Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. MATERIALS AND METHODS: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. RESULTS: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD (P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI (P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups (P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. CONCLUSIONS: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

Disentangling motor planning and motor execution in unmedicated de novo Parkinson's disease patients: An fMRI study.

Many studies have used functional magnetic resonance imaging to unravel the neuronal underpinnings of motor system abnormalities in Parkinson's disease, indicating functional inhibition at the level of basal ganglia-thalamo-cortical motor networks. The study aim was to extend the characterization of functional motor changes in Parkinson's Disease by dissociating between two phases of action (i.e. motor planning and motor execution) during an automated unilateral finger movement sequence with the left and right hand, separately. In essence, we wished to identify neuronal dysfunction and potential neuronal compensation before (planning) and during (execution) automated sequential motor behavior in unmedicated early stage Parkinson's Disease patients. Twenty-two Parkinson's Disease patients (14 males; 53 ±â€¯11 years; Hoehn and Yahr score 1.4 ±â€¯0.6; UPDRS (part 3) motor score 16 ±â€¯6) and 22 healthy controls (14 males; 49 ±â€¯12 years) performed a pre-learnt four finger sequence (index, ring, middle and little finger, in order), either self-initiated (FREE) or externally triggered (REACT), within an 8-second time window. Findings were most pronounced during FREE with the clinically most affected side, where motor execution revealed significant underactivity of contralateral primary motor cortex, contralateral posterior putamen (sensorimotor territory), ipsilateral anterior cerebellum / cerebellar vermis, along with underactivity in supplementary motor area (based on ROI analyses only), corroborating previous findings in Parkinson's Disease. During motor planning, Parkinson's Disease patients showed a significant relative overactivity in dorsolateral prefrontal cortex (DLPFC), suggesting a compensatory overactivity. To a variable extent this relative overactivity in the DLPFC went along with a relative overactivity in the precuneus and the ipsilateral anterior cerebellum/cerebellar vermis Our study illustrates that a refined view of disturbances in motor function and compensatory processes can be gained from experimental designs that try to dissociate motor planning from motor execution, emphasizing that compensatory mechanisms are triggered in Parkinson's Disease when voluntary movements are conceptualized for action.

MicroRNA analysis of gastroenteropancreatic neuroendocrine tumors and metastases.

The incidence of neuroendocrine neoplasias (NEN) continues to increase. Since the primary tumor cannot be diagnosed in some cases of metastatic disease, new biomarkers are clearly needed to find the most probable site of origin. Tissue samples from 79 patients were analyzed and microRNA profiles were generated from a total of 76 primary tumors, 31 lymph node and 14 solid organ metastases. NEN metastases were associated with elevated levels of miR-30a-5p, miR-210, miR-339-3p, miR-345 and miR-660. Three microRNAs showed a strong correlation between proliferation index and metastatic disease in general (miR-150, miR-21 and miR-660). Further, each anatomic location (primary or metastatic) had one or more site-specific microRNAs more highly expressed in these tissues. Comparison between primary tumors and metastases revealed an overlap only in pancreatic (miR-127) and ileal tumors (let-7g, miR-200a and miR-331). This thorough analysis of gastroenteropancreatic neuroendocrine tumors demonstrates site-specific microRNA profiles, correlation with proliferation indices as well as corresponding nodal and distant metastases. Using microRNA profiling might improve NEN diagnostics by linking metastases to a most probable site of origin.

Knockdown of hnRNPK leads to increased DNA damage after irradiation and reduces survival of tumor cells.

Radiotherapy is an important treatment option in the therapy of multiple tumor entities among them head and neck squamous cell carcinoma (HNSCC). However, the success of radiotherapy is limited by the development of radiation resistances. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a cofactor of p53 and represents a potential target for radio sensitization of tumor cells. In this study, we analyzed the impact of hnRNPK on the DNA damage response after gamma irradiation. By yH2AX foci analysis, we found that hnRNPK knockdown increases DNA damage levels in irradiated cells. Tumor cells bearing a p53 mutation showed increased damage levels and delayed repair. Knockdown of hnRNPK applied simultaneously with irradiation reduced colony-forming ability and survival of tumor cells. Taken together, our data shows that hnRNPK is a relevant modifier of DNA damage repair and tumor cell survival. We therefore recommend further studies to evaluate the potential of hnRNPK as a drug target for improvement of radiotherapy success.

Central Pain Processing in Early-Stage Parkinson's Disease: A Laser Pain fMRI Study.

BACKGROUND & OBJECTIVE: Pain is a common non-motor symptom in Parkinson's disease. As dopaminergic dysfunction is suggested to affect intrinsic nociceptive processing, this study was designed to characterize laser-induced pain processing in early-stage Parkinson's disease patients in the dopaminergic OFF state, using a multimodal experimental approach at behavioral, autonomic, imaging levels. METHODS: 13 right-handed early-stage Parkinson's disease patients without cognitive or sensory impairment were investigated OFF medication, along with 13 age-matched healthy control subjects. Measurements included warmth perception thresholds, heat pain thresholds, and central pain processing with event-related functional magnetic resonance imaging (erfMRI) during laser-induced pain stimulation at lower (E = 440 mJ) and higher (E = 640 mJ) target energies. Additionally, electrodermal activity was characterized during delivery of 60 randomized pain stimuli ranging from 440 mJ to 640 mJ, along with evaluation of subjective pain ratings on a visual analogue scale. RESULTS: No significant differences in warmth perception thresholds, heat pain thresholds, electrodermal activity and subjective pain ratings were found between Parkinson's disease patients and controls, and erfMRI revealed a generally comparable activation pattern induced by laser-pain stimuli in brain areas belonging to the central pain matrix. However, relatively reduced deactivation was found in Parkinson's disease patients in posterior regions of the default mode network, notably the precuneus and the posterior cingulate cortex. CONCLUSION: Our data during pain processing extend previous findings suggesting default mode network dysfunction in Parkinson's disease. On the other hand, they argue against a genuine pain-specific processing abnormality in early-stage Parkinson's disease. Future studies are now required using similar multimodal experimental designs to examine pain processing in more advanced stages of Parkinson's disease.

Expression Pattern of CDX2, Estrogen and Progesterone Receptors in Primary Gastroenteropancreatic Neuroendocrine Tumors and Metastases.

BACKGROUND: A significant number of patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) present with metastatic disease and with unknown primary in about 15% of cases. MATERIALS AND METHODS: We analyzed 163 primaries of GEP NET and 115 metastases for expression of caudal type homebox 2 (CDX2), estrogen receptor (ER), progesterone receptor (PR), somatostatin receptor 2a (SSTR2a) and Ki67. RESULTS: PR was most often positive in pancreatic NET and only rarely in non-pancreatic NET (p<0.001). ER was more frequently expressed in non-pancreatic NET (p<0.001) and was more often positive in females than males (p=0.019). CDX2 was positive in all primaries of the duodenum, ileum and appendix, but was also detected in 24% of metastases with pancreatic primary. SSTR2a and Ki67 did not differ significantly between primaries and metastases. CONCLUSION: Our data substantiate the value of PR, ER and CDX2 in GEP NET, and steroid hormone receptors, being differentially expressed in male and female patients. Differences between primaries and metastases were small but potentially relevant.

Functional magnetic resonance imaging of the sensorimotor system in preterm infants.

OBJECTIVE: Preterm birth at <32 weeks' gestational age has a specific predilection for periventricular white matter injury. Early prediction of concomitant motor sequelae is a fundamental clinical issue. Recently, functional MRI was introduced as a noninvasive method for investigating the functional integrity of the neonatal brain. We aimed at implementing a unilateral passive forearm extension/flexion functional MRI paradigm in a routine clinical MRI setup to allow noninvasive mapping of the sensorimotor system in preterm infants and to relate the functional data to structural and behavioral data. PATIENTS AND METHODS: Eight patients (median gestational age: 26.5 weeks; median birth weight: 885 g) were included. The functional MRI was performed at term-equivalent age (median: 39 weeks' postconceptional age) under chloral hydrate (50 mg/kg) sedation. In 5 of 8 patients, functional MRI data acquisition was successful. This resulted in 10 functional data sets (5 for passive stimulation of each forearm). RESULTS: Unilateral stimulation was associated with mainly bilateral activation of the primary sensorimotor cortex (n = 7 of 10 data sets), the prevailing hemodynamic response being a negative blood oxygenation level-dependent signal. Positive blood oxygenation level-dependent response or failure to activate the sensorimotor cortex (n = 3 of 10 data sets) were seen in those patients with aberrant structural/behavioral indices. CONCLUSIONS: Our data show the feasibility of passive unilateral sensorimotor stimulation during neonatal clinical MRI protocols. The bilateral activation pattern observed at this age is compatible with a bilaterally distributed sensorimotor system. Our data validate initial accounts for a raised incidence of negative blood oxygenation level-dependent responses in the primary sensorimotor cortex at this developmental stage. The negative blood oxygenation level-dependent response is likely to reflect a reduction of the oxy/deoxy-hemoglobin ratio during a maturational stage characterized by rapid formation of synapses, yet ineffective processing. Positive blood oxygenation level-dependent responses or failure to activate the sensorimotor cortex may be an early indicator of abnormal development and will have to be followed up carefully.

Identification of desulphoglucosinolates in Brassicaceae by LC/MS/MS: comparison of ESI and atmospheric pressure chemical ionisation-MS.

In order to develop a sensitive method for the detection of desulphoglucosinolates by HPLC-MS, the two most common interfaces for HPLC-MS, atmospheric pressure chemical ionisation (APCI) and ESI, were compared. While working with the APCI-interface the evaporation temperature and corona amperage were optimised. In doing so 300 degrees C and 6 muA proved to be most suitable for aliphatic and indole desulphoglucosinolates. The use of formic acid instead of water in the eluent in HPLC-ESI-MS measurements increased the sensitivity for the indole desulphoglucosinolates in the presence of 1 mM formic acid, while the sensitivity for the aliphatic desulphoglucosinolate desulphoglucoraphanin was substantially increased by the presence of 5 mM formic acid. Using an Agilent ion trap, two optimisation procedures for the MS parameters, smart and expert mode, were available. In smart mode the software optimises several parameters automatically, which is much more time efficient than expert mode, in which the optimisation is done manually. It turned out that ESI-MS is most sensitive in smart mode, while for APCI-MS a higher sensitivity could be gained using the expert mode. Comparing both interfaces, APCI-MS was more sensitive than ESI-MS. However, no additional information, in terms of structure determination, was obtained by APCI-MS.