Vascular Burden Research Articles

Diagnosing vascular cognitive impairment: Current challenges and future perspectives.

Cerebrovascular disease is a major cause of cognitive decline and dementia. This is referred to as vascular cognitive impairment (VCI). Diagnosing VCI is important, among others to optimize treatment to prevent further vascular injury. This narrative review addresses challenges in current diagnostic approaches to VCI and potential future developments. First we summarize how diagnostic criteria for VCI evolved over time. We then highlight challenges in diagnosing VCI in clinical practice: assessment of severity of vascular brain injury on brain imaging is often imprecise and the relation between vascular lesion burden and cognitive functioning shows high intersubject variability. This can make it difficult to establish causality in individual patients. Moreover, because VCI is essentially an umbrella term, it lacks specificity on disease mechanisms, prognosis, and treatment. We see the need for a fundamentally different approach to diagnosing VCI, which should be more dimensional, including multimodal quantitative assessment of injury, with more accurate estimation of cognitive impact, and include biological definitions of disease that can support further development of targeted treatment. Recent developments in the field that can form the basis of such an approach are discussed.

Cardiometabolic and Vascular Disease Factors and Mild Cognitive Impairment and Dementia

Introduction: There is empirical evidence that cardiovascular risk factors and vascular pathology contribute to cognitive impairment and dementia. Methods: We profiled cardiometabolic and vascular disease (CMVD) and CMVD burden in community-living older adults in the Singapore Longitudinal Ageing Study cohort and examined the association of CMVD risk markers with the prevalence and incidence of mild cognitive impairment (MCI) and dementia from a median 3.8 years of follow-up. Results: Prevalent MCI and dementia, compared with normal cognition, was associated with higher proportions of persons with any CMVD, hypertension, diabetes, coronary heart disease, atrial fibrillation, or stroke. Diabetes, stroke, and the number of CMVD risk markers remained significantly associated with dementia or MCI after adjusting for age, sex, formal education level, APOE-ε4 genotype, and level of physical, social, or productive activities, with odds ratios ranging from 1.3 to 5.7. Among cognitively normal participants who were followed up, any CMVD risk factor, dyslipidemia, diabetes, or heart failure at baseline predicted incident MCI or its progression to dementia after adjusting for potential confounders. Conclusion: Older adults with higher burden of CMVD, driven especially by diabetes, are likely to increase the risk of prevalent and incident MCI and dementia.

Incidental DWI Lesions in Patients with Recent Small Subcortical Infarctions

ObjectivesIncidental acute ischemic lesions distinct from the primary neurological insult are identified on diffusion-weighted imaging (DWI) in a number of conditions where cerebral microvascular pathology plays a central role. Another major manifestation of cerebral small vessel disease (CSVD) is ischemic stroke named as recent small subcortical infarction (RSSI). In this study, we sought to identify the prevalence and predictors of incidental DWI lesions in patients with RSSI. Materials and MethodsWe retrospectively analyzed a consecutive series of acute ischemic stroke patients with DWI evidence of acute lesions solely localized to perforator artery territories. Images were evaluated for the presence of additional acute or subacute subcortical DWI lesions, apart from the symptomatic lesion. Clinical features including vascular risk factor burden, together with imaging markers of chronic CSVD, were compared among patients with and without incidental acute or subacute lesions. ResultsAmong 396 patients with no alternate stroke etiology additional incidental subcortical DWI bright lesions were identified in 74 (19%) cases. These lesions were primarily localized in the corona radiata, or centrum semiovale. Patients with incidental DWI lesions were more likely to have a history of hypertension, a higher white matter hyperintensities burden in the periventricular and subcortical region, higher perivascular spaces burden in the basal ganglia, multiple cerebral microbleeds, and multiple chronic lacunes. Presence of multiple chronic lacunes (OR 5.98, 95% CI 3.18-11.24) and ≥2 vascular risk factors (OR 2.03, 95% CI 1.05-3.91) stood out as features significantly associated with incidental DWI lesions in multivariate analysis. ConclusionsOur study shows that acute or subacute ischemic lesions can be incidentally detected in approximately one-fifth of patients with RSSI. This observation suggests that the course of CSVD might be more active, temporally and spatially, in a distinct subgroup of RSSI patients, specifically those with a higher chronic lacune and vascular risk factor burden.

Birth Cohorts and Cognitive Reserve Influence Cognitive Performances in Older Adults.

Evidence suggests birth cohort differences in cognitive performance of older adults. Proxies of cognitive reserve (CR), such as educational attainment and occupational complexity, could also partly account for these differences as they are influenced by the sociocultural environment of the birth cohorts. To predict cognitive performance using birth cohorts and CR and examine the moderating influence of CR on cognitive performance and structural brain health association. Using ADNI data (n = 1628), four birth cohorts were defined (1915-1928; 1929-1938; 1939-1945; 1946-1964). CR proxies were education, occupational complexity, and verbal IQ. We predicted baseline cognitive performances (verbal episodic memory; language and semantic memory; attention capacities; executive functions) using multiple linear regressions with CR, birth cohorts, age, structural brain health (total brain volume; total white matter hyperintensities volume) and vascular risk factors burden as predictors. Sex and CR interactions were also explored. Recent birth cohorts, higher CR, and healthier brain structures predicted better performance in verbal episodic memory, language and semantic memory, and attention capacities, with large effect sizes. Better performance in executive functions was predicted by a higher CR and a larger total brain volume, with a small effect size. With equal score of CR, women outperformed men in verbal episodic memory and language and semantic memory in all cohorts. Higher level of CR predicted better performance in verbal episodic memory, only when total brain volume was lower. Cohort differences in cognitive performance favor more recent birth cohorts and suggests that this association may be partly explained by proxies of CR.

Cerebrospinal Fluid Biomarkers, Brain Structural and Cognitive Performances Between Normotensive and Hypertensive Controlled, Uncontrolled and Untreated 70-Year-Old Adults.

Background: Hypertension is an important risk factor for Alzheimer’s disease (AD). The pathophysiological mechanisms underlying the relationship between AD and hypertension are not fully understood, but they most likely involve microvascular dysfunction and cerebrovascular pathology. Although previous studies have assessed the impact of hypertension on different markers of brain integrity, no study has yet provided a comprehensive comparison of cerebrospinal fluid (CSF) biomarkers and structural brain differences between normotensive and hypertensive groups in a single and large cohort of older adults in relationship to cognitive performances.Objective: The aim of the present work was to investigate the differences in cognitive performances, CSF biomarkers and magnetic resonance imaging (MRI) of brain structure between normotensive, controlled hypertensive, uncontrolled hypertensive, and untreated hypertensive older adults from the Gothenburg H70 Birth Cohort Studies.Methods: As an indicator of vascular brain pathology, we measured white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, enlarged perivascular space (epvs), and fractional anisotropy (FA). To assess markers of AD pathology/neurodegeneration, we measured hippocampal volume, temporal cortical thickness on MRI, and amyloid-β42, phosphorylated tau, and neurofilament light protein (NfL) in cerebrospinal fluid. Various neuropsychological tests were used to assess performances in memory, attention/processing speed, executive function, verbal fluency, and visuospatial abilities.Results: We found more white matter pathology in hypertensive compared to normotensive participants, with the highest vascular burden in uncontrolled participants (e.g., lower FA, more WMHs, and epvs). No significant difference was found in any MRI or CSF markers of AD pathology/neurodegeneration when comparing normotensive and hypertensive participants, nor among hypertensive groups. No significant difference was found in most cognitive functions between groups.Conclusion: Our results suggest that good blood pressure control may help prevent cerebrovascular pathology. In addition, hypertension may contribute to cognitive decline through its effect on cerebrovascular pathology rather than AD-related pathology. These findings suggest that hypertension is associated with MRI markers of vascular pathology in the absence of a significant decline in cognitive functions.

Deep Learning-Assisted Repurposing of Plant Compounds for Treating Vascular Calcification: An In Silico Study with Experimental Validation.

Background Vascular calcification (VC) constitutes subclinical vascular burden and increases cardiovascular mortality. Effective therapeutics for VC remains to be procured. We aimed to use a deep learning-based strategy to screen and uncover plant compounds that potentially can be repurposed for managing VC. Methods We integrated drugome, interactome, and diseasome information from Comparative Toxicogenomic Database (CTD), DrugBank, PubChem, Gene Ontology (GO), and BioGrid to analyze drug-disease associations. A deep representation learning was done using a high-level description of the local network architecture and features of the entities, followed by learning the global embeddings of nodes derived from a heterogeneous network using the graph neural network architecture and a random forest classifier established for prediction. Predicted results were tested in an in vitro VC model for validity based on the probability scores. Results We collected 6,790 compounds with available Simplified Molecular-Input Line-Entry System (SMILES) data, 11,958 GO terms, 7,238 diseases, and 25,482 proteins, followed by local embedding vectors using an end-to-end transformer network and a node2vec algorithm and global embedding vectors learned from heterogeneous network via the graph neural network. Our algorithm conferred a good distinction between potential compounds, presenting as higher prediction scores for the compound categories with a higher potential but lower scores for other categories. Probability score-dependent selection revealed that antioxidants such as sulforaphane and daidzein were potentially effective compounds against VC, while catechin had low probability. All three compounds were validated in vitro. Conclusions Our findings exemplify the utility of deep learning in identifying promising VC-treating plant compounds. Our model can be a quick and comprehensive computational screening tool to assist in the early drug discovery process.

Magnetic susceptibility in the deep gray matter may be modulated by apolipoprotein E4 and age with regional predilections: a quantitative susceptibility mapping study.

To examine the relationship between apolipoprotein E gene (APOE) mutation status and iron accumulation in the deep gray matter of subjects with cognitive symptoms using quantitative susceptibility mapping (QSM). A total of 105 patients with cognitive symptoms were enrolled. QSM data were generated from 3D gradient-echo data using an STI Suite algorithm. A region of interest-based analysis with QSM was performed in the deep gray matter. Differences between APOE4 carriers and non-carriers were assessed by analysis of covariance. Multiple regression analysis was performed to identify the factors associated with magnetic susceptibility. Clinical characters such as age, education, MMSE, vascular risk burden, and systolic blood pressure differ between APOE4 carrier and non-carrier groups. The APOE4 carrier group had higher magnetic susceptibility values than the non-carrier group, with significant differences in the caudate (p = 0.004), putamen (p < 0.0001), and globus pallidus (p < 0.0001) which imply higher iron accumulation. In a multiple regression analysis, APOE4 status was found to be a predictor of magnetic susceptibility value in the globus pallidus (p = 0.03); age for magnetic susceptibility value in the caudate nucleus (p = 0.0064); and age and hippocampal atrophy for magnetic susceptibility value in the putamen (p < 0.05). Our study demonstrates that magnetic susceptibility in globus pallidus is related to APOE4 status while those of caudate and putamen are related to other factors including age. It suggests that brain iron accumulation in the deep gray matter is modulated by APOE4 and age with differential regional predilection.

Vascular burden and genetic risk in association with cognitive performance and dementia in a population-based study.

Vascular risk factors may influence cognitive function and thus represent possible targets for preventive approaches against dementia. Yet it remains unknown, if they associate with cognition independently of the individual genetic risk for dementia. In a population-based study of 1172 community-dwelling individuals aged ≥65 years in Greece, we constructed a vascular burden score (VBS; based on presence of hypertension, diabetes, hyperlipidemia, heart disease, and cerebrovascular disease, range 0-5) and a polygenic risk score (PRS) for clinically-diagnosed Alzheimer's disease (AD) based on 23 genetic variants. We then explored in joint models the associations of the PRS for AD and VBS with global cognitive performance, cognitive performance across multiple cognitive domains, and odds of dementia. The mean age of study participants was 73.9±5.2 years (57.1% females). Both the PRS for AD and VBS were associated with worse global cognitive performance (beta per-SD-increment in PRS: -0.06, 95%CI: -0.10 to -0.02, beta per-point-increment in VBS: -0.05, 95%CI: -0.09 to -0.02), worse performance across individual cognitive domains (memory, executive function, attention, language, visuospatial ability), and higher odds of dementia (OR per-SD increment in PRS: 1.56, 95%CI: 1.17-2.09, OR per-point increment in VBS: 1.38, 95%CI: 1.05-1.81). There was no evidence of an interaction between the two scores. Higher VBS was associated with worse cognitive performance equally across tertiles of the PRS for AD, even among individuals at the highest tertile. Both genetic risk and vascular burden are independently and additively associated with worse cognitive performance and higher odds of dementia.

Vascular cognitive impairment and dementia: An early career researcher perspective.

The field of vascular contributions to cognitive impairment and dementia (VCID) is evolving rapidly. Research in VCID encompasses topics aiming to understand, prevent, and treat the detrimental effects of vascular disease burden in the human brain. In this perspective piece, early career researchers (ECRs) in the field provide an overview of VCID, discuss past and present efforts, and highlight priorities for future research. We emphasize the following critical points as the field progresses: (a) consolidate existing neuroimaging and fluid biomarkers, and establish their utility for pharmacological and non‐pharmacological interventions; (b) develop new biomarkers, and new non‐clinical models that better recapitulate vascular pathologies; (c) amplify access to emerging biomarker and imaging techniques; (d) validate findings from previous investigations in diverse populations, including those at higher risk of cognitive impairment (e.g., Black, Hispanic, and Indigenous populations); and (e) conduct randomized controlled trials within diverse populations with well‐characterized vascular pathologies emphasizing clinically meaningful outcomes.

Plaque-targeted, proteolysis-resistant, activatable and MRI-visible nano-GLP-1 receptor agonist targets smooth muscle cell differentiation in atherosclerosis.

Background: Glucagon-like peptide-1 receptor (GLP-1R) agonists are powerful glycemia-lowering agents, which have systematically been shown to lower cardiovascular events and mortality. These beneficial effects were difficult to pinpoint within atherosclerotic plaque due to lack of particular specificity of such agonists to the vascular cells and an inadequate understanding of the GLP-1R expression in atherosclerosis. Here, we hypothesized that the direct engagement of the GLP-1R in atherosclerosis by targeted agonists will alleviate vascular inflammation and plaque burden, even at a very low dose.Methods: The expression of GLP-1 receptor (GLP-1R, Glp1r mRNA) in human lesions with pathologic intimal thickening, Apoe-/- mouse atheroma and cultured immune/non-immune cells was investigated using genetic lineage tracing, Southern blotting and validated antisera against human GLP-1R. Protease-resistant and “activatable” nanoparticles (NPs) carrying GLP-1R agonist liraglutide (GlpNP) were engineered and synthesized. Inclusion of gadolinium chelates into GlpNP allowed for imaging by MRI. Atherosclerotic Apoe-/- mice were treated intravenously with a single dose (30 µg/kg of liraglutide) or chronically (1 µg/kg, 6 weeks, 2x/week) with GlpNP, liraglutide or control NPs, followed by assessment of metabolic parameters, atheroma burden, inflammation and vascular function.Results: Humal plaque specimens expressed high levels of GLP-1R within the locus of de-differentiated smooth muscle cells that also expressed myeloid marker CD68. However, innate immune cells under a variety of conditions expressed very low levels of Glp1r, as seen in lineage tracing and Southern blotting experiments examining full-length open reading frame mRNA transcripts. Importantly, de-differentiated vascular smooth muscle cells demonstrated significant Glp1r expression levels, suggesting that these could represent the cells with predominant Glp1r-positivity in atherosclerosis. GlpNP resisted proteolysis and demonstrated biological activity including in vivo glycemia lowering at 30 µg/kg and in vitro cholesterol efflux. Activatable properties of GlpNP were confirmed in vitro by imaging cytometry and in vivo using whole organ imaging. GlpNP targeted CD11b+/CD11c+ cells in circulation and smooth muscle cells in aortic plaque in Apoe-/- mice when assessed by MRI and fluorescence imaging. At a very low dose of 1 µg/kg, previously known to have little effect on glycemia and weight loss, GlpNP delivered i.v. for six weeks reduced triglyceride-rich lipoproteins in plasma, plaque burden and plaque cholesterol without significant effects on weight, glycemia and plasma cholesterol levels.Conclusions: GlpNP improves atherosclerosis at weight-neutral doses as low as 1 µg/kg with the effects independent from the pancreas or the central nervous system. Our study underlines the importance of direct actions of GLP-1 analogs on atherosclerosis, involving cholesterol efflux and inflammation. Our findings are the first to suggest the therapeutic modulation of vascular targets by GlpNP, especially in the context of smooth muscle cell inflammation.

Pathomechanisms of Vascular Depression in Older Adults.

Depression in older individuals is a common complex mood disorder with high comorbidity of both psychiatric and physical diseases, associated with high disability, cognitive decline, and increased mortality The factors predicting the risk of late-life depression (LLD) are incompletely understood. The reciprocal relationship of depressive disorder and age- and disease-related processes has generated pathogenic hypotheses and provided various treatment options. The heterogeneity of depression complicates research into the underlying pathogenic cascade, and factors involved in LLD considerably differ from those involved in early life depression. Evidence suggests that a variety of vascular mechanisms, in particular cerebral small vessel disease, generalized microvascular, and endothelial dysfunction, as well as metabolic risk factors, including diabetes, and inflammation that may induce subcortical white and gray matter lesions by compromising fronto–limbic and other important neuronal networks, may contribute to the development of LLD. The “vascular depression” hypothesis postulates that cerebrovascular disease or vascular risk factors can predispose, precipitate, and perpetuate geriatric depression syndromes, based on their comorbidity with cerebrovascular lesions and the frequent development of depression after stroke. Vascular burden is associated with cognitive deficits and a specific form of LLD, vascular depression, which is marked by decreased white matter integrity, executive dysfunction, functional disability, and poorer response to antidepressive therapy than major depressive disorder without vascular risk factors. Other pathogenic factors of LLD, such as neurodegeneration or neuroimmune regulatory dysmechanisms, are briefly discussed. Treatment planning should consider a modest response of LLD to antidepressants, while vascular and metabolic factors may provide promising targets for its successful prevention and treatment. However, their effectiveness needs further investigation, and intervention studies are needed to assess which interventions are appropriate and effective in clinical practice.

Neurodegeneration and Vascular Burden on Cognition After Midlife: A Plasma and Neuroimaging Biomarker Study.

Background and Objectives: Neurodegeneration and vascular burden are the two most common causes of post-stroke cognitive impairment. However, the interrelationship between the plasma beta-amyloid (Aβ) and tau protein, cortical atrophy and brain amyloid accumulation on PET imaging in stroke patients is undetermined. We aimed to explore: (1) the relationships of cortical thickness and amyloid burden on PET with plasma Aβ40, Aβ42, tau protein and their composite scores in stroke patients; and (2) the associations of post-stroke cognitive presentations with these plasma and neuroimaging biomarkers.Methods: The prospective project recruited first-ever ischemic stroke patients around 3 months after stroke onset. The plasma Aβ40, Aβ42, and total tau protein were measured with the immunomagnetic reduction method. Cortical thickness was evaluated on MRI, and cortical amyloid plaque deposition was evaluated by 18F-florbetapir PET. Cognition was evaluated with Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Dementia Rating Scale-2 (DRS-2).Results: The study recruited 24 stroke patients and 13 normal controls. The plasma tau and tau*Aβ42 levels were correlated with mean cortical thickness after age adjustment. The Aβ42/Aβ40 ratio was correlated with global cortical 18F-florbetapir uptake value. The DRS-2 and GDS scores were associated with mean cortical thickness and plasma biomarkers, including Aβ42/Aβ40, tau, tau*Aβ42, tau/Aβ42, and tau/Aβ40 levels, in stroke patients.Conclusion: Plasma Aβ, tau, and their composite scores were associated with cognitive performance 3 months after stroke, and these plasma biomarkers were correlated with corresponding imaging biomarkers of neurodegeneration. Further longitudinal studies with a larger sample size are warranted to replicate the study results.

Amyloid‐independent vascular contributions to cortical atrophy and cognition in a multi‐center mixed cohort with low to severe small vessel disease

AbstractBackgroundSmall vessel disease (SVD) often co‐exists with Alzheimer’s disease (AD) pathology (up to 60%) and may facilitate AD progression. However, SVD is currently not integrated as a pathological factor within the ATN research criteria. Up to now, the majority of studies that investigated effects of SVD on brain atrophy and cognition were limited to either AD cohorts with low SVD burden (e.g., ADNI) or cognitively normal elderly with high SVD burden. Thus, there is a need to investigate the effects of SVD in a cohort spanning low to severe SVD and amyloid‐beta pathology.MethodOur study included 118 subjects in total. Fifty‐nine subjects were recruited in a multi‐site study (MITNEC) from dementia and SVD‐stroke clinics (64% amyloid‐beta+) who had severe SVD burden as quantified by white matter hyperintensity volumes [WMH; median(IQR): 30.2(22.2)cm3] and Fazekas score 2.5‐3. In addition, we included 59 cognitively normal/early‐MCI subjects from ADNI (44% amyloid‐beta+) with low‐to‐moderate WMH [median(IQR): 5.8(9.1)cm3]. We performed vertex‐wise regressions, investigating associations of cortical thickness with amyloid‐beta (18F‐florbetapir‐SUVRpons) or vascular burden (WMH), corrected for WMH or amyloid‐beta, respectively, and age, sex, education. Further, mediation analyses investigated whether the effects of amyloid‐beta or vascular burden on cognition (MMSE, MoCA, Trails‐B, semantic fluency, ANART, and Boston‐naming) were mediated by cortical thickness.ResultWe observed a significant effect of vascular burden on cortical thickness independent of amyloid‐beta. This effect was stronger than the vascular‐independent effect of amyloid‐beta on thickness (Fig. 1). Furthermore, we observed additive effects of vascular burden and amyloid‐beta on cognition (semantic fluency: ß=‐0.29 [p=0.002] and ß=‐0.27 [p=0.001], respectively; Trails‐B: ß=+0.18 [p=0.03] and ß=+0.22 [p=0.02], respectively). Here, the effects on semantic fluency were significantly mediated by cortical thickness (vascular→thickness→semantic: 35% mediation, 95%CI[‐0.19,‐0.02]; amyloid‐beta→thickness→semantic: 19% mediation, 95%CI[‐0.11,‐0.003]) (Fig. 1).ConclusionIn our study of mixed AD/SVD and control subjects, the effect of SVD burden (WMH) exceeded the effect of amyloid‐beta on neurodegeneration alone. Furthermore, vascular burden contributed to semantic loss both directly and through its impact on neurodegeneration. As such, the presence of cerebrovascular comorbidities supports the idea of combinational therapeutic approaches where SVD factors may be targeted alongside amyloid‐beta to halt neurodegeneration and cognitive decline.

Assessing the cumulative impact of vascular burden on structural changes in the brain during ageing

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia. Yet more recent findings from epidemiological and neuropathological studies have revealed the presence of vascular pathology in AD. There is overwhelming evidence from pathological examinations that indicates the presence of ‘mixed cases’ at autopsy. The study aim was to examine whether overall vascular burden measured by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with brain structural changes.MethodIn the first analysis a Voxel Based Morphometry (VBM) multiple regression model was used with group status (60 controls, 74 Mild Cognitive Impairment and 51 AD) and Framingham vascular risk scores as predictors while accounting for age, total intracranial volume, years of education. In the second model a 2x2x2 factorial design with different group comparisons was used with group, APOE ε4 carrier status and Vascular Burden (low vs high load) to understand the interactions across the factors.ResultThe VBM regression model implicated regions that included the thalamus, subcallosal gyrus, precentral and postcentral gyrus, cerebellum, occipital gyri, inferior frontal gyrus, insula and the cuneus.The factorial analysis revealed two different set of interaction effects. There was a APOE x Vascular Burden interaction effect between controls and MCI. The regions implicated in this analysis included the cerebellum, right inferior occipital gyrus, right thalamus, left brainstem, left fusiform gyrus, left precentral and postcentral gyrus and left Insula. There also was a Group x APOE Status x Vascular Burden interaction effect that involved the left brainstem and left parahippocampal gyrus during the transition from MCI and AD.ConclusionThe voxel‐based regression model and the first factorial analysis implicated areas that comprises both cerebellar and subcortical regions that have been previously implicated in dementia with vascular pathology. The areas implicated by vascular pathology have been shown to affect primarily gait, movement and visuospatial abilities. But given that the brainstem and its nuclei are also involved, future studies should look at examining the role of vascular pathology and how it affects the neuromodulatory systems of the brainstem and whether these projections have any effect on the efficient functioning of large‐scale brain networks.

GM6 attenuates Alzheimer's disease pathology through a reduction in fibrinogen levels and by regulation of Aβ, p-tau and inflammation.

Alzheimer's disease (AD) is characterized by cerebral amyloid-b (Ab) deposition, vascular alterations, tau pathology, microglia activation, and inflammation. Vascular dysfunction and amyloid burden are independent and equal predictors of cognitive decline in the elderly, with an additive adverse effect on cognition. Fibrinogen, a blood coagulation protein, is deposited in the AD brain; co-localizes with amyloid plaques, pericyte loss, dystrophic neurites, and activated microglia; and its increased concentrations in plasma and cerebrospinal fluid correlate with brain atrophy in AD patients. GM6 is a derivative of motoneuronotrophic factor (MNTF) which functions as a regulator of key biomarkers and acts upon multiple extracellular receptors to modulate a series of signaling pathways. This study evaluates the effects of GM6 on fibrinogen levels in two animal models of AD. APP and h-tau transgenic mice were treated with GM6 daily for up to 4 months and examined for changes in fibrinogen, Aβ peptide levels, plaques, inflammation, phosphorylated tau (p-tau) as well as behavioral changes associated with disease progression. Fibrinogen levels were determined by ELISA and western blot analysis. When we studied APP transgenic mice treated with GM6 compared to placebo, fibrinogen levels were significantly decreased (75%) along with diminished Aβ peptide levels, attenuation of plaque load, and a reduction in inflammatory biomarkers. In another study of the p-tau formation in the h-tau mice treated with GM6 compared to placebo, again a reduction in fibrinogen was observed along with reduction in p-tau and inflammation biomarker levels. In both transgenic mice, behavioral changes were attenuated with GM6 treatment. In both APP and h-tau mice, inflammation cytokines TNF-α, IL-1β, IL-6, and TGF-β were reduced by 80-90% as previously reported. In conclusion, to counter the additive adverse effect on cognition from vascular dysfunction and amyloid burden, GM6 may be a feasible approach to attenuate Alzheimer's disease pathology through a reduction in fibrinogen levels and by regulation of Ab, p-tau and inflammation.

Determinants of enlarged perivascular spaces (ePVS) on MRI: The Florida Vascular Imaging Phenotypes (FL‐VIP) Study of AD risk

AbstractBackgroundPVS are fluid filled compartments surrounding small intracerebral vessels. They are conduits for fluid transport, exchange, and waste clearance. Their relationship to cardiovascular markers is unknown. We tested whether ePVS counts are affected by vascular risk factors and comorbidities.MethodWe analyzed nondemented subjects’ brains from the FL‐VIP (comprised of 1Florida ADRC participants with available high quality 3T MRI). ePVS were defined as parenchymal hypo/hyperintensities of &lt;3 mm seen on a single axial T1, T2 or FLAIR section through the basal ganglia (BG) and centrum semiovale (CSO). ePVS were defined as parenchymal hyperintensities &lt;3 mm and graded as 0 (none), 1 (&lt;10), 2 (11‐20), 3 (21‐40), and 4 (&gt;40). The side with highest ePVS count was graded. BG and CSO scores were summed to yield a 0‐8 total. Generalized linear models were used to estimate ePVS score associations with demographics, vascular risk factors, and vascular comorbidities (VASCom score).ResultOf 228 non‐demented participants (mean age 72±8 years; 61% women, 60% Hispanic, mean education 15±4 years, 33% ApoE4 carriers), 59% were hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. ePVS scores ranged from 0‐7 (mean 2.5±1.4), 0‐4 for BG (mean 1.3±0.7) and CSO (mean 1.2 ±0.9). Majority of subjects (73%) had a total ePVS score greater than 1. In unadjusted analysis, BG ePVS were correlated with age (r=0.27, P&lt;0.001), hypertension (r=0.19, p=0.008), MI/CHF/Angina (r=0.14, P=0.03), and coronary bypass (r=0.20, P=0.004). CSO ePVS were correlated with age (r=0.23, P=0.0005), obesity (r=‐0.15, p=0.03), and dyslipidemia (r=‐0.14, P=0.04). In multivariable stepwise regression analyses, BG ePVS were associated with age (β=0.024 per year, p=0.0001), being Hispanic (OR=0.21, P=0.035), coronary bypass (OR=0.70, p=0.025), and hypertension (OR =0.17, p=0.079). CSO PeVS were associated with age (β=0.028 per year, P&lt;0.001) and dyslipidemia (OR=‐0.31, P=0.02).ConclusionePVS were more prevalent with aging, greater vascular risk burden, and Hispanic origin. Hypertension, cardiovascular disease and prior coronary bypass surgery were associated with ePVS in BG, but not in CSO. BG ePVS may be an important marker of small vessel disease linking vascular burden and cognitive impairment.

Lower regional cerebrovascular reactivity relates to worse episodic memory among older adults

AbstractBackgroundCerebrovascular reactivity (CVR) measures the ability of the cerebrovasculature to respond to vasoactive stimuli. Decreased CVR in the default mode network (DMN) has been associated with increased vascular risk factor burden. DMN connectivity is fundamentally dependent on vascular compliance, which can be altered in MCI, and may impact episodic memory consolidation. This study cross‐sectionally evaluated whether the topography of CVR is associated with episodic memory performance.MethodVanderbilt Memory &amp; Aging Project participants free of stroke were included (n=117, 76.0±7.3 years, 46% female). Participants underwent neuropsychological assessment and multimodal 3T brain MRI, including T1‐weighted imaging and T2*‐weighted blood‐oxygenation level‐dependent (BOLD‐fMRI) for quantifying CVR. During the BOLD‐fMRI acquisition, a hypercapnic normoxic respiratory challenge was administered by alternating normocapnic normoxia and hypercapnic normoxia (5% CO2/95%‐air) in 90s blocks. BOLD‐fMRI data were time‐delay processed, yielding whole‐brain mapping of the maximum correlation with the gas stimulus (CVRMAX) and time‐to‐max CVR (CVRDELAY). Mean CVR metrics were calculated in atlas‐derived DMN regions. Ordinary least squares regression models related DMN‐CVR to episodic memory performance adjusting for demographics, Framingham Stroke Risk Profile, and apolipoprotein E‐e4 status. Clusters were corrected using family‐wise‐error rate p&lt;0.05.ResultDMN‐CVRMAX was related to episodic memory performance (b=1.0x10‐3, p=0.03) but DMN‐CVRDELAY was not (p=0.09). In voxelwise analysis relating CVRMAX to memory, seven clusters surviving correction were identified, all suggesting lower CVRMAX related to worse memory performance. The peak value of the top cluster was located in the middle temporal gyrus. In voxelwise analysis relating CVRDELAY to memory, 11 clusters surviving correction were identified, all indicating longer CVRDELAY related to worse memory performance. The peak value of the top cluster was located in postcentral gyrus.ConclusionAmong older adults, lower DMN‐CVRMAX is associated with worse episodic memory performance and this association is not confined to the DMN. Associations between regionally reduced vascular compliance and episodic memory may result from vascular impairment of large‐scale brain networks such as the DMN, though these associations should be further explored. T32‐AG058524, IIRG‐08‐88733, R01‐AG034962, R01‐NS100980, K24‐AG046373, P20‐AG068082

Association of tau pathology and vascular risk factor burden with longitudinal measures of plasma neurofilament light

AbstractBackgroundIn the context of Alzheimer’s disease (AD), tau pathology is a major driver of the neurodegenerative cascade that ultimately leads to loss of neurons and synapses. In fact, studies have shown that neurodegeneration is more strongly associated with tau pathology than amyloid‐β (Aβ) accumulation. Although plasma neurofilament light (NfL) is a neuroaxonal damage biomarker that currently is in the research spotlight, the factors influencing the association between its longitudinal trajectory and tau pathology remains unclear. Since vascular risk factors (VRFs) present an important role in AD etiology and progression, here we aimed to determine whether tau pathology, in combination with or independently of VRF burden, is associated with longitudinal plasma NfL trajectory.MethodWe assessed 901 participants [276 CU, 455 MCI and 170 AD] from ADNI with baseline plasma p‐tau181 and [18F]AV45 Aβ‐PET, as well as longitudinal plasma NfL measurements (up to 4 years). Baseline VRF burden was calculated considering the history for cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, stroke or transient ischemic attack, smoking, atrial fibrillation and left ventricular hypertrophy. Individuals were dichotomized as following: elevated VRF burden if ≥2 VRFs (V+), tau positive if plasma p‐tau181 ≥ 17.7 pg/mL (T+) and amyloid positive if global Aβ‐PET SUVR ≥ 1.11 (A+). Subjects who were A‐T+ were excluded. Linear mixed‐effects models (LMMs) were performed to evaluate plasma NfL’s longitudinal trajectories.ResultThe LMMs demonstrated that tau positivity (T+) was significantly associated with a higher rate of longitudinal increase in plasma NfL levels in comparison to the tau‐negative group (Fig. 1). However, analysis dividing the groups both by tau and VRF burden status demonstrated that the rates of increase in plasma NfL were greater only in the presence of both VRF burden and tau positivity (T+V+; t‐value=2.54, p&lt;0.05), when compared to the reference group (T‐V‐; Fig. 2). Moreover, specific slope‐contrast analyses confirmed that only the T+V+ group presented a clearly separate trajectory.ConclusionOur findings suggest that an elevated VRF burden influences the relation between tau pathology and neurodegeneration in AD.Therefore, tau‐mediated neurodegeneration seems to be most relevant in combination with vascular‐mediated neuroaxonal injury. These findings reinforce the pivotal contribution of vascular pathology to AD development.

Higher intraindividual variability in neuropsychological test performance is associated with reduced cerebral blood flow in older adults

AbstractBackgroundIntraindividual variability (IIV) across neuropsychological measures within a single testing session has become a promising sensitive marker predictive of cognitive decline and development of Alzheimer’s disease (AD). We have previously shown that higher IIV is associated with medial temporal lobe atrophy. However, to our knowledge, IIV has yet to be examined in relation to cerebral blood flow (CBF). Therefore, we examined associations between IIV and regional CBF among older adults free of dementia.Method141 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants underwent neuropsychological testing, magnetic resonance imaging (MRI), and florbetapir positron emission tomography (PET) imaging. The IIV index was calculated as the intraindividual standard deviation across 6 demographically‐corrected neuropsychological measures. Mean neuropsychological performance was computed as the mean of the 6 z‐scores. Pulsed arterial spin labeling MRI was used to quantify CBF. Six free‐surfer derived a priori CBF regions of interest were examined: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. PET amyloid‐β (Aβ) positivity was determined using the recommended threshold for cross‐sectional florbetapir of 1.11 using whole cerebellum as the reference region.ResultIn the entire sample, linear regression models showed that after adjusting for age, sex, mean neuropsychological performance, and regional cortical thickness, greater IIV was significantly associated with lower inferior parietal CBF (β=‐2.712, p=.004), inferior temporal CBF (β=‐3.259, p=.001), and reduced entorhinal CBF at trend level (β=‐.407, p=.073). Sensitivity analyses showed that among Aβ+ individuals, greater IIV was significantly associated with lower CBF in inferior parietal (β=‐2.729, p=.018) and inferior temporal regions (β=‐2.704, p=.043). In Aβ‐ individuals, there were no significant associations between IIV and CBF (all ps&gt;.05).ConclusionIIV may be sensitive to early cerebrovascular changes in AD‐vulnerable regions above and beyond demographics, mean neuropsychological performance, and cortical thickness. These relationships were seen among Aβ+ individuals, suggesting that IIV may be a marker of early brain changes among those individuals on the AD continuum. Future studies should examine how IIV may predict future brain and cognitive changes in more diverse samples and among those with greater vascular risk burden.

Retinal vascular abnormalities and blood-retinal barrier breakdown in Alzheimer's disease.

Vascular changes including cerebral amyloid angiopathy (CAA), reduced blood flow, pericyte loss and vascular platelet-derived growth factor receptor-β (PDGFRβ) deficiency have emerged as prominent features of Alzheimer's disease (AD). We previously identified the existence of the pathological hallmarks of AD, amyloid β-protein (Aβ) plaques, along with intracellular and vascular Aβ deposits in the neurosensory retina of AD patients. Data suggest that certain retinal signs manifest early in disease progression and appear similar to those observed in the brain. Yet, retinal vascular abnormalities in AD and their ability to predict cerebral pathology and cognitive decline are poorly understood. Here, we assessed vascular changes including capillary degeneration, PDGFRβ expression, vascular amyloidosis, pericyte loss, and blood-retinal barrier (BRB) permeability in postmortem retinas from a cohort of mild cognitively impaired (MCI) and AD patients. We evaluated retinal cross-sections from pre-defined topographical regions and isolated retinal vascular networks labeled by periodic acid-Schiff or immunofluorescence. We further quantified capillary degeneration, PDGFRβ expression, vascular amyloidosis, and inner BRB tight-junction molecule expression and BRB leakage in transgenic APPSWE /PS1ΔE9 mouse models of AD (ADtg mice) at different disease stages. Early and progressive PDGFRβ deficiency and pericyte loss were found in retinas from AD patients. PDGFRβ deficiency associated with vascular Aβ deposits in postmortem retinas from a cohort of MCI and AD patients. In ADtg mice as compared to age- and sex-matched wild-type mice, we found significant degeneration of retinal capillaries (P<0.0001). ADtg retinas also displayed a substantial vascular PDGFRβ deficiency (∼50% reduction, P=0.0017) and vascular Aβ deposition, which inversely correlated with the extent of degenerated capillaries (Pearson's r=-0.8, P=0.0016). Tight-junction alterations including claudin-1 downregulation and increased BRB permeability were found in ADtg mice. In postmortem retinas from the human cohort, retinal PDGFRβ loss significantly associated with increased retinal vascular Aβ40 and Aβ42 burdens. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were further revealed. Correlations were identified between retinal vascular abnormalities and cerebral Aβ burden, CAA, and clinical status. Overall, the identification of age- and Alzheimer's-dependent retinal capillary degeneration and compromised BRB integrity starting at early disease stages provide novel targets for AD diagnosis and therapy.