Chronic stimulation of the globus pallidus internus for treatment of non-dYT1 generalized dystonia and choreoathetosis: 2-year follow up

OBJECT: The authors studied the long-term efficacy of deep brain stimulation (DBS) of the posteroventral lateral globus pallidus internus up to 2 years postoperatively in patients with primary non-DYT1 generalized dystonia or choreoathetosis. The results are briefly compared with those reported for DBS in DYT1 dystonia (Oppenheim dystonia), which is caused by the DYT1 gene. METHODS: Enrollment in this prospective expanded pilot study was limited to adult patients with severely disabling, medically refractory non-DYT1 generalized dystonia or choreoathetosis. Six consecutive patients underwent follow-up examinations at defined intervals of 3 months, 1 year, and 2 years postsurgery. There were five women and one man, and their mean age at surgery was 45.5 years. Formal assessments included both the Burke-Fahn-Marsden dystonia scale and the recently developed Unified Dystonia Rating Scale. Two patients had primary generalized non-DYT1 dystonia, and four suffered from choreoathetosis secondary to infantile cerebral palsy. Bilateral quadripolar DBS electrodes were implanted in all instances, except in one patient with markedly asymmetrical symptoms. There were no adverse events related to surgery. The Burke-Fahn-Marsden scores in the two patients with generalized dystonia improved by 78 and 71% at 3 months, by 82 and 69% at 1 year, and by 78 and 70% at 2 years postoperatively. This was paralleled by marked amelioration of disability scores. The mean improvement in Burke-Fahn-Marsden scores in patients with choreoathetosis was 12% at 3 months, 29% at 1 year, and 23% at 2 years postoperatively, which was not significant. Two of these patients thought that they had achieved marked improvement at 2 years postoperatively, although results of objective evaluations were less impressive. In these two patients there was a minor but stable improvement in disability scores. All patients had an improvement in pain scores at the 2-year follow-up review. Medication was tapered off in both patients with generalized dystonia and reduced in two of the patients with choreoathetosis. All stimulation-induced side effects were reversible on adjustment of the DBS settings. Energy consumption of the batteries was considerably higher than in patients with Parkinson disease. CONCLUSIONS: Chronic pallidal DBS is a safe and effective procedure in generalized non-DYT1 dystonia, and it may become the procedure of choice in patients with medically refractory dystonia. Postoperative improvement of choreoathetosis is more modest and varied, and subjective ratings of outcome may exceed objective evaluations.

Bullous pemphigoid: therapeutic algrorithm and practical management

Introduction: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucosae. BP typically affects the elderly and manifests with severe itch, localised or generalised eczematous, urticated and/or bullous lesions. Its morbidity and impact on the quality of life are important. The disease is significantly associated with neurological disorders, such as stroke, Parkinson disease, major cognitive impairment and multiple sclerosis. Diagnosis of BP critically relies on immunopathologic examinations, particularly direct immunofluorescence microscopy studies. Areas covered: This paper looks at the evidence of therapies commonly used in bullous pemphigoid. Expert opinion: Treatment of BP has been a challenge, given the relative rarity of the disease, lack of good quality randomised controlled trials, the presence of co-morbidities in the affected elderly population and the high mortality rate. Recent controlled studies have indicated that potent topical corticosteroids constitute a more effective therapy for BP when compared to oral corticosteroids in terms of control of the disease, side effect profile and overall survival. Other therapies have been employed with varying success, but are not validated yet. Improved knowledge of the pathophysiology of BP will hopefully allow the development of new immunomodulatory treatments for this debilitating disease.

Desarollo de un sistema interactivo para estimulación cognitiva en HTML5

En España hay más de 115.500 personas que padecen Parkinson. Esto la convierte en la segunda enfermedad neurodegenerativa más común, por detrás del Alzheimer. La mayoría de los enfermos se encuentran en edades comprendidas entre los 50 y los 80 años, lo que unido al incremento de la esperanza de vida hace que se prevea un incremento del número de enfermos de Parkinson en pocos años. El Parkinson es un desorden crónico y degenerativo que afecta a la parte del cerebro encargada del sistema motor, es decir, la encargada de coordinar la actividad, el tono muscular y los movimientos, así como a las capacidades cognitivas. Esta patología crónica, de momento, no tiene cura. A los pacientes se les aplican tratamientos farmacológicos para frenar la progresión de la enfermedad. Además, se aplican terapias adicionales como la fisioterapia, la logopedia, la musicoterapia, la estimulación cognitiva o la terapia ocupacional. El uso de las Tecnologías de la Información y Comunicaciones en el campo de la estimulación cognitiva permite que personas con deterioro cognitivo puedan realizar sesiones de estimulación desde su domicilio de forma remota, complementando las terapias individuales y/o grupales que haya indicado el terapeuta. Además, evita desplazamientos hasta el centro de atención, que en ocasiones pueden ser difíciles de efectuar por encontrarse en lugares alejados o por problemas de movilidad del afectado. Asimismo, el uso de este tipo tecnología permite que los resultados de los ejercicios realizados por los pacientes se puedan almacenar para que el terapeuta los pueda analizar en cualquier momento y de esta manera ir adecuando la terapia. Finalmente, la plataforma que se propone cuenta con el valor añadido de permitir la interactividad con los terapeutas y la posibilidad de adaptar los ejercicios a cada paciente, según las necesidades que presente cada uno. SUMMARY. In Spain, there are more than 115.500 people with Parkinson disease. Due to this, it is the second most common neurodegenerative disease, only behind Alzheimer's disease. Most patients have ages between 50 and 80 years of age, which together with the increase in life expectancy to provide an increase in the number of patients with Parkinson's in a few years. Most patients have aged between 50 and 80 years old, which together with the increase of life expectancy provide a growth in the number of people with Parkinson’s in a few years. Parkinson's is a chronic and degenerative disorder that affects the part of the brain responsible for the motor system, i.e., responsible for coordinating activity, muscle tone and movements, as well as cognitive abilities. Nowadays, this chronic pathology has no cure. Pharmacological treatments are applied to patients for slowing down the advance of this disease. In addition, there are additional therapies such as physiotherapy, speech therapy, music therapy, cognitive stimulation or occupational therapy. The use of the Information Technologies and Communications in the field of cognitive stimulation allows people with cognitive impairment may carry out stimulation sessions in their home remotely, complementing individual therapies or group therapies provided by the therapist. This minimizes trips to the attention center, which sometimes can be difficult due to they live in remote places or they are mobility-reduced people. In addition, the use of such technology allows that the results of the exercises personalized by patients can store so that the therapist can analyze them at any time and therefore he or she adapts the therapy. Finally, the proposed platform brings the added value of allowing interaction with the therapists and the possibility of adapting the exercises to each patient according to his or her needs.

Memory systems analyses of mnemonic disorders in aging and age-related diseases

The effects upon memory of normal aging and two age-related neurodegenerative diseases, Alzheimer disease (AD) and Parkinson disease, are analyzed in terms of memory systems, specific neural networks that mediate specific mnemonic processes. An occipital memory system mediating implicit visual-perceptual memory appears to be unaffected by aging or AD. A frontal system that may mediate implicit conceptual memory is affected by AD but not by normal aging. Another frontal system that mediates aspects of working and strategic memory is affected by Parkinson disease and, to a lesser extent, by aging. The aging effect appears to occur during all ages of the adult life-span. Finally, a medial-temporal system that mediates declarative memory is affected by the late onset of AD. Studies of intact and impaired memory in age-related diseases suggest that normal aging has markedly different effects upon different memory systems.

Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTP-induced neurotoxicity. The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.

Alterations in energy metabolism, neuroprotection and visual signal transduction in the retina of parkinsonian, MPTP-treated monkeys

Parkinson disease is mainly characterized by the degeneration of dopaminergic neurons in the central nervous system, including the retina. Different interrelated molecular mechanisms underlying Parkinson disease-associated neuronal death have been put forward in the brain, including oxidative stress and mitochondrial dysfunction. Systemic injection of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to monkeys elicits the appearance of a parkinsonian syndrome, including morphological and functional impairments in the retina. However, the intracellular events leading to derangement of dopaminergic and other retinal neurons in MPTP-treated animal models have not been so far investigated. Here we have used a comparative proteomics approach to identify proteins differentially expressed in the retina of MPTP-treated monkeys. Proteins were solubilized from the neural retinas of control and MPTP-treated animals, labelled separately with two different cyanine fluorophores and run pairwise on 2D DIGE gels. Out of >700 protein spots resolved and quantified, 36 were found to exhibit statistically significant differences in their expression levels, of at least ±1.4-fold, in the parkinsonian monkey retina compared with controls. Most of these spots were excised from preparative 2D gels, trypsinized and subjected to MALDI-TOF MS and LC-MS/MS analyses. Data obtained were used for protein sequence database interrogation, and 15 different proteins were successfully identified, of which 13 were underexpressed and 2 overexpressed. These proteins were involved in key cellular functional pathways such as glycolysis and mitochondrial electron transport, neuronal protection against stress and survival, and phototransduction processes. These functional categories underscore that alterations in energy metabolism, neuroprotective mechanisms and signal transduction are involved in MPTPinduced neuronal degeneration in the retina, in similarity to mechanisms thought to underlie neuronal death in the Parkinson’s diseased brain and neurodegenerative diseases of the retina proper.

Articulatory function in hypokinetic dysarthria: An electropalatographic examination of two cases

The present study employed electropalatography (EPG) and a nonspeech measure of lingual function to examine, in detail, the articulatory production deficits of two individuals with Parkinson disease (PD) and hypokinetic dysarthria. Participants read 10 repetitions of CV words contained within the carrier phrase I saw a _ today while wearing an EPG artificial palate. Target consonants included the alveolar stop /t/, lateral approximant /l/, and the alveolar fricative /s/ in the /a/ vowel environment. The results of the two participants were compared to an age-matched control group. Examination of the perceptual features of articulatory production, lingual strength, fine force control and endurance, tongue-palate contact patterns, and segment durations were conducted. Results of the study revealed quite different articulatory deficits in the two participants. Specifically, the articulation of Participant One (P1) was characterized by a fast rate of speech, undershooting of articulatory targets, and reduced duration of consonant closures. In contrast, Participant Two (P2) demonstrated tongue-palate contact patterns indicative of impaired lingual control in the presence of both normal and increased articulatory segment durations. Potential reasons for the differing articulatory deficits were hypothesized. The current study demonstrated that assessment with EPG identified potential causes of consonant imprecision in two individuals with hypokinetic dysarthria. Directions for speech pathology intervention, salient from the results of the study, were also noted.

Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knock-out mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knock-out mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

MEF2C: expression, regulation and interaction with target genes in health and diseases

Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

CDNF and MANF in an experimental model of Parkinson's disease in rats

Parkinson s disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic neurons of the substantia nigra (SN). Current therapies of PD do not stop the progression of the disease and the efficacy of these treatments wanes over time. Neurotrophic factors are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. Neurotrophic factors are attractive candidates for neuroprotective or even neurorestorative treatment of PD. Thus, searching for and characterizing trophic factors are highly important approaches to degenerative diseases. CDNF (cerebral dopamine neurotrophic factor) and MANF (mesencephalic astrocyte-derived neurotrophic factor) are secreted proteins that constitute a novel, evolutionarily conserved neurotrophic factor family expressed in vertebrates and invertebrates. The present study investigated the neuroprotective and restorative effects of human CDNF and MANF in rats with unilateral partial lesion of dopamine neurons by 6-hydroxydopamine (6-OHDA) using both behavioral (amphetamine-induced rotation) and immunohistochemical analyses. We also investigated the distribution and transportation profiles of intrastriatally injected CDNF and MANF in rats. Intrastriatal CDNF and MANF protected nigrostriatal dopaminergic neurons when administered six hours before or four weeks after the neurotoxin 6-OHDA. More importantly, the function of the lesioned nigrostriatal dopaminergic system was partially restored even when the neurotrophic factors were administered four weeks after 6-OHDA. A 14-day continuous infusion of CDNF but not of MANF restored the function of the midbrain neural circuits controlling movement when initiated two weeks after unilateral injection of 6-OHDA. Continuous infusion of CDNF also protected dopaminergic TH-positive cell bodies from toxin-induced degeneration in the substantia nigra pars compacta (SNpc) and fibers in the striatum. When injected into the striatum, CDNF and GDNF had similar transportation profiles from the striatum to the SNpc; thus CDNF may act via the same nerve tracts as GDNF. Intrastriatal MANF was transported to cortical areas which may reflect a mechanism of neurorestorative action that is different from that of CDNF and GDNF. CDNF and MANF were also shown to distribute more readily than GDNF. In conclusion, CDNF and MANF are potential therapeutic proteins for the treatment of PD.

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson`s Disease

Background Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher`s disease, among patients with Parkinson`s disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson`s disease. Methods Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson`s disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. Results All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Conclusions Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson`s disease.

Orthostatic hypotension in Parkinson's disease: association with cognitive decline?

BACKGROUND Orthostatic hypotension is common in Lewy body disorders and may be related to disease progression and the spread of Lewy body pathology. We therefore hypothesize that PD patients with orthostatic hypotension (OH) have a different cognitive profile compared to PD patients without OH. METHODS This cross-sectional study included 175 PD patients. Blood pressure (BP) was measured with a validated digital blood pressure monitor and patients with a systolic BP drop of > or =20 mmHg or a systolic pressure of <90 mm Hg after standing were considered to have OH. Cognition was assessed using MMSE extended by a selection of computerized cognitive tests focusing on reaction time, sustained attention, working memory and episodic verbal and visual memory. RESULTS Eighty-seven (49.7%) of the PD patients had OH. These patients were significantly more impaired in sustained attention and visual episodic memory compared to PD patients without OH. CONCLUSION We conclude that there are differences in the neuropsychological performance of patients with PD and OH, supporting the hypothesis that OH might be a marker for disease progression and cognitive decline in PD.

d-β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease

The heroin analogue 1-methyl-4-phenylpyridinium, MPP+, both in vitro and in vivo, produces death of dopaminergic substantia nigral cells by inhibiting the mitochondrial NADH dehydrogenase multienzyme complex, producing a syndrome indistinguishable from Parkinson's disease. Similarly, a fragment of amyloid protein, Aβ1–42, is lethal to hippocampal cells, producing recent memory deficits characteristic of Alzheimer's disease. Here we show that addition of 4 mM d-β-hydroxybutyrate protected cultured mesencephalic neurons from MPP+ toxicity and hippocampal neurons from Aβ1–42 toxicity. Our previous work in heart showed that ketone bodies, normal metabolites, can correct defects in mitochondrial energy generation. The ability of ketone bodies to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases. These findings further suggest that ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.

Using induced pluripotent stem cells to investigate the mechanistic link between Gaucher disease and Parkinson related synucleinopathies

Dissertação de Mestrado, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015