A C Ludolph

Publications of A C Ludolph

• Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect.

  Authors: Y G Weber, C Kamm, A Suls, J Kempfle, K Kotschet, R Schüle, T V Wuttke, S Maljevic, J Liebrich, T Gasser, A C Ludolph, W Van Paesschen, L Schöls, P De Jonghe, G Auburger, H Lerche

  Neurology. 08/2011; 77(10):959-64.

  Mutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-inducedMutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-induced dyskinesia (PED, DYT18), and absence epilepsy. A large German/Dutch pedigree has formerly been described as paroxysmal choreoathetosis/spasticity (DYT9) and linked close to but not including the SLC2A1 locus on chromosome 1p. We tested whether 1) progressive spastic paraparesis, in addition to PED, as described in DYT9, and 2) autosomal dominant forms of hereditary spastic paraparesis (HSP) without PED are caused by SLC2A1 defects. The German/Dutch family and an Australian monozygotic twin pair were clinically (re-)investigated, and 139 index cases with dominant or sporadic HSP in which relevant dominant genes were partially excluded were identified from databanks. SLC2A1 was sequenced in all cases in this observational study and the functional effects of identified sequence variations were tested in glucose uptake and protein expression assays. We identified causative mutations in SLC2A1 in both families, which were absent in 400 control chromosomes, cosegregated with the affection status, and decreased glucose uptake in functional assays. In the 139 index patients with HSP without paroxysmal dyskinesias, we only identified one sequence variation, which, however, neither decreased glucose uptake nor altered protein expression. This study shows that DYT9 and DYT18 are allelic disorders and enlarges the spectrum of GLUT1 phenotypes, now also including slowly progressive spastic paraparesis combined with PED. SLC2A1 mutations were excluded as a cause of HSP without PED in our cohort.

• [Advanced therapy strategies in neurological diseases: present and perspectives].

  Authors: A C Ludolph, J Kassubek

  Der Nervenarzt. 08/2011; 82(8):955-6.

• [German consortium for frontotemporal lobar degeneration].

  Authors: M Otto, A C Ludolph, B Landwehrmeyer, H Förstl, J Diehl-Schmid, M Neumann, H A Kretzschmar, M Schroeter, J Kornhuber, A Danek

  Der Nervenarzt. 08/2011; 82(8):1002-5.

  Frontotemporal lobar degeneration (FTLD) is an umbrella term for an aetiologically diverse group of neurodegenerative disorders with prominent lobar cortical atrophy. First this disease group wasFrontotemporal lobar degeneration (FTLD) is an umbrella term for an aetiologically diverse group of neurodegenerative disorders with prominent lobar cortical atrophy. First this disease group was restricted to Pick's disease or Pick's complex. Several updates of the clinical classification systems were performed and discussed. Currently we summarize the following diseases under the FTLD spectrum: frontotemporal dementia (FTD) as a behavioural variant, primary non-fluent aphasia (PNFA) and semantic dementia as language variants, amyotrophic lateral sclerosis with FTD (ALS-FTD), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP).From the pathophysiological aspect major progress was made. Neuropathologically FTLDs are now defined based on the molecular composition of these protein accumulations. A major distinction of tau-associated (FTLD-tau) and TDP43-associated (FTLD-TDP43) and to a lesser extend FUS-associated (FTLD-FUS) has been made. Additional risk genes were described. However from the therapeutic perspective even symptomatic therapy is under discussion. A major aim of our consortium is to develop parameters allowing an early diagnosis and follow-up, thus providing effective and objective parameters for therapeutic strategies.

• Reversible Cortical Diffusion Restriction, Hyperperfusion and T2-Hyperintensity Caused by Two Different Types of Epileptic Seizure.

  Authors: A Unrath, H-P Müller, A C Ludolph, J Kassubek

  Clinical neuroradiology. 07/2011;

• Fully automated atlas-based MR imaging volumetry in Huntington disease, compared with manual volumetry.

  Authors: J Kassubek, E H Pinkhardt, A Dietmaier, A C Ludolph, G B Landwehrmeyer, H-J Huppertz

  AJNR. American journal of neuroradiology. 06/2011; 32(7):1328-32.

  The atrophy of the caudate is considered the hallmark of HD-associated neurodegeneration and has high potential as a biomarker in structural MR imaging. This study aimed at comparing automated andThe atrophy of the caudate is considered the hallmark of HD-associated neurodegeneration and has high potential as a biomarker in structural MR imaging. This study aimed at comparing automated and manual caudate volumetry. In this cross-sectional volumetric study in 40 patients with HD and 30 healthy controls, a fully automated caudate measurement by ABV was used for the first time in HD and was directly compared with manual delineation as the generally accepted criterion standard of volumetry. It could be shown that both techniques were able to separate patients and controls to a similar degree. The differences between the 2 volumetric measurements ranged within the limits of agreement; the systematically lower values by manual volumetry were caused by the different assessment of the dorsal caudate tail, which is hard to delineate manually. ABV may be used instead of manual volumetry to quantify caudate volume loss. Additionally, the ABV technique has the advantage of being much faster, is less laborious, and is free of a subjective region-of interest definition. ABV might serve as a tool in potential future clinical trials of disease-modifying treatments in HD.

• Small-fiber neuropathy in patients with ALS.

  Authors: J Weis, I Katona, G Müller-Newen, C Sommer, G Necula, C Hendrich, A C Ludolph, A-D Sperfeld

  Neurology. 06/2011; 76(23):2024-9.

  To investigate the involvement of the epidermal small sensory fibers in the neurodegenerative process in amyotrophic lateral sclerosis (ALS). In the present study, skin biopsies of 28 patients withTo investigate the involvement of the epidermal small sensory fibers in the neurodegenerative process in amyotrophic lateral sclerosis (ALS). In the present study, skin biopsies of 28 patients with ALS were obtained at an average of 34 months after disease onset by history. Protein gene product 9.5 (PGP9.5) immunohistochemistry findings were compared to 17 age-matched controls. The primary endpoint of the study was to evaluate the decrease in the density of small intraepidermal nerve fibers and to compare the prevalence of small-fiber neuropathy in patients with ALS and in controls. We found a significant reduction in epidermal nerve fiber density in the distal calf of patients with ALS (4.8 ± 3.7 fibers/mm vs 12.2 ± 4.6 in age-matched controls, p<0.0001). The extent of fiber loss was age-dependent. Also, the number of subjects with small-fiber neuropathy was significantly higher in the ALS group than in the controls (79% vs 12%). Correspondingly, mild sensory symptoms including diffuse dysesthesias, paresthesias, and hypesthesia were found in 7 patients. In 17 biopsies of patients with ALS, but only in 2 controls, we saw larger (>1.5 μm in diameter) focal swellings of epidermal axons resembling spheroids, suggesting trafficking defects. These results indicate that small, distal epidermal nerve fibers are involved in this disease, supporting the concept of distal axonopathy in ALS.

• Alterations of the corpus callosum as an MR imaging-based hallmark of motor neuron diseases.

  Authors: A Unrath, A C Ludolph, J Kassubek

  AJNR. American journal of neuroradiology. 05/2011; 32(5):E90.

• Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in amyotrophic lateral sclerosis.

  Authors: J Dorst, P Kühnlein, C Hendrich, J Kassubek, A D Sperfeld, A C Ludolph

  Journal of neurology. 12/2010; 258(4):613-7.

  Weight loss is a common phenomenon and an independent prognostic factor in amyotrophic lateral sclerosis (ALS). Several potential causal mechanisms, including intrinsic hypermetabolism and deficientWeight loss is a common phenomenon and an independent prognostic factor in amyotrophic lateral sclerosis (ALS). Several potential causal mechanisms, including intrinsic hypermetabolism and deficient food intake, have been discussed. We investigated the influence of fasting serum glucose, cholesterol, and triglyceride levels at time of diagnosis on survival in ALS. Serum cholesterol (LDL, HDL, and LDL/HDL ratio), triglycerides, and glucose were investigated in 488 patients (age of onset = 57.6 ± 12.6 years) in relation to survival and revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS) data. High serum levels of both fasting cholesterol and triglycerides had a significantly positive effect on survival (p < 0.05). We found a median prolonged life expectancy by 14 months for patients with serum triglyceride levels above the median of 1.47 mmol/l. The results suggest that the lipid metabolism and the nutritional status of ALS patients are important prognostic factors. These parameters should be thoroughly monitored during the clinical management of these patients. In case of progressive loss of body weight, a diet rich in lipids and calories should be considered. However, the final decision whether a lipid-rich diet should be recommended to ALS patients can only be based on a double-blind placebo-controlled interventional trial. Our results further imply that lipid-lowering drugs, e.g., statins, should be applied carefully in ALS patients although individual risk considerations must be made.

• Hippocampal cavities are not associated with cognitive impairment in transient global amnesia.

  Authors: I Uttner, S Weber, W Freund, D Bengel, B Schmitz, A C Ludolph, R Huber

  European journal of neurology : the official journal of the European Federation of Neurological Societies. 12/2010; 18(6):882-7.

  Hippocampal sulcal cavities (HSC) have been speculated to contribute to a higher vulnerability of memory pathways and might be a possible etiological factor in transient global amnesia (TGA).Hippocampal sulcal cavities (HSC) have been speculated to contribute to a higher vulnerability of memory pathways and might be a possible etiological factor in transient global amnesia (TGA). Therefore, we evaluated the influence of HSC on cognitive long-term outcome in TGA-patients. Fourteen otherwise healthy patients with the clinical syndrome of TGA in their history underwent a high-resolution magnetic resolution imaging and a comprehensive neuropsychological test battery. The neuropsychological control group consisted of 15 healthy subjects and was balanced for age, sex and other risk factors as well as intellectual and social status. Magnetic resolution imaging and neuropsychological testing have been performed 1128 days (median) after the TGA. HSC have been detected in nine of the 14 patients and have been bilateral in eight of them. There were no differences in cognitive performance in patients with and without HSC as well as compared to healthy subjects. Even in patients with greater lesion load, only a slight visuospatial deficit was found. Although an increased incidence of HSCs is detected in TGA patients, cavities are not obligatorily in TGA. Moreover, even patients with hippocampal cavities achieve a full neuropsychological recovery independent of the frequency and size of the hippocampal lesions.

• Novel missense and truncating mutations in FUS/TLS in familial ALS.

  Authors: S Waibel, M Neumann, M Rabe, T Meyer, A C Ludolph

  Neurology. 08/2010; 75(9):815-7.

  Mutations in the FUS/TLS gene have been associated with familial amyotrophic lateral sclerosis (FALS). We analyzed the presence and frequency of C-terminal FUS/TLS mutations in a German amyotrophicMutations in the FUS/TLS gene have been associated with familial amyotrophic lateral sclerosis (FALS). We analyzed the presence and frequency of C-terminal FUS/TLS mutations in a German amyotrophic lateral sclerosis (ALS) cohort, including 133 patients with sporadic ALS (SALS) and 58 patients with FALS by sequence analysis of exons 13-15. We identified 2 novel heterozygous FUS/TLS mutations in 4 German ALS families including the novel missense mutation K510R and the truncating mutation R495X. The truncating mutation was associated with an aggressive disease course whereas the K510R mutation showed a mild phenotype with disease duration ranging from 6 to 8 years. No mutation was detected in 133 patients with SALS. Mutations in FUS/TLS account for 7% (4 of 58) of FALS in our German cohort.

• CSF glial markers correlate with survival in amyotrophic lateral sclerosis.

  Authors: S D Süssmuth, A D Sperfeld, A Hinz, J Brettschneider, S Endruhn, A C Ludolph, H Tumani

  Neurology. 03/2010; 74(12):982-7.

  In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), CSF biomarkers are increasingly studied to evaluate their relevance for differential diagnosis, disease progression, andIn neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), CSF biomarkers are increasingly studied to evaluate their relevance for differential diagnosis, disease progression, and understanding of pathophysiologic processes. To identify a biomarker profile of neuronal and glial CSF proteins to discriminate ALS from other motor neuron diseases (MND) and to assess whether baseline levels of CSF measures in ALS are associated with the course of the disease. A total of 122 consecutive subjects with MND were included in this cross-sectional study (ALS, n = 75; lower motor neuron syndrome, n = 39; upper motor neuron diseases, n = 8). Clinical follow-up included 76 patients. We determined baseline levels of protein tau and astroglial S100beta in CSF and microglial sCD14 in CSF and serum in relation to diagnosis, duration of disease, and survival. CSF tau was significantly elevated in ALS and upper motor neuron diseases as compared to lower motor neuron diseases and controls. CSF S100beta levels were significantly lower in lower motor neuron diseases as compared to other MND. CSF concentrations of S100beta and sCD14 correlated with the survival time in patients with ALS. In motor neuron diseases, CSF tau elevation indicates the degeneration of upper motor neurons, while S100 beta and sCD14 may indicate the activation of CNS glial cells. Because S100beta and sCD14 concentrations correlate with survival in amyotrophic lateral sclerosis (ALS), we suppose that the combination of both markers may be useful to obtain prognostic information in patients with ALS.

• A novel presenilin1 mutation (Q223R) associated with early onset Alzheimer's disease, dysarthria and spastic paraparesis and decreased Abeta levels in CSF.

  Authors: I Uttner, J Kirchheiner, H Tumani, F M Mottaghy, E Lebedeva, E Ozer, A C Ludolph, R Huber, C A F von Arnim

  European journal of neurology : the official journal of the European Federation of Neurological Societies. 11/2009;

  Background and purpose: A novel presenilin1 (PSEN1) mutation associated with dementia and spastic paraplegia in a family with five affected individuals is described. The index patient was aBackground and purpose: A novel presenilin1 (PSEN1) mutation associated with dementia and spastic paraplegia in a family with five affected individuals is described. The index patient was a 35-year-old man presenting with cognitive decline, behavioural symptoms, dysarthria, and gait disorder due to spasticity. Methods and results: Genetic analysis revealed a missense mutation Gln223Arg in exon 7. Initial CSF analysis revealed drastically decreased Abeta42 level despite marginally decreased FDG metabolism. Conclusion: Cerebrospinal fluid biomarker analysis might point towards genetic analysis of PSEN1 in patients with positive family history and age of onset below 60 years.

• Quantitative muscle ultrasound in neuromuscular disorders using the parameters 'intensity', 'entropy', and 'fractal dimension'

  Authors: H-J Gdynia, H P Müller, A C Ludolph, H Köninger, R Huber

  European journal of neurology : the official journal of the European Federation of Neurological Societies. 06/2009;

  Background and purpose: Ultrasound is a useful non-invasive instrument in visualizing physiological and pathological morphology in skeletal muscle. Here, we evaluate the possibility that quantitativeBackground and purpose: Ultrasound is a useful non-invasive instrument in visualizing physiological and pathological morphology in skeletal muscle. Here, we evaluate the possibility that quantitative muscle ultrasound using the parameters 'intensity', 'entropy', and 'fractal dimension' is a feasible method to distinguish between dystrophic myopathies (DM), inflammatory myopathies (IM), and motor neuron disorders. Methods: Seven patients with IM, 12 patients with DM, nine patients with motor neuron diseases, and 24 healthy subjects underwent an identical ultrasound examination protocol, applied on gastrocnemius and tibialis anterior muscle. Analysis parameters were applied on grey scale images as well as on gradient images. Results: Statistical evaluation revealed no significant differences in the evaluated parameters for differentiation of the distinct disease groups. Compared with healthy controls however we found statistically significant differences between almost of all the investigated parameters, even in disease cases with clinically unaffected distal musculature. Conclusion: The parameters are able to distinguish between healthy and affected musculature but not between distinct disease entities. Studies are needed to establish whether or not the parameters are helpful to monitor muscle involvement and disease progression in neuromuscular diseases.

• CSF proteome analysis in clinically isolated syndrome (CIS): Candidate markers for conversion to definite multiple sclerosis.

  Authors: H Tumani, V Lehmensiek, D Rau, I Guttmann, G Tauscher, H Mogel, C Palm, V Hirt, S D Suessmuth, I Sapunova-Meier, A C Ludolph, J Brettschneider

  Neuroscience letters. 04/2009; 452(2):214-7.

  Cerebrospinal fluid (CSF) is a promising source of biomarkers in clinically isolated syndrome (CIS), which frequently presents as a first episode of multiple sclerosis (MS). Using the two-dimensionalCerebrospinal fluid (CSF) is a promising source of biomarkers in clinically isolated syndrome (CIS), which frequently presents as a first episode of multiple sclerosis (MS). Using the two-dimensional difference in gel electrophoresis (2-D DIGE), we compared CSF samples from patients with CIS that remained CIS (CIS-CIS, n=8) over a follow-up time of 2 years and from patients with CIS that developed definite MS of the relapsing-remitting subtype (CIS-RRMS, n=8) over the same period. Protein spots that showed significant differences between patients and controls were selected for further analysis by MALDI-TOF mass spectrometry. For validation of identified spots ELISA experiments were performed. We identified one protein that was upregulated in CIS-RRMS (serin peptidase inhibitor) and eight proteins (alpha-1-B-glycoprotein, Fetuin-A, apolipoprotein A4, haptoglobin, human Zinc-alpha-2-glycoprotein (ZAG), Retinol-binding protein, superoxid dismutase 1, transferrin) that were down-regulated in CIS-RRMS vs. CIS-CIS. For Fetuin-A, our findings could be confirmed by ELISA. The pathophysiological role as well as clinical relevance of these candidate proteins in CIS remains to be further clarified by future studies.

• Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

  Authors: A C Ludolph, J Kassubek, B. G. Landwehrmeyer, E Mandelkow, E M Mandelkow, D J Burn, D. Caparros-Lefebvre, K. A. Frey, J G de Yebenes, T Gasser [......] T. Reum, A. Saint-Raymond, J C Steele, M. Tolnay, H Tumani, J C van Swieten, M. T. Vanier, J. P. Vonsattel, S. Wagner, Z K Wszolek

  European journal of neurology : the official journal of the European Federation of Neurological Societies. 04/2009; 16(3):297-309.

  Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. TheseTauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

• Granulomatous myositis mimicking slowly progressive lower motor neuron disease.

  Authors: Hans-Jürgen Gdynia, N Osterfeld, J Dorst, A C Ludolph, C A von Arnim, A-D Sperfeld

  European journal of medical research. 08/2008; 13(7):330-1.

  Here we illustrate a 74-year-old patient presenting with clinical signs of slowly progressive motor neuron disease. After electromyography demonstrated myopathic changes, a skeletal muscle biopsy wasHere we illustrate a 74-year-old patient presenting with clinical signs of slowly progressive motor neuron disease. After electromyography demonstrated myopathic changes, a skeletal muscle biopsy was performed showing histological signs of granulomatous myositis. In extensive diagnostic workup underlying primary granulomas forming diseases were excluded and corticoid therapy was initiated, but without clinical effect. We want to point out that granulomatous myositis should be considered in the differential diagnosis of slowly progressive motor neuron diseases, especially in atypical clinical presentations.

• Sporadic ALS with early-onset respiratory failure is not associated with IGHMBP2 gene mutations.

  Authors: P Kühnlein, A-D Sperfeld, S Endruhn, R Varon, A C Ludolph, C Hübner

  Journal of neurology, neurosurgery, and psychiatry. 07/2008; 79(6):737-8.

• Is spinal epidural lipomatosis an MRI-based diagnosis with clinical implications? A retrospective analysis.

  Authors: E H Pinkhardt, A-D Sperfeld, V Bretschneider, A Unrath, A C Ludolph, J Kassubek

  Acta neurologica Scandinavica. 07/2008; 117(6):409-14.

  OBJECTIVES: Magnetic resonance imaging (MRI) is considered the most sensitive modality for evaluating spinal epidural lipomatosis (SEL) in vivo. The aim of this study was to compare the existing MRIOBJECTIVES: Magnetic resonance imaging (MRI) is considered the most sensitive modality for evaluating spinal epidural lipomatosis (SEL) in vivo. The aim of this study was to compare the existing MRI classifications of SEL and to reevaluate the clinico-radiological correlation of SEL as a pathological entity. MATERIALS AND METHODS: Measurements of the cervical, thoracic and lumbar spine were performed in a retrospective setting within 1406 data sets from the digital MRI archives. RESULTS: It could be shown that the existing MRI classifications developed for different spinal regions complemented each other. However, there was no distinct correlation of these MRI findings with clinical symptoms because other morphological changes existed that probably caused the patients' complaints. CONCLUSION: Existing SEL classifications developed either for the lumbar or the thoracic spine were found to be applicable to both regions, but the very vague association with clinical symptoms should caution against premature conclusions with respect to the clinical significance of SEL.

• Neurodevelopmental and neurodegenerative diseases - is there a pathophysiological link? Attention-deficit/hyperactivity disorder and amyotrophic lateral sclerosis as examples.

  Authors: D Lule, A C Ludolph, A G Ludolph

  Medical hypotheses. 02/2008; 70(6):1133-8.

  Attention-deficit/hyperactivity disorder (ADHD), the most common neurobehavioural disorder and amyotrophic lateral sclerosis (ALS), the most common adult motoneuron disease, may be two distinctAttention-deficit/hyperactivity disorder (ADHD), the most common neurobehavioural disorder and amyotrophic lateral sclerosis (ALS), the most common adult motoneuron disease, may be two distinct entities on first sight. This paper aims to highlight parallels concerning clinical features and neurobiology. The presence of increased physical and psychological activity and largely non-progressive frontal dysfunction associated with impaired executive control and decreased attention are characteristic clinical features of both, ADHD and ALS. At the neurobiological level, there is evidence for hyperactivity in the glutamatergic system and a - potentially related - dopaminergic hypoactivity in ADHD and ALS. The clinical features of ALS resembling ADHD are particularly characteristic for the premorbid stage of the patient. Therefore, we hypothesize that clinical features of ADHD may be a risk factor for the development of ALS. This hypothesis is currently of unknown pathogenetic, but of potential future therapeutic relevance. Our hypothesis of a link between ADHD and ALS could also be considered as an example how research on neurodevelopmental diseases might influence the understanding and possibly the prevention and treatment of neurodegenerative diseases.

• [Amyotrophic lateral sclerosis]

  Authors: R Gastl, A C Ludolph

  Der Nervenarzt. 01/2008; 78(12):1449-57; quiz 1458-9.

  Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the motor system characterized by signs and symptoms of upper and lower motor dysfunction. This results in the presenceAmyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the motor system characterized by signs and symptoms of upper and lower motor dysfunction. This results in the presence of focal amyotrophies and pareses affecting voluntary muscles. Patients die after a few years, in most cases by respiratory failure. ALS is the most frequent motor neuron disease; however, its etiology and pathogenesis are only known in fragments. Its genetic basis is only partially understood and major gaps remain in the understanding of its pathogenesis with the basic principle of selective vulnerability and potentially resulting therapeutic consequences.