Disease-related Abnormalities Research Articles

Convergent Multimodal Imaging Abnormalities in the Dorsal Precuneus in Subjective Cognitive Decline.

A range of imaging modalities have reported Alzheimer's disease-related abnormalities in individuals experiencing subjective cognitive decline (SCD). However, there has been no consistent local abnormality identified across multiple neuroimaging modalities for SCD. We aimed to investigate the convergent local alterations in amyloid-β (Aβ) deposition, glucose metabolism, and resting-state functional MRI (RS-fMRI) metrics in SCD. Fifty SCD patients (66.4±5.7 years old, 19 men [38%]) and 15 normal controls (NC) (66.3±4.4 years old, 5 men [33.3%]) were scanned with both [18F]-florbetapir PET and [18F]-fluorodeoxyglucose PET, as well as simultaneous RS-fMRI from February 2018 to November 2018. Voxel-wise metrics were retrospectively analyzed, including Aβ deposition, glucose metabolism, amplitude of low frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality(DC). The SCD group showed increased Aβ deposition and glucose metabolism (p < 0.05, corrected), as well as decreased ALFF, ReHo, and DC (p < 0.05, uncorrected) in the left dorsal precuneus (dPCu). Furthermore, the dPCu illustrated negative resting-state functional connectivity with the default mode network. Regarding global Aβ deposition positivity, the Aβ deposition in the left dPCu showed a gradient change, i.e., Aβ positive SCD > Aβ negative SCD > Aβ negative NC. Additionally, both Aβ positive SCD and Aβ negative SCD showed increased glucose metabolism and decreased RS-fMRI metrics in the dPCu. The dorsal precuneus, an area implicated in early AD, shows convergent neuroimaging alterations in SCD, and might be more related to other cognitive functions (e.g., unfocused attention) than episodic memory.

Predictors of persistent postural-perceptual dizziness (PPPD) and similar forms of chronic dizziness precipitated by peripheral vestibular disorders: a systematic review

BackgroundThe literature on predictors of persistent postural-perceptual dizziness (PPPD) following peripheral vestibular insults has not been systematically reviewed.MethodsWe systematically reviewed studies on predictors of PPPD and its four predecessors (phobic...

Plasma biomarker profiles in autosomal dominant Alzheimer's disease.

Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease. Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF. Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF. Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.

Measurable Residual Disease Conversion Rate with Consolidation Chemotherapy in Acute Myeloid Leukemia

Background Patients with acute myeloid leukemia (AML) who achieve complete remission (CR) following induction therapy but continue to have measurable residual disease (MRD) have inferior outcomes following allogeneic hematopoietic cell transplant (alloHCT). Determining the historical rate of MRD clearance in response to standard consolidative therapy is needed as an initial step in developing a new therapeutic strategy to clear MRD prior to alloHCT. Methods A multi-institution retrospective analysis was performed on consecutively treated AML patients in morphologic CR with detectable MRD post-induction therapy who received standard chemotherapy consolidation from January 2016 to December 2021. MRD was measured by multiparametric flow cytometry (MPFC, sensitivity 0.01-0.1%), next generation sequencing (NGS, sensitivity 1-5%), real-time quantitative PCR (qPCR, sensitivity 1:100,000-0.5%), and/or fluorescence in situ hybridization (FISH)/karyotype (sensitivity 1-5%). Any detectable disease-related abnormalities were considered to be evidence of MRD for the purpose of this study. Results Eighty-three patients met inclusion criteria for this analysis, with a median age at diagnosis of 51 years (IQR 43-63). Adverse-risk disease by ELN 2017 criteria was observed in 36 patients (43%). The majority received induction therapy with "7+3" (cytarabine + idarubicin or daunorubicin, 77 patients, 93%), and most (71 patients, 86%) required only 1 line of therapy to achieve CR. At the time of CR following induction therapy, 35 patients (42%) had MRD detected by MPFC, 38 patients (46%) had MRD detected by NGS, 10 patients (12%) had MRD detected by qPCR, and 32 patients (39%) were found to have an abnormal FISH or karyotype. Twenty-eight patients had MRD detected by more than 1 method. Consolidation therapy consisted of intermediate-dose cytarabine (defined as <3 g/m2, 41 patients, 49%) or high-dose cytarabine (defined as 3 g/m2, 39 patients, 47%) in all patients, except for 3 who received daunorubicin and cytarabine (liposomal) consolidation. The number of cycles of cytarabine consolidation were 1 cycle (36 patients, 43%), 2 cycles (23 patients, 28%), 3 cycles (15 patients, 18%), and 4 cycles (9 patients, 11%), respectively. Sixteen patients received cytarabine consolidation in combination with another agent including sorafenib (1 patient), midostaurin (10 patients), gilteritinib (1 patient), enasidenib (1 patient), and gemtuzumab (3 patients). In response to consolidation therapy, 27 of the 83 patients with measurable disease converted to MRD-negative (33%) after all given cycles of consolidation cytarabine. Of the 35 patients whose AML had MRD detected by MPFC prior to consolidation, 17 converted to MRD-negative (49%). Of the 38 patients whose AML had MRD detected by NGS prior to consolidation, 6 converted to MRD-negative (16%). Of the 10 patients whose AML had MRD detected by qPCR prior to consolidation, 6 converted to MRD-negative (60%). Of the 32 patients whose AML had MRD detected by FISH or karyotype prior to consolidation, 13 converted to MRD-negative (41%). Of note, 22 patients developed progressive disease following consolidation therapy (and therefore also did not achieve MRD-negativity). Multivariable logistic regression was performed to assess potential associations with MRD conversion during consolidation chemotherapy. Older age decreased the odds of conversion of AML to MRD-negative (OR = 0.96, 95% CI 0.92-1.00, p = 0.04). Higher ELN risk category, higher dose of cytarabine, and more cycles of consolidation did not affect the likelihood of conversion of AML to MRD-negative. Fifty-five patients received alloHCT following consolidation therapy. Thirty-one of these patients had AML with MRD detected post-consolidation, of whom 14 had MRD measured by MPFC. With a median follow-up time of 437 days post-transplant (IQR 151-914), two-year progression-free survival post-transplant was 57% in AML patients with MRD detected post-consolidation compared to 71% in AML patients with no MRD (p = 0.28). Conclusions The rate of MRD eradication with standard consolidation chemotherapy in AML is suboptimal. Combined with the known poor outcomes after alloHCT in patients with AML and detectable MRD pre-transplant, this demonstrates an unmet need to develop a new therapeutic strategy for eradicating MRD after induction therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myeloma bone disease imaging on a 1st-generation clinical photon-counting detector CT vs. 2nd-generation dual-source dual-energy CT

ObjectiveSubjective and objective image quality comparison of bone microstructure and disease-related abnormalities in multiple myeloma patients using a 1st-generation dual-source photon-counting detector CT(DS-PCD-CT) and a 2nd-generation dual-source dual-energy (energy-integrating detector) CT (DS-EID-CT).MethodsFifty multiple myeloma patients (mean age 67.7 ± 10.9 years,16 females) were prospectively enrolled. Unenhanced whole-body CTs were clinically indicated and performed on DS-EID-CT and DS-PCD-CT (median time difference: 12 months). DS-PCD-CT was performed in Quantumplus UHR mode and DS-EID-CT was performed using dual-energy mode. DS-PCD-CT kernel was set at Br64 with Quantum iterative reconstruction strength Q1; for DS-EID-CT a comparable I70f kernel with SAFIRE iterative reconstruction strength 1 was used. Two independent radiologists assessed image quality subjectively using a 5-point Likert scale considering delineation and sharpness of trabecular bone and lytic bone lesions in the spine and pelvic bones. Additionally, ImageJ was used for quantification of bony septa inside the cancellous bone and through or the edges of osteolysis.ResultsOverall quality as well as detectability and sharpness in the delineation of lytic bone lesions were superior for DS-PCD-CT compared with DS-EID-CT (p < 0.0001). The inter-reader agreement for subjective image quality readings showed excellent consistency(α = 94.2–98.8). CTDI and DLP mean values for DS-PCD-CT and DS-EID-CT were 1107.4 ± 247.6 mGy*cm and 8.2 ± 1.8 mGy vs. 1344.3 ± 204.6 mGy*cm and 10.1 ± 1.9 mGy. The quantitative metric for bone microstructure in the femoral head showed significantly better visualization of trabeculae in DS-PCD-CT compared with DS-EID-CT (p < 0.0001). Quantitative analyses of edge sharpness of osteolysis showed significant steeper edges for DS-PCD-CT (p < 0.0001).ConclusionDS-PCD-CT significantly improves spatial resolution of bony microstructure and lytic bone lesions compared to DS-EID-CT.Key Points• Application of photon-counting detector CT is superior to dual-source dual-energy integrating detector in clinical workup of multiple myeloma patients.• Compared to energy integrating detectors, photon-counting detectors significantly increase the spatial resolution of bone microstructure including disease-related lytic bone lesions in patients with multiple myeloma.

Monitoring rapid metabolic changes in health and type-1 diabetes with breath acetone sensors

Routine detection of health parameters is desirable to recognize the early onset of metabolic diseases (e.g., diabetes mellitus) and to personalize their treatment. Promising are non-invasive, affordable and portable technologies, such as breath sensors. Yet, the selective monitoring of breath markers (e.g., acetone for lipolysis) with sensors to track metabolic changes that can reveal disease-related abnormalities remains challenging. Here, subtle breath acetone changes during fasting, exercise and glucose ingestion are tracked in two model situations: Patients suffering from type-1 diabetes mellitus (T1DM) and healthy subjects (total: 19 volunteers) were monitored using chemoresistive sensors based on Si/WO3 nanoparticles. Specifically, each subject cycled after overnight fasting to stimulate fatty acid oxidation followed by an oral glucose tolerance test (OGTT), as monitored by capillary blood glucose and β-hydroxybutyrate (BOHB) concentrations. The sensor recognized accurately the individual breath acetone patterns before and after OGTT (both R2 = 0.9) at negligible interference, for instance, from glucose ingestion-associated volatiles (e.g., ethanol) or isoprene, as confirmed by high-resolution mass spectrometry. Furthermore, distinct differences in the breath acetone patterns of T1DM over healthy subjects were revealed including higher (t-test, p = 0.006) breath acetone ratio 2 h after starting the OGTT. Worth noting is that after glucose intake, breath isoprene steadily increased for T1DM subjects while it remained rather constant for healthy ones, an intriguing observation that requires more research to clarify its biochemical origin and medical relevance.

Gene and protein expression of dorsal root ganglion sensory receptors in normotensive and hypertensive male rats.

The exercise pressor reflex (EPR), a neurocirculatory control mechanism, is exaggerated in hypertensive humans and rats. Disease-related abnormalities within the afferent arm of the reflex loop, including mechano- and metabosensitive receptors located at the terminal end of group III/IV muscle afferents, may contribute to the dysfunctional EPR in hypertension. Using control (WKY) and spontaneous hypertensive (SHR) rats, we examined dorsal root ganglion (DRG) gene and protein expression of molecular receptors recognized as significant determinants of the EPR. Twelve lumbar DRGs (6 left, 6 right) were harvested from each of 10 WKY [arterial blood pressure (MAP): 96 ± 9 mmHg] and 10 SHR (MAP: 144 ± 9 mmHg). DRGs from the left side were used for protein expression (Western blotting; normalized to GAPDH), whereas right-side DRGs (i.e., parallel structure) were used to determine mRNA levels (RNA-sequencing, normalized to TPM). Analyses focused on metabosensitive (ASIC3, Bradykinin receptor B2, EP4, P2X3, TRPv1) and mechanosensitive (Piezo1/2) receptors. Although Piezo1 was similar in both groups (P = 0.75), protein expression for all other receptors was significantly higher in SHR compared with WKY. With the exception of a greater Bradykinin-receptor B2 in SHR (P < 0.05), mRNA expression of all other receptors was not different between groups (P > 0.18). The higher protein content of these sensory receptors in SHR indirectly supports the previously proposed hypothesis that the exaggerated EPR in hypertension is, in part, due to disease-related abnormalities within the afferent arm of the reflex loop. The upregulated receptor content, combined with normal mRNA levels, insinuates that posttranscriptional regulation of sensory receptor protein expression might be impaired in hypertension.

Anomaly detection with vision-based deep learning for epidemic prevention and control

Abstract During the COVID-19 pandemic, people were advised to keep a social distance from others. People’s behaviors will also be noticed, such as lying down because of illness, regarded as abnormal conditions. This paper proposes a visual anomaly analysis system based on deep learning to identify individuals with various anomaly types. In the study, two types of anomaly detections are concerned. The first is monitoring the anomaly in the case of falling in an open public area. The second is measuring the social distance of people in the area to warn the individuals under a short distance. By implementing a deep model named You Only Look Once, the related anomaly can be identified accurately in a wide range of open spaces. Experimental results show that the detection accuracy of the proposed method is 91%. In the social distance, the actual social distance is calculated by calculating the plane distance to ensure that everyone can meet the specification. Integrating the two functions and implementing the environmental monitoring system will make it easier to monitor and manage the disease-related abnormalities on the site.

Evaluation of 2D super-resolution ultrasound imaging of the rat renal vasculature using ex vivo micro-computed tomography

Super-resolution ultrasound imaging (SRUS) enables in vivo microvascular imaging of deeper-lying tissues and organs, such as the kidneys or liver. The technique allows new insights into microvascular anatomy and physiology and the development of disease-related microvascular abnormalities. However, the microvascular anatomy is intricate and challenging to depict with the currently available imaging techniques, and validation of the microvascular structures of deeper-lying organs obtained with SRUS remains difficult. Our study aimed to directly compare the vascular anatomy in two in vivo 2D SRUS images of a Sprague–Dawley rat kidney with ex vivo μCT of the same kidney. Co-registering the SRUS images to the μCT volume revealed visually very similar vascular features of vessels ranging from ~ 100 to 1300 μm in diameter and illustrated a high level of vessel branching complexity captured in the 2D SRUS images. Additionally, it was shown that it is difficult to use μCT data of a whole rat kidney specimen to validate the super-resolution capability of our ultrasound scans, i.e., validating the actual microvasculature of the rat kidney. Lastly, by comparing the two imaging modalities, fundamental challenges for 2D SRUS were demonstrated, including the complexity of projecting a 3D vessel network into 2D. These challenges should be considered when interpreting clinical or preclinical SRUS data in future studies.

Maturity Onset Diabetes of the Young-New Approaches for Disease Modelling.

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.

Rosiglitazone Restores NOS‐Dependent Reactivity of Cerebral Arterioles in Rats Exposed to Prenatal Alcohol

Prenatal alcohol exposure (PAE) is known to have widespread clinical effects on fetal growth and development in humans, but effective treatments are yet unavailable due to our limited knowledge of the underlying pathological mechanisms or suitable molecular targets. Peroxisome proliferator-activated receptor gamma (PPARγ), a member of PPAR family of nuclear receptors present on vascular smooth muscle and endothelium, has been targeted in the treatment of several cardiovascular disease-related abnormalities. Rosiglitazone can activate the PPARγ isoform to bring about its anti-inflammatory and antioxidant potentials required for ameliorating the pathological state. Given that PAE is known to impair responses of cerebral arterioles potentially viaan alteration in oxidative stress, we examined whether acute and chronic treatment with rosiglitazone could restore impaired responses of the cerebral arterioles to NOS-dependent and -independent agonists in rats exposed to alcohol in utero. Twelve to sixteen weeks after birth, we examined reactivity of cerebral arterioles to eNOS- (ADP), nNOS-dependent (NMDA) and NOS-independent (nitroglycerin) agonists in male and female adult rats before and during one-hour-long acute application of rosiglitazone. We found that rosiglitazone enhanced responses of cerebral arterioles to ADP and NMDA in PAE rats when compared to control rats. We also examined the influence of chronic, oral treatment with rosiglitazone (2-3 weeks) on responses of cerebral arterioles in male and female adult rats exposed to alcohol in utero. We found that chronic treatment with rosiglitazone to prevent impaired cerebral vascular function in PAE rats, regardless of their gender. Overall, these studies suggest that PPARγ can restore impaired reactivity in cerebral arterioles to eNOS- and nNOS-dependent agonists during PAE. We speculate that PPARγ activation might be a promising treatment option to reverse the cerebral vascular abnormalities associated with in utero exposure to alcohol. We also believe that our findings may have important implications for the regulation of cerebral blood flow in those that suffer from symptoms associated with Fetal Alcohol Spectrum Disorders (FASD).

Effects of age and sex on eye movement characteristics.

Abnormal eye movements are often associated with psychiatric disorders. Eye movements are sensorimotor functions of the brain, and aging and sex would affect their characteristics. A precise understanding of normal eye movements is required to distinguish disease‐related abnormalities from natural differences associated with aging or sex. To date, there is no multicohort study examining age‐related dependency and sex effects of eye movements in healthy, normal individuals using large samples to ensure the robustness and reproducibility of the results. In this study, we aimed to provide findings showing the impact of age and sex on eye movement measures. The present study used eye movement measures of more than seven hundred healthy individuals from three large independent cohorts. We herein evaluated eye movement measures quantified by using a set of standard eye movement tests that have been utilized for the examination of patients with schizophrenia. We assessed the statistical significance of the effects of age and sex and its reproducibility across cohorts. We found that 4‐18 out of 35 eye movement measures were significantly correlated with age, depending on the cohort, and that 10 of those, which are related to the fixation and motor control of smooth pursuit and saccades, showed high reproducibility. On the other hand, the effects of sex, if any, were less reproducible. The present results suggest that we should take age into account when we evaluate abnormalities in eye movements.

Dehazing buried tissues in retinal fundus images using a multiple radiance pre-processing with deep learning based multiple feature-fusion

Fundus is the inner part of the eye that is noticed while viewing through the pupil during an eye check-up. It’s made up of the retina, the macula and the optic disk. Fundus images are used to inspect and track the progression of disease-related abnormalities. Medical background images taken using high-resolution cameras lack transparency, sharpness, and an optimum level of brightness and contrast. These are critical factors that define the extent at which human experts or automated devices based on artificial intelligence can effectively distinguish between healthy and abnormal tissues. Current work describes a two-stage pre-processing image with deep learning based residual features and dynamic gradient features for enhancing retinal fundus images. In the first stage, a sequence of enhanced images with varying radiance is generated using an image brightening, contrast enhancement, and color restoration algorithm. This stage provides a sufficient improvement in contrast, sharpness and color restoration compared to the original image. But it’s also correlated with a high level of noise. From the visual results, this amount of noise can be detected. It will also decrease the Peak Signal To Noise Ratio (PSNR). Thus the second stage, which serves as a filter which combines the power of the proposed Multiple Feature-Fusion-based Deep Learning Network and the exposures extracted from the first stage image series. The technique is demonstrated in the following sections and tested in depth using a standard data set. Visual and quantitative experiments also indicate that the new approach is also capable of achieving superior performance over existing image dehazing techniques.

Lipocalin-2-induced proliferative endoplasmic reticulum stress participates in Kawasaki disease-related pulmonary arterial abnormalities.

Clinical cases have reported pulmonary arterial structural and functional abnormalities in patients with Kawasaki disease (KD); however, the underlying mechanisms are unclear. In this study, a KD rat model was established via the intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE). The results showed that pulmonary arterial functional and structural abnormalities were observed in KD rats. Furthermore, proliferative endoplasmic reticulum stress (ER stress) was observed in the pulmonary arteries of KD rats. Notably, the level of lipocalin-2 (Lcn 2), a trigger factor of inflammation, was remarkably elevated in the plasma and lung tissues of KD rats; increased Lcn 2 levels following LCWE stimulation may result from polymorphonuclear neutrophils (PMNs). Correspondingly, in cultured pulmonary artery smooth muscle cells (PASMCs), Lcn 2 markedly augmented the cleavage and nuclear localization of activating transcription factor-6 (ATF6), upregulated the transcription of glucose regulated protein 78 (GRP78) and neurite outgrowth inhibitor (NOGO), and promoted PASMCs proliferation. However, proapoptotic C/EBP homologous protein (CHOP) and caspase 12 levels were not elevated. Treatment with 4-phenyl butyric acid (4-PBA, a specific inhibitor of ER stress) inhibited PASMCs proliferation induced by Lcn 2 and attenuated pulmonary arterial abnormalities and right ventricular hypertrophy and reduced right ventricular systolic pressure in KD rats. In conclusion, Lcn 2 remarkably facilitates proliferative ER stress in PASMCs, which probably accounts for KD-related pulmonary arterial abnormalities.

Effect of Fixed-Density Thresholding on Structural Brain Networks: A Demonstration in Cerebral Small Vessel Disease.

A popular solution to control for edge density variability in structural brain network analysis is to threshold the networks to a fixed density across all subjects. However, it remains unclear how this type of thresholding affects the basic network architecture in terms of edge weights, hub location, and hub connectivity and, especially, how it affects the sensitivity to detect disease-related abnormalities. We investigated these two questions in a cohort of patients with cerebral small vessel disease and age-matched controls. Brain networks were reconstructed from diffusion magnetic resonance imaging data using deterministic fiber tractography. Networks were thresholded to a fixed density by removing edges with the lowest number of streamlines. We compared edge length (mm), fractional anisotropy (FA), proportion of hub connections, and hub location between the unthresholded and the thresholded networks of each subject. Moreover, we compared weighted graph measures of global and local connectivity obtained from the (un)thresholded networks between patients and controls. We performed these analyses over a range of densities (2-20%). Results indicate that fixed-density thresholding disproportionally removes edges composed of long streamlines, but is independent of FA. The edges removed were not preferentially connected to hub or nonhub nodes. Over half of the original hubs were reproducible when networks were thresholded to a density ≥10%. Furthermore, the between-group differences in graph measures observed in the unthresholded network remained present after thresholding, irrespective of the chosen density. We therefore conclude that moderate fixed-density thresholds can successfully be applied to control for the effects of density in structural brain network analysis.

Are we listening to everything the PARK genes are telling us?

The cardinal motor symptoms that define Parkinson's disease (PD) clinically have been recognized for over 200 years. That these symptoms arise following the loss of dopamine neurons in the substantia nigra has been known for the last 50. These long-established facts have fueled a broadly held expectation that degenerating dopaminergic neurons alone hold the key to understanding and curing PD. This prevalent expectation is at odds with the observation that many nonmotor symptoms, including depression and cognitive inflexibility among others, can appear years earlier than the overt dopaminergic neuron degeneration that drives motor abnormalities and are not improved by levodopa treatment. Thus, preserving or rescuing dopamine neuron health and function is of paramount importance, but this alone fails to capture the underlying neurobiology of earlier-appearing nonmotor symptoms. Insight into the complete landscape of disease-related abnormalities and the context in which they arise can be gleaned from a more comprehensive consideration of the PARK genes that are known to cause PD. Here, we make the case that a full incorporation of research showing when and where PARK genes are expressed as well as the impact of gene mutation on function throughout life, in tandem with research studying how dopaminergic neuron degeneration begins, is essential for a full understanding of the multi-dimensional etiology of PD. A broad view may also reveal something about long-term adjustments cells and systems make in response to gene mutation and help to identify mechanisms conferring the resilience or susceptibility of some cells and systems over others.

Parkinson’s disease: what the model systems have taught us so far

Parkinson's disease (PD) is a debilitating neurodegenerative disorder, for which people above the age of 60 show an increased risk. Although there has been great advancement in understanding the disease-related abnormalities in brain circuitry and development of symptomatic treatments, a cure for PD remains elusive. The discovery of PD associated gene mutations and environmental toxins have yielded animal models of the disease. These models could recapitulate several key aspects of PD, and provide more insights into the disease pathogenesis. They have also revealed novel aspects of the disease mechanism including noncell autonomous events and spreading of pathogenic protein species across the brain. Nevertheless, none of these models so far can comprehensively represent all aspects of the human disease. While the field is still searching for the perfect model system, recent developments in stem cell biology have provided a new dimension to modelling PD, especially doing it in a patient-specific manner. In the current review, we attempt to summarize the key findings in the areas discussed above, and highlight how the core PD pathology distinguishes itself from other neurodegenerative disorders while also resembling them in many aspects.

Cytogenetic/mutation profile of chronic lymphocytic leukemia/malignant melanoma collision tumors of the skin

BackgroundCollision tumors are rare entities that consist of two histologically distinct tumor types arising in the same anatomic site. An association between chronic lymphocytic leukemia (CLL) and malignant melanoma (MM) has been already described. Up to now, they have been documented only at positive regional lymph nodes while we focused on collision tumor in a skin lesion.Case presentationWe characterized the genomic profile of a skin CLL/MM collision tumor in a patient with a 9-years story of CLL. Typical high-grade genomic biomarkers featured the CLL: the immunoglobulin heavy variable genes were unmutated; a clonal del(11q), involving ATM and BIRC3, was present in the peripheral blood (PB) and skin lesion, while a subclonal large del(13q)/D13S319-RB1 was detected only in the PB. Interestingly, the del(13q) clone, increased from 10% to 46% from diagnosis to relapse. NOTCH1, SF3B1, and TP53 were wild type. The MM lesion carried a BRAFV600E and a TERT promoter mutation.As the family story was consistent with a genetic predisposition to cancer, we performed mutational analysis of genes involved in familial melanoma and CLL, and of BRCA1 and BRCA2. No germinal mutation known to predispose to CLL, MM, or breast cancer was found. Interestingly, conventional cytogenetic detected a constitutional t(12;17)(p13;p13).ConclusionsOur data are consistent with distinct genetic landscape of the two tumors which were characterized by specific disease-related abnormalities. CLL cells carried poor prognostic imbalances, i.e. large deletions of the long arm of chromosomes 11 and 13, while in MM cells two functionally linked mutations, i.e. BRAFV600E and a TERT promoter occurred. Although, known germline variations predisposing to MM and/or CLL were ruled out, genetic counseling suggested the proband family was at high risk for MM.

An Optimized Method for Bayesian Connectivity Change Point Model.

The brain undergoes functional dynamic changes at all times. Investigating functional dynamics has been recently verified to be helpful for detecting psychological conditions and powerful for analyzing disease-related abnormalities of the brain. This article aims to detect functional dynamics. Specifically, we focus on how to effectively distinguish corresponding functional connectivity and change points from functional magnetic resonance imaging (fMRI) data. By combining Bayesian connectivity change point model (BCCPM), a modified genetic algorithm (GA) is presented to optimize the evolutionary procedure toward the most probable distributions of real change points in fMRI. We randomly initialize different binary indicator vectors to represent different distributions of change points. Each indicator vector represents an individual in GA, and together they form an initial population. Then we calculate Bayesian posterior probability and use it as the fitness of each individual. Finally, we evolve individuals of current generation toward the next higher fitness generation by a series of modified genetic operators. After several evolutionary procedures, individuals in the final generation may have outstanding fitness and the one with highest fitness can represent the most likely change point distribution in the corresponding fMRI data. Furthermore, the most probable change point distribution could be resolved. We test the optimized method for BCCPM on several synthesized data sets, and the experimental results verify that the proposed model produces higher accuracy results with lower time consumption. Also, we apply the new model to real block-designed task-based fMRI data set and excellent results are obtained.

Elucidating the aberrant brain regions in bipolar disorder using T1-weighted/T2-weighted magnetic resonance ratio images

Although diffusion tensor imaging (DTI) have revealed brain abnormalities in bipolar disorder (BD) subjects, DTI methods might not detect disease-related abnormalities in the white matter (WM) where nerve fibers are crossing. We investigated BD myelin-related abnormal brain regions in both gray matter and WM for 29 BD and 33 healthy control (HC) participants using T1-weighted (T1w)/T2-weighted (T2w) ratio images that increase myelin-related contrast irrespective of nerve fiber orientation. To check effect of the brain volume, the results were compared with those of voxel-based morphometry (VBM). We found significantly lower T1w/T2w signal intensity in broad WM regions in BD subjects, including the corpus callosum, corona radiata, internal capsule, middle cerebellar peduncle and cerebellum. Regional volume reduction was found in the WM bilateral posterior thalami and retrolenticular part of the internal capsules of BD subjects. We also performed tract-based spatial statistics (TBSS) in 25 BD and 24 HC participants and compared those for the T1w/T2w ratio images. Both methods detected the BD corpus callosum abnormality. Further, the ratio images detected the corona radiata and the cerebellar abnormality in BD. These results suggest that T1w/T2w ratio image analysis could take a complementary role with the DTI method in elucidating myelin-related abnormalities in BD.