Vascular Burden Research Articles

The Relation between Vascular Risk Factors and Flow in Cerebral Perforating Arteries: A 7 Tesla MRI Study

Introduction: Cerebral perforating arteries provide blood supply to the deep regions of the brain. Recently, it became possible to measure blood flow velocity and pulsatility in these small arteries. It is unknown if vascular risk factors are related to these measures. Methods: We measured perforating artery flow with 2D phase-contrast 7 Tesla MRI at the level of the centrum semiovale (CSO) and the basal ganglia (BG) in seventy participants from the Heart Brain Connection study with carotid occlusive disease (COD), vascular cognitive impairment (VCI), or no actual cerebrovascular disease. Vascular risk factors included hypertension, diabetes, hyperlipidemia, and smoking. Results: No consistent relations were found between any of the vascular risk factors and either flow velocity or flow pulsatility, although there was a relation between lower diastolic blood pressure and higher pulse pressure and higher cerebral perforator pulsatility (p = 0.045 and p = 0.044, respectively) at the BG level. Results were similar in stratified analyses for patients with and without a history of cardiovascular disease, or only COD or VCI. Conclusion: We conclude that, cross-sectionally, cerebral perforating artery flow velocity and pulsatility are largely independent of the presence of common vascular risk factors in a population with a mixed vascular burden.

Age-related subtypes of late life depression and mortality: Aprospective clinical cohort study.

Late Life Depression (LLD) is associated with increased mortality rates, but it remains unclear which depressed patients are at increased risk. This study examined the mortality risk of previously identified subgroups of depressed older patients based on age-related clinical features (the presence of physical and cognitive frailty). A six-year follow-up of a clinical cohort study including 375 depressed older patients and 132 non-depressed persons (NESDO). Depressed patients were diagnosed with the Composite International Diagnostic Interview (CIDI) according to DSM-IV criteria and classified by latent profile analysis on depressive symptom severity, cognitive domains and physical frailty. We estimated the hazard rate of mortality for the four depressed subgroups compared to non-depressed persons by applying Cox-regression analyses. Models were adjusted for age, sex and education as confounders and for explanatory variables per pathway in separate models: somatic burden, lifestyle characteristics, vascular burden or inflammation markers. A total of 61/375 (16.3%) depressed patients and 8/132 (6.1%) non-depressed persons died during the 6-year follow-up. Two of the four subgroups (n=186/375 (50%) of the depressed sample) had a higher hazard rate (HR) for mortality compared to non-depressed participants, that is, frail-depressed patients (HR=5.25, [95%-CI: 2.13-13.0]) and pure mild depressed patients (HR=3.32 [95%-CI: 1.46-7.58]) adjusted for confounders. Adding possible underlying pathways did not explain these associations. Age-related features (the presence of physical and cognitive frailty) contribute to the increased mortality risk in late-life depression. Future studies in depressed older patients should study the additional value of a clinical geriatric assessment and integrated treatment aimed to at reduce frailty and ameliorate their mortality risk.

Abstract 96: Temporal Trends in Vascular Risk Factor Burden Among Young Adults With Ischemic Stroke: The Florida Stroke Registry

Introduction: While ischemic stroke (IS) in the young (18-55) is thought to have different etiologies than in older patients, a rise in vascular risk factors (VRFs) among young adults may translate to an IS risk profile similar to the older population. We aimed to examine the prevalence of VRFs and temporal trends in VRF burden among young patients presenting with IS. Methods: Data was prospectively collected by Get With the Guidelines-Stroke® hospitals participating in the Florida Stroke Registry between January 2010 and December 2022. Patients aged 18-55 with a diagnosis of IS were included and separated into two age groups: 18-35 and 36-55. VRFs included hypertension, dyslipidemia, obesity, smoking, atrial fibrillation, coronary artery disease, heart failure, diabetes, and sleep apnea. Multimorbidity was defined as having ≥4 VRFs. Results: 47,792 patients with IS were included (43% female, median age 49, 51% white), comprising 4,275 patients aged 18-35 (8.9%) and 43,517 aged 36-55 (91.1%). The prevalence of each VRF was higher among patients aged 36-55 vs 18-35 (all p values <0.001), and only 15.3% of patients aged 36-55 and 40.0% of patients aged 18-35 had 0 VRFs. African American patients with IS had a significantly higher prevalence of multimorbidity than white or non-white Hispanic patients; specifically in those aged 18-35 (6.1% vs 3.5% vs 3.5%, p <0.001), while those aged 36-55 demonstrated a smaller difference (17.6% vs 17.2% vs 15.4% p <0.001).VRF burden worsened across the study period, with an increase in multimorbidity from 11.2% to 21.7% in patients 36-55 (p<0.0001) and from 1.3% to 6.6% in patients 18-35 (p= 0.0006). Conclusions: Increasingly, young stroke patients have traditional VRFs. The prevalence of multimorbidity disproportionately affects African American patients and has significantly increased over the past 12 years. Efforts targeting VRFs reduction must start as early as possible in light of the rise in VRF burden amongst young IS patients.

Abstract 87: Predictive Scoring System for Pre-Thrombectomy Diagnosis of Intracranial Atherosclerotic Disease LVOS

Introduction: Early identification of intracranial atherosclerotic disease (ICAD) underlying large vessel occlusion strokes (LVOS) may allow for mechanical thrombectomy (MT) optimization. We sought to create a pre-procedural scoring system to predict ICAD. Methods: Retrospective analysis of prospectively collected MT databases from 2 comprehensive stroke centers (derivation and validation) including patients with anterior circulation LVOS. ICAD cases were matched for age / sex (1:1) to non-ICAD controls and stepwise logistic regression utilized for various clinical and radiological (NCCT, CTA and CTP) variables. Calibration slope / intercept as well as the area under curve (auROC) were assessed. Results: Of 2870 MTs within the study period, 174 anterior circulation ICAD (6.6%) were matched with 174 controls (n=348) in the derivation cohort. Multivariable analysis β coefficients lead to a 20 point-scale: absence of AF (5), vascular risk factor burden (1 for each: hypertension, diabetes, smoking, hyperlipidemia), CTA multifocal ICAD (3), absence of cortical infarcts (3), presence of borderzone infarct (3), calcium at the siphon (2). The validation cohort comprised 75 ICAD patients (6.9% of 1359 MTs) and 75 controls. AuROC for the derivation cohort was 0.88(0.84-0.91) while for the validation cohort 0.82(0.73-0.89). Calibration slope and intercept showed a good fit for the development cohort although with overestimated risk for the validation cohort. After intercept adjustment, the overestimation was corrected (intercept 0; 95%CI -0.5-0.5 / slope 0.8 95%CI 0.5-1.1). In the full cohort (n=498), ≥ 11 points showed the best performance for distinguishing ICAD from non-ICAD patients, with a sensitivity 0.71 (0.65-0.78) and specificity 0.82 (0.77-0.87), a positive likelihood ratio of 3.92 (2.92, 5.28) and a negative LR of 0.35 (0.28, 0.44). Scores ≥ 12 showed 90% specificity, although sensitivity of 63% (55%-69%). Conclusion: We developed a predictive scoring system for pre-procedural diagnosis of ICAD LVOS with satisfactory discrimination and calibration based on clinical and non-invasive radiological data.

Vascular risk burden is a key player in the early progression of Alzheimer’s disease

Understanding whether vascular risk factors (VRFs) synergistically potentiate Alzheimer's disease (AD) progression is important in the context of emerging treatments for preclinical AD. In a group of 503 cognitively unimpaired individuals, we tested whether VRF burden interacts with AD pathophysiology to accelerate neurodegeneration and cognitive decline. Baseline VRF burden was calculated considering medical data and AD pathophysiology was assessed based on cerebrospinal fluid (CSF) amyloid-β1–42 (Aβ1–42) and tau phosphorylated at threonine 181 (p-tau181). Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer’s Cognitive Composite. The mean (SD) age of participants was 72.9 (6.1) years, and 220 (43.7%) were men. Linear mixed-effects models revealed that an elevated VRF burden synergistically interacted with AD pathophysiology to drive longitudinal plasma NfL increase and cognitive decline. Additionally, VRF burden was not associated with CSF Aβ1–42 or p-tau181 changes over time. Our results suggest that VRF burden and AD pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive deterioration. In preclinical stages, the combination of therapies targeting VRFs and AD pathophysiology might potentiate treatment outcomes.

Comprehensive allostatic load risk index is associated with increased frontal and left parietal white matter hyperintensities in mid-life cognitively healthy adults

To date, there is a considerable heterogeneity of methods to score Allostatic Load (AL). Here we propose a comprehensive algorithm (ALCS) that integrates commonly used approaches to generate AL risk categories and assess associations to brain structure deterioration. In a cohort of cognitively normal mid-life adults (n = 620, age 51.3 ± 5.48 years), we developed a comprehensive composite for AL scoring incorporating gender and age differences, high quartile approach, clinical reference values, and current medications, to then generate AL risk categories. Compared to the empirical approach (ALES), ALCS showed better model fit criteria and a strong association with age and sex. ALSC categories were regressed against brain and white matter hyperintensity (WMH) volumes. Higher AL risk categories were associated with increased total, periventricular, frontal, and left parietal WMH volumes, also showing better fit compared to ALES. When cardiovascular biomarkers were removed from the ALSC algorithm, only left-frontal WMHV remained associated with AL, revealing a strong vascular burden influencing the index. Our results agree with previous evidence and suggest that sustained stress exposure enhances brain deterioration in mid-life adults. Showing better fit than ALES, our comprehensive algorithm can provide a more accurate AL estimation to explore how stress exposure enhances age-related health decline.

Association of white matter hyperintensities and clinical vascular burden with depressive symptoms in Black older adults.

Black older adults have a higher vascular burden compared to non-Hispanic White (NHW) older adults, which may put them at risk for a form of depression known as vascular depression (VaDep). The literature examining VaDep in Black older adults is sparse. The current study addressed this important gap by examining whether vascular burden was associated with depressive symptoms in Black older adults. Participants included 113 Black older adults from the Healthy Brain Project, a substudy of the Health, Aging, and Body Composition Study. In multiple regression analyses, clinical vascular burden (sum of vascular conditions) and white matter hyperintensity (WMH) volume predicted depressive symptoms as measured by the Center for Epidemiologic Studies Depression Scale, controlling for demographic variables. Follow-up analyses compared the associations in the Black subsample and in 179 NHW older adults. Higher total WMH volume, but not clinically-defined vascular burden, predicted higher concurrent depressive symptoms and higher average depressive symptoms over 4years. Similar associations were found between uncinate fasciculus (UF) WMHs and concurrent depressive symptoms and between superior longitudinal fasciculus WMHs and average depressive symptoms. The association between depressive symptoms and UF WMH was stronger in Black compared to NHW individuals. This research is consistent with the VaDep hypothesis and extends it to Black older adults, a group that has historically been underrepresented in the literature. Results highlight WMH in the UF as particularly relevant to depressive symptoms in Black older adults and suggest this group may be particularly vulnerable to the negative effects of WMH.

The Impact of Atherosclerotic Burden on Vascular Outcomes in Patients with Stroke and Atrial Fibrillation: The ATHENA study.

Introduction: Patients with ischemic stroke (IS) and atrial fibrillation (AF) face a higher risk of recurrent vascular events. This study evaluates the impact of atherosclerotic vascular disease burden across different vascular territories on the risk of vascular events in patients with recent ischemic stroke and AF within 90 days. Patients and Methods: We included patients with IS and AF from the International RAF network in a prospective 90-day follow-up. Atherosclerotic vascular disease was identified by at least one of the following: Symptomatic ischemic heart disease, symptomatic peripheral artery disease, internal carotid stenosis ≥50%, or the presence of plaques in the aorta. The primary outcome was a composite of stroke, transient ischemic attack, systemic embolism, cerebral bleeding, and major extracranial bleeding within 90 days postacute stroke. Patients were categorized into 5 groups based on the number of affected atherosclerotic vascular territories, with those with no atherosclerotic vascular disease as the reference. Kaplan-Meier curves were generated and compared using the log-rank test to determine the predictive value of the number of diseased territories for the risk of events. Data analysis was performed with SPSS/PC Win Package 25.0. Results: Of the 2148 patients (mean age 77.59; 53.86% female), 744 (34.60%) had atherosclerosis. Multivariable analysis revealed that involvement of 3 (hazard ratio [HR] 2.80, 95% confidence interval [CI]: 1.20-6.53) or 4 (HR 6.81, 95% CI: 1.02-36.24) vascular territories was significantly associated with the risk of combined events. Conclusions: In patients with recent ischemic stroke and AF, atherosclerosis across multiple territories correlates with a higher risk of future vascular events.

The association of global vessel width with cognitive decline and cerebral small vessel disease burden in the KaiLuan study.

As the retinal microvasculature shares similarities with the cerebral microvasculature, numerous studies have shown that retinal vascular is associated with cognitive decline. In addition, several population-based studies have confirmed the association between retinal vascular and cerebral small vessel disease (CSVD) burden. However, the association of retinal vascular with CSVD burden as well as cognitive function has not been explored simultaneously. This study investigated the relations of retinal microvascular parameters (RMPs) with CSVD burden and cognitive function. We conducted a cross-sectional study of participants in the KaiLuan study. Data were collected from subjects aged ≥18 years old who could complete retinal photography and brain magnetic resonance imaging (MRI) between December 2020 to October 2021 in the Kailuan community of Tangshan. RMPs were evaluated using a deep learning system. The cognitive function was measured using the Montreal Cognitive Assessment (MoCA). We conducted logistic regression models, and mediation analysis to evaluate the associations of RMPs with CSVD burden and cognitive decline. Of the 905 subjects (mean age: 55.42±12.02 years, 54.5% female), 488 (53.9%) were classified with cognitive decline. The fractal dimension (FD) [odds ratio (OR), 0.098, 95% confidence interval (CI): 0.015-0.639, P=0.015] and global vein width (OR: 1.010, 95% CI: 1.005-1.015, P<0.001) were independent risk factors for cognitive decline after adjustment for potential confounding factors. The global artery width was significantly associated with severe CSVD burden (OR: 0.985, 95% CI: 0.974-0.997, P=0.013). The global vein width was sightly associated with severe CSVD burden (OR: 1.005, 95% CI: 1.000-1.010, P=0.050) after adjusting for potential confounders. The multivariable-adjusted odds ratios (95% CI) in highest tertile versus lowest tertile of global vein width were 1.290 (0.901-1.847) for cognitive decline and 1.546 (1.004-2.290) for severe CSVD burden, respectively. Moreover, CSVD burden played a partial mediating role in the association between global vein width and cognitive function (mediating effect 6.59%). RMPs are associated with cognitive decline and the development of CSVD. A proportion of the association between global vein width and cognitive decline may be attributed to the presence of CSVD burden.

Association of Glycemic Variability With Imaging Markers of Vascular Burden, β-Amyloid, Brain Atrophy, and Cognitive Impairment.

We aimed to investigate the association between glycemic variability (GV) and neuroimaging markers of white matter hyperintensities (WMH), beta-amyloid (Aβ), brain atrophy, and cognitive impairment. This was a retrospective cohort study that included participants without dementia from a memory clinic. They all had Aβ PET, brain MRI, and standardized neuropsychological tests and had fasting glucose (FG) levels tested more than twice during the study period. We defined GV as the intraindividual visit-to-visit variability in FG levels. Multivariable linear regression and logistic regression were used to identify whether GV was associated with the presence of severe WMH and Aβ uptake with DM, mean FG levels, age, sex, hypertension, and presence of APOE4 allele as covariates. Mediation analyses were used to investigate the mediating effect of WMH and Aβ uptake on the relationship between GV and brain atrophy and cognition. Among the 688 participants, the mean age was 72.2 years, and the proportion of female participants was 51.9%. Increase in GV was predictive of the presence of severe WMH (coefficient [95% CI] 1.032 [1.012-1.054]; p = 0.002) and increased Aβ uptake (1.005 [1.001-1.008]; p = 0.007). Both WMH and increased Aβ uptake partially mediated the relationship between GV and frontal-executive dysfunction (GV → WMH → frontal-executive; direct effect, -0.319 [-0.557 to -0.080]; indirect effect, -0.050 [-0.091 to -0.008]) and memory dysfunction (GV → Aβ → memory; direct effect, -0.182 [-0.338 to -0.026]; indirect effect, -0.067 [-0.119 to -0.015]), respectively. In addition, increased Aβ uptake completely mediated the relationship between GV and hippocampal volume (indirect effect, -1.091 [-2.078 to -0.103]) and partially mediated the relationship between GV and parietal thickness (direct effect, -0.00101 [-0.00185 to -0.00016]; indirect effect, -0.00016 [-0.00032 to -0.000002]). Our findings suggest that increased GV is related to vascular and Alzheimer risk factors and neurodegenerative markers, which in turn leads to subsequent cognitive impairment. Furthermore, GV can be considered a potentially modifiable risk factor for dementia prevention.

Nasal delivery of polymeric nanoDisc mobilizes a synergy of central and peripheral amyloid-β clearance to treat Alzheimer's disease.

The disequilibrium of amyloid β-peptide (Aβ) between the central and peripheral pools has been claimed as an initiating event in Alzheimer's disease (AD). In this study, we employ discoidal high-density lipoproteins (HDL-Disc) mimicking Aβ antibody for directional flux of Aβ from central to peripheral catabolism, with desirable safety and translation potential. Structurally, HDL-Disc assembly (polyDisc) is prepared with aid of chitosan derivative polymerization. After intranasal administration and response to slightly acidic nasal microenvironment, polyDisc depolymerizes into carrier-free HDL-Disc with chitosan derivatives that adhere to the mucosal layer to reversibly open tight junctions, helping HDL-Disc penetrate the olfactory pathway into brain. Thereafter, HDL-Disc captures Aβ into microglia for central clearance or ferries Aβ out of the brain for liver-mediated compensatory catabolism. For synergy therapy, intranasal administration of polyDisc can effectively reduce intracerebral Aβ burden by 97.3% and vascular Aβ burden by 73.5%, ameliorate neurologic damage, and rescue memory deficits in APPswe/PS1dE9 transgenic AD mice with improved safety, especially vascular safety. Collectively, this design provides a proof of concept for developing Aβ antibody mimics to mobilize a synergy of central and peripheral Aβ clearance for AD treatment.

Impact of Decreased Visibility of Deep Medullary Veins on White Matter Integrity in Patients with Cerebral Small Vessel Disease.

Based on susceptibility-weighted imaging (SWI) visibility, deep medullary vein (DMV) scores are related to white matter damage (WMD) in patients with cerebral small vessel disease (CSVD). However, whether mechanisms are associated with DMV changes is unclear. We examined extracellular fluid (ECF) roles in white matter associations between DMV scores and white matter integrity (WMI) in patients with CSVD. We examined magnetic resonance imaging (MRI) and clinical data from 140 patients with CSVD. DMV scores (0-18) were assigned on SWI according to DMV anatomic regions and signal continuity/visibility. WMI and ECF volumes were evaluated using free water (FW) and fractional anisotropy (FA) values by diffusion tensor imaging (DTI). DMV scores were independently associated with FA after adjusting for vascular risk factors, age, white matter hyperintensity (WMH) volume, and CSVD burden [β (95% confidence interval (CI)): -0.219 (-0.375, -0.061), p = 0.006]. We also observed a significant indirect effect of DMV scores on FA in white matter (mediated by FW in white matter) after controlling for age, vascular risk factors, WMH volume, and CSVD burden. DMV scores were independently related to WMI and mediated by ECF in the white matter of patients with CSVD.

Effects of Physical Activity, Vascular Burden and Clinical Diagnosis on White Matter Integrity

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia. Both degenerative and vascular pathology tend to contribute to dementia as AD coexists with single or multiple cardiovascular risk factors (vascular burden). Modifiable lifestyle factor such as physical activity has been associated with lower vascular burden (VB) and a lower risk of dementia. To test whether physical activity characterised as being inactive or active helped preserve white matter microstructure in a sample consisting of healthy controls and patients from the clinical AD continuum (mild cognitive impairment to dementia) with either low or high VB.Method213 participants were recruited from three memory clinics and were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Voxel‐wise tract‐based spatial statistics (TBSS) was carried out using a set of 5000 permutations and threshold‐free cluster enhancement (TFCE) to find significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD) and radial diffusivity (RD).ResultParticipants who were physically active had higher FA and lower AxD, MD and RD values relative to the inactive participants. Changes in indices of WM integrity were widespread across the brain covering mainly association and projection tracts but a few commissural tracts. A three‐way interaction effect between Group × Physical Activity × VB was found for FA that was present in mainly projection tracts with a rightward asymmetry along with some association and commissural tracts. Post hocs revealed greater FA in physically active patients with high VB compared with inactive patients with high VB in projection and association/limbic tracts with a rightward asymmetry. Furthermore, the patients with high VB showed higher FA in bilateral projection fibers and cerebellar regions compared with inactive controls with high VB.ConclusionTBSS analysis revealed that high risk patients such as those with high VB achieved the maximum benefit by being physically active as it led to a much greater preservation of white microstructure relative to controls with high VB. This preservation of white matter microstructure was only observed in patients but not in controls.

Prevalence and type of subjective cognitive concerns among participants at baseline and their relationship to cognition and other factors

AbstractBackgroundThe U.S. POINTER study is a phase 3, multicenter, 2‐year randomized controlled trial (RCT) of two lifestyle interventions varying in intensity and format, conducted in older adults living in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Inclusion criteria included specific risk factors (e.g., family history of dementia, vascular risk factors) but not subjective cognitive concerns (SCCs). However, SCCs are likely to be common in this group of at‐risk individuals. U.S. POINTER provides a unique opportunity to evaluate the prevalence of SCCs and their demographic and clinical correlates in an at‐risk group.MethodsRecruitment for the U.S. POINTER study is still ongoing, and the following is based on a partial sample. The sample includes 1811 U.S. POINTER participants with complete baseline data (collected by December 2022), mean age = 68.2y (SD = 5.2), 73.5% are female, 70.2% have18+ years education, and 29.3% are from underrepresented groups. SCCs were measured by the brief 12‐item Everyday Cognition (ECog) questionnaire which includes two items in each of 6 domains: everyday memory, language, visuospatial abilities, planning, organization and divided attention. Responses on the ECog range from 0 = no change/better compared to baseline, 1 = questionably/inconsistently worse, 2 = consistently a little worse, 3 = much worse. Neuropsychological performance was measured using a global composite and episodic memory, executive functioning, and processing speed composites. Other variables included demographics, depression (Geriatric Depression Scale total score; GDS) and sleep (Insomnia severity index (ISI)) and vascular disease burden index.ResultsThirty‐five percent of the cohort endorsed having a subjective complaint on the ECog (score ≥2 on any item). The most frequent complaint was “Remembering where I have placed objects” (23%). SCCs did not differ by age, sex or education. ECog‐12 Total were related to insomnia and depression (p&lt;.0001). After adjusting for age, sex, education, vascular risk burden, GDS and ISI, greater SCC (ECog‐12 Total) was still associated with the global composite and all three domains (ps &lt; 0.003).ConclusionsSCCs, particularly everyday memory complaints, were relatively common in this at‐risk cohort. While SCCs were related to depression and sleep, they were also independently associated with slightly worse cognitive function.

The influence of vascular pathology on the generalizability of machine learning models for cognitive performance estimation

AbstractBackgroundImage‐based machine learning models are promising to aid diagnosis in dementia, e.g. by diagnostic classification or estimating cognitive performance. However, the contribution of vascular pathology is often ignored, although many patients have mixed pathologies. This may hamper model generalizability from research setting to clinical practice, as the models are generally developed on populations with lower vascular burden than is encountered clinically. This study aims to evaluate whether model generalizability is influenced by differences in vascular pathology load between training and test groups, represented by white matter hyperintensities (WMHs).MethodWe developed a convolutional neural network to estimate cognitive performance through ADAS13. We included 4791 timepoints from 1632 ADNI subjects. To mimic differences in vascular burden between research and clinical populations, we split the data into a low, middle and high WMH load group using WMH ratio tertiles (WMH volume corrected for intracranial volume). The model was applied to maps derived from T1‐weighted and FLAIR brain MRI using voxel‐based morphometry: model 1 (gray matter density map (GMDM), age, sex), model 2 (GMDM, WMH density map (WMHDM), age, sex) and model 3 (GMDM, log(WMH ratio), age, sex) (Fig. 1). First, we trained all models on the low WMH load group, meaning to test on the high WMH load group to assess generalizability. Second, we trained models 1 and 2 on all data. Mean Absolute Error (MAE) served as the performance metric.ResultThe models trained on the low WMH load group (MAE = 5.08 – 5.41) performed similar to constant value prediction (MAE = 5.63) (Fig. 2, circles). Using all data, models did train successfully (model 1: MAE = 5.64, model 2: MAE = 6.31, constant value: MAE = 7.39) (Fig. 2, crosses). Because of the suboptimal model training in the low WMH load group, especially for individuals with higher ADAS13 scores which were underrepresented in the data (Fig. 3), we could not evaluate generalizability to the high WMH load group.ConclusionThis study was unable to provide new insight into the influence of vascular pathology on the generalizability of machine learning models in dementia. More clinically representative data is needed, covering the full cognitive performance spectrum and higher vascular pathology loads.

Detecting Alzheimer’s risk with cognitive dispersion on neuropsychological testing

AbstractBackgroundCognitive dispersion refers to the within‐person variability across tasks. Relative to the normative approach, cognitive dispersion may be more sensitive to subtle changes in preclinical Alzheimer’s disease. Greater dispersion has been associated with increased risk for conversion to mild cognitive impairment and faster rates of medial temporal lobe atrophy. This metric can be derived from a regular neuropsychological assessment and complement traditional outcome approaches, particularly in those underrepresented in normative data. This study evaluated cognitive dispersion as an independent predictor of clinical status across racial and ethnic groups.MethodBaseline data on 1811 cognitively unimpaired older adults with high vascular risk from the U.S. POINTER multisite lifestyle intervention study were examined. Sample characteristics included mean age of 68 (SD = 5.2), 70% female, 30% less‐than‐college education, and 29% underrepresented groups (301 Black, 231 Other). Correlations between cognitive dispersion and other brain health risks (vascular, subjective cognitive decline (SCD), physical activity) were tested. Cognitive dispersion was defined as the standard deviation of individuals’ z‐transformed scores of 8 cognitive tests. Vascular risk burden was the sum of 5 conditions (hypertension, diabetes, hypercholesterolemia, heart disease, obesity). Self‐report SCD was measured by the Cognitive Function Instrument (CFI) and Measurement of Everyday Cognition (ECOG12). Logistic Regression Models were fitted to predict Clinical Dementia Global Ratings (CDR 0.5 vs. 0) to evaluate cognitive dispersion as an independent predictor in the whole sample, White participants and Black participants, controlled for demographics, vascular risk, and physical activity. Logistic Regression Models were also evaluated with CFI or ECOG12 as additional covariate.ResultGreater cognitive dispersion was correlated with older age, greater vascular burden and less physical activity, but not SCD. Cognitive dispersion was significantly higher in men, Black participants, and participants with less education. Cognitive dispersion predicted CDR in Black participants (OR = 4.7, p&lt;0.01), and trended in the whole sample (OR = 1.6, p = 0.05), but was not significant in White participants (OR = 1.2, p = 0.63). Results hold when controlled for SCD (Table 1).ConclusionResults supported cognitive dispersion as a sensitive objective metric, in addition to self‐report SCD, to identify individuals showing the earliest clinical signs of decline, particularly among those underrepresented in traditional norms.

Biological and methodological factors underlying a continuous amyloid CSF/PET imbalance model and its association with longitudinal cognition

AbstractBackgroundDiscordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid‐ß (Aß) occurs in up to 20% of individuals. Generally, Aß discordance is defined using binary cut‐offs. Given the methodological limitations of this approach, we propose a continuous Aß CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition.MethodWe included 383 non‐demented subjects (Nunimpaired = 326, Nmildly‐impaired = 57) from the AMYPAD‐PNHS cohort. Z‐scored CSF Aß42 and amyloid‐PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject‐specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance&lt;0 reflecting greater Aß abnormality in CSF relative to PET and Zimbalance&gt;0 greater Aß abnormality in PET relative to CSF (Figure‐1). Linear models adjusted for relevant covariates (Figure‐2) were run between Zimbalance and (1) methodological factors (CSF‐PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p‐tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains.ResultSample characteristics are shown in Table‐1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p‐tau levels were significantly associated with a higher Zimbalance (i.e. greater Aß abnormality in PET relative to CSF) (ß = 0.06±0.03, p = .033) (Figure‐2). In addition, a lower Zimbalance (i.e. greater Aß abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, ß = ‐0.55±0.26, p = .038) and predictive of faster cognitive decline on a language categorical fluency test (ß = ‐0.03±0.02, p = .038) (Figure‐2).ConclusionWe found that methodological factors did not contribute to a continuous model of Aß CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aß relative to soluble Aß being related to increased CSF p‐tau levels and excess pathological levels of soluble Aß relative to aggregated Aß to increased white matter hyperintensities and steeper cognitive decline.

Distinct effects of cholesterol profile components on amyloid and vascular burdens

AbstractBackgroundCholesterol plays important roles in β‐amyloid (Aβ) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aβ and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aβ and CSVD burdens in a large, non‐demented Korean cohort.MethodWe enrolled 1,175 non‐demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aβ PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low‐density lipoprotein cholesterol [LDL‐c], high‐density lipoprotein cholesterol [HDL‐c], and triglyceride) level as a predictor and each image marker (Aβ uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders.ResultIncreased LDL‐c levels (β = 0.014 to 0.115, p = 0.013) were associated with greater Aβ uptake, independent of the APOE e4 allele genotype and lipid‐lowering medication. Decreased HDL‐c levels (β = −0.133 to −0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL‐c levels were also associated with decreased hippocampal volume (direct effect β = −0.053, p = 0.040), which was partially mediated by Aβ uptake (indirect effect β = −0.018, p = 0.006).ConclusionOur findings highlight that increased LDL‐c and decreased HDL‐c levels are important risk factors for Aβ and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL‐c and HDL‐c levels is a potential strategy to prevent dementia.

Biological and methodological factors underlying a continuous amyloid CSF/PET imbalance model and its association with longitudinal cognition

AbstractBackgroundDiscordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid‐β (Aβ) occurs in up to 20% of individuals. Generally, Aβ discordance is defined using binary cut‐offs. Given the methodological limitations of this approach, we propose a continuous Aβ CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition.MethodWe included 383 non‐demented subjects (N unimpaired = 326, N mildly‐impaired = 57) from the AMYPAD‐PNHS cohort. Z‐scored CSF Aβ42 and amyloid‐PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject‐specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance&lt;0 reflecting greater Aβ abnormality in CSF relative to PET and Zimbalance&gt;0 greater Aβ abnormality in PET relative to CSF (Figure‐1). Linear models adjusted for relevant covariates (Figure‐2) were run between Zimbalance and (1) methodological factors (CSF‐PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p‐tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains.ResultSample characteristics are shown in Table‐1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p‐tau levels were significantly associated with a higher Zimbalance (i.e. greater Aβ abnormality in PET relative to CSF) (β = 0.06±0.03, p = .033) (Figure‐2). In addition, a lower Zimbalance (i.e. greater Aβ abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, β = ‐0.55±0.26, p = .038) and predictive of faster cognitive decline on a language categorical fluency test (β = ‐0.03±0.02, p = .038) (Figure‐2).ConclusionWe found that methodological factors did not contribute to a continuous model of Aβ CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aβ relative to soluble Aβ being related to increased CSF p‐tau levels and excess pathological levels of soluble Aβ relative to aggregated Aβ to increased white matter hyperintensities and steeper cognitive decline.

Role of nutrition and metabolic regulation in multidomain trials for dementia risk reduction: findings from FINGER and FINGER 2.0 studies

AbstractBackgroundThe successful FINGER multidomain intervention model combined dietary intervention (healthy Nordic diet) with exercise, cognitive training, social activities, and cardiovascular risk monitoring. The FINGER model is being tested and optimized in the World‐Wide FINGERS network of multidomain dementia prevention trials (45+ countries). Advanced FINGER 2.0 models combine lifestyle interventions with multi‐nutrients and/or putative disease‐modifying drugs.MethodThe 11‐year extended follow‐up of FINGER trial participants (N:1260, at‐risk general population) was completed in Q1‐2023. The MIND‐AD pilot‐trial (N:93, prodromal Alzheimer’s disease (AD)) included medical food (Fortasyn Connect), tested alone or in combination with multidomain lifestyle intervention for 6 months. The MET‐FINGER trial (N:600, at‐risk general population enriched with APOE4‐carriers, 2‐year intervention) includes different dosages of metformin (in combination with upgraded FINGER lifestyle intervention).ResultNew nutrition/metabolic related data will be presented from FINGER where eg. adherence to healthier diet was still relatively high in the multidomain arm after the extended follow‐up. Higher adherence was also related to better cognition. Several dietary and metabolic biomarkers have been analyzed revealing underlying mechanisms and responders (eg persons with insulin resistance, higher HOMA, responded less). In the MIND‐AD trial, participants from 4 European countries were randomized to the multidomain lifestyle intervention alone (N:32), or in combination with medical food (N:31), and 30 to the control group. Adherence was high for all intervention domains (78‐87%). Compared with the control group, the group with lifestyle+medical food showed a decrease in vascular risk burden (P = 0.027) and an increase in healthy diet patterns (P = 0.045), and better cognition after the intervention (CDR‐SOB). There were no significant differences between the lifestyle only and control group. MET‐FINGER trial recruitment started in January 2023 (preliminary data presented).ConclusionLonger‐term dietary and lifestyle changes are feasible and effective in older adults in the at‐risk spectrum of AD/dementia. Beneficial effects (adherence to and effects of interventions) seemed to improve with the inclusion of medical food in prodromal AD. The unique long follow‐up of FINGER provides important information about long‐term effects and methodological aspects. The MET‐FINGER trial will provide data on synergistic effects between FINGER intervention and a drug targeting both glucose metabolism and AD pathology.