Quantitative Gait Impairments in Patients With Stroke or Transient Ischemic Attack: A Population-Based Approach.

BACKGROUND AND PURPOSE: Gait is a complex process involving various cortical and subcortical brain regions. An acute stroke or transient ischemic attack (TIA) may disrupt white and gray matter integrity and, therefore, affect gait in patients without evident neurological signs. We determined whether patients with stroke and TIA experience subtle changes in global gait and several independent gait domains. METHODS: In the population-based Rotterdam Study, 4456 participants (median age, 65 years; 55% women) underwent detailed quantitative gait assessment (GAITRite) between 2009 and 2016. We summarized 30 gait parameters into a global gait score and 7 mutually independent gait domains. First, we assessed the association between prior stroke or TIA and global and domain-specific gait using linear regression models adjusted for age, sex, vascular risk factors, and cognition. Subsequently, we repeated the analysis stratified by the presence of different neurological symptoms in a subgroup of participants with ischemic stroke after study entry. RESULTS: Compared with participants without prior stroke, patients with stroke had a worse global gait (SD, -0.49 [95% CI, -0.64 to -0.34]), especially in the gait domains Pace, Phases, and Turning. The detrimental effect of stroke on gait was amplified in participants with worse cognition. No gait differences were found between participants with and without prior TIA. Ischemic stroke patients without lower limb weakness, loss of coordination, or visuospatial problems still had a worse gait compared with participants without stroke. Stratification by different stroke symptoms showed that different gait domains were affected in each group. CONCLUSIONS: Prior stroke without neurological signs that affect gait is still associated with gait difficulties compared with individuals without stroke. Our study suggests that stroke not only has a direct impact on gait through neurological impairments but also includes an indirect effect possibly through disruption of gray and white matter integrity and accelerated neurodegeneration.

Thinner retinal layers are associated with changes in the visual pathway: A population-based study.

Increasing evidence shows that thinner retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), assessed on optical coherence tomography (OCT), are reflecting global brain atrophy. Yet, little is known on the relation of these layers with specific brain regions. Using voxel-based analysis, we aimed to unravel specific brain regions associated with these retinal layers. We included 2,235 persons (mean age: 67.3 years, 55% women) from the Rotterdam Study (2007-2012) who had gradable retinal OCT images and brain magnetic resonance imaging (MRI) scans, including diffusion tensor (DT) imaging. Thicknesses of peripapillary RNFL and perimacular GCL were measured using an automated segmentation algorithm. Voxel-based morphometry protocols were applied to process DT-MRI data. We investigated the association between retinal layer thickness with voxel-wise gray matter density and white matter microstructure by performing linear regression models. We found that thinner RNFL and GCL were associated with lower gray matter density in the visual cortex, and with lower fractional anisotropy and higher mean diffusivity in white matter tracts that are part of the optic radiation. Furthermore, thinner GCL was associated with lower gray matter density of the thalamus. Thinner RNFL and GCL are associated with gray and white matter changes in the visual pathway suggesting that retinal thinning on OCT may be specifically associated with changes in the visual pathway rather than with changes in the global brain. These findings may serve as a basis for understanding visual symptoms in elderly patients, patients with Alzheimer's disease, or patients with posterior cortical atrophy.

CMPK1 and RBP3 are associated with corneal curvature in Asian populations.

Corneal curvature (CC) measures the steepness of the cornea and is an important parameter for clinically diseases such as astigmatism and myopia. Despite the high heritability of CC, only two associated genes have been discovered to date. We performed a three-stage genome-wide association study meta-analysis in 12 660 Asian individuals. Our Stage 1 was done in multiethnic cohorts comprising 7440 individuals, followed by a Stage 2 replication in 2473 Chinese and Stage 3 in 2747 Japanese. The SNP array genotype data were imputed up to the 1000 Genomes Project Phase 1 cosmopolitan panel. The SNP association with the radii of CC was investigated in the linear regression model with the adjustment of age, gender and principal components. In addition to the known genes, MTOR (also known as FRAP1) and PDGFRA, we discovered two novel genes associated with CC: CMPK1 (rs17103186, P = 3.3 × 10(-12)) and RBP3 (rs11204213 [Val884Met], P = 1.1 × 10(-13)). The missense RBP3 SNP, rs11204213, was also associated with axial length (AL) (P = 4.2 × 10(-6)) and had larger effects on both CC and AL compared with other SNPs. The index SNPs at the four indicated loci explained 1.9% of CC variance across the Stages 1 and 2 cohorts, while 33.8% of CC variance was explained by the genome-wide imputation data. We identified two novel genes influencing CC, which are related to either corneal shape or eye size. This study provides additional insights into genetic architecture of corneal shape.

Retinal ganglion cell neuronal damage in diabetes and diabetic retinopathy.

BACKGROUND: To examine the association of diabetes and diabetic retinopathy (DR) with retinal ganglion cell (RGC) loss. DESIGN: Observational case-control study. PARTICIPANTS: Type 2 diabetes cases and age-gender matched controls without diabetes. METHODS: Spectral-domain optical coherence tomography (OCT) parameters of RGCs were calculated after automated segmentation of macular scans. DR severity was graded on fundus photographs using the modified Airlie House Classification system. Generalized estimating equation was used to compare OCT parameters between cases and controls, adjusted for covariates. MAIN OUTCOME MEASURES: Average ganglion cell-inner plexiform layer (GC-IPL) and average retinal nerve fibre layer (RNFL) thicknesses. RESULTS: We analyzed 227 cases and 227 controls. The mean age (years) of cases was 58.3 and controls was 58.1 (P = 0.13). Among cases, 101 had none, 25 had mild and 101 had moderate or severe DR. Compared with controls, GC-IPL and RNFL were thinner in all cases [mean difference (95% confidence interval [CI]): GC-IPL -4.49 µm (-2.92; -6.06), RNFL -0.93 µm (-0.09; -1.85)], including cases with no DR [mean difference (95% CI), GC-IPL -4.37 µm (-2.72; -6.02), RNFL -1.06 µm (-0.10; -2.02)]. Cases with any DR had thinner GC-IPL than controls [mean difference (95% CI): GC-IPL -4.81 µm (-2.12; -7.50)]. Among cases, subjects with moderate or severe DR had thinner GC-IPL than subjects with no DR [mean difference (95% CI): GC-IPL -2.07 µm (-0.08; -4.07)]. CONCLUSIONS: RGC loss is present in subjects with diabetes and no DR, and is progressive in moderate or severe DR. RGC neuronal damage in diabetes and DR can be clinically detected using OCT.

Prevalence and Risk Factors of Acute Incidental Infarcts.

BACKGROUND AND PURPOSE: The study of silent stroke has been limited to imaging of chronic infarcts; acute incidental infarcts (AII) detected on brain magnetic resonance imaging have been less investigated. This study aims to describe prevalence and risk factors of AII in a community and a clinic-based population. METHODS: Subjects were drawn from 2 ongoing studies: Epidemiology of Dementia in Singapore study, which is a subsample from a population-based study, and a clinic-based case-control study. Subjects from both studies underwent similar clinical and neuropsychological assessments and brain magnetic resonance imaging. Prevalence of AII from these studies was determined. Subsequently, risk factors of AII were examined using multivariable logistic regression models. RESULTS: AII were seen in 7 of 623 (1.2%) subjects in Epidemiology of Dementia in Singapore (mean age, 70.9±6.8 years; 45% men) and in 12 of 389 (3.2%) subjects (mean age, 72.1±8.3 years; 46% men) in the clinic-based study. AII were present in 0.8% of subjects with no cognitive impairment, 1.9% of those with cognitive impairment not dementia, and 4.2% of subjects with dementia. Significant association of AII was found with cerebral microbleeds (≥5) in the Epidemiology of Dementia in Singapore (odds ratio, 6.76; 95% confidence interval, 1.28-35.65; P=0.02) and in the clinic-based cohort (odds ratio, 4.65; 95% confidence interval, 1.39-15.53; P=0.01). There was no association of AII with hypertension, diabetes mellitus, or hyperlipidemia. CONCLUSIONS: AII are more likely to be present in those with cognitive impairment. Although a cause-effect relationship between the presence of AII and cognitive impairment is plausible, the association may be because of under-reporting of symptoms by individuals with cognitive impairment. The association between AII and cerebral microbleeds may indicate cerebral vasculopathy, independent of traditional vascular risk factors.

Intracranial stenosis, cerebrovascular diseases, and cognitive impairment in chinese.

Extracranial carotid artery disease has been shown to be related to cognitive deficits. However, limited data are available on intracranial stenosis (ICS) and cognitive impairment. We investigate the association between ICS and cognitive impairment in Chinese. Subjects (n=278), recruited from the Epidemiology of Dementia in Singapore Study, underwent comprehensive clinical evaluation, neuropsychological testing, and brain magnetic resonance imaging (MRI), including 3-dimensional-time-of-flight magnetic resonance angiography (MRA). Cognitive function was expressed as composite and domain-specific Z-scores. Cognitive impairment no dementia and dementia were diagnosed according to internationally accepted diagnostic criteria. Linear and logistic regression models were adjusted for age, sex, education, vascular risk factors, and other MRI markers. A total of 29 (10.4%) persons had ICS on MRA, which was significantly associated with both composite cognitive Z-scores [mean difference in Z-score, presence vs. absence of ICS: -0.37 (95% confidence interval: -0.63, -0.12)] and specific domains including executive function, language, visuomotor speed, verbal memory, and visual memory. ICS was also related to significant cognitive impairment (odds ratio: 5.10 [1.24 to 21.02]). With respect to other MRI markers, adjusted for the presence of lacunar infarcts, the associations of ICS with both composite and domain-specific Z-scores, and significant cognitive impairment became nonsignificant; however, adjustment for other MRI markers did not alter these associations. In this Chinese population, presence of ICS was associated with cognitive impairment independent of vascular risk factors. These associations may be mediated through the presence of infarcts.

Cerebral microbleeds and cognition: the epidemiology of dementia in Singapore study.

Cerebral microbleeds (CMBs) are considered to be a novel marker of cerebral small vessel disease. However, the link with cognitive impairment remains unclear. We investigated whether CMBs-independent of other traditional markers of cerebral small vessel disease-are related to cognition. Chinese subjects from the population-based Singapore Chinese Eye Study, who failed an initial cognitive screening and were recruited into the ongoing Epidemiology of Dementia in Singapore Study, underwent neuropsychological testing and 3 T brain magnetic resonance imaging. The presence and number of CMBs were graded using Brain Observer Microbleed Scale on susceptibility-weighted images. Other magnetic resonance imaging lesions that were graded included presence of lacunes, white matter lesion, and total brain volumes. A comprehensive neuropsychological battery was administered and cognitive function was summarized as composite and domain-specific Z-scores. Among 282 subjects, 91 had any CMBs (32.3%), of whom 36 (12.8%) had multiple CMBs. CMBs were-independent of cardiovascular risk factors and other markers of cerebral small vessel disease-significantly associated with poorer cognitive function as reflected by composite Z-score (mean difference per CMB increase: -0.06; 95% confidence interval: -0.11, -0.01] and with domain-specific Z-scores including executive function, attention, and visuoconstruction. Among Chinese subjects CMBs were, independent of other concomitant markers of cerebral small vessel disease, associated with poorer cognitive function.

Computer tomography for prediction of cognitive outcomes after ischemic cerebrovascular events.

BACKGROUND: The aim of this study was to evaluate whether parameters noted on a single, acute computed tomographic (CT) scan, are associated with significant cognitive impairment (SCogI), and can help in the prediction of SCogI 3-6 months after stroke or transient ischemic attack (TIA). METHODS: Patients with a recent (≤14 days) ischemic stroke or TIA, without preexisting dementia, underwent noncontrast CT scan within 24 hours of admission. A formal neuropsychologic battery was administered 3-6 months from index stroke. SCogI was defined as moderate cognitively impaired, not demented (CIND) (≥3 domains impaired), and dementia diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Logistic regression models were used to examine associations between CT parameters and SCogI. Receiver operating characteristic analysis with an area under the curve (AUC) was performed to assess discriminatory ability of radiological parameters for SCogI. RESULTS: In all, 318 patients were included: 250 (78.6 %) with ischemic stroke and 68 (21.4%) with TIA; the mean age was 59.8 (±11.4) years. At 3-6 months, 76 (23.9 %) had SCogI (67 CIND moderate and 9 dementia). The presence of significant atrophy (P = .02) and chronic infarcts (P = .03) were associated with SCogI at 3-6 months. A significant increase in AUC was noted after addition of summarized CT results to a clinical score derived from age and baseline Montreal Cognitive Assessment (cutoff 21 of 22) for detection of SCogI: .83 (.78-.89) to .86 (.82-.91); P = .03. CONCLUSIONS: CT parameters are independently associated with SCogI at 3-6 months after an ischemic cerebrovascular event and may be a clinically useful component in predicting for SCogI after stroke.

Systemic associations of dynamic retinal vessel analysis: a review of current literature.

Endothelial dysfunction is a key pathogenic mechanism of CVD. The retinal microvascular network offers a unique, non-invasive window to study endothelial function. Recently, dynamic measurement of retinal vessel caliber using flicker light stimulation has been used to evaluate potential endothelial dysfunction and other mechanisms in CVD. A variety of studies now indicate that retinal vasodilation during flicker light simulation is reduced in diabetes, hypertension, hyperlipidemia and obesity, and may be influenced by age and race/ethnicity. These data suggest that flicker light-induced retinal vasodilation may be a unique and non-invasive measure of endothelial dysfunction. This review focuses recent studies on systemic associations of flicker light-induced retinal vasodilation, and discusses the potential for future research in this area.

Retinal vascular calibers associate differentially with cerebral gray matter and white matter atrophy.

Cerebral small-vessel disease is thought to contribute to brain atrophy, but it remains unclear whether it affects the gray matter and white matter atrophy differentially. Retinal vessels provide a direct measure to study cerebral small-vessel disease in vivo. In a cohort of 1065 persons (mean age, 67.5 y and 51% women), from the population-based Rotterdam Study, we investigated how retinal vascular calibers relate to brain atrophy and to gray matter and white matter atrophy separately. Retinal arteriolar and venular calibers were semiautomatically measured on digitized fundus transparencies. Using automated quantification of MRI scans, we obtained whole-brain volume and volumes of gray matter and white matter. Both narrower arteriolar and wider venular calibers were associated with smaller brain volume, independent from each other. These associations were primarily driven by smaller white matter volume, whereas no associations were seen for gray matter volume. Adjustments for cardiovascular risk factors attenuated the results, but wider venular caliber remained borderline significantly associated with smaller white matter volume. Our data provide evidence that cerebral small-vessel disease contributes to brain atrophy primarily by affecting the cerebral white matter.

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

Prevalence of Cognitive Impairment and Dementia in Malays - Epidemiology of Dementia in Singapore Study.

OBJECTIVE: To study the prevalence of cognitive impairment and dementia in communitydwelling Malays from Singapore; and to examine differences in prevalence among Chinese and Malays. METHODS: Subjects (≥ 60 years) - drawn from the Malay component of the on-going multiethnic Epidemiology of Dementia in Singapore study - were screened using locally validated Abbreviated Mental Test and Progressive Forgetfulness Questionnaire. Subsequently, screen-positive participants underwent detailed neuropsychological assessments and neuroimaging. Cognitive impairment no dementia (CIND) and dementia were diagnosed based on accepted criteria. RESULTS: A total of 966 Malay subjects were included, of whom 102 had CIND-mild, 135 CINDmoderate, and 27 dementia. The overall age-standardized prevalence of any cognitive impairment was 25.5%, including 2% of dementia. The prevalence of any cognitive impairment increased with age from 14·9% in those aged 60-64 years to 40.2% in age ≥80 years. Women had a higher prevalence of CIND and dementia than men. Compared to previously published data from EDIS on Chinese, Malay were nearly twice more likely to have any cognitive impairment (Odds ratios adjusted for age, demographic and cardiovascular risk factors, and ApoEε4 carrier: 2.03, 95% confidence interval: 1.48-2.77). CONCLUSION: Among elderly Malays, the overall prevalence of any cognitive impairment was 25.5%. Even with a similar protocol of recruitment and assessment and adjusting for known risk factors, the prevalence of cognitive impairment was higher in Malays compared to Chinese. Further research is needed to unravel other factors that may underlie these ethnic differences in the occurrence of cognitive impairment.

Impact of birth parameters and early life growth patterns on retinal microvascular structure in children: The Generation R Study.

OBJECTIVE: The aim of the study was to examine the associations of birth outcomes and longitudinally measured fetal and infant growth patterns with retinal vessel calibers in childhood. METHODS: In a population-based prospective cohort study among 4122 children, we measured growth characteristics in second and third trimester of pregnancy, at birth, and at 6, 12, 24, 36, 48, and 72 months. At the age of 6 years, we measured retinal arteriolar and venular calibers from digitized retinal photographs. RESULTS: We observed that compared with term-born children, those born preterm had narrower retinal arteriolar caliber [differences -0.46 standard deviation score (95% confidence interval -0.77 to -0.15) and -0.24 standard deviation score (95% confidence interval -0.42 to -0.05) for children born <34 and 34-37 weeks of gestation, respectively]. Children born with a low birth weight (<2500  g) had narrower retinal arteriolar caliber than children with a normal birth weight, but this association was fully explained by gestational age at birth. Accelerated infant growth until 24 months was associated with narrow retinal arteriolar caliber, especially among preterm-born children (P < 0.05). Early growth measures were not associated with retinal venular caliber. CONCLUSION: Preterm birth and accelerated infant growth are associated with narrower retinal arteriolar caliber in childhood. Whether these microvascular adaptations explain the well known associations of fetal and infant characteristics with cardiovascular disease in later life should be further studied.