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BACKGROUND AND OBJECTIVES: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. METHODS: Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point. RESULTS: For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years. DISCUSSION: Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.
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Demencia , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiología , Demencia/epidemiología , Demencia/etiología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Prospectivos , Estudios de Cohortes , Factores de Riesgo , Progresión de la Enfermedad , Pruebas Neuropsicológicas , Pruebas de Estado Mental y DemenciaRESUMEN
Background: While breast cancer and its treatments may affect cognition, the longitudinal trajectories of cognition among those receiving differing cancer treatment types remain poorly understood. Prior research suggests hippocampal-prefrontal cortex network integrity may influence cognition, although how this network predicts performance over time remains unclear. Methods: We conducted a prospective trial including 69 patients with early-stage breast cancer receiving adjuvant therapy and 12 controls. Longitudinal cognitive testing was conducted at four visits: pretreatment-baseline, 6-7 months, 14-15 months, and 23-24 months. Cognitive composite scores of episodic memory, executive functioning, and processing speed were assessed at each timepoint. Baseline structural MRI was obtained in a subset of these participants, and hippocampal and prefrontal cortex regional volumes were extracted. Results: Longitudinal linear mixed modeling revealed significant group by time interactions on memory performance, controlling for age and education. Post hoc analyses revealed this effect was driven by patients treated with chemotherapy or chemotherapy plus hormone therapy, who demonstrated the least improvement in memory scores over time. Treatment group did not significantly influence the relationship between time and processing speed or executive functioning. Neither pretreatment hippocampal nor prefrontal volume differed between groups, and there were no significant group by time by baseline regional volume effects on cognition. Conclusion: Patients with early-stage breast cancer treated with chemotherapy or chemotherapy plus hormone therapy benefit less from practice effects seen in healthy controls on memory tests. Loss of longitudinal practice effect may be a new and clinically relevant measure for capturing patients' experience of cognitive difficulties after treatment.
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The development of an α-synuclein imaging agent could be transformative for Parkinson's disease research and drug development. The ability to image α-synuclein in the brain would enable tracking of the degree and location of pathology over time and monitoring of therapies aimed at reducing α-synuclein levels. The Michael J. Fox Foundation has assembled a consortium of researchers to develop an α-synuclein radiotracer for use in positron emission tomography (PET) imaging studies. While this poses a number of challenges they should not be insurmountable and lessons learned from the development of tau radiotracers should provide valuable insights.
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Encéfalo/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , alfa-Sinucleína/metabolismo , Biomarcadores , Investigación Biomédica , Encéfalo/patología , Progresión de la Enfermedad , Diagnóstico Precoz , Humanos , Enfermedad de Parkinson/patología , Radiofármacos , alfa-Sinucleína/químicaRESUMEN
BACKGROUND: Putaminal convection-enhanced delivery (CED) of an adeno-associated virus serotype 2 (AAV2) vector, containing the human aromatic L-amino acid decarboxylase (hAADC) gene for the treatment of Parkinson disease (PD), has completed a phase I clinical trial. OBJECTIVE: To retrospectively analyze magnetic resonance imaging (MRI) and positron emission tomography (PET) data from the phase I trial, correlate those data with similar nonhuman primate (NHP) data, and present how such information may improve future PD gene therapy trials in preparation for the initiation of the phase II trial. METHODS: Ten patients with PD had been treated with bilateral MRI-guided putaminal infusions of AAV2-hAADC. MRI and PET scans were obtained at baseline (before vector administration) and at various intervals after treatment. Three normal adult NHPs received similar infusions into the thalamus. Imaging studies for both groups are presented, as well as hAADC immunohistochemistry for the NHPs. RESULTS: Early post-CED MRI confirmed the stereotactic targeting accuracy and revealed T2 hyperintensity around the distal cannula tracts, best seen within 4 hours of surgery. Coregistration of post-CED MRI and PET scans revealed increased PET uptake at the sites of T2 hyperintensity. Similar T2 hyperintensities in NHP MRI correlated with hAADC immunohistochemistry. CONCLUSION: Our analysis confirms the correct targeting of the CED cannula tracts within the target human putamen. Coregistration of MRI and PET confirms colocalization of T2 hyperintensities and increased PET uptake around the distal cannula tracts. Because PET uptake closely correlates with hAADC transgene expression and NHP data confirm this relationship between T2 hyperintensity and hAADC immunohistochemistry, we believe that T2-weighted MRI allows visualization of a significant part of the distribution volume of the hAADC gene therapy. Recommendations for future protocols based on these data are presented.
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Descarboxilasas de Aminoácido-L-Aromático/uso terapéutico , Dependovirus/genética , Terapia Genética/métodos , Imagen por Resonancia Magnética/métodos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/terapia , Tomografía de Emisión de Positrones/métodos , Anciano , Descarboxilasas de Aminoácido-L-Aromático/genética , Femenino , Vectores Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Imagen Molecular/métodos , Enfermedad de Parkinson/genética , Resultado del TratamientoRESUMEN
This study completes the longest known in vivo monitoring of adeno-associated virus (AAV)-mediated gene expression in nonhuman primate (NHP) brain. Although six of the eight parkinsonian NHP originally on study have undergone postmortem analysis, as described previously, we monitored the remaining two animals for a total of 8 years. In this study, NHP received AAV2-human L-amino acid decarboxylase (hAADC) infusions into the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned putamen. Restoration of AADC activity restored normal response to levodopa and gene expression could be quantitated repeatedly over many years by 6-[(18)F]fluoro-meta-tyrosine (FMT)-positron emission tomography (PET) and confirm that AADC transgene expression remained unchanged at the 8-year point. Behavioral assessments confirmed continued, normalized response to levodopa (improvement by 35% over historical controls). Postmortem analysis showed that, although only 5.6 + or - 1% and 6.6 + or - 1% of neurons within the transduced volumes of the striatum were transduced, this still secured robust clinical improvement. Importantly, there were no signs of neuroinflammation or reactive gliosis at the 8-year point, indicative of the safety of this treatment. The present data suggest that the improvement in the L-3,4-dihydroxyphenylalanine (L-Dopa) therapeutic window brought about by AADC gene therapy is pronounced and persistent for many years.
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Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Dependovirus/genética , Macaca mulatta/metabolismo , Animales , Descarboxilasas de Aminoácido-L-Aromático/genética , Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Inmunohistoquímica , Levodopa/metabolismo , Masculino , Microscopía FluorescenteRESUMEN
We investigated the safety and neuroregenerative potential of an adeno-associated virus (AAV2) containing human glial cell line-derived neurotrophic factor (GDNF) in an MPTP primate model of Parkinson's disease. Dopaminergic function was evaluated by positron emission tomography with 6-[(18)F]fluoro-l-m-tyrosine (FMT) before and after AAV2-GDNF or phosphate-buffered saline infusion bilaterally into the putamen. FMT uptake was significantly increased bilaterally in the putamen of AAV2-GDNF but not phosphate-buffered saline-treated animals 6 months after infusion, indicating increased dopaminergic activity in the nigrostriatal pathways. AAV2-GDNF-treated animals also showed clinical improvement without adverse effects. These findings are consistent with our previous report in aged nonhuman primates that showed evidence of enhanced use of striatal dopamine and dopaminergic nigrostriatal innervation. Clinical improvement and evidence of functional recovery in the nigrostriatal pathway, and the absence of adverse effects, support the safety of this approach for the delivery of GDNF over a 6-month period.
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Terapia Genética , Vectores Genéticos/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/terapia , Sustancia Negra/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Macaca mulatta , Masculino , Enfermedad de Parkinson/patología , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Although positron emission tomography (PET) and the aromatic L-amino acid decarboxylase (AADC) tracer 6-[(18)F]fluoro-L-m-tyrosine (FMT) has been used to assess the integrity of the presynaptic dopamine system in the brain, relatively little has been published in terms of brain FMT uptake values especially for normal human subjects. Twelve normal volunteer subjects were scanned using PET and FMT to determine the range of normal striatal uptake values using Patlak graphical analysis. For comparison, seven adult rhesus monkeys were studied and the data analyzed in the same way. A subset of monkeys that were treated with a unilateral intracarotid artery infusion of the dopamine neurotoxin MPTP showed an 87% decrease in striatal FMT uptake. These findings support the use of PET and FMT to image AADC distribution in both normal and diseased brains using Patlak graphical analysis and tissue input functions.
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Dopamine, the major neurotransmitter depleted in Parkinson disease, can be synthesized and regulated in vivo with a combination of intrastriatal AAV-hAADC gene therapy and administration of the dopamine precursor l-Dopa. When tested in MPTP-lesioned monkeys, this approach resulted in long-term improvement in clinical rating scores, significantly lowered l-Dopa requirements, and a reduction in l-Dopa-induced side effects. Positron emission tomography with [(18)F]FMT confirmed persistent AADC activity, demonstrating for the first time that infusion of AAV vector into primate brain results in at least 6 years of transgene expression. AAV-hAADC restores the ability of the striatum to convert l-Dopa into dopamine efficiently. Introduction of this therapy into the clinic holds promise for Parkinson patients experiencing the motor complications that result from escalating l-Dopa requirements against a background of disease progression.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Dependovirus/genética , Terapia Genética , Enfermedades de los Primates/genética , Enfermedades de los Primates/terapia , Animales , Descarboxilasas de Aminoácido-L-Aromático/genética , Conducta Animal , Expresión Génica , Humanos , Inmunohistoquímica , Levodopa/farmacología , Macaca mulatta , Masculino , Tomografía de Emisión de Positrones , Enfermedades de los Primates/inducido químicamente , Enfermedades de los Primates/metabolismo , Factores de TiempoRESUMEN
The main medication for idiopathic Parkinson disease is L-Dopa. Drug efficacy declines steadily in part because the converting enzyme, aromatic L-amino acid decarboxylase (AADC), is lost concomitant with substantia nigra atrophy. Over the past decade, we have developed a gene therapy approach in which AADC activity is restored to the brain by infusion into the striatum of a recombinant adeno-associated virus carrying human AADC cDNA. We report here the results of an investigation of the relationship between vector dose and a series of efficacy markers, such as PET, L-Dopa response, and AADC enzymatic activity. At low doses of vector, no effect of vector was seen on PET or behavioral response. At higher doses, a sharp improvement in both parameters was observed, resulting in an approximate 50% improvement in L-Dopa responsiveness. The relationship between vector dose and AADC enzymatic activity in tissue extracts was linear. We conclude that little behavioral improvement can be seen until AADC activity reaches a level that is no longer rate limiting for conversion of clinical doses of L-Dopa into dopamine or for trapping of the PET tracer FMT. These findings have implications for the design and interpretation of clinical studies of AAV-hAADC gene therapy.
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Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Dependovirus/genética , Terapia Genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Animales , Descarboxilasas de Aminoácido-L-Aromático/genética , Conducta Animal , Humanos , Macaca mulatta , Enfermedad de Parkinson/enzimología , Tomografía de Emisión de Positrones , Factores de TiempoRESUMEN
Striatal neurons convert L-dopa to dopamine (DA) following gene transfer of aromatic L-amino acid decarboxylase (AADC) via adeno-associated virus (AAV) in parkinsonian monkeys. We investigated whether AAV-AADC could reduce or eliminate L-dopa-induced dyskinesias (LIDs) and side effects in MPTP-treated monkeys. Five monkeys were made parkinsonian by bilateral MPTP lesions. The optimal therapeutic dose of L-dopa was determined using an acute dose response regimen. After 3 weeks of chronic L-dopa treatment, AAV-AADC or control vector was bilaterally injected into the striatum. Animals were assessed for 6 months with the same L-dopa dosing as presurgery as well as chronic oral L-dopa treatment. Presurgery LID was observed at doses greater than 5 mg/kg. The AAV-AADC-treated animals displayed an average 7.3-fold decrease in the therapeutic dose of L-dopa throughout the 6-month follow-up period. Only AAV-AADC-treated monkeys were susceptible to dyskinesias even at sub-clinical doses. Immunohistochemical analysis revealed well-delineated foci of AADC within the striatum. These results suggest that high levels of focal DA were generated in response to L-dopa administration and may be responsible for the exacerbation of dyskinesias. This may be similar to focal dopaminergic activity in PD patients that developed off-drug or "runaway" dyskinesias following fetal mesencephalic grafts.
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Antiparkinsonianos/efectos adversos , Dopamina/efectos adversos , Levodopa/efectos adversos , Neuronas/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Animales , Antiparkinsonianos/administración & dosificación , Descarboxilasas de Aminoácido-L-Aromático/fisiología , Conducta Animal/fisiología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Dependovirus/fisiología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Técnicas de Transferencia de Gen , Inmunohistoquímica/métodos , Levodopa/administración & dosificación , Intoxicación por MPTP/complicaciones , Intoxicación por MPTP/tratamiento farmacológico , Macaca mulatta , Imagen por Resonancia Magnética/métodos , Enfermedad de Parkinson Secundaria/patología , Tomografía de Emisión de Positrones/métodos , Factores de TiempoRESUMEN
BACKGROUND: Subcortical ischemic vascular dementia has been ascribed to prominent frontal lobe dysfunction secondary to ischemic lesions in frontothalamic circuits. Whether small-vessel disease in fact predominantly affects the frontal lobes is not well documented. OBJECTIVE: To investigate the effects of subcortical lesions (lacunes and white matter lesions [WML]) on cortical function, as reflected in glucose metabolism and cognitive function, in elderly individuals. DESIGN: Cross-sectional analyses of case series. SETTING: Multicenter, university-based study of subcortical vascular dementia. PATIENTS: Persons with normal cognition, mild cognitive impairment, or dementia and with and without lacunes on magnetic resonance images. MAIN OUTCOME MEASURES: Regional cerebral glucose metabolism, normalized regional metabolic activity, and neuropsychological test scores. Major hypotheses were that volume of lacunes and WML correlate selectively with hypometabolism of prefrontal cortex and failure of executive cognitive ability. RESULTS: Lacunes correlated with metabolic rates in dorsolateral frontal cortex (DLF); WML substantially reduced metabolic rates throughout cortex, most strongly so in DLF. When regional metabolic activity was normalized to whole brain activity, lacunes remained correlated with DLF activity, whereas the WML effect was no longer found, probably because of its general distribution. Regional cerebral glucose metabolism and normalized activity in DLF also correlated with cortical atrophy. Metabolic activity in DLF correlated with executive function, memory, and global cognitive function, while activity in middle temporal gyrus correlated with memory and global function but not executive function. CONCLUSIONS: The metabolic effects of lacunes and WML are most apparent in DLF, but the effects of WML are generalized and frontal hypometabolism correlates with memory and global impairment, cognitive as well as executive function. The effects of subcortical cerebrovascular disease appear to converge on the frontal lobes but are diffuse, complex, and of modest magnitude.
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Infarto Encefálico/fisiopatología , Corteza Cerebral/fisiología , Trastornos del Conocimiento/fisiopatología , Demencia Vascular/fisiopatología , Anciano , Anciano de 80 o más Años , Infarto Encefálico/metabolismo , Infarto Encefálico/patología , Mapeo Encefálico , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Estudios Transversales , Demencia Vascular/metabolismo , Demencia Vascular/patología , Metabolismo Energético/fisiología , Femenino , Glucosa/metabolismo , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Pruebas Neuropsicológicas/estadística & datos numéricos , Tomografía de Emisión de Positrones/métodos , Solución de Problemas/fisiología , Estadística como AsuntoRESUMEN
PET and [18F]fluoro-L-m-tyrosine (FMT) have been used to quantify presynaptic striatal dopamine (DA) function in Parkinson disease (PD) and in primate models of PD. While dynamic imaging and a metabolite-corrected blood input function can be used to determine striatal FMT uptake rate constants (Ki), a simpler analytic approach using shorter imaging times is desirable for clinical studies. We compared the utility of using striatal Ki values versus striatal count ratios in two groups of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Striatal DA content was also measured in one of the groups to evaluate the relationship between the PET measures and an independent measure of striatal dopamine. Striatal Ki values were significantly correlated with striatal count ratios using the cerebellum as the denominator. Both Ki values and ratios were also correlated with striatal DA content. In addition, putamen-cerebellum ratios and putamen Ki values showed similar separation between baseline and post-MPTP values. These findings suggest that a simple ratio approach to analyzing FMT PET data may be a useful alternative to a kinetic approach especially for clinical applications.
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Cuerpo Estriado/diagnóstico por imagen , Dopamina/metabolismo , Procesamiento de Imagen Asistido por Computador/métodos , Trastornos Parkinsonianos/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Terminales Presinápticos/diagnóstico por imagen , Tirosina/análogos & derivados , Animales , Cerebelo/diagnóstico por imagen , Dominancia Cerebral/fisiología , Radioisótopos de Flúor/farmacocinética , Macaca mulatta , Putamen/diagnóstico por imagen , Estadística como Asunto , Tirosina/farmacocinéticaRESUMEN
We sought to identify magnetic resonance- (MR)-imaged structures associated with declarative memory in a community-dwelling sample of elderly Mexican-American individuals with a spectrum of cognitive decline. Measured structures were the hemispheric volumes of the hippocampus (HC), parahippocampal gyrus, and remaining temporal lobes, as well as severity of white matter signal hyperintensities (WMH). Participants were an imaged subsample from the Sacramento Area Latino Study of Aging (SALSA), N = 122. Individuals were categorized as normal, memory impaired (MI), cognitively impaired non-demented (CIND), or demented. We show that WMH was the strongest structural predictor for performance on a delayed free-recall task (episodic memory) in the entire sample. The association of WMH with delayed recall was most prominent in elderly normals and mildly cognitively impaired individuals with no dementia or impairment of daily function. However, the left HC was associated with verbal delayed recall only in people with dementia. The right HC volume predicted nonverbal semantic-memory performance. We conclude that WMH are an important pathological substrate that affects certain memory functions in normal individuals and those with mild memory loss and discuss how tasks associated with WMH may rely upon frontal lobe function.
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Envejecimiento/fisiología , Memoria/fisiología , Características de la Residencia , Anciano , Anciano de 80 o más Años , Encéfalo/fisiología , Demencia/patología , Demencia/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos de la Memoria/fisiopatología , Americanos Mexicanos , Persona de Mediana Edad , Pruebas Neuropsicológicas , Análisis de RegresiónRESUMEN
OBJECTIVE: Abnormal cutaneous vasodilatory responses to the iontophoresis of vasodilators were previously observed in Alzheimer's disease (AD). We sought to replicate these observations and further identify peripheral vascular components of AD pathology. METHODS: Methacholine chloride (MCh), acetylcholine chloride (ACh), and sodium nitroprusside (SNP) were applied iontophoretically to forearm skin. Laser Doppler imaging of treated areas yielded total perfusion response values. RESULTS: Response to MCh was enhanced 78% ( P=0.003 ) in AD subjects under therapy with the acetylcholinesterase inhibitor (AChEI) donepezil ( N=9 ), relative to age- and sex-matched controls ( N=12 ). Significant increases in perfusion were also observed after application of ACh (68%, P=0.03 ) and SNP (46%, P=0.04 ). CONCLUSIONS: A previous study reported attenuated response to ACh in AD. Paradoxically, we observed a substantially enhanced response that is likely a consequence of donepezil therapy. The increased response to the endothelium-independent vasodilator SNP indicates improved general vasodilatory response, perhaps due to preservation of endogenous ACh by donepezil. Cerebral perfusion in response to functional activation may be improved in this way, suggesting a secondary therapeutic mode of donepezil.
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Enfermedad de Alzheimer/tratamiento farmacológico , Indanos/uso terapéutico , Piperidinas/uso terapéutico , Piel/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Análisis de Varianza , Donepezilo , Sinergismo Farmacológico , Femenino , Humanos , Indanos/farmacología , Masculino , Persona de Mediana Edad , Piperidinas/farmacología , Vasodilatación/fisiologíaRESUMEN
We evaluated the effects of estrogen and tamoxifen, a selective estrogen receptor modulator, on positron emission tomography (PET) measures of brain glucose metabolism and magnetic resonance imaging (MRI) measures of hippocampal atrophy. Three groups of postmenopausal women were studied, women taking estrogen (ERT+), women with breast cancer taking tamoxifen (TAM), and women not taking estrogen or tamoxifen (ERT-). All subjects received a PET scan, an MRI scan, and cognitive testing. The TAM group showed widespread areas of hypometabolism in the inferior and dorsal lateral frontal lobes relative to the other two groups. The ERT- group showed lower metabolism in the inferior frontal cortex and temporal cortex with respect to the ERT+ group. The TAM group also showed significantly lower semantic memory scores than the other two groups. Finally, the TAM group had smaller right hippocampal volumes than the ERT+ group, an effect that was of borderline significance. Both right and left hippocampal volumes were significantly smaller than the ERT+ group when a single outlier was removed. The ERT- group had hippocampal volumes that were intermediate to the other two groups. These findings provide physiological and anatomical evidence for neuroprotective effects of estrogen.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Corteza Cerebral/efectos de los fármacos , Terapia de Reemplazo de Estrógeno , Hipocampo/efectos de los fármacos , Imagen por Resonancia Magnética , Tamoxifeno/uso terapéutico , Tomografía Computarizada de Emisión , Anciano , Antineoplásicos Hormonales/efectos adversos , Atrofia , Atención/efectos de los fármacos , Glucemia/metabolismo , Corteza Cerebral/patología , Aprendizaje Discriminativo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Femenino , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/patología , Hipocampo/patología , Humanos , Memoria a Corto Plazo/efectos de los fármacos , Persona de Mediana Edad , Pruebas Neuropsicológicas , Reconocimiento Visual de Modelos/efectos de los fármacos , Tamoxifeno/efectos adversos , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/patología , Aprendizaje Verbal/efectos de los fármacosRESUMEN
Monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been widely used as animal models of Parkinson's disease (PD). Depending on the method of administration different PD models can be developed. Systemic (iv, sc.) MPTP administration can induce an advanced parkinsonian syndrome. However, systemic administration may require intensive animal care after neurotoxin administration, as well as repeated high doses of MPTP to avoid spontaneous recovery. Unilateral intracarotid artery (ICA) MPTP administration induces a stable hemiparkinsonian syndrome, with the advantage of allowing the animal to groom and feed itself and having a control side in the same animal. However, this unilateral syndrome lacks the bilateral characteristics of advanced PD. Bilateral ICA administration can induce a reliable bilateral syndrome but inherent is the risk of severely impairing the animals and leaving them unable to maintain themselves. This report analyzed the PD model induced by administration of unilateral ICA and subsequent intravenous injections of MPTP in rhesus monkeys. The combined method of MPTP administration induces an advanced stable parkinsonian syndrome, in which the ICA injection of MPTP initiates the parkinsonian syndrome primarily in one hemisphere and the subsequent iv. doses (administered as needed) further deplete the dopamine (DA) system to induce a bilateral lesion in a shorter period of time, with fewer side effects. We studied the relationships between the behavioral, biochemical and histochemical changes related to the combined MPTP treatments to further characterize this model. The monkeys were categorized as presenting mild (stage 2) or moderate (stage 3) parkinsonism based on a parkinsonian rating scale. Postmortem biochemical analysis showed massive DA reduction equally in the caudate nucleus and putamen ipsilateral to ICA MPTP infusion, with varying degrees of DA preservation in the contralateral striatum. Differences between stage 2 and stage 3 were attributed to DA concentrations in the caudate nucleus and putamen of the contralateral hemisphere. Tyrosine hydroxylase immunohistochemistry revealed that the midbrain DA neurons of the group A8, A9, and A10 showed differential vulnerability for MPTP. This finding was similar to that observed in idiopathic PD with significant relationships between the clinical stages and cell losses in the group A9 (substantia nigra pars compacta). Positron emission tomography (PET) using [18F] 6-fluoro-L-m- tyrosine (FMT) showed that uptake (Ki) values correlated well with the biochemical data and are good predictors of DA levels in the contralateral striatal regions. Consistent with the immunohistochemical analysis, PET data also showed significant correlations with all groups of the DA cells. Here we describe an animal model that can play an important role in understanding the symptoms and therapeutic basis of PD since different severities of parkinsonian symptoms can be mimicked.
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Modelos Animales de Enfermedad , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/patología , Tirosina/análogos & derivados , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica/efectos de los fármacos , Arterias Carótidas , Cuerpo Estriado/química , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Dopamina/análisis , Femenino , Radioisótopos de Flúor/metabolismo , Histocitoquímica , Humanos , Inyecciones Intraarteriales , Macaca mulatta , Masculino , Neuroquímica , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/fisiopatología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Tomografía Computarizada de Emisión/métodos , Tirosina/metabolismo , Tirosina 3-MonooxigenasaRESUMEN
There is a growing body of evidence suggesting that Alzheimer's disease (AD) and cerebrovascular disease (CVD), two common disorders of aging, are related in ways that extend beyond their coincident co-occurrence. Thus, there is a need to understand how the two pathological processes interact to contribute to dementia. In this article, we review two recent studies from our laboratory that use MRI and PET to begin to reveal the nature and mechanisms of the relationship between AD, CVD, and dementia.
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Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo/patología , Trastornos Cerebrovasculares/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Encéfalo/diagnóstico por imagen , Trastornos Cerebrovasculares/patología , Humanos , CintigrafíaRESUMEN
Nonimmunosuppressant immunophilin ligands have been shown to have neurotrophic properties in rodent models of Parkinson's disease (PD), although little is known about the effects of these ligands in primates. The immunophilin ligand, GPI-1046, promotes the regeneration of dopamine (DA) cells in association with functional recovery in rodent models. We explored the regenerative effects of GPI-1046 in an MPTP primate model of PD. We used single photon emission computed tomography (SPECT) and the DA transporter tracer (DAT), [(123)I]beta-CIT, to evaluate DAT density and clinical recovery before and after treatment with GPI-1046 or vehicle. Subsequent histological studies were also performed. No effects of GPI-1046 were found on any of these measures. These findings show that GPI-1046 does not have regenerative effects in MPTP-treated primates and suggest that there may be species differences with respect to the trophic effects of GPI-1046 on nigrostriatal DA neurons.
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Inmunofilinas/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Regeneración Nerviosa/efectos de los fármacos , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Animales , Inmunofilinas/farmacología , Inmunofilinas/uso terapéutico , Ligandos , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/fisiopatología , Macaca mulatta , Regeneración Nerviosa/fisiología , Pirrolidinas/metabolismoRESUMEN
Evidence from both animals and humans supports a neuroprotective role of oestrogen. Epidemiological studies showing that oestrogen improves cognitive performance in postmenopausal women, clinical trials showing effects of oestrogen on cognition and data suggesting that oestrogen reduces the risk of Alzheimer's disease (AD) led to the proposal that oestrogen may be effective for improving symptoms or slowing decline in women with AD. Studies evaluating oestrogen as a treatment for AD have been performed with mixed findings. While a few studies have found modest improvements, the results have largely been disappointing. However, many of the studies suffer from substantial methodological problems that leave the findings in question. The role of oestrogen for the prevention or treatment of AD is not yet clear, but large, well-controlled, ongoing trials should provide definitive answers to many questions in the near future.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Estrógenos/uso terapéutico , Fármacos Neuroprotectores/farmacología , Encéfalo/patología , Cognición/efectos de los fármacos , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria/efectos de los fármacos , Modelos Químicos , Posmenopausia , RiesgoRESUMEN
A variety of studies have shown an effect of estrogen on dopamine function and suggest that estrogen may modulate central dopaminergic activity. Positron emission tomography (PET) and the dopamine metabolism tracer, [18F]6-fluoro-L-m-tyrosine (FMT) were used to evaluate dopaminergic function in the frontal cortex and striatum in six aged, but pre-menopausal, female monkeys before and after ovariectomy (OVX). Dynamic PET brain uptake data and metabolite-corrected blood input functions were fit to a three-compartment model for FMT uptake. Prior to OVX, all animals showed preferential accumulation of the tracer bilaterally in the striatum and less but measurable activity in the frontal cortex. Paired comparisons showed that there were no significant differences in FMT uptake (K(i)) in either brain region before and after OVX. In addition, FMT uptake did not differ from a group of young adult female monkeys at either time point. These findings may represent a compensatory up-regulation of aromatic L- amino acid decarboxylase (AADC) activity.