Age-Related Macular Degeneration and Incident Stroke: A Systematic Review and Meta-Analysis

Background

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in people over 65 years old in the United States and has been associated with cardiovascular risk and decreased survival. There is conflicting data, however, regarding the contribution of AMD to the prediction of stroke.

Aim

To determine whether AMD is a risk indicator for incident stroke in a meta-analysis of available prospective and retrospective cohort studies published in the English literature.

Methods

We performed a systematic literature search of all studies published in English with Pub Med and other databases from 1966 to August 2014, reporting stroke incidence in patients with macular degeneration. Two investigators independently extracted the data. A random effects model was used to report Odds ratios (OR), with corresponding 95% confidence intervals (CI). Meta-regression using a mixed linear model was used to understand potential heterogeneity amongst studies.

Results

We identified 9 studies that reported stroke incidence in patients with and without early AMD (N = 1,420,978). No significant association was found between early AMD with incident stroke. Combined, these 9 studies demonstrated random effects (OR, 1.12; CI, 0.86–1.47; I² = 96%). Meta-regression on baseline covariates of age, sex, and year of publication did not significantly relate to heterogeneity.

Conclusions

We found no significant relationship between AMD and incident stroke. Further studies are needed to clarify other causes of decreased survival in patients with AMD.     

Prevalence and Genetic Characteristics of Geographic Atrophy among Elderly Japanese with Age-Related Macular Degeneration

Objective

To investigate the prevalence and genetic characteristics of geographic atrophy (GA) among elderly Japanese with advanced age-related macular degeneration (AMD) in a clinic-based study.

Methods

Two-hundred and ninety consecutive patients with advanced AMD were classified into typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP) or geographic atrophy (GA). Genetic variants of ARMS2 A69S (rs10490924) and CFH I62V (rs800292) were genotyped using TaqMan Genotyping Assays. The clinical and genetic characteristics were compared between patients with and without GA.

Results

The number of patients diagnosed as having typical neovascular AMD, PCV, RAP and GA were 98 (33.8%), 151 (52.1%), 22 (7.5%) and 19 (6.6%), respectively. Of 19 patients with GA, 13 patients (68.4%) had unilateral GA with exudative AMD in the contralateral eye. Patients with GA were significantly older, with a higher prevalence of reticular pseudodrusen, bilateral involvement of advanced AMD and T-allele frequency of ARMS2 A69S compared with those with typical AMD and PCV; although there were no differences in the genetic and clinical characteristics among patients with GA and RAP.

Conclusions

The prevalence of GA was 6.6% among elderly Japanese with AMD. Patients with GA and RAP exhibited genetic and clinical similarities.     

Comparison of Outcomes and Costs of Ranibizumab and Aflibercept Treatment in Real-Life

Background

Treatment efficacy and costs of anti-VEGF drugs have not been studied in clinical routine.

Objective

To compare treatment costs and clinical outcomes of the medications when adjusting for patients’ characteristics and clinical status.

Design

Comparative study.

Setting

The largest public ophthalmologic clinic in Switzerland.

Patients

Health care claims data of patients with age-related macular degeneration, diabetic macula edema and retinal vein occlusion were matched to clinical and outcome data.

Measurements

Patients’ underlying condition, gender, age, visual acuity and retinal thickness at baseline and after completing the loading phase, the total number of injections per treatment, the visual outcome and vital status was secured.

Results

We included 315 patients (19595 claims) with a follow-up time of 1 to 99 months (mean 32.7, SD 25.8) covering the years 2006–2014. Mean age was 78 years (SD 9.3) and 200 (63.5%) were female. At baseline, the mean number of letters was 55.6 (SD 16.3) and the central retinal thickness was 400.1 μm (SD 110.1). Patients received a mean number of 15.1 injections (SD 13.7; range 1 to 85). Compared to AMD, adjusted cost per month were significantly higher (+2174.88 CHF, 95%CI: 1094.50–3255.27; p<0.001) for patients with DME, while cost per month for RVO were slightly but not significantly higher. (+284.71 CHF, 95% CI: -866.73–1436.15; p = 0.627).

Conclusions

Patients with DME are almost twice as expensive as AMD and RVO patients. Cost excess occurs with non-ophthalmologic interventions. The currently licensed anti-VEGF medications did not differ in costs, injection frequency and clinical outcomes. Linking health care claims to clinical data is a useful tool to examine routine clinical care.     

Unilateral and Bilateral Cortical Resection: Effects on Spike-Wave Discharges in a Genetic Absence Epilepsy Model

Research Question

Recent discoveries have challenged the traditional view that the thalamus is the primary source driving spike-and-wave discharges (SWDs). At odds, SWDs in genetic absence models have a cortical focal origin in the deep layers of the perioral region of the somatosensory cortex. The present study examines the effect of unilateral and bilateral surgical resection of the assumed focal cortical region on the occurrence of SWDs in anesthetized WAG/Rij rats, a well described and validated genetic absence model.

Methods

Male WAG/Rij rats were used: 9 in the resected and 6 in the control group. EEG recordings were made before and after craniectomy, after unilateral and after bilateral removal of the focal region.

Results

SWDs decreased after unilateral cortical resection, while SWDs were no longer noticed after bilateral resection. This was also the case when the resected areas were restricted to layers I-IV with layers V and VI intact.

Conclusions

These results suggest that SWDs are completely abolished after bilateral removal of the focal region, most likely by interference with an intracortical columnar circuit. The evidence suggests that absence epilepsy is a network type of epilepsy since interference with only the local cortical network abolishes all seizures.     

Reduced Responsiveness to Long-Term Monocular Deprivation of Parvalbumin Neurons Assessed by c-Fos Staining in Rat Visual Cortex

Background

It is generally assumed that visual cortical cells homogeneously shift their ocular dominance (OD) in response to monocular deprivation (MD), however little experimental evidence directly supports this notion. By using immunohistochemistry for the activity-dependent markers c-Fos and Arc, coupled with staining for markers of inhibitory cortical sub-populations, we studied whether long-term MD initiated at P21 differentially affects visual response of inhibitory neurons in rat binocular primary visual cortex.

Methodology/Principal Findings

The inhibitory markers GAD67, parvalbumin (PV), calbindin (CB) and calretinin (CR) were used. Visually activated Arc did not colocalize with PV and was discarded from further studies. MD decreased visually induced c-Fos activation in GAD67 and CR positive neurons. The CB population responded to MD with a decrease of CB expression, while PV cells did not show any effect of MD on c-Fos expression. The persistence of c-Fos expression induced by deprived eye stimulation in PV cells is not likely to be due to a particularly low threshold for activity-dependent c-Fos induction. Indeed, c-Fos induction by increasing concentrations of the GABAA antagonist picrotoxin in visual cortical slices was similar between PV cells and the other cortical neurons.

Conclusion

These data indicate that PV cells are particularly refractory to MD, suggesting that different cortical subpopulation may show different response to MD.     

Dynamic Drusen Remodelling in Participants of the Nutritional AMD Treatment-2 (NAT-2) Randomized Trial

Purpose

To evaluate the dynamic remodeling of drusen in subjects with unilateral neovascular age-related macular degeneration (AMD) receiving a three-year course of oral docosahexaenoic acid (DHA) or placebo.

Setting

Institutional setting.

Methods

Three hundred subjects with age-related maculopathy and neovascular AMD in the fellow eye were randomly assigned to receive either 840 mg/day DHA or placebo for 3 years. Main outcome measures of this post-hoc sub-group analysis were progression of drusen number, total diameter, and total area on fundus photography, and their association with DHA supplementation, socio-demographic and genetic characteristics.

Results

Drusen progression was analyzed in 167 subjects that did not develop CNV (87 that received DHA and 80 that received placebo). None of the drusen remodeling outcomes were significantly associated with DHA supplementation. Total drusen diameter reduction in the inner subfield was significantly associated with age (older patients: r = -0.17; p = 0.003). Women showed a tendency to decreased total drusen diameter in the inner subfield with CFH polymorphism (p = 0.03), where women with TT genotype tended to have a greater reduction in drusen diameter than other genotypes (CC and CT). Drusen area in the inner subfield was more reduced in older patients (r = -0.17) and in women (p = 0.01). Drusen number showed no significant trends.

Conclusions

Dynamic drusen remodeling with net reduction in drusen load over three years was found in patients with exudative AMD in one eye and drusen in the other eye (study-eye). This reduction was correlated with increased age and female gender, and showed a tendency to be influenced by CFH genotype, but did not appear to be affected by DHA supplementation.

Trial Registration

Controlled-Trials.com ISRCTN98246501     

Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment,Depression and Daytime Sleepiness

Objectives

Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM).

Methods

12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects.

Results

Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected.Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex.

Conclusion

GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment, depression and daytime sleepiness, partly indicating involvement of complex neuronal networks.     

Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration: A Meta-Analysis

Importance

The fellow eye of patients with unilateral neovascular age-related degeneration (nAMD) is at increased risk of developing late AMD. Several cohort studies have evaluated the prevalence of pseudodrusen and the association between pseudodrusen and late AMD in the fellow eye of patients with unilateral nAMD. However, these studies have limited sample sizes and their results are inconsistent.

Objective

To evaluate the prevalence rate of pseudodrusen, and the association between pseudodrusen and incidence of late AMD (nAMD and geographic atrophy (GA)) in the fellow eye of patients with unilateral nAMD.

Data Sources

The PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched up to July 2015, as well as other systematic reviews.

Study Selection

All cohort studies for pseudodrusen with late AMD in the fellow eye of patients with unilateral nAMD.

Data Extraction and Synthesis

The numbers of patients with and without pseudodrusen at baseline and the numbers of incident nAMD and GA during follow up among patients with and without pseudodrusen were independently extracted by 2 authors. The results were pooled using random-effects meta-analysis. Heterogeneity was assessed using the I² test.

Main Outcome Measures

Prevalence rate of pseudodrusen, risk ratios (RRs) and their 95% confidence intervals (95% CIs) for associations between pseudodrusen and the incidence of nAMD and GA in the fellow eye.

Results

Five cohort studies (N = 677 patients) from 8 countries across 4 continents were included. The pooled prevalence rate of pseudodrusen in the fellow eye was 48.1% (95% Cl: 36.7–59.5%, I² = 87%). Pseudodrusen were associated with an increased risk of nAMD (RR = 1.54, 95% Cl: 1.10–2.16, I² = 42%), GA (RR = 4.70, 95% Cl: 1.22–18.1, I² = 64%), and late AMD (RR = 2.03, 95% Cl: 1.35–3.06, I² = 60%).

Conclusions

For patients with unilateral nAMD, pseudodrusen were present in about half of the fellow eyes. The presence of pseudodrusen was associated with a 1.5 times higher risk of developing nAMD, a 4.7 times higher risk of developing GA, and a 2 times higher risk of developing late AMD. Pseudodrusen should be considered in evaluating the risk of late AMD development; however, due to considerable heterogeneity across these studies, a larger study is needed to validate these findings.     

Association between Neovascular Age-Related Macular Degeneration and Dementia: A Population-Based Case-Control Study in Taiwan

Background

Most available studies focusing on the association between neovascular age-related macular degeneration (AMD) and dementia have conflicting results. This study aimed to investigate the association between previously diagnosed AMD and dementia using a population-based dataset in Taiwan.

Methods

Data for this case-control study were retrospectively collected from the Taiwan National Health Insurance Research Database. We identified 13,402 subjects who had a diagnosis of dementia as cases, and 40,206 subjects without dementia as controls. A conditional logistic regression was used to examine the association of dementia with previously diagnosed neovascular AMD.

Results

We found that of the study sample of 53,608 subjects, 1.01% had previously diagnosed neovascular AMD, 1.35% and 0.90% for cases and the controls, respectively (p<0.001). The conditional logistic regression analysis suggested that the odds ratio of prior neovascular AMD for cases was 1.37 (95% confidence interval: 1.14~1.65) compared to the controls after adjusting for subjects’ age, monthly income, geographic location, urbanization level, and hyperlipidemia, diabetes, hypertension, stroke, ischemic heart disease, and whether or not a subjects underwent cataract surgery prior to index date than controls.

Conclusions

Dementia subjects were associated with a higher proportion of prior neovascular AMD than were the controls.     

Network Centrality of Resting-State fMRI in Primary Angle-Closure Glaucoma Before and After Surgery

Purpose

Using voxel-wise degree centrality (DC), as measured by resting-state fMRI, we aimed to study alterations in the brain functional networks in patients with primary angle-closure glaucoma (PACG) and to reveal the plastic trajectories of surgery.

Methods

A total of 23 preoperative PACG patients (49.48 ± 14.37 years old) were recruited to undergo a resting-state fMRI scan, and 9 of them were rescanned 3 months after surgery. All PACG patients underwent a complete ophthalmologic examination, including intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness, vertical cup to disc ratio (V C/D), and average cup to disc ratio (A C/D). Another 23 gender- and age-matched healthy controls (48.18 ± 9.40 years old) underwent scanning once for comparison. The group difference in DC was calculated in each voxel, and the correlations between the DC value and each of the clinical variables were analyzed in the PACG patients.

Results

Preoperative PACG (pre-PACG) patients showed significantly decreased DC in the bilateral visual cortices but increased DC in the left anterior cingulate cortex (ACC) and caudate (p < 0.05, corrected) compared with the controls. Statistical analysis showed a significantly negative correlation between DC in the bilateral visual cortices and the IOP score and between DC in the anterior cingulate cortex (ACC) and both the A C/D and V C/D scores in the pre-PACG patients. Three months after surgery, these postoperative PACG (post-PACG) patients showed a significantly increased DC in both the bilateral visual cortices and the left precentral gyrus compared with the pre-PACG patients.

Conclusions

Our results suggest that PACG may contribute to decreased functional centrality in the visual system and to increased degree centrality in cognition-emotional processing regions. Alterations in visual areas seem to parallel the cup to disc ratio, but not the duration of angle closure. The changes of functional centrality in PACG patients after operation may reveal the plasticity or degeneration of the visual-associated brain areas. Our findings may provide further understanding of the pathophysiology of PACG.     

Acute Zonal Occult Outer Retinopathy in Japanese Patients: Clinical Features,Visual Function,and Factors Affecting Visual Function

Purpose

To evaluate the clinical features and investigate their relationship with visual function in Japanese patients with acute zonal occult outer retinopathy (AZOOR).

Methods

Fifty-two eyes of 38 Japanese AZOOR patients (31 female and 7 male patients; mean age at first visit, 35.0 years; median follow-up duration, 31 months) were retrospectively collected: 31 untreated eyes with good visual acuity and 21 systemic corticosteroid-treated eyes with progressive visual acuity loss. Variables affecting the logMAR values of best-corrected visual acuity (BCVA) and the mean deviation (MD) on Humphrey perimetry at initial and final visits were examined using multiple stepwise linear regression analysis.

Results

In untreated eyes, the mean MD at the final visit was significantly higher than that at the initial visit (P = 0.00002). In corticosteroid-treated eyes, the logMAR BCVA and MD at the final visit were significantly better than the initial values (P = 0.007 and P = 0.02, respectively). The final logMAR BCVA was 0.0 or less in 85% of patients. Variables affecting initial visual function were moderate anterior vitreous cells, myopia severity, and a-wave amplitudes on electroretinography; factors affecting final visual function were the initial MD values, female sex, moderate anterior vitreous cells, and retinal atrophy.

Conclusions

Our data indicated that visual functions in enrolled patients significantly improved spontaneously or after systemic corticosteroids therapy, suggesting that Japanese patients with AZOOR have good visual outcomes during the follow-up period of this study. Furthermore, initial visual field defects, gender, anterior vitreous cells, and retinal atrophy affected final visual functions in these patients.     

Proteomics of Vitreous Humor of Patients with Exudative Age-Related Macular Degeneration

Background

There is absence of specific biomarkers and an incomplete understanding of the pathophysiology of exudative age-related macular degeneration (AMD).

Methods and Findings

Eighty-eight vitreous samples (73 from patients with treatment naïve AMD and 15 control samples from patients with idiopathic floaters) were analyzed with capillary electrophoresis coupled to mass spectrometry in this retrospective case series to define potential candidate protein markers of AMD. Nineteen proteins were found to be upregulated in vitreous of AMD patients. Most of the proteins were plasma derived and involved in biological (ion) transport, acute phase inflammatory reaction, and blood coagulation. A number of proteins have not been previously associated to AMD including alpha-1-antitrypsin, fibrinogen alpha chain and prostaglandin H2-D isomerase. Alpha-1-antitrypsin was validated in vitreous of an independent set of AMD patients using Western blot analysis. Further systems biology analysis of the data indicated that the observed proteomic changes may reflect upregulation of immune response and complement activity.

Conclusions

Proteome analysis of vitreous samples from patients with AMD, which underwent an intravitreal combination therapy including a core vitrectomy, steroids and bevacizumab, revealed apparent AMD-specific proteomic changes. The identified AMD-associated proteins provide some insight into the pathophysiological changes associated with AMD.     

Decision-Making in Patients with Hyperthyroidism: A Neuropsychological Study

Introduction

Cognitive and behavioral impairments are common in patients with abnormal thyroid function; these impairments cause a reduction in their quality of life. The current study investigates the decision making performance in patients with hyperthyroidism to explore the possible mechanism of their cognitive and behavioral impairments.

Methods

Thirty-eight patients with hyperthyroidism and forty healthy control subjects were recruited to perform the Iowa Gambling Task (IGT), which assessed decision making under ambiguous conditions.

Results

Patients with hyperthyroidism had a higher score on the Zung Self-Rating Anxiety Scale (Z-SAS), and exhibited poorer executive function and IGT performance than did healthy control subjects. The patients preferred to choose decks with a high immediate reward, despite a higher future punishment, and were not capable of effectively using feedback information from previous choices. No clinical characteristics were associated with the total net score of the IGT in the current study.

Conclusions

Patients with hyperthyroidism had decision-making impairment under ambiguous conditions. The deficits may result from frontal cortex and limbic system metabolic disorders and dopamine dysfunction.     

Cortical Thickness in Dementia with Lewy Bodies and Alzheimer's Disease: A Comparison of Prodromal and Dementia Stages

Objectives

To assess and compare cortical thickness (CTh) of patients with prodromal Dementia with Lewy bodies (pro-DLB), prodromal Alzheimer''s disease (pro-AD), DLB dementia (DLB-d), AD dementia (AD-d) and normal ageing.

Methods

Study participants(28 pro-DLB, 27 pro-AD, 31 DLB-d, 54 AD-d and 33 elderly controls) underwent 3Tesla T1 3D MRI and detailed clinical and cognitive assessments. We used FreeSurfer analysis package to measure CTh and investigate patterns of cortical thinning across groups.

Results

Comparison of CTh between pro-DLB and pro-AD (p<0.05, FDR corrected) showed more right anterior insula thinning in pro-DLB, and more bilateral parietal lobe and left parahippocampal gyri thinning in pro-AD. Comparison of prodromal patients to healthy elderly controls showed the involvement of the same regions. In DLB-d (p<0.05, FDR corrected) cortical thinning was found predominantly in the right temporo-parietal junction, and insula, cingulate, orbitofrontal and lateral occipital cortices. In AD-d(p<0.05, FDR corrected),the most significant areas affected included the entorhinal cortices, parahippocampal gyri and parietal lobes. The comparison of AD-d and DLB-d demonstrated more CTh in AD-d in the left entorhinal cortex (p<0.05, FDR corrected).

Conclusion

Cortical thickness is a sensitive measure for characterising patterns of grey matter atrophy in early stages of DLB distinct from AD. Right anterior insula involvement may be a key region at the prodromal stage of DLB and needs further investigation.     

Association between Blood Lead Levels and Age-Related Macular Degeneration

Purpose

To investigate the association between blood lead levels and prevalence of age-related macular degeneration (AMD).

Methods

A nationwide population-based cross-sectional study included 4,933 subjects aged over 40 years who participated in the 2008–2012 Korean National Health and Nutrition Examination Survey, and for whom fundus photographs were available. All participants underwent a standardized interview, evaluation of blood lead concentration, and a comprehensive ophthalmic examination. Digital fundus photographs (45°) were taken of both eyes under physiological mydriasis. All fundus photographs were graded using an international classification and grading system.

Results

Mean blood lead levels were 3.15 μg/dL in men and 2.27 μg/dL in women (P < 0.001). After adjusting for potential confounders including age, gender, smoking status, total cholesterol levels, triglyceride levels, heart problems and strokes, the adjusted odds ratio (OR) in women for any AMD was 1.86 (95% Confidence Interval [CI], 1.03–3.36) and for early AMD was 1.92 (95% CI, 1.06–3.48), for those in the highest quintile of lead level compared with the lowest quintile. In men, however, blood lead level was not significantly associated with AMD.

Conclusions

Blood lead levels were higher in men, but were only associated with AMD in women. Increased levels of blood lead may be involved in the pathogenesis of AMD development in women.     

Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles: Potential Implications for Age-Related Macular Degeneration

Background

The human retinal pigment epithelium (RPE) plays an important role in the pathogenesis of age related macular degeneration (AMD). AMD is the leading cause of blindness worldwide. There is currently no effective treatment available. Preclinical studies in AMD mouse models are essential to develop new therapeutics. This requires further in-depth knowledge of the similarities and differences between mouse and human RPE.

Methods

We performed a microarray study to identify and functionally annotate RPE specific gene expression in mouse and human RPE. We used a meticulous method to determine C57BL/6J mouse RPE signature genes, correcting for possible RNA contamination from its adjacent layers: the choroid and the photoreceptors. We compared the signature genes, gene expression profiles and functional annotations of the mouse and human RPE.

Results

We defined sets of mouse (64), human (171) and mouse–human interspecies (22) RPE signature genes. Not unexpectedly, our gene expression analysis and comparative functional annotation suggested that, in general, the mouse and human RPE are very similar. For example, we found similarities for general features, like “organ development” and “disorders related to neurological tissue”. However, detailed analysis of the molecular pathways and networks associated with RPE functions, suggested also multiple species-specific differences, some of which may be relevant for the development of AMD. For example, CFHR1, most likely the main complement regulator in AMD pathogenesis was highly expressed in human RPE, but almost absent in mouse RPE. Furthermore, functions assigned to mouse and human RPE expression profiles indicate (patho-) biological differences related to AMD, such as oxidative stress, Bruch’s membrane, immune-regulation and outer blood retina barrier.

Conclusion

These differences may be important for the development of new therapeutic strategies and translational studies in age-related macular degeneration.     

Age and Vascular Burden Determinants of Cortical Hemodynamics Underlying Verbal Fluency

Background

Aging processes and several vascular burden factors have been shown to increase the risk of dementia including Alzheimer''s disease. While pathological alterations in dementia precede diagnosis by many years, reorganization of brain processing might temporarily delay cognitive decline. We hypothesized that in healthy elderly individuals both age-related neural and vascular factors known to be related to the development of dementia impact functional cortical hemodynamics during increased cognitive demands.

Methods

Vascular burden factors and cortical functional hemodynamics during verbal fluency were assessed in 1052 non-demented elderly individuals (51 to 83 years; cross-sectional data of the longitudinal TREND study) using functional near-infrared spectroscopy (fNIRS). The prediction of functional hemodynamic responses by age in multiple regressions and the impact of single and cumulative vascular burden factors including hypertension, diabetes, obesity, smoking and atherosclerosis were investigated.

Results

Replicating and extending previous findings we could show that increasing age predicted functional hemodynamics to be increased in right prefrontal and bilateral parietal cortex, and decreased in bilateral inferior frontal junction during phonological fluency. Cumulative vascular burden factors, with hypertension in particular, decreased left inferior frontal junction hemodynamic responses during phonological fluency. However, age and vascular burden factors showed no statistical interaction on functional hemodynamics.

Conclusion

Based on these findings, one might hypothesize that increased fronto-parietal processing may represent age-related compensatory reorganization during increased cognitive demands. Vascular burden factors, such as hypertension, may contribute to regional cerebral hypoperfusion. These neural and vascular hemodynamic determinants should be investigated longitudinally and combined with other markers to advance the prediction of future cognitive decline and dementia.     

Extensive White Matter Alterations and Its Correlations with Ataxia Severity in SCA 2 Patients

Background

Previous studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo.

Methods

Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA) and mean diffusivity (MD). Significant diffusion differences were correlated with the patient''s ataxia impairment.

Results

Our analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle.

Conclusion

Our findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2.     

Association of Htra1 gene polymorphisms with the risk of developing AMD in Iranian population

Background:

Half of the cases of vision loss in people under 60 years of age have been attributed to age-related macular degeneration (AMD). This is a multifactorial disease with late onset. It has been demonstrated that many different genetic loci are implicated in the risk of developing AMD in different populations. In the current study, we investigated the association of high-temperature ‎requirement A-1 (HTRA1) gene polymorphisms with the risk of developing AMD in the Iranian population.

Methods:

Genomic DNA samples were extracted from 120 patients with AMD and 120 healthy age- and sex-matched controls. A 385 base-pair fragment of the HTRA1 gene promoter region was amplified using the polymerase chain reaction (PCR) technique and sequenced. The frequencies of the alleles were calculated and statistical analysis was performed using SPSS software.

Results:

Our study demonstrated that the rate of polymorphisms rs11200638 -625 G>A and rs2672598 -487T>C were significantly greater in AMD patients than in healthy controls from the Iranian population.

Conclusions:

The results of our study indicate that HTRA1 gene promoter region polymorphisms are associated with the risk of developing AMD in the Iranian population.Key Words: HTRA1, Single Nucleotide Polymorphisms, Macular Degeneration, Iran     

Relationship between G1287A of the NET Gene Polymorphisms and Brain Volume in Major Depressive Disorder: A Voxel-Based MRI Study

Background

Earlier studies implicated norepinephrine transporter (NET) gene (SLC6A2) polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide SLC6A2 polymorphisms, G1287A in exon 9 and T-182C in the promoter region, were found to be associated with MDD in different populations. We investigated the relationship between the brain volume and these two polymorphisms of the SLC6A2 in MDD patients.

Methods

We obtained 3D high-resolution T1-weighted images of 30 first-episode MDD patients and 48 age- and sex-matched healthy subjects (HS). All were divided into 4 groups based on polymorphism of either the G1287A or the T-182C genotype. VBM analysis examined the effects of diagnosis, genotype, and genotype-diagnosis interactions.

Results

Diagnosis effects on the brain morphology were found in the left superior temporal cortex. No significant genotype effects were found in the T-182C and the G1287A. A significant genotype (G1287A)–diagnosis interaction was found in the left dorsolateral prefrontal cortex. No significant genotype (T-182C)–diagnosis interaction effects were observed in any brain region.

Conclusions

In MDD patients there seems to be a relationship between the volume of the dorsolateral prefrontal cortex and polymorphism of the SLC6A2 G1287A gene.