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The identification of interesting patterns and relationships is essential to exploratory data analysis. This becomes increasingly difficult in high dimensional datasets. While dimensionality reduction techniques can be utilized to reduce the analysis space, these may unintentionally bury key dimensions within a larger grouping and obfuscate meaningful patterns. With this work we introduce DimLift , a novel visual analysis method for creating and interacting with dimensional bundles . Generated through an iterative dimensionality reduction or user-driven approach, dimensional bundles are expressive groups of dimensions that contribute similarly to the variance of a dataset. Interactive exploration and reconstruction methods via a layered parallel coordinates plot allow users to lift interesting and subtle relationships to the surface, even in complex scenarios of missing and mixed data types. We exemplify the power of this technique in an expert case study on clinical cohort data alongside two additional case examples from nutrition and ecology. acceptedVersion

ZusammenfassungDie Nervensonografie ist ein relativ neues und patientennahes Verfahren zur Visualisierung der peripheren Nerven von ihren distalen bis zu den proximalen Segmenten. Mithilfe dieser Methode gelingt die Auffindung und anatomisch genaue Lokalisation von peripher-nervalen Läsionen sowie deren ätiologische Zuordnung. Die Nervensonografie kann dabei nervale Engpasssyndrome und deren sekundäre Ursachen relativ sicher diagnostizieren. Auch operativ zu versorgende Faszikeltorsionen lassen sich mithilfe von Ultraschall nachweisen. Weitere Anwendungsgebiete eröffnen sich durch sonografisch geführte Interventionen am peripheren Nerven sowie im Rahmen der intraoperativen Anwendung als Navigationsverfahren. In der interdisziplinären Zusammenarbeit mit den chirurgischen Fachrichtungen liegt der Wert des Nervenultraschalls vor allem in der frühzeitigen Detektion von irreversiblen traumatischen Nervenschädigungen i. S. kompletter Nervendurchtrennungen, die eine frühzeitige operative Versorgung erforderlich machen. Für die neurologische Diagnostik relevant ist die Differenzierung zwischen verschiedenen Polyneuropathieformen. Der vorgelegte Übersichtsartikel soll eine Einführung in das Feld der Nervensonografie geben und die für die chirurgisch relevanten Krankheitsbilder des peripheren Nervensystems wesentlichen Ultraschallbefunde darstellen. Dieses neue bildgebende Verfahren wird zukünftig einer der Schlüssel für den Aufbau von interdisziplinären Kompetenzzentren zur Versorgung von Krankheitsbildern der peripheren Nerven sein.

BACKGROUND: We present one patient with an initial diagnosis of Guillain-Barré syndrome (GBS) and one with Charcot-Marie-Tooth disease (CMT) type 1A. METHODS: Both patients underwent ankle tibial nerve fusion-imaging of high-resolution ultrasound (HRUS) with 7T MR neurography (MRN). RESULTS: In GBS, the nerve was enlarged, T2-hyperintense, and showed increased vascularization 21 months after symptom onset. In CMT1A, the enlarged nerve was T2-isointense with normal endoneurial blood flow. CONCLUSIONS: We demonstrate the utility of 7T-MRN-HRUS-fusion-imaging. In GBS, there was evidence of ongoing inflammation resulting in a changed diagnosis to acute-onset chronic demyelinating polyradiculoneuropathy and maintenance of immunotherapy. By MRN-HRUS-fusion, patients with presumed peripheral axonal degeneration could be shown to display imaging markers associated with peripheral nervous system inflammation. Thus, more accurate identification of a treatable inflammatory component may become possible.

Introduction: Approximately 1 out of 4 stroke patients suffers ischemic stroke secondary to atrial fibrillation (AF). Although indicated, withholding of anticoagulants for secondary prevention is a widespread phenomenon. Objective: We examined the longitudinal change of recommendation and prescription of secondary preventive anticoagulation in AF patients in an acute stroke center setting focusing on the impact of the introduction of direct oral anticoagulants (DOACs) and the change of national stroke prevention guidelines. Methods: Consecutive patients admitted with an acute cerebrovascular ischemic event underwent regular diagnostic work-up. Pseudonymized clinical data were entered into the institution’s stroke registry. In those patients with AF, discharge letters were collected and evaluated for temporal trends and affecting factors of recommended and prescribed antithrombotic secondary medication at the time of discharge from hospital. Results: Of 7,175 patients admitted between January 2009 and December 2018, 1,812 (25.3%) suffered stroke caused by AF. Frequency of patients with recommended anticoagulation increased within the observation period from 66.7 to 95.8% (per year; adjusted odds ratio [OR], 1.309; confidence interval [CI], 1.153–1.486). Independently from this time trend, DOAC approval (adjusted OR, 4.026; CI 1.962–8.265) and guideline change (adjusted OR, 2.184; CI, 1.006–4.743) were associated with an increasing frequency of recommendation for anticoagulation. The rate of patients already receiving recommended anticoagulation for secondary prevention at discharge increased from 42.1 to 62.5%. Introduction of DOACs was not associated with this trend, and guideline change was even associated with decreasing frequency of anticoagulated patients at hospital discharge (adjusted OR, 0.641; CI, 0.414–0.991). Fear of early intracerebral bleeding was the most common reason for withholding anticoagulation (37%) at hospital discharge and stayed stable during the observation period. Conclusions: Changing national guidelines with discard of contraindications for anticoagulation and the introduction of DOACs led to a broader recommendation of oral anticoagulation. However, both, new guidelines and DOACs, were not found to be associated with an increasing percentage of patients discharged from our hospital already on recommended anticoagulant prevention. This might be explained by the decreasing length of hospital stay during the study period and a missing evidence of early bleeding risk of DOACs in patients with acute brain infarction. Evidence-based data to close this therapeutic gap are needed.

Pain currently plays a subordinate role in the clinical care of patients with ALS. We aim to examine epidemiological and clinical characteristics of pain as well as its impact throughout the disease course. During a longitudinal follow-up at three time points, 151 ALS patients from three German outpatient clinics completed the Brief Pain Inventory, ALS-Functional Rating Scale-Extension and ALS Depression Inventory. Analysis of variance and covariance with repeated measures were performed. Pain was prevalent in 56% of the 151 patients at baseline and in 70% of the remaining 40 patients at the third survey. Of the 28 patients with pain who participated in all three surveys, about two thirds suffered from an average pain intensity corresponding to at least moderate pain on the numerical rating scale (NRS ≥ 4). Patients reported different pain qualities and localized the pain most frequently in the extremities, back and neck. Pain moderately impaired the functions of daily living. Pain intensity, pain quality and pain-related impairment did not significantly change over time. One third of the patients suffered from clinically relevant depressive symptoms. However, there was no conclusive evidence of a link between pain intensity and depressive symptoms. Pain is frequent and constitutes an additional strain on ALS patients who have to endure a rapidly progressive and severely debilitating disease. This study contributes to better understanding of the characteristics of pain and its impact on ALS patients throughout the disease course and may thus help to more effectively address this symptom.

Background: Although pain is common in amyotrophic lateral sclerosis (ALS) and an effectively treatable symptom, it is widely under-recognized and undertreated. This study investigates epidemiological and clinical characteristics of pain, its impact and pharmacological treatment in ALS patients. In addition, opportunities for further optimization of pain therapy need to be identified. Methods: Patients from three German ALS outpatient clinics were asked to complete the Brief Pain Inventory and the ALS Functional Rating Scale—Extension and to participate in semi-structured telephone interviews. Results: Of the 150 study participants, 84 patients reported pain. Pain occurred across all disease stages, predominantly in the neck, back and lower extremities. It was described with a broad spectrum of pain descriptors and mostly interfered with activity-related functions. Of the 84 pain patients, 53.8% reported an average pain intensity ≥4 on the numerical rating scale (NRS), indicating pain of at least moderate intensity, and 64.3% used pain medication. Irrespective of the medication type, 20.4% of them had no sufficient pain relief. Thirteen out of 30 patients without pain medication reported an average NRS value ≥4. Eleven of them—mainly in the context of high pain interference with daily functions—were supposed to benefit from adequate pain therapy. However, many patients had relevant concerns and misconceptions about pain therapy. Conclusion: Given the frequency, extent and multi-faceted impact of pain, it is necessary to systematically assess pain throughout the disease course. Potentials to optimize pain therapy were seen in the subset of patients with insufficient pain relief despite medication and in those patients without pain medication but high pain interference. However, there is a need to respond to patients’ barriers to pain therapy.

The hippocampus within the medial temporal lobe is highly vulnerable to age-related pathology such as vascular disease. We examined hippocampal vascularization patterns by harnessing the ultra-high resolution of 7 Tesla magnetic resonance angiography. Dual-supply hemispheres with a contribution of the anterior choroidal artery to hippocampal blood supply were distinguished from single-supply ones with a sole dependence on the posterior cerebral artery. A recent study indicated that a dual vascular supply is related to preserved cognition and structural hippocampal integrity in old age and vascular disease. Here, we examined the regional specificity of these structural benefits at the level of medial temporal lobe sub-regions and hemispheres. In a cross-sectional study with an older cohort of 17 patients with cerebral small vessel disease (70.7 ± 9.0 years, 35.5% female) and 27 controls (71.1 ± 8.2 years, 44.4% female), we demonstrate that differences in grey matter volumes related to the hippocampal vascularization pattern were specifically observed in the anterior hippocampus and entorhinal cortex. These regions were especially bigger in dual-supply hemispheres, but also seemed to benefit from a contralateral dual supply. We further show that total grey matter volumes were greater in people with at least one dual-supply hemisphere, indicating that the hippocampal vascularization pattern has more far-reaching structural implications beyond the medial temporal lobe. A mediation analysis identified total grey matter as a mediator of differences in global cognition. However, our analyses on multiple neuroimaging markers for cerebral small vessel disease did not reveal any evidence that an augmented hippocampal vascularization conveys resistance nor resilience against vascular pathology. We propose that an augmented hippocampal vascularization might contribute to maintaining structural integrity in the brain and preserving cognition despite age-related degeneration. As such, the binary hippocampal vascularization pattern could have major implications for brain structure and function in ageing and dementia independent of vascular pathology, while presenting a simple framework with potential applicability to the clinical setting., Vockert et al. report that an augmented hippocampal vascular supply provides brain structural benefits at multiple levels, including medial temporal lobe substructure volumes and total grey matter volume, leading to improved cognition. Thus, the hippocampal vascular pattern could have major implications for ageing and dementia., Graphical Abstract Graphical Abstract

Background Dyspnea is a cardinal but often underestimated symptom in amyotrophic lateral sclerosis (ALS). The newly developed Dyspnea-ALS-Scale (DALS-15) is highly relevant for therapeutic decisions because dyspnea is a separate criterion to consider noninvasive ventilation (NIV) in ALS. In comparison to the limited effects of neuroprotective compounds, NIV has the greatest impact on survival and improves quality of life. Objective To investigate whether dyspnea corresponds to parameters of respiratory status mainly used in clinical neurological practice. We also investigated if the DALS-15 could help identify patients for consideration of NIV in whom neither spirometry nor blood gas parameters indicate the need for NIV (forced vital capacity (FVC) 2 ≥45 mmHg). Methods Seventy ALS patients with dyspnea according to the DALS-15 obtained blood gas analysis and spirometry (FVC in sitting and supine positions). The supine decline in FVC was calculated. Results There was no linear relationship between dyspnea and spirometry as well as blood gases. 83% of our patients had an upright FVC still greater than 50% and no daytime hypercapnia. Conclusions Our study clearly shows that dyspnea can occur independently of objective indicators of respiratory impairment like spirometry or blood gases. Hence, the DALS-15 covers another aspect of respiratory impairment than these tests and refers to the subjective component of respiratory impairment. It detects dyspnea in a considerable proportion of patients in whom NIV should thus be considered although their spirometric and blood gas results do not point towards NIV. The DALS-15 therefore may help to improve the stratification of patients with respiratory impairment for more efficient symptom management and timely coordination of care.

We sought to identify patients with amyotrophic lateral sclerosis (ALS) who displayed suspected peripheral nervous system (PNS) inflammation to compare them to those with suspected PNS degeneration.We measured sonographic median and ulnar nerve cross-sectional area (CSA) and cerebrospinal fluid albumin/serum albumin ratio (Qalb ) in patients with ALS to classify them as having suspected PNS degeneration (small CSA/low Qalb ) or inflammation (larger CSA/high Qalb ).Fifty-seven percent of patients had suspected PNS degeneration, 21% had suspected PNS inflammation, and 21% displayed suspected 'normal PNS state.' Suspected PNS degeneration was related to classic ALS, shorter disease duration, and a smaller hypoechoic nerve area. Suspected PNS inflammation was associated with men, longer disease duration, and a larger hypoechoic nerve area and was the dominant finding in superoxide dismutase 1 mutation carriers.Our simple approach might aid in the in vivo differentiation of supposed ALS subtypes, those with suspected PNS degeneration vs. inflammation, for stratification in clinical trials. Muscle Nerve 59:567-567, 2019.

The Dual Analysis framework is a powerful enabling technology for the exploration of high dimensional quantitative data by treating data dimensions as first-class objects that can be explored in tandem with data values. In this article, we extend the Dual Analysis framework through the joint treatment of quantitative (numerical) and qualitative (categorical) dimensions. Computing common measures for all dimensions allows us to visualize both quantitative and qualitative dimensions in the same view. This enables a natural joint treatment of mixed data during interactive visual exploration and analysis. Several measures of variation for nominal qualitative data can also be applied to ordinal qualitative and quantitative data. For example, instead of measuring variability from a mean or median, other measures assess inter-data variation or average variation from a mode. In this work, we demonstrate how these measures can be integrated into the Dual Analysis framework to explore and generate hypotheses about high-dimensional mixed data. A medical case study using clinical routine data of patients suffering from Cerebral Small Vessel Disease (CSVD), conducted with a senior neurologist and a medical student, shows that a joint Dual Analysis approach for quantitative and qualitative data can rapidly lead to new insights based on which new hypotheses may be generated.

Several studies suggest a role for the peripheral immune system in the pathophysiology of amyotrophic lateral sclerosis. However, comprehensive studies investigating the intrathecal immune system in amyotrophic lateral sclerosis are rare. To elucidate whether compartment-specific inflammation contributes to amyotrophic lateral sclerosis pathophysiology, we here investigated intrathecal and peripheral immune profiles in amyotrophic lateral sclerosis patients and compared them with controls free of neurological disorders (controls) and patients with dementia or primary progressive multiple sclerosis. Routine CSF parameters were examined in 308 patients, including 132 amyotrophic lateral sclerosis patients. In a subgroup of 41 amyotrophic lateral sclerosis patients, extensive flow-cytometric immune cell profiling in peripheral blood and CSF was performed and compared with data from 26 controls, 25 dementia and 21 multiple sclerosis patients. Amyotrophic lateral sclerosis patients presented with significantly altered proportions of monocyte subsets in peripheral blood and increased frequencies of CD4+ and CD8+ T cells expressing the activation marker HLA-DR in peripheral blood (CD8+) and CSF (CD4+ and CD8+) compared with controls. While dementia and multiple sclerosis patients exhibited a comparable increase in intrathecal CD8+ T-cell activation, CD8+ T-cell activation in the peripheral blood in amyotrophic lateral sclerosis was higher than in multiple sclerosis patients. Furthermore, intrathecal CD4+ T-cell activation in amyotrophic lateral sclerosis surpassed levels in dementia patients. Intrathecal T-cell activation resulted from in situ activation rather than transmigration of activated T cells from the blood. While T-cell activation did not correlate with amyotrophic lateral sclerosis progression, patients with rapid disease progression showed reduced intrathecal levels of immune-regulatory CD56bright natural killer cells. The integration of these parameters into a composite score facilitated the differentiation of amyotrophic lateral sclerosis patients from patients of all other cohorts. To conclude, alterations in peripheral monocyte subsets, as well as increased peripheral and intrathecal activation of CD4+ and CD8+ T cells concomitant with diminished immune regulation by CD56bright natural killer cells, suggest an involvement of these immune cells in amyotrophic lateral sclerosis pathophysiology., Rolfes et al. reported increased frequencies of activated T cells in the peripheral blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients. They provided evidence that patients with rapid disease progression have reduced intrathecal levels of immune-regulatory CD56bright NK cells, suggest an involvement of these cells in disease pathophysiology., Graphical Abstract Graphical Abstract

Background: High-resolution nerve ultrasound (HRUS) has been proven to be a valuable tool in the diagnosis of immune-mediated neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is an important differential diagnosis of CIDP. Until now, there have been no studies that could identify specific HRUS abnormalities in POEMS syndrome patients. Thus, the aim of this study was to assess possible changes and compare findings with CIDP patients. Methods: We retrospectively analyzed HRUS findings in three POEMS syndrome and ten CIDP patients by evaluating cross-sectional nerve area (CSA), echogenicity and additionally calculating ultrasound pattern scores (UPSA, UPSB, UPSC and UPSS) and homogeneity scores (HS). Results: CIDP patients showed greater CSA enlargement and higher UPSS (median 14 vs. 11), UPSA (median 11.5 vs. 8) and HS (median 5 vs. 3) compared with POEMS syndrome patients. However, every POEMS syndrome patient illustrated enlarged nerves exceeding reference values, which were not restricted to entrapment sites. In CIDP and POEMS syndrome, heterogeneous enlargement patterns could be identified, such as inhomogeneous, homogeneous and regional nerve enlargement. HRUS in CIDP patients visualized both increased and decreased echointensity, while POEMS syndrome patients pictured hypoechoic nerves with hyperechoic intraneural connective tissue. Discussion: This is the first study to demonstrate HRUS abnormalities in POEMS syndrome outside of common entrapment sites. Although nerve enlargement was more prominent in CIDP, POEMS syndrome patients revealed distinct echogenicity patterns, which might aid in its differentiation from CIDP. Future studies should consider HRUS and its possible role in determining diagnosis, prognosis and treatment response in POEMS syndrome.

Highlights • Episodic memory function in MND is impaired but does not worsen over time. • The PhG but not the ERC is subject to substance loss with disease progression. • Hippocampal atrophy is related to poorer performance in all memory sub functions. • Memory deficits and medial temporal lobe atrophy are independent of MND phenotype., Memory impairment in motor neuron disease (MND) is still an underrecognized feature and has traditionally been attributed to executive dysfunction. Here, we investigate the rate of memory impairment in a longitudinal cohort of MND patients, its relationship to other cognitive functions and the underlying neuroanatomical correlates. 142 patients with MND and 99 healthy controls (HC) underwent comprehensive neuropsychological testing and structural MRI at 3T up to four times over a period of 18 months. Linear-mixed effects models were fitted to identify changes at baseline and over time in episodic memory function (learning, immediate and delayed recall, recognition), composed cognitive scores (memory, verbal fluency, executive function), and memory-related structural brain regions (hippocampus, entorhinal cortex, parahippocampal gyrus). Associations between episodic memory performance and volumetric or cortical thickness changes of these regions were computed using Pearson's r. Learning, immediate and delayed recall, as well as recognition performance were significantly reduced in MND when compared to controls at baseline. Performances in these subtests improved over time although MND showed less improvement than controls. This relationship did not change when only “classical” ALS patients were considered. Patients with MND showed thinning of the right parahippocampal gyrus (PhG) in comparison to controls that was progressing over time. Bilateral hippocampal atrophy was observed in MND patients with memory impairment after splitting the group according to their overall episodic memory performance, with the right hippocampus shrinking over time. In MND patients, the bilateral hippocampal atrophy was associated with impairment in learning, recall, and recognition at baseline. In contrast, left PhG thinning was associated with a poorer learning performance. These results show that episodic memory impairment in MND is a frequent cognitive dysfunction. Since deficits are not clearly declining with disease course, an early involvement of this cognitive domain in the disease seems probable. The memory performance-dependent atrophy of the hippocampus and PhG provide evidence for a widespread involvement of these non-motor cortical areas in disease pathology.

ObjectiveCerebral microbleeds (MBs) are a common finding in patients with cerebral small vessel disease (CSVD) and Alzheimer disease as well as in healthy elderly people, but their pathophysiology remains unclear. To investigate a possible role of veins in the development of MBs, we performed an exploratory study, assessing in vivo presence of MBs with a direct connection to a vein.Methods7-Tesla (7T) MRI was conducted and MBs were counted on quantitative susceptibility mapping (QSM). A submillimeter resolution QSM-based venogram allowed identification of MBs with a direct spatial connection to a vein.ResultsA total of 51 people (mean age [SD] 70.5 [8.6] years, 37% female) participated in the study: 20 had CSVD (cerebral amyloid angiopathy [CAA] with strictly lobar MBs [n = 8], hypertensive arteriopathy [HA] with strictly deep MBs [n = 5], or mixed lobar and deep MBs [n = 7], 72.4 [6.1] years, 30% female) and 31 were healthy controls (69.4 [9.9] years, 42% female). In our cohort, we counted a total of 96 MBs with a venous connection, representing 14% of all detected MBs on 7T QSM. Most venous MBs (86%, n = 83) were observed in lobar locations and all of these were cortical. Patients with CAA showed the highest ratio of venous to total MBs (19%) (HA = 9%, mixed = 18%, controls = 5%).ConclusionOur findings establish a link between cerebral MBs and the venous vasculature, pointing towards a possible contribution of veins to CSVD in general and to CAA in particular. Pathologic studies are needed to confirm our observations.

Modern neuromuscular electrodiagnosis (EDX) and neuromuscular ultrasound (NMUS) require a universal language for effective communication in clinical practice and research and, in particular, for teaching young colleagues. Therefore, the AANEM and the IFCN have decided to publish a joint glossary as they feel the need for an updated terminology to support educational activities in neuromuscular EDX and NMUS in all parts of the world. In addition NMUS has been rapidly progressing over the last years and is now widely used in the diagnosis of disorders of nerve and muscle in conjunction with EDX. This glossary has been developed by experts in the field of neuromuscular EDX and NMUS on behalf of the AANEM and the IFCN and has been agreed upon by electronic communication between January and November 2019. It is based on the glossaries of the AANEM from 2015 and of the IFCN from 1999. The EDX and NMUS terms and the explanatory illustrations have been updated and supplemented where necessary. The result is a comprehensive glossary of terms covering all fields of neuromuscular EDX and NMUS. It serves as a standard reference for clinical practice, education and research worldwide. HIGHLIGHTS: Optimal terminology in neuromuscular electrodiagnosis and ultrasound has been revisited. A team of international experts have revised and expanded a standardized glossary. This list of terms serves as standard reference for clinical practice, education and research.

Medial temporal lobe dependent cognitive functions are highly vulnerable to hypoxia in the hippocampal region, yet little is known about the relationship between the richness of hippocampal vascular supply and cognition. Hippocampal vascularization patterns have been categorized into a mixed supply from both the posterior cerebral artery and the anterior choroidal artery or a single supply by the posterior cerebral artery only. Hippocampal arteries are small and affected by pathological changes when cerebral small vessel disease is present. We hypothesized, that hippocampal vascularization patterns may be important trait markers for vascular reserve and modulate (i) cognitive performance; (ii) structural hippocampal integrity; and (iii) the effect of cerebral small vessel disease on cognition. Using high-resolution 7 T time-of-flight angiography we manually classified hippocampal vascularization patterns in older adults with and without cerebral small vessel disease in vivo. The presence of a mixed supplied hippocampus was an advantage in several cognitive domains, including verbal list learning and global cognition. A mixed supplied hippocampus also was an advantage for verbal memory performance in cerebral small vessel disease. Voxel-based morphometry showed higher anterior hippocampal grey matter volume in mixed, compared to single supply. We discuss that a mixed hippocampal supply, as opposed to a single one, may increase the reliability of hippocampal blood supply and thereby provide a hippocampal vascular reserve that protects against cognitive impairment.

Ultrasound has revealed cross‐sectional nerve area (CSA) reduction in amyotrophic lateral sclerosis (ALS), but little is known about the sonographic nerve texture beyond CSA alterations. In a large cohort of 177 ALS patients and 57 control subjects, we investigated the covariance and disease‐specific signature of several sonographic texture features of the median and ulnar nerves and their relationship to the patients’ clinical characteristics. ALS patients showed atrophic nerves, a loss of the intranerve structures’ echoic contrast, elevated coarseness, and a trend toward lower cluster shading compared with controls. A reduction in intranerve echoic contrast was related to longer disease duration and poorer functional status in ALS. Sonographic texture markers point toward a significant reorganization of the deep nerve microstructure in ALS. Future studies will be needed to further substantiate the markers’ potential to assess peripheral nerve alterations in ALS.

Objective To investigate underlying cerebral small vessel disease (CSVD) in patients with mixed cerebral hemorrhages patterns and phenotype them according to the contribution of the two most common sporadic CSVD subtypes: cerebral amyloid angiopathy (CAA) vs. hypertensive arteriopathy (HA). Methods Brain MRIs of patients with intracerebral hemorrhages (ICHs) and/or cerebral microbleeds (CMBs) were assessed for the full spectrum of CSVD markers using validated scales: ICHs, CMBs, cortical superficial siderosis (cSS), white matter hyperintensities, MRI-visible perivascular spaces (PVS). PVS predominance pattern was grouped as centrum-semiovale (CSO)-PVS predominance, basal-ganglia (BG)-PVS predominance, CSO-PVS and BG-PVS equality. Patients with mixed cerebral hemorrhages were classified into mixed CAA-pattern or mixed HA-pattern according to the existence of cSS and/or a CSO-PVS predominance pattern and comparisons were performed. Results We included 110 patients with CAA (strictly lobar ICHs/CMBs), 33 with HA (strictly deep ICHs/CMBs) and 97 with mixed lobar/deep ICHs/CMBs. Mixed patients were more similar to HA with respect to their MRI-CSVD markers, vascular risk profile and cerebrospinal fluid (CSF) measures. In the mixed patients, 33 (34%) had cSS, a CSO-PVS predominance pattern, or both, and were defined as mixed CAA-pattern cases. The mixed CAA-pattern patients were more alike CAA patients regarding their MRI-CSVD markers, CSF and genetic profile. Conclusion Our findings suggest that the heterogeneous group of patients with mixed cerebral hemorrhages distribution can be further phenotyped according to the predominant underlying CSVD. cSS presence and a CSO-PVS predominance pattern could serve as strongly suggestive markers of a contribution from CAA among patients with mixed hemorrhages.

We systematically identified and reviewed 29 studies of peripheral nerve ultrasound or magnetic resonance imaging (MRN) in amyotrophic lateral sclerosis (ALS). The majority of the ultrasound studies reported smaller nerves and nerve roots in ALS compared to healthy controls, but there was a large overlap of the cross-sectional nerve area between ALS and controls. Most of the MRN studies confirmed nerve abnormalities demonstrating slight T2 hyperintensities and, sometimes, mild enlargement of more proximal nerve segments (plexus, roots) in ALS. The size of the proximal nerve segments, i.e. nerve roots, is thus somewhat incongruent between nerve ultrasound and MRN in ALS. Peripheral nerve ultrasound has the potential to differentiate between ALS and multifocal motor neuropathy (MMN) in that patients with MMN have significantly larger nerves. Conversely, there is an overlap of MRN abnormalities in ALS and MMN, restricting the techniques' utility in the clinical setting. A subgroup of patients with ALS seems to reveal a sonographic nerve pattern suggesting peripheral nerve inflammation. In the future, combined imaging with nerve ultrasound and MRN assessing parameters such as blood flow or textural markers may aid in the understanding of the deep nerve microstructure down to the fascicle level, and thus, in the classification of the nerve state as more degenerative or more inflammatory in ALS. This systematic review provides evidence that nerve imaging abnormalities are common in ALS.

We aimed to test the hypothesis that in spontaneously hypertensive stroke-prone rats (SHRSP), non-amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17-44 weeks) and 10 age- and sex-matched Wistar control rats, that underwent two-photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy-X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age-dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non-occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy-X04 positivity indicative of cortical CAA. Vascular β-amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post-mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain.

PURPOSE: To investigate the whole-brain landscape of iron-related abnormalities in amyotrophic lateral sclerosis (ALS) by using the in vivo MRI technique of quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: For this prospective study, 28 patients with ALS (mean age, 61 years; age range, 43–77 years; 18 men [mean age, 61 years; range, 43–77 years] and 10 women [mean age, 61 years; range, 47–74 years]) recruited between January 17, 2014, and September 4, 2015, and 39 matched control subjects (mean age, 61 years; age range, 39–77 years; 24 men [mean age, 62 years; range, 39–77 years] and 15 women [mean age, 59 years; range, 39–73 years]) were examined by using structural and susceptibility 3.0-T MRI techniques. Group data were cross sectionally compared with family-wise error (FWE) corrections by using voxel-based morphometry (random-field theory), cortical thickness analysis (Monte Carlo simulated), subcortical volumetry (Bonferroni-corrected Wilcoxon rank-sum testing), and QSM analysis (cluster-enhanced whole-brain permutation testing and Bonferroni-corrected rank-sum testing in regions of interest). In patients with ALS, a potential relationship between diffusion and susceptibility measurements in the corticospinal tracts (CSTs) was also examined by using Spearman rank-correlation tests. RESULTS: Conventional structural measures failed to identify atrophy in the present cohort (FWE P > .05). However, QSM identified several whole-brain abnormalities (FWE P < .05) in ALS. Regionally, higher susceptibility (expressed as means in parts per million ± standard errors of the mean) was confirmed in the motor cortex (ALS = 0.0188 ± 0.0003, control = 0.0173 ± 0.0003; P < .001), the left substantia nigra (ALS = 0.127 ± 0.004, control = 0.113 ± 0.003; P = .008), the right substantia nigra (ALS = 0.141 ± 0.005, control = 0.120 ± 0.003; P < .001), the globus pallidus (ALS = 0.086 ± 0.003, control = 0.075 ± 0.002; P = .003), and the red nucleus (ALS = 0.115 ± 0.004, control = 0.098 ± 0.003; P < .001). Lower susceptibility was found in CST white matter (ALS = −0.047 ± 0.001, control = −0.043 ± 0.001; P = .01). Nigral and pallidal QSM values were cross correlated in ALS (ρ(2) = 0.42, P < .001), a phenomenon visually traceable in many individual patients. QSM in the CST in ALS also correlated with diffusion-tensor metrics in this tract (ρ(2) = 0.25, P = .007). CONCLUSION: Whole-brain MRI quantitative susceptibility mapping analysis is sensitive to tissue alterations in amyotrophic lateral sclerosis that may be relevant to pathologic changes. © RSNA, 2018

We thank the authors for the attention dedicated to our study.1 This work reports the presence of microbleeds (MBs) with a spatial connection to veins, as observed on high-resolution Quantitative Susceptibility Mapping. As we openly discuss, we cannot exclude that this observed spatial relationship is not a casual one; only neuropathologic correlation studies can provide certainty. Considering the predominantly arterial pattern of vascular amyloid-β accumulation in cerebral amyloid angiopathy, alternative vessel pathologies—such as venous collagenosis2—are more likely to play a role.

Introduction. Myasthenia gravis (MG) is an autoimmune disease affecting the peripheral nervous system and causes skeletal muscle weakness. Additionally, systemic inflammation, cognitive deficits and autonomic dysfunction have been described (Gilhus et al., 2019). Here, we investigate structural and functional brain changes in MG patients. Materials & Methods. Eleven MG patients (age: 70.64 ± 9.27; 11 male) were compared to age-, sex- and education-matched healthy controls (age: 70.18 ± 8.98). All patients received cholinesterase inhibitors. Structural brain changes were determined with voxel-based morphometry (VBM) using high-resolution T1-weighted MPRAGE sequences. Functional brain changes were accesed wih a neuropsychological test battery that probed cognitive deficits (MMST), attention, memory and executive functions. Results. MG patients showed significant grey matter volume reductions in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus. Furthermore, MG patients showed significant lower results in working memory (Spatial Span, p = .034, |d| = 1.466) and verbal episodic memory (VLMT, p = .003, |d| = 1.463). Discussion. Our results indicate that MG is associated with structural and functional brain alterations. Especially the grey matter volume changes in the cingulate gyrus and the inferior parietal lobe could be associated with cognitive deficits in memory and executive functions. Future research is needed to replicate this finding in a larger sample size and to investigate structural and functional brain changes in a longitudinal study. Reference Gilhus, Nils Erik; Tzartos, Socrates; Evoli, Amelia; Palace, Jacqueline; Burns, Ted M.; Verschuuren, Jan J. G. M. (2019): Myasthenia gravis. In: Nature reviews. Disease primers 5 (1), S. 30. DOI: 10.1038/s41572-019-0079-y.

Introduction: We aimed to investigate whether sonographic peripheral cross-sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS). Methods: We included 55 ALS patients who had forearm median and ulnar nerve CSA, cerebrospinal fluid (CSF) PGRN and serum PGRN measures available. CSF PGRN was normalized against the CSF/serum albumin ratio (Qalb). Using age, sex, height and weight adjusted general linear models we examined CSA x CSF PGRN interaction effects on various measures. Results: There was a medium-effect size inverse relationship between CSA and CSF PGRN, but not between CSA and serum PGRN. Lower CSA values together with higher CSF PGRN levels were linked to smaller motor amplitudes. Discussion: In ALS, the constellation of peripheral nerve atrophy together with higher CSF PGRN levels indicates pronounced axonal damage. This article is protected by copyright. All rights reserved.

OBJECTIVE: To assess cerebrovascular reactivity in response to a visual task in participants with cerebral amyloid angiopathy (CAA), Alzheimer disease (AD), and mild cognitive impairment (MCI) using fMRI. METHODS: This prospective cohort study included 40 patients with CAA, 22 with AD, 27 with MCI, and 25 healthy controls. Each participant underwent a visual fMRI task using a contrast-reversing checkerboard stimulus. Visual evoked potentials (VEPs) were used to compare visual cortex neuronal activity in 83 participants. General linear models using least-squares means, adjusted for multiple comparisons with the Tukey test, were used to estimate mean blood oxygen level–dependent (BOLD) signal change during the task and VEP differences between groups. RESULTS: After adjustment for age and hypertension, estimated mean BOLD response amplitude was as follows: CAA 1.88% (95% confidence interval [CI] 1.60%–2.15%), AD 2.26% (1.91%–2.61%), MCI 2.15% (1.84%–2.46%), and control 2.65% (2.29%–3.00%). Only patients with CAA differed from controls (p = 0.01). In the subset with VEPs, group was not associated with prolonged latencies or lower amplitudes. Lower BOLD amplitude response was associated with higher white matter hyperintensity (WMH) volumes in CAA (for each 0.1% lower BOLD response amplitude, the WMH volume was 9.2% higher, 95% CI 6.0%–12.4%) but not other groups (p = 0.002 for interaction) when controlling for age and hypertension. CONCLUSIONS: Mean visual BOLD response amplitude was lowest in participants with CAA compared to controls, without differences in VEP latencies and amplitudes. This suggests that the impaired visual BOLD response is due to reduced vascular reactivity in CAA. In contrast to participants with CAA, the visual BOLD response amplitude did not differ between those with AD or MCI and controls.

Summary: Background: To assess the vascular and clinical course of acute symptomatic extracranial internal carotid artery (ICA) occlusion. Patients and methods: Patients with an acute ischemic event in the anterior circulation and corresponding extracranial ICA occlusion at CT angiography and/or color-coded duplex sonography underwent recurrent duplex follow-up for detection of spontaneous recanalization. Stroke recurrence and functional outcome 4.5 months after the ischemic index event assessed by modified Rankin scale served as secondary outcome parameters. Results: 133 patients (91 men, mean age 62.3 years, SD 10.8) demonstrated symptomatic occlusion of the extracranial ICA with open intracranial ICA and open middle cerebral artery and were followed-up for spontaneous recanalization. Twenty-eight recanalized spontaneously, 25 to high-grade focal stenosis within 12 days, revealing an early cumulative recanalization rate of 23 %. Detection of recanalization was independently associated with de novo dual anti-platelet therapy (adjusted odds ratio [OR], 3.24; 95 % confidence interval [CI], 1.34 to 7.80). Ischemic recurrence occurred in 16 patients, of which 10 deemed to be embolic and 5 hemodynamic. Spontaneous ICA recanalization and an exhausted cerebrovascular reserve in the hemisphere distal to the occluded ICA were both independently associated with the occurrence of a recurrent ischemic event at Cox regression. An increasing NIHSS score at admission, a decreasing middle cerebral artery flow velocity and an ischemic recurrence independently predicted poor outcome (modified Rankin scale 3 to 6) in multivariate analysis. Conclusions: Acute symptomatic extracranial ICA occlusion is an unstable condition with frequent spontaneous recanalization to severe stenosis and early embolic stroke recurrence, demanding appropriate prevention especially in those patients with only mild deficit.

Background Dyspnea is frequent in amyotrophic lateral sclerosis (ALS) and one of the most bothersome symptoms. The recently developed Dyspnea-ALS-Scale (DALS-15) is a disease-specific patient-reported outcome to detect and quantify dyspnea. Objectives To analyze in a case-based approach the diagnostic and clinical implications and the benefit of the DALS-15 for individual patients in daily clinical routine. Methods Dyspnea was assessed by the 15-item comprising DALS-15 in two patients with ALS. Spirometry was performed and blood gases were analyzed. Results were evaluated in the clinical context of the respective patients. Results In one patient the presence of dyspnea detected by the DALS-15 indicated noninvasive ventilation (NIV) although forced vital capacity (FVC) and blood gas analysis were well preserved. After NIV implementation, the DALS-15 was helpful to determine the patient’s need for medication, the timing of NIV titration and the adaptation of NIV sessions. In another patient, who was anarthric and no longer able to perform spirometry due to severe bulbar impairment, the DALS-15 allowed a standardized assessment of dyspnea-related distress independently of bulbar dysfunction. Conclusion The DALS-15 provides a deeper insight into the respiratory status of individual patients. It helps to diagnose respiratory impairment in patients in whom NIV should be considered although FVC and blood gas results do not reveal indication for NIV. It is also valuable for the guidance of patients in later stages of respiratory impairment when NIV is already implemented, and in patients with severe bulbar dysfunction. The DALS-15 can improve specific symptom management and coordination of care and therefore has the potential to optimize individual treatment in ALS patients with dyspnea.

Deep perforator arteriopathy (DPA) and cerebral amyloid angiopathy (CAA) are the commonest known cerebral small vessel diseases (CSVD), which cause ischaemic stroke, intracebral haemorrhage (ICH) and vascular cognitive impairment (VCI). While thus far mainly considered as separate entities, we here propose that DPA and CAA share similarities, overlap and interact, so that 'pure' DPA or CAA are extremes along a continuum of age-related small vessel pathologies. We suggest blood-brain barrier (BBB) breakdown, endothelial damage and impaired perivascular β-amyloid (Aβ) drainage are hallmark common mechanisms connecting DPA and CAA. We also suggest a need for new biomarkers (e.g. high-resolution imaging) to deepen understanding of the complex relationships between DPA and CAA.

Objectives: Elevated neurofilament light chain (NFL) levels within the cerebrospinal fluid (CSF) are a biomarker representing axonal neurodegeneration in rapid progressive neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). It is unclear to what extent the levels of NFL increase in the CSF (CSF-NFL) in a chronic neuroinflammatory process with axonal neurodegeneration, as found in primary progressive multiple sclerosis (PPMS).Methods: We used a multicenter approach to statistically compare CSF-NFL levels between PPMS patients (n = 50), ALS patients (n = 50), and healthy controls (n = 50). Clinical findings, including disease duration, expanded disability status scale (EDSS), electrophysiological recordings such as visual evoked potentials or spinal and cerebral MRI, and previously administered treatment were selected as experimental parameters retrospectively.Results: Median [range] CSF-NFL concentrations in PPMS patients were significantly higher than in the controls [1724 (799–4275) pg/ml vs. 1202 (612–2934) pg/ml, p = 0.015], and significantly lower compared to ALS patients [1724 (799–4275) pg/ml vs. 10238 (2610–35138) pg/ml, p < 0.001]. There was no correlation between CSF-NFL and disease duration (p = 0.5), EDSS (p = 0.2) or treatment (p = 0.3).Conclusion: We conclude that CSF-NFL may mirror the proposed slow axonal degeneration in PPMS, but does not reflect the disease severity.

Introduction: In this study we investigated whether peripheral nerve sonography could be used as a biomarker to monitor disease progression in amyotrophic lateral sclerosis (ALS). Methods: In 37 patients, ulnar and median nerve cross-sectional area (CSA) was determined in at least 2 ultrasound sessions; mean follow-up was 14.5 months. Linear mixed-effects models were conducted to analyze time effects on CSA. Results: Ulnar nerve CSA declined significantly at a monthly rate of –0.04 mm (forearm) and –0.05 mm (wrist); the decrease was more pronounced when baseline CSA was greater. To detect a 50% treatment effect on ulnar nerve CSA, 332 patients would need to be entered in a hypothetical randomized, controlled clinical trial. Time had no significant impact on median nerve CSA. Conclusions: Distal ulnar nerve ultrasound may be a useful biomarker to monitor disease progression in ALS, especially as hypothetical treatment effects on CSA seem to be detectable in manageable cohort sizes. Muscle Nerve 54: 391–397, 2016.

While chronic kidney disease seems to be an independent risk factor for cognitive decline, its impact on cerebral amyloid-β (Aβ) depositions, one hallmark of Alzheimer's Disease (AD) pathology, has not been investigated. Utilizing 80 male nontransgenic spontaneously hypertensive stroke prone rats (SHRSP) at various ages (12 to 44 weeks), tubulointerstitial renal damage, prevalence of cerebral microhemorrhages and Aβ accumulations were quantified. Using age-adjusted general linear models we investigated the main and interaction effects of renal damage and cerebral microhemorrhages on cerebral Aβ load. In addition, using post mortem human brain tissue of 16 stroke patients we examined the co-localization of perivascular Aβ deposits and small vessel wall damage. Statistical models revealed an age-independent main effect of tubulointerstitial kidney damage on brain Aβ accumulations, which was reinforced by the consecutive presence of cerebral microhemorrhages. Moreover, cerebral microhemorrhages independently predicted brain Aβ burden in SHRSP. In up to 69% of all human cases perivascular Aβ deposits were detected in the direct vicinity of small vessel wall damage. Our results support the associations between vascular pathology and Aβ deposition, and demonstrate a relationship between chronic kidney disease and cerebral Aβ pathology. Hence, our data suggest that prevention of chronic renal damage may reduce cerebral Aβ pathology.

Bildgebende Verfahren erlauben die Darstellung von Veranderungen des peripher-motorischen Systems bei amyotropher Lateralsklerose (ALS). Die Nervensonografie kann anhand der Messung nervaler Querschnittsflachen bereits heute zwischen ALS, primarer Lateralsklerose (PLS) und multifokaler motorischer Neuropathie (MMN) unterscheiden helfen. Muskelsonografisch lassen sich Faszikulationen u. a. in der Zungenmuskulatur und sogar in klinisch und elektrophysiologisch unauffalligen Muskeln nachweisen. Die Magnetresonanztomografie (MRT) der Zungenmuskulatur kann zur Differenzierung zwischen supra- und infranuklearer bulbarer Symptomatik beitragen. Die MR-Neurografie inklusive des peripheren Diffusion Tensor Imagings (DTI) wird neue Einblicke in die Veranderungen des peripheren Nervensystems bei ALS – auch auf der Faszikelebene – erlauben. Bildgebende Verfahren zur Erfassung der Beteiligung des zweiten Motoneurons konnten insgesamt einen wichtigen Beitrag zur differenzialdiagnostischen Abgrenzung der ALS leisten und damit die fruhzeitige Therapiesteuerung verbessern.

Context There is no evidence-based treatment for fatigue in amyotrophic lateral sclerosis (ALS), and identification of treatable causes determines management strategies. Although dyspnea is a key symptom of ALS and effectively treatable, it has not been sufficiently investigated whether dyspnea may be a fatigue-promoting factor. Objectives To determine the level of fatigue in dyspneic ALS patients and whether fatigue is promoted by dyspnea. We further evaluated the correlation of fatigue with respiratory function tests. Methods About 101 dyspneic patients and 20 matched controls completed the ALS Functional Rating Scale—Extension and the Fatigue Severity Scale. Dyspneic patients additionally completed the Dyspnea-ALS Scale and the ALS Assessment Questionnaire and underwent respiratory function tests (forced vital capacity, sniff nasal inspiratory pressure, mean inspiratory and expiratory pressure with respective relaxation rates, and blood gases). Multiple regression and correlation analyses were conducted. Results Dyspneic patients had significantly higher fatigue scores than nondyspneic patients, and their fatigue significantly affected quality of life. Dyspnea alone explained up to 24% of the variance in fatigue. No associations were observed between fatigue and respiratory function tests. Patients with noninvasive ventilation reported significantly more dyspnea and fatigue. Conclusion Fatigue is a frequent and bothersome symptom in dyspneic ALS patients. Dyspnea-related distress is, in contrast to objective indicators of respiratory impairment, a determining factor of experienced fatigue. There is an urgent need for further symptom relief beyond noninvasive ventilation. Adequate treatment of dyspnea has the potential for synergies in symptom management arising from the association between fatigue and dyspnea.

The study by Gattringer et al.1 of symptomatic patients with a recent small subcortical infarct revealed a dynamic relationship between serum neurofilament light chain (NfL) and microangiopathic MRI changes emphasizing NfL's pivotal role as a new biomarker of active cerebral small vessel disease (CSVD), even if clinically silent. We confirm and extend the authors' findings of CSF NfL by studying an incident chronic CSVD cohort selected through the presence of microhemorrhages (n = 14).2 Compared to controls (n = 33), patients with CSVD displayed significantly higher CSF NfL concentrations (mean [SD] 1.318 [491] vs 11.068 [13.031] pg/mL, F 1 = 8.4, p = 0.006), within the range found in amyotrophic lateral sclerosis (12.016 [9.943] pg/mL, n = 99, F 1 = 0.1, p = 0.7), where increased CSF NfL is already established as a diagnostic biomarker of neuroaxonal injury.3 In chronic CSVD, there was a relationship between CSF NfL, peribasal ganglia white matter hyperintensities ( r = 0.5, p = 0.02),4 and lacunes ( r = 0.5, p = 0.04). Our data support the idea of NfL reflecting CSVD burden. Neurofilaments may also serve as a prognostic/disease activity biomarker in terms of predicting stroke and dementia development.

Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has emerged as putative diagnostic biomarker in amyotrophic lateral sclerosis (ALS), but it remains a matter of debate, whether CSF total tau (ttau), tau phosphorylated at threonine 181 (ptau) and the ptau/ttau ratio could serve as diagnostic biomarker in ALS as well. Moreover, the relationship between CSF NfL and tau measures to further axonal and (neuro)degeneration markers still needs to be elucidated. Our analysis included 89 ALS patients [median (range) age 63 (33-83) years, 61% male, disease duration 10 (0.2-190) months] and 33 age- and sex-matched disease controls [60 (32-76), 49%]. NfL was higher and the ptau/ttau ratio was lower in ALS compared to controls [8343 (1795-35,945) pg/ml vs. 1193 (612-2616), H(1) = 70.8, p

Objective We aimed to assess whether differential peripheral nerve involvement parallels dissociated forearm muscle weakness in amyotrophic lateral sclerosis (ALS). Methods The analysis comprised 41 ALS patients and 18 age-, sex-, height- and weight-matched healthy controls. Strength of finger-extension and -flexion was measured using the Medical Research Council (MRC) scale. Radial, median and ulnar nerve sonographic cross-sectional area (CSA) and echogenicity, expressed by the hypoechoic fraction (HF), were determined. Results In ALS, finger extensors were significantly weaker than finger flexors. Sonographic evaluation revealed peripheral nerve atrophy, affecting various nerve segments in ALS. HF was unaltered. Conclusions This systematic study confirmed a long-observed physical examination finding in ALS – weakness in finger-extension out of proportion to finger-flexion. This phenomenon was not related to any particular sonographic pattern of upper limb peripheral nerve alteration. Significance In ALS, dissociated forearm muscle weakness could aid in the disease’s diagnosis. Nerve ultrasound did not provide additional information on the differential involvement of finger-extension and finger-flexion strength.

Introduction: In this study we sought to determine the cross-sectional area (CSA) of peripheral nerves in patients with distinct subtypes of amyotrophic lateral sclerosis (ALS). Methods: Ulnar and median nerve ultrasound was performed in 78 ALS patients [classic, n=21; upper motor neuron dominant (UMND), n=14; lower motor neuron dominant (LMND), n=20; bulbar, n=15; primary lateral sclerosis (PLS), n=8] and 18 matched healthy controls. Results: Compared with controls, ALS patients had significant, distally pronounced reductions of ulnar CSA (forearm/wrist level) across all disease groups, except for PLS. Median nerve CSA (forearm/wrist level) did not differ between controls and ALS. Conclusion: Ulnar nerve ultrasound in ALS subgroups revealed significant differences in distal CSA values, which suggests it has value as a marker of LMN involvement. Its potential was particularly evident in the UMND and PLS groups, which can be hard to separate clinically, yet their accurate separation has major prognostic implications.

Objective:We investigated corticospinal tract (CST) integrity in the absence of white matter (WM) lesions using diffusion tensor imaging (DTI) in early MS disease stages.Methods:Our study comprised 19 patients with clinically isolated syndrome (CIS), 11 patients with relapsing-remitting MS (RRMS), and 32 age- and sex-matched healthy controls, for whom MRI measures of CST integrity (fractional anisotropy [FA], mean diffusivity [MD]), T1- and T2-based lesion load, and brain volumes were available. The mean (SD) disease duration was 3.5 (2.1) months, and disability score was low (median Expanded Disability Status Scale 1.5) at the time of the study.Results:Patients with CIS and RRMS had significantly lower CST FA and higher CST MD values compared with controls. These findings were present, irrespective of whether WM lesions affected the CST. However, no group differences in the overall gray or WM volume were identified.Conclusions:In early MS disease stages, CST integrity is already affected in the absence of WM lesions or brain atrophy.

Background While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr\(^{−/-}\) mouse model. Methods We used Ldlr\(^{−/-}\) mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr\(^{−/-}\) mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds. Results We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr\(^{−/-}\) mice compared to all other groups (P < 0.05). Ldlr\(^{−/-}\) animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr\(^{−/-}\) mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr\(^{−/-}\) mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions. Conclusions In Ldlr\(^{−/-}\) mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr\(^{−/-}\) mice appear to be an adequate animal model for research into CSVD.

Increasingly, retailers rely on interactive technologies to improve consumers' shopping experiences. On the one side, interactive kiosks and smart mirrors make use of dedicated devices and software to explain, configure, and recommend products. On the other side, computer programs – so-called apps – are installed on the consumer's own device for the same purpose. They can be used at home, or – if installed on a mobile device – in retail outlets or on the move. In all cases, augmented reality (AR) can support these purposes by placing virtual content (e.g. new furniture) in a real environment (the consumer's home). The overall perception and acceptance toward such interactive technologies are discussed in this paper. Users' perceptions and experiences are measured by applying a modified technology acceptance model (TAM). Four experiments, two with marker-based and two with markerless AR apps are presented to support the generalization of the results, the measurement models and the measurement approach. The results are satisfactory with regard to the robustness of the TAM model. However, the relative importance of hedonic (enjoyment, pleasure, fun) and utilitarian (information) aspects varies for different kinds of AR apps and has to be considered for improvement to occur. From a measurement point of view the acquiescence bias has to be dealt with when developing scale items.

Online reviews by users have become an increasingly important source of information. This is true not only for new users of goods or services, but also for their producers. They extend the insight into the acceptance of new goods and services, e.g. at the point of sale, from a mere sales and usage quantity oriented point of view to a cause and effect oriented one. Since online reviews by consumers of many goods and services are nowadays widespread and easily available on the internet, the question arises whether their analysis can replace the more traditional approaches to measure technology acceptance, e.g., using questionnaires with TAM (Technology Acceptance Model) items. This paper tries to answer this question using IKEA׳s mobile catalogue app as an example. For comparisons reasons, data on the acceptance of the current version of this catalogue is collected in four different ways, (1) as answers to batteries of TAM items, (2) as assignments to pre-defined adjective pairs, (3) as textual likes and dislikes of users (simulating online reviews), and (4) as publicly available (real) reviews by users. The source for (1)–(3) is a survey with a sample of respondents, the source for (4) an online forum. The data is analyzed using partial least squares (PLS) for TAM modeling and text mining for pre-processing the textual data. The results are promising: it seems that data collection via surveys can be replaced – with some reservations – by the analysis of publicly available (real) online reviews.

Liver resection is increasingly performed in elderly patients who are suspected of increased postoperative morbidity (PM) and reduced overall survival (OS). Patient selection based on the identification of age-adjusted risk factors may help to decrease PM and OS.Prospectively collected data of 879 patients undergoing elective hepatic resection were analyzed. This population was stratified into three age cohorts:70 years (n = 228; 26 %), 60-69 years (n = 309; 35 %), and60 years (n = 342; 39 %). Multivariate survival analysis was performed.The incidence of severe (p 0.01) and non-surgical (p 0.001) postoperative complications was higher in older compared to younger patients. Major estimated blood loss (EBL; p = 0.039) and comorbidities (p = 0.002) independently increased PM. EBL was comparable between all age cohorts. However, preexisting comorbidities, major EBL, and postoperative complications markedly decreased OS in contrast to younger patients. Adjusted for age, independent predictors of OS were comorbidities (HR = 1.51; p = 0.001), major hepatectomy (HR = 1.33; p = 0.025), increased EBL (HR = 1.32; p = 0.031), and postoperative complications (HR = 1.64; p 0.001).Although increased age should not be a contraindication for liver resection, this study accents the avoidance of major blood loss in elderly patients and a stringent patient selection based on preexisting comorbidities.

There is substantial controversy regarding the causative role of amyloid β (Aβ) deposition in Alzheimer's disease (AD). The cerebrovasculature plays an important role in the elimination of Aβ from the brain and hypertension is a well‐known risk factor for AD. In spontaneously hypertensive stroke‐prone rats (SHRSP), an animal model of chronic arterial hypertension, cerebral small vessel disease (CSVD) leads to age‐dependent parenchymal Aβ accumulation similar to that observed in AD. These data approve the neuropathological link between CSVD and AD, confirm the challenge that parenchymal Aβ deposition is a specific marker for AD and disclose the meaning of SHRSP as valid experimental model to investigate the association between hypertension, CSVD, and Aβ plaques.

Background We aimed to examine whether distinct sonographic gray-scale measures of the peripheral nerve vary between amyotrophic lateral sclerosis (ALS), ALS disease mimics and various neuropathies to ascertain the diagnostic value of high-resolution ultrasound for the differentiation of these disorders. Methods Our analysis comprised n = 54 controls and n = 250 patients (ALS n = 169, hereditary spastic paraplegia [HSP] n = 25 [pure and complex], primary lateral sclerosis [PLS] n = 13, immune-mediated neuropathies [IMNs] n = 12, hereditary demyelinating neuropathies [HDNs] n = 13, hereditary axonal/mixed neuropathies [HMNs] n = 13, hereditary neuropathy with liability to pressure palsy [HNPP] n = 5). Peripheral nerve ultrasound was conducted and offline analysis of median and ulnar nerve segments, each considered as a region of interest (ROI), comprised the calculation of the nerves’ cross sectional area (CSA), median echo intensity (EI), echo variance (EV), fascicular portion (hypoechoic fraction [HF]) and textural correlation (TCOR). As there were no side differences, left- and right-sided measures were averaged. General linear models were conducted to assess group effects on various sonographic measures (significant at p Results Sonographic measures depended on age, sex, height and weight. At entrapment and non-entrapment sites IMNs and HDNs revealed nerve enlargement compared to the remainder, while in HDNs compared to IMNs nerve CSA was even greater (2fold vs. 3fold enlargement compared to controls). In hereditary neuropathies (HDNs, HMNs) median nerve EI was lowest, which was accompanied by high EV, fascicular enlargement (high HF) and alterations of the nerves’ texture (TCOR). In ALS (all subtypes) versus the remainder comprising HSP, PLS and IMNs, ulnar nerve CSA was smaller; moreover, in ALS compared to HSP or axonal/mixed neuropathies (HMNs) the median nerves’ texture pattern (TCOR) was different. In HNPP compared to the remaining groups (except IMNs and HDNs) wrist median nerve CSA (entrapment site) was greater, which was related to fascicular enlargement (high HF). Results remained unchanged after model adjustment for age, sex, height and weight. Conclusion ALS, ALS disease mimics and various neuropathies are not only characterized by distinct sonographic nerve areas, but also reveal in-between-group differences of further sonographic gray-scale nerve measures. Future studies need to address the question how sonographic composite scores could aid in the differentiation between ALS and its disease mimics and how those scores relate to further ultrasound features such as the nerves’ microvascular blood flow.