RESUMO
Electrophysiology has proven invaluable to record neural activity, and the development of Neuropixels probes dramatically increased the number of recorded neurons. These probes are often implanted acutely, but acute recordings cannot be performed in freely moving animals and the recorded neurons cannot be tracked across days. To study key behaviors such as navigation, learning, and memory formation, the probes must be implanted chronically. An ideal chronic implant should (1) allow stable recordings of neurons for weeks; (2) be light enough for use in mice; (3) allow reuse of the probes after explantation. Here, we present the "Apollo Implant", an open-source and editable device that meets these criteria and accommodates up to two Neuropixels 1.0 or 2.0 probes. The implant comprises a "payload" module that is attached to the probe and is recoverable, and a "docking" module that is cemented to the skull. The design is adjustable, making it easy to change the distance between probes, the angle of insertion, and the depth of insertion. We tested the implant across seven labs in head-fixed mice, freely moving mice, and freely moving rats. The number of neurons recorded across days was stable, even after repeated implantations of the same probe. The Apollo implant provides an inexpensive, lightweight, and flexible solution for reusable chronic Neuropixels recordings.
RESUMO
BACKGROUND: Psychotic symptoms and behavioral disturbances are a leading cause of institutionalization in elderly patients with Alzheimer's disease (AD). OBJECTIVES: Elderly nursing home patients (n=105) with possible or probable AD were entered into a multicenter study to determine the long-term efficacy and safety of olanzapine in treatment of psychotic symptoms and behavioral disturbances due to AD. METHODS: Following a double-blind, 6-week exposure to fixed-dose olanzapine (5, 10, or 15 mg/d), patients entered an additional 18-week, open-label, flexible-dose treatment. Baseline was defined from the start of the extension phase. RESULTS: Patients improved significantly on the primary efficacy measure, defined a priori, which consisted of the sum of the Agitation/Aggression, Delusions, and Hallucinations items ('Core':) of the NPI/NH. Olanzapine also significantly improved scores for the NPI/NH total and the Core item-associated Occupational Disruptiveness of the NPI/NH, as well as the BPRS total and CGI Severity-of-Alzheimer's scores. Barnes Akathasia scores improved significantly from baseline, while Simpson-Angus and AIMS scores were not significantly changed. Treatment-emergent symptoms included somnolence, accidental injury, and rash. No significant changes were seen in ECGs, including QT(c) interval, nor in weight or vital signs, including orthostasis. CONCLUSIONS: Low-dose olanzapine appears to be effective and well tolerated for treatment of behavioral disturbances and psychotic symptoms due to AD in elderly patients.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Sintomas Comportamentais/tratamento farmacológico , Pirenzepina/análogos & derivados , Pirenzepina/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/psicologia , Benzodiazepinas , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Instituição de Longa Permanência para Idosos , Humanos , Assistência de Longa Duração , Masculino , Testes Neuropsicológicos , Casas de Saúde , Olanzapina , Pirenzepina/efeitos adversos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Resultado do TratamentoRESUMO
BACKGROUND: Alzheimer's disease (AD) is associated with both cognitive and behavioral symptoms. Agitation, hallucinations, delusions, aggression, irritability, and anxiety are observed in up to 90% of patients with dementia. Although new information has emerged in recent years on the treatment of psychosis and agitation in dementia, very little information is available about the treatment of anxiety symptoms in this population. OBJECTIVES: To assess the efficacy and tolerability of olanzapine in the treatment of significant anxiety symptoms in patients with AD. METHODS: A post hoc analysis of a previously published study was performed. Those post hoc analysis evaluated the response to treatment with olanzapine of a subgroup of AD patients presenting with significant symptoms of anxiety. Patients were considered to have significant symptoms of anxiety if their baseline in the Nursing home version of the Neuropsychiatric Instrument NPI/NH anxiety scores were > or = 2. The analysis included 120 patients. RESULTS: Patients receiving olanzapine 5 mg/d were statistically significantly improved on the NPI/NH Anxiety item compared to those receiving placebo (olanzapine, 5 mg/d: -3.72; placebo: -1.67; p = 0.034). In the group of patients with clinically significant anxiety, somnolence was the only treatment-emergent event that was statistically different in any olanzapine treatment group compared with placebo (olanzapine 5 mg/d: 9 patients [25%], p = 0.034; 10 mg/d: 7 [23%], p = 0.054; 15 mg/d: 7 [26%], p = 0.050; placebo: 1 [3.7%]). When controlling for treatment-emergent somnolence, the improvement in anxiety in the olanzapine 5 mg/d group remained statistically significant (p = 0.049). CONCLUSIONS: These findings suggest that olanzapine could be a safe and effective treatment for anxiety in Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Ansiedade/tratamento farmacológico , Pirenzepina/análogos & derivados , Pirenzepina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Ansiedade/diagnóstico , Ansiedade/psicologia , Benzodiazepinas , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Instituição de Longa Permanência para Idosos , Humanos , Masculino , Testes Neuropsicológicos , Casas de Saúde , Olanzapina , Pirenzepina/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Elderly patients with Alzheimer's disease (AD) commonly exhibit psychotic symptoms, prompting clinicians to administer antipsychotics. This article compares the effects of olanzapine and placebo in the emergence of hallucinations or delusions in AD patients with symptoms of agitation/aggression but little or no psychotic symptomatology at baseline. METHOD: A multicenter, double-blind, placebo-controlled study was conducted in nursing home patients with AD according to DSM-IV criteria and symptoms of agitation/aggression and/or psychosis. Patients (N = 206) were randomly assigned to receive either placebo or fixed-dose olanzapine (5, 10, or 15 mg/day) for up to 6 weeks. This article analyzes data from a subgroup of patients (N = 165) with no or minimal delusions and/or hallucinations at baseline as measured by the Neuropsychiatric Inventory-Nursing Home Version (NPI/NH). Three subsets of patients were identified on the basis of their symptoms at baseline: those with no clinically significant hallucinations, those with no clinically significant delusions, and those with no clinically significant delusions or hallucinations. RESULTS: Of the patients without hallucinations or delusions at baseline (N = 75), the placebo-treated patients showed significantly greater development of these symptoms compared with olanzapine-treated patients overall (NPI/NH hallucinations + delusions mean change score, +2.73 vs. +0.27, p = .006). Similarly, of the patients without baseline hallucinations (N = 153), the placebo-treated patients showed greater hallucinations score increases than did olanzapine-treated patients overall (+1.25 vs. +0.33, p = .026), whereas patients without baseline delusions (N = 87) showed no significant treatment effects. Olanzapine had a favorable safety profile in each patient subset. CONCLUSION: These results suggest that, overall, olanzapine effectively attenuated emergence of psychosis in a short-term trial of patients with Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/uso terapêutico , Casas de Saúde , Pirenzepina/análogos & derivados , Pirenzepina/uso terapêutico , Transtornos Psicóticos/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Agressão/efeitos dos fármacos , Agressão/psicologia , Doença de Alzheimer/psicologia , Benzodiazepinas , Delusões/prevenção & controle , Delusões/psicologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Alucinações/prevenção & controle , Alucinações/psicologia , Humanos , Masculino , Olanzapina , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/psicologia , Transtornos Psicóticos/psicologia , Resultado do TratamentoRESUMO
BACKGROUND: Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. METHODS: A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. RESULTS: Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. CONCLUSION: Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/uso terapêutico , Sintomas Comportamentais/tratamento farmacológico , Casas de Saúde , Pirenzepina/análogos & derivados , Pirenzepina/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Sintomas Comportamentais/psicologia , Benzodiazepinas , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Placebos , Transtornos Psicóticos/psicologia , Resultado do TratamentoRESUMO
OBJECTIVE: This international, multicenter double-blind trial was designed to compare the therapeutic profile of an atypical antipsychotic, olanzapine, with that of a conventional dopamine D2 antagonist, haloperidol. METHOD: A total of 1,996 patients at 174 sites in Europe and North America were randomly assigned to treatment with olanzapine (N = 1,336) or haloperidol (N = 660) over 6 weeks. The primary efficacy analysis involved the mean change from baseline to endpoint in total scores on the Brief Psychiatric Rating Scale (BPRS). Secondary analyses included comparisons of the mean change in positive and negative symptoms, comorbid depression, extrapyramidal symptoms, and overall drug safety. RESULTS: Olanzapine demonstrated clinical results superior to those of haloperidol on overall improvement according to the BPRS and on every secondary measure, including depression. Olanzapine was also associated with significantly fewer discontinuations of treatment due to lack of drug efficacy or adverse events. Substantially more olanzapine-treated patients (66.5%) than haloperidol-treated patients (46.8%) completed 6 weeks of therapy. Statistically significant advantages of olanzapine treatment were related to 1) change in negative symptoms, 2) extrapyramidal symptom profile, 3) effect on prolactin levels, and 4) response rate. CONCLUSIONS: Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenic psychopathology, with a substantially more favorable safety profile, than haloperidol. It meets several of the criteria for a novel atypical antipsychotic agent.
Assuntos
Antipsicóticos/uso terapêutico , Haloperidol/uso terapêutico , Pirenzepina/análogos & derivados , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/epidemiologia , Benzodiazepinas , Comorbidade , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/epidemiologia , Método Duplo-Cego , Europa (Continente) , Feminino , Haloperidol/efeitos adversos , Humanos , Masculino , América do Norte , Olanzapina , Pacientes Desistentes do Tratamento , Pirenzepina/efeitos adversos , Pirenzepina/uso terapêutico , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/psicologia , Esquizofrenia/epidemiologia , Psicologia do Esquizofrênico , Resultado do TratamentoRESUMO
Parkinson's disease, because of its progressive degenerative nature, is associated with increased disability and mortality compared with mortality in the general population. We examined mortality data from three clinical trials involving 1,330 patients with Parkinson's disease treated with pergolide as an adjunct to levodopa or levodopa/carbidopa therapy. The ratio of observed deaths to expected deaths in the general population of the same age, gender, race distribution, and period of observation was 2.3 for the 3 studies combined. The ratio is lower than that in Parkinson's disease patients treated prior to the introduction of levodopa, consistent with ratios with levodopa and levodopa combination therapy. The ratio is slightly higher than in Parkinson's disease patients treated with levodopa and levodopa combination therapy, which may be attributable to differing patient characteristics in the populations studied.
Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/mortalidade , Pergolida/farmacologia , Pergolida/uso terapêutico , Adolescente , Adulto , Idoso , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/metabolismo , Antiparkinsonianos/uso terapêutico , Carbidopa/administração & dosagem , Carbidopa/metabolismo , Carbidopa/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Levodopa/administração & dosagem , Levodopa/metabolismo , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pergolida/administração & dosagem , Taxa de SobrevidaRESUMO
In a patient with progressive supranuclear palsy (PSP) and hypertrophy of the olives, neurons with different forms of argyrophilic degeneration were detected by means of Bodian's silver staining method, i.e., neurofibrillary tangle-bearing neurons in the basal ganglia and brain stem, ballooned argyrophilic neurons in the brain stem, and hypertrophied neurons in the olives. In these cells, the cytoskeleton was investigated to ascertain whether neurons with different cytoskeletal changes contained phosphorylated neurofilaments (P-Nf) in the perikaryon. This study, carried out using two monoclonal antibodies that recognize phosphorylated epitopes of the neurofilament high molecular weight subunits, showed that hypertrophied olivary neurons, most ballooned neurons and a small aliquot of tangle-bearing neurons were labelled. The immunostaining of hypertrophied and ballooned neurons was localized in the whole perikaryon and dendrites, whereas that of tangle-bearing neurons was confined to the tangle. These findings were reproduced in five additional patients (one with hypertrophy of the olives, four with PSP) and demonstrated that, in PSP, the mechanism responsible for tangle formation does not affect the ability of neurons to accumulate P-Nf. This fact suggested that perikaryonal P-Nf accumulation is likely to be part of the cell reaction to abnormal conditions affecting the neuronal cytoskeleton.