a third reported that they had a brother or a sister with a history of the disease. Their average age at APBD onset was 51, and their average age at APBD diagnosis was 57. Previous misdiagnoses were common: 75 were reported. Most were for peripheral neuropathy (60.6%) or spinal stenosis (16.7%). Although our data come from a survey of patients who are demographically similar, they provide a report on the characteristics of patients with APBD and basic information that is essential for studies to develop treatments for the disease.

Social Connectivity is Related to Mild Cognitive Impairment and Dementia.

BACKGROUND: Evidence supports a relationship between loneliness, social isolation, and dementia, but less is known about whether social connections confer protection against cognitive decline in disadvantaged neighborhoods. OBJECTIVE: This longitudinal population-based study examines the relationship between social connectivity and cognitive impairment in a multi-ethnic cohort with low socioeconomic status and high vascular disease risk. METHODS: Northern Manhattan Study participants self-reported frequency of social visits, phone calls, satisfaction with social visits, number of friends, and loneliness at baseline, and were followed prospectively with a series of neuropsychological assessments. Social connectivity was examined in relation to incident mild cognitive impairment (MCI)/dementia using logistic regression adjusting for demographics and vascular risk factors. RESULTS: Among 952 participants (mean age at first neuropsychological assessment = 69±8 years, 62% women, 17% Black, 13% white, 68% Hispanic), 24% developed MCI/dementia. Participants who had phone contact with friends/family 2 + times/week (91%) had a lower odds of MCI/dementia (OR = 0.52, 95% CI = 0.31-0.89), with no association for frequency of in-person visits. Compared to those who were neither socially isolated (≥3 friends) nor lonely (reference, 73%), those who were socially isolated and lonely (3%) had an increased odds of MCI/dementia (OR = 2.89, 95% CI = 1.19-7.02), but differences were not observed for those who were socially isolated but not lonely (10%, OR = 1.05, 95% CI = 0.60-1.84), nor those who were lonely but not isolated (11%, OR = 1.58, 95% CI = 0.97-2.59). CONCLUSION: This study raises the possibility that social connections confer some protection for cognitive health in the face of adversity and supports potential opportunities for community social interventions for improving cognition in disadvantaged populations.

Determinants and Outcomes of Asymptomatic Intracranial Atherosclerotic Stenosis.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and confers a high risk of stroke recurrence, despite aggressive management of risk factors. OBJECTIVES: This study identified the role of risk factors and risk of vascular events in subjects with asymptomatic ICAS for improved risk stratification. METHODS: Stroke-free participants in the NOMAS (Northern Manhattan Study) trial, prospectively followed since 1993, underwent a brain magnetic resonance angiogram from 2003 to 2008. The study rated stenosis in 11 brain arteries as: 0: no stenosis; 1: <50% or luminal irregularities; 2: 50%-69%; and 3: ≥70% stenosis or flow gap. The study ascertained vascular events during the post-magnetic resonance imaging (MRI) period. Proportional odds regression quantified the association of pre-MRI exposures, and proportional hazard adjusted models were built to identify the risk of events in the post-MRI period. RESULTS: The included sample included 1,211 participants from NOMAS (mean age: 71 ± 9 years; 59% women; 65% Hispanic; 45% had any stenosis). Older age (OR: 1.02 per year; 95% CI: 1.01 to 1.04), hypertension duration (OR: 1.01 per year; 95% CI: 1.00 to 1.02), higher number of glucose-lowering drugs (OR: 1.64 per each medication; 95% CI: 1.24 to 2.15), and high-density lipoprotein (OR: 0.96 per mg/dL; 95% CI: 0.92 to 0.99) were associated with ICAS. The highest event risk was noted among participants with ICAS ≥70% (5.5% annual risk of vascular events; HR: 2.1; 95% CI:1.4 to 3.2; compared with those with no ICAS). CONCLUSIONS: ICAS is an imaging marker of established atherosclerotic disease in stroke-free subjects, and incidental diagnosis of ICAS should trigger a thorough assessment of vascular health.

Gut permeability and cognitive decline: A pilot investigation in the Northern Manhattan Study.

BACKGROUND: Gut microbiota may impact cognitive function and decline, though data are limited. This pilot study examines the associations between gut dysbiosis products, plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14), with cognitive decline and immune molecule activation among 40 participants in the longitudinal population-based Northern Manhattan Study. METHODS: We selected stroke- and dementia-free participants at baseline with high activation levels of core components of the immune signaling pathways underlying microbiota metabolite-cognitive associations (IL-1, IL-17, TNF). Participants were followed with up to three complete neuropsychological assessments, at least 5 years apart. RESULTS: Elevated sCD14 was associated with high levels of IL-1 pathway activation (p < 0.05), whereas in samples where only those molecules within the IL-17 and TNF pathways were increased, LPS and sCD14 levels were not elevated. LPS was associated with decline in global cognitive performance over 2-3 assessments (adjusted ß = -0.023 per SD per year, 95% CI:-0.036, -0.010). The association between sCD14 and cognitive decline was marginal (adjusted ß = -0.018 per SD per year, 95% CI:-0.040, 0.004). CONCLUSIONS: These preliminary data support the hypothesis that gut dysbiosis leads to systemic and neuro-inflammation, and subsequently cognitive decline. Further large targeted and untargeted gut microbiota-derived metabolomic studies are needed.

Systolic Blood Pressure and Cognition in the Elderly: The Northern Manhattan Study.

BACKGROUND: Increasing evidence suggests that hypertension is a risk factor for cognitive impairment and dementia. The relationship between blood pressure and cognition in a racially and ethnically diverse population remains unclear. OBJECTIVE: To study association of blood pressure with cognition cross-sectionally and longitudinally in the elderly. METHODS: Participants are stroke-free individuals from the racially and ethnically diverse Northern Manhattan Study (NOMAS) (n = 1215). General linear models are constructed to examine blood pressure in relation to cognition cross-sectionally and longitudinally at a five-year follow-up. RESULTS: We found a cross-sectional association of systolic blood pressure (SBP) with word fluency/semantic memory, executive function, and processing speed/visual motor integration (VMI) function. This association was independent of demographics, vascular risk factors, white matter hyperintensity volume (WMHV), and carotid intima-media thickness (cIMT). The cross-sectional association of SBP with processing speed/VMI and executive function was attenuated after adjusting anti-hypertension medications in the models. Baseline SBP was associated with the change of processing speed/VMI function after adjusting vascular risk factors, WMHV, and cIMT at a 5-year follow-up. This longitudinal association was not found after adjusting anti-hypertension medications in the models. Further analyses revealed that individuals with category SBP from < 120 mmHg to≥140 mmHg had a linear decline in processing speed/VMI function at a 5-year follow-up. CONCLUSION: We show that SBP is negatively associated with cognition cross-sectionally and longitudinally in the elderly. Anti-hypertension treatment eliminates the negative association of SBP with processing speed/VMI function longitudinally. Our findings support the treatment of stage 1 systolic hypertension in the elderly.

Association Between Intracerebral Hemorrhage and Subsequent Arterial Ischemic Events in Participants From 4 Population-Based Cohort Studies.

Importance: Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown. Objective: To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction. Design, Setting, and Participants: An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020. Exposure: Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria. Main Outcomes and Measures: The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications. Results: Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1). Conclusions and Relevance: This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

Race/Ethnic Disparities in Mild Cognitive Impairment and Dementia: The Northern Manhattan Study.

BACKGROUND: Variability in dementia rates across racial and ethnic groups has been estimated at 60%. Studies suggest disparities in Caribbean Hispanic and Black populations, but community-based data are limited. OBJECTIVE: Estimate the prevalence of mild cognitive impairment (MCI) and dementia in the racially and ethnically diverse community-based Northern Manhattan Study cohort and examine sociodemographic, vascular risk factor, and brain imaging correlates. METHODS: Cases of MCI and dementia were adjudicated by a team of neuropsychologists and neurologists and prevalence was estimated across race/ethnic groups. Ordinal proportional odds models were used to estimate race/ethnic differences in the prevalence of MCI or dementia adjusting for sociodemographic variables (model 1), model 1 plus potentially modifiable vascular risk factors (model 2), and model 1 plus structural imaging markers of brain integrity (model 3). RESULTS: There were 989 participants with cognitive outcome determinations (mean age 69±9 years; 68% Hispanic, 16% Black, 14% White; 62% women; mean (±SD) follow-up five (±0.6) years). Hispanic and Black participants had greater likelihood of MCI (20%) and dementia (5%) than White participants accounting for age and education differences. Hispanic participants had greater odds of MCI or dementia than both White and Black participants adjusting for sociodemographic variables, vascular risk factors, and brain imaging factors. White matter hyperintensity burden was significantly associated with greater odds of MCI or dementia (OR = 1.3, 1.1 to 1.6), but there was no significant interaction by race/ethnicity. CONCLUSION: In this diverse community-based cohort, cross-sectional data revealed significant race/ethnic disparities in the prevalence of MCI and dementia. Longer follow-up and incidence data are needed to further clarify these relationships.

Classification of Covert Brain Infarct Subtype and Risk of Death and Vascular Events.

Background and Purpose- To test the hypothesis that covert brain infarcts (CBIs) are more likely to be located in noneloquent brain areas compared with clinical strokes and that CBI etiological subtypes carry a differential risk of vascular events compared with people without CBI. Methods- We used brain magnetic resonance imaging from 1290 stroke-free participants in the NOMAS (Northern Manhattan Study) to evaluate for CBI. We classified CBI as cardioembolic (ie, known atrial fibrillation), large artery atherosclerosis (extracranial and intracranial), penetrating artery disease, and cryptogenic (no apparent cause). CBI localized in the nonmotor areas of the right hemisphere were considered noneloquent. We then evaluated risk of events by CBI subtype with adjusted Cox proportional models. Results- At the time of magnetic resonance imaging, 236 participants (18%) had CBI (144 [61%] distal cryptogenic, 29 [12%] distal cardioembolic, 26 [11%] large artery atherosclerosis, and 37 [16%] penetrating artery disease). Smaller (per mm, odds ratio, 0.8 [0.8-0.9]) and nonbrain stem infarcts (odds ratio, 0.2 [0.1-0.6]) were more likely to be covert. During the follow-up period (10.4±3.1 years), 398 (31%) died (162 [13%] of vascular death) and 117 (9%) had a stroke (99 [85%]) were ischemic. Risks of events varied by CBI subtype, with the highest risk of stroke (hazard ratio, 2.2 [1.3-3.7]) and vascular death (hazard ratio, 2.24 [1.29-3.88]) noted in participants with intracranial large artery atherosclerosis-related CBI. Conclusions- CBI can be classified into subtypes that have differential outcomes. Certain CBI subtypes such as those related to intracranial large artery atherosclerosis have a high risk of adverse vascular outcomes and could warrant consideration of treatment trials.

Association Between Subclinical Brain Infarcts and Functional Decline Trajectories.

OBJECTIVES: To test associations between subclinical brain infarcts (SBIs) and functional decline independently of intervening clinical vascular events and other vascular risk factors. DESIGN: Longitudinal follow-up for a mean 7.3 years. Generalized estimating equation models were used to test associations between SBIs, number of perivascular spaces (PVSs), baseline Barthel Index (BI), and change in BI, adjusting for sociodemographic, vascular, and cognitive risk factors and for stroke and myocardial infarction occurring during follow-up. SETTING: Population-based prospective cohort study. PARTICIPANTS: Stroke-free individuals from the racially and ethnically diverse Northern Manhattan Study (N=1,290). MEASUREMENTS: Annual functional assessments using the BI (range 0-100). RESULTS: Mean age was 70.6 ± 9.0, 40% of participants were male, 66% were Hispanic, 193 (16%) had SBIs, and 508 (42%) had large PVSs. SBIs were not associated with baseline BI. In a fully adjusted model, there was a change in BI of -0.85 points per year (95% confidence interval (CI)=-1.01 to -0.69); those with SBI had an additional change in BI 0f -0.88 points (95% CI=-1.43 to -0.32). There were no associations between PVS and baseline BI or change in BI. CONCLUSION: In a large population-based study, we found a strong and independent association between "subclinical" markers of cerebrovascular injury and important clinical, person-centered functional trajectories. Future research could clarify the evolution of such subclinical markers over time and test strategies to prevent their progression and minimize related disability. J Am Geriatr Soc 66:2144-2150, 2018.

Cerebral white matter disease and functional decline in older adults from the Northern Manhattan Study: A longitudinal cohort study.

BACKGROUND: Cerebral white matter hyperintensities (WMHs) on MRI are common and associated with vascular and functional outcomes. However, the relationship between WMHs and longitudinal trajectories of functional status is not well characterized. We hypothesized that whole brain WMHs are associated with functional decline independently of intervening clinical vascular events and other vascular risk factors. METHODS AND FINDINGS: In the Northern Manhattan Study (NOMAS), a population-based racially/ethnically diverse prospective cohort study, 1,290 stroke-free individuals underwent brain MRI and were followed afterwards for a mean 7.3 years with annual functional assessments using the Barthel index (BI) (range 0-100) and vascular event surveillance. Whole brain white matter hyperintensity volume (WMHV) (as percentage of total cranial volume [TCV]) was standardized and treated continuously. Generalized estimating equation (GEE) models tested associations between whole brain WMHV and baseline BI and change in BI, adjusting for sociodemographic, vascular, and cognitive risk factors, as well as stroke and myocardial infarction (MI) occurring during follow-up. Mean age was 70.6 (standard deviation [SD] 9.0) years, 40% of participants were male, 66% Hispanic; mean whole brain WMHV was 0.68% (SD 0.84). In fully adjusted models, annual functional change was -1.04 BI points (-1.20, -0.88), with -0.74 additional points annually per SD whole brain WMHV increase from the mean (-0.99, -0.49). Whole brain WMHV was not associated with baseline BI, and results were similar for mobility and non-mobility BI domains and among those with baseline BI 95-100. A limitation of the study is the possibility of a healthy survivor bias, which would likely have underestimated the associations we found. CONCLUSIONS: In this large population-based study, greater whole brain WMHV was associated with steeper annual decline in functional status over the long term, independently of risk factors, vascular events, and baseline functional status. Subclinical brain ischemic changes may be an independent marker of long-term functional decline.

Long-Term Exposure to Ambient Air Pollution and Subclinical Cerebrovascular Disease in NOMAS (the Northern Manhattan Study).

BACKGROUND AND PURPOSE: Long-term exposure to ambient air pollution is associated with higher risk of cardiovascular disease and stroke. We hypothesized that long-term exposure to air pollution would be associated with magnetic resonance imaging markers of subclinical cerebrovascular disease. METHODS: Participants were 1075 stroke-free individuals aged ≥50 years drawn from the magnetic resonance imaging subcohort of the Northern Manhattan Study who had lived at the same residence for at least 2 years before magnetic resonance imaging. Cross-sectional associations between ambient air pollution and subclinical cerebrovascular disease were analyzed. RESULTS: We found an association between distance to roadway, a proxy for residential exposure to traffic pollution, and white matter hyperintensity volume; however, after adjusting for risk factors, this relationship was no longer present. All other associations between pollutant measures and white matter hyperintensity volume were null. There was no clear association between exposure to air pollutants and subclinical brain infarcts or total cerebral brain volume. CONCLUSIONS: We found no evidence that long-term exposure to ambient air pollution is independently associated with subclinical cerebrovascular disease in an urban population-based cohort.

Procalcitonin and Midregional Proatrial Natriuretic Peptide as Biomarkers of Subclinical Cerebrovascular Damage: The Northern Manhattan Study.

BACKGROUND AND PURPOSE: Chronic infections and cardiac dysfunction are risk factors for stroke. We hypothesized that blood biomarkers of infection (procalcitonin) and cardiac dysfunction (midregional proatrial natriuretic peptide [MR-proANP]), previously associated with small vessel stroke and cardioembolic stroke are also associated with subclinical cerebrovascular damage, including silent brain infarcts and white matter hyperintensity volume. METHODS: The NOMAS (Northern Manhattan Study) was designed to assess risk factors for incident vascular disease in a multiethnic cohort. A subsample underwent brain magnetic resonance imaging and had blood samples available for biomarker measurement (n=1178). We used logistic regression models to estimate the odds ratios and 95% confidence intervals (95% CIs) for the association of these biomarkers with silent brain infarcts after adjusting for demographic, behavioral, and medical risk factors. We used linear regression to assess associations with log-white matter hyperintensity volume. RESULTS: Mean age was 70±9 years; 60% were women, 66% Hispanic, 17% black, and 15% were white. After adjusting for risk factors, subjects with procalcitonin or MR-proANP in the top quartile, compared with the lowest quartile were more likely to have silent brain infarcts (adjusted odds ratio for procalcitonin, 2.2; 95% CI, 1.3-3.7 and for MR-proANP, 3.3; 95% CI, 1.7-6.3) and increased white matter hyperintensity volume (adjusted mean change in log-white matter hyperintensity volume for procalcitonin, 0.29; 95% CI, 0.13-0.44 and for MR-proANP, 0.18; 95% CI, 0.004-0.36). CONCLUSIONS: Higher concentrations of procalcitonin, a marker of infection, and MR-proANP, a marker of cardiac dysfunction, are independently associated with subclinical cerebrovascular damage. If further studies demonstrate an incremental value for risk stratification, biomarker-guided primary prevention studies may lead to new approaches to prevent cerebrovascular disease.

MRI Markers Predict Cognitive Decline Assessed by Telephone Interview: The Northern Manhattan Study.

BACKGROUND: Brain magnetic resonance imaging (MRI) allows researchers to observe structural pathology that may predict cognitive decline. Some populations are less accessible through traditional in-person visits, and may be under-represented in the literature. METHODS: We examined white matter hyperintensity volume (WMHV) and cerebral parenchymal fraction (CPF) as predictors of cognitive decline measured by a modified Telephone Interview for Cognitive Status (TICS-m) in the Northern Manhattan Stroke Study, a racially and ethnically diverse cohort study. Participants were stroke-free, above 50 years old, and had no contraindications to MRI. A total of 1143 participants had MRI and TICS-m data available [mean age 70 (SD=9), 61% women, 66% Hispanic, 17% Black, 15% white]. RESULTS: Those in the third and fourth quartiles of WMHV had significantly greater decline in TICS-m over time as compared with those in the first quartile (Q3: -0.17 points/year, Q4: -0.30 points/year). Those in the bottom 2 quartiles of CPF had significantly greater decline in TICS-m than those in the top quartile (Q1: -0.3 points/year, Q2: -0.2 points/year). Apolipoprotein E (APOE) e4 allele carriers had greater cognitive decline per unit of CPF. Those with greater CPF preserve TICS-m performance better despite greater WMHV. CONCLUSIONS: Telephone cognitive assessments can detect decline due to white matter lesions and smaller brain volumes.

Fibroblast Growth Factor 23 and Cause-Specific Mortality in the General Population: The Northern Manhattan Study.

CONTEXT: An elevated fibroblast growth factor (FGF) 23 is an independent risk factor for cardiovascular disease and mortality in patients with kidney disease. The relationship between FGF23 and cause-specific mortality in the general population is unknown. OBJECTIVE: To investigate the association of elevated FGF23 with the risk of cause-specific mortality in a racially and ethnically diverse urban general population. DESIGN, SETTING, PARTICIPANTS: The Northern Manhattan Study is a population-based prospective cohort study. Residents who were > 39 years old and had no history of stroke were enrolled between 1993 and 2001. Participants with available blood samples for baseline FGF23 testing were included in the current study (n = 2525). MAIN OUTCOME MEASURES: Cause-specific death events. RESULTS: A total of 1198 deaths (474 vascular, 612 nonvascular, 112 unknown cause) occurred during a median follow-up of 14 years. Compared to participants in the lowest FGF23 quintile, those in the highest quintile had a 2.07-fold higher risk (95% confidence interval [CI], 1.45, 2.94) of vascular death and a 1.64-fold higher risk (95% CI, 1.22, 2.20) of nonvascular death in fully adjusted models. Higher FGF23 was independently associated with increased risk of mortality due to cancer, but only in Hispanic participants (hazard ratio per 1 unit increase in ln FGF23 of 1.87; 95% CI, 1.40, 2.50; P for interaction = .01). CONCLUSIONS: Elevated FGF23 was independently associated with increased risk of vascular and nonvascular mortality in a diverse general population and with increased risk of cancer death specifically in Hispanic individuals.

Fibroblast Growth Factor 23 Is Associated With Subclinical Cerebrovascular Damage: The Northern Manhattan Study.

BACKGROUND AND PURPOSE: Elevated fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked with mortality, cardiovascular events, and stroke. However, the role of FGF23 as a risk factor for subclinical cerebrovascular damage is unclear. METHODS: We used multivariable linear and logistic regression to evaluate associations between FGF23, continuously and by quartiles, with white matter hyperintensity volume, expressed as percent intracranial volume (%ICV), and subclinical brain infarction (SBI) in a community-based stroke-free sample. RESULTS: There were 1170 stroke-free Northern Manhattan Study (NOMAS) participants with FGF23 levels and quantitative magnetic resonance imaging data on white matter hyperintensity volume and SBI. Participants with FGF23 levels in the top quartile (range=85-1425 RU/mL) had greater white matter hyperintensity volume (ß=0.19 %ICV; 95% CI, 0.04-0.33 %ICV; P=0.01) compared with those in the lowest quartile (range=15-49 RU/mL), adjusted for demographics, vascular risk factors, and estimated glomerular filtration rate. These findings remained significant in those without evidence of chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m(2)). Elevated FGF23 was not associated with SBI overall after adjusting for demographic factors and estimated glomerular filtration rate, but sex modified the effect of FGF23 on odds of SBI (P for interaction=0.03). FGF23 was associated with significantly greater odds of SBI only in men (odds ratio, 1.7; 95% CI, 1.1-2.7; P=0.03) after full adjustment. CONCLUSIONS: These cross-sectional community-based data from a diverse urban sample show an association between elevated FGF23 and small vessel disease and magnetic resonance imaging-defined brain infarction in men, independent of chronic kidney disease. Data on elevated FGF23 and subclinical cerebrovascular damage progression are needed.

Ideal Cardiovascular Health and Cognitive Aging in the Northern Manhattan Study.

BACKGROUND: The American Heart Association defined target levels for 7 cardiovascular health (CVH) factors: smoking, body mass index, physical activity, diet, blood pressure, cholesterol, and glucose. We hypothesized that a greater number of American Heart Association ideal CVH metrics would be associated with less decline in cognitive performance in our multiethnic population. METHODS AND RESULTS: A subsample from the population-based Northern Manhattan Study underwent repeated neuropsychological testing (mean interval 6±2 years). Domain-specific Z scores were derived by using factor analysis for the domains of Episodic Memory, Semantic Memory, Executive Function, and Processing Speed, based on initial performance and decline over time. Linear regression models were constructed to examine the relationship between the number of ideal CVH metrics at enrollment with later cognitive performance and decline, adjusting for sociodemographics and magnetic resonance imaging brain markers. Among 1033 participants (mean age at initial cognitive assessment 72±8 years, 39% male, 19% black, 16% white, 65% Hispanic; n=722 with repeat testing), 3% had 0 ideal factors, 15% had 1 factor, 33% had 2 factors, 30% had 3 factors, 14% had 4 factors, 4% had 5 factors, 1% had 6 factors, and 0% had 7 factors. An increasing number of ideal CVH factors was associated with better processing speed at initial assessment and less decline. The association was driven by nonsmoking and glucose. Among those with better cognitive performance at initial assessment, positive associations were observed between the number of ideal CVH factors and less decline in the domains of Executive Function and Episodic Memory. CONCLUSIONS: The number of ideal CVH metrics was associated with less decline in the domains of Processing Speed and, to a lesser extent, of Executive Function and Episodic Memory. Ideal CVH promotion benefits brain health and cognitive aging.

Compensatory intracranial arterial dilatation in extracranial carotid atherosclerosis: the Northern Manhattan study.

BACKGROUND: There is a scarcity of data supporting the association between atherosclerosis and dolichoectasia in unbiased samples. AIMS: To test the hypothesis that the association between dolichoectasia and extracranial carotid atherosclerosis depends on the degree of collateral circulation. METHODS: The Northern Manhattan Study magnetic resonance imaging substudy consists of 1290 participants who remained stroke-free at the time of magnetic resonance imaging. Arterial diameters were collected in all participants with available magnetic resonance angiography. Dolichoectasia was defined as a head-size adjusted diameter >2 standard deviation for each artery. Carotid Doppler was used to evaluate for carotid atherosclerosis (carotid plaque, maximum plaque thickness and carotid intima media thickness). RESULTS: We included 994 participants with available Doppler and magnetic resonance angiography data (mean age 63 years, 60% female). Any dolichoectasia was reported in 16% of participants, 54% had at least one carotid plaque and the mean carotid intima media thickness was 0·92 ± 0·09 mm. After adjusting for demographic and clinical characteristics, there was no association between markers of carotid atherosclerosis and dolichoectasia. However, stratifying by collaterals, it was observed that dolichoectasia was more likely in the anterior and posterior circulations when collaterals were available among participants with carotid atherosclerosis. These associations were confirmed by noting an increment in arterial diameters in the corresponding arteries ipsilateral and contralateral to each carotid as well as in the posterior circulation. CONCLUSIONS: We did not find an association of extracranial carotid atherosclerosis with dolichoectasia. However, we found that dolichoectasia is more frequent when intracranial collaterals are available suggesting a compensatory process that needs further investigation.

Short-term effect of atorvastatin on carotid artery elasticity: a pilot study.

BACKGROUND AND PURPOSE: Few studies have examined the early effects of statins on carotid artery elasticity, a potential surrogate marker of cardiovascular risk. This study examined the short-term effects of atorvastatin 80 mg daily on carotid elasticity measured by high-resolution B-mode ultrasound. METHODS: The study included 40 stroke-free and statin-naive subjects older than age 45 (mean age, 70±7 years; 55% men; 64% Caribbean-Hispanic). Outcome measures included carotid stiffness indices at 14 and 30 days after initiation of treatment. The systolic and diastolic diameters of the right common carotid artery were averaged from multiple B-mode imaging frames. Absolute and relative changes of strain [(systolic diameter-diastolic diameter)/diastolic diameter], stiffness (ß) [ln (systolic/diastolic blood pressure)/strain], and distensibility (1/ß adjusted for wall thickness) from baseline were compared by the repeated measures t test and were considered significant at α=0.05. RESULTS: Baseline mean stiffness was 0.08 (95% confidence interval [CI], 0.06-0.10). It significantly decreased at day 30 to 0.05 (CI, 0.04-0.06; P<0.01). Mean baseline distensibility was 15.25 (CI, 13.18-17.32), increasing significantly at day 30 to 17.23 (CI, 14.01-20.45; P<0.05). An improvement in distensibility of ≥10% from baseline was observed in 29 (73%) subjects. Changes in stiffness and distensibility were maximal among subjects with baseline low-density lipoprotein levels<130 mg/dL. CONCLUSIONS: Short-term treatment with high-dose atorvastatin was associated with improvement in the carotid elasticity metrics. Carotid artery elasticity measured by B-mode ultrasound is a simple noninvasive measure of arterial wall function and may be a useful surrogate end point in clinical trials targeting individuals at increased risk for atherosclerosis.

Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies.

BACKGROUND AND PURPOSE: Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas trials were prospectively designed, randomized, placebo-controlled trials of gavestinel, a glycine-site antagonist and putative neuroprotectant drug administered within 6 hours of suspected ischemic or hemorrhagic stroke. Both trials reported that gavestinel was ineffective in ischemic stroke. This analysis reports the results in those with primary intracerebral hemorrhage. METHODS: The primary hypothesis was that gavestinel treatment did not alter outcome, measured at 3 months by the Barthel Index (BI), from acute intracerebral hemorrhage, based on pooled results from both trials. The BI scores were divided into 3 groups: 95 to 100 (independent), 60 to 90 (assisted independence), and 0 to 55 (dependent) or dead. RESULTS: In total, 3450 patients were randomized in GAIN International (N=1804) and GAIN Americas (N=1646). Of these, 571 were ultimately identified to have spontaneous intracerebral hematoma on baseline head computerized tomography scan. The difference in distribution of trichotomized BI scores at 3 months between gavestinel and placebo was not statistically significant (P=0.09). Serious adverse events were reported at similar rates in the 2 treatment groups. CONCLUSIONS: These observations from the combined GAIN International and GAIN Americas trials suggest that gavestinel is not of substantial benefit or harm to patients with primary intracerebral hemorrhage. These findings are similar to results previously reported in patients with ischemic stroke.