MRI Markers Research Articles

Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease.

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with a higher risk of dementia and, consequently, be not rarely misdiagnosed. In this review, we summarize the current understanding of LBD-AD by discussing the synergistic effects of AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment for use in LBD-AD and their possible diagnostic and prognostic values. AD pathology can be predicted in vivo by means of CSF, MRI and PET markers, whereas the most promising technique to date for identifying Lewy pathology in different biological tissues is the α-synuclein seed amplification assay. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity as in pure AD. Implementing the use of blood-based AD biomarkers might allow faster screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account when considering differential diagnoses of dementia syndromes, to allow prognostic evaluation on an individual level, and to guide symptomatic and disease-modifying therapies.

The memory binding test in a longitudinal study of cognitive aging and preclinical disease.

The Memory Binding Test (MBT) shows promise in detecting early cognitive changes associated with Alzheimer's disease (AD). This study assesses the psychometric properties (i.e., construct and criterion validity, test-retest reliability) of the MBT and its sensitivity to incipient disease and incident cognitive impairment. One hundred forty-nine cognitively unimpaired adults ages 45-85 completed the MBT and neuropsychological tests at baseline; 132 returned for 2-year follow-up. Based on neuroradiological ratings of amyloid positron emission tomography and MRI markers at baseline, they were categorized as healthy (n = 94) or having preclinical disease (n = 55, either on the AD continuum or having non-AD pathologic change). Construct validity was assessed by the associations between MBT scores, demographics, and neuropsychological scores within the healthy group. Criterion validity was assessed by testing how MBT scores correlate with AD biomarkers, differ and discriminate between groups at baseline, and predict incident cognitive impairment. MBT scores decreased with age and were strongly associated with memory and global cognition. MBT scores were largely not associated with amyloid, hippocampal volume, or AD signature cortical volume but related to white matter lesion volume in those with preclinical disease. The preclinical groups performed worse on MBT immediate free recall at baseline than the healthy group, but no scores predicted incident cognitive impairment at follow-up. Most scores demonstrated modest test-retest reliability. This study demonstrates that the MBT has adequate construct validity in cognitively unimpaired adults, moderate sensitivity to preclinical disease cross-sectionally, and limited prognostic utility. Careful consideration of demographic influences on score interpretation remains necessary. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Prevalence and 3-month follow-up of cerebrovascular MRI markers in hospitalized COVID-19 patients: the CORONIS study

PurposeTo investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months.MethodsCORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders.Results125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07–8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%).ConclusionOverall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization.

Lung Function and Brain MRI Outcomes in the Atherosclerosis Risk in Communities Neurocognitive Study.

Brain imaging studies may provide etiologic insight into observed links between lung function and dementia and stroke. We evaluated associations of lung function measures with brain MRI markers of vascular and neurodegenerative disease in the ARIC Neurocognitive Study, as few studies have examined the associations. Lung function was measured at participants' midlife in 1990-1992 (mean age = 56±5 years) and later-life in 2011-2013 (mean age = 76±5 years), and brain MRI was performed in 2011-2013. Linear regression models were used to examine the associations of lung function with brain and white matter hyperintensity (WMH) volumes, and logistic regression models were used for cerebral infarcts and microbleeds, adjusting for potential confounders. In cross-sectional analysis (i.e., examining later-life lung function and MRI markers, n = 1,223), higher forced-expiratory volume in one second (FEV1) and forced vital capacity (FVC) were associated with larger brain and lower WMH volumes [e.g., 8.62 (95% CI:2.54-14.71) cm3 greater total brain volume per one-liter higher FEV1]. No association was seen with microbleeds in the overall sample, but higher FVC was associated with lower odds of microbleeds in never-smokers and higher odds in ever-smokers. In the cross-temporal analysis (i.e., associations with midlife lung function, n = 1,787), higher FVC levels were significantly associated with lower later-life brain volumes. Our results support modest associations of better lung function with less neurodegenerative and cerebrovascular pathology, although findings for microbleeds were unexpected in ever-smokers.

Association of Loneliness with Functional Connectivity MRI, Amyloid-β PET, and Tau PET Neuroimaging Markers of Vulnerability for Alzheimer's Disease.

Loneliness has been declared an "epidemic" associated with negative physical, mental, and cognitive health outcomes such as increased dementia risk. Less is known about the relationship between loneliness and advanced neuroimaging correlates of Alzheimer's disease (AD). To assess whether loneliness was associated with advanced neuroimaging markers of AD using neuroimaging data from Framingham Heart Study (FHS) participants without dementia. In this cross-sectional observational analysis, we used functional connectivity MRI (fcMRI), amyloid-β (Aβ) PET, and tau PET imaging data collected between 2016 and 2019 on eligible FHS cohort participants. Loneliness was defined as feeling lonely at least one day in the past week. The primary fcMRI marker was Default Mode Network intra-network connectivity. The primary PET imaging markers were Aβ deposition in precuneal and FLR (frontal, lateral parietal and lateral temporal, retrosplenial) regions, and tau deposition in the amygdala, entorhinal, and rhinal regions. Of 381 participants (mean age 58 [SD 10]) who met inclusion criteria for fcMRI analysis, 5% were classified as lonely (17/381). No association was observed between loneliness status and network changes. Of 424 participants (mean age 58 [SD = 10]) meeting inclusion criteria for PET analyses, 5% (21/424) were lonely; no associations were observed between loneliness and either Aβ or tau deposition in primary regions of interest. In this cross-sectional study, there were no observable associations between loneliness and select fcMRI, Aβ PET, and tau PET neuroimaging markers of AD risk. These findings merit further investigation in prospective studies of community-based cohorts.

Leptomeningeal enhancement in multiple sclerosis: a focus on patients treated with hematopoietic stem cell transplantation.

Leptomeningeal enhancement (LME) is considered an MRI marker of leptomeningeal inflammation in inflammatory neurological disorders, including multiple sclerosis (MS). To our knowledge, no disease-modifying therapies (DMTs) have been demonstrated to affect LME number or morphology so far. Monocentric study investigating the frequency and number of LME in a cohort of people with (pw)MS who performed a 3 T brain MRI with a standardized protocol (including a post-contrast FLAIR sequence), and exploring the impact of autologous hematopoietic stem cell transplantation (AHSCT) on this marker. In a longitudinal pilot study, consecutive MRIs were also analyzed in a subgroup of pwMS, including patients evaluated both pre- and post-AHSCT. Fifty-five pwMS were included: 24/55 (44%) had received AHSCT (AHSCT group) and 31 other treatments (CTRL group). At least one LME was identified in 19/55 (35%) cases (42 and 29% in the AHSCT and CTRL groups, respectively; p = 0.405). In the AHSCT group, LME number correlated with age at AHSCT (R = 0.50; p = 0.014), but not with age at post-treatment MRI. In the longitudinal pilot study (n = 8), one LME disappeared following AHSCT in 1/4 patients, whereas LME number was unchanged in the remaining four pwMS from the CTRL group. These results suggest that AHSCT may affect development and persistence of LME, strengthening the indication for early use of effective therapies bioavailable within the central nervous system (CNS), and therefore potentially targeting compartmentalized inflammation.

White matter integrity and functional connectivity of the default mode network in acute stroke are associated with cognitive outcome three months post-stroke

BackgroundKnowledge about factors that are associated with post-stroke cognitive outcome is important to identify patients with high risk for impairment. We therefore investigated the associations of white matter integrity and functional connectivity (FC) within the brain's default-mode network (DMN) in acute stroke patients with cognitive outcome three months post-stroke. MethodsPatients aged between 18 and 85 years with an acute symptomatic MRI-proven unilateral ischemic middle cerebral artery infarction, who had received reperfusion therapy, were invited to participate in this longitudinal study. All patients underwent brain MRI within 24–72 h after symptom onset, and participated in a neuropsychological assessment three months post-stroke. We performed hierarchical regression analyses to explore the incremental value of baseline white matter integrity and FC beyond demographic, clinical, and macrostructural information for cognitive outcome. ResultsThe study cohort comprised 34 patients (mean age: 64 ± 12 years, 35% female). The initial median National Institutes of Health Stroke Scale (NIHSS) score was 10, and significantly improved three months post-stroke to a median NIHSS = 1 (p < .001). Nonetheless, 50% of patients showed cognitive impairment three months post-stroke. FC of the non-lesioned anterior cingulate cortex of the affected hemisphere explained 15% of incremental variance for processing speed (p = .007), and fractional anisotropy of the non-lesioned cingulum of the affected hemisphere explained 13% of incremental variance for cognitive flexibility (p = .033). ConclusionsWhite matter integrity and functional MRI markers of the DMN in acute stroke explain incremental variance for post-stroke cognitive outcome beyond demographic, clinical, and macrostructural information.

Plasma trimethylamine N-oxide (TMAO): associations with cognition, neuroimaging, and dementia

BackgroundThe gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine – have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain.MethodsIn the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function.ResultsOverall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses.ConclusionsPlasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.

Enlarged perivascular spaces and their association with motor, cognition, MRI markers and cerebrovascular risk factors in male fragile X premutation carriers

FMR1 premutation carriers (55–200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. In the general population, enlarged perivascular spaces (PVS) are biomarkers of small vessel disease and glymphatic dysfunction and are associated with cognitive decline. Our aim was to determine if premutation carriers show higher ratings of PVS than controls and whether enlarged PVS are associated with motor and cognitive impairment, MRI features of neurodegeneration, cerebrovascular risk factors and CGG repeat length. We evaluated 655 MRIs (1–10 visits/participant) from 229 carriers (164 with FXTAS and 65 without FXTAS) and 133 controls. PVS in the basal ganglia (BG-EPVS), centrum semiovale, and midbrain were evaluated with a semiquantitative scale. Mixed-effects models were used for statistical analysis adjusting for age. In carriers with FXTAS, we revealed that (1) BG-PVS ratings were higher than those of controls and carriers without FXTAS; (2) BG-PVS severity was associated with brain atrophy, white matter hyperintensities, enlarged ventricles, FXTAS stage and abnormal gait; (3) age-related increase in BG-PVS was associated with cognitive dysfunction; and (4) PVS ratings of all three regions showed robust associations with CGG repeat length and were higher in carriers with the MCP sign than carriers without the sign. This study demonstrates clinical relevance of PVS in FXTAS especially in the basal ganglia region and suggests microangiopathy and dysfunctional cerebrospinal fluid circulation in FXTAS physiopathology.

Perivascular Spaces, Diffusivity Along Perivascular Spaces, and Free Water in Cerebral Small Vessel Disease.

Previous studies have linked the MRI measures of perivascular spaces (PVSs), diffusivity along the perivascular spaces (DTI-ALPS), and free water (FW) to cerebral small vessel disease (SVD) and SVD-related cognitive impairments. However, studies on the longitudinal associations between the three MRI measures, SVD progression, and cognitive decline are lacking. This study aimed to explore how PVS, DTI-ALPS, and FW contribute to SVD progression and cognitive decline. This is a cohort study that included participants with SVD who underwent neuroimaging and cognitive assessment, specifically measuring Mini-Mental State Examination (MMSE), cognitive index, and processing speed, at 2 time points. Three MRI measures were quantified: PVS in basal ganglia (BG-PVS) volumes, FW fraction, and DTI-ALPS. We performed a latent change score model to test inter-relations between the 3 MRI measures and linear regression mixed models to test their longitudinal associations with the changes of other SVD MRI markers and cognitive performances. In baseline assessment, we included 289 participants with SVD, characterized by a median age of 67.0 years and 42.9% women. Of which, 220 participants underwent the follow-up assessment, with a median follow-up time of 3.4 years. Baseline DTI-ALPS was associated with changes in BG-PVS volumes (β = -0.09, p = 0.030), but not vice versa (β = -0.08, p = 0.110). Baseline BG-PVS volumes were associated with changes in white matter hyperintensity (WMH) volumes (β = 0.33, p-corrected < 0.001) and lacune numbers (β = 0.28, p-corrected < 0.001); FW fraction was associated with changes in WMH volumes (β = 0.30, p-corrected < 0.001), lacune numbers (β = 0.28, p-corrected < 0.001), and brain volumes (β = -0.45, p-corrected < 0.001); DTI-ALPS was associated with changes in WMH volumes (β = -0.20, p-corrected = 0.002) and brain volumes (β = 0.23, p-corrected < 0.001). Furthermore, baseline FW fraction was associated with decline in MMSE score (β = -0.17, p-corrected = 0.006); baseline FW fraction and DTI-ALPS were associated with changes in cognitive index (FW fraction: β = -0.25, p-corrected < 0.001; DTI-ALPS: β = 0.20, p-corrected = 0.001) and processing speed over time (FW fraction: β = -0.29, p-corrected < 0.001; DTI-ALPS: β = 0.21, p-corrected < 0.001). Our results showed that increased BG-PVS volumes, increased FW fraction, and decreased DTI-ALPS are related to progression of MRI markers of SVD, along with SVD-related cognitive decline over time. These findings may suggest that the glymphatic dysfunction is related to SVD progression, but further studies are needed.

Serum and cerebrospinal fluid neurofilament light chain and glial fibrillary acid protein levels in early and advanced stages of cerebral amyloid Angiopathy

BackgroundNeurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking.We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA.MethodsFor this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aβ40 and Aβ42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups.ResultsWe included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years).In presymptomatic D-CAA, only GFAP in CSF (7.7*103pg/mL vs. 4.4*103pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*102pg/mL vs. 7.8*102pg/mL; P=0.01 and GFAP:11.4*103pg/mL vs. 7.5*103pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*102pg/mL vs 7.8*102pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aβ42 levels (P=0.01/0.02).ConclusionsGFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA.

Identification of Distinct Brain MRI Phenotypes and Their Association With Long-Term Dementia Risk in Community-Dwelling Older Adults.

Individual brain MRI markers only show at best a modest association with long-term occurrence of dementia. Therefore, it is challenging to accurately identify individuals at increased risk for dementia. We aimed to identify different brain MRI phenotypes by hierarchical clustering analysis based on combined neurovascular and neurodegenerative brain MRI markers and to determine the long-term dementia risk within the brain MRI phenotype subgroups. Hierarchical clustering analysis based on 32 combined neurovascular and neurodegenerative brain MRI markers in community-dwelling individuals of the Age-Gene/Environment Susceptibility Reykjavik Study was applied to identify brain MRI phenotypes. A Cox proportional hazards regression model was used to determine the long-term risk for dementia per subgroup. We included 3,056 participants and identified 15 subgroups with distinct brain MRI phenotypes. The phenotypes ranged from limited burden, mostly irregular white matter hyperintensity (WMH) shape and cerebral atrophy, mostly irregularly WMHs and microbleeds, mostly cortical infarcts and atrophy, mostly irregularly shaped WMH and cerebral atrophy to multiburden subgroups. Each subgroup showed different long-term risks for dementia (min-max range hazard ratios [HRs] 1.01-6.18; mean time to follow-up 9.9 ± 2.6 years); especially the brain MRI phenotype with mainly WMHs and atrophy showed a large increased risk (HR 6.18, 95% CI 3.37-11.32). Distinct brain MRI phenotypes can be identified in community-dwelling older adults. Our results indicate that distinct brain MRI phenotypes are related to varying long-term risks of developing dementia. Brain MRI phenotypes may in the future assist in an improved understanding of the structural correlates of dementia predisposition.

Progressive Age-Associated Blood-Brain Barrier Leak/Dysfunction-Nexus of Neurodegenerative Disease Using MRI Markers to Identify Preclinical Disease and Potential New Targets for Future Treatments.

This review article focuses on the upstream pertinent pathophysiology leading to neurodegenerative disease. Specifically, the nexus appears to be blood-brain barrier (BBB) leakiness resulting in a two-prong inflammatory disease spectrum damaging the microvasculature and corrupting protein synthesis and degradation with accumulating misfolded toxic proteins. The suboptimal results of removing misfolded proteins mean a new approach to disease in the preclinical state is required aimed at other targets. Validated noninvasive imaging and serologic biomarkers of early preclinical disease implemented in the high-risk patient cohort along with periodic surveillance once effective treatments are developed will be required. This review discusses the physiology and pathophysiology of the BBB, new MRI imaging techniques identifying the leak, and altered fluid dynamic effects in the preclinical state. The risk factors for disease development, preventative measures, and potential treatment targets are also discussed.

Visit-to-visit blood pressure variability and progression of white matter hyperintensities over 14 years

Purpose: There is evidence that blood pressure variability (BPV) is associated with cerebral small vessel disease (SVD) and may therefore increase the risk of stroke and dementia. It remains unclear if BPV is associated with SVD progression over years. We examined whether visit-to-visit BPV is associated with white matter hyperintensity (WMH) progression over 14 years and MRI markers after 14 years. Materials and methods: We included participants with SVD from the Radboud University Nijmegen Diffusion tensor Magnetic resonance-imaging Cohort (RUNDMC) who underwent baseline assessment in 2006 and follow-up in 2011, 2015 and 2020. BPV was calculated as coefficient of variation (CV) of BP at all visits. Association between WMH progression rates over 14 years and BPV was examined using linear-mixed effects (LME) model. Regression models were used to examine association between BPV and MRI markers at final visit in participants. Results: A total of 199 participants (60.5 SD 6.6 years) who underwent four MRI scans and BP measurements were included, with mean follow-up of 13.7 (SD 0.5) years. Systolic BPV was associated with higher progression of WMH (β = 0.013, 95% CI 0.005 − 0.022) and higher risk of incident lacunes (OR: 1.10, 95% CI 1.01–1.21). There was no association between systolic BPV and grey and white matter volumes, Peak Skeleton of Mean Diffusivity (PSMD) or microbleed count after 13.7 years. Conclusions: Visit-to-visit systolic BPV is associated with increased progression of WMH volumes and higher risk of incident lacunes over 14 years in participants with SVD. Future studies are needed to examine causality of this association.

Associations between multidomain modifiable dementia risk factors with AD biomarkers and cognition in middle-aged and older adults

This study aimed to determine associations between modifiable dementia risk factors (MDRF), across domains mood symptomatology, lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology, with cognition, beta-amyloid (Aβ) and tau, and brain volume. Middle-aged/older adults (n=82) enrolled in a sub-study of the Healthy Brain Project completed self-report questionnaires and a neuropsychological battery. Cerebrospinal fluid levels of Aβ 1–42, total tau (t-tau), and phosphorylated tau (p-tau181) (Roche Elecsys), and MRI markers of hippocampal volume and total brain volume were obtained. Participants were classified as no/single domain risk (≤1 domains) or multidomain risk (≥2 domains). Compared to the no/single domain risk group, the multidomain risk group performed worse on the Preclinical Alzheimer’s Cognitive Composite (d=0.63, p=.005), and Executive Function (d=0.50, p=.016), and had increased p-tau181 (d=0.47, p=.042) and t-tau (d=0.54, p=.021). In middle-aged/older adults, multidomain MDRFs were related to increases in tau and worse cognition, but not Aβ or brain volume. Findings suggest that increases in AD biomarkers are apparent in midlife, particularly for individuals with greater burden, or variety of MDRFs.

Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (β = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (β = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Propofol anesthesia improves stroke outcomes over isoflurane anesthesia-a longitudinal multiparametric MRI study in a rodent model of transient middle cerebral artery occlusion.

General anesthesia is routinely used in endovascular thrombectomy procedures, for which volatile gas and/or intravenous propofol are recommended. Emerging evidence suggests propofol may have superior effects on disability and/or mortality rates, but a mode-of-action underlying these class-specific effects remains unknown. Here, a moderate isoflurane or propofol dosage on experimental stroke outcomes was retrospectively compared using serial multiparametric MRI and behavioral testing. Adult male rats (N = 26) were subjected to 90-min filament-induced transient middle cerebral artery occlusion. Diffusion-, T2- and perfusion-weighted MRI was performed during occlusion, 0.5 h after recanalization, and four days into the subacute phase. Sequels of ischemic damage-blood-brain barrier integrity, cerebrovascular reactivity and sensorimotor functioning-were assessed after four days. While size and severity of ischemia was comparable between groups during occlusion, isoflurane anesthesia was associated with larger lesion sizes and worsened sensorimotor functioning at follow-up. MRI markers indicated that cytotoxic edema persisted locally in the isoflurane group early after recanalization, coinciding with burgeoning vasogenic edema. At follow-up, sequels of ischemia were further aggravated in the post-ischemic lesion, manifesting as increased blood-brain barrier leakage, cerebrovascular paralysis and cerebral hyperperfusion. These findings shed new light on how isoflurane, and possibly similar volatile agents, associate with persisting injurious processes after recanalization that contribute to suboptimal treatment outcome.

The Glymphatic Response to the Development of Type 2 Diabetes.

The glymphatic system has recently been shown to be important in neurological diseases, including diabetes. However, little is known about how the progressive onset of diabetes affects the glymphatic system. The aim of this study is to investigate the glymphatic system response to the progressive onset of diabetes in a rat model of type 2 diabetic mellitus. Male Wistar rats (n = 45) with and without diabetes were evaluated using MRI glymphatic tracer kinetics, functional tests, and brain tissue immunohistochemistry. Our data demonstrated that the contrast agent clearance impairment gradually progressed with the diabetic duration. The MRI data showed that an impairment in contrast clearance occurred prior to the cognitive deficits detected using functional tests and permitted the detection of an early DM stage compared to the immuno-histopathology and cognitive tests. Additionally, the quantitative MRI markers of brain waste clearance demonstrated region-dependent sensitivity in glymphatic impairment. The improved sensitivity of MRI markers in the olfactory bulb and the whole brain at an early DM stage may be attributed to the important role of the olfactory bulb in the parenchymal efflux pathway. MRI can provide sensitive quantitative markers of glymphatic impairment during the progression of DM and can be used as a valuable tool for the early diagnosis of DM with a potential for clinical application.

Abstract WMP70: Neuroradiological Markers of Cerebral Small Vessel Disease in Adults With Congenital Heart Disease After Fontan Surgery

Introduction: Fontan surgery performed during childhood enhances the lifespan and quality of life of patients with critical congenital heart disease. Post-Fontan circulation may impact function in multiple organ systems, but its long term effects on the brain microvasculature are not well characterized. We investigated brain MRI markers of cerebral small vessel disease (SVD) after exposure to Fontan circulation. Methods: We reviewed medical records and MRI images of 34 adults followed in an academic medical center after Fontan surgery, who had brain MRI for any reason from 08/01/1995-03/01/2022. We characterized Fontan physiological stage (a standardized measure of disease severity) at time of MRI, and identified SVD markers, including deep silent brain infarcts, small perivascular spaces in the basal ganglia, microhemorrhages, and white matter hyperintensities. We calculated SVD scores using a standardized scale of 0-4, where scores of ≥2 indicate moderate to severe SVD. We created ordinal logistic regression models to test the association between physiological stage and SVD score. Results: Characteristics of the patients are summarized in the Table, and distribution of SVD scores in the Figure. Adjusting for age at MRI, there was no association between physiological stage of disease and higher SVD score. Conclusion: In our sample of 34 young adult patients with long term exposure to Fontan circulation, the majority had evidence of moderate to severe SVD, which was not predicted by physiological stage of disease at time of MRI. Exposure to Fontan circulation may be associated with early onset of cerebral SVD, suggesting increased long term risk of stroke and dementia.

Abstract TP21: Consequences of Atrial Fibrillation Burden on Deep Cerebral Hemodynamic Related Structural Brain Damage

Background: Recent data using ultrahigh-resolution brain MRI suggests that atrial fibrillation (AF) has adverse effects on wall shear stress and blood flow in lenticulostriate arteries (LSA). The structural consequences of such pathophysiological alterations and whether they contribute to cognitive impairment in AF are not known. We hypothesized that the AF burden is associated with the severity of MRI markers of ischemic and hemorrhagic injury related to LSA disease. Methods: We analyzed data from 560 patients with AF and no clinical history of stroke or neurodegenerative disease, who received brain MRIs at a tertiary referral center. Neuroimaging data were collected by a stroke neurologist who was blinded to the clinical data. The presence of paroxysmal/persistent vs permanent AF was the main measure of AF burden. The imaging outcome variables were counts of deep lacunes, deep cerebral microbleeds (dCMB), and presence of a peri-basal ganglia white matter hyperintensity pattern (peri-BG WMH). Results: The mean age of the 560 AF patients was 73 + 11 and 212 (38%) patients were female. Mean CHA 2 DS 2 -VASc was 3.4 + 1.5 and 86 (15.4%) had permanent atrial fibrillation. Deep lacunes were found in 26.6%, dCMBs in 6.3% and a peri-BG WMH pattern in 2.7% of patients. In univariate analyses, the presence of permanent AF was associated with higher mean deep lacune counts (0.84 vs 0.51, p=0.026), higher mean dCMB counts (0.25 vs 0.1, p=0.018), and peri-BG WMH pattern (7.1% vs 1.9%, p=0.016) when compared to paroxysmal/persistent AF. In separate multivariable analyses, permanent AF type remained an independent predictor of dCMBs (p=0.019) and peri-BG WMH pattern (p=0.028) after controlling for age, sex, and vascular risk factors. Permanent AF also showed a tendency for independent association with deep lacunes (p=0.06) in a similar model. Discussion: Our results show that AF burden independently correlates with parenchymal MRI markers of LSA disease in patients without history of stroke. Such deep brain damage might contribute to AF-induced cognitive changes. The effects of better rhythm control on visible brain damage and cognitive changes should be studied in randomized trials.