Plenary VEarly Career Researchers (ECR) SessionPlenary VIConcluding Comments
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SELF-REPORTED COGNITIVE DECLINE, EMOTIONAL SYMPTOMS, AND DAYTIME SLEEP AFTER ISCHEMIC STROKE
Introduction: After stroke, emotional symptoms (such as depression or anxiety), cognitive decline and increased daytime sleep are common. However, the relationship between these sequelae remains unclear. We aimed to study if (1) self-reported cognitive decline and emotional symptoms 3 months after hospital discharge predict increased self-reported daytime sleep at 1 year, and if (2) increased daytime sleep at 3 months predicts emotional symptoms and cognitive decline at 1 year.
Method: Data of ischemic stroke patients without previous history of dementia or depression were collected 3 months and 1 year after hospital discharge using postal surveys. Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Self-reported increase in daytime sleep and decline in concentration and memory were each assessed with one dichotomous item. Multiple linear and binary logistic regression was used to estimate the relationship of daytime sleep with cognitive decline and emotional symptoms, controlling for age, sex and stroke severity (NIH Stroke Scale, NIHSS).
Results: In 140 patients (baseline-NIHSS mean and standard deviation (M±SD)=3.6±4.3; MMSE 25.2±4.9; age 73.2±10.9) 27.7% reported increased daytime sleep at 3 months, and 37.1% at 1 year. Self-reported decline in memory and concentration, as well as higher HADS-A and HADS-D scores at 3 months were significantly associated with increased daytime sleep at 1 year (Bonferroni-corrected p<.00625; concentration: OR 4.9 (1.9-13.0); memory: OR 4.2 (1.8-9.7); HADS-D: OR 1.2 (1.0-1.3); HADS-A: OR 1.2 (1.1-1.3)). Daytime sleep at 3 months was not significantly associated with self-reported cognitive decline or with emotional symptoms at 1 year.
Conclusion: Patients with higher levels of emotional symptoms and self-reported cognitive decline at 3 months are at a higher risk for increased daytime sleep at 1 year. Interventions targeting emotional symptoms and cognitive decline may prevent excessive daytime sleep and secure patients’ engagement in rehabilitation and successful recovery.
Neurospychology; Cognitive and emotional symptoms
Relationships between Myeloperoxidase and the Cognitive and Neuroimaging Correlates of Mild Vascular Cognitive Impairment
Mild vascular cognitive impairment (mVCI) presents with both cognitive impairment and vascular dysfunction, but the underlying disease pathophysiology is not well understood. Recent studies suggest a role of innate immune activity, including neutrophils, in cognitive decline. Myeloperoxidase (MPO), an enzyme found in neutrophils, has been shown to play a role in vascular and cognitive dysfunction. This study explores the associations of MPO with disease markers of mVCI, specifically verbal memory and neural white matter damage. Patients were recruited during intake from a cardiac rehabilitation program. Clinical history of vascular disease, and the core criteria for Subcortical Ischemic MCI, described in Gorelick et al. 201l, including cognitive deficits and neuroimaging results were used to make the diagnosis of mVCI. Verbal memory, a cognitive domain affected in mVCI populations, was assessed using the Hopkins Verbal Learning Test- Revised (HVLT-R). Plasma MPO concentration was measured using enzyme-linked immunosorbent assay in fasting blood and white matter hyperintensity (WMH) volumes were measured using a 3T MRI scanner. Multiple linear regression models were used for the statistical analyses, while controlling for the following covariates: body mass index (BMI) and education for verbal memory outcomes; and age and resting systolic blood pressure (RSBP) for WMH volume outcomes. In n= 27 patients (age= 67.2 ± 7.5, male%= 74%, BMI= 29.4 ± 5.3), plasma MPO was negatively associated with verbal memory (β= -2.28, p=0.04), particularly word recognition (β= -3.51, p=0.01), after controlling for education and BMI. Elevated MPO was associated with higher periventricular WMH volumes (β= 0.74, p=0.03), before controlling for age and RSBP, but not with deep WMH volume. The results of this study suggest that neutrophils, specifically MPO, may be involved in the pathophysiology of mVCI and may be facilitating its effects on cognition via affecting the neuroimaging correlates of the disease.
THE RELATIONSHIP BETWEEN COGNITIVE RESERVE AND CHANGE IN COGNITION DURING THE FIRST THREE MONTHS POST-STROKE
Reduced memory and executive function (EF) are commonly seen post-stroke. Cognitive reserve (CR), the brain’s ability to adapt from damage and degeneration, has been suggested to protect cognitive function. However, these relationships are not sufficiently studied post-stroke. This study examined the association between CR and cognitive function one-week to three-months post-stroke. Additionally, we wanted to see if higher CR is associated with more improvement in memory and executive domains.
79 patients with ischemic stroke (MMSE>23) were assessed with a battery of neuropsychological tests within one-week and followed up at three-months post-stroke. Composite variables for memory (using subtests from WAIS-III, WMS-III and the Rey Auditory Verbal Learning Test) and EF (using subtests from WAIS-III, D-KEFS and Halstead-Reitan test batteries) were calculated for both timepoints, then variables measuring change in memory and EF respectively. Years of education, occupation (using ISCO-88) and IQ (using the National Adult Reading Test and two subtests from WASI) were used as CR proxies. Multiple linear regression was used to estimate the relationship of CR proxies with cognitive change, controlling for age and sex.
The patients’ mean (M) age was 64.42(SD=8.97), day one NIHSS M=3.56(3.25), three-months NIHSS M=0.66(1.59) and education M=11.01(2.95). 34% of patients were female. IQ was significantly (p<.001) associated with memory and EF at one-week (β =.48, and β=.63) and at three-months (β =.67 and β =.68). Occupation and education were not significantly associated with memory and EF at one-week or three-months. Changes in memory and EF were not significantly associated with IQ, education or occupation.
Out of the CR proxies used only IQ was shown to be significantly associated with cognitive function post-stroke. None of the CR proxies were significantly related to changes in cognition, indicating that CR may not promote improvement of cognitive function during the first three months post-stroke.
Neurofilament light level correlates with brain atrophy and cognitive and motor performance in subjects with cerebral white matter hyperintensities
The usefulness of neurofilament light (NfL) as a biomarker for small vessel disease (SVD) has not yet been established. We examined the relationship between NfL level, neuroimaging changes, and clinical findings in subjects with varying degrees of white matter hyperintensities (WMH).
A subgroup of participants (n=35) in the Helsinki SVD Study underwent an analysis of NfL in cerebrospinal fluid (CSF) and plasma as well as a brain MRI and neuropsychological and motor performance assessments. Evaluation of WMH and structural brain volumes were obtained with automatic segmentation.
CSF NfL did not correlate significantly with total WMH volume (r=0.278, p=0.105). However, strong correlations were observed between CSF NfL level and volumes of cerebral grey matter (r=-0.569, p<0.001), cerebral cortex (r=-0.563, p<0.001), and hippocampi (r=-0.492, p=0.003). CSF NfL was also consistently associated with performance in global cognition (r=-0.403, p =0.016), executive functions (r=-0.402, p=0.017), memory (r=-0.463, p=0.005), and processing speed (r=-0.386, p=0.022). In motor skills tests, CSF NfL was correlated with Timed Up and Go test results (r=0.531, p=0.001), and gait speed (r=-0.450, p=0.007), but not with results in single-leg stance test. Plasma NfL level showed the same correlations but somewhat weaker.
NfL level was strongly related to global gray matter and hippocampal atrophy, but not with WMH severity. NfL was also consistently associated with cognitive and motor performance. Our results suggest that NfL generally reflects frailty in the central nervous system (CNS).
Prevalence of cognitive impairment and dementia in a multi-ethnic elderly cohort the Singapore Epidemiology of Eye Diseases study (SEED)
Singapore is a multi-ethnic country and the burden of dementia is increasingly severer due to the rapid aging population. The various risks of dementia by ethnicity lead to an urgent need to update the prevalence of dementia by different ethnic groups.
To estimate the prevalence of cognitive impairment and dementia and compare the results by different ethic and age groups.
Epidemiology of Dementia in Singapore (EDIS) was a 2-phase community-based study. Subjects who screened as cognitive vulnerability through the validated Abbreviated Mental Test (AMT) and the Progressive Forgetting Self-Report (PFQ) at phase 1 were examined by comprehensive clinical evaluation for cognitive impairment and dementia at phase 2.
Among 3780 subjects (aged ≥60 years) at phase 1, 957 were entered into phase 2. Results from phase 2 showed 669 (17.7%) with cognitive impairment, 307 with cognitive impairment with no dementia (CIND)-Mild, 316 with CIND-Moderate and 46 with dementia. The overall age and race standardized prevalence was 2.51%(95%CI=[2.0%-3.1%]) for dementia, 6.32%(95%CI=[5.5%-7.2%]) for CIND-Mild and 8.12%(95%CI=[7.2%-9.1%]) for CIND-Moderate. With increasing age, the prevalence of dementia increased from 0.07% (65-69) to 37.5% (≥85). Prevalence of dementia were 2.45%, 2.34% and 1.32% among Chinese, Malay and Indians respectively.
The prevalence of dementia remains high, suggesting the importance of long-term dementia monitoring and intervention. Noting the various prevalence of dementia between the three ethnic groups, further study should explore possible demographic and clinical indicators associated with the different risks.
ASSOCIATION OF CEREBRAL SMALL VESSEL DISEASE BURDEN WITH BRAIN STRUCTURE AND COGNITIVE AND VASCULAR RISK TRAJECTORIES IN MID-TO-LATE LIFE
Objective: To characterize the longitudinal lifestyle, cognitive and brain structural determinants of total cerebral small vessel disease (SVD) burden in older ages.
Methods: Participants were 623 community-dwelling adults (mean age 69.96 SD 5.18, 79% men) from the Whitehall II Imaging Sub-study with multi-modal MRI acquired between 2012-2016. We used linear mixed effect models to investigate associations of SVD burden with up to 25-year retrospective trajectories of vascular risk and cognitive performance, assessed at 5-year intervals between 1991-2016. General linear modelling was used to investigate concurrent associations with (1) retrospective trajectories of vascular risk factors and cognitive decline, (2) concurrent grey matter (GM) density and white matter (WM) microstructure, and (3) whether these associations were modified by cognitive status (Montreal Cognitive Assessment, MoCA).
Results: Severe SVD burden was associated with higher mean arterial pressure throughout midlife (β 3.36, 95% CI [0.42-6.30]), and faster cognitive decline in phonemic fluency (β -0.07, 95% CI [-0.13–-0.01]), and verbal reasoning (β -0.05, 95% CI [-0.11–-0.001]). Moreover, SVD burden was related to reduced GM volumes in 9.7% of total GM, and widespread WM microstructural decline (FWE-corrected p < 0.05). Notably, the latter association was most pronounced in individuals who showed cognitive impairments on MoCA (F3,608 = 2.14, p = 0.007).
Conclusion: Total SVD burden in older age is associated with higher midlife blood pressure, faster cognitive decline, and poorer indicators of cerebral GM density and WM microstructure. These findings highlight the importance of managing midlife vascular health to preserve brain structure and cognitive functions.
PREVALENCE AND CORRELATES OF WHITE MATTER HYPERINTENSITIES IN ROYAL CANADIAN AIRFORCE PILOTS AND AIRCREW
Background: White matter hyperintensities (WMH) of presumed vascular origin are commonly observed on MRI in older adults and patients with neurodegenerative and neurovascular disease. A recent series of studies examining WMH in United States Air Force U-2 pilots found higher WMH burden was associated with lower cognitive performance in otherwise healthy, high-functioning individuals.
Purpose: To present preliminary findings for a study that will examine the prevalence and correlates of WMH in Royal Canadian Airforce (RCAF) Pilots and aircrew.
Methods: Our goal is to enroll N=50 study participants from the RCAF with anticipated exposure to low ambient pressures (including fast jet pilots, parachutists involved in high altitude parachute operations, and aviation physiology technicians). The comprehensive test protocol includes a battery of cognitive measures, standard laboratory tests, cardiac bubble agitated saline contrast echo study, blood proteomic multiplex array analysis, and MRI. Quantification of WMH will be performed using a standardized and validated neuroimaging pipeline. The following preliminary partial correlation results between head-size corrected WMH volumes and cognitive performance are based on the currently acquired sub-sample of the total target study participants (N=30, 60%).
Results: A negative correlation was demonstrated between WMH volumes and N-back test performance (1-back D prime: rho=-0.552, p=0.006), delayed-matching-to-sample test performance (DMTS % accuracy: rho=-0.439, p=0.036), and the Shipley-2 vocabulary crystallized IQ (standard score: rho=-0.424, p=0.044), after controlling for Framingham risk, depression (~BDI), metabolic syndromes (BP, glucose, HDL, etc.), inflammation (hs-CRP), and mild traumatic brain injury.
Conclusions: These preliminary results suggest that increases in WMH volume, potentially due to occupational exposure to low ambient pressures from high altitude operations, may be associated with subtle cognitive impairment. In order to further elucidate the potential pathological mechanisms involved, future results will include analyses of the cardiac bubble saline contrast echo, blood proteomics, and relative comparisons with the NATO working group.
Neuropsychiatric symptoms accelerate cognitive impairment associated with small vessel disease
Background: Neuropsychiatric symptoms are related to disease progression and cognitive decline over time in cerebral small vessel disease (SVD) characterised by white matter hyperintensities (WMH). How neuropsychiatric symptoms relate to cognitive functioning in the presence of WMH is less well understood. We investigated the occurrence of neuropsychiatric symptoms and their relationship between cognitive performance and functional abilities in subjects with varying degrees of WMH.
Methods: The Helsinki Small Vessel Disease Study recruited 152 subjects, who underwent brain MRI, comprehensive neuropsychological evaluations, and assessment of neuropsychiatric symptoms using the Neuropsychiatric Inventory Questionnaire (NPI-Q) filled in by an informant (n=134). Functional abilities were assessed using the Amsterdam Instrumental Activities of Daily Living (A-IADL) questionnaire.
Results: NPI-Q total score correlated significantly with WMH volume (rs=0.20, p=0.019) and inversely with A-IADL score (rs=-0.41, p<0.001), but it was not related to age, education or sex. In total, 34% of the subjects had one or more informant evaluated neuropsychiatric symptoms. The most common symptoms were depression (19%), irritability (16%), apathy (9%), night time disruptive behaviours (11%) and changes in appetite (9%). Linear regressions adjusted for age and education revealed no significant main effects between neuropsychiatric symptoms and cognitive performance. However, significant interactions were found between neuropsychiatric symptoms and WMH on cognitive composite scores for global cognition, processing speed, executive functions and memory as shown in Figure 1. Linear regressions adjusted for age and education also showed significant main effects between neuropsychiatric symptoms and A-IADL as well as WMH and A-IADL.
Conclusions: Neuropsychiatric symptoms associate with stronger impact of WMH on cognitive impairment. Furthermore, the presence of neuropsychiatric symptoms is related to worse functional abilities. Neuropsychiatric symptoms should be routinely assessed in SVD as they are related to worse cognitive and functional outcomes.
Discriminant Validity of the Progressive Forgetfulness Question in a Stepwise Dementia Screening Approach in a Singaporean Elderly Population
Objective: To investigate the diagnostic utility of a self-reported assessment of progressively forgetfulness question (PFQ) , as compared to other commonly used screening tools, in detecting dementia or cognitive impairment (CI) in an elderly community in Singapore.
Methods: This is a two-phased community-based studyamong elderly Singaporeans (age≥60). Participants who were screened as positive at phase I by the validated Abbreviated Mental Test (AMT) and PFQ entered phase II. During phase II, participants were administered the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and a formal neuropsychological battery. No Cognitive Impairment (NCI), Cognitive Impairment-No Dementia (CIND), were diagnosed by the results of a locally validated neuropsychological battery. Dementia was diagnosed by DSM-IV criteria. All discriminatory indices were calculated to determine the diagnostic utility of the PFQ against and in combination of the MMSE， MoCA and AMT.
Results: A total of 918 participants were included in the analysis. The PFQ showed good sensitivity (75.1%) and excellent NPV (95.4%) for ruling out healthy elderly at the phase I. At the phase II, the PFQ had excellent sensitivity but poor specificity in detecting CI (sensitivity=96.9%, specificity=3.3%), high risk (sensitivity=96.3%, specificity=3.2%) and dementia (sensitivity=93.3%, specificity=3.2%). The AUCs for MoCA(0.95), MMSE(0.94) and AMT(0.93) is greater then among participants who reported PFQ=yes than those who reported PFQ=no (MoCA=0.87, MMSE=0.83 and AMT=0.74).
Conclusion: Asking for the PFQ can facilitate case finding of dementia on the scale of a large population. Additionally, a stepwise way using the PFQ is recommended when detecting dementia among the elderly.
cognitive screening tool
DOES WHITE MATTER HYPERINTENSITY LOCATION PREDICT COGNITIVE IMPAIRMENT IN AN ELDERLY POPULATION?
Cerebral small vessel disease is associated with lacunar stroke and is responsible for up to 45% of dementias. A key neuroimaging feature of the disease is white matter hyperintensities (WMH). Increasing WMH volume predicts poorer cognition, but the association is inconsistent. The location of the lesions may be important. This study used ADNI data from elderly participants (n=599, mean age 72.1±7.2 years) with mixed cognition (191 cognitively normal, 408 cognitively impaired). WMH volume was quantified from T2-weighted FLAIR and T1-weighted images with the lesion segmentation toolbox, creating lesion binary maps. These were used to assess the relationship between strategic WMH location and cognition in both voxel-based and tract-based analyses. The average binary maps for both cognitive groups were remarkably similar (Figure 1). In the voxel-based analysis, participant MoCA score (standardised as a z-score against the cognitively normal mean score) was multiplied with their binary lesion map so that each voxel represented a WMH-weighted z-score. The mean weighted z-score for each voxel was then calculated to produce a cognitive risk map (Figure 2). Clusters of voxels, located mainly in the anterior and superior corona radiata, were associated with worse cognition (Figure 2). In the tract-based analysis, only the cognitively impaired participants were included to identify tracts most strongly associated with cognitive impairment. Multiple linear regression of tracts against MoCA scores (Figure 3) found that the WMH in the superior longitudinal fasciculus was significantly negatively associated with MoCA score (R2= -0.393, p=0.035), whereas global WMH volume did not correlate with cognition (R2= 0.159, p=0.256). The association of the anterior corona radiata and the superior longitudinal fasciculus with cognition, particularly executive function as assessed by MoCA, expands on previous literature, whilst the lack of the association with global WMH suggests that tract-specific WMH volume is more closely associated with cognitive impairment.
Vascular Risk Factors
MICROSTRUCTURAL CHANGES IN THE PENUMBRAS OF CEREBRAL SMALL VESSEL DISEASE LESIONS ARE ASSOCIATED WITH COGNITION AND SLEEP
Objective: To investigate microstructural changes of the penumbra layers surrounding different cerebrovascular disease lesion sub-types and associations with cognition and sleep quality.
Methods: We examined 146 participants with cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. Periventricular and deep white matter hyperintensities (p/dWMH), lacunes, and perivascular spaces (PVS) were segmented from structural MRI. Using diffusion MRI, fractional anisotropy (FA) and mean diffusivity (MD) were estimated from the penumbra layers surrounding each lesion sub-type. Linear regression models were used to examine diffusion metrics within each lesion type (central), outermost penumbra layer (distal), across the penumbra gradients (slope), and for all normal appearing WM (global). Associations with Processing Speed, Executive Function, Memory, Visuospatial Reasoning and sleep quality (PSQI) were examined, controlling for demographics, vascular risk factors, sleep medications and sleep apnea.
Results: FA and MD were significantly different between penumbra layers of all lesion sub-types (all p<0.0001). Central: Linear regressions revealed FA within pWMH was associated with memory (β=-0.19, p=0.04); MD within dWMH with processing speed (β=-0.23, p=0.03), and memory (β=-0.2, p=0.05). Sleep analysis revealed MD within dWMH was associated with PSQI (β=-1.22, p<0.001). Distal: FA in the outermost NAWM layer of BG-PVS was associated with visuospatial (β=0.31, p=0.04), processing speed (β=0.4, p=0.004), and executive function (β=0.29, p=0.02); and FA in the outermost NAWM layer of lacunes was associated with executive function (β=0.52, p=0.005). Slope: FA slope of pWMH penumbra was associated with memory (β=0.22, p=0.02) and executive function (β=0.19, p=0.02); and, MD slope of dWMH was associated with processing speed (β=0.26, p=0.01), and executive function (β=0.18, p=0.04). Sleep analysis revealed the MD slope of dWMH was associated with PSQI (β=1.13, p<0.001).
Interpretation: These findings suggest that white matter alterations that extend beyond the vascular lesions demarcated on standard structural MRI may be associated with poor sleep quality and cognitive dysfunction.
THE BRAIN RENIN-ANGIOTENSIN SYSTEM IS ALTERED IN AGE AND ALZHEIMER'S DISEASE
The renin-angiotensin system (RAS) regulates systemic blood pressure but functions independently within organs including the brain. Although systemic RAS is downregulated with age, localised organ-specific RAS becomes overactivated with age and may predispose to the onset of disease. In Alzheimer’s disease (AD), a shift in the balance of RAS towards classical RAS (cRAS) activation and loss of protective counter-regulatory (rRAS) have been reported. In this study, we have explored age- and disease-related changes in brain RAS, specifically the expression and enzyme activities of ACE-1 and ACE-2 (central mediators of the cRAS and rRAS pathways respectively).
Human post-mortem brain tissue with no neurodegenerative clinical diagnosis was used to investigate the effect of age (n=132; 19-80y) and tissue with known Braak stage was used to investigate the effect of AD (n=120). ACE-1 and ACE-2 protein levels were measured by ELISA and enzyme activities were measured by fluorogenic peptide activity assays. Ang-II levels were measured by an in-house direct ELISA.
In normal ageing, ACE-1 and Ang-II levels increased with age (p=0.0001, p<0.0001, respectively) and correlated against each other (r=0.2986, p=0.0065). In contrast, ACE-1 enzyme activity was reduced with age (p<0.0001), particularly after the age of 65, and was negatively correlated with Ang-II (r=-0.3913, p=0.0002). ACE-2 level and activity were unaltered in the ageing cohort. In AD, ACE-1 enzyme activity was increased (p=0.0281), specifically in Braak tangle stage III-IV i.e. at an intermediate stage. ACE-1 and Ang-II protein level were unchanged; as was ACE-2 level and activity.
We have shown that brain RAS is altered with normal ageing and in the early stages of AD. We suggest that a protective feedback mechanism, mediated by Ang-II, prevents overactivation of the ACE-1 enzyme and is dysregulated in the early stages of AD. These findings provide further insight into the potential role of RAS in AD.
Vascular Risk Factors
Gait and Falls in Cerebral Amyloid Angiopathy
Cerebral amyloid angiopathy (CAA) is characterized by vascular amyloid deposition. Little is known about the gait profile of CAA. We sought to determine whether gait was impaired in CAA, and whether it was related to falls or fear of falling.
Participants (29 CAA, 47 normal controls [NC], 24 mild cognitive impairment [MCI], and 16 Alzheimer’s disease with dementia [AD]; Table 1) completed gait assessments using the ProtoKinetics Zeno Walkway, consisting of three passes at a preferred pace and three dual task walks (counting backwards, naming animals, and serial sevens). Gait parameters were subdivided into four domains: rhythm (cadence, stride time, and swing time), pace (speed, stride length, and double support), postural control (stride width and stride width variability), and variability (variability of stride time, stride length, and double support percent) . Models were adjusted for age, sex, and height. Participants completed the Falls and Balance questionnaire, in which they provided the number of falls in the last year and a score on a scale of 0-10 of their fear of falling.
Rhythm and pace were impaired in CAA during preferred pace and dual task conditions, to a similar degree as in AD (Table 2). Gait parameters were not associated with number of falls (Table 3). However, in both CAA participants and all participants combined, better scores on pace and variability were associated with less fear of falling (Table 3).
Gait is impaired in CAA compared to NC and to a similar extent in AD and is associated with greater fear of falling. Further research is needed to establish the underlying causes and other consequences of gait impairment in CAA.
HIGHER TOTAL CHOLESTEROL IN APOE4 CARRIERS CONTRIBUTES TO ALZHEIMER’S DISEASE RISK: FINDINGS FROM THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE
APOE ε4 allele is the greatest genetic risk factor for Alzheimer’s disease (AD), yet mechanisms underlying its risk conferral are not well understood. APOE is involved in blood lipid metabolism. While the literature suggests relationships between high total cholesterol (TC), APOE ε4 allele, and AD, reports of TC in relation to AD are conflicting and obviate the need for further investigation. We analyzed data from 1,534 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants to examine the relationship between TC and APOE risk for AD. Participants were grouped by APOE status as either APOE2+ (ε2/ε2 and ε2/ε3 genotypes), APOE3 (ε3/ε3 genotype), or APOE4+ (ε4/ε4 and ε4/ε3 genotypes). Diagnostic groups included cognitively normal (N = 404), mild cognitive impairment due to AD (MCI; N = 833), AD (N = 297), and composite dementia (CD; AD or MCI, N = 1,130). Generalized linear modeling was used to compare TC levels across APOE and diagnostic groups. Mendelian randomization was performed to assess whether APOE’s relationship with AD is mediated by TC. APOE4+ carriers had higher TC compared to APOE3 (p = 0.002) and APOE2+ (p = 0.04) carriers. TC levels were also higher in AD (p < 0.001), MCI (p < 0.01), and CD (p < 0.01) compared to CN. Mendelian randomization revealed that APOE4+ carriers had higher log odds ratios (LOR) per mg/dL increase in TC for MCI (LOR 0.10, 95% confidence interval (CI) 0.04-1.99), AD (LOR 0.19, 95% CI 0.09-3.99), and CD (LOR 0.12, 95% CI 0.06-2.45) compared to APOE3 carriers. Our results suggest that higher TC combined with lesser ability of APOE4+ carriers to metabolize it may, at least in part, underlie AD risk. Our findings highlight a possible mechanism by which APOE confers AD risk and suggest a potential for AD risk modification through maintenance of healthy TC levels.
Funding: Michelle Dunk was partially supported by the Summer Graduate Research Fellowship through the University of Wisconsin – Milwaukee. ADNI data collection and sharing were funded by the National Institutes of Health Grant U01 AG024904 and Department of Defense award number W81XWH-12-2-0012.
Vascular Risk Factors
Modelling Alzheimer’s Disease through Environmentally Induced Neurovascular Dysfunction within an In Vitro Cell Model
Exposure to urban particulate matter has detrimental effects on cerebrovascular integrity associated with Alzheimer’s disease (AD) risk. Fine particles <2.5 μm (PM2.5) continually bioaccumulate within the neurovascular parenchyma, exacerbating oxidative stress, inflammation and misfolded protein accumulation observed in the early stages of AD. Considering astroglia undergo activation of molecular programs in response to pathological stimuli, initiation of reactive reprogramming induced by PM2.5 may elucidate disease-specific reactive phenotypes. The aim of this study is to assess the effects of PM2.5-induced astroglial reactivity on neurovascular communication as an early indicator of neurodegeneration and AD-like pathology using a human cell model. Primary astrocytes were characterized for their functional and physiological properties including reactive capacity as measured through cytokine release. Neurovascular intercellular communication between astrocytes and brain microvascular endothelial cells (BMECs) was evaluated by measuring transendothelial electrical resistance (TEER), indicating barrier functionality over time within a transwell-type neurovascular unit model. Short-term exposure to PM2.5 led to an increased astroglial release of proinflammatory cytokine IL-6, similar to the acute response measured from prolonged treatment with cytokines IL-1b and TNF-a. Co-culture of untreated astrocytes and BMECs led to significantly higher TEER values when compared with monocultures. These data suggest a distinct molecular response from primary astrocytes in relation to physiologically accurate concentrations of PM2.5. Given the effect of astrocytes on endothelial barrier maintenance, expanding on these findings to address the effect of this reactive state on adjacent neurovascular cell types will procure a robust understanding of the wider cerebrovascular effects of environmental pollution.
Blood Brain Barrier
ENDOTHELIN-1-MEDIATED CONTRACTION OF HUMAN BRAIN PERICYTES IS DYSREGULATED IN THE PRESENCE OF Aβ1-40
Vascular dysfunction and brain ischemia are defining pathologies of vascular dementia, and are increasingly recognised as underestimated contributors to cognitive decline and disease pathology in Alzheimer’s disease (AD). Pericytes are critical for dynamic regulation of cerebral blood flow, and are damaged and degenerate in AD. Vascular abnormalities in AD correlate with elevated levels of the potent vasoconstrictor peptide endothelin-1 (EDN1). We hypothesise that dysregulated EDN1-mediated pericyte contraction is a major contributor to cerebral hypoperfusion in AD.
This study aimed to characterise EDN1-mediated contraction of foetal and adult human brain-derived pericytes and determine whether Aβ modifies the contractile response. An electrical impedance assay was used to assess pericyte contraction in response to EDN1. We used BQ123 and BQ788, to characterise the role of EDN1 type-A and type-B receptors respectively and monitored the effects of pre-exposure of pericytes to Aβ peptides for 1 and 24 h. Change in calculated cell index was used to reflect rates of contraction (acute response <30 mins) and proliferation (chronic response 48 hours).
EDN1 treatment caused a dose-dependent contraction of foetal pericytes at 1nM (p=0.0283), 0.01µM (p=0.0035), 0.1µM (p=0.0022) and 1µM (p=0.0003) EDN1. Adult pericytes were less sensitive to EDN1 and contracted at 0.1µM (p=0.0008) and 1µM (p<0.0001) EDN1 only. Pre-treatment with BQ123, but not BQ788, prevented the contraction of foetal and adult pericytes. Exposure to Aβ1-40 for 24 hours significantly impaired EDN1-mediated contraction of foetal pericytes (p=0.0249).
These data indicate that EDN1-mediated pericyte contraction occurs via EDNRA and that pre-exposure to Aβ1-40 impairs pericyte contraction. Studies are underway to determine how Aβ peptides regulate EDN1-mediated pericyte contractility and to explore differences between foetal and adult-derived cells.
Vascular Risk Factors
LOW CAROTID END DIASTOLIC VELOCITY IS ASSOCIATED WITH WHITE MATTER HYPERINTENSITIES AND CORTICAL ATROPHY IN THE SWEDISH "GOOD AGING IN SKÅNE" STUDY
AIM The relationship between hemodynamic properties of the larger arteries and cerebral small vessel disease (CSVD) is not yet fully understood. Our aim was to study the prevalence and interrelations between magnetic resonance (MR) markers of CSVD and specific brain atrophies, and their association to carotid artery duplex flow parameters.
METHOD We investigated a population based randomised cohort of older adults (n=391) aged 70-87, in the Swedish Good Aging in Skåne (GÅS) Study. Exclusion criteria was Peak Systolic Velocity ≥ 120 cm/s. Peak Systolic Velocity (PSV) and End Diastolic Velocity (EDV) were assessed by carotid duplex, and resistivity index (RI) and Pulsatility Index (PI) were calculated using the Pourcelot and Goslin formula. Nine radiological findings were investigated by visual rating scales: white matter changes (WMC) using Fazekas´ scale, pontine white matter changes (PMC), microbleeds (<2-5 mm) (MB), lacunar infarctions (<10mm) (LAC), medial temporal lobe atrophy (MTA) according to Schelten´s scale, global cortical atrophy (GCA) according to Pasquier´s scale, parietal atrophy (KPA) according to Koedam´s scale, precuneus atrophy (PA) and central atrophy (CA). Hierarchical cluster analysis was performed to investigate CSVD covariance, and regression models were used to test for associations to carotid flow parameters.
RESULTS Pathologies were found in 80% of subjects and distribution of CSVD was heterogenic. EDV in common carotid arteries (CCA) was associated with “moderate/severe WMC” (OR:0.92; p=0.004), KPA (OR:0.94; p=0.022), PA (OR:0.94; p=0.022), GCA (OR:0.90; p=0.013), “number of MRI pathologies” (β-0.07; p<0.001) and “total MRI-burden score” (β-0.11; p<0.001), adjusted for age and sex. The latter three were associated with pulsatility and resistivity indexes.
CONCLUSION: Low mean EDV, proposed as a marker of arteriosclerosis, was associated with signs of CSVD and patterns of brain atrophy, indicating a vascular component in the process of brain aging.
Vascular Risk Factors
Serum Placental Growth Factor as a Marker of Cerebrovascular Disease burden in patients with Alzheimer’s Disease
Background: Cerebrovascular diseases (CeVD) have been identified as an important determinant of the progression of Alzheimer’s disease (AD). Development of robust blood-based biomarkers provide critical tools to assess studies on diagnosis and treatments of AD with concomitant CeVD. Here, we investigated the potential of circulating placental growth factor (PlGF), a potent pro-angiogenic factor that has been related to endothelial dysfunction and vascular inflammation, in preclinical stages of cognitive impairment and in AD, as well as its associations with MRI markers of CeVD in an Asian memory clinic cohort.
Methods: 109 patients with AD, 76 with cognitively impaired no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional study. All subjects underwent 3T brain MRI to assess markers of CeVD; white matter hyperintensities (WMHs, measured by ARWMC scores), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays and normalized by log 2 transformation. Information on demographical characteristics and vascular risk factors were collected.
Results: PlGF was signiﬁcantly elevated in AD compared to NCI controls (p=0.044), but not in CIND. Stratified analysis revealed that higher PlGF concentrations were found in AD only in the presence of significant CeVD (p<0.001). Among the MRI markers of CeVD assessed, PlGF levels were significantly higher in subjects with confluent WMHs (ARWMC scores ≥ 8) (p<0.001) and CMBs (p=0.016). Subsequent multivariate regression analyses showed that PlGF was significantly associated with WMHs (mean difference [β] 2.69, 95% CI 0.95 – 4.42, p=0.003) and CMBs (rate ratio [RR] 1.99, 95% CI 1.03 – 3.86, p=0.041) independent of vascular risk factors and other relevant CeVD markers in AD.
Conclusions: Serum PlGF has potential clinical utility as a biomarker for the presence of CeVD such as WMH and CMBs in AD. Future longitudinal studies are needed to assess the utility of PlGF as a prognostic marker of AD with concomitant CeVD.
Association Between Blood Pressure Variability with Dementia and Cognitive Impairment: A Systematic Review and Meta-analysis
Background: Research consistently links high blood pressure variability (BPV) with stroke and cerebrovascular disease as well as adverse cardiovascular outcomes. However, the association between BPV with dementia and cognitive impairment is inconsistent. Moreover, it remains uncertain whether BPV holds more significance in understanding vascular contributions to cognitive impairment by comparison to the more established risk factor of mean blood pressure.
Methods: A systematic search of PubMed, Embase, PsycINFO and Scopus was performed until May 2021 for studies that quantified the association between resting BPV with dementia or cognitive impairment in adults. A multilevel meta-analysis was employed, which included effect sizes for both BPV and mean BP, with a combined end-point of dementia or cognitive impairment as primary outcome. Secondary outcomes were dementia subtypes, cognitive impairment, cognitive decline, as well as domain-specific cognitive function (both r and d family effect sizes).
Results: The primary analysis included 54 effect sizes extracted from 20 studies in primarily older adults, with a total analytical sample of n=7,899,697. Multilevel meta-analysis showed that higher systolic BPV (OR=1.25 [95% CI, 1.16-1.35]), mean systolic pressure (OR=1.12 [95% CI, 1.02-1.29]), diastolic BPV (OR=1.20 [95% CI, 1.12-1.29]) and mean diastolic pressure (OR=1.16 [95% CI, 1.04-1.29]) were associated with the primary outcome of dementia and cognitive impairment. A direct comparison of effect sizes showed that mean BP effect sizes were less strong than BPV effect sizes (OR=0.92 [95% CI, 0.87-0.97], p<0.01), indicating that the relative contribution of BPV exceeded that of mean BP. However, methodological and statistical heterogeneity was high. Secondary analyses were less consistent as to whether BPV and mean BP were differentially associated with dementia sub-types and cognitive domains.
Conclusion: The available evidence indicated that BPV was more strongly associated with dementia and cognitive impairment than mean blood pressure in primarily older adult samples.
Vascular Risk Factors
The Relationship of Acute Delirium with Cognitive and Psychiatric symptoms after Stroke: A longitudinal study- Vilde Nerdal (Norway)
Objectives: Delirium is a common complication in the acute phase of cerebrovascular events. The condition is often overlooked, and the long-term consequences poorly understood. This study aims to examine whether acute delirium in stroke predicts more severe cognitive and emotional symptoms over the course of three years.
Method: 169 stroke-survivors (48.5% women, mean (SD) age: 72.4 (13.0); National Institutes of Health Stroke Scale (NIHSS): 3.61 (5.0)) were screened for delirium by the Confusion Assessment Method (CAM) during the first two days of hospital stay. All procedures were part of the longitudinal multicenter Nor-COAST study. Global cognition was measured by the Montreal Cognitive Assessment Test (MoCA) and emotional symptoms were measured using the Hospital Anxiety and Depression Scale (HADS) at 3, 18, and 36 months. Mixed-model linear regression was applied with MoCA and HADS scores as dependent variables. Independent variables were delirium, time and their interaction. The analyses were adjusted for age, gender, education, NIHSS-score, and premorbid dementia.
Results: 24 patients met the criteria for delirium (Age: 79.0 (7.7); NIHSS: 5.3 (5.7)), while 145 were non-delirious (Age: 71.3 (13.4); NIHSS: 3.1 (4.0)). Delirium was associated with poorer global cognition (MoCA) at 18 (p = .017) and 36 months (p = .024). HADS scores were higher for patients with delirium at 18 (p = .001) and 36 months (p = .003). The group differences in mean scores were highest at 36 months for MoCA (21.97 (1.2) vs. 24.86 (.38)) and at 18 months for HADS (13.36 (1.73) vs. 7.11 (.57)). Conclusion: The results suggest that delirium predicts poorer long-term outcomes after stroke, both for general cognition and emotional symptoms. Focus on prevention and adequate assessment, as well as treatment and long-term follow up can be important contributions for decreasing the burden of post-stroke disability.
SMALL AND LARGE MRI-VISIBLE PERIVASCULAR SPACES IN THE BASAL GANGLIA OF PARKINSON’S DISEASE PATIENTS
Background: MRI-visible perivascular spaces in the basal ganglia (BG-PVS) are typically considered to be asymptomatic; however, there is evidence to suggest that they may be a marker of motor disability in Parkinson’s disease (PD). Additionally, recent studies suggest a difference in the pathogenesis and risk profile between small (≤3 mm in diameter) and large (>3 mm in diameter) PVS.
Purpose: To examine small and large BG-PVS and their association with disease severity in PD patients.
Methods: Patients were recruited from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). MRI-based measures included BG-PVS, lacunes, periventricular and deep white matter hyperintensities (p/dWMH). Summary scores from Parts I-IV of the Movement Disorders Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) were used to assess disease severity. Partial Spearman’s correlation and negative binomial regression models adjusted for multiple comparisons using the Benjamin-Hochberg false discovery rate were applied to the data. All analyses accounted for age, sex, education, HbA1C, cholesterol, systolic BP, smoking, lacunes, and WMH.
Results: PD patients with only small BG-PVS demonstrated an association with Part I (p<0.01, 95% C.I.: 0.005, 0.023) and Part II (p<0.01, 95% C.I.: 0.004, 0.023) of the MDS-UPDRS, whereas patients with large BG-PVS demonstrated an association with Part III (p<0.0001, 95% C.I.: 0.012, 0.027) and Part IV (p<0.001, 95% C.I.: 0.015, 0.05). Additionally, only small BG-PVS were correlated with pWMH (rho=0.26, p=0.015), no other significant correlations were found.
Conclusions: These findings suggest that small BG-PVS are more likely to impact PD-related motor and non-motor aspects of experiences in daily living (assessed by MDS-UPDRS Parts I-II), while large BG-PVS are more likely to impact the motor signs and treatment-related motor complications (Parts III-IV). Additionally, the small BG-PVS may be more of an indicator of global small vessel disease severity, given its independent correlation with pWMH that was not demonstrated with large BG-PVS.
ANGIOTENSINOGEN, ACE-1 AND ACE-2 IN ALZHEIMER’S DISEASE AND VASCULAR DEMENTIA
Alteration of the renin angiotensin system (RAS) within the brain potentially contributes to the pathogenesis of Alzheimer`s disease (AD). ACE1 encodes angiotensin II converting enzyme-1 (ACE-1), a rate-limiting enzyme in the classical renin-angiotensin system (cRAS) responsible for the conversion of Ang-I (generated from angiotensinogen) to Ang-II. ACE-2 is the central enzyme in the generation of Ang (1-7) from Ang II and is a central mediator of the counterregulatory RAS (rRAS) arm. In this study, we investigated the mRNA expression of of ACE1, ACE2 and AGT, and protein levels of ACE1 and AGT in the frontal cortex in AD and examined their associations with the ACE1 variant (rs4343) (a proxy marker for the more commonly studied indel polymorphism) which is an established risk factor for AD.
We studied 95 dementia cases including AD, Mixed, and VaD, and 50 control brains from the South West Dementia Brain Bank, University of Bristol. The mRNA expression levels of ACE1, ACE2 and AGT were quantified with TaqMan™ real-time RT-PCR. ACE-1 and AGT levels were measured by sandwich ELISA in frontal cortex in dementia and control samples in a larger cohort (n=251) for which we have previously obtained data on ACE1 (rs4343) polymorphism by PCR.
AGT and ACE2 mRNA were expressed at significantly lower levels in the frontal cortex in AD (relative to GFAP, an astrocytic calibrator gene) (p=0.002 and 0.03, respectively). ACE1 mRNA expression and ACE-1 protein levels were unchanged in AD. The reduction of AGT mRNA level was most pronounced in heterozygous (I/D) individuals compared to homozygous (D/D) individuals (p=0.04).
These results suggest that altered of expression of ACE2 and AGT may contribute to the progression of AD. Further work is underway to determine the cell-specific distribution of RAS in the brain.
Social Cognition is Associated with General Cognitive Function Post-Stroke
Objective: The DSM-5 introduces social cognition as one of six cognitive domains that may be impaired in post-stroke neurocognitive disorder. Social cognition refers to processing of information about other people’s thoughts and emotions, which may be affected in many clinical populations. However, how it presents in the stroke population has not yet been sufficiently described. Impairment in abilities such as emotion recognition and theory of mind (understanding and considering the mental state of another) may have far-reaching consequences for rehabilitation, returning to society, and relating to others. The aim of this study was to examine the association between social cognition and general cognitive function post-stroke.
Method: 29 patients (76% male, mean age 67.8, SD=10.5) diagnosed with stroke three years ago were included. All patients were part of the longitudinal multicentre Nor-COAST cohort study and had been followed up with regular intervals since the acute phase. A neuropsychological test battery was administered as part of an additional follow-up. General cognitive function was measured by the Mini Mental State Examination (MMSE), while social cognition was measured using the Hinting Task (theory of mind) and Pictures of Facial Affect (emotion recognition). Regression analysis was then used to examine the association between general cognitive function and performance on the social cognition tests. The results were controlled for age as well as sex, due to the higher percentage of men in the sample.
Results: A better performance on MMSE was associated with better performance in emotion recognition (p=.02, R2=.30, β=.42). No significant association was found between MMSE and the theory of mind task (p>.05).
Conclusion: Results support the hypothesis that there is a relationship between general cognitive function and ability to identify emotions in others 3 years post-stroke. Further exploration of this association is warranted.
FIBRINOGEN ACTIVATES MICROGLIA AND DRIVES EXTRACELLULAR VESICLE MEDIATED PROPAGATION OF PRO-INFLAMMATORY SIGNALING
Aging and cerebral small vessel disease (SVD) have deleterious effects on the white matter of the brain including an increase in pro-inflammatory microglia and blood-brain barrier dysfunction, evidenced by upregulation of NFkB and NLRP3 inflammasome signaling pathways and extravasation of serum fibrinogen, respectively. Despite the importance of these two features of aging and SVD, the interactions between blood-brain barrier dysfunction and microglia activity remains unclear. In this study we investigate whether exposure to low doses of fibrinogen can induce persistent activation of microglia cells. We further investigate a potential role for extracellular vesicles (EVs) in the propagation of pro-inflammatory signaling between microglia. For dose determination acute exposure experiments, BV2-microglia were exposed to a range of fibrinogen doses (0.01-4 mg/ml) for three hours. EVs were collected and isolated from fibrinogen exposed cells for cargo analysis and applied to naïve cells (2k-12k EVs/cell). To model persistent fibrinogen exposure, cells were treated with either fibrinogen or fibrinogen EVs every 3 hours for 9 hours. RNA was collected after 3, 6, and 9 and 12 hours and pro-inflammatory transcript expression was measured. Microglia acutely upregulated transcription of pro-inflammatory signaling molecules IL-6, IL1β, iNOS and NLRP3 in a dose-dependent manner following exposure to fibrinogen. Furthermore, EVs-derived from fibrinogen exposed microglia transported fibrinogen and upregulated levels of IL1β, IL-6 and NLRP3 in naïve cells. Repeated exposure to either fibrinogen or fibrinogen-derived EVs resulted in increased and sustained upregulation of pro-inflammatory transcript levels. Fibrinogen induced robust microglia activation at concentrations 20-fold lower than circulating-plasma levels, suggesting that leakage through the blood brain barrier is sufficient for the induction of pro-inflammatory microglia. EV-mediated signaling may represent a novel mechanism enhancing fibrinogen-induced microglial activity. Future work investigating EV-mediated propagation in vivo will improve our understanding of blood-brain barrier dysfunction and microglia activation in the context of aging and SVD.
PREVALANCE OF, AND RISK FACTORS FOR, VASCULAR COGNITIVE IMPAIRMENT IN CADASIL
CADASIL is the most common monogenic form of stroke and is also associated with early onset dementia. We determined the prevalence of vascular cognitive impairment (VCI) in a cohort of CADASIL patients and which factors were associated with VCI risk.
Cognition was assessed in genetically confirmed CADASIL patients (n = 176) and healthy controls (n = 265) using the Brief Memory and Executive Test (BMET) and Montreal Cognitive Assessment (MoCA). We determined the prevalence of VCI and its associations with clinical risk factors, mutation location (EGFr 1-6 versus EGFr 7-34), and MRI markers (lacunes, white matter hyperintensity volume, brain volume and cerebral microbleeds).
CADASIL patients (Mean (SD) age 50.95 (11.3)) had significantly worse performance across all domains of the BMET than controls (Mean (SD) age 52.37 (7.93)), with worst performance on the letter sequencing task (figure 1). VCI, defined using the BMET, was present in 39.8% of the CADASIL group and 10.2% of controls. VCI, defined using the MoCA, was present in 48.9% of the CADASIL group and 21.1% of controls.
While controlling for age and sex, history of stroke was associated with increased VCI on the BMET (OR 2.10, 95% CI [1.06, 4.17] p = 0.03) and on the MoCA (OR 2.55, 95% CI [1.24, 5.24] p = 0.01). There was no relationship of VCI to sex, cardiovascular risk factors or mutation site. Lacune count was the only MRI parameter independently associated with VCI on the BMET, after controlling for other MRI parameters, (OR: 1.67, 95% CI [1.14, 2.44], p = 0.008).
VCI is present in 40-50% of CADASIL patients with a mean age of 50 years. Reductions were seen across all cognitive domains including memory. Stroke and lacune count on MRI were both independent predictors of VCI on the BMET. No association was found with mutation site.