Pneumothorax with Bullous Lesions as a Late Complication of Covid-19 Pneumonia: A Report on Two Clinical Cases.

BACKGROUND: Coronavirus-19 disease (COVID-19) primarily affects the respiratory tract, causing viral pneumonia with fever, hypoxemia, and cough. Commonly observed complications include acute respiratory failure, liver or kidney injury, and cardiovascular or neurologic symptoms. In some patients, inflammatory damage results in long-term complications, such as pulmonary fibrosis, chronic pulmonary thrombotic microangiopathy, or neurologic symptoms. The development of spontaneous pneumothorax is reported as a rare complication mainly in consequence to mechanic ventilation in the criticall ill. CASE REPORT: We report 2 cases of patients with COVID-19 pneumonia complicated by spontaneous pneumothorax and bullous lesions of the lung. Bilateral giant bullae were observed in 1 of the cases. This complication occurred after an initial resolvement of respiratory symptoms (day 16 and day 29 after COVID-19 treatment was started). Initially, both patients had shown a rather mild course of COVID-19 pneumonia and no mechanical ventilatory support had been necessary. Why Should an Emergency Physician Be Aware of This?: In both cases, COVID-19 caused alveolar damage and the formation of thoracic bullae with consequent spontaneous pneumothorax as a serious complication. Emergency physicans must be aware of this complication even if the initial COVID-19 symptoms have resolved. © 2021 Elsevier Inc.

Ischemic stroke is associated with the ABO locus: the EuroCLOT study.

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

Subclinical hyperthyroidism is a risk factor for poor functional outcome after ischemic stroke.

BACKGROUND AND PURPOSE: Subclinical hyperthyroidism is associated with adverse cardiovascular events, including stroke and atrial fibrillation. However, its impact on functional outcome after stroke remains unexplored. METHODS: A total of 165 consecutively recruited patients admitted for ischemic stroke were included in this observational prospective study. Blood samples were taken in the morning within 3 days after symptom onset, and patients were divided into the following 3 groups: subclinical hyperthyroidism (0.1< thyroid-stimulating hormone ≤ 0.44 µU/mL), subclinical hypothyroidism (2.5 ≤ thyroid-stimulating hormone <20 µU/mL), and euthyroid state (0.44< thyroid-stimulating hormone <2.5 µU/mL). Patients with overt thyroid dysfunction were excluded. Follow-up took place 3 months after stroke. Primary outcome was functional disability (modified Rankin Scale), and secondary outcome was level of dependency (Barthel Index). Ordinal logistic regression analysis was used to adjust for possible confounders. Variables previously reported to be affected by thyroid function, such as atrial fibrillation, total cholesterol, or body mass index, were included in an additional model. RESULTS: Nineteen patients (11.5%) had subclinical hyperthyroidism, and 23 patients (13.9%) had subclinical hypothyroidism. Patients with subclinical hyperthyroidism had a substantially increased risk of functional disability 3 months after stroke compared with subjects with euthyroid state (odds ratio, 2.63; 95% confidence interval, 1.02-6.82, adjusted for age, sex, smoking status, and time of blood sampling). The association remained significant, when including the baseline NIHSS, TIA, serum CRP, atrial fibrillation, body mass index, and total cholesterol as additional variables (odds ratio, 3.95; 95% confidence interval, 1.25-12.47), and was confirmed by the secondary outcome (Barthel Index: odds ratio, 9.12; 95% confidence interval, 2.08-39.89). CONCLUSIONS: Subclinical hyperthyroidism is a risk factor for poor outcome 3 months after ischemic stroke.

17q25 Locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status.

BACKGROUND AND PURPOSE: Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. METHODS: We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. RESULTS: Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. CONCLUSIONS: This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.

Identification of a strategic brain network underlying processing speed deficits in vascular cognitive impairment.

Patients with vascular cognitive impairment (VCI) commonly exhibit deficits in processing speed. This has been attributed to a disruption of frontal-subcortical neuronal circuits by ischemic lesions, but the exact mechanisms and underlying anatomical structures are poorly understood. We set out to identify a strategic brain network for processing speed by applying graph-based data-mining techniques to MRI lesion maps from patients with small vessel disease. We studied 235 patients with CADASIL, a genetic small vessel disease causing pure VCI. Using a probabilistic atlas in standard space we first determined the regional volumes of white matter hyperintensities (WMH) and lacunar lesions (LL) within major white matter tracts. Conditional dependencies between the regional lesion volumes and processing speed were then examined using Bayesian network analysis. Exploratory analysis identified a network of five imaging variables as the best determinant of processing speed. The network included LL in the left anterior thalamic radiation and the left cingulum as well as WMH in the left forceps minor, the left parahippocampal white matter and the left corticospinal tract. Together these variables explained 34% of the total variance in the processing speed score. Structural equation modeling confirmed the findings obtained from the Bayesian models. In summary, using graph-based models we identified a strategic brain network having the highest predictive value for processing speed in our cohort of patients with pure small vessel disease. Our findings confirm and extend previous results showing a role of frontal-subcortical neuronal circuits, in particular dorsolateral prefrontal and cingulate circuits, in VCI.

Extensive white matter hyperintensities may increase brain volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: The extent of white matter hyperintensities (WMH) is associated with cerebral atrophy in elderly people. WMH is a radiological hallmark of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), but their relationship with brain volume remains poorly understood. The association between WMH and brain volume was analyzed in a large population of patients with CADASIL. METHODS: Demographic and MRI data of 278 patients recruited from a prospective cohort study were analyzed. Volumes of WMH and lacunar infarcts, number of cerebral microbleeds, and brain parenchymal fraction were measured. Multivariate analysis was used to study the impact of WMH on brain volume at baseline. RESULTS: In univariate analyses, brain parenchymal fraction was negatively associated with age, male sex, and all MRI markers. Multiple regression modeling showed that brain parenchymal fraction was inversely related to age, number of cerebral microbleeds, and normalized volume of lacunar infarcts but positively related to normalized volume of WMH (P<0.001). This positive relationship was independent of the presence/absence of lacunar infarcts or of cerebral microbleeds. Subgroup analysis showed that this association was significant in subjects having normalized volume of WMH ≥6.13 or brain parenchymal fraction ≥86.37% (median values, both P≤0.001). CONCLUSIONS: The results of the present study suggest that extensive WMH may be associated with increase of brain volume in CADASIL. In this disorder, WMH may be related not only to loss of white matter components, but also to a global increase of water content in the cerebral tissue.

[Diagnostics of Interstitial Lung Diseases - Practical Instructions with a Focus on Rheumatologic Systemic Diseases]. / Diagnostik interstitieller Lungenerkrankungen ­ Handlungsempfehlung mit Fokus auf rheumatologische Systemerkrankungen.

Interstitial lung diseases (ILD) are etiologically heterogeneous with unknown and known causes like rheumatologic systemic diseases differing in their therapeutic and prognostic consequences. In consensus between pulmonologists, rheumatologists, radiologists, and pathologists, we developed practical instructions for ILD diagnosis in rheumatologic systemic diseases, in particular because ILD can present in early stages of rheumatic systemic diseases. ILD diagnosis is based on clinical assessment results including a detailed medical history, physical examination, focused laboratory tests, radiology with a high-resolution computed tomography, lung function, and histopathology also to differentiate it from cardiac and infection associated lung diseases. The ILD diagnosis is made in a multidisciplinary discussion leading to therapeutic and prognostic consequences. The occurrence of acute exacerbations is especially critical. They are often the causes for ILD progression and are associated with considerable mortality.

Adenocarcinoma of the esophagogastric junction: neoadjuvant radiochemotherapy and radical surgery : early results and toxicity.

PURPOSE: To retrospectively evaluate treatment results and toxicity following a combined approach consisting of neoadjuvant radiochemotherapy and radical surgery in advanced adenocarcinoma of the esophagus and gastroesophageal junction. PATIENTS AND METHODS: Between 2005 and 2009, a total of 41 consecutive patients with newly diagnosed nonmetastatic adeno-carcinoma of the esophagus and the esophagogastric junction were evaluated, of whom 23 received neoadjuvant radiochemo-therapy (RCT). A total dose of 50.4 Gy with 2 cycles of simultaneous cisplatin/5-fluorouracil (FU) or Taxol/FU-chemotherapy were applied. A radical transthoracic subtotal esophageal and proximal gastric resection through a right thoracoabdominal laparotomy with intrathoracic anastomosis was performed 6-8 weeks following RCT. This was combined with a two-field lymphadenectomy of mediastinal and abdominal lymph nodes. Standard histopathological evaluation included the application of regression grading according to Werner and Höfler. Toxicity was recorded on the basis of CTC criteria; survival curves were calculated according to Kaplan-Meier. V10, V15, and V20 data were correlated with pulmonary toxicity. RESULTS: Overall survival for all 23 patients was 61% at 3 years. Of the original 23 patients, 18 (78%) patients proceeded to radical surgery. Reasons for no surgery included advanced age of 79, 82, and 86 years (n = 3), severe comorbidity (n = 1), and progression during radiochemotherapy (n = 1). Surgical morbidity (grade 3-4) and mortality rates were 35% and 6%, respectively. Resurgery was necessary in 3 cases (18%). Clear resection margins were achieved in 17 of 18 patients (94%). Twelve of 18 (67%) patients initially diagnosed with T3 tumors and 3 of 3 patients with T4 tumors experienced downstaging. The ypN0 rate was 12 of 18 patients (67%). Out of a total of 18 patients, regression grading revealed < 10% viable cells in 8 (44%) including 3 cases (17%) with complete regression, 10-50% viable cells in 9 (50%) and > 50% viable cells in 1 patient. During the postoperative course or thereafter, 8 of 23 (35%) patients experienced pulmonary complications including pneumonia and/or pneumonitis. V10 > 20% (p = 0.019), V15 > 13% (p = 0.008), and V20 > 10% (p = 0.008) were associated with a significant increase in the rate of pulmonary toxic effects. CONCLUSION: Neoadjuvant radiochemotherapy in patients with advanced adenocarcinoma of the esophagogastric junction followed by thoracoabdominal surgery is a feasible concept. Significant tumor regression in 44% of the patients and an ypN0 rate in 67% of the patients may favor this approach due to its high efficacy. However, to avoid toxic pulmonary effects constraints for low-dose radiation volume parameters need specific attention.

Bronchoscopic performance of bronchoalveolar lavage in germany - a call for standardization.

BACKGROUND: Bronchoalveolar lavage (BAL) is a widely used clinical tool in diagnosing interstitial lung diseases. Although there are recommendations and guidelines, the procedure is not completely standardized. Varying approaches likely influence the conclusiveness of BAL data and may be one reason for the divergent judgement of their value between different centers. OBJECTIVES: To evaluate how BAL is performed in Germany using an electronically based survey. METHODS: We conducted a cross-sectional online survey among all members of the German Respiratory Society. RESULTS: 608 members responded to the survey and of these 500 perform lavages. Most bronchoscopists (344/500) do not use a tube and have no anesthesiologist present during the procedure (405/500). Propofol is used by 76.8% and midazolam by 67.9% (n = 405), often in combination. A major difference was noted regarding the total volume of instillation. Many respondents use a predefined fixed amount of instilled volume (202/500), whereas an almost equal number use variable volumes based on the recovery (196/500). The minimum recovery volume predefined by 217/499 ranged from 3-150 ml (median 30 ml; mean 42.2 ± 55.1 ml). Most respondents did not transport their samples in special medium (61.5%) or on ice (72.8%). The average time between recovery and arrival at the lab was 115.6±267.0 min (n = 323). CONCLUSION: This study shows the broad spectrum of variations in the performance of BAL in Germany, which could have a negative effect on the method's clinical value. There is a need for training and standardization of BAL performance.

Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke.

OBJECTIVE: Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk. METHODS: In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1,090 cases, 1,244 control subjects) and the United Kingdom (758 cases, 872 control subjects, 3 SNPs). SNPs significantly associated with ischemic stroke or individual stroke subtypes in either of the screening samples were subsequently genotyped in 2,528 additional cases and 2,189 additional control subjects from Europe and North America. RESULTS: Genotyping of the screening samples demonstrated associations between seven SNPs and atherosclerotic stroke (all p < 0.05). Analysis of the full sample confirmed associations between six SNPs and atherosclerotic stroke in multivariate analyses controlling for demographic variables, coronary artery disease, myocardial infarction, and vascular risk factors (all p < 0.05). The odds ratios for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled odds ratio of 1.21 (95% confidence interval, 1.07-1.37) under both fixed- and random-effects models (p = 0.002). The point estimate for the population attributable risk is 20.1% for atherosclerotic stroke. INTERPRETATION: The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke appears to be independent of its relation to coronary artery disease and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease.

Genetic variation in the lymphotoxin-alpha pathway and the risk of ischemic stroke in European populations.

BACKGROUND AND PURPOSE: Several genes involved in the lymphotoxin-alpha cascade (LTA, LGALS2, and PSMA6) have been linked with the risk of myocardial infarction. Here, we present a comprehensive analysis of these genes in patients with ischemic stroke (IS). METHODS: Twenty-three single nucleotide polymorphisms (SNPs) from LTA, LGALS2, and PSMA6 were genotyped in 601 German IS patients and 736 matched controls. SNPs and haplotypes were tested for association with overall IS, large vessel stroke, and cardioembolic stroke. Significant associations were replicated in an independent sample of 843 IS cases and 933 controls from the UK. RESULTS: Only one SNP (rs1048990 in PSMA6) showed association with overall IS, but this was not replicated in the UK sample. Three SNPs showed significant associations with stroke subtypes (P<0.05), but none of these associations could be replicated in the UK population. CONCLUSIONS: Genetic variation in the lymphotoxin-alpha cascade (LTA, LGALS2, and PSMA6) is not a major risk factor for IS.

Regulation and function of neuronal GTP-Ras in facial motor nerve regeneration.

Activation of Ras into the GTP-binding, 'ON' state is a key switch in the neurotrophin-mediated neuronal survival and neurite outgrowth, in vitro as well as in vivo. In the current study we explored changes in GTP-Ras levels following facial nerve injury and the ensuing regeneration and the effects of perturbing these changes in vivo using synapsin-promoter mediated neuronal expression of constitutively active Val12H-Ras (synRas). Quantification of GTP-Ras and total Ras revealed a precipitous drop in the relative GTP-Ras levels in the axotomized facial motor nucleus, to 40% of normal levels at 2 days after cut, followed by a partial recovery to 50-65% at 4-28 days. On western blots, control and axotomized nuclei from synRas mutants showed a 2.2- and 2.5-fold elevation in GTP-Ras, respectively, compared with their wild type littermate controls (p < 5%, anova, TUKEY post-hoc), with the levels in the axotomized synRas nucleus slightly but not significantly above that in the uninjured littermate control (p = 9.9%). Similar increase was also observed in the pERK but not pAKT targets of the Ras cascade. This moderate elevation of GTP-Ras strongly curtailed post-traumatic neuronal cell death (-65%), the influx of T-cells (-48%) as well as other parameters of neuroinflammatory response. Although synRas did not affect the speed of axonal regeneration or functional recovery it caused a very pronounced increase in central axonal sprouting. These current data emphasize the role of reduced active Ras, and by extension, the reduced overall level of retrograde neurotrophin signalling after axotomy, in mediating post-traumatic cell death and inflammation and in restricting the sprouting response. Moreover, the neuroprotective and central sprouting-enhancing effects of neuronal Val12H-Ras could help promote recovery in CNS injury.

Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke.

OBJECTIVE: To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome-wide association study. METHODS: We genotyped 1,661 Icelandic IS patients and 10,815 control subjects using the Infinium HumanHap300 chip (Illumina, San Diego, CA). A total of 310,881 single nucleotide polymorphisms (SNPs) were tested for association with IS, and the most significant signals were replicated in two large European IS sample sets (2,224 cases/2,583 control subjects). Two SNPs, rs2200733 and rs10033464, were tested further in additional European IS samples (2,327 patients and 16,760 control subjects). RESULTS: In the Icelandic samples and the two replication sets combined, rs2200733 associated significantly with cardioembolic stroke (CES) (odds ratio [OR], 1.54; p = 8.05 x 10(-9)). No other variants associated with IS or any of its subtypes. rs2200733 associated significantly with IS in all sample sets combined (OR, 1.26; p = 2.18 x 10(-10)), and both rs2200733 and its neighbour, rs10033464 associated strongly with CES (rs2200733: OR, 1.52; p = 5.8 x 10(-12); rs10033464: OR, 1.27; p = 6.1 x 10(-4)). Interestingly, rs2200733 also showed significant association to IS not classified as CES. INTERPRETATION: We discovered that variants previously shown to associate with atrial fibrillation (AF), rs2200733 and rs10033464, significantly associated with IS, with the strongest risk for CES. The association with noncardiogenic stroke is intriguing and suggests that atrial fibrillation may be underdiagnosed in patients presenting with stroke. This discovery may have implications for workup and treatment of IS.

Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with an increased risk of ischemic stroke in white Europeans.

BACKGROUND AND PURPOSE: Genetic variation in the EPHX2 gene region has been reported to influence susceptibility to ischemic stroke in blacks. We assessed the role of this gene region in white Europeans and performed analyses with regard to stroke subtypes. METHODS: Twenty-six single nucleotide polymorphisms in the EPHX2 gene region were genotyped in 601 patients with ischemic stroke and 736 matched controls. Cases were subtyped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system. Analyses were done on single markers and haplotypes using a sliding-window approach. RESULTS: Three single nucleotide polymorphisms showed associations with an increased risk for ischemic stroke (allelic models; all P

Genetic variation in members of the leukotriene biosynthesis pathway confer an increased risk of ischemic stroke: a replication study in two independent populations.

BACKGROUND AND PURPOSE: The recent finding that genetic variants in 5-lipoxygenase activating protein and leukotriene A4 hydrolase may confer an increased risk of ischemic stroke has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a case control replication methodology, all members of the leukotriene synthesis pathway and their receptors were examined for genetic variants, which may act as risk factors for all ischemic stroke and stroke subtypes. METHODS: A case control methodology using a UK stroke cohort (872 cases, 933 controls) was adopted, with additional 5-lipoxygenase activating protein genotyping and replication of positive findings undertaken in an independent stroke population from Germany (601 cases, 736 controls). RESULTS: Association was identified with variants in 5-lipoxygenase activating protein, leukotriene C4 synthase (leukotriene A4 hydrolase),and the leukotriene B4 receptor complex. Differing risks were identified for ischemic stroke subtypes. A variant in leukotriene C4 synthase was found to confer a 1.5-fold increase in risk of small vessel disease (RR, 1.515; 1.041 to 2.262; P=0.043) with replication in an independent cohort showing a similar risk (RR, 1.687; 1.065 to 2.675; P=0.026). A haplotype in the leukotriene B4 receptor complex was found to confer a 2.3-fold increase in risk of cardioembolic stroke (RR, 2.118; 1.194 to 3.760; P=0.01) and replication in a German cohort revealed a similar risk with a second distinct haplotype (RR, 2.060; 1.162 to 3.665; P=0.013). CONCLUSIONS: Genetic variation in leukotriene pathway members and their receptors confer an increased risk of ischemic stroke in 2 independent populations. These risks show different magnitudes depending on ischemic stroke subtype.

Variation in the PDE4D gene and ischemic stroke risk: a systematic review and meta-analysis on 5200 cases and 6600 controls.

BACKGROUND AND PURPOSE: PDE4D was identified as the first novel gene associated with ischemic stroke risk. Replication studies have produced conflicting results, but many have been small and underpowered. Meta-analysis provides a method to combine this data and determine in a larger sample size whether the association with PDE4D can be replicated. METHODS: A meta-analysis of all PDE4D variants investigated in relation to ischemic stroke has been undertaken. Analysis of any variant appearing in 2 or more replication studies was included; this comprised 6 single nucleotide polymorphisms together with allele 0 of minisatellite AC008818 and the G0 haplotype. A total of 16 studies were identified, allowing examination of up to 5216 cases and 6615 controls for a single variant. Analyses were performed including all data, excluding data from the original report (providing true replication data), and for individual stroke subtypes and limited to white ethnicity. RESULTS: No individual single nucleotide polymorphism was associated with all ischemic stroke cases. Allele 0 of AC008818 and haplotype G0 carriers was associated with increased risk (relative risk, 1.12; 95 CI, 1.01 to 1.25; P=0.03 and relative risk, 1.18; 95% CI, 1.05 to 1.33; P=0.007), but these associations became nonsignificant after exclusion of the original study from the analysis (relative risk, 1.06; 95% CI, 0.94 to 1.20; P=0.34 and relative risk, 1.16; 95% CI, 1.00 to 1.34; P=0.06, respectively). Analyzing only whites, the majority of cases studied, did not result in a significant association for any analysis. Few robust associations were found with individual stroke subtypes. CONCLUSIONS: No genetic variant examined in PDE4D showed a robust and reproducible association to ischemic stroke. Any association that may exist is likely to be weak and potentially restricted to specific populations.

Measurement of brain atrophy in subcortical vascular disease: a comparison of different approaches and the impact of ischaemic lesions.

Measurement of brain atrophy has been proposed as a surrogate marker in MS and degenerative dementias. Although cerebral small vessel disease predominantly affects white and subcortical grey matter, recent data suggest that whole brain atrophy is also a good indicator of clinical and cognitive status in this disease. Automated methods to measure atrophy are available that are accurate and reproducible in disease-free brains. However, optimal methods in small vessel disease have not been established and the impact of ischaemic lesions on different techniques has not been explored systematically. In this study, three contrasting techniques -- Statistical Parametric Mapping 5 (SPM5), SIENAX and BrainVisa -- were applied to measure cross-sectional atrophy (brain parenchymal fraction or BPF) in a large (n=143) two-centre cohort of patients with CADASIL, a genetic model of small vessel disease. All three techniques showed similar sensitivity to trends in BPF associated with age and lesion load. No single technique was particularly vulnerable to error as a result of lesions. Provided major errors in registration were excluded by visual inspection, manual correction of segmentations had a negligible impact with mean errors of 0.41% for SIENAX and 0.46% for BrainVisa. BPF correlated strongly with global cognitive function and physical disability, independent of the technique used. Correlation coefficients with the Minimental State Examination score were: BrainVisa 0.58, SIENAX 0.58, SPM5 0.60 (for all, p<0.001). These results suggest that all three methods can be applied reliably in patients with ischaemic lesions. Choice of analysis approach for this kind of clinical question will be determined by factors other than their robustness and precision, such as a desire to explore subtle localised changes using extensions of these processing tools.