RESUMO
BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common form of dementia. Current symptomatic treatment with medications remains inadequate. Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a potential new treatment option in dementias. OBJECTIVE: To assess the safety and tolerability of low frequency (20 Hz) NBM DBS in DLB patients and explore its potential effects on both clinical symptoms and functional connectivity in underlying cognitive networks. METHODS: We conducted an exploratory randomised, double-blind, crossover trial of NBM DBS in six DLB patients recruited from two UK neuroscience centres. Patients were aged between 50 and 80 years, had mild-moderate dementia symptoms and were living with a carer-informant. Patients underwent image guided stereotactic implantation of bilateral DBS electrodes with the deepest contacts positioned in the Ch4i subsector of NBM. Patients were subsequently assigned to receive either active or sham stimulation for six weeks, followed by a two week washout period, then the opposite condition for six weeks. Safety and tolerability of both the surgery and stimulation were systematically evaluated throughout. Exploratory outcomes included the difference in scores on standardised measurements of cognitive, psychiatric and motor symptoms between the active and sham stimulation conditions, as well as differences in functional connectivity in discrete cognitive networks on resting state fMRI. RESULTS: Surgery and stimulation were well tolerated by all six patients (five male, mean age 71.33 years). One serious adverse event occurred: one patient developed antibiotic-associated colitis, prolonging his hospital stay by two weeks. No consistent improvements were observed in exploratory clinical outcome measures, but the severity of neuropsychiatric symptoms reduced with NBM DBS in 3/5 patients. Active stimulation was associated with functional connectivity changes in both the default mode network and the frontoparietal network. CONCLUSION: Low frequency NBM DBS can be safely conducted in DLB patients. This should encourage further exploration of the possible effects of stimulation on neuropsychiatric symptoms and corresponding changes in functional connectivity in cognitive networks. TRIAL REGISTRATION NUMBER: NCT02263937.
Assuntos
Núcleo Basal de Meynert/fisiopatologia , Estimulação Encefálica Profunda/métodos , Doença por Corpos de Lewy/terapia , Idoso , Idoso de 80 Anos ou mais , Estimulação Encefálica Profunda/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
An 87-year-old man with dementia with Lewy bodies, living in residential aged care, exhibited rapid functional decline and weight loss associated with injurious falls over 9 months. Independent clinicians (geriatrician and exercise physiologist) assessed him during an extended wait-list period prior to his commencement of a pilot exercise trial. The highly significant role of treatable factors including polypharmacy, sarcopenia and malnutrition as contributors to frailty and rapid functional decline in this patient are described. The results of a targeted intervention of deprescribing, robust exercise and increased caloric intake on his physical and neuropsychological health status are presented. This case highlights the need to aggressively identify and robustly treat reversible contributors to frailty, irrespective of advanced age, progressive 'untreatable' neurodegenerative disease and rapidly deteriorating health in such individuals. Frailty is not a contraindication to robust exercise; it is, in fact, one of the most important reasons to prescribe it.
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Desprescrições , Terapia por Exercício , Idoso Fragilizado , Doença por Corpos de Lewy/terapia , Desnutrição/dietoterapia , Sarcopenia/terapia , Acidentes por Quedas , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Humanos , MasculinoRESUMO
INTRODUCTION: Quality of life (QOL) assessments allow for more complete evaluation of patients' lived experiences in relation to chronic conditions, such as Parkinson's disease (PD). In palliative care, such instruments are vital to ensure QOL issues are catalogued and addressed for patients. However, little is known regarding the psychometric properties of quality of life scales for use in palliative care for PD, specifically. METHODS: 210 participants with parkinsonian disorders, who participated in a larger palliative intervention clinical trial, completed four quality of life scales (PDQ-39, PROMIS-29, QOL-AD, and McGill QOL) at baseline and post-intervention. Psychometric properties, including internal consistency and concurrent validity, were examined. Factor analyses were performed to evaluate relationships between scale items. Minimal clinically important differences (MCID) and responsiveness were calculated for each scale. RESULTS: All scales demonstrated good internal consistency and concurrent validity. Factor analyses revealed few deviations from the defined subdomains of the scales. Mean absolute MCID values were estimated at 12.7, 10.9, 3.9, and 18.9 for PDQ-39, PROMIS-29, QOL-AD, and McGill QOL, respectively. The PDQ-39 and PROMIS-29 demonstrated higher responsiveness to palliative intervention, while the QOL-AD was more responsive in the control group. CONCLUSIONS: The PDQ-39, PROMIS-29, QOL-AD, and McGill QOL are all valid for use in PD palliative care, though subdomains of the scales in this population may differ slightly from those initially defined. We recommend the use of PDQ-39 and PROMIS-29 as outcome measures in clinical trials for palliative care in PD, though the QOL-AD may be superior for tracking disease progression.
Assuntos
Progressão da Doença , Avaliação de Resultados em Cuidados de Saúde/normas , Cuidados Paliativos , Doença de Parkinson/terapia , Transtornos Parkinsonianos/terapia , Psicometria/normas , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Doença por Corpos de Lewy/terapia , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/terapia , Avaliação de Resultados da Assistência ao Paciente , Psicometria/instrumentação , Psicometria/métodos , Reprodutibilidade dos Testes , Paralisia Supranuclear Progressiva/terapiaRESUMO
This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.
Assuntos
Gerenciamento Clínico , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/terapia , Inibidores da Colinesterase/uso terapêutico , Terapia Genética/tendências , Humanos , Doença por Corpos de Lewy/imunologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/imunologia , Doença de Parkinson/terapia , Piperidinas/uso terapêutico , Transplante de Células-Tronco/tendências , Ureia/análogos & derivados , Ureia/uso terapêutico , alfa-Sinucleína/imunologiaRESUMO
Synucleinopathies are a group of neurodegenerative disorders sharing the common feature of misfolding and accumulation of the presynaptic protein α-synuclein (α-syn) into insoluble aggregates. Within this diverse group, Dementia with Lewy Bodies (DLB) is characterized by the aberrant accumulation of α-syn in cortical, hippocampal, and brainstem neurons, resulting in multiple cellular stressors that particularly impair dopamine and glutamate neurotransmission and related motor and cognitive function. Recent studies show that murine neural stem cell (NSC) transplantation can improve cognitive or motor function in transgenic models of Alzheimer's and Huntington's disease, and DLB. However, examination of clinically relevant human NSCs in these models is hindered by the challenges of xenotransplantation and the confounding effects of immunosuppressant drugs on pathology and behavior. To address this challenge, we developed an immune-deficient transgenic model of DLB that lacks T-, B-, and NK-cells, yet exhibits progressive accumulation of human α-syn (h-α-syn)-laden inclusions and cognitive and motor impairments. We demonstrate that clinically relevant human neural progenitor cells (line CNS10-hNPCs) survive, migrate extensively and begin to differentiate preferentially into astrocytes following striatal transplantation into this DLB model. Critically, grafted CNS10-hNPCs rescue both cognitive and motor deficits after 1 and 3 months and, furthermore, restore striatal dopamine and glutamate systems. These behavioral and neurochemical benefits are likely achieved by reducing α-syn oligomers. Collectively, these results using a new model of DLB demonstrate that hNPC transplantation can impact a broad array of disease mechanisms and phenotypes and suggest a cellular therapeutic strategy that should be pursued. Stem Cells Translational Medicine 2017;6:1477-1490.
Assuntos
Doença por Corpos de Lewy/terapia , Células-Tronco Neurais/transplante , Transplante de Células-Tronco/métodos , alfa-Sinucleína/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Células Cultivadas , Humanos , Memória , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , NeurogêneseRESUMO
Recent developments in induced pluripotent stem cell (iPSC) technology have facilitated, and have contributed to overcome the difficulty of modeling dementia caused by Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD), etc. The following models using iPSCs were reported: the pathophysiology caused by gene mutations such as presenilin or amyloid ß precursor protein in AD, α-synuclein in DLB, and microtubule-associated protein tau, fused in sarcoma, progranulin, or chromosome 9 open reading frame 72 in FTLD, anti-AD drug screening, sortilin-related receptor L 1 haplotype influence in sporadic AD, and amyloid ß secretion in Down syndrome. Patient-specific iPSC could be expected to reveal the disease pathology and lead to drug discoveries for dementia patients.
Assuntos
Doença de Alzheimer/terapia , Demência Frontotemporal/terapia , Células-Tronco Pluripotentes Induzidas/metabolismo , Doença por Corpos de Lewy/terapia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/metabolismo , Animais , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/transplante , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologiaRESUMO
The lack of effective therapies for neurodegenerative disorders is one of the most relevant challenges of this century, considering that, as the global population ages, the incidence of these type of diseases is quickly on the rise. Among these disorders, synucleinopathies, which are characterized by the abnormal accumulation and spreading of the synaptic protein alpha-synuclein in the brain, already constitute the second leading cause of parkinsonism and dementia in the elderly population. Disorders with alpha-synuclein accumulation include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Numerous therapeutic alternatives for synucleinopathies are being tested in pre-clinical models and in the clinic; however, only palliative treatments addressing the dopaminergic deficits are approved to date, and no disease-modifying options are available yet. In this article, we provide a brief overview of therapeutic approaches currently being explored for synucleinopathies, and suggest possible explanations to the clinical trials outcomes. Finally, we propose that a deeper understanding of the pathophysiology of synucleinopathies, together with a combination of therapies tailored to each disease stage, may lead to better therapeutic outcomes in synucleinopathy patients. Synucleinopathies, neurodegenerative disorders characterized by the abnormal accumulation of the protein alpha-synuclein, constitute the second leading cause of parkinsonism and dementia in the elderly population, however, no disease-modifying options are available yet. In this review, we summarize the therapeutic approaches currently being explored for synucleinopathies, suggest possible explanations to the clinical outcomes, and propose areas of further therapeutic improvement. This article is part of a special issue on Parkinson disease.
Assuntos
Demência/metabolismo , Demência/terapia , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , alfa-Sinucleína/metabolismo , Animais , Ensaios Clínicos como Assunto/métodos , Demência/diagnóstico , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/terapia , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/metabolismo , Atrofia de Múltiplos Sistemas/terapia , Doença de Parkinson/diagnóstico , Transplante de Células-Tronco/métodos , Transplante de Células-Tronco/tendências , alfa-Sinucleína/antagonistas & inibidoresRESUMO
Accumulation of α-synuclein (α-syn) into insoluble aggregates occurs in several related disorders collectively referred to as synucleinopathies. To date, studies have used neural stem cells (NSCs) to examine questions about α-syn propagation, but have overlooked the therapeutic potential of NSC transplantation to modulate cognition in disorders such as dementia with Lewy bodies or Parkinson's disease dementia. Here, we show that striatal transplantation of NSCs into aged α-syn transgenic mice significantly improves performance in multiple cognitive and motor domains. This recovery is associated with NSC expression of brain-derived neurotrophic factor (BDNF), which restores depleted levels and modulates dopaminergic and glutamatergic systems. Most importantly, transplantation of BDNF-depleted NSCs fails to improve behavior, whereas AAV-mediated BDNF delivery mimics the benefits of NSC transplantation, supporting a critical role for this neurotrophin in functional improvement. Thus, NSC transplantation could offer a promising approach to treat the understudied yet devastating cognitive components of many synucleinopathies.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição , Doença por Corpos de Lewy/terapia , Locomoção , Células-Tronco Neurais/transplante , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Células Cultivadas , Corpo Estriado/citologia , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Doença por Corpos de Lewy/genética , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , alfa-Sinucleína/genéticaRESUMO
BACKGROUND AND OBJECTIVES: The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimer's disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease dementia, Huntington's disease, prion diseases, normal-pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published by June 2011. The evidence was classified (I, II, III, IV) and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS AND CONCLUSIONS: New recommendations and good practice points are made for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers. All recommendations were revised as compared with the previous EFNS guidelines. The specialist neurologist together with primary care physicians play an important role in the assessment, interpretation and treatment of symptoms, disability and needs of dementia patients.
Assuntos
Demência , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Demência/diagnóstico , Demência/terapia , Demência Vascular/diagnóstico , Demência Vascular/terapia , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/terapia , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/terapia , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/terapia , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/terapia , Encefalite Límbica/diagnóstico , Encefalite Límbica/terapia , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia , Afasia Primária Progressiva não Fluente/diagnóstico , Afasia Primária Progressiva não Fluente/terapia , Doenças Priônicas/diagnóstico , Doenças Priônicas/terapia , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/terapiaRESUMO
Como es sabido, la enfermedad de Parkinson suele presentar una evolución crónica, prolongada, e insidiosa. Para la cual aún no se disponen de terapéuticas efectivas que curen a dicha enfermedad, si no se posee un arsenal de fármacos (agonistas dopaminérgicos) capaces de mitigar los síntomas, mejorar y prolongar la calidad de vida y enlentecer el propio desarrollo de la enfermedad, que lleva hacia un deterioro profundo de la motricidad, funcionalidad y de las funciones neurocognitivas. También es sabida la asociación de la enfermedad de Parkinson con la demencia por la misma enfermedad. Pero a lo largo de ella, con o sin demencia, se suelen presentar en una proporción importante, una serie de síntomas asociados neuropsiquiátricos (NP), y neuroconductuales (NC) que hay que diferenciar si son producto de la propia enfermedad de Parkinson, o son desencadenados por el tratamiento. Algunos de estos síntomas asociados, los más importantes en cuanto a su frecuencia y gravedad sobre todo asociados a demencia son, depresión, excitación psicomotriz, ideación patológica, delirios, alucinaciones visuales, síndrome confusional (delirium), trastornos del sueño, ansiedad, apatía. Estos síntomas agravan la evolución de la propia enfermedad de Parkinson y la demencia asociada haciendo que su pronóstico se torne más desfavorable, y más deteriorante, afectando también a los cuidadores y alterando la calidad de vida del paciente y su entorno. En este trabajo me propongo dar una noción básica de dichos trastornos para su rápido reconocimiento y tratamiento, teniendo en cuenta la posible polifarmacia en estos pacientes, con las implicancias de las interacciones farmacológicas. La rápida resolución de estos síntomas asociados a la EP, con o sin demencia redundará en un menor deterioro funcional del paciente, mejorando su pronóstico y la calidad de vida del propio paciente y sus cuidadores.
Throughout the progression of Parkinson's disease, whether or not with dementia, a series of associated neuropsychiatric and neurobehavioral symptoms may appear, such as depression, anxiety, psychomotor agitation, delirium, visual hallucinations, confusional syndrome (delirium), sleep disorders, apathy, which aggravate the patients' prognosis and accelerate their overall deterioration and the quality of life of them and the people around them. The prompt identification and management of these associated neuropsychiatric and neurobehavioral symptoms, considered in conjunction with the possible pharmacological interactions among polymedicated patients, shall result in the patients' better quality of life and a more favorable prognosis.
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Humanos , Agonistas de Dopamina/uso terapêutico , Qualidade de Vida/psicologia , Demência/patologia , Demência/terapia , Diagnóstico Precoce , Doença de Parkinson/psicologia , Doença de Parkinson/terapia , Doença por Corpos de Lewy/terapia , Manifestações NeurocomportamentaisRESUMO
The number of patients with young onset dementia (YOD) (that is before age 65) is estimated at 32,000 in France, and 5000 with onset dementia before 60 years. These patients differ from older ones by the greater number of rares causes (29%), heterogeneity of the presentation among the usual diseases, such as non-amnestic phenotypes of Alzheimer's disease, high frequency of frontal symptoms, and possible genetic origin. These aspects must be taken into account for the diagnosis, often more difficult than in older ones because patients have a little knowledge of the YOD, excepted in the genetics forms. YOD patients can still work or drive a car, and we should choose between the respect for autonomy and the security for the patient and their carers. YOD patients can be more often included in pharmacological trials because they have lower associated disorders. Individual non-pharmacological treatment should be priviledged because they don't easily accept collective activities with other patients over 60 years of age. Excepted for the very young patients (onset before 45), the survival is longer than in late onset dementia, with sometimes severe behavioral problems related to frontal syndrome. In France, the caregiving at home has been improved since the possibility for the YOD patients to receive a financial assistance reserved for the disabled patients, but admission to a nursing home before 60 is very difficult and increases the caregiver burden and perception of unfairness. There is a discrimination between young or older demented patients related to the great difficulty to meet the needs of younger patients, due to the rigidity of the medical and social systems. The presentation of a limited offer for the YOD patients must initiate reflections on our capacities to respect the autonomy and the dignity of the Alzheimer's patients regardless of age.
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Doença de Alzheimer/diagnóstico , Demência Vascular/diagnóstico , Ética Médica , Demência Frontotemporal/diagnóstico , Acessibilidade aos Serviços de Saúde/ética , Doença por Corpos de Lewy/diagnóstico , Programas Nacionais de Saúde/ética , Fatores Etários , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/mortalidade , Doença de Alzheimer/terapia , Cuidadores/ética , Efeitos Psicossociais da Doença , Demência Vascular/genética , Demência Vascular/mortalidade , Demência Vascular/terapia , Definição da Elegibilidade/ética , Feminino , França , Demência Frontotemporal/genética , Demência Frontotemporal/mortalidade , Demência Frontotemporal/terapia , Instituição de Longa Permanência para Idosos/ética , Humanos , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/mortalidade , Doença por Corpos de Lewy/terapia , Masculino , Pessoa de Meia-Idade , Casas de Saúde/ética , Prevalência , Política Pública , Fatores de Risco , Previdência Social/ética , Taxa de SobrevidaRESUMO
Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are common causes of motor and cognitive deficits and are associated with the abnormal accumulation of alpha-synuclein (α-syn). This study investigated whether passive immunization with a novel monoclonal α-syn antibody (9E4) against the C-terminus (CT) of α-syn was able to cross into the CNS and ameliorate the deficits associated with α-syn accumulation. In this study we demonstrate that 9E4 was effective at reducing behavioral deficits in the water maze, moreover, immunization with 9E4 reduced the accumulation of calpain-cleaved α-syn in axons and synapses and the associated neurodegenerative deficits. In vivo studies demonstrated that 9E4 traffics into the CNS, binds to cells that display α-syn accumulation and promotes α-syn clearance via the lysosomal pathway. These results suggest that passive immunization with monoclonal antibodies against the CT of α-syn may be of therapeutic relevance in patients with PD and DLB.
Assuntos
Imunização Passiva/métodos , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/terapia , alfa-Sinucleína/genética , Animais , Anticorpos Monoclonais/metabolismo , Comportamento Animal , Linhagem Celular Tumoral , Modelos Animais de Doenças , Imuno-Histoquímica/métodos , Doença por Corpos de Lewy/imunologia , Lisossomos/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Degeneração Neural/patologia , RatosRESUMO
Dementia with Lewy bodies (DLB) has recently often been reported to exhibit various psychiatric symptoms. However, some DLB patients do not present typical clinical courses or psychiatric symptoms. We report two DLB patients with characteristic psychiatric symptoms: a depressive state and anxiety in the early stage, and auditory hallucination, delusion of guilt, and catatonia in the later stage. Pharmacotherapy was ineffective, but electroconvulsive therapy proved to have a marked effect. The clinical course represents the symptomatic concept of "late catatonia," which Sommer first reported in 1910 and Kocha later reappraised. In Japan, this has been prevailing as a useful concept in the field of clinical geriatric psychiatry. We discuss what to consider and how to treat DLB patients including those with atypical courses and psychiatric symptoms. We consider and treated them as "late catatonia", with a favorable response to treatment. There is an important viewpoint which helps us understand the process. The viewpoint is to distinguish between "genera" and "types" of mental illnesses as inherited from classical psychopathology to modern psychiatry. DLB corresponds to "genera" and late catatonia to "types." In treating DLB patients with atypical symptoms and courses, it appears clinically very important to think more about late catatonia, exhibiting characteristic symptoms. This also reveals the usefulness of understanding and treating such cases based on the concept of "genera" and "types."
Assuntos
Catatonia/complicações , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/terapia , Idoso , Eletroconvulsoterapia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Current experimental gene therapy approaches for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) include the use of viral vectors expressing antiapoptosis genes, neurotrophic factors and dopaminergic system enzymes. However, since increasing evidence favors a role for alpha-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block alpha-synuclein accumulation. beta-Synuclein, the nonamyloidogenic homologue of alpha-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding beta-synuclein might provide a novel approach to the development of experimental treatments for PD and DLB. To assess this possibility and to better understand the mechanisms involved, a lentiviral vector expressing human (h) beta-synuclein (lenti-beta-synuclein) was tested in a transgenic (tg) mouse model of halpha-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-beta-synuclein reduced the formation of halpha-synuclein inclusions and the accumulation of halpha-synuclein in synapses and ameliorated the neurodegenerative alterations in the tg mice. Both in vivo and in vitro coimmunoprecipitation and immunoblot experiments show that the mechanisms of beta-synuclein neuroprotection involve binding of this molecule to halpha-synuclein and Akt, resulting in the decreased aggregation and accumulation of halpha-synuclein in the synaptic membrane. Together, these data further support a role for beta-synuclein in regulating the conformational state of alpha-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.