tAD Patients Research Articles

Neurofunctional Correlates of Activities of Daily Living in Patients with Posterior Cortical Atrophy

AbstractBackgroundResearch on posterior cortical atrophy (PCA) has concentrated on cognitive decline, especially visual processing deficits. However, few studies have focused on the activities of daily living (ADL), and no study has investigated the neurometabolic basis of ADL impairments. We aimed to identify regions of hypometabolism associated with ADL in PCA patients.MethodTwenty‐nine PCA patients, 35 typical Alzheimer’s disease (tAD) patients, and 26 healthy volunteers were recruited. Each subject completed a scale for total ADL [TADL, including basic ADL (BADL) and instrumental ADL (IADL) subscales] and 18F fluorodeoxyglucose positron emission tomography. Voxel‐wise multivariable regression analysis was conducted at the level of the whole‐brain, PCA‐related hypometabolism patterns, and PCA‐specific hypometabolism patterns.ResultThe general cognitive status of PCA patients was similar to tAD patients; however, they performed worse in TADL, BADL, and IADL. In all analysis levels, TADL was associated with the bilateral parietal lobe, including the right superior parietal lobe, right inferior parietal cortex, right angular gyrus, and left superior parietal lobe. BADL was associated with the bilateral parietal lobe located in the right superior parietal lobe, right inferior parietal cortex, and left superior parietal lobe. IADL was associated with the bilateral superior parietal lobe. Bilateral superior parietal lobe hypometabolism was associated with TADL, BADL, and IADL.ConclusionHypo‐metabolism in the bilateral superior parietal lobes contributes to the decline of ADL in PCA, which is a promising target for future non‐invasive neuromodulation interventions.

BIOS-01. EFFICACY AMONG THERAPEUTICALLY EFFECTIVE ABSORBED DOSE PATIENTS IN RESPECT-GBM PHASE I OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOBLASTOMA (RGBM) COMPARED TO AN EXTERNAL CONTROL ARM (ECA)

Abstract BACKGROUND ReSPECT-GBM is a Phase 1/2 study of 186RNL administered by convection enhanced delivery (CED) in patients with rGBM. In Phase I, 15 of 24 patients have achieved a therapeutic absorbed dose defined as > 100 Gy. Based on prior work establishing the comparability of a bevacizumab (Bev) comparator to inform early-phase CED study results, OS of the 15 TAD patients were compared to a Bev ECA. METHODS Recent Bev-treated rGBM clinical trial patients meeting the same eligibility criteria as patients in the ReSPECT-GBM study were identified from the Medidata Enterprise Data Store of aggregated and deidentified patient-level historical clinical trial data. Propensity score (PS) methods were used to select the ECA and align the baseline characteristics of the Bev patients to the ReSPECT TAD cohort. OS estimates were generated using the weighted Kaplan-Meier method and compared with a weighted 2-sample 2-sided log-rank test at α = 0.05 based on a data cut-off of December 2022. RESULTS Baseline characteristics of the ReSPECT TAD and ECA patients were well-aligned after PS modeling. Although not achieving statistical significance due to small sample sizes (median OS 12.2 vs 10.1 months, hazard ratio 0.63, 95% CI: 0.26, 1.52), comparison of OS between the ReSPECT TAD and ECA patients demonstrate consistently longer OS at each 6-month interval: 6 months: 85.1% vs 73.3%, 12 mos: 51.1% vs 30.3%, 18 months: 30.6% vs 25.4%, 24 months: 30.6% vs 3.5%. CONCLUSIONS Single-arm studies can be challenging to interpret. By comparing the ReSPECT-GBM outcomes to an ECA of similar patients with balanced baseline characteristics, we can better appreciate the treatment effect of 186RNL administered via CED. The current results are encouraging, and updated results reflecting current follow-up will be presented at the meeting.

Tomo-seq identifies NINJ1 as a potential target for anti-inflammatory strategy in thoracic aortic dissection

BackgroundThoracic aortic dissection (TAD) is a life-threatening disease caused by an intimal tear in the aorta. The histological characteristics differ significantly between the tear area (TA) and the distant area. Previous studies have emphasized that certain specific genes tend to cluster at the TA. Obtaining a thorough understanding of the precise molecular signatures near the TA will assist in discovering therapeutic strategies for TAD.MethodsWe performed a paired comparison of the pathological patterns in the TA with that in the remote area (RA). We used Tomo-seq, genome-wide transcriptional profiling with spatial resolution, to obtain gene expression signatures spanning from the TA to the RA. Samples from multiple sporadic TAD patients and animal models were used to validate our findings.ResultsPathological examination revealed that the TA of TAD exhibited more pronounced intimal hyperplasia, media degeneration, and inflammatory infiltration compared to the RA. The TA also had more apoptotic cells and CD31+α-SMA+ cells. Tomo-seq revealed four distinct gene expression patterns from the TA to the RA, which were inflammation, collagen catabolism, extracellular matrix remodeling, and cell stress, respectively. The spatial distribution of genes allowed us to identify genes that were potentially relevant with TAD. NINJ1 encoded the protein-mediated cytoplasmic membrane rupture, regulated tissue remodeling, showed high expression levels in the tear area, and co-expressed within the inflammatory pattern. The use of short hairpin RNA to reduce NINJ1 expression in the beta-aminopropionitrile-induced TAD model led to a significant decrease in TAD formation. Additionally, it resulted in reduced infiltration of inflammatory cells and a decrease in the number of CD31+α-SMA+ cells. The NINJ1-neutralizing antibody also demonstrated comparable therapeutic effects and can effectively impede the formation of TAD.ConclusionsOur study showed that Tomo-seq had the advantage of obtaining spatial expression information of TAD across the TA and the RA. We pointed out that NINJ1 may be involved in inflammation and tissue remodeling, which played an important role in the formation of TAD. NINJ1 may serve as a potential therapeutic target for TAD.

Neurofunctional Correlates of Activities of Daily Living in Patients with Posterior Cortical Atrophy.

Research on posterior cortical atrophy (PCA) has focused on cognitive decline, especially visual processing deficits. However, few studies have examined the impact of PCA on activities of daily living (ADL) and the neurofunctional and neuroanatomic bases of ADL. To identify brain regions associated with ADL in PCA patients. A total of 29 PCA patients, 35 typical Alzheimer's disease (tAD) patients, and 26 healthy volunteers were recruited. Each subject completed an ADL questionnaire that included basic and instrumental subscales (BADL and IADL, respectively), and underwent hybrid magnetic resonance imaging and 18F fluorodeoxyglucose positron emission tomography. Voxel-wise regression multivariable analysis was conducted to identify specific brain regions associated with ADL. General cognitive status was similar between PCA and tAD patients; however, the former had lower total ADL scores and BADL and IADL scores. All three scores were associated with hypometabolism in bilateral parietal lobes (especially bilateral superior parietal gyri) at the whole-brain level, PCA-related hypometabolism level, and PCA-specific hypometabolism level. A cluster that included the right superior parietal gyrus showed an ADL×group interaction effect that was correlated with the total ADL score in the PCA group (r = -0.6908, p = 9.3599e-5) but not in the tAD group (r = 0.1006, p = 0.5904). There was no significant association between gray matter density and ADL scores. Hypometabolism in bilateral superior parietal lobes contributes to a decline in ADL in patients with PCA and can potentially be targeted by noninvasive neuromodulatory interventions.

Clinical and metabolic imaging features of late-onset and early-onset posterior cortical atrophy.

Late-onset (LO) and early-onset (EO) dementia show neurobiological and clinical differences. Clinical and 18 fluoro-deoxy-glucose positron emission tomography (FDG-PET) features of LO and EO posterior cortical atrophy (LO_PCA, EO_PCA), the visual variant of Alzheimer's disease (AD), were compared. LO_PCA patients were also compared with a group of patients with LO typical AD (tAD). Thirty-seven LO_PCA patients (onset age ≥ 65 years), 29 EO_PCA patients and 40 tAD patients who all underwent a standard neuropsychological battery were recruited; PCA patients were also assessed for the presence of posterior signs and symptoms. Brain FDG-PET was available in 32 LO_PCA cases, 23 EO_PCA cases and all tAD cases, and their scans were compared with scans from 30 healthy elderly controls. Within the entire PCA sample FDG uptake was also correlated with age at onset as a continuous variable. The main difference between the two PCA groups was a higher prevalence of Bálint-Holmes symptoms in EO cases, which was associated with the presence of severe bilateral occipito-temporo-parietal hypometabolism, whilst LO_PCA patients showed reduction of FDG uptake mainly in the right posterior regions. The latter group also showed mesial temporal hypometabolism, similarly to the tAD group, although with a right rather than left lateralization. Correlation analysis confirmed the association between older age and decreased limbic metabolism and between younger age and decreased left parietal metabolism. The major involvement of the temporal cortex in LO cases and of the parietal cortex in EO cases reported previously within the AD spectrum holds true also for the visual variant of AD.

Regional white matter hyperintensities in posterior cortical atrophy and logopenic progressive aphasia

White matter hyperintensities (WMH) are markers of cerebral small vessel disease and are associated with higher risk of typical amnestic Alzheimer's disease (tAD). Little is known about the frequency and distribution of WMH in atypical variants of AD, including logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). We investigated WMHs in 75 LPA, 39 PCA, and 50 tAD patients and associations with age, beta-amyloid PET burden, and cognition. PCA had greater subcortical WMHs in right occipital, parietal, and temporal lobes compared to LPA, and greater parieto-occipital subcortical and occipital periventricular WMHs than tAD. LPA had greater subcortical WMHs in left parietal lobe and deep white matter WMHs than PCA, and greater fronto-occipital subcortical and occipital periventricular WMHs than tAD. Total WMH increased with increasing age but was not related to beta-amyloid burden. Greater WMH was associated with visuoperceptual performance in LPA and PCA after correcting for atrophy. WMH topography differs across AD variants. Further work is needed to determine whether they reflect cerebrovascular disease or regionally specific neurodegenerative changes.

Metabolomic Profile Reveals That Ceramide Metabolic Disturbance Plays an Important Role in Thoracic Aortic Dissection.

AimsThoracic aortic dissection (TAD) is a life-threatening disease with no effective drug therapy thus far. New therapeutic targets and indications for timely surgical intervention are urgently needed. Our aim is to investigate new pathological mechanisms and potential biomarkers of TAD through global metabolomic profiling of aortic aneurysm and dissection patients.Methods and ResultsWe performed untargeted metabolomics to determine plasma metabolite concentrations in an aortic disease cohort, including 70 thoracic aortic aneurysm (TAA) and 70 TAD patients, as well as 70 healthy controls. Comparative analysis revealed that sphingolipid, especially its core metabolite C18-ceramide, was significantly distinguished in TAD patients but not in TAA patients, which was confirmed by subsequent quantitative analysis of C18-ceramide in a validation cohort. By analyzing our existing multiomics data in aortic tissue in a murine TAD model and TAD patients, we found that an enhanced ceramide de novo synthesis pathway in macrophages might contribute to the elevated ceramide. Inhibition of the ceramide de novo synthesis pathway by myriocin markedly alleviated BAPN-induced aortic inflammation and dissection in mice. In vitro studies demonstrated that exogenous C18-ceramide promoted macrophage inflammation and matrix metalloprotein (MMP) expression through the NLRP3-caspase 1 pathway. In contrast, inhibition of endogenous ceramide synthesis by myriocin attenuated lipopolysaccharide (LPS)-induced macrophage inflammation.ConclusionsOur findings demonstrated that ceramide metabolism disturbance might play a vital role in TAD development by aggravating aortic inflammation through the NLRP3 pathway, possibly providing a new target for pharmacological therapy and a potential biomarker of TAD.

Distinct brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer’s disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

Impaired visual search in posterior cortical atrophy vs. typical Alzheimer's disease

BackgroundPosterior cortical atrophy (PCA) is a neurocognitive disorder characterized by difficulty localizing in space. Recognizing PCA is important because it is usually missed early in its course and may result from a number of neurological disorders other than Alzheimer's disease (AD). ObjectiveThis study aimed to clarify whether impaired visual search tasks of spatial localization distinguished patients with PCA from those with other more typical dementias as well as from healthy control (HC) subjects. MethodsTwelve patients meeting neuroimaging-supported Consensus Criteria for PCA, 12 comparably advanced patients with amnestic-predominant typical AD (tAD), and 24 HC participants were compared on tests of untimed and timed visual search, spatial neglect, mental rotation, environmental orientation, visuospatial construction, and face recognition. ResultsOnly abnormalities in untimed and timed visual search and environmental orientation distinguished the PCA patients from both the tAD group and the HC group without also distinguishing the tAD patients from HC's. The PCA patients also had a tendency to greater difficulty scanning left hemispace compared to HC's. Visuospatial constructions, although worse in PCA, and face recognition were impaired in both dementia groups. ConclusionsThese findings support the concept of PCA as a disorder of spatial processing and localization, indicating that visual search tasks are particularly sensitive and specific for detecting PCA and distinguishing it from more typical dementia syndromes.

CLINICAL EFFECTIVENESS OF TRANS-ARTICULAR VERSUS RETRO-ARTICULAR DRILLING OF STABLE OSTEOCHONDRITIS DISSECANS OF THE KNEE: A, PROSPECTIVE RANDOMIZED CONTROLLED TRIAL BY THE ROCK STUDY GROUP

Background:The most common presentation of knee osteochondritis dissecans (OCD) is a stable lesion on the lateral aspect of the medial femoral condyle (MFC) in an adolescent or pre-adolescent athlete. Standard of care for conservative treatment, include activity modification and weight bearing protection. Failed conservative management often leads arthroscopy and drilling of the lesion. Two different primary drilling techniques have been utilized, but no prospective studies have compared their relative effectiveness.Hypothesis/Purpose:The study hypothesis was that trans-articular (TAD) and retro-articular drilling (RAD) would demonstrate similar rates of healing, times to return to sports, and patient-reported outcome scores (PROs).Methods:Skeletally immature (n=113) patients presenting with radiograph indicated stable OCD of the MFC who did not demonstrate healing despite a minimum of 3 months of non-operative treatment were prospectively enrolled and randomized to TAD or RAD, for which 17 surgeon-investigators (at 14 centers, representing all major regions in the U.S.). Serial radiographs were obtained every 6 weeks to assess healing, and PROs were obtained at 6 months, 12 months, and 24 months. Twelve patients were due to lesion instability detected at the time of surgery,Results:Ninety-one study subjects were included, consisting of 51 TAD and 40 RAD patients, with the two groups being of similar age (12.6 years vs. 11.9 years), sex distribution (45% vs. 27% female, p=0.081), and 2-year PRO response rate (both 90%). No significant difference between TAD and RAD was detected in follow-up Pedi-IKDC, Lysholm, Marx knee activity score, or KOOS QOL scores (Table 1). Revision/additional OCD surgery occurred in 10% of patients in RAD and 4% in TAD. 71% of TAD patients reached a ‘healed’ status at a mean of 1.15 years, compared with 58% RAD patients at a mean of 1.06 years.Conclusion:While both primary forms of OCD drilling (TAD and RAD) showed consistent post-operative healing, achieving a completely ‘healed’ status was often a more prolonged process, taking approximately 1 year, despite clinical improvement being achieved much sooner. While PROs were similar between drilling techniques, revision surgery rates were more than twice as common with RAD compared with TAD but the overall risk was low and the Absolute Risk was only 6%.

Trans-articular versus Retro-articular Drilling of Stable Osteochondritis Dissecans of the Knee: A Prospective Randomized Controlled Trial by the ROCK Multicenter Study Group

Objectives:The most common presentation of knee osteochondritis dissecans (OCD) is a stable lesion on the lateral aspect of the medial femoral condyle (MFC) in an adolescent or pre-adolescent athlete. The standard of care for primary treatment is non-operative, and includes rest/activity modification and often weight bearing protection or bracing. Failed conservative management often leads arthroscopy and drilling of the lesion. Two different primary drilling techniques have been utilized, but no prospective studies have compared their relative effectiveness. The study hypothesis was that retro-articular drilling (RAD), the slightly newer technique, would not be inferior to trans-articular (TAD), with regard to rate of healing, time to return to sports (RTS), and patient-reported outcome scores (PROs).Methods:Skeletally immature (n=113) patients presenting with MRI-confirmed stable OCD of the MFC who did not demonstrate substantial healing after a minimum of 3 months of non-operative treatment were prospectively enrolled by one of seventeen surgeon-investigators (at 14 centers, representing all major geographic regions in the U.S.) and randomized to TAD or RAD. Post-operatively, serial radiographs were obtained every 6 weeks to assess healing, and PROs were obtained at 6 months, 12 months, and 24 months. Twelve patients were closed out at time of surgery due to lesion instability detected during arthroscopy. Power analysis determined that in order to detect a difference in 2-year IKDC score between RA and TA groups with 80% power, sample sizes of 37 subjects per group would be required if the true standard deviation were 15. This analysis was based on conducting an independent samples Student’s t-test with alpha set to 5%.Results:Ninety-one study subjects were included, consisting of 51 TAD and 40 RAD patients, respectively, with the two groups being similar in age (12.6 years vs. 11.9 years), sex distribution (45% vs. 27% female, p=0.081), and 2-year PRO response rate (both 90%). No significant differences between TAD and RAD were detected in follow-up Pedi-IKDC, Lysholm, Marx knee activity score, or KOOS QOL scores (Table 1). Revision/additional OCD surgery occurred in 10% of patients in RAD and 4% in TAD (p=0.40). 73% of TAD patients reached a ‘healed’ status at a mean of 1.15 years, compared with 60% RAD patients at a mean of 1.21 years.Conclusions:While both primary forms of OCD drilling (TAD and RAD) showed consistent post-operative healing, achieving a completely ‘healed’ status was often a more prolonged process, taking approximately 1 year, despite clinical improvement and RTS being achieved much sooner. PROs were similar between drilling techniques. Significantly higher powered studies are needed to better elucidate the greater revision surgery rates in RAD compared with TAD, but overall risk is low and absolute risk only 6%. The current data support either drilling technique, which may be technically simpler, without the need for fluoroscopy, with TAD, and may be more protective of the chondral articular surface with RAD.

Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis

BackgroundThoracic aortic dissection (TAD) is a severe disease with limited understandings in its pathogenesis. Altered DNA methylation has been revealed to be involved in many diseases etiology. Few studies have examined the role of DNA methylation in the development of TAD. This study explored alterations of the DNA methylation landscape in TAD and examined the potential role of cell-free DNA (cfDNA) methylation as a biomarker in TAD diagnosis.ResultsAscending aortic tissues from TAD patients (Stanford type A; n = 6) and healthy controls (n = 6) were first examined via whole-genome bisulfite sequencing (WGBS). While no obvious global methylation shift was observed, numerous differentially methylated regions (DMRs) were identified, with associated genes enriched in the areas of vasculature and heart development. We further confirmed the methylation and expression changes in homeobox (Hox) clusters with 10 independent samples using bisulfite pyrosequencing and quantitative real-time PCR (qPCR). Among these, HOXA5, HOXB6 and HOXC6 were significantly down-regulated in TAD samples relative to controls. To evaluate cfDNA methylation pattern as a biomarker in TAD diagnosis, cfDNA from TAD patients (Stanford type A; n = 7) and healthy controls (n = 4) were examined by WGBS. A prediction model was built using DMRs identified previously from aortic tissues on methylation data from cfDNA. Both high sensitivity (86%) and specificity (75%) were achieved in patient classification (AUC = 0.96).ConclusionsThese findings showed an altered epigenetic regulation in TAD patients. This altered epigenetic regulation and subsequent altered expression of genes associated with vasculature and heart development, such as Hox family genes, may contribute to the loss of aortic integrity and TAD pathogenesis. Additionally, the cfDNA methylation in TAD was highly disease specific, which can be used as a non-invasive biomarker for disease prediction.

Cortical diffusivity investigation in posterior cortical atrophy and typical Alzheimer\u2019s disease

ObjectivesTo investigate the global cortical and regional quantitative features of cortical neural architecture in the brains of patients with posterior cortical atrophy (PCA) and typical Alzheimer’s disease (tAD) compared with elderly healthy controls (HC).MethodsA novel diffusion MRI method, that has been shown to correlate with minicolumnar organization changes in the cerebral cortex, was used as a surrogate of neuropathological changes in dementia. A cohort of 15 PCA patients, 23 tAD and 22 healthy elderly controls (HC) were enrolled to investigate the changes in cortical diffusivity among groups. For each subject, 3 T MRI T1-weighted images and diffusion tensor imaging (DTI) scans were analysed to extract novel cortical DTI derived measures (AngleR, PerpPD and ParlPD). Receiver operating characteristics (ROC) curve analysis and the area under the curve (AUC) were used to assess the group discrimination capability of the method.ResultsThe results showed that the global cortical DTI derived measures were able to detect differences, in both PCA and tAD patients compared to healthy controls. The AngleR was the best measure to discriminate HC from tAD (AUC = 0.922), while PerpPD was the best measure to discriminate HC from PCA (AUC = 0.961). Finally, the best global measure to differentiate the two patient groups was ParlPD (AUC = 0.771). The comparison between PCA and tAD patients revealed a different pattern of damage within the AD spectrum and the regional comparisons identified significant differences in key regions including parietal and temporal lobe cortical areas. The best AUCs were shown by PerpPD right lingual cortex (AUC = 0.856), PerpPD right superior parietal cortex (AUC = 0.842) and ParlPD right lateral occipital cortex (AUC = 0.826).ConclusionsDiagnostic group differences were found, suggesting that the new cortical DTI analysis method may be useful to investigate cortical changes in dementia, providing better characterization of neurodegeneration, and potentially aiding differential diagnosis and prognostic accuracy.

Increased Circulating Angiopoietin-Like Protein 8 Levels Are Associated with Thoracic Aortic Dissection and Higher Inflammatory Conditions

PurposeThoracic aortic dissection (TAD) is characterized by an inflammatory response. Angiopoietin-like protein 8 (ANGPTL8) is a hormone involved in the regulation of lipid metabolism and inflammation. However, the relationship between ANGPTL8 and TAD remains unknown.MethodsThis case-control study included 78 TAD patients and 72 controls. The aortic diameter was evaluated by computed tomography and used to assess TAD severity. Circulating ANGPTL8 levels were measured by enzyme-linked immunosorbent assay. Associations of ANGPTL8 with TAD were determined by multivariate logistic regression.ResultsSerum ANGPTL8 levels were significantly higher in TAD patients compared with controls (562.50 ± 20.84 vs. 419.70 ± 22.65 pg/mL, respectively; P < 0.001). After adjusting for confounding factors, circulating ANGPTL8 levels were an independent risk factor for TAD (odds ratio = 1.587/100 pg ANGPTL8, 95% confidence interval [CI] = 1.121–2.247, P < 0.001) and positively associated with diameter (β = 1.081/100 pg ANGPTL8, 95% CI = 0.075–2.086, P = 0.035) and high-sensitivity C-reactive protein (hs-CRP) (β = 0.845/100 pg ANGPTL8, 95% CI = 0.020–1.480, P = 0.009). The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8, hs-CRP, and D-dimer was 0.927, and the specificity and sensitivity were 98.46% and 79.49%, respectively. ANGPTL8 was significantly increased in TAD tissue compared with controls. In vitro, ANGPTL8 was increased in angiotensin II (AngII)-treated macrophages and vascular smooth muscle cells (VSMCs), while ANGPTL8 siRNA-mediated knockdown decreased inflammatory factors in AngII-treated macrophages and decreased apoptosis in AngII-treated VSMCs.ConclusionANGPTL8 is associated with TAD occurrence and development, which may involve pro-inflammatory effects on macrophages. ANGPTL8 combined with D-dimer and hs-CRP might be a useful clinical predictor of TAD.Trial RegistrationChiCTR-COC-17010792 http://www.chictr.org.cn/showproj.aspx?proj=18288

Long-term survival and frequency of reinterventions after proximal aortic surgery: a retrospective study†.

We sought to analyse perioperative outcome, long-term mortality, frequency and causes of reintervention, and survival benefit in a contemporary cohort of patients undergoing proximal thoracic aortic surgery. Participants comprised all patients undergoing open surgery for proximal thoracic aortic aneurysm (TAA) (n = 319) and thoracic aortic dissection type A (TAD) (n = 229) during 2005-2014 at the Department of Thoracic Surgery, Uppsala University Hospital. Long-term survival was compared to age- and sex-matched controls. Perioperative mortality and morbidity, event-free survival and causes of reoperation were also analysed. Long-term mortality was normalized in patients with TAA, and a survival benefit was seen as early as 20 months when corrected for time lost due to perioperative mortality. Long-term survivors undergoing surgery for TAD, on the other hand, had a 10-year mortality of 130% [95% confidence interval (95% CI) 120-140%] compared to age- and sex-matched controls. Moreover, their event-free survival was half that of patients with TAA (hazard ratio 2.3; 95% CI 1.7-3.2). Reintervention (i.e. reoperation or thoracic endovascular aortic repair) was also twice as common in the TAD patients (odds ratio 2.0; 95% CI 1.1-3.5). The dominant causes for reoperation among TAD patients were aortic insufficiency, aortic arch aneurysm and infection. Surgery for TAA is relatively safe, normalizes long-term mortality and confers an early survival benefit. However, TAD surgery carries a high risk of perioperative mortality and morbidity, as well as increased long-term mortality and risk of reintervention.

Expression of platelet-derived growth factor B is upregulated in patients with thoracic aortic dissection

ObjectiveThoracic aortic dissection (TAD) is a serious condition requiring urgent treatment to avoid catastrophic consequences. The inflammatory response is involved in the occurrence and development of TAD, possibly potentiated by platelet-derived growth factors (PDGFs). This study aimed to determine whether expression of PDGF-B (a subunit of PDGF-BB) was increased in TAD patients and to explore the factors responsible for its upregulation and subsequent effects on TAD. MethodsFull-thickness ascending aorta wall specimens from TAD patients (n = 15) and control patients (n = 10) were examined for expression of PDGF-B and its receptor (PDGFRB) and in terms of morphology, inflammation, and fibrosis. Blood samples from TAD and control patients were collected to detect plasma levels of PDGF-BB and soluble elastins. ResultsExpression levels of PDGF-B, PDGFRB, and collagen I were significantly enhanced in ascending aorta wall specimens from TAD patients compared with controls. Furthermore, soluble elastic fragments and PDGF-BB were significantly increased in plasma from TAD patients compared with controls, and numerous irregular elastic fibers and macrophages were seen in the ascending aorta wall in TAD patients. ConclusionsAn increase in elastic fragments in the aorta wall might be responsible for inducing the activation and migration of macrophages to injured sites, leading to elevated expression of PDGF-B, which in turn induces deposition of collagen, disrupts extracellular matrix homeostasis, and increases the stiffness of the aorta wall, resulting in compromised aorta compliance.

Lateral parietal contributions to memory impairment in posterior cortical atrophy.

ObjectivePosterior cortical atrophy (PCA) is a neurodegenerative syndrome characterised by progressive impairment in visuospatial and perceptual function. Recent findings show that memory functioning can also be compromised early in the course of disease. In this study, we investigated the neural basis of memory impairment in PCA, and hypothesised that correlations would be observed with parietal cortex rather than classic medial temporal memory structures.MethodsEighteen PCA patients, 15 typical Alzheimer's disease (tAD) patients and 21 healthy controls underwent memory testing with the Rey Auditory Verbal Learning Test (RAVLT) word list and MRI. Voxel-based morphometry (VBM) was used to identify regions in the parietal and medial temporal lobes that correlated with memory performance.ResultsCompared with controls, PCA patients were impaired at learning, immediate and delayed recall and recognition of the RAVLT. Learning rate and immediate recall was significantly better in PCA compared to tAD, whereas there was no difference in delayed recall. Recognition memory also was not statistically different between patient groups, but PCA patients made significantly more false positive errors than tAD patients. VBM analysis in the PCA patients revealed a significant correlation between total learning and grey matter density in the right supramarginal gyrus, right angular gyrus and left postcentral gyrus. The left post central gyrus also significantly correlated with immediate and delayed recall and with recognition memory. No correlations were detected in the medial temporal lobe.ConclusionsThe findings provide novel evidence that early verbal memory impairment is frequently observed in PCA, and is associated with damage to lateral parietal structures. The results have implications for the diagnosis and management of PCA.

Clinical and neuroimaging differences between posterior cortical atrophy and typical amnestic Alzheimer's disease patients at an early disease stage.

To identify clinical and neuroimaging characteristics between posterior cortical atrophy (PCA) and typical amnestic Alzheimer’s disease (tAD) patients at an early disease stage, 16 PCA and 13 age-matched tAD patients were enrolled. Compared with tAD patients, PCA patients showed higher mean recognition and recall test scores, and lower mean calculation, spatial attention, shape discrimination, and writing test scores. Mean right hippocampal volume was larger in PCA patients compared with tAD patients, while cortical gray matter (GM) volume of bilateral parietal and occipital lobes was smaller in PCA patients. Further, when compared with tAD patients, significant hypometabolism was observed in bilateral parietal and occipital lobes, particularly the right occipitotemporal junction in PCA patients. Additionally, there were significant positive correlations in recognition and recall scores with hippocampal volumes. In PCA patients, calculation and visuospatial ability scores are positively associated with GM volume of parietal and occipital lobes. And only spatial attention and shape discrimination scores are positively associated with regional glucose metabolism of parietal and occipital lobes. Therefore, PCA patients display better recognition and recall scores, which are associated with larger hippocampal volumes and poorer performance in visual spatial tasks because of marked GM atrophy and hypometabolism of parietal and occipital lobes.

Reduced relapse rate in upfront tandem autologous/reduced-intensity allogeneic transplantation in multiple myeloma only results in borderline non-significant prolongation of progression-free but not overall survival

Reduced relapse rate in upfront tandem autologous/reduced-intensity allogeneic transplantation in multiple myeloma only results in borderline non-significant prolongation of progression-free but not overall survival

Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients.

BackgroundHeritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported.MethodsWe performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative.ResultsA mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N = 3), TGFBR2 (N = 1) and COL3A1 (N = 2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS.ConclusionNGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0221-6) contains supplementary material, which is available to authorized users.