Subclinical Brain Research Articles

Cardiac Biomarkers, Subclinical Brain Vascular Changes, and Cognitive Decline: Post Hoc Analysis of the SPRINT Trial.

The association between subclinical cardiovascular disease (CVD) and cognitive decline in hypertensive adults and the underlying brain pathologies remain unclear. It is also undetermined whether intensifying blood pressure (BP) treatment slows down cognitive decline associated with subclinical CVD. We conducted a post hoc analysis of the Systolic Blood Pressure Intervention Trial. Subclinical CVD at baseline was identified by elevated levels of high-sensitivity cardiac troponin T (hs-cTnT≥14ng/L) and N-terminal pro-B-type natriuretic peptide (NT-proBNP≥125 pg/mL). Global cognitive function and domain-specific measures (memory, processing speed, language, and executive function) were assessed at baseline and follow-up (years 2, 4, and 6) in 2733 participants. White matter lesions, cerebral blood flow, and brain tissue volume were assessed by MRI at baseline and years 4 in a subset of 639 participants. Both elevated hs-cTnT and NT-proBNP levels at baseline were associated with accelerated cognitive decline across all domains after adjusting for potential confounding factors. The group with elevated levels of both cardiac biomarkers showed the fastest decline, with a larger annual decline rate of 0.033 (95% CI: 0.024-0.041) in the z-score of global cognitive function compared to the group with normal levels. Elevated levels of both biomarkers were also associated with a faster progression in white matter lesions, but not with changes in total brain tissue volume or cerebral blood flow. Intensive BP treatment did not attenuate these associations compared to standard treatment. Subclinical CVD may contribute to faster white matter lesion progression and accelerated cognitive decline in patients with hypertension, regardless of intensive BP treatment.

Changes in Cerebral Hemodynamics and Progression of Subclinical Vascular Brain Disease: A Population-Based Cohort Study.

Cerebral hypoperfusion is associated with vascular brain injury and neurodegeneration, but their longitudinal relationship is largely unknown, especially in healthy older adults. We investigated the longitudinal relationship between cerebral hemodynamics and subclinical vascular brain disease in community-dwelling older adults without stroke or dementia at baseline. Participants underwent brain magnetic resonance imaging scans every 3 to 4 years between 2005 and 2016. Cerebral blood flow (CBF) was measured through 2-dimensional phase-contrast magnetic resonance imaging; the cerebrovascular resistance index (CVRi) was defined as the ratio of mean arterial blood pressure to total CBF. Simultaneous progression in subclinical brain disease was evaluated through repeated magnetic resonance imaging assessment of white matter hyperintensities (WMH), cerebral microbleeds, lacune, and brain atrophy. The longitudinal relationship was estimated using generalized estimating equations, with adjustment for age, sex, smoking habits, body mass index, systolic blood pressure (for CBF measures), lipid level, history of diabetes and cardiovascular disease, and the baseline burden of magnetic resonance imaging markers. Among 3623 older adults (mean age, 61.4±9.3 years; 54.6% women), large decreases and increases in CBF and increases in CVRi over time were associated with white matter hyperintensity progression. The risk ratios for white matter hyperintensity progression were 1.36 (95% CI, 1.19-1.55) for large decreases in total CBF (lowest quartile), 1.02 (95% CI, 0.91-1.14) for moderate decreases (second quartile), and 1.28 (95% CI, 1.14-1.45) for large increases (highest quartile), compared with stable CBF (third quartile). The corresponding risk ratios for changes in CVRi were 1.13 (95% CI, 1.00-1.30), 1.25 (95% CI, 1.09-1.43), and 1.33 (95% CI, 1.16-1.52) for the second to fourth (versus lowest) quartiles, respectively, showing a dose-response relationship. The changes in CBF also demonstrate a similar U-shaped association with the progression of brain atrophy and incident microbleeds, whereas increases in CVRi were associated with lower microbleed risk. Longitudinal changes in CBF and CVRi may capture distinct pathophysiologies linking cerebral hemodynamics to subclinical brain disease, extending beyond single-time point measurements.

Retinal Microperimetry as a Novel Tool for Early Detection of Subclinical Cognitive Dysfunction and Brain Damage in Type 1 Diabetes: A Pilot Study.

Retinal microperimetry (MPR) is a non-invasive method that measures retinal light sensitivity (RS) and gaze fixation stability (GFS). MPR has been described as a marker of cognitive impairment in people with Type 2 diabetes, but it has never been assessed in people with Type 1 diabetes (T1D). Our group described subclinical cognitive alterations, structural brain differences, and increased levels of light chain neurofilament (NfL) in people with T1D and impaired awareness of hypoglycaemia. To measure RS and GFS using MPR in individuals with T1D and evaluate its correlation with neuropsychological assessment, plasma NfL levels and CGM-derived glucometric parameters. to evaluate the possible differences of RS and GFS in people with T1D depending on hypoglycaemia awareness. Pilot observational study, people with T1D without clinical cognitive impairment, moderate-severe retinopathy or glaucoma. MPR was performed with MAIA3. A total of 30 subjects were studied: 40% women, age 58 ± 11 years; T1D duration 31 ± 9 years, mild retinopathy 33%. RS was 27.5 dB (26.1-28.3) and GFS(%) 97.6% (93.5%-99.5%). We found a correlation between RS and memory alteration tests (p = 0.016) and between GFS(%) and a composite of attention and executive neuropsychological tests (p = 0.025). An inverse correlation between GFS and time below range was found. No correlation was found with NfL. This first exploratory study in people with T1D supports the potential utility of MPR as a screening tool for subclinical neurocognitive alterations in this population.

P-Wave Duration Is Associated With Aging Patterns in Structural Brain Networks.

Impaired cardiac function is associated with cognitive impairment and brain imaging features of aging. Cardiac arrhythmias, including atrial fibrillation, are implicated in clinical and subclinical brain injuries. Even in the absence of a clinical diagnosis, subclinical or prodromal substrates of arrhythmias, including an abnormally long or short P-wave duration (PWD), a measure associated with atrial abnormalities, have been associated with stroke and cognitive decline. However, the extent to which PWD has subclinical influences on overall aging patterns of the brain is not clearly understood. Here, using neuroimaging and ECG data from the UK Biobank, we use a novel regional "brain age" method to identify the brain aging networks associated with abnormal PWD. We find associations between short PWD and accelerated brain aging in the sensorimotor, frontoparietal, ventral attention, and dorsal attention networks, even in the absence of overt cardiac diseases. These findings contribute to our understanding of the relationship between PWD and structural brain aging. This work emphasizes the need for continued study designs that consider brain-based outcomes related to abnormally short PWD.

Cardiac Biomarkers, Subclinical Brain Vascular Changes, and Cognitive Decline: Post Hoc Analysis of the SPRINT Trial

AbstractBackgroundSubclinical cardiovascular disease (CVD), assessed by high‐sensitivity cardiac troponin T (hs‐cTnT) and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), is linked to cognitive decline, but the associations in hypertensive adults and the underlying brain pathologies remain unclear. It is also undetermined whether an intensive blood pressure treatment compared to a standard treatment may slow down cognitive decline associated with subclinical CVD.MethodWe conducted a post hoc analysis of the Systolic Blood Pressure Intervention Trial, where older adults with hypertension were randomized to an intensive treatment (systolic blood pressure (SBP) target of < 120 mm Hg) or standard treatment (< 140 mm Hg). Serum hs‐cTnT and NT‐proBNP concentrations were measured at baseline, with elevated levels defined as ≥ 14 ng/L for hs‐cTnT and ≥ 125 pg/mL for NT‐proBNP. Global and domain‐specific (memory, processing speed, language, and executive function) cognitive function was assessed using a battery of neuropsychological tests at baseline and during the follow‐up (year 2, year 4, and year 6) in 2733 participants with biomarker measurements. White matter lesions, cerebral blood flow, and brain tissue volume were assessed by brain MRI at baseline and 4 years of follow‐up in a subset of 639 participants.ResultElevated levels of both hs‐cTnT and NT‐proBNP were associated with accelerated decline in cognitive function across all four domains after adjusting for potential confounding factors. The group with elevated levels of both cardiac biomarkers showed the fastest decline, with a greater annual decline rate of 0.033 (95% CI, 0.024 to 0.041) in standardized z‐score of global cognitive function compared to the group with normal hs‐cTnT and NT‐proBNP. Elevated levels of both cardiac biomarkers were also associated with a faster progression in white matter lesions, but not with changes in total brain tissue volume and cerebral blood flow. Intensive SBP treatment did not attenuate these associations compared to standard treatment (all P for interaction > 0.05).ConclusionElevated hs‐cTnT and NT‐proBNP levels were associated with accelerated cognitive decline and progression of white matter lesions regardless of SBP treatment assignment. Subclinical CVD may contribute to the progression of white matter lesions and thus leads to accelerated cognitive decline.

Brain morphometry in hepatic Wilson disease patients.

Wilson disease (WD) primarily presents with hepatic and neurological symptoms. While hepatic symptoms typically precede the neurological manifestations, copper accumulates in the brain already in this patient group and leads to subclinical brain MRI abnormalities including T2 hyperintensities and atrophy. This study aimed to assess brain morphological changes in mild hepatic WD. WD patients without a history of neurologic symptoms and decompensated cirrhosis and control participants underwent brain MRI at 3T scanner including high-resolution T1-weighted images. A volumetric evaluation was conducted on the following brain regions: nucleus accumbens, caudate, pallidum, putamen, thalamus, amygdala, hippocampus, midbrain, pons, cerebellar gray matter, white matter (WM), and superior peduncle, using Freesurfer v7 software. Whole-brain analyses using voxel- and surface-based morphometry were performed using SPM12. Statistical comparisons utilized a general linear model adjusted for total intracranial volume, age, and sex. Twenty-six WD patients with mild hepatic form (30 ± 9 years [mean age ± SD]); 11 women; mean treatment duration 13 ± 12 (range 0-42) years and 28 healthy controls (33 ± 9 years; 15 women) were evaluated. Volumetric analysis revealed a significantly smaller pons volume and a trend for smaller midbrain and cerebellar WM in WD patients compared to controls. Whole-brain analysis revealed regions of reduced volume in the pons, cerebellar, and lobar WM in the WD group. No significant differences in gray matter density or cortical thickness were found. Myelin or WM in general seems vulnerable to low-level copper toxicity, with WM volume loss showing promise as a marker for assessing brain involvement in early WD stages.

Association of cognitive and structural correlates of brain aging and incident epilepsy. The Framingham Heart Study.

Late-onset epilepsy has the highest incidence among all age groups affected by epilepsy and often occurs in the absence of known clinical risk factors such as stroke and dementia. There is increasing evidence that brain changes contributing to epileptogenesis likely start years before disease onset, and we aim to relate cognitive and imaging correlates of subclinical brain injury to incident late-onset epilepsy in a large, community-based cohort. We studied Offspring Cohort of the Framingham Heart Study participants 45 years or older, who were free of prevalent stroke, dementia, or epilepsy, and had neuropsychological (NP) evaluation and brain magnetic resonance imaging (MRI). Cognitive measures included Visual Reproduction Delayed Recall, Logical Memory Delayed Recall, Similarities, Trail Making Test B minus A (TrTB-TrTA; attention and executive function), and a global measure of cognition derived from principal component analysis. MRI measures included total cerebral brain volume, cortical gray matter volume (CGMV), white matter hyperintensity volume (WMHV), and hippocampal volume. Incident epilepsy was identified through a review of administrative data and medical records. Cox proportional hazards regression models were used for the analyses. All analyses were adjusted for age, sex, and educational level (cognition only). Among participants who underwent NP testing (n = 2349, 45.81% male), 31 incident epilepsy cases were identified during follow-up. Better performance on the TrTB-TrTA was associated with a lower risk of developing epilepsy (hazard ratio [HR] .25, 95% confidence interval [CI] .08-.73; p = .011). In the subgroup of participants with MRI (n = 2056, 46.01% male), 27 developed epilepsy. Higher WMHV was associated with higher epilepsy risk (HR 1.5, 95%CI 1.01-2.20; p = .042), but higher CGMV (HR .73, 95% CI .57-.93; p = .001) was associated with lower incidence of epilepsy. Better performance on the (TrTB-TrTA), a measure of executive function and attention, and higher cortical volumes are associated with lower risk of developing epilepsy. Conversely, higher WMHV, a measure of occult vascular injury, increases the risk. Our study shows that non-invasive tests performed in mid-life may help identify people at risk for developing epilepsy later in life.

Sex-Specific Vulnerabilities to Subclinical Vascular Brain Injury in Early Late-Life: The Framingham Heart Study.

Subclinical vascular brain injury is an increasingly recognized risk factor for stroke and dementia. Despite well-established sex differences in vascular risk and disease prevalence, the impact of sex on drivers of subclinical vascular brain injury remains unclear, presenting a barrier to developing sex-specific prevention guidelines. We aimed to establish the extent to which sex moderates associations between vascular risk factors and magnetic resonance imaging (MRI) measures of subclinical brain injury in stroke-free older adults. We leveraged cross-sectional data from 1,579 stroke- and dementia-free Framingham Heart Study Offspring participants at exam 8 (age 65.7 ± 8.8 years, 53% women). Vascular risks were assessed using components of the Framingham Stroke Risk Profile (FSRP) and diastolic blood pressure (DBP). White matter hyperintensity volume (WMH), total cerebral brain volume (TBV), and covert brain infarcts were quantified using MRI. We examined whether vascular risk factors were associated with MRI measures across the combined cohort, and then determined whether sex modified these associations. Higher FSRP and specifically systolic blood pressure (SBP) were associated with greater WMH. These associations were stronger in women and remained after adjusting for menopause age and hormone therapy use. By contrast, diabetes and lower DBP were associated with smaller TBV primarily in men. The DBP-atrophy relationship was only observed in men with declining DBP or prior hypertension. Our findings highlight differential vulnerability to the impact of vascular risk factors on white matter health in women and global atrophy in men, supporting the development of sex-specific guidelines to better preserve vascular brain health in aging. ANN NEUROL 2024.

Imaging signs of carotid plaque vulnerability predict subclinical neurological events in asymptomatic patients: the carotid artery multi-modality imaging prognostic study

Abstract Background Carotid artery plaques should be considered for invasive treatment if diameter stenoses is ≥60%, in the presence of clinical and/or imaging characteristics associated with an increased risk of ipsilateral stroke, such as intraplaque haemorrhage (IPH) or lipid-rich necrotic core (LRNC). However, little is known about plaque’s characteristics in patients with <60% stenoses. Purpose To evaluate the prevalence and significance of imaging signs of plaque vulnerability in patients with asymptomatic <60% carotid artery stenoses. Methods In the Carotid Artery Multi-modality imaging Prognostic (CAMP) study (granted by Bando Ricerca Salute 2018 - Regione Toscana) we prospectively enrolled 200 patients with asymptomatic, mild/moderate (40-60%) carotid artery stenoses, as assessed at Doppler ultrasound (DUS). All patients were evaluated with multimodality imaging, including computed tomography angiography (CTA), magnetic resonance angiography (MRA) and brain magnetic resonance imaging (MRI), whenever not contraindicated. A subgroup of 75 patients underwent also a 18[F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). A thorough clinical, biochemical, cardiological and neurological evaluation was performed in all patients. Results Imaging signs of plaque vulnerability were frequent (IPH and/or LRNC at MRA were found in 26.3% patients, plaque ulceration at CTA was found in 36.7% of patients). No difference in the prevalence of cardiovascular risk factors was noted in those with and without signs of vulnerability. Subclinical embolic brain infarctions at brain MRI were found in 8.8% of patients at enrollment. These patients had more frequently a LRNC at MRA than patients without subclinical embolic brain infarctions (50% vs 17%, p<0.05), lower estimated glomerular filtration rate (55±8 vs 73±23 mL/min/1.73mq, p<0.001), higher troponin HS values (16±4 vs 12±8 ng/ml, p<0.05). Presence of LRNC at MRA was the only predictor of embolic lesions at MRI (odds ratio 4.86, 95% confidence interval 1.08-21.8, p<0.05). Conclusions Imaging signs of vulnerability are highly prevalent in patients with asymptomatic intermediate carotid artery stenosis. Presence of a LRNC at MRA is associated with subclinical embolic brain infarcts. The use of non-invasive multi-imaging can better characterize carotid plaques, independent of the degree of stenosis, and help identifying a subgroup of patients at higher risk of events.

Clinical and subclinical acute brain injury caused by invasive cardiovascular procedures.

Over the past 50 years, the number and invasiveness of percutaneous cardiovascular procedures globally have increased substantially. However, cardiovascular interventions are inherently associated with a risk of acute brain injury, both periprocedurally and postprocedurally, which impairs medical outcomes and increases health-care costs. Current international clinical guidelines generally do not cover the area of acute brain injury related to cardiovascular invasive procedures. In this international Consensus Statement, we compile the available knowledge (including data on prevalence, pathophysiology, risk factors, clinical presentation and management) to formulate consensus recommendations on the prevention, diagnosis and treatment of acute brain injury caused by cardiovascular interventions. We also identify knowledge gaps and possible future directions in clinical research into acute brain injury related to cardiovascular interventions.

Family history of dementia and brain health in childhood and middle age: a prospective community-based study

We aimed to determine the association of family history of dementia with structural brain measures and cognitive performance in childhood and mid-life adulthood. We studied 1,259 parents (mean age: 47.3 years, range 31.9–67.4) and 866 of their children (mean age [range] at brain MRI: 9.9 years [8.8–11.9], and for cognition: 13.5 years [12.6–15.8]) of the population-based Generation R Study. Parents filled in a questionnaire on family history, and both parents and children underwent cognitive assessment and neuroimaging. Of all participants, 109 parents (8.6%) reported a parental family history of dementia and 73 children (8.4%) had a grandparental history of dementia with mean age of dementia diagnosis in those affected 75 years (± 7.3). We observed no associations of dementia family history with cognitive ability in either parents or their children, except for worse Purdue pegboard in parents with a parental history of dementia, compared to those without (mean difference [95%CI]: -1.23 [-2.15; -0.31], test range: 21–52). In parents and children, neuroimaging measures did not differ significantly by family history. Results did not depend on age, sex, and APOE genotype. Family history of dementia was associated with worse manual dexterity in mid-life adulthood, but not with any other measures of cognitive ability or subclinical brain health in childhood and mid-life. These findings suggest that the association of family history with dementia risk is due chiefly to neurodegenerative rather than neurodevelopmental processes, and might first present with reduced motor skills.

Subclinical brain manifestations of repeated mild traumatic brain injury are changed by chronic exposure to sleep loss, caffeine, and sleep aids

IntroductionAfter mild traumatic brain injury (mTBI), the brain is labile for weeks and months and vulnerable to repeated concussions. During this time, patients are exposed to everyday circumstances that, in themselves, affect brain metabolism and blood flow and neural processing. How commonplace activities interact with the injured brain is unknown. The present study in an animal model investigated the extent to which three commonly experienced exposures—daily caffeine usage, chronic sleep loss, and chronic sleep aid medication—affect the injured brain in the chronic phase. MethodsSubclinical trauma by repeated mTBIs was produced by our head rotational acceleration injury model, which causes brain injury consistent with the mechanism of concussion in humans. Forty-eight hours after a third mTBI, chronic administrations of caffeine, sleep restriction, or zolpidem (sedative hypnotic) began and were continued for 70 days. On Days 30 and 60 post injury, resting state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were performed. ResultsChronic caffeine, sleep restriction, and zolpidem each changed the subclinical brain characteristics of mTBI at both 30 and 60 days post injury, detected by different MRI modalities. Each treatment caused microstructural alterations in DTI metrics in the insular cortex and retrosplenial cortex compared with mTBI, but also uniquely affected other gray and white matter regions. Zolpidem administration affected the largest number of individual structures in mTBI at both 30 and 60 days, and not necessarily toward normalization (sham treatment). Chronic sleep restriction changed local functional connectivity at 30 days in diametrical opposition to chronic caffeine ingestion, and both treatment outcomes were different from sham, mTBI-only and zolpidem comparisons. The results indicate that commonly encountered exposures modify subclinical brain activity and structure long after healing is expected to be complete. ConclusionsChanges in activity and structure detected by fMRI are widely understood to reflect changes in the functions of the affected region which conceivably underlie mTBI neuropathology and symptomatology in the chronic phase after injury.

Uncovering the hidden effects of repetitive subconcussive head impact exposure: A mega-analytic approach characterizing seasonal brain microstructural changes in contact and collision sports athletes.

Repetitive subconcussive head impacts (RSHI) are believed to induce sub-clinical brain injuries, potentially resulting in cumulative, long-term brain alterations. This study explores patterns of longitudinal brain white matter changes across sports with RSHI-exposure. A systematic literature search identified 22 datasets with longitudinal diffusion magnetic resonance imaging data. Four datasets were centrally pooled to perform uniform quality control and data preprocessing. A total of 131 non-concussed active athletes (American football, rugby, ice hockey; mean age: 20.06 ± 2.06 years) with baseline and post-season data were included. Nonparametric permutation inference (one-sample t tests, one-sided) was applied to analyze the difference maps of multiple diffusion parameters. The analyses revealed widespread lateralized patterns of sports-season-related increases and decreases in mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across spatially distinct white matter regions. Increases were shown across one MD-cluster (3195 voxels; mean change: 2.34%), one AD-cluster (5740 voxels; mean change: 1.75%), and three RD-clusters (817 total voxels; mean change: 3.11 to 4.70%). Decreases were shown across two MD-clusters (1637 total voxels; mean change: -1.43 to -1.48%), two RD-clusters (1240 total voxels; mean change: -1.92 to -1.93%), and one AD-cluster (724 voxels; mean change: -1.28%). The resulting pattern implies the presence of strain-induced injuries in central and brainstem regions, with comparatively milder physical exercise-induced effects across frontal and superior regions of the left hemisphere, which need further investigation. This article highlights key considerations that need to be addressed in future work to enhance our understanding of the nature of observed white matter changes, improve the comparability of findings across studies, and promote data pooling initiatives to allow more detailed investigations (e.g., exploring sex- and sport-specific effects).

Association of aortic valve calcium with dementia and stroke: The Multi-Ethnic Study of Atherosclerosis

Background and aimsCalcific aortic valve disease is associated with increased thrombin formation, platelet activation, decreased fibrinolysis, and subclinical brain infarcts. We examined the long-term association of aortic valve calcification (AVC) with newly diagnosed dementia and incident stroke in the Multi-Ethnic Study of Atherosclerosis (MESA). MethodsAVC was measured using non-contrast cardiac CT at Visit 1. We examined AVC as a continuous (log-transformed) and categorical variable (0, 1–99, 100–299, ≥300). Newly diagnosed dementia was adjudicated using International Classification of Disease codes. Stroke was adjudicated from medical records. We calculated absolute event rates (per 1000 person-years) and multivariable adjusted Cox proportional hazards ratios (HR). ResultsOverall, 6812 participants had AVC quantified with a mean age of 62.1 years old, 52.9 % were women, and the median 10-year estimated atherosclerotic cardiovascular disease (ASCVD) risk was 13.5 %. Participants with AVC >0 were older and less likely to be women compared to those with AVC=0. Over a median 16-year follow-up, there were 535 cases of dementia and 376 cases of stroke. The absolute risk of newly diagnosed dementia increased in a stepwise pattern with higher AVC scores, and stroke increased in a logarithmic pattern. In multivariable analyses, AVC was significantly associated with newly diagnosed dementia as a log-transformed continuous variable (HR 1.09; 95 % CI 1.04–1.14) and persons with AVC ≥300 had nearly a two-fold higher risk (HR 1.77; 95 % CI 1.14–2.76) compared to those with AVC=0. AVC was associated with an increased risk of stroke after adjustment for age, sex, and race/ethnicity, but not after adjustment for ASCVD risk factors. ConclusionsAfter multivariable adjustment, AVC >0 was significantly associated with an increased risk of newly diagnosed dementia, but not incident stroke. This suggests that AVC may be an important risk factor for the long-term risk of dementia beyond traditional ASCVD risk factors.

#2929 Plasma levels of brain injury markers NfL and GFAP are independently predicted by glomerular filtration rate in patients with chronic kidney disease

Abstract Background and Aims Patients with chronic kidney disease (CKD) have a high prevalence of cerebrovascular disease and cognitive impairment. The aim of the present study was to measure brain injury biomarkers in plasma in a cohort of patients with CKD stages 3 and 4, without a diagnosis of cerebrovascular disease, and to determine factors that independently predicted plasma levels of these biomarkers. Method This was a cross-sectional cohort study including 110 patients with CKD stages 3 and 4, and 55 healthy, matched, controls, recruited from the outpatient clinic at Sahlgrenska university hospital, Gothenburg, Sweden. None of the included study subjects had a diagnosis of cerebrovascular disease, cognitive impairment, or any other neurological disease. Plasma concentrations of neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated Tau (p-Tau231) were analyzed with ultrasensitive single molecule array (SIMOA). Measured GFR (mGFR) was determined by plasma clearance of ⁵¹Cr-EDTA. Values are medians [interquartile range]. For linear regression analyses standardised beta coefficients (β) are presented. Results Characteristics of CKD patients and healthy controls are presented in Table 1. Plasma concentrations of NfL (37.5 [22.1-47.5] vs. 13.4 [10.5-16.7] ng/L, p < 0.001), p-Tau231 (25.7 [19.1-38.7] vs. 13.9 [10.5-16.3] ng/L, p < 0.001) and GFAP (190 [140-281] vs. 153 [116-211] ng/L, p = 0.001) were significantly elevated in patients with CKD vs. controls. In CKD patients, mGFR showed statistically significant inverse correlations to plasma concentrations of NfL, p-Tau231, and GFAP (Table 2). In multiple regression analyses, mGFR was associated with plasma levels of NfL (β = −0.457, p < 0.001) and GFAP (β = −0.322, p < 0.001) independently of diabetes, age, troponin-T, b-hemoglobin, and aortic pulse-wave velocity. However, mGFR was not significantly associated with plasma levels of p-Tau231 in a multiple regression analysis. Conclusion Plasma levels of brain injury markers NfL, p-Tau231 and GFAP were elevated in patients with CKD stages 3 and 4, without a history of cerebrovascular disease, compared to healthy controls. Furthermore, mGFR independently predicted plasma concentrations of NfL and GFAP in multiple regression models. These results raise the possibility that reduced GFR per se may be associated with subclinical brain injury.

Combined brain-heart MRI identifies cardiac and white matter lesions in patients with systemic lupus erythematosus and/or antiphospholipid syndrome: A pilot study

BackgroundAntiphospholipid syndrome (APS) can occur primarily (PAPS) or secondary to another autoimmune disease (SAPS), most commonly systemic lupus erythematosus (SLE). Recently, we reported that subclinical brain involvement was highly prevalent in patients with autoimmune diseases, including SLE. We aimed to investigate whether patients with SLE, PAPS or SAPS and cardiac symptoms showed differences in cardiac/brain involvement based on combined brain–heart magnetic resonance imaging (MRI). MethodsWe prospectively recruited 15 patients with SAPS (86 % with SLE) and 3 patients with PAPS and compared their MRI findings to those of 13 patients with SLE from our previous publication. All patients underwent routine cardiovascular/neurological examination and standard echocardiography. ResultsNo patients had abnormalities in routine clinical workup/echocardiography. The vast majority had white matter hyperintensities (WMHs) and all had evidence of myocardial fibrosis and/or inflammation. Patients with SAPS had a lower median WMH number [1.00 (1.00, 2.00)] than those with PAPS [3.00 (2.50, 3.00)] or SLE [2.00 (2.00, 3.00)] (p = 0.010). Subcortical and deep WM were highly prevalent. Periventricular WMHs were more frequent in patients with SLE [6 (46.2 %)] or PAPS [2 (66.7 %)] (p = 0.023). Higher lesion burdens (1 WMH vs. 2 WMHs vs. ≥ WMHs) were associated with the presence of cardiac fibrosis [3 (33.3 %) vs. 10 (83.3) vs. 7 (77.8), p = 0.039] and affected the deep and periventricular WM (p < 0.001 for both). ConclusionIn patients with PAPS, SAPS or SLE, cardiac symptoms and normal routine workup, combined brain–heart MRI identified abnormalities in both organs in the majority of patients. Combined brain–heart MRI offers excellent diagnostic value, but its incorporation into routine clinical practice should be further investigated.Clinical relevance statementCombined brain–heart magnetic resonance imaging in antiphospholipid syndrome may help to assess the presence of abnormalities in both organs.

Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.

Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

Intensive Blood Pressure Treatment and Subclinical Brain Infarcts: A Secondary Analysis of SPRINT (Systolic Pressure Intervention Trial).

Subclinical brain infarcts (SBI) increase the risk for stroke and dementia, but whether they should be considered equivalent to symptomatic stroke when determining blood pressure targets remains unclear. We tested whether intensive systolic blood pressure (SBP) treatment reduced the risk of new SBI or stroke and determined the association between SBI and cognitive impairment. In this secondary analysis of SPRINT (Systolic Pressure Intervention Trial), participants ≥50 years old, with SBP 130-180mmHg and elevated cardiovascular risk but without known clinical stroke, dementia, or diabetes, were randomized to intensive (<120mmHg) or standard (<140mmHg) SBP treatment. Brain magnetic resonance images collected at baseline and follow-up were read for SBI. The occurrence of mild cognitive impairment (MCI) or probable dementia (PD) was evaluated. For 667 participants at baseline, SBI were identified in 75 (11%). At median 3.9 years follow-up, 12 of 457 had new SBI on magnetic resonance imaging (5 intensive, 7 standard), whereas 8 had clinical stroke (4 per group). Baseline SBI (subhazard ratio [sHR] = 3.90; 95% CI 1.49 to 10.24; p = 0.006), but not treatment group, was associated with new SBI or stroke. For participants with baseline SBI, intensive treatment reduced their risk for recurrent SBI or stroke (sHR = 0.050; 95% CI 0.0031 to 0.79; p = 0.033). Baseline SBI also increased risk for MCI or PD during follow-up (sHR = 2.38; 95% CI 1.23 to 4.61; p = 0.010). New cerebral ischemic events were infrequent, but intensive treatment mitigated the increased risk for participants with baseline SBI, indicating primary prevention SBP goals are still appropriate when SBI are present. ANN NEUROL 2024;95:866-875.

Plasma neurofilament light and brain volumetric outcomes among middle‐aged urban adults

AbstractBackgroundElevated plasma neurofilament light chain (NfL) is associated with dementia, but the specific underlying mechanisms are largely unknown. We examined cross‐sectional and longitudinal relationships of plasma NfL with selected brain structural magnetic resonance imaging (sMRI) prognostic markers of dementia, namely global and cortical brain, hippocampal and white matter lesion volumes (WMLV).MethodData were extracted from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, selecting participants with complete v1 (2004‐2009) and v2 (2009‐2013) plasma NfL exposure and ancillary sMRI data at vscan (2011‐2015, n = 179, mean v1 to vscan time: 5.4y). Multivariable‐adjusted linear regression models were conducted, overall, by sex, and by race, correcting for multiple testing with q‐values.ResultNfL(v1) (Loge transformed) had a moderately strong association with larger WMLV at follow‐up vscan visit, after a period of 5‐6 years of follow‐up, overall (β = +2.131±0.660, b = +0.29, p = 0.001, q = 0.0029). Moreover, a 1 unit increase in NfLv2 was linked to a left hippocampal volume that was lower by 125 mm3 (p = 0.004, q = 0.015), using minimally adjusted models and mainly among males. Associations were largely unaltered by further adjustment for downstream health‐related factors.ConclusionIn summary, plasma NfL may be an independent medium‐term (within 5 years) marker for increase in WMLV, and a short term (within 1 year) marker for smaller hippocampal volumes normalized to the intracranial volume, independently of other confounding factors. Therefore, plasma NfL holds promise as a blood‐based marker to predict future subclinical brain pathologies in middle‐aged adults.

Imaging signs of vulnerability, neurological events and cognitive impairment in asymptomatic carotid artery stenosis: results from the Carotid Artery Multi-modality imaging Prognostic (CAMP) study

Abstract Background Carotid artery plaques with imaging signs of vulnerability, such as ulceration, intraplaque haemorrhage (IPH) or a lipid-rich necrotic core (LRNC), are associated with a high risk of ischemic stroke, and are reported to be considered for invasive treatment if % diameter stenoses ≥60. Little is known about their fate in patients with &amp;lt;60% stenoses. Purpose To evaluate the prevalence of ulceration, IPH and LRNC and their characteristics in patients with asymptomatic, non-significant (&amp;lt;60%) carotid artery stenoses. Methods One hundred and twenty-one patients with asymptomatic, unilateral, mild/moderate (40-60%) carotid artery stenoses at Doppler ultrasound (DUS), were prospectively evaluated with computed tomography angiography (CTA), magnetic resonance angiography (MRA) and brain magnetic resonance imaging (MRI). IPH and LRNC were defined at MRA, while ulceration was defined at CTA. Verbal and memory skills were tested by the Fifteen Reye’s Words and other standardized tests. Results At least one sign of vulnerability (IPH, LRNC or ulceration) was detected in 51.6% patients. Signs of vulnerability were more frequent in patients with ≥50% stenoses compared with those with &amp;lt;50% at DUS (62.5% vs 27.6%, p=0.002). No difference in the prevalence of cardiovascular risk factors was present in those with and without signs of vulnerability (Table). An ulceration at CTA was significantly associated with presence of IPH or LRNC even after adjustment for the degree of stenosis (OR 4.2, 95% CI 1.3-13.2; OR 4.0, 95% CI 1.4-11.2). Subclinical embolic brain infarctions were found in 10% of patients. A higher prevalence of LRNC was found in patients with brain infarctions (50% vs 17%, p&amp;lt;0.05). Patients with either IPH or LRNC performed worse at standardized tests of cognitive impairment (score 1.6±1.1 vs 2.2±1.4, p&amp;lt;0.05). Conclusions Imaging signs of vulnerability are highly prevalent in patients with asymptomatic intermediate carotid artery stenosis, and can be detected in more than one fourth of patients with a non-significant plaque in terms of degree of stenosis. Plaque ulceration at CTA is independently associated with LRNC and IPH at MRA, independent of the degree of stenosis. Plaques with LRNC are associated with subclinical embolic brain infarcts and a worse cognitive performance.TableFigure