Vitamin D3 deficiency and osteopenia in spastic paraplegia type 5 indicate impaired bone homeostasis.

Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessively inherited movement disorder characterized by progressive spastic gait disturbance and afferent ataxia. SPG5 is caused by bi-allelic loss of function mutations in CYP7B1 resulting in accumulation of the oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol in serum and cerebrospinal fluid of SPG5 patients. An effect of 27- hydroxycholesterol via the estrogen and liver X receptors was previously shown on bone homeostasis. This study analyzed bone homeostasis and osteopenia in 14 SPG5 patients as a non-motor feature leading to a potential increased risk for bone fractures. T-Scores in CT bone density measurements were reduced, indicating osteopenia in SPG5 patients. Further, we analyzed various metabolites of bone homeostasis by ELISA in serum samples of these patients. We identified a lack of vitamin D3 metabolites (Calcidiol and Calcitriol), an increase in Sclerostin as a bone formation/mineralization inhibiting factor, and a decrease in cross-linked N-telopeptide of type I collagen (NTX), a marker indicating reduced bone resorption. As statin treatment has been found to lower oxysterol levels, we evaluated its effect in samples of the STOP-SPG5 trial and found atorvastatin to normalize the increased sclerostin levels. In summary, our study identified osteopenia as a non-motor feature in SPG5 and suggests the need for vitamin D3 substitution in SPG5 patients. Sclerostin may be considered a therapeutic target and biomarker in upcoming therapeutical trials in SPG5.

[Interdisciplinary networks in diseases of peripheral nerves-Exemplified by the Tübingen nerve team]. / Interdisziplinäre Netzwerke bei Erkrankungen der peripheren Nerven ­ am Beispiel des Tübinger Nerve Teams.

BACKGROUND: Nerve damage can be autoimmune inflammatory, metabolic or traumatic, among others, and can be difficult to differentiate. OBJECTIVE: What are the advantages of interdisciplinary networks and how do they work? MATERIAL AND METHOD: Field report with case presentation from the University Hospital Tübingen in cooperation with the BG Accident Clinic Tübingen. CONCLUSION: Interdisciplinary networks improve the care of our patients and also serve as regular multidisciplinary continuing education.

[Choosing the right imaging for the diagnostics and assessment of the course of peripheral nerve injuries]. / Die Wahl der richtigen Bildgebung zur Diagnostik und Verlaufsbeurteilung peripherer Nervenverletzungen.

BACKGROUND: Nerve injuries are a frequent problem in routine clinical practice and require intensive interdisciplinary care. OBJECTIVE: The current status of imaging to confirm the diagnosis of nerve injuries is described. The role of high-resolution ultrasound and magnetic resonance imaging (MRI) in the diagnostics and follow-up of peripheral nerve injuries is elaborated. MATERIAL AND METHODS: Review of the current state of imaging to confirm the diagnosis of nerve injuries. RESULTS: Depending on the suspected site of damage, the primary domain of magnetic resonance (MR) imaging (MR neurography) is injuries in the region of the spine, nerve roots, brachial plexus and lumbar plexus, pelvis and proximal thigh. In contrast, in other peripheral nerve lesions of the extremities the advantages of high-resolution nerve ultrasound in a dynamic setting predominate. The MR neurography is indicated here, especially in the frequent bottleneck syndromes and only in very isolated and selected cases. CONCLUSION: In addition to a correct anatomical assignment, the timely decision for a possible intervention and the appropriate concomitant treatment are an important basis for a favorable prognosis of nerve injuries. Imaging techniques should therefore be used early in the diagnostics and follow-up controls of peripheral nerve injuries.

Clinical-Radiological Mismatch in Multiple Sclerosis Patients during Acute Relapse: Discrepancy between Clinical Symptoms and Active, Topographically Fitting MRI Lesions.

BACKGROUND: Relapses in multiple sclerosis (MS) patients are usually defined as subacute clinical symptoms that last for at least 24 h. To validate a clinical relapse on magnetic resonance imaging (MRI), an anatomically fitting lesion with gadolinium enhancement in the central nervous system (CNS) would be mandatory. The aim of this study was to validate clinical relapses in regard to the concomitant detection of active, anatomically fitting MRI lesions. METHODS: We performed a retrospective analysis of 199 MS patients with acute relapse who had received an MRI scan before the initiation of methylprednisolone (MPS) therapy. Clinical data and MRIs were systematically reanalyzed by correlating clinical symptoms with their anatomical representation in the CNS. Patients were then categorized into subgroups with a clinical-radiological match (group 1) or clinical-radiological mismatch (group 2) between symptoms and active, topographically fitting lesions and further analyzed in regard to clinical characteristics. RESULTS: In 43% of our patients, we observed a clinical-radiological mismatch (group 2). Further analysis of patient characteristics showed that these patients were significantly older at the time of relapse. MS patients in group 2 also showed a significantly longer disease duration and significantly more previous relapses when compared to group 1. Comparing symptom clusters, the appearance of motor dysfunction during the current relapse was significantly more frequent in group 2 than in group 1. The overall dose of MPS treatment was significantly lower in group 2 than in group 1 with a similar treatment response in both groups. CONCLUSIONS: The substantial clinical-radiological mismatch during acute relapse in our study could be explained by several factors, including a psychosomatic component or disturbance of network connectivity. Alternatively, secondary progression or a diffuse neuro-inflammatory process might cause clinical symptoms, especially in older patients with a longer disease duration. As a consequence, treatment of clinical relapses and the definition of breakthrough disease should be reconsidered in regard to combined clinical and MRI criteria and/or additional biomarkers. Further studies are necessary to address the contribution of diffuse neuro-inflammation to the clinical presentation of symptoms.

Speech and Nonspeech Parameters in the Clinical Assessment of Dysarthria: A Dimensional Analysis.

Nonspeech (or paraspeech) parameters are widely used in clinical assessment of speech impairment in persons with dysarthria (PWD). Virtually every standard clinical instrument used in dysarthria diagnostics includes nonspeech parameters, often in considerable numbers. While theoretical considerations have challenged the validity of these measures as markers of speech impairment, only a few studies have directly examined their relationship to speech parameters on a broader scale. This study was designed to investigate how nonspeech parameters commonly used in clinical dysarthria assessment relate to speech characteristics of dysarthria in individuals with movement disorders. Maximum syllable repetition rates, accuracies, and rates of isolated and repetitive nonspeech oral-facial movements and maximum phonation times were compared with auditory-perceptual and acoustic speech parameters. Overall, 23 diagnostic parameters were assessed in a sample of 130 patients with movement disorders of six etiologies. Each variable was standardized for its distribution and for age and sex effects in 130 neurotypical speakers. Exploratory Graph Analysis (EGA) and Confirmatory Factor Analysis (CFA) were used to examine the factor structure underlying the diagnostic parameters. In the first analysis, we tested the hypothesis that nonspeech parameters combine with speech parameters within diagnostic dimensions representing domain-general motor control principles. In a second analysis, we tested the more specific hypotheses that diagnostic parameters split along effector (lip vs. tongue) or functional (speed vs. accuracy) rather than task boundaries. Our findings contradict the view that nonspeech parameters currently used in dysarthria diagnostics are congruent with diagnostic measures of speech characteristics in PWD.

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia.

BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. CONCLUSIONS: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The prodromal phase of hereditary spastic paraplegia type 4: the preSPG4 cohort study.

This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-ß (Aß). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aß to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.

Cortical reactivity to transcranial magnetic stimulation predicts risk of post-stroke delirium.

OBJECTIVE: Post-stroke delirium (PSD) is a frequent and with regard to outcome unfavorable complication in acute stroke. The neurobiological mechanisms predisposing to PSD remain poorly understood, and biomarkers predicting its risk have not been established. We tested the hypothesis that hypoexcitable or disconnected brain networks predispose to PSD by measuring brain reactivity to transcranial magnetic stimulation with electroencephalography (TMS-EEG). METHODS: We conducted a cross-sectional study in 33 acute stroke patients within 48 hours of stroke onset. Brain reactivity to single-pulse TMS of dorsolateral prefrontal cortex, primary motor cortex and superior parietal lobule of the right hemisphere was quantified by response intensity, effective connectivity, perturbational complexity index (PCIST), and natural frequency of the TMS-EEG response. PSD development was clinically tracked every 8 hours before and for 7 days following TMS-EEG. RESULTS: Fourteen patients developed PSD while 19 patients did not. The PSD group showed lower excitability, effective connectivity, PCIST and natural frequency compared to the non-PSD group. The maximum PCIST over all three TMS sites demonstrated largest classification accuracy with a ROC-AUC of 0.943. This effect was independent of lesion size, affected hemisphere and stroke severity. Maximum PCIST and maximum natural frequency correlated inversely with delirium duration. CONCLUSIONS: Brain reactivity to TMS-EEG can unravel brain network states of reduced excitability, effective connectivity, perturbational complexity and natural frequency that identify acute stroke patients at high risk for development of delirium. SIGNIFICANCE: Findings provide novel insight into the pathophysiology of pre-delirium brain states and may promote effective delirium prevention strategies in those patients at high risk.

Proof of principle for the clinical use of a CE-certified automatic imaging analysis tool in rare diseases studying hereditary spastic paraplegia type 4 (SPG4).

Usage of MR imaging biomarkers is limited to experts. Automatic quantitative reports provide access for clinicians to data analysis. Automated data analysis was tested for usability in a small cohort of patients with hereditary spastic paraplegia type 4 (SPG4). We analyzed 3T MRI 3D-T1 datasets of n = 25 SPG4 patients and matched healthy controls using a commercial segmentation tool (AIRAscore structure 2.0.1) and standard VBM. In SPG4 total brain volume was reduced by 27.6 percentiles (p = 0.001) caused mainly by white matter loss (- 30.8th, p < 0.001) and stable total gray matter compared to controls. Brain volume loss occurred in: midbrain (- 41.5th, p = 0.001), pons (- 36.5th, p = 0.02), hippocampus (- 20.9th, p = 0.002), and gray matter of the cingulate gyrus (- 17.0th, p = 0.02). Ventricular volumes increased as indirect measures of atrophy. Group comparisons using percentiles aligned with results from VBM analyses. Quantitative imaging reports proved to work as an easily accessible, fully automatic screening tool for clinicians, even in a small cohort of a rare genetic disorder. We could delineate the involvement of white matter and specify involved brain regions. Group comparisons using percentiles provide comparable results to VBM analysis and are, therefore, a suitable and simple screening tool for all clinicians with and without in-depth knowledge of image processing.

Spotting lesions in thorax X-rays at a glance: holistic processing in radiology.

Radiologists often need only a glance to grasp the essence of complex medical images. Here, we use paradigms and manipulations from perceptual learning and expertise fields to elicit mechanisms and limits of holistic processing in radiological expertise. In the first experiment, radiologists were significantly better at categorizing thorax X-rays when they were presented for 200 ms in an upright orientation than when they were presented upside-down. Medical students, in contrast, were guessing in both situations. When the presentation time was increased to 500 ms, allowing for a couple more glances, the radiologists improved their performance on the upright stimuli, but remained at the same level on the inverted presentation. The second experiment circumvented the holistic processing by immediately cueing a tissue within the X-rays, which may or may not contain a nodule. Radiologists were again better than medical students at recognizing whether the cued tissue was a nodule, but this time neither the inverted presentation nor additional time affected their performance. Our study demonstrates that holistic processing is most likely a continuous recurring process which is just as susceptible to the inversion effect as in other expertise domains. More importantly, our study also indicates that holistic-like processing readily occurs in complex stimuli (e.g., whole thorax X-rays) but is more difficult to find in uniform single parts of such stimuli (e.g., nodules).

Detection of spinal long fiber tract degeneration in HSP: Improved diffusion tensor imaging.

Spinal diffusion tensor imaging (sDTI) is still a challenging technique for selectively evaluating anatomical areas like the pyramidal tracts (PT), dorsal columns (DC), and anterior horns (AH) in clinical routine and for reliably quantifying white matter anisotropy and diffusivity. In neurodegenerative diseases, the value of sDTI is promising but not yet well understood. The objective of this prospective, single-center study was to evaluate the long fiber tract degeneration within the spinal cord in normal aging (n = 125) and to prove its applicability in pathologic conditions as in patients with molecular genetically confirmed hereditary spastic paraplegias (HSP; n = 40), a prototypical disease of the first motor neuron and in some genetic variants with affection of the dorsal columns. An optimized monopolar Stejskal-Tanner sequence for high-resolution, axial sDTI of the cervical spinal cord at 3.0 T with advanced standardized evaluation methods was developed for a robust DTI value estimation of PT, DC, and AH in both groups. After sDTI measurement at C2, an automatic motion correction and an advanced semi-automatic ROI-based, standardized evaluation of white matter anisotropy and diffusivity was performed to obtain regional diffusivity measures for PT, DC, and AH. Reliable and stable sDTI values were acquired in a healthy population without significant decline between age 20 and 65. Reference values for PT, DC, and AH for fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were established. In HSP patients, the decline of the long spinal fiber tracts could be demonstrated by diffusivity abnormalities in the pyramidal tracts with significantly reduced PTFA (p < 0.001), elevated PTRD (p = 0.002) and reduced PTMD (p = 0.003) compared to healthy controls. Furthermore, FA was significantly reduced in DCFA (p < 0.001) with no differences in AH. In a genetically homogeneous subgroup of SPG4 patients (n = 12) with affection of the dorsal columns, DCRD significantly correlated with the overall disease severity as measured by the Spastic Paraplegia Rating Scale (SPRS) (r = - 0.713, p = 0.009). With the most extensive sDTI study in vivo to date, we showed that axial sDTI combined with motion correction and advanced data post-processing strategies enables robust measurements and is ready to use, allowing recognition and quantification of disease- and age-related changes of the PT, DC, and AH. These results may also encourage the usage of sDTI in other neurodegenerative diseases with spinal cord involvement to explore its capability as selective biomarkers.

Regional computed tomography perfusion deficits in patients with hypoglycemia: two case reports.

BACKGROUND: Hypoglycemia in patients with diabetes mellitus, particularly type 1 can mimic acute ischemic stroke by causing focal neurological deficits. In acute ischemic stroke, the interpretation of emergency imaging including computed tomography with angiography and perfusion is crucial to guide revascularizing therapy including intravenous thrombolysis. However, different metabolic abnormalities and stroke mimics can cause focal hypoperfusion. METHODS: We describe two type 1 diabetes patients presenting with acute focal neurological deficits and hypoglycemia, who underwent multimodal computed tomography and follow-up imaging. CASE PRESENTATION: Patient 1, a 20-year-old man presented with aphasia and interstitial glucose level of 54 mg/dl. Patient 2, a 77-year-old man presented with aphasia, mild right-sided brachiofacial paresis and interstitial glucose level of 83 mg/dl. On brain imaging, no acute infarct signs were noted. Yet, both had focal left hemispheric cerebral hypoperfusion without large-vessel occlusion or stenosis. Due to persistent symptoms after normalization of blood glucose and despite a perfusion imaging pattern that was interpretated as non-typical for ischemia, both patients underwent thrombolysis without any complications. CONCLUSION: Computed tomography perfusion might help to discriminate hypoglycemia with focal neurological signs from acute stroke, but further evidence is needed.

Personalized neurorehabilitative precision medicine: from data to therapies (MWKNeuroReha) - a multi-centre prospective observational clinical trial to predict long-term outcome of patients with acute motor stroke.

BACKGROUND: Stroke is one of the most frequent diseases, and half of the stroke survivors are left with permanent impairment. Prediction of individual outcome is still difficult. Many but not all patients with stroke improve by approximately 1.7 times the initial impairment, that has been termed proportional recovery rule. The present study aims at identifying factors predicting motor outcome after stroke more accurately than before, and observe associations of rehabilitation treatment with outcome. METHODS: The study is designed as a multi-centre prospective clinical observational trial. An extensive primary data set of clinical, neuroimaging, electrophysiological, and laboratory data will be collected within 96 h of stroke onset from patients with relevant upper extremity deficit, as indexed by a Fugl-Meyer-Upper Extremity (FM-UE) score ≤ 50. At least 200 patients will be recruited. Clinical scores will include the FM-UE score (range 0-66, unimpaired function is indicated by a score of 66), Action Research Arm Test, modified Rankin Scale, Barthel Index and Stroke-Specific Quality of Life Scale. Follow-up clinical scores and applied types and amount of rehabilitation treatment will be documented in the rehabilitation hospitals. Final follow-up clinical scoring will be performed 90 days after the stroke event. The primary endpoint is the change in FM-UE defined as 90 days FM-UE minus initial FM-UE, divided by initial FM-UE impairment. Changes in the other clinical scores serve as secondary endpoints. Machine learning methods will be employed to analyze the data and predict primary and secondary endpoints based on the primary data set and the different rehabilitation treatments. DISCUSSION: If successful, outcome and relation to rehabilitation treatment in patients with acute motor stroke will be predictable more reliably than currently possible, leading to personalized neurorehabilitation. An important regulatory aspect of this trial is the first-time implementation of systematic patient data transfer between emergency and rehabilitation hospitals, which are divided institutions in Germany. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov ( NCT04688970 ) on 30 December 2020.

What do we know about dynamic glucose-enhanced (DGE) MRI and how close is it to the clinics? Horizon 2020 GLINT consortium report.

Cancer is one of the most devastating diseases that the world is currently facing, accounting for 10 million deaths in 2020 (WHO). In the last two decades, advanced medical imaging has played an ever more important role in the early detection of the disease, as it increases the chances of survival and the potential for full recovery. To date, dynamic glucose-enhanced (DGE) MRI using glucose-based chemical exchange saturation transfer (glucoCEST) has demonstrated the sensitivity to detect both D-glucose and glucose analogs, such as 3-oxy-methyl-D-glucose (3OMG) uptake in tumors. As one of the recent international efforts aiming at pushing the boundaries of translation of the DGE MRI technique into clinical practice, a multidisciplinary team of eight partners came together to form the "glucoCEST Imaging of Neoplastic Tumors (GLINT)" consortium, funded by the Horizon 2020 European Commission. This paper summarizes the progress made to date both by these groups and others in increasing our knowledge of the underlying mechanisms related to this technique as well as translating it into clinical practice.

GLINT: GlucoCEST in neoplastic tumors at 3 T-clinical results of GlucoCEST in gliomas.

OBJECTIVE: Clinical relevance of dynamic glucose enhanced (DGE) chemical exchange saturation transfer (CEST) imaging has mostly been demonstrated at ultra-high field (UHF) due to low effect size. Results of a cohort study at clinical field strength are shown herein. MATERIALS AND METHODS: Motion and field inhomogeneity corrected T1ρ-based DGE (DGE⍴) images were acquired before, during and after a D-glucose injection with 6.3 s temporal resolution to detect accumulation in the brain. Six glioma patients with clear blood-brain barrier (BBB) leakage, two glioma patients with suspected BBB leakage, and three glioma patients without BBB leakage were scanned at 3 T. RESULTS: In high-grade gliomas with BBB leakage, D-glucose uptake could be detected in the gadolinium (Gd) enhancing region as well as in the tumor necrosis with a maximum increase of ∆DGE⍴ around 0.25%, whereas unaffected white matter did not show any significant DGE⍴ increase. Glioma patients without Gd enhancement showed no detectable DGE⍴ effect within the tumor. CONCLUSION: First application of DGE⍴ in a patient cohort shows an association between BBB leakage and DGE signal irrespective of the tumor grade. This indicates that glucoCEST corresponds more to the disruptions of BBB with Gd uptake than to the molecular tumor profile or tumor grading.

The anterior and medial thalamic nuclei and the human limbic system: tracing the structural connectivity using diffusion-weighted imaging.

The limbic system is a phylogenetically old, behaviorally defined system that serves as a center for emotions. It controls the expression of anger, fear, and joy and also influences sexual behavior, vegetative functions, and memory. The system comprises a collection of tel-, di-, and mesencephalic structures whose components have evolved and increased over time. Previous animal research indicates that the anterior nuclear group of the thalamus (ANT), as well as the habenula (Hb) and the adjacent mediodorsal nucleus (MD) each play a vital role in the limbic circuitry. Accordingly, diffusion imaging data of 730 subjects obtained from the Human Connectome Project and the masks of six nuclei (anterodorsal, anteromedial, anteroventral, lateral dorsal, Hb, and MD) served as seed regions for a direct probabilistic tracking to the rest of the brain using diffusion-weighted imaging. The results revealed that the ANT nuclei are part of the limbic and the memory system as they mainly connect via the mammillary tract, mammillary body, anterior commissure, fornix, and retrosplenial cortices to the hippocampus, amygdala, medio-temporal, orbito-frontal and occipital cortices. Furthermore, the ANT nuclei showed connections to the mesencephalon and brainstem to varying extents, a pattern rarely described in experimental findings. The habenula-usually defined as part of the epithalamus-was closely connected to the tectum opticum and seems to serve as a neuroanatomical hub between the visual and the limbic system, brainstem, and cerebellum. Finally, in contrast to experimental findings with tracer studies, directly determined connections of MD were mainly confined to the brainstem, while indirect MD fibers form a broad pathway connecting the hippocampus and medio-temporal areas with the mediofrontal cortex.