RESUMO
PURPOSE: To examine whether or not a mobile integrated health (MIH) program may improve health-related quality of life while reducing emergency department (ED) transports, ED admissions, and inpatient hospital admissions in frequent utilizers of ED services. METHODS: A small retrospective evaluation assessing pre- and post-program quality of life, ED transports, ED admissions, and inpatient hospital admissions was conducted in patients who frequently used the ED for non-emergent or emergent/primary care treatable conditions. RESULTS: Pre- and post-program data available on 64 program completers are reported. Of those with mobility problems (n=42), 38% improved; those with problems performing usual activities (N=45), 58% reported improvement; and of those experiencing moderate to extreme pain or discomfort (N=48), 42% reported no pain or discomfort after program completion. Frequency of ED transports decreased (5.34±6.0 vs. 2.08±3.3; p <0.000), as did ED admissions (9.66±10.2 vs. 3.30±4.6; p<0.000), and inpatient hospital admissions (3.11±5.5 vs. 1.38±2.5; p=0.003). CONCLUSION: Results suggest that MIH participation is associated with improved quality of life, reduced ED transports, ED admissions, and inpatient hospital admissions. The MIH program may have potential to improve health outcomes in patients who are frequent ED users for non-emergent or emergent/primary care treatable conditions by teaching them how to proactively manage their health and adhere to therapeutic regimens. Programmatic reasons for these improvements may include psychosocial bonding with participants who received in-home care, health coaching, and the MIH team's 24/7 availability that provided immediate healthcare access.
Assuntos
Serviços Médicos de Emergência/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Unidades Móveis de Saúde/organização & administração , Atenção Primária à Saúde , Qualidade de Vida , Adulto , Atenção à Saúde , Feminino , Educação em Saúde , Acessibilidade aos Serviços de Saúde , Visita Domiciliar , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Projetos Piloto , Texas , Transporte de Pacientes/estatística & dados numéricosRESUMO
BACKGROUND: Risks prediction models of 30-day all-cause hospital readmissions are multi-factorial. Severity of illness (SOI) and risk of mortality (ROM) categorized by All Patient Refined Diagnosis Related Groups (APR-DRG) seem to predict hospital readmission but lack large sample validation. Effects of risk reduction interventions including providing post-discharge outpatient visits remain uncertain. We aim to determine the accuracy of using SOI and ROM to predict readmission and further investigate the role of outpatient visits in association with hospital readmission. METHODS: Hospital readmission data were reviewed retrospectively from September 2012 through June 2015. Patient demographics and clinical variables including insurance type, homeless status, substance abuse, psychiatric problems, length of stay, SOI, ROM, ICD-10 diagnoses and medications prescribed at discharge, and prescription ratio at discharge (number of medications prescribed divided by number of ICD-10 diagnoses) were analyzed using logistic regression. Relationships among SOI, type of hospital visits, time between hospital visits, and readmissions were also investigated. RESULTS: A total of 6011 readmissions occurred from 55,532 index admissions. The adjusted odds ratios of SOI and ROM predicting readmissions were 1.31 (SOI: 95 % CI 1.25-1.38) and 1.09 (ROM: 95 % CI 1.05-1.14) separately. Ninety percent (5381/6011) of patients were readmitted from the Emergency Department (ED) or Urgent Care Center (UCC). Average time interval from index discharge date to ED/UCC visit was 9 days in both the no readmission and readmission groups (p > 0.05). Similar hospital readmission rates were noted during the first 10 days from index discharge regardless of whether post-index discharge patient clinic visits occurred when time-to-event analysis was performed. CONCLUSIONS: SOI and ROM significantly predict hospital readmission risk in general. Most readmissions occurred among patients presenting for ED/UCC visits after index discharge. Simply providing early post-discharge follow-up clinic visits does not seem to prevent hospital readmissions.
Assuntos
Assistência ao Convalescente , Assistência Ambulatorial/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Adulto , Grupos Diagnósticos Relacionados , Feminino , Pessoas Mal Alojadas , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
OBJECTIVE: Homeless patients are a vulnerable population with a higher incidence of using the emergency department (ED) for noncrisis care. Multiple charity programs target their outreach toward improving the health of homeless patients, but few data are available on the effectiveness of reducing ED recidivism. The aim of this study is to determine whether inappropriate ED use for nonemergency care may be reduced by providing charity insurance and assigning homeless patients to a primary care physician (PCP) in an outpatient clinic setting. METHODS: A retrospective medical records review of homeless patients presenting to the ED and receiving treatment between July 2013 and June 2014 was completed. Appropriate vs inappropriate use of the ED was determined using the New York University ED Algorithm. The association between patients with charity care coverage, PCP assignment status, and appropriate vs inappropriate ED use was analyzed and compared. RESULTS: Following New York University ED Algorithm standards, 76% of all ED visits were deemed inappropriate with approximately 77% of homeless patients receiving charity care and 74% of patients with no insurance seeking noncrisis health care in the ED (P=.112). About 50% of inappropriate ED visits and 43.84% of appropriate ED visits occurred in patients with a PCP assignment (P=.019). CONCLUSIONS: Both charity care homeless patients and those without insurance coverage tend to use the ED for noncrisis care resulting in high rates of inappropriate ED use. Simply providing charity care and/or PCP assignment does not seem to sufficiently reduce inappropriate ED use in homeless patients.
Assuntos
Instituições de Caridade/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Mau Uso de Serviços de Saúde/estatística & dados numéricos , Pessoas Mal Alojadas/estatística & dados numéricos , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Cognitive decline in Parkinson's disease (PD) is a critical premotor sign that may occur in approximately 40% of PD patients up to 10 years prior to clinical recognition and diagnosis. Delineating the mechanisms and specific behavioral signs of cognitive decline associated with PD prior to motor impairment is a critical unmet need. Rodent PD models that have an impairment in a cognitive phenotype for a time period sufficiently long enough prior to motor decline can be useful to establish viable candidate mechanisms. Arguably, the methods used to evaluate cognitive decline in rodent models should emulate methods used in the assessment of humans to optimize translation. Premotor cognitive decline in human PD can potentially be examined in the genetically altered PINK1-/- rat model, which exhibits a protracted onset of motor decline in most studies. To increase translation to cognitive assessment in human PD, we used a modified non-water multiple T-maze, which assesses attention, cognitive flexibility, and working memory similarly to the Trail Making Test (TMT) in humans. Similar to the deficiencies revealed in TMT test outcomes in human PD, 4-month-old PINK1-/- rats made more errors and took longer to complete the maze, despite a hyperkinetic phenotype, compared to wild-type rats. Thus, we have identified a potential methodological tool with cross-species translation to evaluate executive functioning in an established PD rat model.
RESUMO
Cognitive decline in Parkinson's disease (PD) emerges up to 10 years before clinical recognition. Neurobiological mechanisms underlying premotor cognitive impairment in PD can potentially be examined in the PINK1 -/- rat, which exhibits a protracted motor onset. To enhance translation to human PD cognitive assessments, we tested a modified multiple T-maze, which measures cognitive flexibility similarly to the Trail-Making Test in humans. Like human PD outcomes, PINK1 -/- rats made more errors and took longer to complete the maze than wild types. Thus, we have identified a potential tool for assessing cross-species translation of cognitive functioning in an established PD animal model.
RESUMO
Parkinson's disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6-7 months) and aged (18-19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA levels in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor decline.
Assuntos
Envelhecimento , Corpo Estriado , Dopamina , Proteínas Quinases , Substância Negra , Tirosina 3-Mono-Oxigenase , Animais , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/deficiência , Proteínas Quinases/metabolismo , Substância Negra/metabolismo , Envelhecimento/genética , Masculino , Ratos , Dopamina/metabolismo , Corpo Estriado/metabolismo , Atividade Motora/fisiologia , Atividade Motora/genética , Ratos TransgênicosRESUMO
Parkinson's disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6-7 months) and aged (18-19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA content in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor impairment.
RESUMO
Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) patients points to activation of neurobiological mechanisms that may be targetable by therapeutic approaches. However, evidence for AE-related recovery of striatal dopamine (DA) signaling or tyrosine hydroxylase (TH) loss has been inconsistent in rodent studies. This ambiguity may be related to the timing of AE intervention in relation to the status of nigrostriatal neuron loss. Here, we replicated human PD at diagnosis by establishing motor impairment with >80% striatal DA and TH loss prior to initiating AE, and assessed its potential to alleviate motor decline and restore DA and TH loss. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), biomarkers of human PD severity, changed in response to AE. 6-hydroxydopamine (6-OHDA) was infused unilaterally into rat medial forebrain bundle to induce progressive nigrostriatal neuron loss over 28 days. Moderate intensity AE (3× per week, 40 min/session), began 8-10 days post-lesion following establishment of impaired forelimb use. Striatal tissue DA, TH protein and mRNA, and serum levels of NfL/GFAP were determined 3-wks after AE began. Despite severe striatal DA depletion at AE initiation, forelimb use deficits and hypokinesia onset were alleviated by AE, without recovery of striatal DA or TH protein loss, but reduced NfL and GFAP serum levels. This proof-of-concept study shows AE alleviates motor impairment when initiated with >80% striatal DA loss without obligate recovery of striatal DA or TH protein. Moreover, the AE-related reduction of NfL and GFAP serum levels may serve as objective blood-based biomarkers of AE efficacy.
Assuntos
Biomarcadores , Corpo Estriado , Dopamina , Oxidopamina , Condicionamento Físico Animal , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase , Animais , Ratos , Tirosina 3-Mono-Oxigenase/metabolismo , Oxidopamina/toxicidade , Masculino , Corpo Estriado/metabolismo , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/métodos , Biomarcadores/sangue , Dopamina/metabolismo , Dopamina/sangue , Proteína Glial Fibrilar Ácida/metabolismo , Proteína Glial Fibrilar Ácida/sangue , Índice de Gravidade de Doença , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/metabolismo , Doença de Parkinson/sangue , Terapia por Exercício/métodosRESUMO
Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinson's disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment across all studies began â¼8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), and is later than the timing of GDNF treatment in preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemi-parkinsonian rats to determine if expression of GDNF family receptor, GFR-α1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) lesion. Whereas GDNF expression changed minimally, GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-α1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred that returned to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-α1 and RET expression between the striatum and SN, and cell-specific differences in GFR-α1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. Significance Statement: Although preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, clinical data supporting its efficacy to alleviate motor impairment in Parkinson's disease patients remains uncertain. Using the established 6-OHDA hemi-parkinsonian rat model, we determined whether expression of its cognate receptors, GFR-α1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-α1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-α1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-α1 may be a critical element that determines GDNF efficacy following striatal delivery. Highlights: GDNF expression was minimally affected by nigrostriatal lesionGDNF family receptor, GFR-α1, progressively decreased in striatum and in TH neurons in SN.GFR-α1 expression decreased along with TH neurons as lesion progressedGFR-α1 increased bilaterally in GFAP+ cells suggesting an inherent response to offset TH neuron lossRET expression was severely reduced in striatum, whereas it increased in SN early after lesion induction.
RESUMO
Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinson's disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment began â¼8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), which represents a time point of initiating GDNF treatment later than reported in some preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemiparkinsonian rats to determine if expression of GDNF family receptor, GFR-α1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) hemilesion. Whereas GDNF expression changed minimally, GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-α1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred, returning to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-α1 and RET expression between the striatum and SN, and cell-specific differences in GFR-α1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors thus appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. SIGNIFICANCE STATEMENT: Although preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, there is uncertainty if it can alleviate motor impairment in Parkinson's disease patients. Using the established 6-OHDA hemiparkinsonian rat model, we determined whether expression of its cognate receptors, GFR-α1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-α1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-α1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-α1 may be a critical element that determines GDNF efficacy following striatal delivery.
Assuntos
Doença de Parkinson , Animais , Ratos , Corpo Estriado/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Oxidopamina/toxicidade , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Compensatory mechanisms that augment dopamine (DA) signaling are thought to mitigate onset of hypokinesia prior to major loss of tyrosine hydroxylase (TH) in striatum that occurs in Parkinson's disease. However, the identity of such mechanisms remains elusive. In the present study, the rat nigrostriatal pathway was unilaterally-lesioned with 6-hydroxydopamine (6-OHDA) to determine whether differences in DA content, TH protein, TH phosphorylation, or D1 receptor expression in striatum or substantia nigra (SN) aligned with hypokinesia onset and severity at two time points. In striatum, DA and TH loss reached its maximum (>90%) 7 days after lesion induction. However, in SN, no DA loss occurred, despite â¼60% TH loss. Hypokinesia was established at 21 days post-lesion and maintained at 28 days. At this time, DA loss was â¼60% in the SN, but still of lesser magnitude than TH loss. At day 7 and 28, ser31 TH phosphorylation increased only in SN, corresponding to less DA versus TH protein loss. In contrast, ser40 TH phosphorylation was unaffected in either region. Despite DA loss in both regions at day 28, D1 receptor expression increased only in lesioned SN. These results support the concept that augmented components of DA signaling in the SN, through increased ser31 TH phosphorylation and D1 receptor expression, contribute as compensatory mechanisms against progressive nigrostriatal neuron and TH protein loss, and may mitigate hypokinesia severity.
Assuntos
Hipocinesia , Tirosina 3-Mono-Oxigenase , Animais , Ratos , Fosforilação , Dopamina , Neurônios , Oxidopamina/toxicidade , Substância NegraRESUMO
Background: Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) points to a CNS response that could be targeted by therapeutic approaches, but recovery of striatal dopamine (DA) or tyrosine hydroxylase (TH) has been inconsistent in rodent studies. Objective: To increase translation of AE, 3 components were implemented into AE design to determine if recovery of established motor impairment, concomitant with >80% striatal DA and TH loss, was possible. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), blood-based biomarkers of disease severity in human PD, were affected. Methods: We used a 6-OHDA hemiparkinson rat model featuring progressive nigrostriatal neuron loss over 28 days, with impaired forelimb use 7 days post-lesion, and hypokinesia onset 21 days post-lesion. After establishing forelimb use deficits, moderate intensity AE began 1-3 days later, 3x per week, for 40 min/session. Motor assessments were conducted weekly for 3 wks, followed by determination of striatal DA, TH protein and mRNA, and NfL and GFAP serum levels. Results: Seven days after 6-OHDA lesion, recovery of depolarization-stimulated extracellular DA and DA tissue content was <10%, representing severity of DA loss in human PD, concomitant with 50% reduction in forelimb use. Despite severe DA loss, recovery of forelimb use deficits and alleviation of hypokinesia progression began after 2 weeks of AE and was maintained. Increased NfLand GFAP levels from lesion were reduced by AE. Despite these AE-driven changes, striatal DA tissue and TH protein levels were unaffected. Conclusions: This proof-of-concept study shows AE, using exercise parameters within the capabilities most PD patients, promotes recovery of established motor deficits in a rodent PD model, concomitant with reduced levels of blood-based biomarkers associated with PD severity, without commensurate increase in striatal DA or TH protein.
RESUMO
BACKGROUND: Rodent Parkinson's disease (PD) models are valuable to interrogate neurobiological mechanisms of exercise that mitigate motor impairment. Translating these mechanisms to human PD must account for physical capabilities of the patient. OBJECTIVE: To establish cardiovascular parameters as a common metric for cross-species translation of aerobic exercise impact. METHOD: We evaluated aerobic exercise impact on heart rate (HR) in 21 early-stage PD subjects (Hoehn Yahr ≤1.5) exercising in non-contact boxing training for ≥3 months, ≥3x/week. In 4-month-old Pink1 knockout (KO) rats exercising in a progressively-increased treadmill speed regimen, we determined a specific treadmill speed that increased HR to an extent similar in human subjects. RESULTS: After completing aerobic exercise for â¼30âmin, PD subjects had increased HRâ¼35% above baseline (â¼63% maximum HR). Motor and cognitive test results indicated the exercising subjects completed the timed up and go (TUG) and trail-making test (TMT-A) in significantly less time versus exercise-naïve PD subjects. In KO and age-matched wild-type (WT) rats, treadmill speeds of 8-10âm/min increased HR up to 25% above baseline (â¼67% maximum HR), with no further increases up to 16âm/min. Exercised KO, but not WT, rats showed increased locomotor activity compared to an age-matched exercise-naïve cohort at 5 months old. CONCLUSION: These proof-of-concept results indicate HR is a cross-species translation parameter to evaluate aerobic exercise impact on specific motor or cognitive functions in human subjects and rat PD models. Moreover, a moderate intensity exercise regimen is within the physical abilities of early-stage PD patients and is therefore applicable for interrogating neurobiological mechanisms in rat PD models.
Assuntos
Doença de Parkinson , Animais , Teste de Esforço , Terapia por Exercício/métodos , Frequência Cardíaca , Humanos , Lactente , Doença de Parkinson/genética , RatosAssuntos
Instituições de Caridade/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Mau Uso de Serviços de Saúde/estatística & dados numéricos , Pessoas Mal Alojadas/estatística & dados numéricos , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Feminino , Humanos , MasculinoRESUMO
OBJECTIVE: An exploratory, cross-sectional study examined personal, clinical, and treatment characteristics among non-Hispanic Caucasian, non-Hispanic African American, and Hispanic indigent, inner-city clients with co-occurring disorders. METHODS: Men and women, 20-50 years old who met DSM-IV criteria for concurrent mood and substance use disorders were eligible. Inpatients, persons in detoxification programs, or incarcerated inmates were excluded. Assessments covered sociodemographic characteristics, clinical diagnoses, substance use, psychosocial variables, health care utilization and treatment history. RESULTS: Two hundred volunteers were screened, and 145 were eligible to enroll. Racial ethnic group differences in the distribution of mood and substance use disorders and medical diseases were evident. Receiving psychiatric treatment and psychiatric medications significantly differed among racial ethnic groups with Caucasians more likely to receive these services than African Americans or Hispanics. African Americans and Hispanics were also more likely than Caucasians to test positive for their drug of choice and for other drugs as well. Serious medical illnesses were evident in about half of the sample, and the distributions of these illnesses significantly differed among racial ethnic groups. There were no significant differences in hospitalization or emergency room visits among racial ethnic groups. CONCLUSIONS: Indigent, inner-city clients have multiple psychiatric and medical problems that warrant continuity of care. However, few doctor's visits for medical illnesses, lack of psychotropic medications, staggering unemployment, and homelessness were common in our sample. These results present healthcare and social service professionals with potentially serious treatment challenges. Better recognition and understanding of racial ethnic needs in those with co-occurring disorders are needed.
RESUMO
IMPORTANCE: Epidemiologists report a 56% increased risk of veterans with (+) mild traumatic brain injury (mTBI) developing Parkinson's disease (PD) within 12-years post-injury. The most relevant contributors to this high risk of PD in veterans (+) mTBI is unknown. As cognitive problems often precede PD diagnosis, identifying specific domains most involved with mTBI-related PD onset is critical. OBJECTIVES: To discern which cognitive domains underlie the mTBI-PD risk relationship proposed in epidemiology studies. DESIGN AND SETTING: This exploratory match-controlled, cross-sectional study was conducted in a medical school laboratory from 2017-2020. PARTICIPANTS: Age- and IQ-matched veterans with (+) and without mTBI, non-veteran healthy controls, and IQ-matched non-demented early-stage PD were compared. Chronic neurological, unremitted/debilitating diseases, disorders, dementia, and substance use among others were excluded. EXPOSURE: Veterans were or were not exposed to non-penetrating combat-related mTBI occurring within the past 7-years. No other groups had recent military service or mTBI. MAIN OUTCOMES / MEASURES: Cognitive flexibility, attention, memory, visuospatial ability, and verbal fluency were examined with well-known standardized neuropsychological assessments. RESULTS: Out of 200 volunteers, 114 provided evaluable data. Groups significantly differed on cognitive tests [F (21,299) = 3.09, p<0.0001]. Post hoc tests showed veterans (+) mTBI performed significantly worse than matched-control groups on four out of eight cognitive tests (range: p = .009 to .049), and more often than not performed comparably to early-stage PD (range: p = .749 to .140). CONCLUSIONS AND RELEVANCE: We found subtle, premature cognitive decline occurring in very specific cognitive domains in veterans (+) mTBI that would typically be overlooked in a clinic setting, This result potentially puts them at-risk for continual cognitive decline that may portend to the eventual onset of PD or some other neurodegenerative disease.
Assuntos
Concussão Encefálica/psicologia , Disfunção Cognitiva/etiologia , Doença de Parkinson/psicologia , Veteranos/psicologia , Idoso , Depressão/psicologia , Humanos , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/psicologiaRESUMO
Up to 23% of newly diagnosed, non-demented, Parkinson's disease (PD) patients experience deficits in executive functioning (EF). In fact, EF deficits may occur up to 39-months prior to the onset of motor decline. Optimal EF requires working memory, attention, cognitive flexibility, and response inhibition underlying appropriate decision-making. The capacity for making strategic decisions requires inhibiting imprudent decisions and are associated with noradrenergic and dopaminergic signaling in prefrontal and orbitofrontal cortex. Catecholaminergic dysfunction and the loss of noradrenergic and dopaminergic cell bodies early in PD progression in the aforementioned cortical areas likely contribute to EF deficits resulting in non-strategic decision-making. Thus, detecting these deficits early in the disease process could help identify a significant portion of individuals with PD pathology (14-60%) before frank motor impairment. A task to evaluate EF in the domain of non-strategic decision-making might be useful to indicate the moderate loss of catecholamines that occurs early in PD pathology prior to motor decline and cognitive impairment. In this review, we focus on the potential utility of the Iowa Gambling Task (IGT) for this purpose, given significant overlap between in loss of dopaminergic and noradrenergic cells bodies in early PD and the deficits in catecholamine function associated with decreased EF. As such, given the loss of catecholamines already well-underway after PD diagnosis, we evaluate the potential utility of the IGT to identify the risk of therapeutic non-compliance and a potential companion approach to detect PD in premotor stages.
Assuntos
Jogo de Azar , Doença de Parkinson , Catecolaminas , Humanos , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/diagnósticoRESUMO
Glial cell line-derived neurotrophic factor (GDNF) improved motor function in Parkinson's disease (PD) patients in Phase I clinical trials, and these effects persisted months after GDNF discontinuation. Conversely, phase II clinical trials reported no significant effects on motor improvement vs placebo. The disease duration and the quantity, infusion approach, and duration of GDNF delivery may affect GDNF efficacy in PD treatment. However, identifying mechanisms activated by GDNF that affect nigrostriatal function may reveal additional avenues to partially restore nigrostriatal function. In PD and aging models, GDNF affects tyrosine hydroxylase (TH) expression or phosphorylation in substantia nigra (SN), long after a single GDNF injection in striatum. In aged rats, the GDNF family receptor, GFR-α1, increases TH expression and phosphorylation in SN. To determine if GFR-α1 could be a mechanistic link in long-term GDNF impact, we conducted two studies; first to determine if a single unilateral striatal delivery of GDNF affected GFR-α1 and TH over time (1 day, 1 week, and 4 weeks) in the striatum or SN in aged rats, and second, to determine if soluble GFR-α1 could mitigate TH loss following 6-hydroxydopamine (6-OHDA) lesion. In aged rats, GDNF bilaterally increased ser31 TH phosphorylation and GFR-α1 expression in SN at 1 day and 4 weeks after GDNF, respectively. In striatum, GFR-α1 expression decreased 1 week after GDNF, only on the GDNF-injected side. In 6-OHDA-lesioned rats, recombinant soluble GFR-α1 mitigated nigral, but not striatal, TH protein loss following 6-OHDA. Together, these results show GDNF has immediate and long-term impact on dopamine regulation in the SN, which includes a gradual increase in GFR-α1 expression that may sustain TH expression and dopamine function therein.
Assuntos
Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Oxidopamina/toxicidade , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Envelhecimento/metabolismo , Animais , Dopamina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Substância Negra/metabolismoRESUMO
Methamphetamine (MA) exposure may increase the risk of motor or cognitive impairments similar to Parkinson's disease (PD) by middle age. Although damage to nigrostriatal or mesoaccumbens dopamine (DA) neurons may occur during or early after MA exposure, overt PD-like symptoms at a younger age may not manifest due to compensatory mechanisms to maintain DA neurotransmission. One possible compensatory mechanism is increased tyrosine hydroxylase (TH) phosphorylation. In the rodent PD 6-OHDA model, nigrostriatal lesion decreases TH protein in both striatum and substantia nigra (SN). However, DA loss in the SN is significantly less than that in the striatum. An increase in ser31 TH phosphorylation in the SN may increase TH activity in response to TH loss. To determine if similar compensatory mechanisms may be engaged in young mice after MA exposure, TH expression, phosphorylation, and DA tissue content were evaluated, along with dopamine transporter expression, 21 days after cessation of MA (24â¯mg/kg, daily, 14 days). DA tissue content was unaffected by the MA regimen in striatum, nucleus accumbens, SN, or ventral tegmental area (VTA), despite decreased TH protein in SN and VTA. In the SN, but not striatum, ser31 phosphorylation increased over 2-fold. This suggests that increased ser31 TH phosphorylation may be an inherent compensatory mechanism to attenuate DA loss against TH loss, similar to that in an established PD model. These results also indicate the somatodendritic compartments of DA neurons are more vulnerable to TH protein loss than terminal fields following MA exposure.
Assuntos
Inibidores da Captação de Dopamina/administração & dosagem , Dopamina/metabolismo , Metanfetamina/administração & dosagem , Serina/metabolismo , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Distribuição Aleatória , Substância Negra/efeitos dos fármacos , Fatores de TempoRESUMO
Identifying lifestyle strategies and allied neurobiological mechanisms that reduce aging-related motor impairment is imperative, given the accelerating number of retirees and increased life expectancy. A physically active lifestyle prior to old age can reduce risk of debilitating motor decline. However, if exercise is initiated after motor decline has begun in the lifespan, it is unknown if aging itself may impose a limit on exercise efficacy to decelerate further aging-related motor decline. In Brown-Norway/Fischer 344 F1 hybrid (BNF) rats, locomotor activity begins to decrease in middle age (12-18 months). One mechanism of aging-related motor decline may be decreased expression of GDNF family receptor, GFRα-1, which is decreased in substantia nigra (SN) between 12 and 30 months old. Moderate exercise, beginning at 18 months old, increases nigral GFRα-1 and tyrosine hydroxylase (TH) expression within 2 months. In aged rats, replenishing aging-related loss of GFRα-1 in SN increases TH in SN alone and locomotor activity. A moderate exercise regimen was initiated in sedentary male BNF rats in a longitudinal study to evaluate if exercise could attenuate aging-related motor decline when initiated at two different ages in the latter half of the lifespan (18 or 24 months old). Motor decline was reversed in the 18-, but not 24-month-old, cohort. However, exercise efficacy in the 18-month-old group was reduced as the rats reached 27 months old. GFRα-1 expression was not increased in either cohort. These studies suggest exercise can decelerate motor decline when begun in the latter half of the lifespan, but its efficacy may be limited by age of initiation. Decreased plasticity of GFRα-1 expression following exercise may limit its efficacy to reverse motor decline.