Locomotor activity and evoked dopamine release are reduced in mice overexpressing A30P-mutated human alpha-synuclein

We have generated a transgenic mouse line overexpressing mutated human A30P alpha-synuclein under the control of the prion-related protein promoter. Immunohistology revealed mutated human A30P alpha-synuclein protein in numerous brain areas, but no gross morphological changes, Lewy bodies, or loss of dopaminergic cell bodies. The transgenic mice displayed decreased locomotion, impaired motor coordination, and balance. In vivo voltammetry showed that A30P mice responded to longer stimulation of the ascending dopaminergic pathways with less dopamine release in striatum and had a slower rate of dopamine decline after repeated stimulations or after alpha-methyl-p-tyrosine-HCl treatment. However, dopamine re-uptake or transporter levels were similar in transgenic and control mice. Our data provide evidence that overexpression of mutated human A30P alpha-synuclein in mice leads to a reduced size of the dopamine storage pool. This is in agreement with the previously postulated involvement of alpha-synuclein in the turnover of transmitter vesicles and may explain the observed motor deficits in A30P mice.     

Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial

BACKGROUND: There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. METHODS: Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. FINDINGS: Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days. INTERPRETATION: Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. FUNDING: National Health and Medical Research Council of Australia.     

Injections of the neuroprotective peptide NAP to newborn mice attenuate head-injury-related dysfunction in adults

The prophylactic neuroprotective effects of NAP, a femtomolar-acting neuroprotective peptide were tested in a mouse model of head trauma. NAP was injected for the first 3 weeks of life and head injury was initiated at 4 months. After trauma, mice were tested for their performance by evaluating damaged motor ability, balance and alertness. Comparison of the performance 1 h and 1 week after injury indicated that NAP treatment resulted in faster and enhanced recovery. In a 5-day Morris water maze test with mice suffering moderate to severe injuries, only the NAP-treated group learned to find the hidden platform in the maze. Furthermore, NAP treatment resulted in decreased mRNA expression of the inflammation marker, Mac-1. Thus, a potentially new prophylactic treatment against neurodegeneration is suggested.     

Effect of motor training involving the less-affected side (MTLA) in post-stroke subjects: a pilot randomized controlled trial

Abstract

Introduction:

Poststroke, less-severe motor impairment occurs on the ipsilesional side of body. The objective of the present study was to evaluate the effectiveness of the motor training involving the less-affected side (MTLA) in stroke.

Methods:

This was a randomized, controlled, double-blinded pilot study conducted in the occupational therapy unit of a rehabilitation Institute. A convenience sample of 35 stroke subjects (mean poststroke duration, 28.76 weeks) was randomized into two groups (the experimental group: 17 and control group: 18). Thirty-two participants completed the entire study protocol. The experimental group and control group were provided MTLA and neurophysiological-based conventional therapy respectively. Both the groups received 24 treatment sessions (60 minutes each) over the period of two months. The Affected side was assessed using Brunnstrom recovery stage (BRS) and Fugl-Meyer assessment (FMA) whereas the less-affected side was evaluated by Minnesota manual dexterity test (MMDT), Purdue peg board test (PPBT) and Manual Muscle Testing (MMT).

Results:

Postintervention, the less-affected side of experimental group demonstrated significant improvement for MMDT (P = 0.003), PPBT (P = 0.01) and MMT (P?< 0.001 to 0.043) in comparison to the control group. Further, as compared to the control group, the experimental group exhibited positive significant change for the measure of affected side [BRS (P < 0.001) and FMA (P < 0.001 to 0.03)] at post assessment.

Conclusion:

MTLA enhanced the muscle strength, dexterity and coordination of the less-affected side as well as the motor recovery of the affected side in poststroke hemiparetic subjects.     

Amantadine and ketamine-induced improvement of motor coordination in lurcher mutant mice

The effects of amantadine and ketamine were compared to a placebo in a coat-hanger test on lurcher mutant mice. This test measures motor coordination and is dependent on cerebellar functioning. Both drugs improved motor coordination of the cerebellar mutants in that the time taken to reach the side-bar according to a 2 paw criterion was decreased during the drugged condition in comparison to the non-drugged condition. This result indicates that NMDA receptor antagonists may improve motor coordination in animals with cerebellar disease.     

A pilot trial of levetiracetam in eyelid myoclonia with absences (Jeavons syndrome)

OBJECTIVE: Eyelid myoclonia with absences (EMA) or Jeavons syndrome characterized by eyelid myoclonia (EM) (with or without absences), eye closure-induced EEG paroxysms, and photosensitivity. We conducted an open-label trial of levetiracetam in EMA. PATIENTS AND METHODS: Patients were recruited in different Italian Epilepsy Centres. Levetiracetam was administrated at starting dose of 10 mg/kg/day up to 50-60 mg/kg/day in two doses. Treatment period included a 5-6 week up-titration phase and a 12-week evaluation phase. The number of days with EM (i.e., days with seizures, DwS) and number of generalized tonic-clonic seizures (GTCS) were evaluated. Analysis of intent-to-treat population was performed using Fisher's and Wilcoxon tests. RESULTS: Thirty-five patients (23 F) with a mean age of 19 +/- 6 years were recruited. Twenty-seven had previously undergone one to five adequate trials of antiepileptic drugs. The median number of DwS/month was 12 +/- 8.2. Twenty-one patients experienced GTCS (median number/month: 1 +/- 0.2). Thirty-four subjects completed the trial. Levetiracetam was well tolerated (mean dose: 1985 mg/day). Responders were 28/35 (80%) patients, nine taking levetiracetam as monotherapy. Six patients were seizure-free, 15 had > or =75% and seven >50% seizure reduction. GTCS remitted in 14 out of 21 (66.6%) patients. The number/month of DwS (median: 12 vs 5; p = 0.0001) and of GTCS (median: 1 vs 0; p = 0.0001) decreased compared to baseline period. Disappearance or clear reduction in paroxysmal abnormalities at eye closure occurred in 20 of the responders and photoparoxysmal response in 19. Mean follow-up was 23.9 +/- 18.5 months. CONCLUSION: Levetiracetam is effective and well tolerated in EMA. Placebo-controlled studies should confirm these findings.     

Early and selective reduction of NOP56 (Asidan) and RNA processing proteins in the motor neuron of ALS model mice

Abstract

Objective: There is increasing evidence to support that altered RNA processing is implicated in the pathogenesis of motor neuron degeneration of amyotrophic lateral sclerosis (ALS). We evaluate the expression of three RNA processing-related proteins in ALS model mice in this study.

Methods: We analyzed expression and distribution patterns of three RNA processing-related proteins, nucleolar protein (NOP) 56 (identified as causative gene for spinocerebellar ataxia (SCA) 36, nicknamed Asidan), TDP-43, and fused in sarcoma/translocated in liposarcoma (FUS) in lumbar and cervical cords, hypoglossal nucleus, cerebral motor cortex, and cerebellum of transgenic (Tg) SOD1 G93A ALS model mice throughout the course of motor neuron degeneration.

Results: Compared to age-matched wild type (WT) mice, Tg mice showed progressive reduction of NOP56 levels in the large motor neurons of lumbar and cervical cords from the early-symptomatic stage (14 weeks of age) to the end stage of the disease (18 weeks). TDP-43 and FUS protein levels showed a later decrease in the nucleus of large motor neuron at 18 weeks (end stage of the disease). These changes were not observed in the primary motor cortex of the cerebrum as well as molecular and granular layers and Purkinje cells in the cerebellum.

Discussion: The present study suggests a progressive loss of these three nuclear proteins and subsequent RNA processing problems including a novel gene relating to ALS (NOP56) under the motor neuron degeneration.     

A pilot open-label trial of citalopram for restless activity and aberrant motor behaviors in Alzheimer disease.

OBJECTIVE: In a prospective, open-label pilot study in probable-Alzheimer disease (AD) outpatients, the authors investigated the efficacy of citalopram to reduce restless activity and aberrant motor behaviors. METHODS: Nineteen subjects were evaluated with Neuropsychiatric Inventory subscale and total scores. RESULTS: There was a significant decline in aberrant motor behaviors and overall behavior problems at 4, 8, and 12 weeks. CONCLUSION: This study provides initial evidence that citalopram may be effective in reducing aberrant motor behaviors in AD. However, because of the potential biases of an open-label study, these findings need to be confirmed in a larger, controlled trial.     

Positive PsychoTherapy in ABI Rehab (PoPsTAR): A pilot randomised controlled trial

Psychological distress is common following acquired brain injury (ABI), but the evidence base for psychotherapeutic interventions is small and equivocal. Positive psychotherapy aims to foster well-being by increasing experiences of pleasure, engagement and meaning. In this pilot trial, we investigated the feasibility and acceptability of brief positive psychotherapy in adults with ABI and emotional distress. Participants were randomised to brief positive psychotherapy plus usual treatment, or usual treatment only. Brief positive psychotherapy was delivered over eight individual out-patient sessions, by one research psychologist. A blinded assessor administered the Depression Anxiety Stress Scales (DASS-21) and the Authentic Happiness Inventory (AHI) at 5, 9 and 20 weeks post-baseline. Of 27 participants randomised (median age 57; 63% male; 82% ischaemic stroke survivors; median 5.7 months post-injury), 14 were assigned to positive psychotherapy, of whom 8 completed treatment. The intervention was feasible to deliver with excellent fidelity, and was acceptable to participants. Retention at 20 weeks was 63% overall. A full-scale trial would need to retain n?=?39 per group to end-point, to detect a significant difference in change scores on the DASS-21 Depression scale of 7 points (two-tailed alpha?=?.05, power?=?.80). Trials including an active control arm would require larger sample sizes. We conclude that a full-scale trial to investigate efficacy is warranted.     

Development of the gross motor function classification system (1997)

To address the need for a standardized system to classify the gross motor function of children with cerebral palsy, the authors developed a five-level classification system analogous to the staging and grading systems used in medicine. Nominal group process and Delphi survey consensus methods were used to examine content validity and revise the classification system until consensus among 48 experts (physical therapists, occupational therapists, and developmental pediatricians with expertize in cerebral palsy) was achieved. Interrater reliability (kappa) was 0.55 for children less than 2 years of age and 0.75 for children 2 to 12 years of age. The classification system has application for clinical practice, research, teaching, and administration.     

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.     

The motor cortex of the brush-tailed possum (Trichosurus vulpecula): motor representation, motor function and the pyramidal tract

Brief anodal shocks applied to the cerebral cortex of the brush-tailed possum (Trichosurus vulpecula) evoked discrete movements of the contralateral fore- and hindlimbs. In 17 possums, unilateral lesions were made in the motor cortex and the resultant corticospinal degeneration was studied with the Nauta-Gygax²⁴ technique. The corticospinal tract was traced contralaterally to T₁₀ in the dorsal funiculus and to T₇in the lateral funiculus. Preterminal degeneration was observed in Rexed's laminae IV–VII and occasionally in laminae III and VIII. In no instances were fibres traced to motoneurones. After cortical ablation, the possums exhibited no defect of gait or climbing ability in the cage and no consistent disturbance of posture when sitting. However, specific tests involving grasping, holding and placing revealed temporary motor deficits in the fore- and hindlimbs when large areas of motor cortex were ablated. The results have been compared with similar studies on other mammals, in particular those with prehensile limbs.     

A pilot, double-blind, placebo-controlled trial of pregabalin (Lyrica) in the treatment of essential tremor.

We performed a pilot, double-blind, placebo-controlled, randomized trial to evaluate the efficacy and tolerability of pregabalin (PGB, Lyrica), an antiepileptic agent, in treating essential tremor (ET). Twenty two patients with ET were randomly assigned to receive PGB or placebo. PGB was initiated at 50 mg/day and was escalated by 75 mg/day every 4 days to a maximum dose of 600 mg/day. Patients were evaluated by accelerometry and the Fahn-Tolosa-Marin (FTM) rating scale. There was a significant reduction in tremor amplitude in the PGB group compared with the placebo group, as measured by accelerometry, at a mean dose of 286.76+/-100.05 mg/day. Action tremor limb scores on the FTM also improved in the PGB group compared with the placebo group (P-value for multilevel modeling=0.04). PGB was fairly well tolerated, with about one-third of patients dropping out of the study because of adverse events. PGB provided significant improvements in accelerometry and in action tremor limb scores on the FTM. However, larger studies are needed to further evaluate the potential effect of PGB on ET.     

Acute reduction and long-term improvement of chorea with ceruletide (cholecystokinin analogue)

We studied the effects of ceruletide, a cholecystokinin analogue, on choreic involuntary movement in several neurological diseases by clinical scoring and electromyography in 11 patients. Ceruletide brought about a brief reduction of choreic movement reaching its maximum within 60 min and another long-lasting improvement over several weeks by single administration. The levels of homovanillic acid in cerebrospinal fluid before treatment were significantly higher in cases with long-lasting improvement than those in cases without improvement. We suggest that ceruletide may reduce choreic movement for a long period through effects on the central dopamine system and speculate that such a long-term effect may be accounted for by the change in transmission after the second messengers in neurons.     

Cell systems and the toxic mechanism(s) of alpha-synuclein

Mutations in the SNCA gene are causal for familial Parkinson disease/Lewy body disease. alpha-Synuclein is a small acidic protein that binds loosely to the surface of vesicles and may play a role in synaptic dynamics, although its normal function remains somewhat unclear. What is clear is that point mutations or increased expression of wild type alpha-synuclein causes disease. A great deal of literature supports the overall hypothesis that alpha-synuclein is damaging to neurons because it is inherently prone to aggregation; mutations or increased concentration of the protein both increase this tendency. An unproven, but popular, contention is that the toxic species are small oligomers that are relatively soluble, which may react with membranes to damage key processes within the cell. The details of this process, especially in determining the order of events and the requirement of particular processes in cell death, are unclear. Derangements in vesicle processing, including synaptic function, protein turnover, mitochondrial function and oxidative stress, have all been suggested to occur. Whether there is a sequence of events or whether these are interacting effects is unclear, but the outcome is to trigger cell death, by both apoptotic and non-apoptotic mechanisms depending on the system studied. In this article, we develop a framework for thinking about alpha-synuclein in terms of initiating events and secondary processes that are required to trigger neuronal dysfunction and cell death.     

Impairment of hippocampal gamma-frequency oscillations in vitro in mice overexpressing human amyloid precursor protein (APP)

Alzheimer's disease is associated with a dramatic decline in cognitive performance including hippocampal-dependent memory. We have investigated one feature of hippocampal activity related to memory, the gamma (30-80 Hz)-frequency rhythm. Hippocampal slices from mice overexpressing the human amyloid precursor protein (APP)(SWE) mutation (TAS10) were compared at 8 and 16 months of age with wild-type littermates. In slices obtained from TAS10 mice aged 8 months the gamma-frequency activity evoked with bath application of 200 nm kainate was significantly (P < 0.05; n = 8 slices, five animals) impaired (area power, 5956 +/- 2487 microV(2)) compared to slices from wild-type animals (area power, 18 256 +/- 7880 microV(2)). At 16 months of age there was no longer a significant difference (P > 0.05; n = 11 slices from five animals) between slices from TAS10 and wild-type control mice as the wild-type mice now exhibited a marked age-dependent reduction in gamma-frequency activity (TAS10 area power, 5751 +/- 1573 microV(2); wild-type area power = 5379 +/- 1454 microV(2)). Although no dense-core plaques were evident at 8 months there was detectable amyloid labelling in the TAS10 mice which might account for the deficits in gamma activity observed at this age. Dense plaques were clearly evident in the TAS10, but not wild-type, mice at 16 months of age but no further reductions in gamma-frequency activity were seen in the TAS10 mice. These data suggest that deficits in network function in Alzheimer's disease occur early and are not directly correlated to amyloid load.     

Autonomic function in hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease)

Autonomic tests of heart rate and blood pressure control using both invasive and noninvasive techniques were performed on 11 patients with hereditary motor and sensory neuropathy (HMSN) types 1, and 4 patients with HMSN type 2. The results were compared with those of 76 control subjects. No significant difference was found between the patient and control groups. Impairment of sweating on the extremities was found in patients with HMSN types 1 and 2, consistent with distal degeneration of sympathetic fibers in peripheral nerves, but there were no abnormalities of cardiovascular reflex control mechanisms.