RESUMO
OBJECTIVE: To understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery. METHODS: Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 µl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 µl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 µl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes. RESULTS: MRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life. INTERPRETATION: Novel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714.
Assuntos
Descarboxilases de Aminoácido-L-Aromático/genética , Terapia Genética/métodos , Imageamento por Ressonância Magnética/métodos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/genética , Putamen/diagnóstico por imagem , Adulto , Idoso , Descarboxilases de Aminoácido-L-Aromático/administração & dosagem , Feminino , Técnicas de Transferência de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/terapiaRESUMO
Disrupted cholinergic neurotransmission plays a central role in Alzheimer's disease, medication-induced memory impairment, and delirium. At the systems level, this suggests anticholinergic drugs may alter the activity and interplay of anatomically distributed neural networks critical for memory function. Using a network-sensitive imaging technique (functional connectivity MRI) and a double-blind, crossover design, we examined the consequences of anticholinergic drug administration on episodic memory and functional network architecture in a group of clinically normal elderly. We observed that low-dose scopolamine (0.2 mg IV) decreased episodic memory performance and selectively decreased connectivity strength in 3 of 7 cortical networks. Both memory and connectivity effects were independent of ß-amyloid burden. Drug-induced connectivity changes within the Default and Salience networks, as well as reductions in the strength of anticorrelation between these 2 networks, were sufficient to fully statistically mediate the effects of scopolamine on memory performance. These results provide experimental support for the importance of the Default and Salience networks to memory performance and suggest scopolamine-induced amnesia is underpinned by disrupted connectivity within and between these 2 networks. More broadly, these results support the potential utility of fcMRI as tool examine the systems-level pharmacology of psychoactive drugs.
Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas Colinérgicos/farmacologia , Memória Episódica , Memória/efeitos dos fármacos , Escopolamina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Feminino , Neuroimagem Funcional , Voluntários Saudáveis , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais , Tomografia por Emissão de Pósitrons , TiazóisRESUMO
OBJECTIVE: We hypothesized that specific mutations in the ß-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685.
Assuntos
Disfunção Cognitiva/genética , Progressão da Doença , Doença de Gaucher/genética , Glucosilceramidase/genética , Doença de Parkinson/genética , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/etiologia , Feminino , Doença de Gaucher/complicações , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicaçõesRESUMO
OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies), and Parkinson disease (PD). There are no data on such risks in a population-based sample. METHODS: Cognitively normal subjects aged 70 to 89 years in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15-month intervals. In a Cox proportional hazards model, we measured the risk of developing MCI, dementia, and PD among the exposed (probable RBD [pRBD](+)) and unexposed (pRBD(-)) cohorts. RESULTS: Forty-four subjects with pRBD(+) status at enrollment (median duration of pRBD features was 7.5 years) and 607 pRBD(-) subjects were followed prospectively for a median of 3.8 years. Fourteen of the pRBD(+) subjects developed MCI, and 1 developed PD (15/44 = 34% developed MCI/PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD(+) subjects were at increased risk of MCI/PD (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.3-3.9; p = 0.005). Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI/PD (HR, 1.05 per 10 years; 95% CI, 0.84-1.3; p = 0.68). INTERPRETATION: In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI/PD over 4 years.
Assuntos
Disfunção Cognitiva/epidemiologia , Doença de Parkinson/epidemiologia , Vigilância da População , Transtorno do Comportamento do Sono REM/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/psicologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Doença de Parkinson/psicologia , Vigilância da População/métodos , Estudos Prospectivos , Transtorno do Comportamento do Sono REM/psicologia , Fatores de RiscoRESUMO
Many people with rapid eye movement (REM) sleep behavior disorder (RBD) have an underlying synucleinopathy, the most common of which is Lewy body disease. Identifying additional abnormal clinical features may help in identifying those at greater risk of evolving to a more severe syndrome. Because gait disorders are common in the synucleinopathies, early abnormalities in gait in those with RBD could help in identifying those at increased risk of developing overt parkinsonism and/or cognitive impairment. We identified 42 probable RBD subjects and 492 controls using the Mayo Sleep Questionnaire and assessed gait velocity, cadence, and stride dynamics with an automated gait analysis system. Cases and controls were similar in age (79.9 ± 4.7 and 80.1 ± 4.7, P = 0.74), Unified Parkinson's Disease Rating Scale Part III (UPDRS) score (3.3 ± 5.5 and 1.9 ± 4.1, P = 0.21) and Mini-Mental State Examination scores (27.2 ± 1.9 and 27.7 ± 1.6, P = 0.10). A diagnosis of probable RBD was associated with decreased velocity (-7.9 cm/s; 95% confidence interval [CI], -13.8 to -2.0; P < 0.01), cadence (-4.4 steps/min; 95% CI, -7.6 to -1.3; P < 0.01), significantly increased double limb support variability (30%; 95% CI, 6-60; P = 0.01), and greater stride time variability (29%; 95% CI, 2-63; P = 0.03) and swing time variability (46%; 95% CI, 15-84; P < 0.01). Probable RBD is associated with subtle gait changes prior to overt clinical parkinsonism. Diagnosis of probable RBD supplemented by gait analysis may help as a screening tool for disorders of α-synuclein.
Assuntos
Transtornos Neurológicos da Marcha/etiologia , Transtorno do Comportamento do Sono REM/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Humanos , Modelos Lineares , Masculino , Escalas de Graduação Psiquiátrica , Psicometria , Índice de Gravidade de DoençaRESUMO
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
Assuntos
Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Proteínas/genética , Idade de Início , Idoso , Afasia Primária Progressiva/genética , Afasia Primária Progressiva/psicologia , Proteína C9orf72 , Cromossomos Humanos Par 9/genética , Estudos de Coortes , DNA/genética , Expansão das Repetições de DNA/genética , Feminino , Florida/epidemiologia , Heterozigoto , Humanos , Processamento de Imagem Assistida por Computador , Peptídeos e Proteínas de Sinalização Intercelular/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Testes Neuropsicológicos , Doença de Parkinson/genética , Tomografia por Emissão de Pósitrons , Progranulinas , Sistema de Registros , Tomografia Computadorizada de Emissão de Fóton Único , População Branca , Proteínas tau/genéticaRESUMO
In this paper we question the guidance offered to neurologists by the Ethics, Law and Humanities Committee of the American Academy of Neurology (Larriviere, Williams, Rizzo & Bonnie, 2009) on how to respond to requests for "neuroenhancement": the use of pharmaceuticals to enhance cognitive function in cognitively normal people. The guidance assumes that the benefits of using neuroenhancers will prove to outweigh the risks in the absence of any evidence that this is the case. However, the principle of nonmaleficence dictates that the use of these drugs by healthy people should not be condoned before reliable evidence for their short and long term safety and efficacy is at hand. The proposed ethical framework for neuroenhancement prescribing also neglects the broader social implications of condoning such practices. The adoption of these guidelines by neurologists could have adverse social and medical effects that need to be more carefully considered.
Assuntos
Melhoramento Biomédico , Cognição/efeitos dos fármacos , Prescrições de Medicamentos , Neurologia/ética , Nootrópicos/farmacologia , Melhoramento Biomédico/ética , Melhoramento Biomédico/métodos , Melhoramento Biomédico/normas , Prescrições de Medicamentos/normas , HumanosRESUMO
INTRODUCTION: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with synucleinopathies. In 2012, we reported an increased risk of mild cognitive impairment (MCI) and Parkinson disease (PD) in cognitively normal Olmsted County, Minnesota, residents, aged 70 to 89 years with probable RBD. Here, we examine their progression to dementia and other neurodegenerative phenotypes. METHODS: Fifteen participants with RBD who were diagnosed with either MCI or PD were longitudinally followed, and their subsequent clinical courses were reviewed. RESULTS: Over 6.4 ± 2.9 years, six of the 14 participants with MCI developed additional neurodegenerative signs, five of whom had Lewy body disease features. Four of them progressed to dementia at a mean age 84.8 ± 4.9 years, three of whom met the criteria for probable dementia with Lewy bodies. One subject with PD developed MCI, but not dementia. DISCUSSION: Our findings from the population-based sample of Olmsted County, Minnesota, residents suggest that a substantial number of RBD patients tend to develop overt synucleinopathy features over time, and RBD patients who develop MCI and subsequent dementia have clinical features most consistent with dementia with Lewy bodies.
RESUMO
Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alzheimer's Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.
RESUMO
BACKGROUND: Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. METHODS: In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10â000 training and test sets randomly generated from the entire study population. FINDINGS: 3200 patients with Parkinson's disease who were longitudinally assessed with 27â022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and ß-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19â127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10â000 randomly resampled subsets. INTERPRETATION: Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. FUNDING: National Institutes of Health, US Department of Defense.
Assuntos
Disfunção Cognitiva/diagnóstico , Demência/diagnóstico , Progressão da Doença , Doença de Parkinson/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Disfunção Cognitiva/etiologia , Demência/etiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
OBJECTIVE: To better understand cross-sectional relationships between CSF and PET measures of tau pathology, we compared regional and global measures of (18)F-T807 (AV-1451) PET to CSF protein levels of total tau (t-tau), phosphorylated tau (p-tau), and ß-amyloid 1-42 (Aß42). METHODS: T-tau, p-tau, and Aß42 levels were assessed using INNOTEST xMAP immunoassays. Linear regression was used to compare regional and global measures of (18)F-T807 standardized uptake value ratios (SUVR) to CSF protein levels using data from 31 cognitively unimpaired elderly participants in the Harvard Aging Brain study. RESULTS: After controlling for sex and age, total cortical (18)F-T807 binding was significantly correlated with p-tau (partial r = 0.48; p < 0.01) and at trend level with t-tau (partial r = 0.30; p = 0.12). Regional (18)F-T807 measures were more strongly correlated with CSF protein levels than the global measure, with both t-tau and p-tau significantly correlated with (18)F-T807 SUVR in entorhinal, parahippocampal, and inferior temporal cortical regions (partial r = 0.53-0.73). Peak correlations between CSF and PET measures of tau were similar to those between CSF and PET measures of amyloid burden. Finally, we observed significantly higher temporal T807 SUVR in individuals with high amyloid burden. CONCLUSIONS: These data support the link between (18)F-T807 PET and CSF measures of tau pathology. In these cognitively normal individuals with (18)F-T807 binding largely restricted to the temporal lobe, (18)F-T807 SUVR in temporal regions appeared more reflective of CSF t-tau and p-tau than a total cortical measure.
Assuntos
Encéfalo/diagnóstico por imagem , Carbolinas/farmacocinética , Lobo Temporal/diagnóstico por imagem , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Estudos Transversais , Feminino , Avaliação Geriátrica , Humanos , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Fosforilação , Tomografia por Emissão de Pósitrons , Lobo Temporal/efeitos dos fármacosRESUMO
Dementia with Lewy bodies is an under-recognized disease; it is responsible for up to 20 % of all dementia cases. Accurate diagnosis is essential because the management of dementia with Lewy bodies is more complex than many neurodegenerative diseases. This is because alpha-synuclein, the pathological protein responsible for dementia with Lewy bodies (and Parkinson's disease), produces symptoms in multiple domains. By dividing the symptoms into cognitive, neuropsychiatric, movement, autonomic, and sleep categories, a comprehensive treatment strategy can be achieved. Management decisions are complex, since the treatment of one set of symptoms can cause complications in other symptom domains. Nevertheless, a comprehensive treatment program can greatly improve the patient's quality of life, but does not alter the progression of disease. Cholinesterase inhibitors are effective for cognitive and neuropsychiatric symptoms; rivastigmine has the widest evidence base. Special care needs to be taken to avoid potentially fatal idiopathic reactions to neuroleptic medications; these should be used for short periods only when absolutely necessary and when alternative treatments have failed. Pimavanserin, a selective serotonin 5-HT2A inverse agonist, holds promise as an alternative therapy for synuclein-associated psychosis. Levodopa/carbidopa treatment of parkinsonism is often limited by dopa-induced exacerbations of neuropsychiatric and cognitive symptoms. Autonomic symptoms are under-recognized complications of synucleinopathy. Constipation, urinary symptoms and postural hypotension respond to standard medications. Rapid eye movement sleep behavior disorder is highly specific (98 %) to the synucleinopathies. Nonpharmacological treatments, melatonin and clonazepam are all effective.
Assuntos
Meningite Asséptica/induzido quimicamente , Triazinas/efeitos adversos , Adulto , Feminino , Humanos , Lamotrigina , RecidivaRESUMO
Low levels of serotonin may reduce the density of the serotonin transporter (SERT) by either increasing trafficking or reducing synthesis; a "neuroadaptive response". To determine whether 3,4-methylenedioxymethamphetamine (MDMA)-induced reductions in SERT density could be related to such a mechanism, p-chlorophenylalanine or MDMA was administered to rats, and brain serotonin and SERT density were measured. As expected, both treatments led to serotonin depletion 1, 7 and 14 days later. However, only MDMA reduced SERT density. This observation suggests that MDMA-induced reductions in SERT density do not represent neuroadaptive responses to decreased levels of brain serotonin, but may occur in response to some other stimulus or to the neurotoxic effects of MDMA.
Assuntos
Proteínas de Transporte/metabolismo , Fenclonina/farmacologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Proteínas do Tecido Nervoso , Serotoninérgicos/farmacologia , Serotonina/metabolismo , Animais , Autorradiografia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Córtex Cerebelar/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Paroxetina/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
OPINION STATEMENT: Dementia with Lewy bodies (DLB) is a multisystem disorder with diverse disease expression. A treatment regime restricted to the cognitive aspects of the disease does no favor to patients. Instead, patients should be educated to recognize the symptoms of this multisystem involvement. There are no treatments that slow the progression of disease, but symptomatic treatments can be effective. When thinking about treatment, we find it useful to divide the symptoms and signs into five categories: (a) cognitive features, (b) neuropsychiatric features, (c) motor dysfunction, (d) autonomic dysfunction, and (e) sleep dysfunction. Clinicians, funding bodies and industry are increasingly recognizing the importance of this common and debilitating disease.
RESUMO
STUDY OBJECTIVES: Sleep deprivation and daytime somnolence impair numerous aspects of physical, cognitive, and memory performance. However, most studies examining the effect of somnolence on brain function focus on acute sleep restriction in young adults. We examine the relationship between chronic daytime somnolence and connectivity in six brain networks in both young and elderly subjects using stimulus-free resting-state functional magnetic resonance imaging. DESIGN: Cross-sectional. SETTING: Outpatient research at the Massachusetts General Hospital. PARTICIPANTS: Young (n = 27) and elderly (n = 84) healthy, cognitively normal volunteers. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Compared with young subjects, cognitively normal elderly adults report less daytime somnolence on the Epworth Sleepiness Scale (ESS) (P = 0.019) and display reduced default mode network (DMN) connectivity (P = 0.004). Across all subjects, increasing daytime sleepiness was associated with decreasing functional connectivity in the DMN (P = 0.003, partial r of ESS = -0.29). There was no difference in the slope of this relationship between young adults and elderly subjects. No other cortical networks were correlated with daytime sleepiness. Daytime sleepiness and DMN connectivity were not related to sex, brain structure, or body mass index. CONCLUSIONS: These findings suggest that daytime sleepiness is associated with impaired connectivity of the DMN in a manner that is distinct from the effects of aging. This association is important to consider in any study using DMN connectivity as a biomarker. Additionally, these results may help identify those subjects at risk for future memory decline.
Assuntos
Encéfalo/fisiopatologia , Distúrbios do Sono por Sonolência Excessiva/fisiopatologia , Vias Neurais/fisiopatologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Neuroimagem Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes NeuropsicológicosRESUMO
OBJECTIVE: To determine the risk factors associated with dementia with Lewy bodies (DLB). METHODS: We identified 147 subjects with DLB and sampled 2 sex- and age-matched cognitively normal control subjects for each case. We also identified an unmatched comparison group of 236 subjects with Alzheimer disease (AD). We evaluated 19 candidate risk factors in the study cohort. RESULTS: Compared with controls, subjects with DLB were more likely to have a history of anxiety (odds ratio; 95% confidence interval) (7.4; 3.5-16; p < 0.0001), depression (6.0; 3.7-9.5; p < 0.0001), stroke (2.8; 1.3-6.3; p = 0.01), a family history of Parkinson disease (PD) (4.6; 2.5-8.6; p < 0.0001), and carry APOE ε4 alleles (2.2; 1.5-3.3; p < 0.0001), but less likely to have had cancer (0.44; 0.27-0.70; p = 0.0006) or use caffeine (0.29; 0.14-0.57; p < 0.0001) with a similar trend for alcohol (0.65; 0.42-1.0; p = 0.0501). Compared with subjects with AD, subjects with DLB were younger (72.5 vs 74.9 years, p = 0.021) and more likely to be male (odds ratio; 95% confidence interval) (5.3; 3.3-8.5; p < 0.0001), have a history of depression (4.3; 2.4-7.5; p < 0.0001), be more educated (2.5; 1.1-5.6; p = 0.031), have a positive family history of PD (5.0; 2.4-10; p < 0.0001), have no APOE ε4 alleles (0.61; 0.40-0.93; p = 0.02), and to have had an oophorectomy before age 45 years (7.6; 1.5-39; p = 0.015). CONCLUSION: DLB risk factors are an amalgam of those for AD and PD. Smoking and education, which have opposing risk effects on AD and PD, are not risk factors for DLB; however, depression and low caffeine intake, both risk factors for AD and PD, increase risk of DLB more strongly than in either.
Assuntos
Doença de Alzheimer/complicações , Demência/etiologia , Corpos de Lewy , Doença por Corpos de Lewy/complicações , Doença de Parkinson/complicações , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Estudos de Casos e Controles , Feminino , Humanos , Doença por Corpos de Lewy/diagnóstico , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: To validate a questionnaire focused on REM sleep behavior disorder (RBD) in a community-based sample. BACKGROUND: RBD is a parasomnia manifested by recurrent dream enactment behavior during REM sleep. While confirmation of RBD requires the presence of REM sleep without atonia on polysomnography (PSG), a screening measure for RBD validated in older adults would be desirable for clinical and research purposes. METHODS: We had previously developed the Mayo Sleep Questionnaire (MSQ) to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of subjects' bed partners with the findings on PSG. All subjects recruited from 10/04 to 12/08 in the Mayo Clinic Study of Aging--a population-based study of aging in Olmsted County, Minnesota--who had also undergone a previous PSG were the focus of this analysis. RESULTS: The study sample included 128 subjects (104 male; median age 77 years [range 67-90]), with the following clinical diagnoses at baseline assessment: normal (n = 95), mild cognitive impairment (n = 30), and mild Alzheimer disease (n = 3). Nine (5%) subjects had RBD based on history and PSG evidence of REM sleep without atonia. The core question on recurrent dream enactment behavior yielded sensitivity (SN) of 100% and specificity (SP) of 95% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD improved specificity. CONCLUSIONS: These data suggest that the MSQ has adequate SN and SP for the diagnosis of RBD among elderly subjects in a community-based sample.