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1.
Ann Neurol ; 81(1): 117-128, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27997036

RESUMEN

OBJECTIVE: Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases. METHODS: We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death. RESULTS: The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments. INTERPRETATION: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117-128.


Asunto(s)
Encéfalo/patología , Carbolinas/metabolismo , Tauopatías/patología , Proteínas tau/genética , Anciano , Autorradiografía , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Flúor/metabolismo , Neuroimagen Funcional , Humanos , Masculino , Persona de Mediana Edad , Mutación , Tomografía de Emisión de Positrones , Ensayo de Unión Radioligante , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/patología , Tauopatías/diagnóstico por imagen , Tauopatías/metabolismo , Tritio/metabolismo , Proteínas tau/metabolismo
2.
J Neurol Neurosurg Psychiatry ; 89(10): 1024-1031, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-28986472

RESUMEN

OBJECTIVE: The semantic variant of primary progressive aphasia (svPPA) is typically associated with frontotemporal lobar degeneration (FTLD) with longTAR DNA-binding protein (TDP)-43-positive neuropil threads and dystrophic neurites (type C), and is only rarely due to a primary tauopathy or Alzheimer's disease. We undertook this study to investigate the localisation and magnitude of the presumed tau Positron Emission Tomography (PET) tracer [18F]Flortaucipir (FTP; also known as T807 or AV1451) in patients with svPPA, hypothesising that most patients would not show tracer uptake different from controls. METHODS: FTP and [11C]Pittsburgh compound B PET imaging as well as MRI were performed in seven patients with svPPA and in 20 controls. FTP signal was analysed by visual inspection and by quantitative comparison to controls, with and without partial volume correction. RESULTS: All seven patients showed elevated FTP uptake in the anterior temporal lobe with a leftward asymmetry that was not observed in healthy controls. This elevated FTP signal, largely co-localised with atrophy, was evident on both visual inspection and quantitative cortical surface-based analysis. Five patients were amyloid negative, one was amyloid positive and one has an unknown amyloid status. CONCLUSIONS: In this series of patients with clinical profiles, structural MRI and amyloid PET imaging typical for svPPA, FTP signal was unexpectedly elevated with a spatial pattern localised to areas of atrophy. This raises questions about the possible off-target binding of this tracer to non-tau molecules associated with neurodegeneration. Further investigation with autopsy analysis will help illuminate the binding target(s) of FTP in cases of suspected FTLD-TDP neuropathology.


Asunto(s)
Afasia Progresiva Primaria/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Afasia Progresiva Primaria/metabolismo , Encéfalo/metabolismo , Carbolinas , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen
3.
J Neurol Neurosurg Psychiatry ; 88(6): 491-497, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28416565

RESUMEN

OBJECTIVE: Adverse early-life events are predisposing factors for functional neurological disorder (FND) and post-traumatic stress disorder (PTSD). Cingulo-insular regions are implicated in the biology of both conditions and are sites of stress-mediated neuroplasticity. We hypothesised that functional neurological symptoms and the magnitude of childhood abuse would be associated with overlapping anterior cingulate cortex (ACC) and insular volumetric reductions, and that FND and PTSD symptoms would map onto distinct cingulo-insular areas. METHODS: This within-group voxel-based morphometry study probes volumetric associations with self-report measures of functional neurological symptoms, adverse life events and PTSD symptoms in 23 mixed-gender FND patients. Separate secondary analyses were also performed in the subset of 18 women with FND to account for gender-specific effects. RESULTS: Across the entire cohort, there were no statistically significant volumetric associations with self-report measures of functional neurological symptom severity or childhood abuse. In women with FND, however, parallel inverse associations were observed between left anterior insular volume and functional neurological symptoms as measured by the Patient Health Questionnaire-15 and the Screening for Somatoform Symptoms Conversion Disorder subscale. Similar inverse relationships were also appreciated between childhood abuse burden and left anterior insular volume. Across all subjects, PTSD symptom severity was inversely associated with dorsal ACC volume, and the magnitude of lifetime adverse events was inversely associated with left hippocampal volume. CONCLUSIONS: This study reveals distinct cingulo-insular alterations for FND and PTSD symptoms and may advance our understanding of FND. Potential biological convergence between stress-related neuroplasticity, functional neurological symptoms and reduced insular volume was identified.


Asunto(s)
Corteza Cerebral/diagnóstico por imagen , Maltrato a los Niños/diagnóstico , Maltrato a los Niños/psicología , Trastornos de Conversión/diagnóstico por imagen , Trastornos de Conversión/psicología , Giro del Cíngulo/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador , Imagenología Tridimensional , Imagen por Resonancia Magnética , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/psicología , Trastornos Psicofisiológicos/diagnóstico por imagen , Trastornos Psicofisiológicos/psicología , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/psicología , Adulto , Corteza Cerebral/fisiopatología , Niño , Trastornos de Conversión/fisiopatología , Dominancia Cerebral/fisiología , Femenino , Sustancia Gris/diagnóstico por imagen , Giro del Cíngulo/fisiopatología , Humanos , Acontecimientos que Cambian la Vida , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/fisiopatología , Tamaño de los Órganos/fisiología , Trastornos Psicofisiológicos/fisiopatología , Estadística como Asunto , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/fisiopatología
4.
Neuroimage Clin ; 25: 102115, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31865024

RESUMEN

The middle longitudinal fascicle (MdLF) is a recently delineated association cortico-cortical fiber pathway in humans, connecting superior temporal gyrus and temporal pole principally with the angular gyrus, and is likely to be involved in language processing. However, the MdLF has not been studied in language disorders as primary progressive aphasia (PPA). We hypothesized that the MdLF will exhibit evidence of neurodegeneration in PPA patients. In this study, 20 PPA patients and 25 healthy controls were recruited in the Primary Progressive Aphasia program in the Massachusetts General Hospital Frontotemporal Disorders Unit. We used diffusion tensor imaging (DTI) tractography to reconstruct the MdLF and extract tract-specific DTI metrics (fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity (MD) and axial diffusivity (AD)) to assess white matter changes in PPA and their relationship with language impairments. We found severe WM damage in the MdLF in PPA patients, which was principally pronounced in the left hemisphere. Moreover, the WM alterations in the MdLF in the dominant hemisphere were significantly correlated with impairments in word comprehension and naming, but not with articulation and fluency. In addition, asymmetry analysis revealed that the DTI metrics of controls were similar for each hemisphere, whereas PPA patients had clear laterality differences in MD, AD and RD. These findings add new insight into the localization and severity of white matter fiber bundle neurodegeneration in PPA, and provide evidence that degeneration of the MdLF contribute to impairment in semantic processing and lexical retrieval in PPA.


Asunto(s)
Afasia Progresiva Primaria/patología , Afasia Progresiva Primaria/fisiopatología , Imagen de Difusión Tensora/métodos , Sustancia Gris/patología , Lóbulo Parietal/patología , Lóbulo Temporal/patología , Sustancia Blanca/patología , Anciano , Afasia Progresiva Primaria/diagnóstico por imagen , Femenino , Sustancia Gris/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/patología , Lóbulo Parietal/diagnóstico por imagen , Semántica , Lóbulo Temporal/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen
5.
Cortex ; 94: 27-38, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28711815

RESUMEN

Geschwind Syndrome, a characteristic behavioral syndrome frequently described in patients affected by temporal lobe epilepsy (TLE), consists of the following features: hyper-religiosity, hypergraphia, hyposexuality, and irritability. Here we report the 9-year-clinical course of a case of Geschwind Syndrome that developed as a first and salient clinical expression of right temporal lobe variant of frontotemporal lobar degeneration (FTLD). Only one patient affected by frontotemporal dementia has previously been shown to present with Geschwind Syndrome. MS presented at age 73 with 3 years of personality and behavioral symptoms. Her early symptoms primarily included hyper-religiosity, hypergraphia, and poor emotional regulation (irritability, impulsivity, disinhibition, egocentric behavior). Over nine years, other cognitive functions (word retrieval, memory coding and recall, set-shifting, famous face and building recognition) became affected; however, hyper-religiosity, hypergraphia, and scarce emotional control remained her most prominent deficits. Longitudinal cortical thickness and volumetric analyses revealed early atrophy in the right temporal pole, right amygdala, and right hippocampus, which progressively affected homologous regions in the left hemisphere. The present case describes an unusual clinical picture associated with frontotemporal dementia (FTD), in which the most salient symptoms originated and remained consistent with Geschwind Syndrome.


Asunto(s)
Trastornos del Conocimiento/patología , Emociones/fisiología , Degeneración Lobar Frontotemporal/patología , Lóbulo Temporal/patología , Anciano , Atrofia/complicaciones , Atrofia/diagnóstico por imagen , Atrofia/patología , Atrofia/psicología , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/psicología , Femenino , Degeneración Lobar Frontotemporal/complicaciones , Degeneración Lobar Frontotemporal/diagnóstico por imagen , Degeneración Lobar Frontotemporal/psicología , Humanos , Genio Irritable/fisiología , Estudios Longitudinales , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Tamaño de los Órganos , Lóbulo Temporal/diagnóstico por imagen
6.
JAMA Neurol ; 74(4): 427-436, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28241163

RESUMEN

Importance: Previous postmortem studies have long demonstrated that neurofibrillary tangles made of hyperphosphorylated tau proteins are closely associated with Alzheimer disease clinical phenotype and neurodegeneration pattern. Validating these associations in vivo will lead to new diagnostic tools for Alzheimer disease and better understanding of its neurobiology. Objective: To examine whether topographical distribution and severity of hyperphosphorylated tau pathologic findings measured by fluorine 18-labeled AV-1451 ([18F]AV-1451) positron emission tomographic (PET) imaging are linked with clinical phenotype and cortical atrophy in patients with Alzheimer disease. Design, Setting, and Participants: This observational case series, conducted from July 1, 2012, to July 30, 2015, in an outpatient referral center for patients with neurodegenerative diseases, included 6 patients: 3 with typical amnesic Alzheimer disease and 3 with atypical variants (posterior cortical atrophy, logopenic variant primary progressive aphasia, and corticobasal syndrome). Patients underwent [18F]AV-1451 PET imaging to measure tau burden, carbon 11-labeled Pittsburgh Compound B ([11C]PiB) PET imaging to measure amyloid burden, and structural magnetic resonance imaging to measure cortical thickness. Seventy-seven age-matched controls with normal cognitive function also underwent structural magnetic resonance imaging but not tau or amyloid PET imaging. Main Outcomes and Measures: Tau burden, amyloid burden, and cortical thickness. Results: In all 6 patients (3 women and 3 men; mean age 61.8 years), the underlying clinical phenotype was associated with the regional distribution of the [18F]AV-1451 signal. Furthermore, within 68 cortical regions of interest measured from each patient, the magnitude of cortical atrophy was strongly correlated with the magnitude of [18F]AV-1451 binding (3 patients with amnesic Alzheimer disease, r = -0.82; P < .001; r = -0.70; P < .001; r = -0.58; P < .001; and 3 patients with nonamnesic Alzheimer disease, r = -0.51; P < .001; r = -0.63; P < .001; r = -0.70; P < .001), but not of [11C]PiB binding. Conclusions and Relevance: These findings provide further in vivo evidence that distribution of the [18F]AV-1451 signal as seen on results of PET imaging is a valid marker of clinical symptoms and neurodegeneration. By localizing and quantifying hyperphosphorylated tau in vivo, results of tau PET imaging will likely serve as a key biomarker that links a specific type of molecular Alzheimer disease neuropathologic condition with clinically significant neurodegeneration, which will likely catalyze additional efforts to develop disease-modifying therapeutics.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Carbolinas/metabolismo , Corteza Cerebral/patología , Tomografía de Emisión de Positrones , Proteínas tau/metabolismo , Atrofia/diagnóstico por imagen , Atrofia/etiología , Corteza Cerebral/diagnóstico por imagen , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radiofármacos/metabolismo , Estudios Retrospectivos
7.
Acta Neuropathol Commun ; 5(1): 75, 2017 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-29047416

RESUMEN

[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer's disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptake has also consistently been observed in midbrain, basal ganglia and choroid plexus in elderly individuals regardless of their clinical diagnosis, including clinically normal whose brains are not expected to harbor tau pathology in those areas. We and others have shown that [F-18]-AV-1451 exhibits off-target binding to neuromelanin, melanin and blood products on postmortem material; and this is important for the correct interpretation of PET images. In the present study, we further investigated [F-18]-AV-1451 off-target binding in the first autopsy-confirmed Parkinson's disease (PD) subject who underwent antemortem PET imaging. The PET scan showed elevated [F-18]-AV-1451 retention predominantly in inferior temporal cortex, basal ganglia, midbrain and choroid plexus. Neuropathologic examination confirmed the PD diagnosis. Phosphor screen and high resolution autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of neuromelanin-containing neurons in the substantia nigra, leptomeningeal melanocytes adjacent to ventricles and midbrain, and microhemorrhages in the occipital cortex (all reflecting off-target binding), in addition to incidental age-related neurofibrillary tangles in the entorhinal cortex. Additional legacy postmortem brain samples containing basal ganglia, choroid plexus, and parenchymal hemorrhages from 20 subjects with various neuropathologic diagnoses were also included in the autoradiography experiments to better understand what [F-18]-AV-1451 in vivo positivity in those regions means. No detectable [F-18]-AV-1451 autoradiographic binding was present in the basal ganglia of the PD case or any of the other subjects. Off-target binding in postmortem choroid plexus samples was only observed in subjects harboring leptomeningeal melanocytes within the choroidal stroma. Off-target binding to parenchymal hemorrhages was noticed in postmortem material from subjects with cerebral amyloid angiopathy. The imaging-postmortem correlation analysis in this PD case reinforces the notion that [F-18]-AV-1451 has strong affinity for neurofibrillary tau pathology but also exhibits off-target binding to neuromelanin, melanin and blood components. The robust off-target in vivo retention in basal ganglia and choroid plexus, in the absence of tau deposits, meningeal melanocytes or any other identifiable binding substrate by autoradiography in the PD case reported here, also suggests that the PET signal in those regions may be influenced, at least in part, by biological or technical factors that occur in vivo and are not captured by autoradiography.


Asunto(s)
Carbolinas , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Anciano , Anciano de 80 o más Años , Autorradiografía , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mapeo Encefálico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología
8.
JAMA Neurol ; 73(11): 1334-1341, 2016 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-27654968

RESUMEN

IMPORTANCE: The causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB and PD dementia, but their contribution to these diseases during life is unknown. OBJECTIVE: To contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center's memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET). EXPOSURES: Imaging with fluorine 18-labeled AV-1451 ([18F]AV-1451) (formerly known as [18F]T807), [11C]PiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale. MAIN OUTCOMES AND MEASURES: Main outcomes were differentiation of diagnostic groups on the basis of [18F]AV-1451 binding, the association of [18F]AV-1451 binding with [11C]PiB binding, and the association of [18F]AV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function. RESULTS: In patients with DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased [18F]AV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical [18F]AV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical [11C]PiB retention. For DLB and PD-impaired patients, greater [18F]AV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score. CONCLUSIONS AND RELEVANCE: Patients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau copathology in the Lewy body diseases.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Carbolinas , Disfunción Cognitiva , Enfermedad por Cuerpos de Lewy , Neocórtex/metabolismo , Enfermedad de Parkinson , Tomografía de Emisión de Positrones/métodos , Proteínas tau/metabolismo , Anciano , Compuestos de Anilina , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Estudios Transversales , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neocórtex/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Tiazoles
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