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Biomedical subjects

A C Ludolph

Publications and source records attributed to A C Ludolph.

At least 19 recordsLinked to original sources
PubMed2007

[Adult-onset neuronal ceroid lipofuscinosis].

Neuronal ceroid lipofuscinoses are a heterogenous group of genetic progressive neurodegenerative disorders. Curative therapeutic strategies are not known. These are largely diseases of childhood; adult-onset forms are rare and poorly characterized. The classical adult variant is CLN4 (Kufs' disease), in which autosomal-recessive and autosomal dominant forms are known. Furthermore the "classic infantile" CLN1, caused by a deficiency of the enzyme palmitoylprotein-thioesterase, may be of adult onset Neuronal ceroid lipofuscinoses in adulthood are multifaceted diseases. Their clinical picture is mainly characterized by progressive dementia, seizures, and extrapyramidal motor symptoms. In contrast to the infantile forms, visual loss is an uncommon feature that appears only in adult CLN1 but not CLN4, which may be helpful in clinical differential diagnosis.

Adult↗
PubMed2006

Benign symmetric lipomatosis with axonal neuropathy and abnormalities in specific mitochondrial tRNA regions.

Benign symmetric lipomatosis, also called Madelung's disease, is characterized by lipomata and fatty infiltrations. Involvement of the nervous system has occasionally been described, mitochondrial dysfunctions have been suggested. We report a 55 year old male suffering from benign symmetric lipomatosis with associated axonal neuropathy and hyperlipoproteinemia. He showed a remarkable phenotype of neuropathy i.e. no sensory disturbance, ubiquitous fasciculations and muscle cramps, furthermore reduced COX activity and abnormalities in specific mitochondrial tRNA regions.

Axons↗
PubMed2006

Axonal damage markers in cerebrospinal fluid are increased in ALS.

OBJECTIVE: To test whether biomarkers for axonal degeneration correlated with clinical subtypes and were of use in predicting progression of ALS. METHODS: Patients with ALS (n = 69), patients with Alzheimer disease (AD; n = 73), and age-matched controls (n = 33) were included in this prospective study. CSF levels of tau protein and neurofilaments (NfHSMI35) were measured using ELISA. In 49 patients with ALS, follow-up data were available (median follow-up 7 months). RESULTS: CSF levels of NfHSMI35 were five times higher in patients with ALS (1.7 ng/mL) than in controls (0.3 ng/mL, p < 0.001) and 10 times higher than in patients with AD (0.14 ng/mL, p < 0.001). NfHSMI35 values were also higher in patients with upper motor neuron-dominant ALS than in patients with typical ALS (upper motor neuron + lower motor neuron) at p = 0.02. Values of NfHSMI35 were higher in ALS of more rapid progression. The values of NfH and tau did not correlate with CSF protein content. CONCLUSIONS: The authors propose that axonal damage markers in CSF may discriminate between subtypes of ALS and that they could be used as markers for therapeutic trials. CSF NfH was superior to tau in these discriminations.

Adult↗
PubMed2006

A dynein mutation attenuates motor neuron degeneration in SOD1(G93A) mice.

Cu/Zn SOD1(G93A) transgenic mice develop phenotypical hallmarks of ALS and serve therefore as an established model to study the molecular mechanisms underlying this disease. Recent reports demonstrate that mutations in the motor protein dynein in Legs at odd angles (Loa) and Cramping (Cra1) mice lead to similar but milder phenotypes. Surprisingly, double transgenic mice (Loa/SOD1(G93A)) have been recently shown to attenuate rather than to accelerate the phenotypical expression of motor neuron degeneration. These results raise the question whether other functional relevant mutations in dynein cause a similar effect. To address this question, we have cross-bred SOD1(G93A) with Cra1/+ mice. These double transgenic mice show an attenuated decline of both motor activity and body weight and an increase of survival time compared to SOD1(G93A) mice. Thus, this study confirms that mechanisms associated with dynein such as retrograde axonal transport may play an important role in SOD1(G93A-) toxicity on motor neurons.

Animals↗
PubMed2006

Cardiomyopathy in motor neuron diseases.

OBJECTIVE: Myocardial involvement in motor neuron diseases (MND) is an uncommon feature. In amyotrophic lateral sclerosis (ALS) abnormalities of the autonomic nervous system affecting cardiac function have been described, for the hereditary spastic paraplegias (HSP) comparable manifestations are unknown. This study observed ALS and HSP patients with coexisting cardiomyopathy without major cardial risk factors. METHODS: Four patients with definite ALS and two pHSP patients. In all patients detailed clinical, cardiological, electrophysiological and laboratory data were analysed. In two ALS patients skeletal muscle biopsy was performed. RESULTS: In all investigated MND patients cardiomyopathy was present. Beside hyperlipoproteinaemia and mild hypertension in one case, none of the patients showed major cardiovascular risk factors. There was no evidence for a secondary cause of cardiomyopathy like coronary heart disease, myocarditis, or mitochondrial damage mimicking MND. CONCLUSION: This report could not conclude that the occurrence of cardiomyopathy is rare logically. Although an underlying pathophysiological cause was not obvious, it is proposed that in all MND patients a routine cardiological evaluation should be performed.

Aged↗
PubMed2005

Targeted antioxidative and neuroprotective properties of the dopamine agonist pramipexole and its nondopaminergic enantiomer SND919CL2x [(+)2-amino-4,5,6,7-tetrahydro-6-Lpropylamino-benzathiazole dihydrochloride].

Pramipexole has been shown to possess neuroprotective properties in vitro that are partly independent of its dopaminergic agonism. The site of neuroprotective action is still unknown. Using [(3)H]pramipexole, we show that the drug enters and accumulates in cells and mitochondria. Detoxification of reactive oxygen species (ROS) by pramipexole is shown in vitro and in vivo by evaluating mitochondrial ROS release and aconitase-2 activity, respectively. Pramipexole and its (+)-enantiomer SND919CL2X [low-affinity dopamine agonist; (+)2-amino-4,5,6,7-tetrahydro-6-l-propylamino-benzathiazole dihydrochloride] possess equipotent efficacy toward hydrogen peroxide and nitric oxide generated in vitro and inhibit cell death in glutathione-depleted neuroblastoma cells. IC(50) values ranged from 15 to 1000 microM, consistent with the reactivity of the respective radical and the compartmentalization of ROS generation and ROS detoxification. Finally, both compounds were tested in superoxide dismutase 1-G93A mice, a model of familial amyotrophic lateral sclerosis. SND919CL2X (100 mg/kg) prolongs survival time and preserves motor function in contrast to pramipexole (3 mg/kg), which shows an increase in running wheel activity before disease onset, presumably caused by the dopaminergic agonism. We conclude that both enantiomers, in addition to their dopaminergic activity, are able to confer neuroprotective effects by their ability to accumulate in brain, cells, and mitochondria where they detoxify ROS. However, a clinical use of pramipexole as a mitochondria-targeted antioxidant is unlikely, because the high doses needed for antioxidative action in vitro are not accessible in vivo due to dopaminergic side effects. In contrast, SND919CL2X may represent the prototype of a mitochondria-targeted neuroprotectant because it has the same antioxidative properties without causing adverse effects.

Aconitate Hydratase↗
PubMed2005

[Hereditary hemorrhagic telangiectasia. A rare treatable cause of stroke].

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease of the vascular connective tissue. Pulmonary arteriovenous and cerebral vascular malformations are risk factors for serious neurological complications such as paradoxical embolism and intracranial hematomas. We describe two patients with HHT and pulmonary arteriovenous malformations suffering from stroke caused by paradoxical embolism. In both cases, fistulas were successfully treated by embolisation and no further cerebral ischemic events occurred. In ischemic strokes of unknown origin, HHT should be considered as a possible diagnosis with effective treatment options.

Adult↗
PubMed2004

The advanced glycation end-product N epsilon-(carboxymethyl)lysine level is elevated in cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

Oxidative stress is involved in the aetiopathogenesis of amyotrophic lateral sclerosis (ALS), a fatal degenerative disorder. To test whether oxidative stress in ALS is increased and confined to the central nervous system, we have measured the glycoxidation product N(epsilon)-(carboxymethyl)lysine (CML) in serum and cerebrospinal fluid (CSF) samples by means of a novel enzyme immunoassay. Significant increases of CSF/serum ratio of CML in ALS patients (n = 25) as compared to normal controls (n = 20, p = 0.001) and to Alzheimer disease patients (n = 9, p = 0.029) suggest intrathecal production of this glycoxidation product. Measurement of CML levels may provide a novel diagnostic tool and may supplement current monitoring strategies in interventional trials.

Adult↗
PubMed2004

High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.

UNLABELLED: Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. METHODS: 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP's were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an "intent-to-treat" (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. RESULTS: Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. CONCLUSION: Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.

The authors report mutation screening of the p150 subunit of dynactin (DCTN1) and the cytoplasmic dynein heavy chain (DNCHC1) genes in 250 patients with ALS and 150 unrelated control subjects. Heterozygous missense mutations of the DCTN1 gene were detected in one apparently sporadic case of ALS (T1249I), one individual with familial ALS (M571T), two patients with familial ALS, and two unaffected relatives in the same kindred (R785W). The allelic variants of the DCTN1 gene may represent a previously unknown genomic risk factor for ALS.

Aged↗
PubMed2004

Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration.

The carrier molecule that transports dopamine (DA) into dopamine neurons by an electrogenic, Na(+)- and Cl(-)-transport-coupled mechanism is known as the dopamine transporter (DAT). This uptake system is exclusively expressed in DA neurons with significantly higher levels of DAT expression in cells of the substantia nigra pars compacta than those of the ventral tegmental area and arcuate hypothalamic neurons. The expression density of DAT strongly correlates with the extent of DA cell loss in Parkinson's disease (PD). There are also DAT gene polymorphisms associated with PD. These data suggest a role of the DAT in the pathogenesis of PD. Though selective for its respective neurotransmitter, the DAT can also transport synthetic/natural analogues of the transmitter. Should such compounds interact with vital intracellular structures, their penetration into the neuron might have significant consequences. This sequence of toxic events could indeed demonstrated for the synthetic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces selective degeneration of DA neurons characteristic of PD. Dopaminergic toxicity of its active metabolite 1-methyl-4-pyridinium (MPP(+)) is mediated by the DAT through accumulation into DA neurons, where it inhibits mitochondrial complex I activity. Various endogenous and exogenous heterocyclic molecules, which are structurally related to MPTP/MPP(+), such as isoquinolines and beta-carbolines, have been reported to exhibit similar toxic properties on DA cells, which are conferred by their uptake by the DAT. Taken together, there is large body of evidence from morphological, molecular biological and toxicological studies indicating that the DAT might be responsible for the selectivity of DA cell death in PD.

Animals↗
PubMed2004

Reduced reactivation rate in mutant CuZnSOD and progression rate of amyotrophic lateral sclerosis.

Mutations in the SOD1 gene are associated with familial amyotrophic lateral sclerosis (fALS). The mechanisms by which these mutations lead to anterior horn cell loss are unknown, however, increased binding of Hsps on the demetallated mutant SOD1 has been described which would make the HSPs unavailable for other purposes, and reduce the SOD1 concentration in mitochondria, thereby creating a proapoptotic situation finally leading to motor neuron death. Here we report the recombinant expression of four human copper/zinc superoxide dismutase (CuZnSOD) variants, including the wild-type enzyme and mutant proteins associated with familial ALS. The bacterial expression level of soluble mutated proteins was influenced by the mutations leading to drastically reduced levels of soluble CuZnSOD. Simultaneously, increasing levels of insoluble and probably aggregated mutated CuZnSOD were identified in bacterial cell pellets. In addition, altered reactivation kinetics of the purified mutant apoproteins after expression in bacterial culture was shown. Biophysical and biochemical analysis showed that zinc incorporation is severely reduced in the CuZnSOD proteins associated with the most severely forms of fALS (A4V, G93A). These data indicate that a reduced holoenzyme formation rate of mutant enzymes may be a critical factor in the etiopathology of fALS.

Alanine↗
PubMed2004

Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus?

OBJECTIVES: In animal models and in vitro studies leptomeninges have been shown to be the origin of neurotrophic substances that support the survival and growth of neuronal cells. Because dementia is associated with neuronal loss, we investigated whether leptomeningeal dysfunction may be involved in the pathogenesis of dementia disorders. METHODS: We analysed the cerebrospinal fluid (CSF) concentrations of the leptomeningeal derived beta trace protein, beta2 microglobulin, and cystatin C. RESULTS: There was a statistically significant difference of the CSF beta trace protein levels among different groups. Patients with idiopathic normal pressure hydrocephalus (NPH) (17.5 (SD 4.3) mg/l) showed significantly lower CSF beta trace protein levels than patients with Alzheimer's disease (23.8 (6.2) mg/l), depression (24.2 (7.3) mg/l), and normal controls (25.3 (4.9) mg/l). To patients with vascular dementia (20.1 (5.6) mg/l) and frontotemporal dementia (21.9 (7.0) mg/l), the difference was not significant. There was no significant difference regarding the CSF and serum concentrations of beta2 microglobulin or cystatin C among the different groups. CONCLUSIONS: We conclude that leptomeningeal dysfunction may be involved in certain types of dementia such as NPH and that reduced CSF beta trace protein levels in patients with NPH may aid in differentiating this difficult to diagnose disorder from other syndromes such as Alzheimer's disease.

Aged↗
PubMed2004

Topography of cerebral atrophy in early Huntington's disease: a voxel based morphometric MRI study.

OBJECTIVES: To analyse grey matter changes in early stages of Huntington's disease using magnetic resonance imaging (MRI) and the technique of voxel based morphometry (VBM). METHODS: Forty four patients with a molecularly confirmed clinical diagnosis of Huntington's disease based on the presence of motor signs were included in the study. Patients were clinically rated using the Unified Huntington's Disease Rating Scale; all were in early clinical stages of the disease (that is, Shoulson stages I and II). High resolution volume rendering MRI scans (MP-RAGE) were acquired. MRI data were volumetrically analysed in comparison to an age matched normal database by VBM, using statistical parametric mapping (SPM99). RESULTS: In Huntington's disease, robust regional decreases in grey matter density (p<0.001, corrected for multiple comparisons)-that is, atrophy-were found bilaterally in striatal areas as well as in the hypothalamus and the opercular cortex, and unilaterally in the right paracentral lobule. The topography of striatal changes corresponded to the dorso-ventral gradient of neuronal loss described in neuropathological studies. Stratification according to clinical severity showed a more widespread involvement extending into the ventral aspects of the striatum in the group of more severely affected patients. CONCLUSIONS: The topography of cerebral volume changes associated with Huntington's disease can be mapped using VBM. It can be shown that cerebral grey matter changes co-vary with clinical severity and CAG repeat length.

Adult↗
PubMed2003

High rate of constitutional chromosomal rearrangements in apparently sporadic ALS.

Of 85 patients with ALS, the authors identified 3 patients with balanced translocations and 2 patients with pericentric inversions, all affecting distinct chromosomal loci. The high rate of constitutional aberrations (5.9%) suggests that ALS is, in part, associated with recombination-based rearrangements of genomic sequences.

Adult↗