Four-hundred and fifty-one blood samples from Scandinavian patients with motor neuron disease were analysed for mutations in the CuZn-superoxide dismutase gene. Forty-one (9.6%) of the 427 patients with the amyotrophic lateral sclerosis (ALS) form of the disease were found to have a disease-associated mutation, and 14 of these patients were apparently sporadic cases. A mutation was found in 12 of the 51 families with recognized familial ALS. The five different mutations found (Ala4Val, Val14Gly, Asp76Tyr, Asp90Ala, Gly127insTGGG) have different genetic characteristics and are associated with very variable phenotypes spanning from rapidly progressing disease with only lower motor neuron signs to very slowly progressing disease with both the upper and lower motor neuron systems affected. The patients showed different sites of onset, though the progressive bulbar palsy form of the disease appears to be rare among patients with a CuZn-superoxide dismutase mutation. The progression of motor signs and symptoms followed the same basic pattern in patients with different mutations. Extra-motor system symptoms were frequent among patients with a CuZn-superoxide dismutase mutation. The results suggest that patients with mutations in the CuZn-superoxide dismutase gene constitute one disease entity. The Val14Gly and Asp76Tyr mutations have not been reported before, and the latter is the first mutation to be found in exon 3 of the CuZn-superoxide dismutase gene.

The results of this long-term study confirm earlier findings indicating that selegiline delays the progression of the signs and symptoms of Parkinson disease.

Prompted by previous reports on muscle thixotropy, we have investigated changes in inherent and reflex stiffness of the finger flexor muscles of human subjects at rest, following transient conditioning manoeuvres involving contractions and/or length changes of the finger flexors. The stiffness measurements were combined with electromyographic recordings from forearm and hand muscles and with microneurographic recordings of afferent stretch responses in finger flexor nerve fascicles. Finger flexor stiffness was evaluated by measuring (a) the flexion angle of the metacarpo-phalangeal joints at which the system during rest balanced the force of gravity and (b) the speed and amplitude of angular finger extensions induced by recurrent extension torque pulses of constant strength delivered by a torque motor. In the latter case, extension drifts in the resting position of the fingers were prevented by a weak flexion bias torque holding the fingers in a pre-determined, semiflexed position against a stop-bar. Stiffness changes following passive large amplitude finger flexions and extensions were studied in subjects with nerve blocks or nerve lesions preventing neurally mediated contractions in the forearm and hand muscles. Inherent stiffness was enhanced following transient finger flexions and reduced following transient finger extensions. The after-effects gradually declined during observation periods of several minutes. Similar results were obtained in subjects with intact innervation who succeeded during the pre- and post-conditioning periods in keeping the arm and hand muscles relaxed (i.e. showed no electromyographic activity). In these subjects it was also found that the after-effects were similar for active and passive finger movements and that isometric voluntary finger flexor contractions loosened the system in a way similar to finger extensions. In some subjects electromyographic reflex discharges appeared in the finger flexors in response to the extension test pulses. When elicited by small ramp stretch stimuli of constant amplitude, the stretch reflex responses were found to vary in strength in parallel with the changes in inherent stiffness following the various conditioning manoeuvres. The strength of the multi-unit afferent stretch discharges in the muscle nerve, used as index of muscle spindle stretch sensitivity, varied in parallel with the changes in inherent stiffness. Post-manoeuvre changes in muscle spindle stretch sensitivity were seen also when the spindles were de-efferented by a nerve block proximal to the recording site. The results can be explained in terms of thixotropic behaviour of extra- and intrafusal muscle fibres.(ABSTRACT TRUNCATED AT 400 WORDS)

No abstract

Selegiline delayed significantly the need to start levodopa in early PD. After a 2-month washout period (before the start of levodopa therapy) no significant symptomatic effect of selegiline was seen in comparison with the placebo group, supporting the concept of neuroprotective properties of the drug.

SUMMARY1. Different techniques were used to generate sudden ramp extension movements of the wrist while the subjects were either relaxed or maintaining a weak voluntary contraction in the wrist flexors. Afferent responses to the displacements were recorded with a tungsten micro-electrode inserted into a fascicle of the median nerve supplying one of the wrist flexor muscles, and e.m.g. responses were recorded with needle electrodes inserted into the same muscle.2. With the wrist flexors either relaxed or contracting, extensions at 100-200'/sec for 60-70 msec (generated by either an hydraulic motor or a torque motor) produced segmented afferent responses with two to four afferent bursts, separated by intervals of 20-30 msec. The successive neural peaks, occuring during the stretch phase, were correlated to mechanical vibrations sensed by a strain gauge and sometimes also by a wrist goniometer. With the flexor muscles contracting, the successive peaks in the neurogram were followed by similar peaks in the e.m.g, the delay between neural and e.m.g. peaks being 20-25 msec.3. Small abrupt extension movements of 1-2°lasting only 10-15 msec often produced segmented afferent responses with one neural burst occuring during the stretch phase and another 15-20 msec later, corresponding to a mechanical oscillatory event succeeding the stretch. The oscillation and the second neural burst were not present with small extension movements of smooth onset and halt. With the flexor muscles contracting, stimuli producing one afferent burst produced only one e.m.g. peak, whereas double-peaked afferent discharges produced double-peaked e.m.g. responses, the delay between individual neural e.m.g. peaks being 20-25 msec.4. Similar segmentation of the neural stretch responses was seen when abrupt displacements were produced by electrically induced muscle twitches, by manual pulls on a spring attached to the hand or by the subject making fast voluntary wrist extensions. This grouping of afferent discharges was seen in both multi-unit and in single-unit recordings from fibres identified as group Ia afferents. 6. For imposed movements with a duration of 60-70 msec the successive e.m.g. peaks caused a fused reflex contraction, appearing as a torque trace deflexion, starting at about the time when the movement ended and reaching its peak within about 40 msec. With longer-lasting movements the mechanical reflex response accompanying the successive e.m.g. bursts, appeared as a decelerative force, starting to oppose the ongoing movement about 60 msec after its start. Mechanical consequences of stretch reflex contractions starting after, rather than during, the stretch movement are discussed.

SUMMARY1. Experiments were performed to check the validity of previous claims concerning the 'long-loop' aetiology of 'late' reflex electromyogram (e.m.g.) responses to muscle stretch in man. The primary aim was to investigate whether observations previously presented in favour of the 'long-loop hypothesis' are explicable also in terms of the 'resonance hypothesis', according to which the 'late' reflex components represent spinal, short-latency responses to intramuscular oscillations initiated by the impact.2. The contracting wrist flexors of healthy subjects were exposed to trains of recurrent 25-50 Hz stretch stimuli (wrist torque pulses). Each of the initial two or three pulses in the train was followed by e.m.g. peaks with a latency of 20-25 msec. The e.m.g. peaks driven in this way had the following characteristics in common with the successive two or three e.m.g. peaks which were induced by single ramp stretches or tendon taps. (a) Changes in stimulus parameters which altered the strength of the initial e.m.g. peak often had an opposite effect on the strength of the succeeding peak(s). Muscle vibration which attenuated the initial peak often enchanted the succeeding one(s). (b) The initial e.m.g. peak was less affected than the succeeding peak(s) by the subjects' attempts to respond with rapid 'resist' or 'let go' reactions.3. Intramuscular oscillations (monitored by a needle accelerometer) and e.m.g. responses evoked by single ramp stretches and/or tendon taps were also studied in the long thumb flexor, the calf muscles and the masseter muscle. In the thumb flexor, the initial accelerometer deflexion was only rarely succeeded by a short latency e.m.g.peak, but the succeeding wave in the needle accelerogram was followed by such a peak, appearing about 40 msec after stimulus application. By contrast, the calf muscles and the jaw elevators exhibited a high amplitude, short-latency e.m.g. response to the first but only rarely to the second intramuscular oscillation wave.4. The interval between initial and second e.m.g. peaks following tendon taps was longer for calf muscles than for wrist flexors and longer for wrist flexors than for jaw elevators. Similar differences were observed with respect to the intervals between the damped intramuscular oscillations initiated by the impacts.5. Without denying the existence of 'long-loop reflexes' it is concluded that the characteristics of the 'late' reflex responses to muscle stretch in man are explicable also in terms of the 'resonance hypothesis'.

Dopaminergic receptor properties in the striatum of patients with Parkinson's disease (PD) and Huntington's chorea (HD) were studied by positron emission tomography (PET), using 11C-N-methyl-spiperone as a dopamine D2 receptor ligand. The time-dependent regional radioactive uptake in the caudate nucleus and the putamen was measured and fitted to a 3-compartment pharmacokinetic model. The rate constant k3 for specific binding to the receptor compartment in the striatum was determined in relation to the binding in regions with a low density of specific binding sites, such as the cerebellum and the frontal cortex . k3, which is a measure of the receptor density, was reduced in one patient with HD but less affected in PD in comparison with healthy controls. The pattern of k3 values calculated from the 6 PD patients is discussed in relation to any side-to-side differences in dopamine receptor densities in hemiparkinsonism and to possible "hypersensitivity" of dopamine receptors in the early stage of the disease and down-regulation in more advanced disease.