Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

BACKGROUND: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. METHODS: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. RESULTS: We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (ß±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. CONCLUSIONS: Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

Menopause Status Moderates Sex Differences in Tau Burden: A Framingham PET Study.

OBJECTIVE: Women have a higher lifetime risk of Alzheimer's disease (AD) than men. Among cognitively normal (CN) older adults, women exhibit elevated tau positron emission tomography (PET) signal compared with men. We explored whether menopause exacerbates sex differences in tau deposition in middle-aged adults. METHODS: 328 CN participants from the Framingham Study (mean age = 57 years (±10 years), 161 women, of whom, 104 were post-menopausal) underwent tau and ß-amyloid (Aß)-PET neuroimaging. We examined global Aß-PET, and tau-PET signal in 5 regions identified a priori as demonstrating significant sex differences in older adults (in temporal, inferior parietal, middle frontal, and lateral occipital regions). We examined sex and menopause status-related differences in each region-of-interest, using linear regressions, as well as interactions with Aß and APOEε4 genotype. RESULTS: Women exhibited higher tau-PET signal (p < 0.002), and global Aß-PET (p = 0.010), than men in inferior parietal, rostral middle frontal, and lateral occipital regions. Compared with age-matched men, post-menopausal women showed significantly higher tau-PET signal in parieto-occipital regions (p < 0.0001). By contrast, no differences in tau-PET signal existed between pre-menopausal women and men. Aß-PET was not associated with menopausal status or age. Neither Aß-PET nor APOEε4 status moderated sex or menopause associations with tau-PET. INTERPRETATION: Clear divergence in tauopathy between the sexes are apparent approximately 20 years earlier than previously reported. Menopause status moderated sex differences in Aß and tau-PET burden, with tau first appearing post-menopause. Sex and menopause differences consistently appeared in middle frontal and parieto-occipital regions but were not moderated by Aß burden or APOEε4, suggesting that menopause-related tau vulnerability may be independent of AD-related pathways. ANN NEUROL 2022;92:11-22.

Antithrombotic therapy after acute ischemic stroke in patients with atrial fibrillation.

BACKGROUND AND PURPOSE: For patients with atrial fibrillation and ischemic stroke (IS), current guidelines recommend oral anticoagulation (OAC) alone for secondary prevention of IS. In a large prospective cohort of patients with acute IS and atrial fibrillation, we determine the association between antithrombotic regimen on discharge and risk of major vascular events. METHODS: Prospective cohort of consecutive patients included in the Ontario Stroke Registry. Multivariable Cox proportional hazard models were used to determine the association between antithrombotic regimen on discharge and time to death or admission for recurrent IS, myocardial infarction, or major bleeding. RESULTS: Two thousand one hundred sixty-two patients were hospitalized atrial fibrillation and acute IS. At discharge, 8.0% were prescribed no antithrombotic therapy, 21.6% antiplatelet therapy alone, 39.3% OAC (warfarin) alone, and 31.1% combination OAC and antiplatelet therapy. Compared with OAC alone (hazard ratio [HR], 1.0), no antithrombotic therapy (HR, 1.51; 95% confidence interval, 1.23-1.86) and antiplatelet therapy (HR, 1.31; 95% confidence interval, 1.14-1.50) were associated with an increased risk of the primary composite outcome, whereas combination OAC and antiplatelet therapy was associated with a trend toward a reduced risk (HR, 0.91; 95% confidence interval, 0.80-1.04 overall and HR, 0.79; 95% confidence interval, 0.61-1.02 in those with coronary heart disease). Results were consistent in those with severe stroke: HR 1.58 (95% CI, 1.21-2.06), 1.34 (95% CI, 1.09-1.63), and 0.91 (95% CI, 0.74-1.11), respectively. CONCLUSIONS: Contrary to current guidelines, 30% of patients with atrial fibrillation and recent IS are not prescribed any OAC therapy on discharge, whereas a further 30% are prescribed combination OAC and antiplatelet therapy. Combination OAC and antiplatelet therapy in patients at high cardiovascular risk requires evaluation in clinical trials, particularly with the newer OACs, given their more favorable risk-benefit ratio compared with warfarin.

Transesophageal echocardiography in patients with cryptogenic ischemic stroke: a systematic review.

BACKGROUND: The clinical utility of routine transesophageal echocardiography (TEE) for patients with unexplained ischemic stroke is controversial. We performed a systematic review to determine the frequency of detection of new cardiac findings in patients with cryptogenic ischemic stroke (IS) undergoing transesophageal echocardiography (TEE). METHODS: Systematic review and meta-analysis of cohort studies of consecutive patients with "cryptogenic" IS undergoing TEE after routine etiologic workup. Patients were categorized into 2 groups: A (< 55 years) and B (≥ 55 years). Outcomes included proportion of patients with new TEE-detected cardiac findings and proportion of patients commenced on oral anticoagulation after TEE. RESULTS: Twenty-seven studies were included (n = 5,653). We identified significant heterogeneity among studies and report a range of prevalence rates and I2 statistic as our primary analysis. Prevalence of individual cardiac findings on TEE varied significantly among studies; patent foramen ovale (A: 12.0%-57.8%, I2 = 89.9%; B: 3.9%-43.5%, I2 = 86.7%), atrial septal aneurysm (A: 0-48.9%, I2 = 91.9%; B: 3.5%-25.0%, I2 = 84.5%), left atrial thrombus (A: 0-10.9%, I2 = 61.1%; B: 0-21.2%, I2 = 91.7%), spontaneous echo contrast (A: 0-11.9%, I2 = 57.2%; B: 0-21.3%, I2 = 89.8%), and aortic atheroma (A: 0-9.6%, I2 = 53.8%; B: 2.8%-44.4%, I2 = 89.7%). Definitions of common findings were not provided for many studies. Five studies (n = 591) reported on the proportion of patients who were commenced on anticoagulant therapy after TEE (range 0-30.7%). CONCLUSIONS: Routine TEE in patients with cryptogenic IS identifies cardiac findings in a large proportion. However, there is marked interstudy variation in the definition and prevalence of common findings. Transesophageal echocardiography-detected findings prompted the introduction of anticoagulant therapy in up to one-third of patients. However, these were mostly not for established guideline-based indications based on randomized controlled trial evidence. It is unclear if routine use of TEE in patients with cryptogenic IS is indicated.

Vascular risk factors, cardiovascular disease and functional impairment in community-dwelling adults.

BACKGROUND: Older adults report preservation of functional independence as one of the most important constructs of successful ageing. Vascular risk factors may increase the risk of functional impairment due to clinical and subclinical vascular disease. OBJECTIVE: To describe the association between vascular risk factors and impaired ability to perform daily living activities, independent of established cardiovascular disease. METHODS: We conducted an analysis of the Clarity Cohort, which is a cross-sectional study of 9,816 community-dwelling Irish adults. Of the total cohort, 3,499 completed standardized self-reported health questionnaires, which included questions on activities of daily living. Functional impairment was defined as self-reported impairment in self-care, mobility or household tasks. Using logistic regression analyses, we determined the association between vascular risk factors and functional impairment, independent of demographics, prior coronary artery disease, stroke, congestive heart failure, and peripheral vascular disease. RESULTS: Functional impairment was reported in 40.4% (n = 1,413) of the cohort overall and in 23% of those with established cardiovascular disease. The mean age was 66.2 ± 10.3 years, 52% of the cohort were aged over 65 and 45.6% were male. Some difficulty with instrumental activities of daily living was reported by 35.4% (n = 1,240) while 29.4% (n = 1,029) reported some difficulty with basic activities of daily living. On multivariable analysis, older age [OR 1.03 (1.02, 1.04) per year], current smoking [OR 1.43 (1.08, 1.89)], atrial fibrillation [OR 1.68 (1.07, 2.65)], former alcohol use [OR 1.87 (1.36, 2.57)] and prior stroke [OR 1.91 (1.24, 2.93)] were associated with an increased risk of functional impairment. Older age leaving education [OR 0.96 (0.94, 0.99)], non-use of alcohol [OR 0.76 (0.61, 0.93)] and increased high-density lipoprotein levels [OR 0.70 (0.56, 0.88)] were associated with reduced risk of functional impairment. CONCLUSIONS: Independent of established cardiovascular disease, some vascular risk factors are associated with functional impairment. Modification of these risk factors is expected to have a large impact on preservation of functional independence through prevention of overt and covert vascular disease.

Associations of Plasma Tau with Amyloid and Tau PET: Results from the Community-Based Framingham Heart Study.

Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-ß deposition in the precuneus region (ß±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.

Clinical Reasoning: A 25-Year-Old Woman With Eye Swelling and Headache.

Cerebral venous sinus thrombosis (CVST) is uncommon. Risk factors include inherited and acquired factors. Rapid diagnosis and treatment is essential and can help prevent complications, which can include seizures and visual disturbance. A 25-year-old woman with a background history of CVST and intermittent warfarin use presented to the hospital in 2021 with a 3-month history of progressive eye swelling and headache. Her headache was located in the right frontal region and worsened with movement. Her workup was consistent with recurrent CVST and dural arteriovenous fistula. IR-guided embolization of the fistulas and stenting of her sinuses was performed. She was treated with dual antiplatelet therapy and therapeutic tinzaparin. Her symptoms improved markedly over several days, with improvement in headache and visual acuity. This case illustrates the potential for severe complications including visual disturbance in untreated CVST, as well as the importance of a thorough history and examination in aiding the recognition of the condition.

Population attributable fraction of hypertension for dementia: global, regional, and national estimates for 186 countries.

Background: Quantifying the proportion of dementia attributable to highly prevalent modifiable risk factors, such as hypertension, is important in informing effective dementia prevention strategies. We aim to quantify the population attributable fraction (PAF) of hypertension for dementia (the proportion of dementia cases that would not occur if hypertension was eliminated) at global, regional, and national levels. Methods: In this study, we searched international and governmental websites for global, regional, and national data reporting population hypertension (according to 10-year age categories) and dementia prevalence. MEDLINE was searched for studies reporting the risk of dementia from age at hypertension diagnosis from database inception to December 31, 2022. Longitudinal observational studies with >500 participants reporting hazard ratios by age at hypertension diagnosis for risk of future all-cause dementia were eligible for inclusion. Studies excluded had cross-sectional methodology, specific vascular dementia or 'cognitive impairment' outcomes, and no age-specific metrics of association reported. The PAF of hypertension for dementia was calculated globally and for each country and region worldwide. Findings: Data from the Global Burden of Disease, United Nations Population Prospectus, NCD Risk Factor Collaboration, UK Biobank, and Atherosclerosis Risk in Communities Study were obtained. 186 countries reported dementia and hypertension prevalence data. The global PAF of hypertension for dementia was 15.8% [95% Credible Interval (CI), 8.8%-22.7%]. Latin America and the Caribbean (18.0% [95% CI, 9.4%-26.6%]), and Europe (17.2% [95% CI, 9.6%-24.7%]) had the highest PAF of hypertension for dementia. Hypertension diagnosed between the ages of 30-44 had the highest age-specific global attributable fraction for dementia (8.4% [95% CI, 3.4%-13.5%]), followed by ages 45-54 (2.92% [ 95% CI, 0.96%-4.88%]), 55-64 (2.59% [95% CI, 1.15%-4.03%]) and 65-74 (1.82% [95% CI, -2.31%-5.96%]). Interpretation: The population attributable risk of hypertension for dementia is 15.8%, suggesting that optimal detection and treatment, particularly at midlife, has the potential to markedly reduce the global burden of dementia. Funding: Wellcome Trust; Health Research Board of Ireland; Alzheimer's Association.

Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging.

BACKGROUND: Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults. OBJECTIVE: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome. METHODS: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up). RESULTS: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities. CONCLUSIONS: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

Which risk factors are more associated with ischemic stroke than intracerebral hemorrhage in patients with atrial fibrillation?

BACKGROUND AND PURPOSE: The decision to prescribe oral anticoagulant therapy in patients with atrial fibrillation is based on an assessment of the competing risks of ischemic stroke and major bleeding, of which intracerebral hemorrhage (ICH) is the most important type. We sought to determine the comparative importance of risk factors for ischemic stroke and ICH in patients with acute stroke and atrial fibrillation with particular emphasis on risk factors common to both stroke types. METHODS: Consecutive patients with acute ischemic stroke or ICH and atrial fibrillation included in the Registry of the Canadian Stroke Network constituted the cohort. Multivariable logistic regression analysis was used to determine the association between baseline risk factors and presentation with ICH versus ischemic stroke. Risk factors included: (1) those previously reported to be risk factors for both ischemic stroke and major bleeding (particularly ICH) ("shared" risk factors, including age, alcohol, hypertension, diabetes mellitus, renal impairment, prior stroke/transient ischemic attack and preadmission dementia); and (2) other risk factors associated with either stroke subtype alone. RESULTS: A total of 3197 patients presented with atrial fibrillation and acute stroke, of which 12.2% presented with ICH. Of the "shared" risk factors, age (OR, 1.19; 95% CI, 1.06-1.34 per decade) and prior stroke/transient ischemic attack (OR, 1.45; 95% CI, 1.12-1.87) were more associated with ischemic stroke than ICH, whereas a history of hypertension (OR, 0.89; 95% CI, 0.68-1.17), diabetes mellitus (OR 1.23; 95% CI, 0.92-1.64), renal impairment (OR, 1.28; 95% CI, 0.95-1.71), and alcohol intake were not more strongly associated with either stroke subtype. CONCLUSION: Of the risk factors known to be associated with both ischemic stroke and ICH in patients with atrial fibrillation, we found that none had a stronger association with ICH. Older age was more strongly associated with ischemic stroke than ICH.

Preventing cardiovascular disease in primary care: role of a national risk factor management program.

BACKGROUND: Heartwatch, a structured risk factor modification program for secondary prevention of cardiovascular (CV) disease (CVD) in primary care, is associated with improvements in CV risk factors in participating patients. However, it is not known whether Heartwatch translates into reductions in clinically important CV events. OBJECTIVE: The aim of the study was to determine the association between participation in Heartwatch and future risk of CV events in patients with CVD. METHODS: The study consisted of a prospective cohort of 1,609 patients with CVD in primary care practices. Of these, 97.5% had data available on Heartwatch participation status, of whom 15.2% were Heartwatch participants. Cox proportional hazards models were used to determine the association between Heartwatch participation and risk of the CV composite (CV death, nonfatal myocardial infarction, heart failure, and nonfatal stroke). All-cause mortality and CV mortality were secondary outcome measures. RESULTS: During follow-up, the CV composite occurred in 208 patients (13.6%). Of Heartwatch participants, 8.4% experienced the CV composite compared with 14.5% of nonparticipants (P = .003). Participation in Heartwatch was associated with a significantly reduced risk of the CV composite (hazard ratio [HR] 0.52, 95% CI, 0.31-0.87), CV mortality (HR 0.31, 95% CI, 0.11-0.89), and all-cause mortality (HR 0.32, 95% CI, 0.15-0.68). Heartwatch participation was also associated with greater reductions in mean systolic blood pressure (P = .047), mean diastolic blood pressure (P < .001), and greater use of secondary preventative therapies for CVD, such as lipid-lowering agents (P < .001), ß-blockers (P < .001), and angiotensin-converting enzyme inhibitors (P < .001). CONCLUSION: Heartwatch is associated with a reduced risk of major vascular events and improved risk factor modification, supporting its potential as a nationwide program for secondary prevention of CVD.

Determining Vascular Risk Factors for Dementia and Dementia Risk Prediction Across Mid- to Later-Life: The Framingham Heart Study.

BACKGROUND AND OBJECTIVES: The association between vascular risk factors and dementia varies with age making generalisability of dementia risk prediction rules to individuals of different ages challenging. We determined the most important vascular risk factors for inclusion in age-specific dementia risk scores. METHODS: Framingham Heart Study Original and Offspring cohort participants with available data on the Framingham Stroke Risk Profile (FSRP) at mid-life(age 55; n=4899, 57% women), late-life(ages 65 or 70), or later-life(ages 75 or 80[n=2386, 62% women]) were followed for 10-year incident dementia risk from ages 65, 70, 75 and 80. RESULTS: Age- and sex-adjusted mid-life risk factors associated with 10-year risk of dementia from age 65 included FSRP (HR 1.16, 95% CI 1.06-1.26, per 1-SD increment in log-transformed score), diabetes mellitus (DM, HR 4.31, 95% CI 1.97-9.43) and systolic blood pressure (SBP, HR 1.12, 95% CI 1.02-1.24, per 10mmHg increment). Late-life risk factors associated with 10-year incident dementia from ages 65 or 70 included FSRP (age 65 only: HR 1.06, 95% CI 1.02-1.10), antihypertensive use (age 65 reported: HR 1.66, 95% CI 1.12-2.46), DM (age 65 reported: HR 1.96, 95% CI 1.09-3.52), atrial fibrillation (age 65 reported: HR 2.30, 95% CI 1.00-5.27), non-stroke cardiovascular disease (nsCVD, age 65 reported: HR 1.95, 95% CI 1.24-3.07) and stroke (age 70 only: HR 3.61, 95% CI 2.21-5.92). Later-life risk factors associated with 10-year incident dementia from ages 75 or 80 included antihypertensive use (age 80 only: HR 0.74, 95% CI 0.62-0.89), DM (age 80 reported: HR 1.40, 95% CI 1.04-1.89), atrial fibrillation (age 80 reported: HR 1.43, 95% CI 1.07-1.92) and stroke (age 80 reported: HR 1.63, 95% CI 1.13-2.35). In stepwise models, SBP and DM at age 55, nsCVD at age 65, DM and stroke at ages 70 and 75, and DM, stroke and use of antihypertensives (protective) at age 80 were the most important vascular risk factors for dementia. DISCUSSION: Our findings support the use of age-specific dementia risk scores which should prioritise including, at age 55, SBP and DM; age 65, nsCVD; ages 70 and 75, DM and stroke; and age 80, DM, stroke and antihypertensive use.

Identifying Blood Biomarkers for Dementia Using Machine Learning Methods in the Framingham Heart Study.

Blood biomarkers for dementia have the potential to identify preclinical disease and improve participant selection for clinical trials. Machine learning is an efficient analytical strategy to simultaneously identify multiple candidate biomarkers for dementia. We aimed to identify important candidate blood biomarkers for dementia using three machine learning models. We included 1642 (mean 69 ± 6 yr, 53% women) dementia-free Framingham Offspring Cohort participants attending examination, 7 who had available blood biomarker data. We developed three machine learning models, support vector machine (SVM), eXtreme gradient boosting of decision trees (XGB), and artificial neural network (ANN), to identify candidate biomarkers for incident dementia. Over a mean 12 ± 5 yr follow-up, 243 (14.8%) participants developed dementia. In multivariable models including all 38 available biomarkers, the XGB model demonstrated the strongest predictive accuracy for incident dementia (AUC 0.74 ± 0.01), followed by ANN (AUC 0.72 ± 0.01), and SVM (AUC 0.69 ± 0.01). Stepwise feature elimination by random sampling identified a subset of the nine most highly informative biomarkers. Machine learning models confined to these nine biomarkers showed improved model predictive accuracy for dementia (XGB, AUC 0.76 ± 0.01; ANN, AUC 0.75 ± 0.004; SVM, AUC 0.73 ± 0.01). A parsimonious panel of nine candidate biomarkers were identified which showed moderately good predictive accuracy for incident dementia, although our results require external validation.

Blood Phosphorylated Tau 181 as a Biomarker for Amyloid Burden on Brain PET in Cognitively Healthy Adults.

BACKGROUND: Plasma phosphorylated-tau181 (p-tau181) is a promising biomarker for Alzheimer's disease (AD) and may offer utility for predicting preclinical disease. OBJECTIVE: To evaluate the prospective association between plasma p-tau181 and amyloid-ß (Aß) and tau-PET deposition in cognitively unimpaired individuals. METHODS: Plasma p-tau181 levels were measured at baseline in 52 [48% women, mean 64.4 (SD 5.5) years] cognitively unimpaired Framingham Offspring cohort participants using samples stored between 2011-2014 who subsequently underwent 11C-Pittsburgh Compound-B (PiB)-PET and/or 18F-Flortaucipir (FTP)-PET scans (n = 18 with tau-PET) a mean of 6.8 (SD 0.6) years later. Our primary outcomes included Aß-precuneus, Aß-FLR (frontal, lateral, and retrosplenial cortices) and tau-global composite region PET deposition. Secondary outcomes included individual regional Aß and tau PET-deposition. P-tau181 was compared with plasma neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in predicting PET outcomes. RESULTS: P-tau181 was associated with increased Aß deposition in the FLR (ß±SE, 1.25±0.30, p < 0.0001), precuneus (1.35±0.29, p < 0.001), and other cortical regions. Plasma NFL (1.30±0.49, p = 0.01) and GFAP (1.46±0.39, p < 0.001) were also associated with FLR Aß deposition. In models including all three biomarkers adjusted for age, sex, APOE E4 allele, AD polygenic risk score and cortical atrophy score, p-tau181 (0.93±0.31, p < 0.01, R2 = 0.18) and GFAP (0.93±0.41, p = 0.03, R2 = 0.11), but not NFL (0.25±0.51, p = 0.62, R2 = 0.01), were associated with FLR-Aß deposition. Plasma p-tau181 was not associated with tau-PET burden. CONCLUSION: In cognitively unimpaired adults, elevated plasma p-tau181 is associated with future increased Aß deposition across multiple brain regions. Our results highlight the potential utility of p-tau181 as a blood-biomarker to screen for brain-amyloid deposition in cognitively healthy individuals in a community-setting.

Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study.

BACKGROUND: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia. OBJECTIVE: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer's disease (AD) dementia. METHODS: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998-2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance. RESULTS: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18-2.64) and AD dementia (HR 1.76, 95% CI 1.11-2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (ß±SE, -0.28±0.11, p = 0.01) and hippocampal volumes (-0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, -0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1). CONCLUSION: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

Interleukin-6 Interacts with Sleep Apnea Severity when Predicting Incident Alzheimer's Disease Dementia.

Because of their roles as potential risk factors, we evaluated whether obstructive sleep apnea (OSA) severity interacts with interleukin-6 (IL-6) in predicting incident dementia of the Alzheimer's type (DAT). In 269 dementia-free participants, IL-6 and the apnea-hypopnea index (AHI) were measured at baseline and incident DAT was surveilled for up to 22.8 years. Cox models revealed a significant interaction: In the lowest IL-6 quartile only, a higher AHI was associated with an elevated risk of DAT. The association between OSA severity and incident DAT might be especially apparent in the absence of inflammation or absence of potential benefits from IL-6.

Systemic inflammation as a moderator between sleep and incident dementia.

STUDY OBJECTIVES: To determine whether C-reactive protein (CRP), a marker of systemic inflammation, moderates the association between sleep and incident dementia. METHODS: We studied Framingham Heart Study participants who completed at baseline a serum CRP assessment and in-home polysomnography to measure sleep duration, sleep efficiency, sleep latency, wake after sleep onset (WASO), number of awakenings, arousal index, and apnea-hypopnea index. Participants were divided into groups according to their CRP level: low (<1 mg/L), average (1-3 mg/L), and high inflammation (>3 mg/L). Surveillance for outcomes (incident all-cause and Alzheimer's disease [AD] dementia) commenced at baseline and continued up to 22.5 years. RESULTS: In 291 participants (mean age 67.5 ± 4.9 years, 51.6% men) followed for 13.4 ± 5.4 years, we observed 43 cases of all-cause dementia, 33 of which were clinically consistent with AD. Whereas no direct association between CRP or sleep exposures was observed with incident dementia, CRP levels interacted with nighttime wakefulness when predicting both incident all-cause and AD dementia. In the high CRP group, longer WASO (hazard ratio [HR], 2.89; 95% CI, 1.31-6.34) and more nighttime awakenings (HR, 4.55; 95% CI, 1.19-17.38) were associated with higher risk of incident dementia. In the low CRP group, fewer nighttime awakenings were associated with a higher risk of incident dementia (HR, 0.07; 95% CI, 0.01-0.68). CONCLUSIONS: Our findings suggest that inflammation moderates the association between sleep, particularly nighttime wakefulness, and dementia risk. The presence of inflammation may be an important determinant in evaluating how sleep disturbances relate to neurodegeneration.

Growth Differentiation Factor 15 and NT-proBNP as Blood-Based Markers of Vascular Brain Injury and Dementia.

Background GDF15 (growth differentiation factor 15) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community-based cohort. Methods and Results Plasma GDF15 (n=1603) and NT-proBNP levels (n=1590) (53% women; mean age, 68.7 years) were measured in dementia-free Framingham Offspring cohort participants at examination 7 (1998-2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8-year follow-up, 131 participants developed dementia. On multivariable Cox proportional-hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all-cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log-transformed biomarker value, 1.54 [95% CI, 1.22-1.95] and 1.37 [95% CI, 1.03-1.81], respectively), whereas higher plasma NT-proBNP was also associated with an increased risk of all-cause dementia (HR, 1.32; 95% CI, 1.05-1.65). Elevated GDF15 was associated with lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT-proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25; 95% CI, 0.05-0.45). Conclusions Elevated plasma GDF15 and NT-proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in individuals aged >60 years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, indicating their potential value in predicting incident dementia.