Yi Ting Ong

Microvascular network alterations in the retina of patients with Alzheimer's disease

Although cerebral small‐vessel disease has been implicated in the development of Alzheimers disease (AD), the cerebral microcirculation is difficult to visualize directly in vivo. Because the retina provides a noninvasive window to assess the microcirculation, we determined whether quantitatively measured retinal microvascular parameters are associated with AD.

Retinal ganglion cell analysis using high-definition optical coherence tomography in patients with mild cognitive impairment and Alzheimer's disease.

BACKGROUNDnAlzheimers disease (AD) is a neurodegenerative disorder with emerging evidence that it is associated with retinal ganglion cell loss; however, few data exist to establish this association.nnnOBJECTIVEnTo determine whether macular ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL), as quantitatively measured by non-invasive in vivo spectral-domain optical coherence tomography (SD-OCT), are altered in patients with AD and mild cognitive impairment (MCI).nnnMETHODSnPatients with AD and MCI were recruited from dementia/memory clinics, and cognitively normal controls were selected from the Singapore Epidemiology of Eye Disease program. SD-OCT (Cirrus HD-OCT, software version 6.0.2, Carl Zeiss Meditec Inc, Dublin, CA) was used to measure the GC-IPL and RNFL thicknesses.nnnRESULTSnCompared with cognitively normal controls (n = 123), patients with AD (n = 100) had significantly reduced GC-IPL thicknesses in all six (superior, superonasal, inferonasal, inferior, inferotemporal, and superotemporal) sectors (mean differences from -3.42 to -4.99 μm, all p < 0.05) and reduced RNFL thickness in superior quadrant (-6.04 μm, p = 0.039). Patients with MCI (n = 41) also had significantly reduced GC-IPL thicknesses compared with controls (mean differences from -3.62 to -5.83 μm, all p < 0.05). Area under receiver operating characteristic curves of GC-IPL were generally higher than that of RNFL to discriminate AD and MCI from the controls.nnnCONCLUSIONSnOur data strengthens the link between retinal ganglion cell neuronal and optic nerve axonal loss with AD, and suggest that assessment of macular GC-IPL can be a test to detect neuronal injury in early AD and MCI.

Retinal Microvascular Changes and Risk of Stroke The Singapore Malay Eye Study

Background and Purpose— To examine the relationship between retinal microvascular measures and incident stroke in an Asian Malay population. Methods— We conducted a prospective, population-based cohort study of Asian Malay persons 40 to 80 years at baseline. Retinal microvascular signs were assessed from baseline retinal photographs including quantitative retinal microvascular parameters (caliber, branching angle, tortuosity, and fractal dimension) and qualitative retinopathy signs. Incident stroke cases were identified during the follow-up period. Cox proportional-hazards regression and incremental usefulness analysis (calibration, discrimination, and reclassification) were performed. Results— A total of 3189 participants were free of prevalent stroke at baseline. During the follow-up (median, 4.41 years), 51 (1.93%) participants had an incident stroke event. In Cox proportional-hazards models adjusting for established stroke predictors (age, sex, systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, smoking, glycosylated hemoglobin, and antihypertensive medication), retinopathy (hazard ratio, 1.94; 95% confidence interval, 1.01–3.72) and larger retinal venular caliber (hazard ratio, 3.28; 95% confidence interval, 1.30–8.26, comparing fourth versus first quartiles) were associated with risk of stroke. Compared with the model with only established risk factors, the addition of retinal measures improved the prediction of stroke (C-Statistic 0.826 versus 0.792; P=0.017) and correctly reclassified 5.9% of participants with incident stroke and 3.4% of participants with no incident stroke. Conclusions— Retinal microvascular changes are related to an increased risk of stroke in Asian Malay, consistent with data from white populations. Retinal imaging improves the discrimination and stratification of stroke risk beyond that of established risk factors by a significant but small margin.

Retinal vascular fractal dimension is associated with cognitive dysfunction.

Fractal analysis is a method used to quantify the geometric branching complexity and density of retinal vessels. This study examined the relationship of retinal vascular fractal dimension and other retinal vascular parameters with cognitive dysfunction in an older Asian population. Subjects aged 60 years and older from the Singapore Malay Eye Study were selected for analysis. Retinal vascular fractal dimension (Df) and other quantitative retinal vascular parameters (branching angle, tortuosity, and caliber) were measured based on a standardized grading protocol from photographs of the retinal fundus using a computer-assisted program. Qualitative retinal signs were also assessed from photographs. Cognitive dysfunction was defined as a locally validated Abbreviated Mental Test (AMT) score ≤6/10 in participants with 0-6 years of formal education and an AMT score ≤8/10 in those with more than 6 years of formal education. Cognitive dysfunction was identified in 262 of the 1202 participants (21.8%). Decreased retinal vascular Df was significantly associated with lower AMT score (P = .019). In multivariate logistic regression analysis, participants with lower retinal vascular Df values were more likely to have cognitive dysfunction (odds ratio, 1.71; 95% confidence interval, 1.03-2.82, comparing the lowest and highest Df quintiles). In subgroup analysis stratified for cardiovascular risk factors, this association was present in participants with hypertension and current smokers. Other retinal vascular signs were not associated with cognitive dysfunction. Decreased retinal vascular Df is associated with cognitive dysfunction in older persons. Rarefaction of the retinal vasculature may reflect similar changes in the cerebral microvasculature that may contribute to cognitive deterioration.

Hypertensive Retinopathy and Risk of Stroke

Although assessment of hypertensive retinopathy signs has been recommended for determining end-organ damage and stratifying vascular risk in persons with hypertension, its value remains unclear. In this study, we examine whether hypertensive retinopathy predicts the long-term risk of stroke in those with hypertension. A total of 2907 participants with hypertension aged 50 to 73 years at the 1993 to 1995 examination, who had gradable retinal photographs, no history of diabetes mellitus, stroke, and coronary heart disease at baseline and data on incident stroke, were included from the Atherosclerosis Risk in Communities (ARIC) Study. Retinal photographs were assessed for hypertensive retinopathy signs and classified as none, mild, and moderate/severe. Incident events of any stroke, cerebral infarction, and hemorrhagic stroke were identified and validated. After a mean follow-up period of 13.0 years, 165 persons developed incident stroke (146 cerebral infarctions and 15 hemorrhagic strokes). After adjusting for age, sex, blood pressure, and other risk factors, persons with moderate hypertensive retinopathy were more likely to have stroke (moderate versus no retinopathy: multivariable hazard ratios, 2.37 [95% confidence interval, 1.39–4.02]). In participants with hypertension on medication with good control of blood pressure, hypertensive retinopathy was related to an increased risk of cerebral infarction (mild retinopathy: hazard ratio, 1.96 [95% confidence interval, 1.09–3.55]; and moderate retinopathy: hazard ratio, 2.98 [95% confidence interval, 1.01–8.83]). Hypertensive retinopathy predicts the long-term risk of stroke, independent of blood pressure, even in treated patients with hypertension with good hypertension control. Retinal photographic assessment of hypertensive retinopathy signs may be useful for assessment of stroke risk.

Retinal imaging: a first report of the retinal microvasculature in acute mild traumatic brain injury.

Mild traumatic brain injury (mTBI) accounts for 90% of all brain trauma. As only 15% of mTBI patients will have an identifiable intracranial lesion on brain computed tomography 1, injury is often considered as ‘insignificant’ when compared with the devastating and highly visible sequelae that follows severe TBI. Nevertheless, the lingering postconcussive symptoms (PCS) reported by patients after TBI are now well recognized and particularly so in returning Operation Iraqi and Operation Enduring Freedom veterans 2. However, how can the risk of PCS be assessed in the absence of a diagnostic test? Of relevance here, and in the context of a potential candidate clinical ‘biomarker’, is the relationship already described between retinal microvascular signs (e.g. retinopathy, retinal venular widening, increased arteriolar and venular tortuosity) and brain damage because of cerebral ischaemia after stroke 3 and cardiovascular disease 4. To our knowledge, no study has explored the potential utility of retinal microvascular signs using retinal photography after mTBI. Here, we describe the results of a ‘first of kind’ pilot clinical investigation. n nAfter obtaining ethics institutional review board approval, patients between the ages of 21 and 70 years (Glasgow Coma Scale 13–15) presenting with two or more PCS and warranting overnight hospital observation were eligible. Uncooperative or confused patients and those with pre-existing comorbidity known to incur pathological changes in cerebral vessels were excluded. Optic disc-centred and macula-centred retinal fundus images were taken from each eye using a nonmydriatic digital camera (Canon CR-DGi with a 20D SLR back; Canon, Tokyo, Japan) after pupil dilatation with 1% tropicamide eye drops (Mydriacyl; Alcon Pte Ltd., Singapore) following a standard protocol. A trained grader, masked to the participants’ characteristics, performed the grading on the retinal images at the Singapore Eye Research Institute (SERI) Image Reading Centre. Quantitative assessment of the retinal microvascular network and retinal vascular parameters (vessel calibre, fractal dimensions, tortuosity and bifurcation) were measured using a semiautomated computer-based program (Singapore I Vessel Assessment) 5. All mTBI patients recruited into the study were invited to return to the emergency department (ED) for repeat retinal photography at the 6-month time-point after recruitment. n nOver 5 months, 43 patients who presented to the ED with mTBI were screened for study inclusion. The majority had one or more comorbidities or had one PCS only and therefore did not fulfil the eligibility criteria. Of the eligible patients (within age range, no pre-existing comorbidity, n=9), only four adult men (Indian, Chinese, Malay race) aged 21–44 (median 24.5) years provided their consent for retinal photography on admission to the ED and at follow-up and the bimonthly telephone assessment. To appreciate the appearance and values for retinal vascular parameters (retinal signs) of mTBI patients, data from an existing healthy control group, and age-matched, sex-matched and race-matched to the patients, were compared. We found that arteriolar and venular tortuosity was significantly increased after mTBI (Table u200b(Table1).1). These findings remained consistent after additional adjustment for age in an analysis of covariance model. For the remaining retinal vascular parameters investigated (calibre, fractal dimensions and branching angle, Table u200bTable1),1), no significant differences were observed between mTBI patients and the matched controls. None of the recruited patients had signs of retinopathy. Only one patient attended for follow-up retinal images at the 6-month time-point. Here, a slight reduction in retinal vascular calibre for both eyes (right eye 217u2009μm at baseline vs. 211u2009μm at the 6-month follow-up; and left eye 225 vs. 219u2009μm) was noted, but other vascular parameters remained unchanged. By superimposing the baseline and 6-month retinal images, no differences in network density and vessel trajectories were noted. n n n nTable 1 n nComparison of retinal vascular parameters: for patients with mTBI and age group–sex–race-matched controls

HIGH-DEFINITION OPTICAL COHERENCE TOMOGRAPHY AND MRI-DEFINED NEUROIMAGING MARKERS IN AN ASIAN POPULATION

DSM-IV symptoms for major depressive disorder in the past 2 weeks. GEE models were used to assess the association between baseline hippocampal volume relative to intracranial volume with depressive symptoms at multiple time points during follow-up. An interaction term between hippocampal volume and time as dummy variable for each time point was included to examine the temporal relatio nship. Results: The overall response on the repeated PHQ-9 assessments varied between 86% and 97%. Median (10 th -90 th percentile) score on the PHQ-9 was 3 (0-8). Mean (SD) total hippocampus volumewas 5.96 (0.68) mL.We found a significant interaction between baseline hippocampal volume and time (p-value interaction 1⁄4 0.044) indicating that the temporal course of depressive symptoms differed over time according baseline to hippocampal volume. Visualizing the temporal course of depressive symptoms showed that patients with relatively small hippocampal volume (lowest quartile) had a more fluctuating course of depressive symptoms compared to patients with relatively large hippocampal volume (upper three quartiles) (Figure 1).Conclusions: Smaller hippocampal volume was associated with a higher level and more fluctuating course of depressive symptoms over 7 years of follow-up. The finding that the depressive symptoms were not stable but fluctuated over time, emphasized the importance of repeated measurements of depressive symptoms during follow-up.

403 RETINAL MICROVASCULAR GEOMETRIC PARAMETERS AND COGNITIVE IMPAIRMENT

Background: Although midlife hypertension may be related to the development of dementia in late life, there are conflicting findings about the role of late-life hypertension. Novel retinal imaging allows non-invasive assessment of retinal microvascular geometry that may reflect small vessel damage from hypertension. We examined these geometric parameters in relation to cognitive impairment. Methods: This study is part of the Singapore Chinese Eye Study (40–80 years). Subjects aged 60 years and over were invited to undergo clinical assessments, neuropsychological testing and brain magnetic resonance imaging. Novel retinal microvascular geometry parameters include both focal (tortuosity, branching angle, and caliber) and global (fractal dimension) features. Cognitive function was categorized into no cognitive impairment (NCI), mild cognitive impairment no dementia (mild-CIND), moderate-CIND and dementia (moderate-CIND and dementia combined into one group for analysis) using previously validated criteria. Logistic regression models were used adjusting for age and gender, and additionally for education level, hypertension, diabetes mellitus and hyperlipidemia. Results: We included 216 participants (mean age: 70.5 years); 74 persons had CIND-mild, 55 CIND-moderate and 6 dementia. Smaller retinal arteriolar and venular fractal dimension was associated with both mild-CIND (odds ratio (OR) per standard deviation decrease: 1.50; 95% CI: 1.02–2.09) and moderate-CIND/dementia (OR: 1.71; 95% CI: 1.15–2.54). Other retinal microvascular geometry parameters were not related to cognitive impairment. Adjustments for other factors did not alter these results. Conclusions: Persons with smaller retinal fractal dimension were more likely to have cognitive impairment. This association may reflect sparser cerebral vascular network in persons with cognitive impairment.