First-in-human pilot trial of combined intracoronary and intravenous mesenchymal stem cell therapy in acute myocardial infarction.

Background: Acute ST-elevation myocardial infarction (STEMI) elicits a robust cardiomyocyte death and inflammatory responses despite timely revascularization. Objectives: This phase 1, open-label, single-arm, first-in-human study aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in STEMI patients with impaired left ventricular ejection fraction (LVEF 30-49%) following successful reperfusion by percutaneous coronary intervention. Methods: Consenting patients received the first dose of UMSC01 through IC injection 4-5 days after STEMI followed by the second dose of UMSC01 via IV infusion 2 days later. The primary endpoint was occurrence of any treatment-related adverse events and the secondary endpoint was changes of serum biomarkers and heart function by cardiac magnetic resonance imaging during a 12-month follow-up period. Results: Eight patients gave informed consents, of whom six completed the study. None of the subjects experienced treatment-related serious adverse events or major adverse cardiovascular events during IC or IV infusion of UMSC01 and during the follow-up period. The NT-proBNP level decreased (1362 ± 1801 vs. 109 ± 115 pg/mL, p = 0.0313), the LVEF increased (52.67 ± 12.75% vs. 62.47 ± 17.35%, p = 0.0246), and the wall motion score decreased (26.33 ± 5.57 vs. 22.33 ± 5.85, p = 0.0180) at the 12-month follow-up compared to the baseline values. The serial changes of LVEF were 0.67 ± 3.98, 8.09 ± 6.18, 9.04 ± 10.91, and 9.80 ± 7.56 at 1, 3, 6, and 12 months, respectively as compared to the baseline. Conclusion: This pilot study shows that combined IC and IV transplantation of UMSC01 in STEMI patients with impaired LVEF appears to be safe, feasible, and potentially beneficial in improving heart function. Further phase 2 studies are required to explore the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.

Differential Associations of White Matter Brain Age With Language-Related Mechanisms in Word-Finding Ability Across the Adult Lifespan.

Research on cognitive aging has established that word-finding ability declines progressively in late adulthood, whereas semantic mechanism in the language system is relatively stable. The aim of the present study was to investigate the associations of word-finding ability and language-related components with brain aging status, which was quantified by using the brain age paradigm. A total of 616 healthy participants aged 18-88 years from the Cambridge Centre for Ageing and Neuroscience databank were recruited. The picture-naming task was used to test the participants' language-related word retrieval ability through word-finding and word-generation processes. The naming response time (RT) and accuracy were measured under a baseline condition and two priming conditions, namely phonological and semantic priming. To estimate brain age, we established a brain age prediction model based on white matter (WM) features and estimated the modality-specific predicted age difference (PAD). Mass partial correlation analyses were performed to test the associations of WM-PAD with the cognitive performance measures under the baseline and two priming conditions. We observed that the domain-specific language WM-PAD and domain-general WM-PAD were significantly correlated with general word-finding ability. The phonological mechanism, not the semantic mechanism, in word-finding ability was significantly correlated with the domain-specific WM-PAD. In contrast, all behavioral measures of the conditions in the picture priming task were significantly associated with chronological age. The results suggest that chronological aging and WM aging have differential effects on language-related word retrieval functions, and support that cognitive alterations in word-finding functions involve not only the domain-specific processing within the frontotemporal language network but also the domain-general processing of executive functions in the fronto-parieto-occipital (or multi-demand) network. The findings further indicate that the phonological aspect of word retrieval ability declines as cerebral WM ages, whereas the semantic aspect is relatively resilient or unrelated to WM aging.

Fluid intelligence is associated with cortical volume and white matter tract integrity within multiple-demand system across adult lifespan.

BACKGROUND: Fluid intelligence (Gf) is the innate ability of an individual to respond to complex and unexpected situations. Although some studies have considered that the multiple-demand (MD) system of the brain was the biological foundation for Gf, further characterization of their relationships in the context of aging is limited. The present study hypothesized that the structural metrics of the MD system, including cortical thickness, cortical volumes, and white matter (WM) tract integrity, was the brain correlates for Gf across the adult life span. Partial correlation analysis was performed to investigate whether the MD system could still explain Gf independent of the age effect. Moreover, the partial correlations between Gf and left/right structural metrics within the MD regions were compared to test whether the correlations displayed distinct lateralization. METHODS: The participants were recruited from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) databank, comprising the images of 603 healthy participants aged 18-88 years acquired on a 3-T system. The MRI data included high-resolution T1-weighted and diffusion-weighted images, from which gray matter and WM structural metrics of the MD system were analyzed, respectively. The structural metrics of gray matter were quantified in terms of cortical volume/thickness of five pairs of cortical regions, and those of WM were quantified in terms of the mean axial diffusivity (DA), radial diffusivity (DR), mean diffusivity (DM), and generalized fractional anisotropy (GFA) on five pairs of tracts. Partial correlation controlling for age and sex effects, was performed to investigate the associations of Gf scores with the mean DA, DR, DM and GFA of all tracts in the MD system, those of left and right hemispheric tracts, and those of each tract. Fisher's exact test was used to compare the partial correlations between left and right MD regions. RESULTS: The linear relationship between cortical volumes and Gf was evident across all levels of the MD system even after controlling for age and sex. For the WM integrity, diffusion indices including DA, DR, DM and GFA displayed linear relationships with Gf scores at various levels of the MD system. Among the 10 WM tracts connecting the MD regions, bilateral superior longitudinal fasciculus I and bilateral frontal aslant tracts exhibited the strongest and significant associations. Our results did not show significant inter-hemispheric differences in the associations between structural metrics of the MD system and Gf. CONCLUSION: Our results demonstrate significant associations between Gf and both cortical volumes and tract integrity of the MD system across the adult lifespan in a population-based cohort. We found that the association remained significant in the entire adult lifespan despite simultaneous decline of Gf and the MD system. Our results suggest that the MD system might be a structural underpinning of Gf and support the fronto-parietal model of cognitive aging. However, we did not find hemispheric differences in the Gf-MD correlations, not supporting the hemi-aging hypothesis.

Gene therapy improves brain white matter in aromatic l-amino acid decarboxylase deficiency.

OBJECTIVE: Children with aromatic l-amino acid decarboxylase (AADC) deficiency suffer from severe motor dysfunction. Restoration of dopamine levels in the putamen by gene therapy has led to significant improvement in motor function. This study explored brain structure changes in patients. METHODS: Brain diffusion tensor imaging (DTI) was performed before and 12 months after gene therapy. Whole-brain tract-specific analysis was performed to assess white matter microstructural integrity. RESULTS: In the 8 patients (aged 1.67-8.42 years) enrolled in the study, gene therapy did not affect macroscopic structure. DTI before gene therapy revealed lower total mean fractional anisotropy (FA) values in patients than in the age-matched pretreatment controls (p = 0.017; median difference = -0.0136; 95% confidence interval [CI] [-0.0319, -0.0126]). After gene therapy, total mean FA increased (p = 0.012, median difference = 0.0211, 95% CI [0.0094, 0.0456]), and the values in the patients were not different from the age-matched posttreatment controls. Increase in total mean FA after gene therapy in patients was correlated with their increase in motor score (r = 0.846; p = 0.008), but was inversely correlated with their ages at the time of gene therapy (r = -0.754; p = 0.031). Corticospinal tracts, and the thalamic radiation and callosal fibers involving motor function, improved after gene therapy. INTERPRETATION: Improvement in the microstructural integrity of white matter tracts is associated with the improvement in motor function following gene therapy. Ann Neurol 2019;85:644-652.

Quantifying Differences and Similarities in Whole-Brain White Matter Architecture Using Local Connectome Fingerprints.

Quantifying differences or similarities in connectomes has been a challenge due to the immense complexity of global brain networks. Here we introduce a noninvasive method that uses diffusion MRI to characterize whole-brain white matter architecture as a single local connectome fingerprint that allows for a direct comparison between structural connectomes. In four independently acquired data sets with repeated scans (total N = 213), we show that the local connectome fingerprint is highly specific to an individual, allowing for an accurate self-versus-others classification that achieved 100% accuracy across 17,398 identification tests. The estimated classification error was approximately one thousand times smaller than fingerprints derived from diffusivity-based measures or region-to-region connectivity patterns for repeat scans acquired within 3 months. The local connectome fingerprint also revealed neuroplasticity within an individual reflected as a decreasing trend in self-similarity across time, whereas this change was not observed in the diffusivity measures. Moreover, the local connectome fingerprint can be used as a phenotypic marker, revealing 12.51% similarity between monozygotic twins, 5.14% between dizygotic twins, and 4.51% between none-twin siblings, relative to differences between unrelated subjects. This novel approach opens a new door for probing the influence of pathological, genetic, social, or environmental factors on the unique configuration of the human connectome.

Heterogeneous Aging Effects on Functional Connectivity in Different Cortical Regions: A Resting-State Functional MRI Study Using Functional Data Analysis.

Brain aging is a complex and heterogeneous process characterized by the selective loss and preservation of brain functions. This study examines the normal aging effects on the cerebral cortex by characterizing changes in functional connectivity using resting-state fMRI data. Previous resting-state fMRI studies on normal aging have examined specific networks of the brain, whereas few studies have examined cortical-cortical connectivities across the entire brain. To characterize the effects of normal aging on the cerebral cortex, we proposed the Pearson functional product-moment correlation coefficient for measuring functional connectivity, which has advantages over the traditional correlation coefficient. The distinct patterns of changes in functional connectivity within and among the four cerebral lobes clarified the effects of normal aging on cortical function. Besides, the advantages of the proposed approach over other methods considered were demonstrated through simulation comparisons. The results showed heterogeneous changes in functional connectivity in normal aging. Specifically, the elderly group exhibited enhanced inter-lobe connectivity between the frontal lobe and the other lobes. Inter-lobe connectivity decreased between the temporal and parietal lobes. The results support the frontal aging hypothesis proposed in behavioral and structural MRI studies. In conclusion, functional correlation analysis enables differentiation of changes in functional connectivities and characterizes the heterogeneous aging effects in different cortical regions.

Endocardial Remodeling in Heart Failure Patients with Impaired and Preserved Left Ventricular Systolic Function--A Magnetic Resonance Image Study.

Left ventricular (LV) trabeculation has been studied in certain forms of cardiomyopathy. However, the changes of LV endocardial trabeculation during the remodeling process leading to heart failure (HF) are unclear. Seventy-four patients with systolic heart failure (SHF), 65 with heart failure with preserved ejection fraction (HFpEF) and 61 without HF were prospectively enrolled. All subjects received magnetic resonance imaging (MRI) study including cine, T1 and late gadolinium enhancement (LGE) images. Trabecular-papillary muscle (TPM) mass, fractal dimension (FD) and extracellular volume (ECV) were derived. The results showed that TPM mass index was higher in patients with SHF than that in patients with HFpEF and non-HF. The TPM mass-LV mass ratio (TPMm/LVM) was higher in SHF group than that in HFpEF and non-HF. FD was not different among groups. The presence of LGE was inversely associated with TPM mass index and TPMm/LVM while the ECV were positively associated with TPMm/LVM. The FD was positively associated with LV chamber size. In conclusion, TPM increases in patients with SHF and are probably related to myocardial cell hypertrophy and fibrotic repair during remodeling. The FD increases with the dilatation of LV chamber but remain unchanged with the deterioration of LV function.

Brain imaging signatures of the relationship between epidermal nerve fibers and heat pain perception.

Although the small-diameter primary afferent fibers in the skin promptly respond to nociceptive stimuli and convey sensory inputs to the central nervous system, the neural signatures that underpin the relationship between cutaneous afferent fibers and pain perception remain elusive. We combined skin biopsy at the lateral aspect of the distal leg, which is used to quantify cutaneous afferent fibers, with fMRI, which is used to assess brain responses and functional connectivity, to investigate the relationship between cutaneous sensory nerves and the corresponding pain perception in the brain after applying heat pain stimulation to the dorsum of the right foot in healthy subjects. During painful stimulation, the degree of cutaneous innervation, as measured by epidermal nerve fiber density, was correlated with individual blood oxygen level-dependent (BOLD) signals of the posterior insular cortex and of the thalamus, periaqueductal gray, and rostral ventromedial medulla. Pain perception was associated with the activation of the anterior insular cortex and with the functional connectivity from the anterior insular cortex to the primary somatosensory cortex during painful stimulation. Most importantly, both epidermal nerve fiber density and activity in the posterior insular cortex showed a positive correlation with the strength of coupling under pain between the anterior insular cortex and the primary somatosensory cortex. Thus, our findings support the notion that the neural circuitry subserving pain perception interacts with the cerebral correlates of peripheral nociceptive fibers, which implicates an indirect role for skin nerves in human pain perception.

Improvement of Cerebral Glucose Metabolism in Symptomatic Patients With Carotid Artery Stenosis After Stenting.

PURPOSE: Neurocognitive performance among patients with carotid artery stenosis or occlusion may deteriorate because of chronic cerebral hypoperfusion. Carotid artery stenting (CAS) has been reported to improve cerebral perfusion and neurocognitive function. The purpose of the study was to evaluate cerebral metabolism using F-fluorodeoxyglucose (FDG) positron emission tomography (PET) after CAS. METHODS: Nineteen consecutive patients (15 men, 69 ± 13 years) with carotid artery stenosis or occlusion and cerebral ischemia detected on brain perfusion computed tomography (CT) or magnetic resonance imaging (MRI) were enrolled. Four patients had bilateral lesions, and 15 subjects had previous ischemic stroke. Neurocognitive function (NCF) assessments and brain FDG PET scans were performed before and 19 ± 7 (12-31) months after the procedure. RESULTS: The procedural success rate of CAS was 70%. Two patients were excluded from the study because of procedural complications. No new cerebral ischemic events or neurologic deaths occurred during follow-up of 44 ± 11 (15-54) months. Significant improvements were observed in the Mini-Mental State Examination (before, 26.06 ± 3.32 versus after, 28.13 ± 2.8; P = 0.0016), the verbal fluency test (26.81 ± 7.82 versus 30.75 ± 9.58; P = 0.0378), and marginal upgrading in the Alzheimer Disease Assessment Scale-Cognitive Subtest (7.19 ± 7.59 versus 5.63 ± 5.90; P = 0.0523). Six of 9 patients who underwent successful CAS showed improvement of cerebral glucose metabolism. Of the 4 patients with recanalization failure, 2 exhibited decline in ipsilateral glucose metabolism. Cerebral FDG metabolism improved in patients with successful CAS (P = 0.038), although there was a weak correlation between interval change of NCF tests and brain FDG metabolism. CONCLUSIONS: Successful CAS may improve long-term cerebral glucose metabolism and neurocognitive function in patients with chronic severe carotid stenosis or occlusion.

Altered white matter tract property related to impaired focused attention, sustained attention, cognitive impulsivity and vigilance in attention-deficit/ hyperactivity disorder.

BACKGROUND: The neural substrate for clinical symptoms and neuropsychological performance in individuals with attention-deficit/hyperactivity disorder (ADHD) has rarely been studied and has yielded inconsistent results. We sought to compare the microstructural property of fibre tracts associated with the prefrontal cortex and its association with ADHD symptoms and a wide range of attention performance in youth with ADHD and healthy controls. METHODS: We assessed youths with ADHD and age-, sex-, handedness-, coil- and intelligence-matched controls using the Conners' Continuous Performance Test (CCPT) for attention performance and MRI. The 10 target tracts, including the bilateral frontostriatal tracts (caudate to dorsolateral prefrontal cortex, ventrolateral prefrontal cortex and orbitofrontal cortex), superior longitudinal fasciculus (SLF) and cingulum bundle were reconstructed using diffusion spectrum imaging tractography. We computed generalized fractional anisotropy (GFA) values to indicate tract-specific microstructural property. RESULTS: We included 50 youths with ADHD and 50 healthy controls in our study. Youths with ADHD had lower GFA in the left frontostriatal tracts, bilateral SLF and right cingulum bundle and performed worse in the CCPT than controls. Furthermore, alteration of the right SLF GFA was most significantly associated with the clinical symptom of inattention in youths with ADHD. Finally, youths with ADHD had differential association patterns of the 10 fibre tract GFA values with attention performance compared with controls. LIMITATIONS: Ten of the youths with ADHD were treated with methylphenidate, which may have long-term effects on microstructural property. CONCLUSION: Our study highlights the importance of the SLF, cingulum bundle and frontostriatal tracts for clinical symptoms and attention performance in youths with ADHD and demonstrates the involvement of different fibre tracts in attention performance in these individuals.

Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration.

Small-fiber neuropathy (SFN) is hallmarked by degeneration of small unmyelinated peripheral nerve fibers in the skin. Traditionally, it has been considered as a pure disorder of the peripheral nervous system. Nevertheless, previous work found that dysfunction of skin nerves led to abnormal recruitment of pain-related regions, suggesting that the brain may be affected in SFN. This report combined structural and functional magnetic resonance imaging to identify structural and functional changes in the brain of 19 patients with SFN compared with 17 healthy controls. We applied tensor-based morphometry to detect brain structural alterations in SFN. Greater volume reduction in pain-processing regions, particularly the bilateral anterior cingulate cortices (ACCs), was associated with greater depletion of intraepidermal nerve fibers, a pathological biomarker of skin nerve degeneration. Based on the hypothesis that structural alterations in the pain-processing regions might impair their functional connectivity, we further applied psychophysiological interaction analysis to assess functional connectivity of the ACCs during noxious heat stimulation. There was significant reduction in functional connectivity from the ACCs to the limbic areas (the parahippocampal gyrus and the posterior cingulate cortex), pain-processing area (the insula), and visuospatial areas (the cuneus). Moreover, the degree of reduction in functional connectivity for the ACC to the amygdala and the precuneus was linearly correlated with the severity of intraepidermal nerve fiber depletion. Our findings suggest that SFN is not a pure peripheral nervous system disorder. The pain-related brain networks tend to break into functionally independent components, with severity linked to the degree of skin nerve degeneration.

MRI evaluation of the adaptive response of the contralateral kidney following nephrectomy in patients with renal cell carcinoma.

PURPOSE: To study the adaptive responses of the contralateral kidney and its association with renal outcome in patients with renal cell carcinoma (RCC) following radical nephrectomy (RN). MATERIALS AND METHODS: Eleven patients with RCC scheduled for RN and 15 control patients scheduled for adrenalectomy (Control) were prospectively recruited. All subjects underwent 4 MRI studies: 1 before surgery and 3 at 1 week, 1 month and 3 months after surgery, respectively. T2-weighted imaging and dynamic contrast-enhanced imaging were performed to estimate the renal volume and renal blood flow (RBF) of the contralateral kidney, respectively. The patients' serum creatinine levels were examined to determine the estimated glomerular filtration rate (e-GFR). The changes in renal volume at 3 months and both RBF and e-GFR during the serial follow-up were compared and associations between both of them were measured in both groups. RESULTS: In the RN group, RBF increased at 1 week (2.78 ± 0.93 mL/min/g, P = 0.002) and 1 month (2.65 ± 0.85 mL/min/g, P = 0.002), compared with presurgical values (1.94 ± 0.61 mL/min/g), and it returned to presurgical levels at 3 months (2.11 ± 0.73 mL/min/g, P = 0.432). In contrast, e-GFR decreased at 1 week (56.4 ± 20.3 mL/min/1.73 m(2) , P = 0.049) and 1 month (52.4 ± 18.8 mL/min/1.73 m(2) , P = 0.027), compared with presurgical values (66.3 ± 18.3 mL/min/1.73 m(2) ), and it returned to presurgical levels at 3 months (73.3 ± 29.5 mL/min/1.73 m(2) , P = 0.496). The renal volume increased at 3 months compared with baseline (198 ± 87 versus 329 ± 175 mL, P < 0.001). The change in renal volume was correlated with the change in RBF at 1 week (r = 0.609, P = 0.047). CONCLUSION: In patients with RCC following RN, an early increase in RBF of the contralateral kidney is associated with late renal hypertrophy which might normalize glomerular hyperfiltration and restore renal function.

CXCR4 Antagonist TG-0054 Mobilizes Mesenchymal Stem Cells, Attenuates Inflammation, and Preserves Cardiac Systolic Function in a Porcine Model of Myocardial Infarction.

Interaction between chemokine stromal cell-derived factor 1 and the CXC chemokine receptor 4 (CXCR4) governs the sequestration and mobilization of bone marrow stem cells. We investigated the therapeutic potential of TG-0054, a novel CXCR4 antagonist, in attenuating cardiac dysfunction after myocardial infarction (MI). In miniature pigs (minipigs), TG-0054 mobilized CD34(+)CXCR4(+), CD133(+)CXCR4(+), and CD271(+)CXCR4(+) cells into peripheral circulation. After isolation and expansion, TG-0054-mobilized CD271(+) cells were proved to be mesenchymal stem cells (designated CD271-MSCs) since they had trilineage differentiation potential, surface markers of MSCs, and immunosuppressive effects on allogeneic lymphocyte proliferation. MI was induced in 22 minipigs using balloon occlusion of the left anterior descending coronary artery, followed by intravenous injections of 2.85 mg/kg of TG-0054 or saline at 3 days and 7 days post-MI. Serial MRI analyses revealed that TG-0054 treatment prevented left ventricular (LV) dysfunction at 12 weeks after MI (change of LV ejection fraction from baseline, -1.0 ± 6.2% in the TG-0054 group versus -7.9 ± 5.8% in the controls). The preserved cardiac function was accompanied by a significant decrease in the myocardial expression of TNF-α, IL-1ß, and IL-6 at 7 days post-MI. Moreover, the plasma levels of TNF-α, IL-1ß, and IL-6 were persistently suppressed by the TG-0054 treatment. Infusion of TG-0054-mobilized CD271-MSCs reduced both myocardial and plasma cytokine levels in a pattern, which is temporally correlated with TG-0054 treatment. This study demonstrated that TG-0054 improves the impaired LV contractility following MI, at least in part, by mobilizing MSCs to attenuate the postinfarction inflammation. This insight may facilitate exploring novel stem cell-based therapy for treating post-MI heart failure.

CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF.

OBJECTIVES: The purpose of this study was to investigate diffuse myocardial fibrosis in patients with systolic heart failure (SHF) and in patients with heart failure with preserved ejection fraction (HFpEF) and the association with diastolic dysfunction of the left ventricle (LV). BACKGROUND: Increased diffuse myocardial fibrosis may impair LV diastolic function. However, no study has verified the association between the degree of diffuse myocardial fibrosis and the severity of impaired diastolic function in SHF and HFpEF. METHODS: Forty patients with SHF, 62 patients with HFpEF, and 22 patients without HF underwent cardiac magnetic resonance (CMR), including T1 mapping and cine CMR on a 3-T system. Extracellular volume fraction (ECV), a measure of diffuse myocardial fibrosis, was quantified from T1 mapping. Systolic and diastolic functions of the LV were assessed by cine CMR. The ECV values and LV functional indexes were compared among the 3 groups. Associations between ECV and LV diastolic function were also investigated. RESULTS: Compared with patients without HF, significantly higher ECV was found in patients with SHF (31.2% [interquartile range (IQR): 29.0% to 34.1%] vs. 27.9% [IQR: 26.2% to 29.4%], p < 0.001) and HFpEF (28.9% [IQR: 27.8% to 31.3%] vs. 27.9% [IQR: 26.2% to 29.4%], p = 0.006). Peak filling rate, a diastolic functional index assessed by cine CMR, was significantly decreased in patients with SHF (1.00 s(-1) [IQR: 0.79 to 1.49 s(-1)] vs. 3.86 s(-1) [IQR: 3.34 to 4.48 s(-1)], p < 0.001) and HFpEF (2.89 s(-1) [IQR: 2.13 to 3.50 s(-1)] vs. 3.86 s(-1) [IQR: 3.34 to 4.48 s(-1)], p < 0.001). Myocardial ECV was significantly correlated with peak filling rate in the HFpEF group (r = -0.385, p = 0.002), but no correlation was found in the SHF and non-HF groups (r = 0.030, p = 0.856 and r = -0.238, p = 0.285, respectively). CONCLUSIONS: In patients with HF, only those with HFpEF show a significant correlation between increased diffuse myocardial fibrosis and impaired diastolic function. Diffuse myocardial fibrosis plays a unique role in the pathogenesis of HFpEF.

Cingulum correlates of cognitive functions in patients with mild cognitive impairment and early Alzheimer's disease: a diffusion spectrum imaging study.

Diffusion spectrum imaging (DSI) of MRI can detect neural fiber tract changes. We investigated integrity of cingulum bundle (CB) in patients with mild cognitive impairment (MCI) and early Alzheimer's disease (EAD) using DSI tractography and explored its relationship with cognitive functions. We recruited 8 patients with MCI, 9 with EAD and 15 healthy controls (HC). All subjects received a battery of neuropsychological tests to access their executive, memory and language functions. We used a 3.0-tesla MRI scanner to obtain T1- and T2-weighted images for anatomy and used a pulsed gradient twice-refocused spin-echo diffusion echo-planar imaging sequence to acquire DSI. Patients with EAD performed significantly poorer than the HC on most tests in executive and memory functions. Significantly smaller general fractional anisotropy (GFA) values were found in the posterior and inferior segments of left CB and of the anterior segment of right CB of the EAD compared with those of the HC. Spearman's correlation on the patient groups showed that GFA values of the posterior segment of the left CB were significantly negatively associated with the time used to complete Color Trails Test Part II and positively correlated with performance of the logical memory and visual reproduction. GFA values of inferior segment of bilateral CB were positively associated with the performance of visual recognition. DSI tractography demonstrates significant preferential degeneration of the CB on the left side in patients with EAD. The location-specific degeneration is associated with corresponding declines in both executive and memory functions.

Conductive channels identified with contrast-enhanced MR imaging predict ventricular tachycardia in systolic heart failure.

OBJECTIVES: This study evaluated whether the conductive channel (CC) identified by late gadolinium enhanced-cardiac magnetic resonance (LGE-CMR) is associated with ventricular tachycardia (VT) in patients with systolic heart failure (HF). BACKGROUND: One recent study demonstrated that the CC formed by heterogeneous tissue within the core scar could be detected by LGE-CMR and that the CC is responsible for clinical VT. We hypothesized that the CC could help identify HF patients at risk for VT. METHODS: A total of 63 patients from a CMR database with left ventricular ejection fraction (LVEF) below 50% and with hyperenhancement on LGE-CMR were included. The cine and LGE images were analyzed to derive the LV function and scar characteristics, and to identify the CC. The outcomes, including VT, ventricular fibrillation (VF), and total mortality, were obtained by reviewing medical records. RESULTS: After a median 1,379 (interquartile range: 271 to 1,896) days of follow-up, 8 patients had VT/VF attacks and 14 patients died. Among the CMR-measured parameters, only the probability of identifying the CC by LGE-CMR was higher in patients with VT/VF than those without VT/VF (75.0% vs. 16.4%, p < 0.001). The probability of identifying the CC was also higher in the total mortality group than the survival group (50.0% vs. 16.3%, p = 0.004). The other LGE-CMR variables were not significantly different between the 2 groups. A univariate Cox regression model showed that CC identification was positively associated with VT/VF attacks (hazard ratio [HR]: 27.032, 95% confidence interval [CI]: 3.291 to 222.054, p = 0.002) and excess total mortality (HR: 4.766, 95% CI: 1.643 to 13.824, p = 0.004). The LVEF was inversely associated with VT/VF attacks (HR: 0.119, 95% CI: 0.015 to 0.977, p = 0.048) and excess total mortality (HR: 0.491, 95% CI: 0.261 to 0.925, p = 0.028) during follow-up. CONCLUSIONS: We demonstrated that CC identification using LGE-CMR can help identify HF patients at risk for VT/VF.

Effect of aging on the cerebral processing of thermal pain in the human brain.

The perception of pain changes as people age. However, how aging affects the quality of pain and whether specific pain-processing brain regions mediate this effect is unclear. We hypothesized that specific structures in the cerebral nociceptive system mediate the effect of aging on the variation in different pain psychophysical measures. We examined the relationships between painful heat stimulation to the foot and both functional magnetic resonance imaging signals and gray matter volume in 23 healthy subjects (aged 25∼71 years). Increased age was related to decreased subjective ratings of overall pain intensity and the "sharp" quality of pain. Group activation maps of multiple linear regression analyses revealed that age predicted responses in the middle insular cortex (IC) and primary somatosensory cortex (S1) to pain stimuli after controlling for their gray matter volumes. Blood oxygenation level-dependent signals in the contralateral middle IC and S1 were related to ratings of "sharpness," but not any affective descriptors of pain. Importantly, activity in the contralateral middle IC specifically mediated the effect of age on overall pain perception, whereas activity in the contralateral S1 mediated the relationship between age and sharp sensation to pain. The analyses of gray matter volume revealed that key nociceptive cerebral regions did not undergo significant age-related gray matter loss. However, the volume of the cingulate cortex covaried with pain perception after adjusting for corresponding neural activity to pain. These results suggest that age-related functional alterations in pain-processing regions are responsible for changes in pain perception during normal aging.

fMRI evidence of degeneration-induced neuropathic pain in diabetes: enhanced limbic and striatal activations.

Persistent neuropathic pain due to peripheral nerve degeneration in diabetes is a stressful symptom; however, the underlying neural substrates remain elusive. This study attempted to explore neuroanatomical substrates of thermal hyperalgesia and burning pain in a diabetic cohort due to pathologically proven cutaneous nerve degeneration (the painful group). By applying noxious 44°C heat stimuli to the right foot to provoke neuropathic pain symptoms, brain activation patterns were compared with those of healthy control subjects and patients with a similar degree of cutaneous nerve degeneration but without pain (the painless group). Psychophysical results showed enhanced affective pain ratings in the painful group. After eliminating the influence of different pain intensity ratings on cerebral responses, the painful group displayed augmented responses in the limbic and striatal structures, including the perigenual anterior cingulate cortex (ACC), superior frontal gyrus, medial thalamus, anterior insular cortex, lentiform nucleus (LN), and premotor area. Among these regions, blood oxygen level-dependent (BOLD) signals in the ACC and LN were correlated with pain ratings to thermal stimulations in the painful group. Furthermore, activation maps of a simple regression analysis as well as a region of interest analysis revealed that responses in these limbic and striatal circuits paralleled the duration of neuropathic pain. However, in the painless group, BOLD signals in the primary somatosensory cortex and ACC were reduced. These results suggest that enhanced limbic and striatal activations underlie maladaptive responses after cutaneous nerve degeneration, which contributed to the development and maintenance of burning pain and thermal hyperalgesia in diabetes.

Response to comment on "the geometric structure of the brain fiber pathways".

In response to Catani et al., we show that corticospinal pathways adhere via sharp turns to two local grid orientations; that our studies have three times the diffusion resolution of those compared; and that the noted technical concerns, including crossing angles, do not challenge the evidence of mathematically specific geometric structure. Thus, the geometric thesis gives the best account of the available evidence.

Dynamic contrast-enhanced MRI in advanced nonsmall-cell lung cancer patients treated with first-line bevacizumab, gemcitabine, and cisplatin.

PURPOSE: To investigate dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of advanced nonsmall-cell lung cancer (NSCLC) patients treated with the antiangiogenic agent bevacizumab combined with gemcitabine and cisplatin as first-line treatment. MATERIALS AND METHODS: All patients were enrolled for MRI and computed tomography (CT) before and after the first three courses of bevacizumab combination chemotherapy. Pharmacokinetic parameters (K(trans), k(ep), v(e), v(p)) derived from DCE MRI were computed for the main mass. Parametric histogram analysis was obtained to evaluate changes of the internal tumor composition and for correlation with tumor response measured on CT. RESULTS: After three cycles of treatment, 11 patients showed decreased tumor size and a decreased value of all MR-derived pharmacokinetic parameters. Among these parameters, there was a significant decrease of mean and standard deviation of the K(trans) histogram as well as a decrease of mean of the k(ep) histogram (P < 0.05). Tumors with larger mean values of rate constant k(ep) (P < 0.0001) and smaller standard deviation of volume of extravascular extracellular space fraction v(e) (P < 0.0001) on histograms before chemotherapy were considered predictors for treatment response. CONCLUSION: DCE MRI enables a functional analysis of the treatment response of NSCLC. MRI parametric histogram has the potential to predict early treatment response of combined bevacizumab, gemcitabine, and cisplatin.