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Biomedical subjects

T Klockgether

Publications and source records attributed to T Klockgether.

At least 181 records · Page 10Linked to original sources
PubMed1993

Magnetic resonance imaging in hereditary and idiopathic ataxia.

We used magnetic resonance imaging (MRI) to study brain and spinal cord morphology in hereditary and idiopathic ataxia. Our interest was in whether the classical neuropathologic categories--cerebellar cortical atrophy (CCA), olivopontocerebellar atrophy (OPCA), and spinal atrophy (SA)--could be identified in vivo and which clinical phenotype corresponded to which morphologic category. To this end, we measured the size of the cerebellar vermis, cerebellar hemispheres, fourth ventricle, middle cerebellar peduncles, basis pontis, medulla oblongata, and cervical spinal cord on T1-weighted images of 61 patients and 24 healthy controls. Five patients with Friedreich's ataxia (n = 7) and all with late-onset Friedreich's ataxia (n = 3) had SA without major involvement of the brainstem or cerebellum. Morphologic findings in patients with early-onset cerebellar ataxia with retained tendon reflexes (n = 11) were heterogeneous: six patients had MRI findings compatible with CCA, and two patients had a combination of SA and CCA. The three remaining patients had an atypical pattern of atrophy. Similarly, the morphologic changes in patients with autosomal-dominant cerebellar ataxia with additional noncerebellar symptoms (ADCA-I; n = 13) were nonuniform: atrophic changes typical for CCA, OPCA, or SA were each present in one case, four patients had a combination of OPCA and SA, and the remaining patients could not be assigned to one of the morphologic categories. In autosomal-dominant cerebellar ataxia with a pure cerebellar syndrome (ADCA-III; n = 6), all patients except one had CCA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The coordination of posture and voluntary movement in patients with cerebellar dysfunction.

Postural adjustments associated with the task of rising on tiptoes were investigated in a reaction time paradigm in 10 normal subjects and 18 patients with cerebellar disorders. Cerebellar dysfunction was due to either degenerative cerebellar disease, tumor, or ischemia. Displacements of the center of foot pressure (CFP) were recorded. The task, accomplished by the triceps surae muscle (executional activity, mean latency of 411 ms), is mechanically effective only if the center of gravity has been shifted forward in advance. To this effect, a phasic burst of preparatory EMG activity in the tibialis anterior normally occurs at a mean latency of 163 ms, shifting the center of gravity forward. Shortly thereafter, activity of the quadriceps femoris (175 ms) extends the knee and aids the forward shift of the center of gravity. Different aspects of this motor sequence were disturbed in individual patients: Latencies of preparatory and executional activity were uncorrelated in 15 of the 18 patients. Executional (n = 16) or preparatory (n = 13) EMG activity was tonic instead of phasic. Latencies of either preparatory or executional EMG activities or both were prolonged (n = 10). The time interval between motor preparation and execution was increased (n = 9). The trial-to-trial variability of biomechanical parameters and EMG latency was increased. Preparatory EMG activity in the quadriceps was entirely missing (n = 9), resulting in knee bending at the unsuccessful attempt to rise on tiptoes. Patients who were most severely affected had no preparatory activity at all (n = 2), and therefore were unable to perform the task.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

The competitive NMDA antagonist CGP40.116 enhances L-dopa response in MPTP-treated marmosets.

Experiments in MPTP-treated non-human primates testing potential antiparkinsonian action have shown both, beneficial and adverse effects of gutamate receptor antagonists. To investigate this matter further, the novel competitive NMDA antagonist CGP40.116 was administered systemically to three adult MPTP-treated marmosets. When coadministered subcutaneously with a subthreshold dose of L-DOPA, 2 mg/kg, CGP40.116 25-250 micrograms/kg, increased locomotor activity. However, when administered alone, CGP40.116 had no effect on locomotor activity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys.

Abnormally increased subthalamic nucleus output to the internal pallidal segment and the reticular part of the substantia nigra plays a critical pathophysiological role in the development of parkinsonism. Because synaptic transmission of subthalamic output is glutamatergic and mediated, in part, by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, AMPA receptor antagonists may possess antiparkinsonian properties. We report that in monoamine-depleted rats, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) (Novo-Nordisk, Copenhagen, Denmark)--a selective antagonist of the AMPA subtype of glutamate receptor--suppressed muscular rigidity but had no effect on akinesia. NBQX microinjected into the subthalamic nucleus, internal pallidal segment, and reticular part of the substantia nigra, but not into the laterodorsal neostriatum of the rats, stimulated locomotor activity and reduced muscular rigidity. In aged Rhesus monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills. NBQX also potentiated the antiparkinsonian effects of L-3,4-dihydroxyphenylalanine in both rats and monkeys. Blockade of excitatory synaptic transmission by AMPA receptor antagonists may provide a new therapeutic strategy for Parkinson's disease (PD).

Animals↗
PubMed1991

Paradoxical anticonvulsant activity of the gamma-aminobutyrate antagonist bicuculline methiodide in the rat striatum.

Bicuculline methiodide (BMI), a gamma-aminobutyrate (GABA) antagonist, is a powerful convulsant agent when injected into the cerebral ventricles, amygdala, hippocampus, thalamus, neocortex, and deep prepiriform cortex in rats. In contrast, bilateral microinjection of BMI into the rat striatum confers protection against seizures induced by the cholinergic agonist pilocarpine (380 mg/kg, i.p.), with an ED50 of 94 fmol (range 45-195 fmol). No topographical variation in the anticonvulsant action of BMI was detected throughout rostrocaudal and dorsoventral aspects of the striatum. The anticonvulsant action of BMI in the striatum was reversed by coadministration of the GABA agonist muscimol or by blocking GABA-mediated inhibition in either the substantia nigra pars reticulata or in the entopeduncular nucleus. The results show that blockade of GABA-mediated inhibition in the striatum has a powerful anticonvulsant effect in the pilocarpine model, suggesting that GABAergic transmission in the striatum modulates the seizure propagation in the forebrain.

Animals↗
PubMed1991

Early onset cerebellar ataxia with retained tendon reflexes. Clinical, electrophysiological and MRI observations in comparison with Friedreich's ataxia.

Fourteen patients with the clinical diagnosis of early onset cerebellar ataxia with retained tendon reflexes (EOCA) were examined and compared with 11 patients with Friedreich's ataxia (FA). The mean age of onset in EOCA was 15.9 +/- 6.0 yrs (FA: 14.0 +/- 5.7 yrs). Annual progression rate and the percentage of patients who were wheelchair-bound was lower in EOCA as compared with FA, although the difference did not reach statistical significance. The latency until becoming wheelchair-bound, however, was significantly longer in EOCA than in FA. The segregation ratio in EOCA was significantly lower than 0.25. Clinically, EOCA and FA patients presented with a progressive cerebellar syndrome. Associated symptoms, such as muscle wasting, sensory disturbances, foot deformity, scoliosis and electrocardiographic abnormalities were encountered less frequently in EOCA than in FA patients. The electrophysiological findings in EOCA were variable and pointed to axonal degeneration in peripheral nerves and central pathways. Posturographic measurements revealed a higher incidence of anteroposterior sway direction in EOCA as compared with FA, suggesting a cerebellar type of ataxia in EOCA. Eleven out of the 14 EOCA patients had cerebellar atrophy in MRI. The characteristic MRI finding in FA was upper cervical cord shrinkage and only minor atrophy of the cerebellum. The demonstration of cerebellar atrophy in the majority of EOCA patients supports the view that EOCA is distinct from FA. It is uncertain, however, whether EOCA is a homogenous disease entity or a group of phenotypically similar syndromes.

Action Potentials↗
PubMed1990

Differential effects of the excitatory amino acid antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), on spinal reflex activity in mice.

Intrathecal administration of the preferential quisqualate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in anesthetized mice depressed Hoffmann (H)-reflexes, while flexor reflexes remained unaffected. The depressant effect of CNQX on H-reflexes was dose-dependent (range 0.1-10 nmol). The intrathecal administration of the selective N-methyl-d-aspartate (NMDA) antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) reduced flexor reflexes (range 10-100 nmol) and had no effect on H-reflexes. These results suggest that H-reflexes in mice are mediated by spinal non-NMDA receptors, while flexor reflexes involve NMDA receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1990

Blockade of excitatory neurotransmission in the globus pallidus induces rigidity and akinesia in the rat: implications for excitatory neurotransmission in pathogenesis of Parkinson's diseases.

Bilateral microinjections of the selective N-methyl-D-aspartate (NMDA) antagonist, (-)-2-amino-7-phosphonoheptanoate (AP7), 0.02-0.5 nmol, into the globus pallidus and ventral-posterior portions of the caudate-putamen result in an increase in the muscle tone (rigidity) and catalepsy (akinesia) in rats. NMDA blocked the actions of AP7 on motility in sensitive regions of the globus pallidus and caudate-putamen. Topographical differences in the action of AP7 in the striatum were detected in the dorsal-ventral and rostral-caudal direction. Microinjections of AP7 into the nucleus accumbens induced neither an increase in the muscle tone nor catalepsy in rats, while ventral regions of the caudate-putamen were sensitive to both actions of AP7. Microinjections of AP7 into the dorsal caudate-putamen resulted in a moderate or no increase in the muscle tone. AP7 failed to induce catalepsy from dorsal regions of the caudate-putamen. These data identify the globus pallidus and a defined subregion of the caudate-putamen as crucial sites where excitatory neurotransmission acts to regulate the final set-point of the respective output neurons providing modulation of the passage of motor information through the basal ganglia.

2-Amino-5-phosphonovalerate↗
PubMed1990

The entopeduncular nucleus regulates muscle tone in genetically spastic rats: role of substance P and gamma-aminobutyric acid.

Microinjections of the substance P (SP) antagonist (D-pro2,D-phe7,D-trp9)-SP, or the gamma-aminobutyric acid (GABA) agonist, muscimol, into the entopeduncular nucleus reduced muscle tone in genetically spastic rats in a dose- and time-dependent manner. Similar injections into the ventral thalamus, zona incerta or amygdala had no effect on muscle tone. The muscle relaxant effect of (D-pro2,D-phe7,D-trp9)-SP injected into the entopeduncular nucleus was blocked by co-injections of SP, and that of muscimol by the GABAA antagonist, bicuculline methiodide. These results suggest that SP- and GABA-dependent mechanisms in the entopeduncular nucleus mediate regulation of the muscle tone.

Animals↗
PubMed1990

Substantia nigra: a site of action of muscle relaxant drugs.

Sites of action of centrally active muscle relaxant drugs are not well defined. Clinical experience with such drugs suggests that the spinal cord may be one of the important regions from which pathologically increased muscle tone may be relieved. Supraspinal centers that may also be involved in the expression of muscle relaxant action have not yet been defined. We report here that microinjections of therapeutically relevant muscle relaxants into the midbrain tegmentum of genetically spastic rats decrease muscle tone. The substantia nigra is the region from which midazolam, baclofen, and tizanidine (drugs used clinically in the treatment of spasticity), or gamma-vinyl-GABA, (-)-2-amino-7-phosphonoheptanoate, and [D-pro2-D-phe7-D-trp9]-substance P (experimental drugs active in animal models of spasticity), reduce muscle tone in genetically spastic rats and Hoffmann reflexes in normal rats. The effects of muscle relaxant drugs are topographically restricted to the substantia nigra pars reticulata and are receptor specific. These observations disclose a previously unknown function of the substantia nigra in mediating muscle relaxation.

Animals↗
PubMed1990

NMDA antagonists potentiate antiparkinsonian actions of L-dopa in monoamine-depleted rats.

Systemically administered N-methyl-D-aspartate (NMDA) antagonists, MK-801 ((+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate) and CPP (3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate), potentiate the ability of L-dopa (L-3,4-dihydroxyphenylalanine) to reverse akinesia and to alleviate muscular rigidity in monoamine-depleted rats. On the basis of these findings, it is proposed that NMDA antagonists may be beneficial as adjunctive treatment in the therapy of Parkinson's disease. CPP locally injected into the subthalamic nucleus, entopeduncular nucleus--the rat homologue of the internal pallidal segment--or substantia nigra pars reticulata of monoamine-depleted rats stimulates locomotor activity and alleviates rigidity, whereas local microinjection of CPP into the neostriatum is ineffective. These results make it unlikely that the neostriatum is the site of the antiparkinsonian action of NMDA antagonists in monoamine-depleted rats, whereas the subthalamic nucleus, internal pallidal segment, and substantia nigra pars reticulata appear to be important for the effects of NMDA antagonists.

Animals↗
PubMed1990

Dopamine control of seizure propagation: intranigral dopamine D1 agonist SKF-38393 enhances susceptibility to seizures.

The involvement of dopamine (DA) in human and experimental epilepsy has been discounted as DAergic drugs have little effect on convulsions. This work presents evidence that bilateral microinjection of the DAD1 agonist SKF-38393 into the substantia nigra enhances the susceptibility of rats to seizures, with an ED50 of 20 pmol (range 13-31 pmol), converting subconvulsant doses of the cholinergic agonist pilocarpine (200 mg/kg; i.p.) into convulsant ones. The proconvulsant action of SKF-38393 was reversed by blocking D1-mediated transmission in the substantia nigra with the D1 antagonist SCH-23390. The D2 agonist LY-171555 did not modulate the threshold for limbic seizures when injected into the substantia nigra. In the striatum, the D2 agonist LY-171555 protected rats against limbic seizures induced by systemic administration of pilocarpine (380 mg/kg; i.p.), with an ED50 of 2 pmol (range 1.4-2.8 pmol). The anticonvulsant action of LY-171555 in the striatum was reversed by haloperidol. The D1 agonist SKF-38393 did not affect pilocarpine seizures following administration into the striatum. Systemic administration of DAergic drugs showed that the D1 agonist SKF-38393 decreased the threshold for pilocarpine seizures, with an ED50 of 0.81 mg/kg (range 0.45-1.47 mg/kg), whereas the D2 agonist LY-171555 had no effect on susceptibility of rats to pilocarpine. The proconvulsant action of SKF-38393 was blocked by the D1 antagonist SCH-23390. These results suggest that DA differentially modulates seizure threshold in the forebrain acting via D1 mechanisms in the substantia nigra and D2 mechanisms in the striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

The development of infratentorial atrophy in patients with idiopathic cerebellar ataxia of late onset: a CT study.

The development of infratentorial atrophy in six patients suffering from idiopathic cerebellar ataxia of late onset was studied by a retrospective evaluation of consecutive computed tomography (CT) scans. Four patients had evidence of olivopontocerebellar atrophy (OPCA) both on clinical testing and magnetic resonance imaging (MRI). In these four patients, atrophy of the cerebellum and brain stem became visible at the same time and progressed in a roughly parallel manner, whereas in the remaining two the brain stem was left intact. In all patients with OPCA, definite brain-stem atrophy was visible earlier than the appearance of non-cerebellar clinical symptoms. The present data suggest that CT investigations at regular intervals may be of prognostic value in cerebellar ataxias.

Adult↗
PubMed1990

Idiopathic cerebellar ataxia of late onset: natural history and MRI morphology.

Twenty eight patients with the clinical diagnosis of idiopathic late onset cerebellar ataxia were examined clinically and by magnetic resonance imaging (MRI) or computed tomography (CT). In addition, the clinical records of all patients were analysed retrospectively. On the basis of their clinical presentation they were subdivided into patients with a pure cerebellar syndrome (n = 9) and patients with a cerebellar syndrome and additional non-cerebellar symptoms (n = 13). No attempts were made to classify patients with a disease duration of less than four years (n = 6) because the retrospective analysis showed that the disease started almost invariably with a pure cerebellar syndrome and additional symptoms came later. Patients with a lasting pure cerebellar syndrome had a significantly better prognosis than patients with additional non-cerebellar involvement (annual progression rate rate: 0.40 versus 0.80). Calculated median lifetime from onset of symptoms was 20.7 years in patients with a pure cerebellar syndrome and 7.7 years in patients with additional non-cerebellar symptoms. Among the latter, disease progression was faster the earlier non-cerebellar symptoms occurred. All of them presented with Parkinsonian symptoms, whereas bulbar symptoms, vertical gaze paresis, pyramidal deficits, dementia and urinary incontinence were encountered less frequently. MRI or CT showed cerebellar atrophy without apparent involvement of brainstem structures in all patients with a pure cerebellar syndrome suggesting the diagnosis of cerebellar cortical atrophy (CA). The majority of the patients with additional non-cerebellar symptoms had evidence of an atrophy of the cerebellum and the brainstem suggesting the presence of olivo-ponto-cerebellar atrophy (OPCA). In two of them, however, MRI morphology was not compatible with the diagnosis of OPCA.

Adult↗