Systemic Vascular Risk Research Articles

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Vascular risk profile and changes of arterial hypertension after surgical revascularization in adult Moyamoya patients

Moyamoya disease (MMD) is a rare stenoocclusive cerebral vasculopathy often treated by neurosurgical revascularization using extracranial-intracranial bypasses to prevent ischemic or hemorrhagic events. Little is known about the vascular risk profile of adult MMD patients compared to the general population. We therefore analyzed 133 adult MMD patients and compared them with data from more than 22,000 patients from the German Health Update database. Patients with MMD showed an age- and sex-adjusted increased prevalence of arterial hypertension, especially in women between 30 and 44 years and in patients of both sexes between 45 and 64 years. Diabetes mellitus was diagnosed significantly more frequently in MMD patients with increasing age, whereas the vascular risk profile in terms of obesity, nicotine and alcohol consumption was similar to that of the general population. Antihypertensive medication was changed one year after surgical revascularization in 67.5% of patients with a tendency towards dose reduction in 43.2% of all patients. After revascularization, physicians need to be aware of a high likelihood of changes in arterial hypertension and should adjust all other modifiable systemic vascular risk factors to achieve the best treatment possible.

Cerebrovascular disease emerges with age and Alzheimer’s disease in adults with Down syndrome

Adults with Down syndrome have a genetic form of Alzheimer’s disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer’s Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25–72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

Can Optical Coherence Tomography Angiography be a Useful Adjunctive Diagnostic Tool in Patient with Non Arteritic Ischaemic Optic Neuropathy?

Abstract
 Introduction : Perfusion deficiency of the optic nerve head is presumed to have an immense role in the pathogenesis of non-arteritic ischaemic optic neuropathy (NAION). Optical coherence tomography angiography (OCTA) is a non-invasive method that can assess posterior pole vasculature at multiple levels. Thus, these case series want to compare the OCTA in the acute (before four weeks) and chronic phases (after six weeks) of NAION with their fellow unaffected eyes to give an overview of vasculature changes in NAION.
 Case Illustration : This case series consists of four patients with NAION. Half of them came with a sudden painless blurry vision, and the remaining presented with an abrupt visual field defect. All of them have diabetes mellitus and hypertension. None of them have superimposed vascular pathology. The first OCTA was taken within seven days of the first symptoms, and the second OCTA was taken more than six weeks after.
 Discussion : The high percentage of systemic vascular risk factors and the acute onset supported the vascular occlusive hypothesis in the pathogenesis of NAION. Meanwhile, the OCTA provides an actual overview of the vasculature changes. Microvasculature is more likely to expand in the acute phase, and a more significant expansion was found in greater optic disc edema. On the other hand, microvascular tend to attenuate in the chronic phase, representing the pruning of capillaries. A swept-source OCTA with deeper penetration might give a better peripapillary choriocapillaris image in the acute phase.
 Conclusion : OCTA is a promising adjunctive tool for diagnosing and monitoring progression in patients with NAION.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau.

Associations between vascular health, brain stiffness and global cognitive function.

Vascular brain injury results in loss of structural and functional connectivity and leads to cognitive impairment. Its various manifestations, including microinfarcts, microhaemorrhages and white matter hyperintensities, result in microstructural tissue integrity loss and secondary neurodegeneration. Among these, tissue microstructural alteration is a relatively early event compared with atrophy along the aging and neurodegeneration continuum. Understanding its association with cognition may provide the opportunity to further elucidate the relationship between vascular health and clinical outcomes. Magnetic resonance elastography offers a non-invasive approach to evaluate tissue mechanical properties, providing a window into the microstructural integrity of the brain. This retrospective study evaluated brain stiffness as a potential biomarker for vascular brain injury and its role in mediating the impact of vascular dysfunction on cognitive impairment. Seventy-five participants from the Mayo Clinic Study of Aging underwent brain imaging using a 3T MR imager with a spin-echo echo-planar imaging sequence for magnetic resonance elastography and T1- and T2-weighted pulse sequences. This study evaluated the effects of vascular biomarkers (white matter hyperintensities and cardiometabolic condition score) on brain stiffness using voxelwise analysis. Partial correlation analysis explored associations between brain stiffness, white matter hyperintensities, cardiometabolic condition and global cognition. Mediation analysis determined the role of stiffness in mediating the relationship between vascular biomarkers and cognitive performance. Statistical significance was set at P-values < 0.05. Diagnostic accuracy of magnetic resonance elastography stiffness for white matter hyperintensities and cardiometabolic condition was evaluated using receiver operator characteristic curves. Voxelwise linear regression analysis indicated white matter hyperintensities negatively correlate with brain stiffness, specifically in periventricular regions with high white matter hyperintensity levels. A negative association between cardiovascular risk factors and stiffness was also observed across the brain. No significant patterns of stiffness changes were associated with amyloid load. Global stiffness (µ) negatively correlated with both white matter hyperintensities and cardiometabolic condition when all other covariables including amyloid load were controlled. The positive correlation between white matter hyperintensities and cardiometabolic condition weakened and became statistically insignificant when controlling for other covariables. Brain stiffness and global cognition were positively correlated, maintaining statistical significance after adjusting for all covariables. These findings suggest mechanical alterations are associated with cognitive dysfunction and vascular brain injury. Brain stiffness significantly mediated the indirect effects of white matter hyperintensities and cardiometabolic condition on global cognition. Local cerebrovascular diseases (assessed by white matter hyperintensities) and systemic vascular risk factors (assessed by cardiometabolic condition) impact brain stiffness with spatially and statistically distinct effects. Global brain stiffness is a significant mediator between vascular disease measures and cognitive function, highlighting the value of magnetic resonance elastography-based mechanical assessments in understanding this relationship.

Systemic vascular risk, white matter injury, and relative cerebral blood flow independently contribute to cognitive decline beyond amyloid and tau burden

AbstractBackgroundAge, systemic vascular risk factors, white matter injury, cerebral blood flow, amyloid, and tau burden are well‐established contributors to late‐life cognitive decline. Given the strong relationship among these measures, we proposed a model to extract latent factors and isolate domain‐specific measures that underlie cognitive decline in preclinical AD.MethodData were available for 166 cognitively unimpaired older adults from Harvard Aging Brain Study (Table1). We used the following measures: 1) cortical amyloid burden from PiB‐PET; 2) inferior temporal cortex FTP‐PET; 3) relative cerebral blood flow (R1) from dynamically‐acquired PiB‐PET; 4) white matter hyperintensities (WMH) from FLAIR‐MRI; 5) Peak width of skeletonized mean diffusivity (PSMD) from DTI‐MRI; 6) gray matter volume (GMV) from MPRAGE‐MRI; 7) Framingham Heart Study cardiovascular disease risk (CVD); 8) Preclinical Alzheimer Cognitive Composite‐5 (PACC). We extracted slopes using linear mixed effect models for longitudinal PACC decline and GMV atrophy (follow‐up = 7.4±2.8 years). The remaining data were obtained from baseline. We used exploratory factor analysis (varimax rotations) to extract orthogonal factors. These factors were used in a regression model to explain PACC decline. We next examined whether GMV atrophy acts as a mediator of factors and PACC decline. Subsequently, we investigated whether factors interact to further explain PACC decline.ResultsOriginal variables were highly interrelated (Figure1A) and correlated with PACC decline (Figure1B). Scree test showed 6 factors were sufficient (cumulative variance:96%, Figure2A). All factors except Factor5 (age) independently explained PACC decline (Figure2B, r2 = 0.44). Including GMV atrophy removed effect of Factor1 (white matter injury, Figure2B, r2 = 0.51). Factor3 (amyloid) interacted with Factor1 and Factor4 (tau) in explaining PACC decline (Figure2C, r2 = 0.58).ConclusionLatent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow (but not age) independently explain cognitive decline beyond amyloid and tau burden in this preclinical AD cohort. GMV atrophy mediates these associations with the strongest effect on white matter injury suggesting a strong link between white matter injury and neurodegeneration. These results suggest that current markers of cerebrovascular injury contribute to cognitive decline beyond systemic vascular risk (CVD), amyloid, and tau burden. The mechanism by which systemic vascular risk impacts cognition requires further explication.

Longitudinal white matter hyperintensities in Down’s syndrome

AbstractBackgroundDown’s syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD). Typically not complicated by systemic vascular risk factors, the DS population represents a unique opportunity to unravel the complex relationship between AD and cerebrovascular disease. Here, we aim at studying the evolution over time of white matter hyperintensities (WMHs), a key hallmark of cerebrovascular disease frequently found in AD, and to assess their topographical progression and associations with AD biomarkers in adults with DS.MethodThis longitudinal study included 43 DS adults (age = 39.8±10.4y; females = 41.9%; n = 37 asymptomatic AD, n = 6 symptomatic AD) and 81 euploid controls (age = 53.7±6.2y; females = 67.3%) from the Down‐Alzheimer Barcelona Neuroimaging Initiative, with at least 2 MRI visits with T1 and FLAIR acquisitions (time delay = 3.4±1.6y). WMHs were segmented using the Lesion Prediction Algorithm implemented in the Lesion Segmentation Toolbox (SPM12). WMH volumes were extracted in 36 regions of interest and used to compute total and regional annual volume changes. Non‐parametric statistical tests were performed to assess the effect of disease severity on WMH volume changes over time and define associations between longitudinal WMHs and baseline demographic and genetic data, and fluid biomarkers.ResultTotal annual WMH volume change increased in symptomatic DS compared to both asymptomatic DS and controls (Figure 1A). Regionally, WMH load increased in regions showing WMH at baseline in all groups (Figure 2). These changes were greater and more distributed, involving layers more distant from the ventricles (especially in occipito‐parietal regions) in symptomatic DS. Age, but not sex, intellectual disability, or APOEε4 status, was associated with longitudinal WMH in DS (Figure 1B‐F): the annual WMH volume changes in DS differed from controls at age ∼45y. Finally, WMH volume changes were negatively related to CSF‐Aβ42/40 and positively related to plasma and CSF ptau‐181 and neurofilament light (Figure 3).ConclusionPathological increases in WMH volume start ∼10 years before the mean age at onset for AD (53.8y) in DS and relate to underlying AD pathology and neurodegeneration. Regional analyses suggest that WMH volume changes increase with disease progression and progressively involve deeper white matter areas. Together, these results support that WMHs are tightly related to AD pathogenesis.

Plasma Alzheimer biomarker correlates of cerebrovascular disease in adults with Down syndrome

AbstractBackgroundBy age 40 over 90% of adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology and most progress to dementia. Despite having fewer systemic vascular risk factors than neurotypical adults, recent studies demonstrate evidence of significant cerebrovascular disease in individuals with DS that track with the clinical progression of AD, suggesting a role for cerebrovascular disease that is not attributable solely to exposure to vascular risk factors. In the current study, we examined the codependency between white matter hyperintensity (WMH) volume, a marker of small vessel cerebrovascular disease, and AD pathophysiology, indexed with plasma AD biomarkers, in adults with DS.MethodOne hundred eighty‐seven participants from the Alzheimer Biomarkers Consortium – Down Syndrome (mean[SD] = 45.1[9.4] years) with available MRI and plasma biomarker data were included in the study. Whole‐brain WMH volumes were derived from T2‐weighted FLAIR MRI scans with in‐house software and plasma p‐tau217, Aβ42/Aβ40, and neurofilament light (NfL) concentrations were measured with SIMOA assays. Separate general linear models tested the association of WMH volume with each of the three biomarker concentrations; subsequent models were stratified by age, based on the median (46 years old).ResultHigher WMH volume was associated with increased p‐tau217 and NfL concentrations but not with Aβ. In stratified analyses, the association between WMH and NfL concentration was stronger in younger adults than in older adults whereas the association between WMH and p‐tau217 concentration was stronger in older adults than in younger adults.ConclusionOur findings suggest a co‐dependency of cerebrovascular disease with tau pathology and neurodegeneration in adults with Down syndrome. Cerebrovascular disease may promote neurodegenerative changes in early adulthood and tau changes in later adulthood. The additional or alternative possibility that tau and neurodegeneration promote white matter changes cannot be ruled out in these cross sectional analyses. Future work will address the relative temporal emergence of these markers in adults with DS.

6 Exercise Induced Growth Factor Increases Directly and Indirectly Reduce Systemic Vascular Risk Parameters: Translational Project Amongst Midlife Human and Animal Models of Preclinical Alzheimer’s disease and Vascular Dementia

Objective:Using a humanized APOE3/4 (Alzheimer’s disease genetic risk allele) mouse model we investigated the potential modulating effects of exercise on systemic risk factors and the ability of this mouse model to translate to active or sedentary, midlife, human participants. We present preliminary results of an ongoing, translational pilot study.Participants and Methods:26 Midlife individuals, ages 40-65, were recruited from the community and dichotomized into active or sedentary groups following health screening and cognitive assessment. Blood samples were drawn from human participants for lipid assessment and other general health measures as well as peripheral growth factors concentrations (VEGF, BDNF and FGF21). Traditional, transgenic mouse models have helped the scientific community to understand biological mechanisms of Alzheimer’s disease (AD), but they do not develop significant neuronal loss, a hallmark of AD pathology. The MODEL-AD consortium has created a new “humanized” APOE4 model that has the human APOE4 allelic sequence in place of the mouse APOE gene; the model has shown known human phenotypes including deficits in cholesterol trafficking, amyloid clearance and BBB integrity. Of upmost importance, this model does not develop a full AD phenotype indicating that additional genetics and/or environmental factors are required as would be seen in human populations. We used males and females of this model to complete identical sedentary and active measures of each APOE genotype.Results:Lipid and general health marker assessment between mouse and human were similar and reproduced published literature. In both humans and mice we saw increased total cholesterol and HDL in active females and decreased total cholesterol and HDL in active males. We also saw similar relationships between APOE genotype, sex, and activity with regards to triglycerides. Although total cholesterol, HDL and LDL measures are the primary lipids needed to confirm or deny translation, other lipid measurements were not equivalent between the two models. Growth factor assessment in both species are also similar and reproduce published literature with regards to VEGF and BDNF as we see trending elevated levels in the active group. Less published on is the finding seen between active females and these elevated growth factors levels; our results indicates that although elevated as a result of exercise, this increase may be more prominent in females.Conclusions:Based on the results found here we conclude that The Jackson Laboratory’s humanized APOE3/4 mouse model is a translatable model of vascular dysfunction, dementia and Alzheimer’s disease. We also conclude that exercise modulates these aspects by growth factor activation and increases resulting in downstream effects that reduce peripheral vascular risk factors and therefore reduce the risk of Alzheimer’s disease as a result of neuroinflammation. Complete, APOE genotype results from human participants are still ongoing. Descriptive analysis is limited by human samples size.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease

Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = -3.1 [P = .002]; ADNI: t = -5.6 [P < .001]; HABS: t = -2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001). The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Paracentral acute middle maculopathy progressing to central retinal artery occlusion following coronavirus disease vaccination: a multimodal imaging report

Background: Coronavirus disease (COVID-19) vaccines can cause adverse ocular effects, including vascular insults, acute macular neuroretinopathy, paracentral acute middle maculopathy (PAMM), ophthalmic vein thrombosis, Graves’ disease, arteritic anterior ischemic optic neuropathy (A-AION), and nonarteritic AION. Here, we report a case of unilateral PAMM progressing to central retinal artery occlusion (CRAO) after COVID-19 vaccination, identified using multimodal imaging.&#x0D; Case Presentation: A 24-year-old healthy man presented with unilateral progressive blurring of vision in the right eye. He had a recent history of fever without rashes 2 weeks after coronavirus disease vaccination. He was diagnosed with PAMM in the right eye at a local hospital and treated with a tapering dose of oral steroids. At presentation, he showed progressive blurring of vision in the right eye and the best-corrected distance visual acuity (BCDVA) was 20/60. The anterior segment was normal. Fundus examination revealed a pale optic disc with arteriolar attenuation and barrage laser scarring at the inferotemporal periphery. CRAO was diagnosed based on the right eye findings. The patient underwent multimodal imaging, including wide-field fundus photography using Optos® (Optos Carfornia®, Optos Inc., Dunfermline, United Kingdom), multicolor imaging with Spectralis™ (Heidelberg Retinal Angiograph; Heidelberg Engineering, Inc., Dossenheim, Germany), fundus fluorescence angiography (Heidelberg Retinal Angiograph; Heidelberg Engineering, Inc., Dossenheim, Germany), and optical coherence tomography angiography (ANGIOVUE, OPTOVUE, Inc., Fremont, CA, USA) using the split-spectrum amplitude-decorrelation angiography algorithm. The condition progressed from PAMM to CRAO during the oral steroid treatment course. At the 2-month follow-up, the right eye BCDVA had improved to 20/50, with fundus findings remaining the same as at the previous visit.&#x0D; Conclusions: This was the first report of a young patient with PAMM presenting with focal vascular occlusion that evolved to global occlusion in the form of CRAO in the absence of systemic vascular risk factors and with a normal coagulation profile. This case suggests that arterial occlusion may exert a temporary effect secondary to COVISHIELD™ vaccination. Randomized controlled trials and case – control studies on the role of vaccination in precipitating thromboembolic events in healthy individuals would provide insight into the causation.

Regional White Matter Hyperintensities and Alzheimer's Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment.

Alzheimer's disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ 40, Aβ 42, Aβ 42/Aβ 40 ratio, phosphorylated tau-181 [p-tau181], and total tau [t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181, t-tau, and Aβ 40), particularly among APOE ɛ 4 carriers (independent of Aβ 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ 42/Aβ 40. In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65+ years), independent of Aβ 42/Aβ 40 and p-tau181. These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ 42/Aβ 40) in parietal WMHs.

Cerebrovascular injury markers explain the effect of systemic vascular risk on cognitive decline in older adults with lower amyloid burden

AbstractBackgroundSystemic vascular risk is a well‐established contributor to late‐life cognitive decline, yet the mechanism is not completely understood. We investigated whether neuroimaging‐based measures of vascular injury (white matter hyperintensity (WMH) volume, Peak width of Skeletonized Mean Diffusivity (PSMD), and relative cerebral blood flow (rCBF)) could explain the effect of systemic vascular risk on cognitive decline using longitudinal data from the Harvard Aging Brain Study.MethodWe used the Framingham Heart Study cardiovascular disease risk score (FHS‐CVD) as an index of systemic vascular risk. We extracted WMH from structural MRI (https://hypermapp3r.readthedocs.io/) and PSMD from diffusion MRI (http://www.psmdmarker.com). We performed kinetic modeling on dynamically‐acquired PiB‐PET data to extract 1) amyloid burden as the distribution volume ratio (PiB‐DVR) and 2) relative tracer delivery (PiB‐R1 via MRTM reference‐tissue analysis as a proxy of rCBF). Global cognition was assessed using Preclinical Alzheimer Cognitive Composite (PACC).We considered two linear mixed effect models to examine whether cerebrovascular injury markers could explain the FHS‐CVD effect on PACC change over time: 1) FHS‐CVD on PACC change controlling for age, sex, years of education, and PiB‐DVR; 2) the previous model including WMH, PSMD, and PIB‐R1. Analyses were stratified by high (PiB+) and low (PiB‐) baseline amyloid burden.ResultFigure 1 illustrates the relationships between demographics and neuroimaging measures at baseline. Table 1 shows the demographics and study information. We observed a significant effect of FHS‐CVD on PACC change (PiB‐: t=‐3.9, p&lt;0.001 (Table 2); PiB+: t=‐2.6, p=0.008). When the cerebrovascular injury markers were included in the model, the effect of FHS‐CVD was reduced in the PiB‐ group while PSMD and PiB‐R1 explained PACC change (Table 3; Figure 2). The second model fit was significantly better than the first model (L.ratio= 25.9, p&lt;0.001). The effects remained significant after controlling for gray matter volume. In contrast, cerebrovascular injury measures did not explain the effect of FHS‐CVD on PACC change in the PIB+ group.ConclusionThese results demonstrate that cerebrovascular injury largely explains the effect of systemic vascular risk on cognitive decline in older adults with lower amyloid burden suggesting mechanisms by which a higher systemic vascular risk impacts brain function.

AI‐based software for cardiovascular disease assessment

AbstractThe healthcare burden of cardiovascular disease remains a priority. Understanding their underlying mechanisms and improving identification of people with higher systemic vascular risk profile with non‐invasive examinations seem to be crucial. In Ophthalmology, retinal imaging is simple, non‐invasive and it can provide in vivo insight of the retinal microcirculation. For more than 10 years, research teams have been working on software developed to allow automatic analysis of the retinal vascular network from different imaging technique (fundus photographs, oct‐angiography or adaptive optics…) and to provide a description of the geometric characteristics of its arterial and venous components. At the same time, research teams have explored the pathophysiological association between macro vascular and micro vascular alterations. Thus, retinal microcirculation could be considered as a witness of the systemic cardiovascular status. New approach with retinal images dataset and artificial intelligence algorithms recently strengthened the interest of retinal microvascular biomarker. Deep learning and machine learning algorithms provided very thorough description of the retinal vascular network. Moreover, they were able to assess strong associations between retinal features and calcium heart score or biological age for example. Thus, the interest of retinal biomarker in terms of screening, monitoring or prediction of cardiovascular disease is very promising.

Progressive white matter injury in autosomal dominant Alzheimer’s disease is strongly associated with cerebral microbleeds and neurodegeneration

AbstractBackgroundWhite matter (WM) injury visible on MRI is a common finding in Alzheimer’s disease (AD) and is often attributed to small vessel ischemic changes secondary to increased systemic vascular risk. Increased WM injury has been associated with the progression of Autosomal Dominant AD (ADAD), though ADAD pathogenic variant carriers are relatively young and may not have elevated vascular risk factors. We hypothesized that WM injury in ADAD may reflect worsening of cerebral amyloid angiopathy (CAA) and neurodegeneration. Here we examine this hypothesis using cross‐sectional and longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN).MethodMRI data from ADAD pathogenic variant carriers (n=223) and non‐carriers (n=136) were used in the present study (Table 1). We extracted FreeSurfer‐based WM lesion (WML) volume from T1‐weighted images (hypointensities). Cortical microbleed (CMB) burden was assessed visually on susceptibility weighted/T2*‐weighted gradient echo images by experienced radiologists (blineded to the mutation status) at the Mayo Clinic in Rochester. Linear regression models compared WML volume at baseline in people with and without CMB. Linear mixed effect models assessed the relationships between longitudinal WML and both CMBs and FreeSurfer‐based total gray matter (GM) volume. Models were corrected for age and estimated years to symptom onset (EYO).ResultGreater baseline WML volume was seen in ADAD carriers vs. non‐carriers, particularly close to the age of estimated symptom onset. Baseline WML volume was greater in carriers with CMBs compared to those without (t=2.9, p=0.003, Figure 1). Longitudinal increase in WML amongst ADAD pathogenic variant carriers with CMBs was estimated to be 214 mm3/year greater than that amongst carriers without CMBs (t=4.1, p&lt;0.001, Figure 2). Independent of this CMB effect, decreasing GM volume was strongly associated with increasing longitudinal WML volume (t=‐6.2, p&lt;0.001, Figure 3). Similar analyses in the non‐carrier group yielded no significant findings.ConclusionConsistent with prior reports, WML volume was increased in ADAD pathogenic variant carriers. However, the results here suggest WML in ADAD may not solely be due to small vessel ischemic changes, but rather may be a result of worsening CAA and more rapid neurodegeneration.

High Altitude as a Risk Factor for the Development of Nonarteritic Anterior Ischemic Optic Neuropathy.

Episodic high-altitude exposure leads to optic disc edema and retinopathy. It is uncertain whether high-altitude exposure is a risk factor for nonarteritic anterior ischemic optic neuropathy (NAION). We performed a single-center, retrospective, cross-sectional case study of 5 patients with high-altitude-associated NAION (HA-NAION) from April 2014 to April 2019. Main study parameters included known vascular risk factors for NAION, evolution of visual acuity, visual field, optic disc, and macula measurements. We studied 5 eyes of 5 patients with HA-NAION that occurred at 7,000-9,000 ft above sea level, 28 patients with classic NAION that developed at sea level (normal altitude NAION or NA-NAION), and 40 controls. All 5 patients with HA-NAION had clinically confirmed NAION by a neuro-ophthalmologist within 3-21 days of onset and comprehensive follow-up evaluations (average follow-up of 23 months). Other than high-altitude exposure, 4 of 5 patients had undiagnosed obstructive sleep apnea (OSA, apnea-hypopnea index 5.4-22.2) and 1 had systemic vascular risk factors. All patients had disc-at-risk in the contralateral eye. The best-corrected distance visual acuity was 20/20 to 20/70 (median logMAR 0) at presentation and 20/70 to counting finger (median logMAR 0) at ≥6 months. Automated static perimetry revealed average mean deviation of -18.6 dB at presentation and -22.1 dB at ≥6 months. The average retinal nerve fiber layer was 244 µm (80-348 µm) at onset and 59 µm (55-80 µm) at ≥6 months. The average ganglion cell complex thickness was 50 µm (43-54 µm) at onset and 52 µm (50-55 µm) at ≥6 months. The patients with OSA were started on home continuous positive airway pressure treatment. Visual outcomes were similar in patients with HA-NAION and NA-NAION. - After addressing all NAION risk factors, no new events occurred in the HA-NAION group within 2-8 years with or without repeat high-altitude exposure. NAION can occur under high-altitude conditions. HA-NAION is associated with relatively younger age at onset, disc-at-risk, and OSA. These patients exhibit a relatively progressive course of vision loss after initial onset and severe thinning of optic nerves on optical coherence tomography. Treatment for OSA is recommended, especially with repeated high-altitude exposure.

Association of β-Amyloid and Vascular Risk on Longitudinal Patterns of Brain Atrophy.

Vascular risk factors and elevated β-amyloid (Aβ) are commonly observed together among older adults. Here, we examined the interactive vs independent effects of systemic vascular risk and Aβ burden on longitudinal gray matter atrophy and how their co-occurrence may be related to cognitive decline in a cohort of clinically normal adults. A secondary goal was to examine whether vascular risk influences gray matter atrophy independently from markers of white matter injury. Participants were 196 adults (age 73.8 ± 6.1 years) from the Harvard Aging Brain Study. Baseline Aβ burden was quantified with Pittsburgh compound B PET. Baseline vascular risk was measured with the Framingham Heart Study cardiovascular disease risk score. Brain atrophy was quantified longitudinally with structural MRI over a median of 4.50 (±1.26) years. Cognition was assessed yearly with the Preclinical Alzheimer Cognitive Composite over a median of 6.25 (±1.40) years. Linear mixed-effects models examined vascular risk and Aβ burden as interactive vs independent predictors of gray matter atrophy, with adjustment for age, sex, years of education, APOE ε4 status, intracranial volume (when appropriate), and their interactions with time. In subsequent models, we adjusted for markers of white matter injury to determine whether vascular risk accelerated brain atrophy independently from diffusion- and fluid-attenuated inversion recovery (FLAIR)-based markers. Mediation analyses examined whether brain atrophy mediated the interactive association of vascular risk and Aβ burden on cognitive decline. Higher vascular risk and elevated Aβ burden interacted to predict more severe atrophy in frontal and temporal lobes, thalamus, and striatum. Higher Aβ burden, but not vascular risk, was associated with more severe atrophy in parietal and occipital lobes, as well as the hippocampus. Adjusting for diffusion- and FLAIR-based markers of white matter injury had little impact on the above associations. Gray matter atrophy mediated the association between vascular risk and cognitive decline at higher levels of Aβ burden. We observed an interaction between elevated vascular risk and higher Aβ burden with longitudinal brain atrophy, which in turn influenced cognitive decline. These results support vascular risk factor management as a potential intervention to slow neurodegeneration and cognitive decline in preclinical Alzheimer disease.

Prevalence of various risk factors associated with new-onset epilepsy after the age of 50: a retrospective population-based study.

Population-based studies of epilepsy risk factors are rare. We aimed to evaluate the prevalence of various risk factors associated with new-onset epilepsy after the age of 50 years. We included all incident cases in North Macedonia between 2015 and 2018. Study participants were ascertained from the national healthcare platform. We performed a retrospective analysis of Electronic Health Records of 2,367 patients (1,017 females and 1,350 males) whose epileptic seizures started after the age of 50 years. Patients were stratified into 10-year age groups. The most common risk factor for new-onset epilepsy in our cohort was stroke, which was associated with new-onset epilepsy in 20% of patients aged 50-59 years and almost 50% of patients aged 70-79 years. The second most frequent risk factor was neoplasm in patients aged 50-69 years and dementia in patients older than 70 years. The other pre-existing conditions included: metabolic disorders, traumatic brain injury, and postencephalitic and inflammatory diseases. Chronic alcoholism was the most common metabolic risk factor associated with new-onset epilepsy and accounted for 84% of cases in this subgroup. Only metabolic disorders were significantly more frequent in males than in females (p<0.00001). We did not identify any epilepsy risk factor in 967 patients (41%). Systemic vascular risk factors were frequent in our cohort: 1,574 patients had hypertension (66%) and 449 patients had diabetes (19%), and 339 had both conditions (14%). We found that structural lesions were the most prevalent risk factor associated with new-onset epilepsy in middle-aged and elderly patients. Recognition of possibly modifiable factors associated with late-onset epilepsy could have a positive impact on reducing the risk of developing epilepsy.

Evaluation of the radial peripapillary capillary density in unilateral branch retinal vein occlusion and the unaffected fellow eyes.

Background:Given that unilateral branch retinal vein occlusion (BRVO) and glaucoma share common systemic vascular risk factors, the fellow eyes of patients with BRVO may be at increased risk of glaucoma.Objectives:To analyze the radial peripapillary capillary density (RPCD) in eyes with unilateral BRVO and their unaffected fellow eyes using optical coherence tomography angiography (OCTA).Design:Cross-sectional, prospective study.Methods:The study included 120 eyes of 80 patients: 40 affected eyes of BRVO, 40 fellow eyes of BRVO, and 40 control eyes. The RPCD, retinal nerve fiber layer thickness (RNFLT) were analyzed using OCTA.Results:RPCDs in the whole image, peripapillary region, all the hemispheres, and quadrants were statistically lower in the affected eyes than in both the fellow and control eyes (p < 0.05 for all). RPCD values in the whole image and the peripapillary region were significantly lower in the fellow eyes than in the control eyes (p = 0.013, and p = 0.021, respectively). RNFLTs in the peripapillary region, inferior hemisphere and inferior quadrant were significantly lower in the affected eyes than in the control eyes (p < 0.05 for all). No significant differences were detected between the fellow eyes and the control eyes in term of RNFLT values in any regions (p > 0.05 for all).Conclusion:Lower RPCD values despite similar RNFLT values were observed in the fellow eyes of patients with unilateral BRVO compared with healthy controls. These results may indicate the shared vascular mechanisms and risk factors that account for the development of BRVO and glaucoma.