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BACKGROUND: Serum-measured fragments of Tau cleaved by ADAM-10 (Tau-A) and Caspase-3 (Tau-C) have been found linked to change in cognitive function and risk of dementia. OBJECTIVES: 1) To determine the discriminatory abilities of Tau-A, and Tau-C in subjects with either mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or AD dementia compared to a control group. 2) To determine if there is a relation between Tau-A, and Tau-C and established cerebrospinal fluid (CSF) markers of AD- ß-Amyloid1-42 (AB42), Phosphorylated-tau-181 (p-tau), and total-tau. 3) To determine if Tau-A and Tau-C are associated with progression rate from MCI due to AD to AD dementia. DESIGN: Cross-sectional and a substudy using a retrospective cohort design. SETTING: Memory clinic derived subjects contributing to the Danish Dementia Biobank. PARTICIPANTS: Cognitively unimpaired subjects (n=49), patients with mild cognitive impairment (MCI) due to AD (n=45), and Alzheimer's dementia (n=52). MEASUREMENTS: Competitive enzyme-linked immunosorbent assay (ELISA)-measured serum levels of Tau-A, and Tau-C. RESULTS: The ratio between Tau-A and Tau-C differed between the three groups (p=0.015). Age- and sex-adjusted Tau-A differed between groups with lower ratios being associated with more severe disease (p=0.023). Tau-C was trending towards significant correlation to CSF-levels of AB42 (Pearson correlation coefficient 0.164, p=0.051). Those with Tau-C-levels in the 2nd quartile had a hazard ratio (HR) of 2.91 (95% CI 1.01 - 8.44, p=0.04) of progression compared to those in the 1st quartile. Those in the 3rd quartile was found to have a borderline significant (p=0.055) HR of 2.63 (95% CI 0.98 - 7.05) when compared to those in the lowest quartile. CONCLUSIONS: Tau-A and the ratio between Tau-A and Tau-C showed significant differences between groups and were correlated to CSF-AB42. Tau-C values in the middle range were associated with faster progression from MCI to dementia. This pilot study adds to the mounting data suggesting serum-measured Tau-A and Tau-C as biomarkers useful in relation to diagnosis and progression rate in AD but need further validation.
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Enfermedad de Alzheimer , Biomarcadores , Disfunción Cognitiva , Progresión de la Enfermedad , Proteínas tau , Humanos , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Masculino , Femenino , Anciano , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Estudios Transversales , Estudios Retrospectivos , Persona de Mediana Edad , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Demencia/sangre , Estudios de Cohortes , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
BACKGROUND AND PURPOSE: The Normal Pressure Hydrocephalus Radscale is a combined scoring of 7 different structural imaging markers on preoperative brain CT or MR imaging in patients with idiopathic normal pressure hydrocephalus: callosal angle, Evans Index, Sylvian fissure dilation, apical sulcal narrowing, mean temporal horn diameter, periventricular WM lesions, and focal sulcal dilation. The purpose of this retrospective study was to assess the performance of the Normal Pressure Hydrocephalus Radscale in distinguishing idiopathic normal pressure hydrocephalus shunt responders from nonresponders. MATERIALS AND METHODS: The preoperative MR imaging and CT scans of 119 patients with idiopathic normal pressure hydrocephalus were scored using the Normal Pressure Hydrocephalus Radscale. A summary shunt-response score assessed within 6 months from ventriculoperitoneal shunt surgery, combining the effect on cognition, gait, and urinary incontinence, was used as a reference. The difference between the mean Normal Pressure Hydrocephalus Radscale for responders and nonresponders was tested using the Student t test. The area under the curve was calculated for the Normal Pressure Hydrocephalus Radscale to assess shunt response. To ascertain reproducibility, we assessed the interobserver agreement between the 2 independent observers as intraclass correlation coefficients for the Normal Pressure Hydrocephalus Radscale for 74 MR imaging scans and 19 CT scans. RESULTS: Ninety-four (79%) of 119 patients were shunt responders. The mean Normal Pressure Hydrocephalus Radscale score for shunt responders was 8.35 (SD, 1.53), and for nonresponders, 7.48 (SD, 1.53) (P = .02). The area under the curve for the Normal Pressure Hydrocephalus Radscale was 0.66 (range, 0.54-0.78). The intraclass correlation coefficient for the Normal Pressure Hydrocephalus Radscale was 0.86 for MR imaging and 0.82 for CT. CONCLUSIONS: The Normal Pressure Hydrocephalus Radscale showed moderate discrimination for shunt response but cannot, on its own, be used for selecting patients with idiopathic normal pressure hydrocephalus for shunt surgery.
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Hidrocéfalo Normotenso , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/cirugía , Humanos , Hidrocéfalo Normotenso/complicaciones , Hidrocéfalo Normotenso/diagnóstico por imagen , Hidrocéfalo Normotenso/cirugía , Neuroimagen/métodos , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Acute Tryptophan Depletion (ATD) is a dietary method used to modulate central 5-HT to study the effects of temporarily reduced 5-HT synthesis. The aim of this study is to evaluate a novel method of ATD using a gelatin-based collagen peptide (CP) mixture. We administered CP-Trp or CP+Trp mixtures to 29 healthy volunteers; 13 from a randomized, double-blinded crossover study and sixteen from a randomized, double-blinded study run in our laboratory. Plasma amino acids, mood, side effects, cortisol concentrations, mean arterial blood pressure and heart rate were measured at multiple time-points. Repeated measures analysis of variance and Wilcoxon or Mann-Whitney U non-parametric tests were used to analyze the effects of intervention. Intake of the CP-Trp mixture efficiently reduced plasma Trp; however, the CP+Trp mixture induced a large significant increase in plasma Trp. No other significant effects of CP-Trp compared to CP+Trp were observed. The transient increase in plasma Trp after CP+Trp may impair comparison to the CP-Trp and we therefore recommend in future studies to use a smaller dose of Trp supplement to the CP mixture.
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Dieta , Triptófano/sangre , Adolescente , Adulto , Afecto , Análisis de Varianza , Colágeno , Estudios Cruzados , Método Doble Ciego , Femenino , Gelatina , Humanos , Hidrocortisona/metabolismo , Masculino , Resultado del Tratamiento , Triptófano/administración & dosificación , Adulto JovenRESUMEN
OBJECTIVE: To investigate whether the cumulative number, duration and subtypes (severity and presence of psychotic features) of previous episodes of depression in patients with unipolar depressive disorder in a remitted state are associated with decreased global cognitive function. METHODS: Via the Danish registers individuals between 40 and 80 years of age were identified: (1) patients with a diagnosis of unipolar disorder at their first discharge from a psychiatric hospital in the period 1994 to 2002, and (2) gender and age matched control individuals. The participants were assessed with the Cambridge Cognitive Examination (CAMCOG), which provides a composite measure of global cognitive function. RESULTS: A total of 88 patients and 50 controls accepted our invitation to participate, fulfilled the selection criteria and were included in the study. The cumulative duration of depressive episodes was associated with a decreased CAMCOG score adjusted for age, gender, education, premorbid IQ and residual depressive symptoms (B=-0.14, 95% C.I. (-0.26, -0.02), R(2)adj=0.31, P=.02). Significant associations were also found between CAMCOG score and the cumulative duration and total number of depressive episodes with psychotic features, respectively. CONCLUSION: Our findings suggest that cognitive dysfunction is associated with the cumulative duration of depressive episodes, and that, in particular, depressive episodes with psychotic features in the course of illness may be a significant predictor of future impairment of cognitive function.
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Trastornos del Conocimiento/psicología , Cognición/fisiología , Trastorno Depresivo/psicología , Adulto , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/complicaciones , Trastorno Depresivo/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Sistema de Registros , Índice de Severidad de la EnfermedadRESUMEN
The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North, South, West) and investigated with biannual follow-up over 2 years. Primary outcomes were cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Participant cognitive function declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances (NPI scale) was linear. Neither scale showed regional differences, and progression of the disease was similar across Europe despite different health care systems. Functional decline (ADL, IADL) tended to progress more rapidly in Southern Europe (p=0.09), while progression of caregiver burden (Zarit Burden Interview) was most rapid in Northern Europe (5.6 pts/y, p=0.04). Incidences of hospital admission (10.44, 95%CI: 8.13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe. In general cognitive and functional decline was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden.
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Enfermedad de Alzheimer/epidemiología , Progresión de la Enfermedad , Anciano , Enfermedad de Alzheimer/diagnóstico , Europa (Continente) , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Factores SocioeconómicosRESUMEN
OBJECTIVE: Decreased levels of peripheral brain-derived neurotrophic factor (BDNF) have been associated with depression. It is uncertain whether abnormally low levels of BDNF in blood are present beyond the depressive state and whether levels of BDNF are associated with the course of clinical illness. METHOD: Whole-blood BDNF levels were measured in blood samples from patients with unipolar disorder in a sustained state of clinical remission and in a healthy control group. Participants were recruited via Danish registers, a method that benefits from the opportunity to obtain well-matched community-based samples as well as providing a high diagnostic validity of the patient sample. RESULTS: A total of 85 patients and 50 controls were included in the study. In multiple linear regression analyses, including the covariates age, gender, 17-item Hamilton Depression Rating Scale scores, body-mass index, education, smoking and physical exercise, patients with unipolar depressive disorder had decreased levels of BDNF compared to healthy control individuals [B = -7.4, 95% CI (-11.2, -3.7), = 0.21 P < 0.001]. No association between course of clinical illness and BDNF levels was present. CONCLUSION: Whole-blood BDNF levels seem to be decreased in patients remitted from unipolar depressive disorder, suggesting that neurotrophic changes may exist beyond the depressive state.
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Factor Neurotrófico Derivado del Encéfalo/sangre , Trastorno Depresivo Mayor/sangre , Índice de Severidad de la Enfermedad , Adulto , Biomarcadores/sangre , Dinamarca/epidemiología , Trastorno Depresivo Mayor/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Análisis de Regresión , Inducción de Remisión , Adulto JovenRESUMEN
INTRODUCTION: The added diagnostic value of (11)C-PiB-PET for the assessment of the accumulation of cortical beta-amyloid in memory clinic patients with uncertain diagnosis remains undetermined. METHODS: All patients who underwent PiB-PET at the Copenhagen Memory Clinic between March 2008 and November 2011 were included in this uncontrolled, retrospective study. The standard diagnostic evaluation program included physical and neurological examination, cognitive and functional assessment, a cranial CT or MRI, functional imaging and cerebrospinal fluid sampling. Based on anonymized case reports, three experienced clinicians reached a consensus diagnosis and rated their confidence in the diagnosis before and after disclosure of PiB-PET ratings. PiB-PET scans were rated as either positive or negative. RESULTS: A total of 57 patients (17 females, 30 males; age 65.7 years, range 44.2-82.6) were included in the study. Twenty-seven had a positive PiB-PET scan. At the first diagnostic evaluation, 16 patients were given a clinical Alheimer's disease diagnosis (14 PiB positive). Of the 57 patients, 13 (23%) were diagnostically reclassified after PiB-PET ratings were disclosed. The clinicians' overall confidence in their diagnosis increased in 28 (49%) patients. CONCLUSION: PiB-PET adds to the specialist clinical evaluation and other supplemental diagnostic investigations in the diagnostic classification of patients with uncertain diagnosis in a specialized memory clinic.
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Previous studies of patients with Alzheimer's disease (AD) have described reduced brain serotonin 2A (5-HT(2A)) receptor density. It is unclear whether this abnormality sets in early in the course of the disease and whether it is related to early cognitive and neuropsychiatric symptoms. We assessed cerebral 5-HT(2A) receptor binding in patients with mild cognitive impairment (MCI) and related 5-HT(2A) receptor binding to clinical symptoms. Sixteen patients with MCI of the amnestic type (mean age 73, mean MMSE 26.1) and 17 age and sex matched control subjects were studied with MRI and [(18)F]altanserin PET in a bolus-infusion approach. A significant global reduction of 20-30% in 5-HT(2A) binding (atrophy corrected) was found in most neocortical areas. Reduced 5-HT(2A) binding in the striatum correlated significantly with Neuropsychiatric Inventory depression and anxiety scores. We conclude that widespread reductions in 5-HT(2A) receptor binding were found in amnestic MCI, pointing at the presence of serotonergic dysfunction in prodromal AD. This may provide some of the pathophysiological background for the neuropsychiatric symptoms found in early AD.
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Amnesia/metabolismo , Trastornos del Conocimiento/metabolismo , Cuerpo Estriado/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Anciano , Anciano de 80 o más Años , Regulación hacia Abajo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Unión Proteica , Distribución TisularRESUMEN
The aim of this study was to describe the present involvement of neurologists in dementia management in European countries. Data were obtained from a questionnaire that members of The European Federation of Neurological Societies Scientific Panel on Dementia responded to. Information was obtained from 25 countries in Europe. A progressive decrease in the teaching activity from medical school to board-certified neurologists was reported. Teaching of medical students in dementia is obligatory in most countries, whereas there is no formal obligatory education in dementia after graduation from medical school. Further, in only half of the countries that responded to the questionnaire, obligatory courses in dementia are part of the training in neurology. Except for one country, the post-graduate training programs of board-certified neurologists do not include dementia as an obligatory topic. In only 10 of 25 countries, guidelines for neurologists on dementia evaluation have been published in local language. It is recommended to include obligatory teaching and training in dementia in the catalogue of minimum requirements for specialist training in neurology and this teaching should also be part of the ongoing update of certified neurologists.
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Centros Médicos Académicos/tendencias , Demencia/diagnóstico , Demencia/terapia , Educación Médica Continua/tendencias , Educación de Postgrado en Medicina/tendencias , Neurología/educación , Centros Médicos Académicos/normas , Centros Médicos Académicos/estadística & datos numéricos , Educación Médica Continua/normas , Educación Médica Continua/estadística & datos numéricos , Educación de Postgrado en Medicina/normas , Educación de Postgrado en Medicina/estadística & datos numéricos , Europa (Continente) , Humanos , Comunicación Interdisciplinaria , Internado y Residencia/normas , Internado y Residencia/estadística & datos numéricos , Internado y Residencia/tendencias , Grupo de Atención al Paciente , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To evaluate current hypothesis regarding the pathophysiology of obsessive-compulsive disorder (OCD) by studying the serotonin receptor binding in patients with OCD using single photon emission computerized tomography (SPECT). METHOD: We studied nine patients (four men and five women, age range 21-56 years) fulfilling the DMS-III-R criteria for OCD using SPECT and the serotonin transporter (SERT) tracer (123)I-beta-CIT. SERT binding potential (BP2) was determined by Logan plot derived from seven scans obtained during 10-400 min. RESULTS: The binding of (123)I-beta-CIT in midbrain-pons was reduced in OCD patients when compared with controls (BP2 0.97 +/- 0.07 vs. 0.84 +/- 0.12, P = 0.011). There was no correlation between BP2 and any of the clinical variables (age at onset, disease duration, and Yale-Brown Obsessive-Compulsive Scale score). CONCLUSION: This study suggests a reduced serotonergic input into the fronto-subcortical circuits in OCD, thereby diminishing the inhibitory regulation of serotonin on these circuits.
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Mesencéfalo/diagnóstico por imagen , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Puente/diagnóstico por imagen , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Tomografía Computarizada de Emisión de Fotón Único , Adulto , Cocaína/análogos & derivados , Cocaína/farmacocinética , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/fisiopatología , Humanos , Radioisótopos de Yodo/farmacocinética , Masculino , Mesencéfalo/fisiopatología , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , Trastorno Obsesivo Compulsivo/fisiopatología , Puente/fisiopatología , Valores de Referencia , Estadística como AsuntoRESUMEN
Quantification of regional cerebral glucose metabolism (CMRglc) using positron emission tomography and 18F-fluorodeoxyglucose (PET-FDG) requires knowledge of the correction factor between FDG and glucose net clearance, the FDG lumped constant (LC). Because diverging values for LC have been obtained, the authors reevaluated LC by measuring the ratio of the cerebral net extraction fractions of FDG (E*) and glucose (E) from arteriovenous cerebral measurements. Thirty subjects were studied (mean age = 25 +/- 4 years): 12 during a programed infusion of FDG and 18 after a bolus injection of FDG. In the infusion study, LC was calculated as the ratio E*/E. In the bolus study, E* was calculated from the slope of a Patlak-Gjedde plot. Lumped constant was significantly smaller in the infusion study as compared with the bolus study (0.48 +/- 0.16 vs. 0.81 +/- 0.27, P < 0.001). In 4 subjects studied during continuous FDG infusion for 2.5 hours, LC decreased to 0.36 +/- 0.11. These results suggest that the "steady-state" method underestimates LC because E* continues to decline because of significant labeled product. Further, the authors provide evidence for resetting of LC toward a greater value. The subsequent resetting of CMRglc provides a physiologically more meaningful estimate and allows for comparison of CMRglc values between different methodologies.
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Encéfalo/metabolismo , Glucosa/metabolismo , Fluorodesoxiglucosa F18 , Humanos , Tomografía Computarizada de EmisiónRESUMEN
It is controversial whether transport adaptation takes place in chronic or acute hyperglycemia. Blood-brain barrier glucose permeability and regional brain glucose metabolism (CMR(glc)) was studied in acute hyperglycemia in six normal human subjects (mean age, 23 yr) using the double indicator method and positron emission tomography and [(18)F]fluorodeoxyglucose as tracer. The Kety-Schmidt technique was used for measurement of cerebral blood flow (CBF). After 2 h of hyperglycemia (15.7 +/- 0.7 mmol/L), the glucose permeability-surface area product from blood to brain remained unchanged (0.050 +/- 0.008 vs. 0.059 +/- 0.031 mL/100 g.min). The unidirectional clearance of [(18)F]fluorodeoxyglucose (K(1)*) was reduced from 0.108 +/- 0.011 to 0.061 +/- 0.005 mL/100 g.min (P < 0.0004). During hyperglycemia, global CMR(glc) remained constant (21.4 +/- 1.2 vs. 23.1 +/- 2.2 micromol/100 g.min, normo- and hyperglycemia, respectively). Except for a significant increase in white matter CMR(glc), no regional difference in CMR(glc) was found. Likewise, CBF remained unchanged. The reduction in K(1)* was compatible with Michaelis-Menten kinetics for facilitated transport. Our findings indicate no major adaptational changes in the maximal transport velocity or affinity to the blood-brain barrier glucose transporter. Finally, hyperglycemia did not change global CBF or CMR(glc).
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Barrera Hematoencefálica , Encéfalo/metabolismo , Glucosa/metabolismo , Hiperglucemia/metabolismo , Adulto , Transporte Biológico , Circulación Cerebrovascular , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVES: Increasing evidence suggests that metabolic changes predate neuronal death in Huntington's disease and emission tomography methods (PET and SPECT) have shown changes in glucose consumption and receptor function in early and possibly even presymptomatic disease. Because the GABA(A)-benzodiazepine receptor complex (BZR) is expressed on virtually all cerebral neurons BZR density images may be used to detect neuronal death. In this study the regional cerebral [(123)I]iomazenil binding to BZR was determined in patients with Huntington's disease and normal controls by a steady state method and SPECT. METHODS: Seven patients mildly to moderately affected by Huntington's disease and seven age matched controls were studied. Brain CT was performed on all subjects. In each subject two [(123)I]iomazenil-SPECT measurements were acquired-one with and one without infusion of flumazenil. The affinity constant of flumazenil (Kd) was calculated from the paired distribution volumes (DV) and the free plasma flumazenil concentration. The distribution volume of [(123)I]iomazenil in the unblocked condition (DV(0)) reflects the ratio between BZR density and Kd. RESULTS: Flumazenil Kd was similar in the Huntington's disease group and the control group (11.3 v 11.2 mM). For the Huntington's disease group a 31% reduction in striatal DV(0) (p=0.03) was found. In the cortical regions, DV(0) was similar in patients and in controls. In Huntington's disease, DV(0) correlated significantly with functional capacity (p=0.04) and chorea symptoms (p=0.02). The clinically least affected patients displayed DV(0)s within the range of those of the control group (19-35 ml/ml). CONCLUSIONS: The finding of an unchanged Kd of flumazenil in patients indicates that the BZR is functionally intact in Huntington's disease. That is, the reduction in DV(0) for BZR represents a selective decrease in the number of striatal BZRs. DV(0) significantly correlated with functional loss and [(123)I]iomazenil-SPECT could be an important tool for validation of the effect of future therapeutic strategies aimed at limiting oxidative stress and free radicals in Huntington's disease.
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Flumazenil , Enfermedad de Huntington/diagnóstico por imagen , Radioisótopos de Yodo , Receptores de GABA-A/análisis , Adulto , Femenino , Flumazenil/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Dipyridamole is used for secondary prophylaxis in ischemic stroke and as a vasodilator agent in myocardial scintigraphy. An important side effect to administering dipyridamole is headache. The aim of the current study was to investigate the effects of dipyridamole on cerebral blood flow, large artery diameter, and headache induction. Twelve healthy subjects were included in this single-blind placebo-controlled study in which placebo (0.9% NaCl) and dipyridamole 0.142 mg/kg x min were administered intravenously over 4 minutes 1 hour apart. Blood flow velocity in the middle cerebral artery (Vmax) was recorded by transcranial Doppler and regional cerebral blood flow in the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133Xenon-inhalation. Blood pressure, heart rate, and pCO2 were measured repeatedly. Headache response was scored every 10 minutes on a verbal scale from 0 to 10 (10 = worst). Dipyridamole caused a decrease in pCO2 (P < 0.001). pCO2 corrected rCBFmca was 41.7 +/- 6.9 mL/100 g x min after placebo versus 41.2 +/- 6.9 after dipyridamole (P > or = 0.05). pCO2 corrected Vmca decreased 8.4% +/- 11.7 (P < 0.001) after dipyridamole, indicating a mean 5.6% +/- 6.7 (P = 0.005) relative increase of the arterial diameter. After dipyridamole the median peak headache score was 2 (range 0 to 7) compared with 0 (range 0 to 3) after placebo (P = 0.02). Dilatation of the middle cerebral artery outlasted the headache response. In conclusion, dipyridamole causes a modest pCO2 independent dilatation of the MCA, which is time-linked to the onset, but not to the cessation, of headache.
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Arterias Cerebrales/efectos de los fármacos , Arterias Cerebrales/fisiopatología , Dipiridamol/administración & dosificación , Cefalea/etiología , Vasodilatadores/administración & dosificación , Adolescente , Adulto , Femenino , Cefalea/fisiopatología , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Vasodilatación/efectos de los fármacosRESUMEN
The vasodilating properties of the non-selective phosphodiesterase (PDE) inhibitor pentoxifylline were evaluated. Pentoxifylline has been reported to increase cerebral blood flow (CBF) and improve recovery rate of stroke patients. Whether these results are due to a dilating effect on arteries or to other mechanisms is not clear. In the present double-blind crossover study, 10 healthy subjects received pentoxifylline 300 mg or placebo intravenously on separate days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial Doppler and rCBF was measured using (133)Xenon-inhalation SPECT. High-frequency ultrasound was used for measurements of temporal and radial artery diameter. Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) concentrations were assessed in plasma. Except for increased heart rate (P < 0.05), systolic blood pressure (P < 0.05) and plasma cAMP (P < 0.001), no significant differences in CBF, rCBF(mca) or plasma cGMP were seen between placebo and pentoxifylline infusion. During pentoxifylline infusion, V(mca) decreased 7.2% (SD 12.0; P < 0.05) and temporal artery diameter increased 9.0% (SD 7.0; P < 0.001), suggesting minor dilatation of the large arteries. However, this change was not significantly different from placebo. In conclusion, pentoxifylline 300 mg had no effect on rCBF. A possible minor dilatation of the middle cerebral artery and the temporal artery cannot be excluded. Any potential clinical effect of pentoxifylline is most likely mediated through non-vascular mechanisms.
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Encéfalo/irrigación sanguínea , Arteria Cerebral Media/fisiología , Pentoxifilina/farmacología , Adulto , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Arteria Cerebral Media/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Proyectos Piloto , Valores de Referencia , Flujo Sanguíneo Regional/efectos de los fármacos , Ultrasonografía Doppler TranscranealRESUMEN
Progression rates of Alzheimer's disease (AD) vary considerably, and they are particularly difficult to predict in patients with mild cognitive impairment. We performed a prospective multicenter cohort study in 186 patients with possible or probable AD, mostly with presenile onset. In a cross-sectional analysis at entry, impairment of glucose metabolism in temporoparietal or frontal association areas measured with positron emission tomography was significantly associated with dementia severity, clinical classification as possible versus probable AD, presence of multiple cognitive deficits and history of progression. A prospective longitudinal analysis showed a significant association between initial metabolic impairment and subsequent clinical deterioration. In patients with mild cognitive deficits at entry, the risk of deterioration was up to 4.7 times higher if the metabolism was severely impaired than with mild or absent metabolic impairment. Copyrightz1999S.KargerAG, Basel
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Neocórtex/metabolismo , Anciano , Algoritmos , Enfermedad de Alzheimer/diagnóstico por imagen , Estudios Transversales , Progresión de la Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neocórtex/diagnóstico por imagen , Pruebas Neuropsicológicas , Pronóstico , Radiofármacos , Caracteres Sexuales , Tomografía Computarizada de EmisiónRESUMEN
The effect of hyperinsulinemia on glucose blood-brain barrier (BBB) transport and cerebral metabolism (CMRglc) was studied using the intravenous double-indicator method and positron emission tomography using [18F]fluorodeoxyglucose as tracer (PET-FDG). Sixteen normal healthy control subjects (25 +/- 4 years old) were studied twice during a euglycemic and a euglycemic-hyperinsulinemic condition. Our hypothesis was that high physiologic levels of insulin did not affect the BBB transport or net metabolism of glucose. During insulin infusion, arterial plasma insulin levels increased from 48.5 to 499.4 pmol/l. The permeability-surface area products for glucose and FDG BBB transport obtained with the double-indicator method remained constant during hyperinsulinemia. Similarly using PET-FDG, no changes were observed in the unidirectional clearance of FDG from blood to brain. k2* (FDG transport from brain to blood) increased significantly by 15 and 18% (gray and white matter, respectively), and k4* (dephosphorylation of FDG) increased by 18%. The increase in k2* may be caused by insulin inducing a decrease in the available FDG brain pool. The increase in k4* may be related to an increased loss of labeled products during insulin fusion. Irrespective of these changes, CMRglc remained unchanged in all brain regions. We conclude that hyperinsulinemia within the normal physiologic range does not affect BBB glucose transport or net cerebral glucose metabolism.
Asunto(s)
Glucemia/metabolismo , Barrera Hematoencefálica/fisiología , Encéfalo/metabolismo , Insulina/sangre , Adulto , Transporte Biológico Activo , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Masculino , Permeabilidad , Radiofármacos/farmacocinética , Valores de Referencia , Distribución Tisular , Tomografía Computarizada de EmisiónRESUMEN
BACKGROUND: This study re-evaluates previously published data on blood-brain barrier transfer coefficients in humans exposed to high insulin levels. DESIGN: In this study of seven volunteers, global blood-brain barrier permeability to glucose and phenylalanine was measured by means of the intracarotid double-indicator method before, during, and after an insulin-glucose clamp. Data were reanalyzed by means of a mathematical model that takes capillary heterogeneity and labelled glucose backflux from the brain into account. RESULTS: The permeability-surface area product (PS) for glucose transport from the blood into the brain, PS1, was 0.145 (0.102-0.211) (median and quartiles), 0.146 (0.113-0.259), and 0.157 (0.133-0.181) ml g-1 min-1 before, during, and after insulin challenge, respectively. In six of the subjects, PS for transport from brain to blood over the brain glucose distribution volume, PS2/Ve decreased under hyperinsulinemia, from a baseline value of 6.56 (3.0-14.9) to 3.86 (1.41-5.32), and restored to a value of 3.8 (2.8-12.1) min-1 after insulin challenge. This decrease in PS2/Ve is probably due to an increase in the brain glucose distribution volume induced by an insulin induced increased intracellular glucose uptake during the experiment. For phenylalanine (n = 5), PS1 was unchanged before, during, and after insulin challenge. In hyperinsulinemia, PS3/Ve for phenylalanine decreased in all subjects. CONCLUSION: We conclude that acutely elevated high plasma insulin levels in humans does not alter the brain uptake of glucose or phenylalanine from the blood. It seems, however, that high plasma insulin levels induce an increase in the movement of D-glucose and L-phenylalanine from the brain interstitial fluid into the intracellular compartment.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Glucosa/metabolismo , Insulina/administración & dosificación , Adolescente , Adulto , Transporte Biológico Activo/efectos de los fármacos , Glucemia/metabolismo , Femenino , Humanos , Insulina/sangre , Cinética , Masculino , Persona de Mediana Edad , Fenilalanina/sangre , Fenilalanina/metabolismoRESUMEN
In the clinical setting it has been shown that activation will increase cerebral glucose uptake in excess of cerebral oxygen uptake. To study this phenomenon further, this study presents an experimental setup that enables precise determination of the ratio between cerebral uptake of glucose and oxygen in the awake rat. Global CBF was measured by the Kety-Schmidt technique, and the ratio between cerebral uptake rates for oxygen, glucose, and lactate was calculated from cerebral arterial-venous differences. During baseline conditions, rats were kept in a closed box designed to minimize interference. During baseline conditions CBF was 1.08 +/- 0.25 mL x g(-1) x minute(-1), and the cerebral oxygen to glucose uptake ratio was 5.5. Activation was induced by opening the sheltering box for 6 minutes. Activation increased CBF to 1.81 mL x g(-1) x minute(-1). During activation cerebral glucose uptake increased disproportionately to cerebral oxygen uptake, and the cerebral oxygen to glucose uptake ratio was 4.2. The accumulated excess glucose uptake during 6 minutes of activation amounted to 2.4 micromol/g. Activation was terminated by closure of the sheltering box. In the postactivation period, the cerebral oxygen to glucose uptake ratio rose to a maximum of 6.4. This response is exactly opposite to the excess cerebral glucose uptake observed during activation.
Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Circulación Cerebrovascular , Glucosa/metabolismo , Consumo de Oxígeno , Animales , Glucemia/metabolismo , Presión Sanguínea , Dióxido de Carbono/sangre , Cinética , Masculino , Oxígeno/sangre , Presión Parcial , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo RegionalRESUMEN
The lumped constant defined as the conversion factor between the net uptake of fluoro-2-deoxy-D-glucose (FDG) and glucose was calculated from global CMRglc and from positron emission tomography (PET) using FDG as tracer (CMRFDG). Fifteen healthy, normal volunteers (mean age 24 +/- 4 years) were studied. Global CBF and CMRglc were measured with the Kety-Schmidt technique using 133Xe as tracer, and values were corrected for errors from incomplete diffusion equilibrium for inert gas tracer between brain tissue and cerebral venous blood. Measurements of CMRFDG were obtained with PET using the dynamic and single-scan methods and the K1-k3 model. Measurements with the Kety-Schmidt technique and PET-FDG were performed simultaneously. Global CBF was 47.1 +/- 8.0 mL.100 g-1.min-1, and CMRglc was 22.8 +/- 4.1 mumol.100 g-1.min-1. No difference in CMRFDG was found with the two methods (17.8 +/- 1.6 and 18.2 +/- 1.3 mumol .100 g-1.min-1, dynamic and single scan methods, respectively). Accordingly, the lumped constant ranged from 0.80 +/- 0.16 to 0.82 +/- 0.15, with a mean value of 0.81 +/- 0.15. The mean ratio between phosphorylation of FDG and glucose (k3*/k3) was 0.39 +/- 0.25. The discrepancy between the lumped constant determined in this study and previously obtained values can be explained partly by methodologic problems, and we conclude that most of the discrepancy results from previous overestimation of global CBF.