Biomedical subjects

A C Ludolph

Publications and source records attributed to A C Ludolph.

At least 37 records · Page 2Linked to original sources

PubMed2002

[Clinically atypical CJD: diagnostic relevance of cerebrospinal fluid markers and molecular genetic analysis?].

HISTORY AND CLINICAL FINDINGS: A 66-year-old woman with known remitting depressive episodes was admitted to a psychiatric hospital where a severe major depression was diagnosed. The patient failed to respond to SSRI medication. In addition, she developed a pronounced speech disturbance and gait ataxia. Therefore she was referred to the department of neurology 5 months after disease onset. She presented with a predominant cerebellar syndrome. Because of a severe dysarthria testing of cognitive functions were impossible. INVESTIGATIONS: EEG revealed a general slowing of the basic activity. Periodic sharp wave complexes were not seen during the entire disease course. Cerebrospinal fluid analysis (CSF) was normal with regard to cell count and blood-csf-barrier function. 14- 3-3 proteins were detected in CSF, and CSF levels of tau-protein and neuron-specific enolase were strongly elevated. A point mutation was detected at codon 196 (E196K) of the prion proteine gene. In addition, codon 129 was found homozygous for valine. TREATMENT AND COURSE: During the following 10 weeks the patient developed pyramidal and extrapyramidal signs, myoclonus and akinetic mutism. Complications were decubital ulcers and infections of the urinary tract. The myoclonus slightly regressed following treatment with benzodiazepines. The patient died 9 months after disease onset. CONCLUSION: A rapid disease course and typical changes of surrogate markers in CSF may support the in-vivo diagnosis of CJD despite incomplete clinical criteria (e. g. lack of dementia). In such cases, detection of mutations by molecular genetic analysis is of importance to further support the diagnosis of CJD.

Aged↗

PubMed2002

Transient Global Amnesia. Evidence against vascular ischemic etiology from diffusion weighted imaging.

The etiology of Transient Global Amnesia (TGA) is still obscure. Diffusion-Weighted-Imaging (DWI) provides conflicting evidence concerning a possible vascular ischemic cause in mesiotemporal structures including the hippocampal region. The question remains open whether conflicting observations resulted from different observation times. DWI was performed at a time interval with known sensitivity for detection of ischemia. Ten patients (5 male, 5 female; mean age of 63 +/- 9, range 41-71 years) with typical TGA were investigated at an average delay of 18 hours (range 6 to 44 hours) between onset of symptoms and magnetic resonance imaging (transversal DW-, T1W- and T2W-MRI). Five patients received apparent-diffusion-coefficient (ADC)-mapping. Cerebrovascular studies (ECG, TTE and extra/transcranial dopplersonographic and duplexultrasonic investigation) and EEG were normal in all patients. DW-MRI-sequences and ADC-maps, if performed, were normal in all patients. Conventional T2W-MRI in 3 out of 10 patients showed microangiopathic subcortical changes and lacunar strokes of older origin. We conclude that TGA does not result from a vascular ischemic etiology in the majority of cases.

Adult↗

PubMed2002

Alternative splicing of the 5'-sequences of the mouse EAAT2 glutamate transporter and expression in a transgenic model for amyotrophic lateral sclerosis.

Glutamate-mediated neurotoxicity and a reduced expression of the excitatory amino acid transporter 2 (EAAT2) have been described in the pathogenesis of several acute and chronic neurological conditions. EAAT2 is the major carrier of glutamate in the mammalian brain. However, the principles of EAAT2 expression regulation are not fully understood. For the human brain, extensive alternative splicing of the EAAT2 RNA has been shown. To delineate the complex RNA regulation of EAAT2 we investigated whether the murine species is a suitable model for the study of EAAT2 splicing events. We identified five splice variants (mEAAT2/5UT1-5) encoding different 5'-untranslated sequences and two distinct N-termini of the putative EAAT2 polypeptide. In the murine CNS we found a region-specific expression pattern of the novel 5'-variants of EAAT2 as shown by in situ hybridization, dot blotting and competitive reverse transcription polymerase chain reaction. Furthermore, we performed an expression analysis of the EAAT2 splice variants in the spinal cord of a transgenic model (SOD1G93A) of amyotrophic lateral sclerosis, a motor neurone disease for which altered splicing of EAAT2 has been discussed. We found an increased expression of mEAAT2/5UT4 and a reduction of mEAAT2/5UT5 in the early course of the disease. We conclude that alternative splicing of 5'-sequences may contribute to the regional expression of the EAAT2 RNA and was altered in the pre-symptomatic stage of the SOD1G93A-mouse model for amyotrophic lateral sclerosis.

5' Untranslated Regions↗

PubMed2002

Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized by the occurrence of bilateral vestibular schwannomas, various brain and spinal tumours as well as peripheral nerve tumours, cutaneous tumours and juvenile posterior lenticular opacity. NF2 is caused by mutations in both alleles of a tumour suppressor gene coding for a protein called schwannomin or merlin. It is suggested that the development of NF2 tumours is caused by complete inactivation of the merlin/schwannomin gene. Interestingly, in a NF2 mouse model, peripheral nerve pathology was more frequently described than schwannomas. However, review of the literature shows that patients suffering from NF2 seldom have unexplained clinical features of peripheral nerve lesion unrelated to tumour masses. Single case reports describe sural nerve biopsies, which histologically show onion-bulb-like formations, seemingly originating from Schwann cells. We have conducted a systematic investigation to determine the occurrence and aetiology of peripheral nerve involvement in NF2 patients. We investigated 15 patients with definite NF2 and in 10 of these found electrophysiological evidence of neuropathy. In this study we present the classification of neuropathy, correlation to clinical findings, and histological findings of a sural nerve biopsy. We conclude that peripheral neuropathy, mostly of axonal type, is a common clinical finding in NF2. We hypothesize that the aetiology of this frequent peripheral neuropathy syndrome in NF2 is caused by compression effects of multiple tumourlets, originating along the length of the peripheral nerves on adjacent nerve fibres, by local influences of the endoneurial pathological cells on adjacent nerve fibres and/or the inability of these cells to properly adhere to, or ensheath, the axon.

Adult↗

PubMed2001

Imaging and neurochemical markers for diagnosis and disease progression in ALS.

Based on the development of a transgenic animal model, an increasing number of experimental strategies have revealed the potential to modify the selective degeneration of motor neurons, a feature unique to motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The translation of this success into therapeutic effects in human diseases is a challenge of the future. For this purpose, tools must be developed which serve as diagnostic and surrogate markers for diagnosis and disease progression. Currently, to understand the pathogenesis of the spinal cord disease, the focus remains on more traditional electrodiagnostic techniques. For the characterization of the involvement of brain structures, imaging techniques are increasingly explored. This review focuses on the use of imaging techniques as surrogate markers for the involvement of the brain in motor neuron disorders, but also tries to point out that the final goal will be the development of cheap biochemical markers for the screening of populations at risk.

Amyotrophic Lateral Sclerosis↗

PubMed2001

Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family.

BACKGROUND: Generalized epilepsy with febrile seizures plus (GEFS(+)) is a recently described benign childhood-onset epileptic syndrome with autosomal dominant inheritance. The most common phenotypes are febrile seizures (FS) often with accessory afebrile generalized tonic-clonic seizures (GTCS, FS(+)). In about one third, additional seizure types occur, such as absences, myoclonic, or atonic seizures. So far, three mutations within genes encoding subunits of neuronal voltage-gated Na(+) channels have been found in GEFS(+) families, one in SCN1B (beta(1)-subunit) and two in SCN1A (alpha-subunit). METHODS: The authors examined the phenotypic variability of GEFS(+) in a five-generation German family with 18 affected individuals. Genetic linkage analysis was performed to exclude candidate loci. RESULTS: Inheritance was autosomal dominant with a penetrance of about 80%. A variety of epilepsy phenotypes occurred predominantly during childhood. Only four individuals showed the FS or FS(+) phenotype. The others presented with different combinations of GTCS, tonic seizures, atonic seizures, and absences, only in part associated with fever. The age at onset was 2.8 +/- 1.3 years. Interictal EEG recordings showed rare, 1- to 2-second-long generalized, irregular spike-and-wave discharges of 2.5 to 5 Hz in eight cases and additional focal parietal discharges in one case. Linkage analysis excluded the previously described loci on chromosomes 2q21-33 and 19q13. All other chromosomal regions containing known genes encoding neuronal Na(+) channel subunits on chromosomes 3p21-24, 11q23, and 12q13 and described loci for febrile convulsions on chromosomes 5q14-15, 8q13-21, and 19p13.3 were also excluded. CONCLUSION: These results indicate further clinical and genetic heterogeneity in GEFS(+).

Adult↗

PubMed2001

CSF filtration is an effective treatment of Guillain-Barré syndrome: a randomized clinical trial.

OBJECTIVE: To compare CSF filtration (CSFF) and plasma exchange (PE) in the treatment of patients with Guillain-Barré syndrome (GBS). METHODS: In a prospective controlled clinical trial, 37 patients with acute GBS were randomized to receive either CSFF or PE. Inclusion criteria were fulfillment of National Institute of Neurological and Communicative Disorders and Stroke criteria and disability to walk >5 m unassisted. RESULTS: With similar baseline features in both groups (initial disability grades on the six-point grading scale of the GBS Study Group) the primary outcome variable (improvement within 28 days after randomization) was almost identical (test for equivalence p = 0.0014), the mean grade values being 0.82 in the CSFF group and 0.80 in the PE group. After 56 days, 56% (9 of 16 patients) of the CSFF group and 37% (7 of 19 patients) of the PE group had reached grade 2 (i.e., ability of unassisted walking >5 m). After 6 months, the probability to reach grade 2 was about 80% in both groups. In the CSFF group, transient pleocytosis occurred without apparent clinical complications. Clinically relevant complications were higher in the PE-treated group. CONCLUSIONS: Although the number of patients was small, the authors found that the treatment of GBS with CSFF is at least as effective as with PE. CSFF might work by removing from the CSF inflammatory mediators, autoantibodies, or other factors.

Adult↗

PubMed2001

Superoxide dismutase mutations of familial amyotrophic lateral sclerosis and the oxidative inactivation of calcineurin.

Approximately 10% of all familial cases of amyotrophic lateral sclerosis (fALS) are linked to mutations in the SOD1 gene, which encodes the copper/zinc superoxide dismutase (CuZnSOD). Recently, wild-type CuZnSOD was shown to protect calcineurin, a calcium/calmodulin-regulated phosphoprotein phosphatase, from inactivation by reactive oxygen species. We asked whether the protective effect of CuZnSOD on calcineurin is affected by mutations associated with fALS. For this, we monitored calcineurin activity in the presence of mutant and wild-type SOD. We found that the degree of protection against inactivation of calcineurin by different SOD mutants correlates with the severity of the phenotype associated with the different mutations, suggesting a potential role for calcineurin-SOD1 interaction in the etiology of fALS.

Amyotrophic Lateral Sclerosis↗

PubMed2001

Chemical preconditioning in mice is not mediated by upregulation of nitric oxide synthase isoforms.

Ischemic preconditioning requires increased nitric oxide (NO) production. However, NO may also trigger delayed neuronal death cascades. The goal therefore was to investigate nitric oxide synthase (NOS) isoforms (neuronal NOS: nNOS; endothelial NOS: eNOS; inducible NOS: iNOS) with reverse transcriptase-polymerase chain reaction in hippocampal slices from control mice and slices prepared upon preconditioning in vivo (single intraperitoneal injection of 20 mg/kg body weight 3-nitropropionate (3NP)). One hour after preconditioning nNOS (108+/-34%, mean+/-SD), eNOS (93+/-34%), and iNOS (282+/-261%) remained at control levels. Similarly, nNos, eNOS, and iNOS stayed at control level 12, 24, and 72 h after preconditioning with 3NP. Incubation of slices, however, drastically increased iNOS (1676+/-818, P<0.01). We conclude that chemical preconditioning other than ischemic preconditioning may not increase potentially harmful nitric oxide synthase isoforms.

Animals↗

PubMed2001

Calcineurin A and calbindin immunoreactivity in the spinal cord of G93A superoxide dismutase transgenic mice.

A qualitative immunohistochemical study was performed on calcineurin A- and calbindin-positive neurons in the spinal cord of transgenic mice, an animal model of amyotrophic lateral sclerosis, carrying the G93A mutation of the Cu/Zn-superoxide dismutase gene. The results show that calcineurin A-immunoreactive motoneurons are affected by the neurodegenerative process; in contrast, calbindin-positive cells are selectively spared. The findings suggest that calcineurin plays a role as an accessory factor responsible for selective vulnerability in the neurodegenerative process of amyotrophic lateral sclerosis.

Animals↗

PubMed2001

[Normal and pathological aging of the brain].

The number of people of old age in western countries is growing, leading to an increased prevalence of degenerative brain diseases. These diseases are widely regarded as a limiting factor of quality of life in old age. The possibilities to maintain intellectual performance of the brain even in old age historically met with scepticism and diseases like Alzheimer's or Parkinson's disease were accepted as an inevitable consequence of aging. "The older, the sicker." However, during recent years new concepts were developed: The physiologic aging of the brain is distinct from diseases of the brain occurring during old age and pathogenesis of degenerative brain diseases is increasingly revealed. This results in novel, even neuroprotective, therapy strategies, implying that these diseases cannot only be seen as inevitable and incurable, but also as a target for prevention and symptomatic and causal therapy strategies.

Aged↗

PubMed2001

[Tauopathies--a new class of neurodegenerative diseases].

Recently it was shown by several research groups that mutations in the gene encoding for the tau protein associated with microtubuli on chromosome 17 caused a distinct form of dementia named frontotemporal dementia and parkinsonism (FTDP-17). This disease includes familial asymmetrical frontal and, in the further course, frontotemporal dementia, parkinsonism, which is often initially sensitive to levodopa, signs of upper motor neuron degeneration, and, less commonly, amyotrophy. Tau is an intracellular protein of the cytoskeleton, which is responsible for the arrangement and stabilization of microtubuli. The discovery of mutations in the tau gene causing a distinct neurodegenerative disease in humans has firmly established the importance of the tau gene for neurodegenerative processes, not only in tauopathies but also in other degenerative disorders with tau pathology, such as corticobasal degeneration, supranuclear progressive paralysis, amyotropic lateral sclerosis, parkinsonism-dementia complex of Guam, and Alzheimer's disease. Our experience with patients suffering from PTDP-17 shows that its phenotype varies more than was described in the first consensus conferences. In the future, it will be important to designate the diagnostic gold standard not by clinical description, but etiologic classification.

Amyotrophic Lateral Sclerosis↗

PubMed2001

Nuclear shrinkage in live mouse hippocampal slices.

Brain slices are used extensively for biochemical, electrophysiological and molecular investigations. However, only the time frame for electrophysiological and biochemical investigations has as yet been defined. The goal of the present study was to investigate the time course of nuclear structure in live brain slices. Hippocampal slices (300 microm) were prepared from male CD1 mice (25-30 g), stained with Hoechst 33342 (10 microM), calcein-AM (2 microM) and ethidium homodimer (4 microM), and imaged with single- and dual-photon microscopy. The volume of CA1 pyramidal cell nuclei decreased from 759+/-229 microm3 in 40-50 microm depth 25 min after preparation to 453+/-169 microm3 (P<0.001) after 60 min, 315+/-112 microm3 (P<0.001) after 120 min and 128+/-71 microm3 (P<0.001) after 8 h. Similar results were obtained on a prolonged time scale in 70-80 microm depth and with an accelerated time scale in 20-30 microm depth. Live-dead staining showed that cell damage is progressing from the surface to deeper layers of the slices in a time-dependent fashion. We conclude that nuclei of CA1 hippocampal pyramidal cells show a time- and depth-dependent shrinkage converging 8 h after slice preparation to a volume of 90-130 microm; in any depth between 20 and 80 microm. The nucleus in the superficial 80 microm of each side appears dysfunctional even at times suitable for electrophysiological and biochemical experimentation in hippocampal slices. Molecular analysis of cell regulation in brain slices may, therefore, be time-dependently distorted by progressing cell death in at least half of the tissue under investigation.

Absorptiometry, Photon↗

PubMed2001

A novel calcineurin splice variant that modifies calcineurin activity.

Calcineurin is a Ca(2+)/calmodulin dependent phosphoprotein phosphatase implicated in a wide range of disorders. Here, we report the cloning of a novel calcineurin A alpha splice variant that lacks both the catalytic and calcineurin B binding domains. Biochemical analysis revealed a stimulating effect on calcineurin activity at low calcium concentrations as well as protein-protein interaction with the catalytic calcineurin holoenzyme. By Western blot analysis, expression of similar short splice variants could be seen in the spinal cord of an animal model of familial amyotrophic lateral sclerosis, suggesting a role of these new variants in motor neuron disease.

Amino Acid Sequence↗

PubMed2001

Standards of palliative care for patients with amyotrophic lateral sclerosis: results of a European survey.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) may be viewed as a paradigmatic disease for palliative care in neurodegenerative disorders. However, standards of care for ALS are known anecdotally to differ between and even within countries. METHOD: A survey was conducted among the members of the European ALS Study Group on standards of palliative care in the clinical management of patients with ALS and their families, by means of a questionnaire of 111 questions in the following areas: giving the diagnosis, treatment of symptoms, nutrition, community services, respiratory support, and terminal care. Of 110 questionnaires sent out, 73 (66%) were completed and returned from 18 countries, including all major ALS centres in Europe. RESULTS: The main areas of consensus included: presenting the diagnosis in the presence of a relative (85%) and offering a short-term follow-up (90%), regular weight checks (82%), availability of percutaneous endoscopic gastrostomy (PEG) (94%), and discussion of respiratory issues (90%). The main differences between centres concerned symptomatic drug treatment, availability of services, ventilation and terminal care. An additional survey shows considerable interest by the centres in palliative care trials. CONCLUSION: Great efforts are made by the centres to offer the best possible palliative care to ALS patients. The discrepancies in the type of care offered might be resolved by adopting common standards, on the basis of available evidence and mutual consensus. Several areas of ALS patient care would benefit from controlled studies to establish an evidence base for treatment decisions.

Amyotrophic Lateral Sclerosis↗

PubMed2001

Impaired RNA splicing of 5'-regulatory sequences of the astroglial glutamate transporter EAAT2 in human astrocytoma.

A loss of the glutamate transporter EAAT2 has been reported in the neoplastic transformation of astrocytic cells and astrocytoma. The RNA expression of EAAT2 and five 5'-regulatory splice variants was investigated to identify alterations of the post-transcriptional EAAT2 gene regulation in human astrocytic tumours. Three known (EAAT2, HBGTII, and HBGTIIC) and two novel (EAAT2/3 and EAAT2/31) EAAT2 transcripts originating from alternative splicing of 5'-regulatory sequences were subject to an RNA expression analysis using reverse transcription and competitive PCR. Specimens of astrocytoma World Health Organisation (WHO) grade I-IV in 14 patients and control brain tissue obtained from three normal persons were studied. The main EAAT2 RNA was found to be equally expressed in normal human brain and astrocytic tumour samples. By contrast, the expression pattern of four 5'-variants of the transporter transcript was altered in the investigated series of astrocytoma compared with normal brain. HBGTII, HBGTIIC, and EAAT2/3 were amplified from seven and four tumours and one sample, respectively. EAAT2/31 was expressed in none of the tumour specimens studied. In conclusion, in astrocytic tumours of different histopathological grades there was a substantial reduction of RNA splicing events in EAAT2. The impairment of EAAT2 splicing indicates an altered expression which is not primarily involved in the tumorigenesis but may contribute to some biological properties of astrocytoma such as oedema, necrosis, and tumour related seizures.

Alternative Splicing↗

PubMed2001

Pharmacological treatment of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from chronic and selective loss of motor neurons in the brain and spinal cord. In 1993, the etiology of ALS has been clarified for a small sub-group of patients with an autosomal-dominant form of this disease. About 10 percent of familial ALS patients have been associated with more than 50 mutations of the gene of the Cu/Zn superoxide dismutase (SOD1). Mutations in the SOD1 gene account for 1 percent of all ALS patients and have therefore limited epidemological and clinical relevance; however, they are of fundamental importance for the understanding of the ALS pathogenesis, and the development of neuroprotective strategies. In two double-blind and placebo-controlled studies the membrane stabilisator riluzole has been shown to be the first neuroprotective compound with a significant effect on survival of ALS patients. The neuroprotective approach reduced therapeutic nihilism in ALS and is a first step in the treatment of this devastating disease.

Amyotrophic Lateral Sclerosis↗

PubMed2000

In vivo imaging of activated microglia using [11C]PK11195 and positron emission tomography in patients after ischemic stroke.

Neuroprotective strategies are currently being developed for stroke patients. Although the focus is on the development of early treatment the importance of late pathogenetic events is increasingly recognized. To investigate the microglial reaction in stroke we used a marker for activated microglia, [11C]PK11195, and PET in five patients with ischemic stroke 5-53 days after infarction. In one patient serial measurements were made. We demonstrated in each individual and at each point in time that a microglial reaction takes place in the area where T1 weighted MRI (magnetic resonance imaging) shows intensity changes. We consider this PET method as a promising tool to study the late pathogenetic consequences of cerebral infarction and to evaluate neuroprotective strategies with respect to the consequences of the microglial activation.

Adult↗