Therapy of Parkinson's Disease Subtypes.

Early descriptions of subtypes of Parkinson's disease (PD) are dominated by the approach of predetermined groups. Experts defined, from clinical observation, groups based on clinical or demographic features that appeared to divide PD into clinically distinct subsets. Common bases on which to define subtypes have been motor phenotype (tremor dominant vs akinetic-rigid or postural instability gait disorder types), age, nonmotor dominant symptoms, and genetic forms. Recently, data-driven approaches have been used to define PD subtypes, taking an unbiased statistical approach to the identification of PD subgroups. The vast majority of data-driven subtyping has been done based on clinical features. Biomarker-based subtyping is an emerging but still quite undeveloped field. Not all of the subtyping methods have established therapeutic implications. This may not be surprising given that they were born largely from clinical observations of phenotype and not in observations regarding treatment response or biological hypotheses. The next frontier for subtypes research as it applies to personalized medicine in PD is the development of genotype-specific therapies. Therapies for GBA-PD and LRRK2-PD are already under development. This review discusses each of the major subtyping systems/methods in terms of its applicability to therapy in PD, and the opportunities and challenges designing clinical trials to develop the evidence base for personalized medicine based on subtypes.

ALS phenotype is influenced by age, sex, and genetics: A population-based study.

OBJECTIVE: To assess the determinants of amyotrophic lateral sclerosis (ALS) phenotypes in a population-based cohort. METHODS: The study population included 2,839 patients with ALS diagnosed in Piemonte, Italy (1995-2015). Patients were classified according to motor (classic, bulbar, flail arm, flail leg, predominantly upper motor neuron [PUMN], respiratory) and cognitive phenotypes (normal, ALS with cognitive impairment [ALSci], ALS with behavioral impairment [ALSbi], ALSci and ALSbi combined [ALScbi], ALS-frontotemporal dementia [FTD]). Binary logistic regression analysis was adjusted for sex, age, and genetics. RESULTS: Bulbar phenotype correlated with older age (p < 0.0001), women were more affected than men at increasing age (p < 0.0001), classic with younger age (p = 0.029), men were more affected than women at increasing age (p < 0.0001), PUMN with younger age (p < 0.0001), flail arm with male sex (p < 0.0001) and younger age (p = 0.04), flail leg with male sex with increasing age (p = 0.008), and respiratory with male sex (p < 0.0001). C9orf72 expansions correlated with bulbar phenotype (p < 0.0001), and were less frequent in PUMN (p = 0.041); SOD1 mutations correlated with flail leg phenotype (p < 0.0001), and were less frequent in bulbar (p < 0.0001). ALS-FTD correlated with C9orf72 (p < 0.0001) and bulbar phenotype (p = 0.008), ALScbi with PUMN (p = 0.014), and ALSci with older age (p = 0.008). CONCLUSIONS: Our data suggest that the spatial-temporal combination of motor and cognitive events leading to the onset and progression of ALS is characterized by a differential susceptibility to the pathologic process of motor and prefrontal cortices and lower motor neurons, and is influenced by age, sex, and gene variants. The identification of those factors that regulate ALS phenotype will allow us to reclassify patients into pathologically homogenous subgroups, responsive to targeted personalized therapies.

Historical and conceptual aspects of motor disorders in the psychoses.

Historical epistemology is a useful method to understand the longitudinal construction of the movement disorders in psychiatry. Four periods can be identified in such a process. The first, extending from Classical times to the work of Griesinger, included disorders such as catalepsy, crocidism, epilepsy and paralysis. The second period, stretching from Griesinger to Kahlbaum, concentrated on the study of melancholia attonita, stupor and catatonia. The third period, covering the time from Kahlbaum to WWI, witnessed important conceptual shifts such as: the transformation of madness into psychoses; the redefinition of movement and motility in psychiatry; the appearance of self-contained syndromes as dyskinesias, tics, akathisia, complex disorders like the cases of encephalitis lethargica, etc.; the advent of functional and psychodynamic explanations; and the description by Wernicke, Kleist and others of the motility psychoses. The fourth period stretches from WWI to the present and since it corresponds to the views and work reported in the rest of this Special issue it has not been touched upon in this paper. In spite of an increasing methodological refinement, empirical research is yet to clarify what is the clinical meaning of the movement disorders in the context of the psychoses and to explain whether such disorders are primary (i.e. issuing directly from the brain and parallel to the rest of psychotic symptomatology) or secondary (i.e. mediated by cognitive and emotional phenomena characteristic of the psychoses).

[Genuine motor phenomena in schizophrenic psychoses : Theoretical background and definition of context]. / Genuine motorische Phänomene bei schizophrenen Psychosen : Theoretischer Hintergrund und Kontextdefinition.

Besides positive and negative symptoms, motor abnormalities have been increasingly recognized as central symptoms of schizophrenia. Recent investigations of antipsychotic-naive first-episode patients with schizophrenia found significantly higher rates of genuine motor abnormalities (GMA) when compared to healthy individuals. The first part of this article introduces the historical and clinical background of GMA in schizophrenia. In the second part the relevance of scientific research and clinical implication of GMA in schizophrenia are discussed. Finally, this article aims at presenting a conceptual framework and a reference system involving both genuine and drug-induced motor abnormalities. The future clinical implications of GMA research are presented and multimodal and transdiagnostic studies are advocated. Future research on GMA will not only essentially enrich the formation of psychiatric theories but also promote progress in clinical neuroscience.

Bone health in cerebral palsy and introduction of a novel therapy / A saúde do osso na paralisia cerebral e a introdução de uma nova terapia

ABSTRACT Objective To assess the bone health status of children with cerebral palsy and the therapeutic effect of denosumab in a subgroup of children with cerebral palsy and decreased bone mass. Methods Children with cerebral palsy were evaluated according to their motor disability score (classification system gross motor functions III to V), bone density and bone turnover markers. Dual X-ray energy absorption was used to measure the lumbar spine, and total body, except the head. Thereafter a group of children with cerebral palsy and osteoporosis was treated with denosumab, a fully human monoclonal antibody. Bone turnover markers were measured before and three months after treatment. Results Reduction in bone mineral density was observed, particularly in children with greater impairment evaluated by the motor score. Decreased bone turnover markers were found in a selected group of children three months after exposure to denosumab. Conclusion Bone loss was present in children with significant impairment of motor function, as well as decreased serum levels of bone resorption markers with new forms.

RESUMO Objetivo Avaliar o estado de saúde dos ossos em crianças com paralisia cerebral e o efeito terapêutico do denosumabe em um subgrupo de crianças com paralisia cerebral e redução da massa óssea. Métodos Crianças com paralisia cerebral foram avaliadas de acordo com seu escore de incapacidade motora (sistema de classificação para funções motoras grossas, de III a V), e marcadores de turnover ósseo. Dual de absorção de energia de raios X foi utilizado para medir a coluna lombar e total do corpo menos cabeça. Posteriormente, um grupo de crianças com paralisia cerebral e osteoporose foi tratado com denosumabe, um anticorpo monoclonal totalmente humano. Marcadores de remodelação óssea foram medidos antes e três meses após o tratamento. Resultados Houve uma redução da densidade óssea, particularmente em crianças com maior comprometimento do escore motor; os marcadores de remodelação óssea diminuíram em um grupo selecionado de crianças três meses depois de terem sido expostas ao denosumabe. Conclusão A perda óssea esteve presente em crianças com importante comprometimento das funções motoras, além da redução nos níveis séricos de marcadores de reabsorção óssea com novos tratamentos.

Bone health in cerebral palsy and introduction of a novel therapy.

OBJECTIVE: To assess the bone health status of children with cerebral palsy and the therapeutic effect of denosumab in a subgroup of children with cerebral palsy and decreased bone mass. METHODS: Children with cerebral palsy were evaluated according to their motor disability score (classification system gross motor functions III to V), bone density and bone turnover markers. Dual X-ray energy absorption was used to measure the lumbar spine, and total body, except the head. Thereafter a group of children with cerebral palsy and osteoporosis was treated with denosumab, a fully human monoclonal antibody. Bone turnover markers were measured before and three months after treatment. RESULTS: Reduction in bone mineral density was observed, particularly in children with greater impairment evaluated by the motor score. Decreased bone turnover markers were found in a selected group of children three months after exposure to denosumab. CONCLUSION: Bone loss was present in children with significant impairment of motor function, as well as decreased serum levels of bone resorption markers with new forms.

Estudo comparativo dos marcos do desenvolvimento motor das crianças com Síndrome de Down em relação à escala evolutiva de Denver II / Comparative study of motor milestones development of children with Down syndrome in relation to Denver II scale

Objetivo: Esta pesquisa tem como objetivo comparar os marcos motores das crianças com Síndrome de Down (SD) em relação à escala de Denver II. Métodos: Foram incluídas na pesquisa as crianças com diagnóstico de SD, de ambos os sexos, com faixa etária menor que 18 meses e que participavam do programa de intervenção precoce na Associação dos Pais e Amigos dos Excepcionais (APAE), Maceió/AL, sendo excluídas as que não possuíam diagnóstico de SD, maiores de 18 meses e as que abandonaram o programa. Participaram da pesquisa 12 crianças. Foi realizada a coleta de dados e a avaliação do desenvolvimento das crianças utilizando a Escala de Denver II. Após o período de acompanhamento, as crianças foram divididas em dois grupos e posteriormente se fez uma correlação entre os fatores de risco e a presença de atraso no desenvolvimento. Os dados foram analisados por meio das estatísticas descritiva e analítica e do Teste de Fischer cujo nível de significância foi de 5 por cento. Resultados: Verificou-se o alcance nos marcos motores objetivados em 66,66 por cento, sendo a média de idade de aquisição de 5,5 meses, 11,11 meses, 13 meses e 23 meses, respectivamente para a aquisição do controle de cabeça, do sentar, ficar de pé e andar em relação à escala de Denver II. Conclusão: Há a existência de um atraso nas aquisições motoras das crianças com SD em relação à Escala de Denver II, mesmo quando submetidas à intervenção precoce, porém ele pode ser minimizado principalmente quando ocorre uma participação efetiva dos pais na terapia, freqüência regular e início precoce do tratamento.

Objective: The aim of this research was to compare children’s motor milestones with Down Syndrome (DS) in relation to Denver II scale. Methods: This research was composed by children with clinic diagnosis of DS, both gender, age group below 18 months who were participating to a precocious intervention program carried out in the Association of Parents and Friends of Disabled Individuals (APAE), Maceió/AL. Children with no diagnosis of DS, above 18 months and those who abandoned the program were excluded. After a period of follow-up, the children were divided into two groups and then a correlation between risk factors and development delay was observed. Data was analyzed based on a descriptive and analytical statistics and Fischer test with significance level of 5 percent. Results: It was observed the range of motor milestones in 66.66 percent and average age of acquisition 5.5 months, 11.11 months, 13 months and 23 months, respectively for the acquisition of head control, sitting down, standing up and walking according to Denver’s II scale. Conclusion: We conclude that children with SD exhibit motor delay in relation to Denver’s II scale, even when they are submitted to the precocious intervention, but can be minimized specially when parents participate effectively during therapy, regular periodicity and start treatment earlier.