Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease : additional results from the AMBAR study

This study was designed to detect structural and functional brain changes in Alzheimer's disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) were performed. MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18 FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG. (AMBAR trial registration: EudraCT#: 2011-001,598-25; ClinicalTrials.gov ID: NCT01561053). The online version contains supplementary material available at 10.1007/s00259-022-05915-

Cortical metabolic and structural differences in patients with chronic migraine. An exploratory 18FDG-PET and MRI study

Migranya crònica; Gruix cortical; NeuroimatgeMigraña crónica; Espesor cortical; NeuroimagenChronic migraine; Cortical thickness; NeuroimagingBackground To describe interictal brain structural and metabolic differences between patients with episodic migraine (EM), chronic migraine (CM) and healthy controls (HC). Methods This is an exploratory study including right-handed age-matched women with EM, CM and HC. On the same day, a sequential interictal scan was performed with 18FDG-PET and MRI. 3D T1-weighted images were segmented with FreeSurfer, normalized to a reference atlas and the mean values of metabolism, cortical thickness (CTh) and local gyrification index (IGI) were determined. Groups were compared using age-adjusted linear models, corrected for multiple comparisons. 18FDG-PET measurements between groups were also analysed adjusting by patient’s age, CTh and lGI. The variables independently associated with diagnosis were obtained using a logistic regression analysis. Results Fifteen patients (8 EM, 7 CM) and 11 HC were included. Morphometric data showed an increased CTh in 6 frontal areas (L/R-Caudal Middle Frontal, L/R-Rostral Middle Frontal, L-Medial Orbitofrontal and L-Superior Frontal) in CM patients compared to HC without differences for IGI. The structural adjusted analysis in CM showed a statistically significantly hypometabolism in 9 frontal areas (L-Lateral Orbitofrontal, L/R-Medial Orbitofrontal, L-Frontal Superior, R-Frontal pole, R-Parts Triangularis, L/R-Paracentral and R-Precentral) and 7 temporal areas (L/R-Insula, L/R-Inferior temporal, L/R-Temporal pole and R-Banks superior temporal sulcus) compared to HC. EM patients presented intermediate metabolic values ​​between EM and HC (non-significant). Conclusions CM patients showed frontotemporal hypometabolism and increased frontal cortical thickness when compared to HC that may explain some cognitive and behavioural pain-processing and sensory integration alterations in CM patients. Combined information from sequential or simultaneous PET and MRI could optimize the study of complex functional neurological disorders such as migraine.The project leading to these results has received funding The Headache Study Group Grant 2016 of Spanish Neurological Society and Mutual Medica Grant 2016 and “La Caixa” Foundation under the project code LCF/PR/PR16/151110005

Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin

Altres ajuts: This study was funded by Grifols. [...] James T. Becker (Department of Psychiatry, Neurology and Psychology. University of Pittsburgh, Pittsburgh PA, USA) read and commented on an earlier draft of the manuscript. Jordi Bozzo PhD, CMPP (Grifols) is acknowledged for medical writing and editorial assistance in the preparation of the manuscript.Recently, modifications of Aβ levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. Patients received between 3 and 18 PE with albumin (Albutein ® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam ®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion

Papel de la imagen molecular con PET-FDG cerebral como biomarcador en pacientes con enfermedad de Alzheimer

Introducció: La demència afecta a més de 50 milions de persones a tot el món; la forma més comú és la Malaltia d'Alzheimer (MA) i és una de les causes principals de discapacitat i dependència en els adults. Actualment no hi ha tractament curatiu per a la malaltia, encara que hi ha diverses teràpies en estudi. AMBAR, és un tractament destinat a reduir la progressió de la MA a través del recanvi plasmàtic periòdic. Les tècniques de neuroimatge ofereixen informació estructural i funcional sobre el sistema nerviós central. La interpretació qualitativa de les imatges de PET-FDG ofereix un bon rendiment diagnòstic per a la pràctica clínica habitual, però no té una bona reproductibilitat interobservador i no permet determinar exactament el grau d'afectació de la malaltia més enllà d'una escala categòrica. L'anàlisi quantitativa permet obtenir mesures numèriques fiables i reproduïbles. Les eines existents requereixen personal experimentat i extreuen una gran quantitat de paràmetres que són difícils d'interpretar. Objectiu: Estudiar el defecte inicial, la progressió de pèrdua metabòlica i les diferències entre grups de tractament en la població de l'assaig clínic AMBAR (pacients amb MA lleu i moderada), mitjançant un nou mètode de quantificació. Material i Mètodes: AMBAR és un estudi prospectiu, aleatoritzat i controlat realitzat a 41 centres d'Espanya i Estats Units. S'hi van incloure 322 pacients (54% van ser dones), edat mitjana 69,0 ± 7,7 anys, amb MA lleu o moderada. Van ser aleatoritzats i assignats a l'atzar a 4 braços, tres grups amb tractament (A,B,C) i un grup placebo. A tots ells se'ls va realitzar un PET-FDG i una RM a l'inici i al finalitzar el tractament (als 14 mesos). Es va dissenyar el mètode ImEdS, basat en SPM i anàlisi de volums d'interès, amb el que es van crear imatges paramètriques i biomarcadors relacionats amb el metabolisme, el percentatge i la severitat de defecte metabòlic com a indicadors de fàcil interpretació del dany neuronal. Es va crear una base de dades de referència normal i es van determinar els llindars de normalitat per als biomarcadors. Resultats: ImEdS va mostrar valors de rendiment diagnòstic superiors al 89% (amb una Sensibilitat>89% i una Especificitat>91% per als tres biomarcadors), millorant l'anàlisi visual i obtenint resultats d'interpretació equivalents a l'anàlisi amb SPM. Es va trobar un patró inicial d'alteració metabòlica i una progressió de pèrdua metabòlica significativa entre els dos punts temporals (principalment en cingulat posterior i les escorces parietotemporal i estenent-se a l'escorça frontal) a tots els grups de tractament. Els pacients amb EA lleu van presentar poques pèrdues i en poques àrees, a diferència dels pacients amb EA moderada, que van presentar una pèrdua important de metabolisme, més extensa i intensa, amb més severitat dels territoris posteriors i estenent-se a territoris anteriors. De tots els grups de tractament, el C, és el que va mostrar menor progressió entre els dos punts temporals. Això suggereix que aquest és el que mostra una major eficàcia, amb un alentiment de la pèrdua de metabolisme cerebral en relació amb el patró d'evolució de la MA. Conclusions: L'anàlisi amb ImEdS va permetre mesurar de manera objectiva l'evolució temporal i la resposta a un tractament d'una població amb MA lleu a moderada, a través de la combinació d'imatges paramètriques i la integració d'aquestes troballes en 3 mesures simples que actuen com biomarcadors de la neurodegeneració. Això és especialment interessant per correlacionar amb altres variables clíniques o terapèutiques i podria permetre identificar aquells factors relacionats amb la resposta al tractament. És una eina amb potencial d'aplicabilitat clínica alt especialment per a professionals menys especialitzats, per a pacients incipients i/o pacients amb seguiment longitudinal.Introducción: La demencia afecta a más de 50 millones de personas en todo el mundo; la forma más común es la Enfermedad de Alzheimer (EA) y es una de las principales causas de discapacidad y dependencia en los adultos. Actualmente no existe tratamiento curativo para la enfermedad, aunque hay varias terapias en estudio. AMBAR, es un tratamiento destinado a reducir la progresión de la EA a través del recambio plasmático periódico. Las técnicas de neuroimagen ofrecen información estructural y funcional sobre el sistema nervioso central. La interpretación cualitativa de las imágenes de PET-FDG ofrece un buen rendimiento diagnóstico para la práctica clínica habitual, pero carece de una buena reproductibilidad interobservador y no permite determinar exactamente el grado de afectación de la enfermedad más allá de una escala categórica. El análisis cuantitativo permite obtener mediciones numéricas fiables y reproducibles. Las herramientas existentes requieren de personal experimentado y extraen una gran cantidad de parámetros que son difíciles de interpretar. Objetivo: Estudiar el defecto inicial, la progresión de pérdida metabólica y las diferencias entre grupos de tratamiento en la población del ensayo clínico AMBAR (pacientes con EA leve y moderada), mediante un nuevo método de cuantificación. Material y Métodos: AMBAR es un estudio prospectivo, aleatorizado y controlado realizado en 41 centros de España y Estados Unidos. Se incluyeron 322 pacientes (54% fueron mujeres), edad promedio 69,0 ± 7,7 años, con EA leve o moderada. Fueron aleatorizados y asignados al azar en 4 brazos, tres grupos con tratamiento (A,B,C) y un grupo placebo. A todos ellos se les realizó un PET-FDG y una RM al inicio y al finalizar el tratamiento (a los 14 meses). Se diseñó el método ImEdS, basado en SPM y análisis de volúmenes de interés, con el que se crearon imágenes paramétricas y biomarcadores relacionados con el metabolismo, el porcentaje y la severidad de defecto metabólico como indicadores de fácil interpretación del daño neuronal. Se creó una base de datos de referencia normal y se determinaron los umbrales de normalidad para los biomarcadores. Resultados: ImEdS mostró valores de rendimiento diagnóstico superiores al 89% (con una Sensibilidad>89% y una Especificidad>91% para los tres biomarcadores), mejorando el análisis visual y obteniendo resultados de interpretación equivalentes al análisis con SPM. Se encontró un patrón inicial de alteración metabólica y una progresión de pérdida metabólica significativa entre los dos puntos temporales (principalmente en cingulado posterior y las cortezas parietotemporal y extendiéndose a córtex frontal) en todos los grupos de tratamiento. Los pacientes con EA leve presentaron pocas pérdidas y en pocas áreas, a diferencia de los pacientes con EA moderada, que presentaron una pérdida importante de metabolismo, más extensa e intensa, con mayor severidad de los territorios posteriores y extendiéndose a territorios anteriores. De todos los grupos de tratamiento, el C, es el que mostró menor progresión entre los dos puntos temporales. Esto sugiere que éste es el que muestra una mayor eficacia, con un enlentecimiento de la pérdida de metabolismo cerebral en relación con el patrón de evolución de la EA. Conclusiones: El análisis con ImEdS permitió medir de forma objetiva la evolución temporal y la respuesta a un tratamiento de una población con EA leve a moderada, a través de la combinación de imágenes paramétricas y la integración de estos hallazgos con 3 medidas simples que actúan como biomarcadores de la neurodegeneración. Esto es de especial interés para correlacionar con otras variables clínicas o terapéuticas y podría permitir identificar aquellos factores relacionados con la respuesta al tratamiento. Es una herramienta con un alto potencial de aplicabilidad clínica especialmente para profesionales menos especializados, para pacientes incipientes y/o pacientes con seguimiento longitudinal.Introduction: Dementia affects over 50 million people worldwide. Its most common form is Alzheimer disease (AD), which is one of the main causes of disability and dependence in adults. No curative treatment has been developed for this pathology to date, although several therapies are presently being studied. AMBAR is a treatment that aims to reduce the progres-sion of AD through periodic plasmatic exchange. Neuroimaging techniques offer structural and functional information about the central nerv-ous system. The visual interpretation of these images (qualitative) shows a good diagnostic performance for routine clinical practice but lacks good interobserver reproducibility and the assessment of these images does not allow us to determine the exact degree of disease in-volvement beyond a categorical scale. The quantitative analysis of images allows us to obtain reliable and reproducible numerical measurements. The presently available tools require skilled staff, and all entail the extraction of a large quantity of parameters that are often difficult to interpret. Objective: To study each patient's initial metabolic defect, progression of metabolic decline and differences between treatment groups in the population of the AMBAR clinical trial (pa-tients with mild to moderate AD) with a new quantification method. Material and Methods: The AMBAR study is a prospective randomised controlled study carried out in 41 centres in Spain and the USA. A total of 322 patients (54% women) with mild to mod-erate AD were included, mean age 69.0 ± 7.7 years. They were randomly assigned to four arms - three treatment group (A, B and C) and one placebo. All patients underwent FDG-PET and MRI at the beginning and the end of the treatment (at 14 months). A new volumetric region of interest SPM-based approach was designed to create parametric images and biomarkers related to the global metabolism, the percentage and severity of the metabolic defect as simple objective quantitative indicators of neuronal damage. A normal ref-erence database was created and the normality thresholds for each biomarker were deter-mined. Results: The method showed diagnostic performance rates >89% (sensitivity >89%, specific-ity >91% for the three global biomarkers), improved the visual analysis and obtained interpre-tation results equivalent to SPM. A pattern of initial metabolic alteration and a progression of significant metabolic loss were observed between the two time points (especially in the posterior cingulate region and parie-totemporal cortices, spreading to the frontal cortex) in all the treatment groups. Patients with mild AD only showed little decline in few areas; in contrast, patients with moderate AD pre-sented a more significant, extensive and intense loss of metabolism, more severe in the poste-rior territories, spreading to the anterior territories. Patients in group C showed the least pro-gression between the two time points. This suggests a greater efficacy of this treatment in this group of patients (Group C), with a slower decline of brain metabolism in relation to the pattern of evolution of Alzheimer's disease. Conclusions: The analysis with this new method allowed to objectively measure the temporal evolution and treatment response in patients with mild to moderate AD, through the combi-nation of parametric images and the integration of these findings with 3 simple measures that represent biomarkers of neurodegeneration. This information may be of special interest to correlate with other clinical or therapeutic variables and may allow the identification of factors related to patients' response to treatment. This method represents a tool with a high potential for clinical applicability, especially for less specialised professionals, patients with incipient alterations and those on longitudinal follow-up

Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin

Altres ajuts: This study was funded by Grifols. [...] James T. Becker (Department of Psychiatry, Neurology and Psychology. University of Pittsburgh, Pittsburgh PA, USA) read and commented on an earlier draft of the manuscript. Jordi Bozzo PhD, CMPP (Grifols) is acknowledged for medical writing and editorial assistance in the preparation of the manuscript.Recently, modifications of Aβ levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. Patients received between 3 and 18 PE with albumin (Albutein ® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam ®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion