Appearance Of Motor Deficits Research Articles

Role of Early Intravenous Immunoglobulins in Halting Clinical and Radiographic Disease Progression in Rasmussen Encephalitis

BackgroundRasmussen encephalitis (RE) is a rare progressive presumed autoimmune disorder characterized by pharmacoresistant epilepsy and progressive motor and cognitive deterioration. Despite immunomodulation, more than half of the patients with RE ultimately require functional hemispherotomy. In this study, we evaluated the potential beneficial effects of early initiation of immunomodulation in slowing disease progression and preventing the need for surgical interventions. MethodsA retrospective chart review over a 10-year period was conducted at the American University of Beirut Medical Center to identify patients with RE. Data were collected on seizure characteristics, neurological deficits, electroencephalography, brain magnetic resonance imaging results (including volumetric analyses for an objective assessment of radiographic progression), and treatment modalities. ResultsSeven patients met the inclusion criteria for RE. All patients received intravenous immunoglobulins (IVIGs) as soon as the diagnosis was entertained. Five patients with only monthly to weekly seizures at the time of IVIG initiation had favorable outcomes without resorting to surgery, along with a relative preservation of the gray matter volumes in the affected cerebral hemispheres. Motor strength was preserved in those patients, and three were seizure free at their last follow-up visit. The two patients who required hemispherotomy were already severely hemiparetic and experiencing daily seizures at the time of IVIG initiation. ConclusionsOur data suggest that the early initiation of IVIG as soon as a diagnosis of RE is suspected, and particularly before the appearance of motor deficits and intractable seizures, can maximize the beneficial effects of immunomodulation in terms of controlling seizures and reducing the rate of cerebral atrophy.

Translational Modeling of Psychomotor Function in Normal and AD-Pathological Aging With Special Concerns on the Effects of Social Isolation.

One year after the start of the COVID-19 pandemic, its secondary impacts can be globally observed. Some of them result from physical distancing and severe social contact restrictions by policies still imposed to stop the fast spread of new variants of this infectious disease. People with Alzheimer's disease (AD) and other dementias can also be significantly affected by the reduction of their activity programs, the loss of partners, and social isolation. Searching for the closest translational scenario, the increased mortality rates in male 3xTg-AD mice modeling advanced stages of the disease can provide a scenario of “naturalistic isolation.” Our most recent work has shown its impact worsening AD-cognitive and emotional profiles, AD-brain asymmetry, and eliciting hyperactivity and bizarre behaviors. Here, we further investigated the psychomotor function through six different psychomotor analysis in a set of 13-month-old 3xTg-AD mice and their non-transgenic counterparts with normal aging. The subgroup of male 3xTg-AD mice that lost their partners lived alone for the last 2–3 months after 10 months of social life. AD's functional limitations were shown as increased physical frailty phenotype, poor or deficient psychomotor performance, including bizarre behavior, in variables involving information processing and decision-making (exploratory activity and spontaneous gait), that worsened with isolation. Paradoxical muscular strength and better motor performance (endurance and learning) was shown in variables related to physical work and found enhanced by isolation, in agreement with the hyperactivity and the appearance of bizarre behaviors previously reported. Despite the isolation, a delayed appearance of motor deficits related to physical resistance and tolerance to exercise was found in the 3xTg-AD mice, probably because of the interplay of hyperactivity and mortality/survivor bias. The translation of these results to the clinical setting offers a guide to generate flexible and personalized rehabilitation strategies adaptable to the restrictions of the COVID-19 pandemic.

Partial depletion of dopaminergic neurons in the substantia nigra impairs olfaction and alters neural activity in the olfactory bulb

Olfactory dysfunction is a major non-motor symptom that appears during the early stages of Parkinson’s Disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra (SN). Depletion of SN dopaminergic neurons by 6-hydroxydopamine (6-OHDA) is widely used as a model for PD and ultimately results in motor deficits. However, it is largely unknown whether olfactory behavior and, more importantly, neural activity in the olfactory bulb (OB) are impaired prior to the appearance of motor deficits. We partially depleted the SN dopaminergic population in mice by injection of 6-OHDA. Seven days after injection of 6-OHDA, motor ability was unchanged but olfactory-driven behaviors were significantly impaired. Injection of 6-OHDA into the SN significantly increased the power of the ongoing local field potential in the OB for all frequency bands, and decreased odor-evoked excitatory beta responses and inhibitory high-gamma responses. Moreover, 6-OHDA treatment led to increased odor-evoked calcium responses in the mitral cells in the OB of awake mice. These data suggest that the olfactory deficits caused by depletion of the SN dopaminergic population are likely due to abnormal hyperactivity of the mitral cells in the OB.

Age-dependent alpha-synuclein accumulation and aggregation in the colon of a transgenic mouse model of Parkinson\u2019s disease

BackgroundParkinson’s disease (PD) is one of the most common neurodegenerative diseases, neuropathologically characterized by misfolded protein aggregation, called Lewy bodies and Lewy neurites. PD is a slow-progressive disease with colonic dysfunction appearing in the prodromal stage and lasting throughout the course of the disease.MethodsIn order to study PD pathology in the colon, we examined the age-dependent morphological and pathological changes in the colon of a PD mouse model expressing human wildtype α-synuclein (α-syn) fused with the green fluorescent protein (GFP), under the endogenous mouse α-syn promoter.ResultsWe observed an age-dependent progressive expression and accumulation of α-syn-GFP in the enteric neurons of Meissner’s (submucosal) and Auerbach’s (myenteric) plexuses of the colon. Additionally, the phosphorylation of α-syn at serine 129 also increased with age and the aggregation of α-syn-GFP coincided with the appearance of motor deficits at 9 months of age. Furthermore, α-syn (-GFP) distinctly co-localized with different subtypes of neurons, as identified by immunohistochemical labeling of vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and calretinin.ConclusionsOur results show the development of α-syn pathology in the enteric neurons of the colon in a PD mouse model, which coincide with the appearance of motor deficits. Our mouse model possesses the potential and uniqueness for studying PD gastrointestinal dysfunction.

Peripheral Administration of Tetanus Toxin Hc Fragment Prevents MPP+ Toxicity In Vivo.

Several studies have shown that intrastriatal application of 1-methyl-4-phenylpyridinium (MPP+) produces similar biochemical changes in rat to those seen in Parkinson's disease (PD), such as dopaminergic terminal degeneration and consequent appearance of motor deficits, making the MPP+ lesion a widely used model of parkinsonism in rodents. Previous results from our group have shown a neuroprotective effect of the carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) under different types of stress. In the present study, pretreatment with the intraperitoneal injection of Hc-TeTx in rats prevents the decrease of tyrosine hydroxylase immunoreactivity in the striatum due to injury with MPP+, when applied stereotaxically in the striatum. Similarly, striatal catecholamine contents are restored, as well as the levels of two other dopaminergic markers, the dopamine transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2). Additionally, uptake studies of [3H]-dopamine and [3H]-MPP+ reveal that DAT action is not affected by Hc-TeTx, discarding a protective effect due to a reduced entry of MPP+ into nerve terminals. Behavioral assessments show that Hc-TeTx pretreatment improves the motor skills (amphetamine-induced rotation, forelimb use, and adjusting steps) of MPP+-treated rats. Our results lead us to consider Hc-TeTx as a potential therapeutic tool in pathologies caused by impairment of dopaminergic innervation in the striatum, as is the case of PD.

The BACHD Rat Model of Huntington Disease Shows Specific Deficits in a Test Battery of Motor Function.

Rationale: Huntington disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and neuropsychiatric symptoms. HD is usually diagnosed by the appearance of motor deficits, resulting in skilled hand use disruption, gait abnormality, muscle wasting and choreatic movements. The BACHD transgenic rat model for HD represents a well-established transgenic rodent model of HD, offering the prospect of an in-depth characterization of the motor phenotype.Objective: The present study aims to characterize different aspects of motor function in BACHD rats, combining classical paradigms with novel high-throughput behavioral phenotyping.Methods: Wild-type (WT) and transgenic animals were tested longitudinally from 2 to 12 months of age. To measure fine motor control, rats were challenged with the pasta handling test and the pellet reaching test. To evaluate gross motor function, animals were assessed by using the holding bar and the grip strength tests. Spontaneous locomotor activity and circadian rhythmicity were assessed in an automated home-cage environment, namely the PhenoTyper. We then integrated existing classical methodologies to test motor function with automated home-cage assessment of motor performance.Results: BACHD rats showed strong impairment in muscle endurance at 2 months of age. Altered circadian rhythmicity and locomotor activity were observed in transgenic animals. On the other hand, reaching behavior, forepaw dexterity and muscle strength were unaffected.Conclusions: The BACHD rat model exhibits certain features of HD patients, like muscle weakness and changes in circadian behavior. We have observed modest but clear-cut deficits in distinct motor phenotypes, thus confirming the validity of this transgenic rat model for treatment and drug discovery purposes.

Peripheral and central neuronal ATF3 precedes CD4 + T-cell infiltration in EAE

Experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis produced by immunization with myelin oligodendrocyte glycoprotein (MOG) and adjuvants, results from profound T-cell mediated CNS demyelination. EAE is characterized by progressive, ascending motor dysfunction and symptoms of ongoing pain and hypersensitivity, in some cases preceding or concomitant with the motor deficits. In this regard, the EAE model mimics major features of multiple sclerosis, where a central neuropathic pain state is common. Although the latter condition is presumed to arise from a CNS loss of inhibitory controls secondary to the demyelination, dysfunction of sensory neurons may also contribute. Based on our previous studies that demonstrated the utility of monitoring expression of activating transcription factor 3 (ATF3), a sensitive marker of injured sensory neurons, here we followed both ATF3 and CD4+ T cells invasion of sensory ganglia (as well as the CNS) at different stages of the EAE model. We found that ATF3 is induced in peripheral sensory ganglia and brainstem well before the appearance of motor deficits. Unexpectedly, the ATF3 induction always preceded T cell infiltration, typically in adjacent, but non-overlapping regions. Surprisingly, control administration of the pertussis toxin and/or Complete Freund's adjuvants, without MOG, induced ATF3 in sensory neurons. In contrast, T cell infiltration only occurred with MOG. Taken together, our results suggest that the clinical manifestations in the EAE result not only from central demyelination but also from neuronal stress and subsequent pathophysiology of sensory neurons.

Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington's disease

Huntington's disease (HD) is a devastating neurodegenerative disease characterized by a progressive decline in motor abilities, as well as in cognitive and social behaviors. Most of these behavioral deficits are recapitulated in the R6/1 transgenic mouse, which can therefore be used as an experimental model to identify the neurobiological substrates of HD pathology and to design novel therapeutic approaches. The endocannabinoid system (ECS) is a relevant candidate to participate in the etiopathology of HD as it is a key modulator of brain function, especially in areas primarily affected by HD dysfunction such as the striatum. Thus, some studies have demonstrated an association between HD progression and alterations in the expression of several ECS elements, thereby suggesting that improving ECS function may constitute a useful strategy to eliminate or at least delay the appearance of HD symptoms. Here this hypothesis was specifically tested by evaluating whether the administration of a well-characterized cannabinoid receptor agonist (WIN 55,212), either acutely or chronically, improves the HD-like symptoms in R6/1 mice. While acute treatment did not change the behavioral phenotype of transgenic animals, chronic administration was able to prevent the appearance of motor deficits, to increase the number of striatal huntingtin inclusions and to prevent the loss of striatal medium-sized spiny neurons, without affecting the social or cognitive alterations. These findings suggest that prolonged administration of cannabinoid receptor agonists could be an appropriate strategy for selectively improving motor symptoms and stimulating neuroprotective processes in HD patients.

A Tale of Two Maladies? Pathogenesis of Depression with and without the Huntington’s Disease Gene Mutation

Huntington’s disease (HD) is an autosomal dominant disorder caused by a tandem repeat expansion encoding an expanded tract of glutamines in the huntingtin protein. HD is progressive and manifests as psychiatric symptoms (including depression), cognitive deficits (culminating in dementia), and motor abnormalities (including chorea). Having reached the twentieth anniversary of the discovery of the “genetic stutter” which causes HD, we still lack sophisticated insight into why so many HD patients exhibit affective disorders such as depression at very early stages, prior to overt appearance of motor deficits. In this review, we will focus on depression as the major psychiatric manifestation of HD, discuss potential mechanisms of pathogenesis identified from animal models, and compare depression in HD patients with that of the wider gene-negative population. The discovery of depressive-like behaviors as well as cellular and molecular correlates of depression in transgenic HD mice has added strong support to the hypothesis that the HD mutation adds significantly to the genetic load for depression. A key question is whether HD-associated depression differs from that in the general population. Whilst preclinical studies, clinical data, and treatment responses suggest striking similarities, there are also some apparent differences. We discuss various molecular and cellular mechanisms which may contribute to depression in HD, and whether they may generalize to other depressive disorders. The autosomal dominant nature of HD and the existence of models with excellent construct validity provide a unique opportunity to understand the pathogenesis of depression and associated gene-environment interactions. Thus, understanding the pathogenesis of depression in HD may not only facilitate tailored therapeutic approaches for HD sufferers, but may also translate to the clinical depression which devastates the lives of so many people.

In this issue: Proteomics – Clinical Applications 12/2008

AbstractIn this issue of Proteomics – Clinical Applications you will find the following highlighted articles:Looking through the leftoversThe magic in conditioned medium has been recognized for decades but exactly what it was and how it worked has only begun to come to light more recently. Byproducts of metabolic activity are easy to spot, more challenging are the secreted growth factors and other types of communication molecules. Ogura et al. looked at the litter that surrounded various cancer cells as a potential gold mine. It took only a bit of RP‐HPLC and MALDI‐TOF panning to turn up nuggets of pro‐ and pre‐proneurotensin/neuromedin N (pre‐proNT/NTN), good candidates for small‐cell lung cancer biomarkers. Pre‐proNT/NTN was found in medium from 4 out of 7 different small‐cell lung carcinomas but 0 out of 8 non‐small‐cell carcinomas.Ogura, S.‐i. et al., Proteomics Clin. Appl. 2008, 2, 1620–1627.Hunting for Huntington'sCreating animal models of inherited human diseases is not always a simple issue of replacing an animal gene with the human equivalent. Huntington's Disease (HD), caused at least in part by the development of expanded polyglutamine (CAG)n sequences in the huntingtin gene, has been modeled in mice with n>60 (CAG)n sequences but this leads to expression as a juvenile form of the disease. Nguyen et al. have developed transgenic rats that come much closer to the pattern of adult human HD in the character and time of appearance of motor deficits, cognitive decline, and emotional disturbance. After thorough micro array evaluation of the rat model at ages 3 and 12 months, these researchers argue that they are much closer to a system suitable for selection and application of biomarkers and potential therapeutics.Nguyen, H. P. et al., Proteomics Clin. Appl. 2008, 2, 1638–1650.Bifunctional assay means less workTo be able to have your cake and eat it, too, is one of those things economists tell us is impossible. Don't tell Rader et al. though. They are investigating methods to simplify and speed up human papilloma virus (HPV) biomarker screening from the same sample. This would be very useful for cervical cancer staging, still a problem despite the recent introduction and growing use of a vaccine for the most frequent cancer‐causing HPV types. Cervical samples were collected into a tube containing an RNA stabilizing reagent, from which proteins could be extracted and freed of cervical mucus. RNA could be extracted from the same samples with Trizol reagent according to the manufacturer's directions. Proteins recovered were cleanly analyzed by 2‐D DIGE and Western blots; total RNA could be analyzed on human cDNA arrays.Rader, J. S. et al., Proteomics Clin. Appl. 2008, 2, 1658–1669.

Cover Picture: Proteomics – Clinical Applications 12/2008

AbstractIn this issue of Proteomics – Clinical Applications you will find the following highlighted articles:Looking through the leftoversThe magic in conditioned medium has been recognized for decades but exactly what it was and how it worked has only begun to come to light more recently. Byproducts of metabolic activity are easy to spot, more challenging are the secreted growth factors and other types of communication molecules. Ogura et al. looked at the litter that surrounded various cancer cells as a potential gold mine. It took only a bit of RP‐HPLC and MALDI‐TOF panning to turn up nuggets of pro‐ and pre‐proneurotensin/neuromedin N (pre‐proNT/NTN), good candidates for small‐cell lung cancer biomarkers. Pre‐proNT/NTN was found in medium from 4 out of 7 different small‐cell lung carcinomas but 0 out of 8 non‐small‐cell carcinomas.Ogura, S.‐i. et al., Proteomics Clin. Appl. 2008, 2, 1620–1627.Hunting for Huntington'sCreating animal models of inherited human diseases is not always a simple issue of replacing an animal gene with the human equivalent. Huntington's Disease (HD), caused at least in part by the development of expanded polyglutamine (CAG)n sequences in the huntingtin gene, has been modeled in mice with n>60 (CAG)n sequences but this leads to expression as a juvenile form of the disease. Nguyen et al. have developed transgenic rats that come much closer to the pattern of adult human HD in the character and time of appearance of motor deficits, cognitive decline, and emotional disturbance. After thorough micro array evaluation of the rat model at ages 3 and 12 months, these researchers argue that they are much closer to a system suitable for selection and application of biomarkers and potential therapeutics.Nguyen, H. P. et al., Proteomics Clin. Appl. 2008, 2, 1638–1650.Bifunctional assay means less workTo be able to have your cake and eat it, too, is one of those things economists tell us is impossible. Don't tell Rader et al. though. They are investigating methods to simplify and speed up human papilloma virus (HPV) biomarker screening from the same sample. This would be very useful for cervical cancer staging, still a problem despite the recent introduction and growing use of a vaccine for the most frequent cancer‐causing HPV types. Cervical samples were collected into a tube containing an RNA stabilizing reagent, from which proteins could be extracted and freed of cervical mucus. RNA could be extracted from the same samples with Trizol reagent according to the manufacturer's directions. Proteins recovered were cleanly analyzed by 2‐D DIGE and Western blots; total RNA could be analyzed on human cDNA arrays.Rader, J. S. et al., Proteomics Clin. Appl. 2008, 2, 1658–1669.

Consequences of partial and severe dopaminergic lesion on basal ganglia oscillatory activity and akinesia

Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 microg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 microg of 6-OHDA reduced the number of TH+ neurons in the SN by approximately 60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 microg of 6-OHDA showed a marked reduction of TH+ cells in the SN ( approximately 75%) and VTA ( approximately 55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 microg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and approximately 70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease.

Hordotomija u lecenju bolnih stanja

During the time interval from January 1978 to January 2003, total of 128 chordotomy procedures have been done due to cancer's pain at the Institute of neurosurgery in Clinical Centre of Serbia. That pain has been mostly of uncontrolled intensity and it was resistant on applieed conservative treatment. Bilateral chordotomy has been performed in 6 patients only in exceptional cases when fixed paraplegia has proved; unilateral chordotomy has been performed in 122 cases. Bilateral chordotomy is much more dangerous than unilateral one because of greater posibility of appearance of motor deficits, sphincteral disturbances or subsequent formed pain. This procedure has several negative aspects. Firstly, it is an opened surgical intervention in general anesthesia and therefore, there is no communication with patient. We had a habit to perform DREZ surgery rather than chordotomy when ever it has been indicated. In 80.1% of all cases, the successfulness of surgery has been marked as excellent, in 15.2% of all cases, it has been marked as good, and in 4.7% of all cases, bad outcome has been detected. The rate of complication was 4.4%.

Beneficial Effects of Lysine Acetylsalicylate, a Soluble Salt of Aspirin, on Motor Performance in a Transgenic Model of Amyotrophic Lateral Sclerosis

We have studied the effect of lysine acetylsalicylate (LAS; Aspegic), a soluble salt of aspirin, on motor deficits in transgenic mice expressing a human superoxide dismutase SOD1 mutation (Gly-93→Ala), an animal model of familial amyotrophic lateral sclerosis (FALS). In nontreated FALS mice, motor impairments appear at 12–14 weeks of age, whereas paralysis is not observed before 20 weeks of age. Life expectancy is 140–170 days. Early treatment with LAS from 5 weeks of age delayed the appearance of motor deficits in FALS mice as measured by extension reflex, loaded grid, and rotarod tests. This beneficial effect of treatment was maintained up to 18 weeks of age, until just before onset of end-stage disease. When treatment was started at 13 weeks, no significant beneficial effect was observed. These results demonstrate that chronic LAS treatment is able to delay the appearance of reflex, coordination, and muscle strength deficits in this animal model of ALS if the treatment is started early enough. However, neither the onset of paralysis nor end-stage disease were improved by the LAS treatment. In the absence of an effect on survival, the functional improvement demonstrated here is probably the maximum that this demanding model could allow. Although other properties of LAS may have contributed to its beneficial effect, we suggest that the antioxidant properties of aspirin are responsible for the positive effects in this model and support the use of antioxidants as effective therapy for ALS.

Deficits in operant behaviour in monkeys treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Six adult Macaca fascicularis monkeys were trained to perform an instrumentally conditioned, visually-guided forearm reaching task for fruit juice reinforcement. Once animals were overtrained on this task, they were given intravenous injections of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (0.15 to 0.33 mg/kg). Animals were tested daily for performance in the previously learned behavioural task and were assessed daily for abnormalities in motor functioning. Monkeys developed deficits in operant task performance characterized by termination of responses after an initial series of responses and long pauses between responses. Once an animal stopped responding to the task, responses could often be reinitiated if the experimenter guided the monkey through the task. This type of performance deficit was seen both before and without the appearance of distinct parkinsonian motor signs. Animals which developed motor signs had extensive ventral mesencephalic cell loss while an animal with performance deficits but without motor signs had cell loss restricted to the ventral substantia nigra pars compacta. The results demonstrate that operant performance deficits can be observed in MPTP-treated monkeys independent of the appearance of motor deficits.