RESUMO
Neuroinflammation is a significant contributor to Alzheimer's disease (AD). Until now, PET imaging of the translocator protein (TSPO) has been widely used to depict the neuroimmune endophenotype of AD. The aim of this review was to provide an update to the results from 2018 and to advance the characterization of the biological basis of TSPO imaging in AD by re-examining TSPO function and expression and the methodological aspects of interest. Although the biological basis of the TSPO PET signal is obviously related to microglia and astrocytes in AD, the observed process remains uncertain and might not be directly related to neuroinflammation. Further studies are required to re-examine the cellular significance underlying a variation in the PET signal in AD.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Humanos , Microglia/metabolismo , Doenças Neuroinflamatórias , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA/metabolismoRESUMO
Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer's disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [18F]THK5317, [11C]PIB and [18F]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56). In total, 11 patients declined cognitively over time, while 9 remained cognitively stable. The accuracy of baseline [18F]THK5317 binding in temporal areas was excellent at predicting future cognitive decline (area under the receiver operating curve 0.84-1.00) and the biomarker levels were strongly associated with the rate of cognitive decline (ß estimate -33.67 to -31.02, p < 0.05). The predictive accuracy of the other baseline biomarkers was poor (area under the receiver operating curve 0.58-0.77) and their levels were not associated with the rate of cognitive decline (ß estimate -4.64 to 15.78, p > 0.05). Baseline [18F]THK5317 binding and CSF tau levels were more strongly associated with the MMSE score at follow-up than at baseline (p < 0.05). These findings support a temporal dissociation between tau deposition and cognitive impairment, and suggest that [18F]THK5317 predicts future cognitive decline better than other biomarkers. The use of imaging markers for tau pathology could prove useful for clinical prognostic assessment and screening before inclusion in relevant clinical trials.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Compostos de Anilina , Biomarcadores , Disfunção Cognitiva/diagnóstico por imagem , Estudos Transversais , Humanos , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Quinolinas , Proteínas tauRESUMO
Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using 11C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer's disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with 3H-PiB, 3H-MK6240-3H-THK5117, and 3H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AßPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AßPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable 3H-THK5117 and 3H-deprenyl brain homogenate binding was observed for AßPParc, PSEN1ΔE9, and sAD, respectively. Some differences were observed between 3H-MK6240 and 3H-THK5117 in ADAD. A positive correlation between 3H-deprenyl and 3H-THK5117 binding was observed in AßPParc, while no such correlation was found in PSEN1ΔE9 and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in the AßPParc cases, high regional tau and astrocyte binding was observed. The lack of correlation between 3H-deprenyl and 3H-THK5117 binding in PSEN1ΔE9 and sAD in contrast of the positive correlation observed in the AßPParc cases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.
Assuntos
Doença de Alzheimer , Astrócitos , Doença de Alzheimer/genética , Amiloide , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Astrócitos/metabolismo , Encéfalo/metabolismo , Humanos , Placa Amiloide , Tomografia por Emissão de Pósitrons , Presenilina-1 , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
INTRODUCTION: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. METHODS: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice. RESULTS: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. DISCUSSION: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results.
RESUMO
INTRODUCTION: The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) Prognostic and Natural History Study (PNHS) aims at understanding the role of amyloid imaging in the earliest stages of Alzheimer's disease (AD). AMYPAD PNHS adds (semi-)quantitative amyloid PET imaging to several European parent cohorts (PCs) to predict AD-related progression as well as address methodological challenges in amyloid PET. METHODS: AMYPAD PNHS is an open-label, prospective, multi-center, cohort study recruiting from multiple PCs. Around 2000 participants will undergo baseline amyloid positron emission tomography (PET), half of whom will be invited for a follow-up PET 12 at least 12 months later. RESULTS: Primary include several amyloid PET measurements (Centiloid, SUVr, BPND , R1 ), and secondary are their changes from baseline, relationship to other amyloid markers (cerebrospinal fluid and visual assessment), and predictive value of AD-related decline. EXPECTED IMPACT: Determining the role of amyloid PET for the understanding of this complex disease and potentially improving secondary prevention trials.
Assuntos
Doença de Alzheimer , Amiloide/metabolismo , Biomarcadores/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Progressão da Doença , Europa (Continente) , Feminino , Voluntários Saudáveis , Humanos , Estudos Longitudinais , Masculino , Estudos ProspectivosRESUMO
PURPOSE: Studies comparing CSF and PET tau biomarkers have included only commercial CSF assays examining specific phosphorylation sites (e.g. threonine 181, P-tau181p) and mid-domain tau (i.e. total tau, T-tau). Moreover, these studies did not examine CSF tau levels in relation to cerebral glucose metabolism. We thus aimed to examine CSF tau measures, using both commercial and novel assays, in relation to [18F]THK5317 (tau) and [18F]FDG PET (glucose metabolism). METHODS: Fourteen Alzheimer's disease (AD) patients (seven prodromal, seven dementia) underwent [18F]THK5317 and [18F]FDG PET studies, with follow-up performed in ten subjects (six prodromal, four dementia) after 17 months. In addition to commercial assays, novel measures capturing N-terminus+mid-domain (tau N-Mid) and C-terminally truncated (tau-368) fragments were included. RESULTS: While the levels of all forms of CSF tau were found to be inversely associated with baseline [18F]FDG uptake, associations with baseline [18F]THK5317 uptake varied in relation to the degree of isocortical hypometabolism ([18F]FDG SUVR). Changes in the levels of the novel CSF markers tracked longitudinal changes in tracer uptake better than changes in P-tau181p and T-tau levels, and improved concordance with dichotomized regional [18F]THK5317 measures. CONCLUSION: Our findings suggest that neurodegeneration may modulate the relationship between CSF and PET tau biomarkers, and that, by comparison to P-tau181p and T-tau, tau-368 and tau N-Mid may better capture tau pathology and synaptic impairment.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/metabolismo , Feminino , Fluordesoxiglucose F18 , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Cross-sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information. METHODS: We included 16 patients with Alzheimer's disease who completed follow-up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed-effects models and annual percentage change maps were used to examine longitudinal change. RESULTS: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317. DISCUSSION: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Glucose/metabolismo , Perfusão , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Compostos de Anilina , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Estudos Transversais , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , QuinolinasRESUMO
Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-ß, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-ß plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-ß plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-ß plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-ß plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-ß plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-ß plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Gliose/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/tendências , Adulto , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Estudos Transversais , Feminino , Seguimentos , Gliose/genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Placa Amiloide/genéticaRESUMO
PURPOSE: The aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [(18)F]THK5317 (also known as (S)-[(18)F]THK5117) retention in different stages of Alzheimer's disease; and study any associations with markers of hypometabolism and amyloid-beta deposition. METHODS: Thirty-three individuals were enrolled, including nine patients with Alzheimer's disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer's disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [(18)F]THK5317, [(11)C] Pittsburgh compound B ([(11)C]PIB), and [(18)F]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [(11)C]PIB-positive (n = 11) and MCI [(11)C]PIB-negative (n = 2) groups. RESULTS: Test-retest variability for [(18)F]THK5317-PET was very low (1.17-3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [(11)C]PIB-positive) and dementia-stage Alzheimer's disease had significantly higher [(18)F]THK5317 retention than healthy controls (p = 0.002 and p = 0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [(18)F]THK5317 retention and [(18)F]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [(18)F]THK5317 and [(11)C]PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [(11)C]PIB but high [(18)F]THK5317 retentions with a different regional distribution from that in Alzheimer's disease patients. CONCLUSIONS: The tau-specific PET tracer [(18)F]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Quinolinas , Adulto , Idoso , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinolinas/metabolismo , Traçadores Radioativos , Adulto JovemRESUMO
BACKGROUND: Few patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease. CASE PRESENTATION: We document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14-3-3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on (18)F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5 years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease. CONCLUSIONS: This comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed.
Assuntos
Síndrome de Creutzfeldt-Jakob/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Proteínas 14-3-3/líquido cefalorraquidiano , Adulto , Encéfalo/patologia , Transtornos Cognitivos/diagnóstico , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagem , Síndrome de Creutzfeldt-Jakob/patologia , Delusões/diagnóstico , Diagnóstico Diferencial , Evolução Fatal , Fluordesoxiglucose F18 , Seguimentos , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Neuroimagem/métodos , Transtornos Parkinsonianos/diagnóstico , Tomografia por Emissão de Pósitrons/métodosRESUMO
PURPOSE: AV-45 amyloid biomarker is known to show uptake in white matter in patients with Alzheimer's disease (AD), but also in the healthy population. This binding, thought to be of a non-specific lipophilic nature, has not yet been investigated. The aim of this study was to determine the differential pattern of AV-45 binding in white matter in healthy and pathological populations. METHODS: We recruited 24 patients presenting with AD at an early stage and 17 matched, healthy subjects. We used an optimized positron emission tomography-magnetic resonance imaging (PET-MRI) registration method and an approach based on an intensity histogram using several indices. We compared the results of the intensity histogram analyses with a more canonical approach based on target-to-cerebellum Standard Uptake Value (SUVr) in white and grey matter using MANOVA and discriminant analyses. A cluster analysis on white and grey matter histograms was also performed. RESULTS: White matter histogram analysis revealed significant differences between AD and healthy subjects, which were not revealed by SUVr analysis. However, white matter histograms were not decisive to discriminate groups, and indices based on grey matter only showed better discriminative power than SUVr. The cluster analysis divided our sample into two clusters, showing different uptakes in grey, but also in white matter. CONCLUSION: These results demonstrate that AV-45 binding in white matter conveys subtle information not detectable using the SUVr approach. Although it is not more efficient than standard SUVr in discriminating AD patients from healthy subjects, this information could reveal white matter modifications.
Assuntos
Doença de Alzheimer/metabolismo , Compostos de Anilina/metabolismo , Etilenoglicóis/metabolismo , Substância Cinzenta/metabolismo , Substância Branca/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Amiloide/metabolismo , Estudos de Casos e Controles , Análise por Conglomerados , Análise Discriminante , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Ligação Proteica , Substância Branca/diagnóstico por imagemRESUMO
Understanding the relationship between blood nutrients and neurodegeneration could contribute to devising strategies for preventing Alzheimer's disease. We investigated the associations between fatty acids, vitamins D, B6, B12, folate, homocysteine, and the cerebral load of amyloid ß (Aß). This cross-sectional study included 177 older adults (70-96 years, 65% female) with objective cognitive impairment, prefrail, or frail. Cerebral Aß load was determined using positron emission tomography Standardized Uptake Value ratios. Fatty acids were assessed in erythrocytes, vitamins D and homocysteine in serum, and the other vitamins in plasma. Linear regression models corrected for multiple comparisons evaluated the associations between each nutrient and Aß. The principal component factor followed by linear regression grouped the fatty acids strongly correlated (factor) and associated with Aß. Higher concentrations of polyunsaturated fatty acids (PUFAs): clupanodonic acid (22:5n-3; ß: -0.13; pâ =â .001), mead acid (20:3n-9; ß: -0.07; pâ =â .036), and adrenic acid (22:4n-6; ß: -0.05; pâ =â .031) were associated with lower global Aß load, whereas linoleic acid (18:2n-6) was associated with higher global Aß load (ß: 0.18; pâ =â .042). Clupanodonic acid was inversely associated with Aß in all cerebral regions except the thalamus. The factor composed of mead, clupanodonic, and arachidonic (20:4n-6) acids was associated with a lower global Aß load (ß: -0.02; pâ =â .002). Some erythrocyte PUFAs were inversely associated with Aß load in the brain, and most of them were metabolites of the essential fatty acids linoleic and α-linolenic. Given the cross-sectional design, these results must be carefully interpreted, and longitudinal studies are needed.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Idoso , Feminino , Humanos , Masculino , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores , Estudos de Coortes , Estudos Transversais , Ácidos Graxos/metabolismo , Homocisteína , Tomografia por Emissão de Pósitrons , VitaminasRESUMO
Artificial intelligence (AI) is revolutionizing the field of medical imaging, holding the potential to shift medicine from a reactive "sick-care" approach to a proactive focus on healthcare and prevention. The successful development of AI in this domain relies on access to large, comprehensive, and standardized real-world datasets that accurately represent diverse populations and diseases. However, images and data are sensitive, and as such, before using them in any way the data needs to be modified to protect the privacy of the patients. This paper explores the approaches in the domain of five EU projects working on the creation of ethically compliant and GDPR-regulated European medical imaging platforms, focused on cancer-related data. It presents the individual approaches to the de-identification of imaging data, and describes the problems and the solutions adopted in each case. Further, lessons learned are provided, enabling future projects to optimally handle the problem of data de-identification. CRITICAL RELEVANCE STATEMENT: This paper presents key approaches from five flagship EU projects for the de-identification of imaging and clinical data offering valuable insights and guidelines in the domain. KEY POINTS: ΑΙ models for health imaging require access to large amounts of data. Access to large imaging datasets requires an appropriate de-identification process. This paper provides de-identification guidelines from the AI for health imaging (AI4HI) projects.
RESUMO
We report the case of a 37-year-old man suffering from insidious visual agnosia and spastic paraparesis due to a PSEN1 mutation. His mother was diagnosed with Alzheimer disease after a biopsy. He was assessed by multimodal neuroimaging, including new in vivo positron emission tomography amyloid imaging (F-AV45). His data were compared with those from healthy participants and patients with sporadic predemential Alzheimer disease. He exhibited posterior cortical thickness reduction, posterior hypometabolism, and increased amyloid ligand uptake in the posterior cortex and the striatum. We show that F-AV45 positron emission tomography allows visualization of the unusual pattern of amyloid deposits that co-localize with cortical atrophy in this genetic form of Alzheimer disease.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Etilenoglicóis , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Adulto , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Fluordesoxiglucose F18 , Humanos , Masculino , Fenótipo , Presenilina-1/genéticaRESUMO
Importance: Amyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect. Objective: To assess the clinical effect of amyloid PET in memory clinic patients. Design, Setting, and Participants: The AMYPAD-DPMS is a prospective randomized clinical trial in 8 European memory clinics. Participants were allocated (using a minimization method) to 3 study groups based on the performance of amyloid PET: arm 1, early in the diagnostic workup (within 1 month); arm 2, late in the diagnostic workup (after a mean [SD] 8 [2] months); or arm 3, if and when the managing physician chose. Participants were patients with subjective cognitive decline plus (SCD+; SCD plus clinical features increasing the likelihood of preclinical Alzheimer disease), mild cognitive impairment (MCI), or dementia; they were assessed at baseline and after 3 months. Recruitment took place between April 16, 2018, and October 30, 2020. Data analysis was performed from July 2022 to January 2023. Intervention: Amyloid PET. Main Outcome and Measure: The main outcome was the difference between arm 1 and arm 2 in the proportion of participants receiving an etiological diagnosis with a very high confidence (ie, ≥90% on a 50%-100% visual numeric scale) after 3 months. Results: A total of 844 participants were screened, and 840 were enrolled (291 in arm 1, 271 in arm 2, 278 in arm 3). Baseline and 3-month visit data were available for 272 participants in arm 1 and 260 in arm 2 (median [IQR] age: 71 [65-77] and 71 [65-77] years; 150/272 male [55%] and 135/260 male [52%]; 122/272 female [45%] and 125/260 female [48%]; median [IQR] education: 12 [10-15] and 13 [10-16] years, respectively). After 3 months, 109 of 272 participants (40%) in arm 1 had a diagnosis with very high confidence vs 30 of 260 (11%) in arm 2 (P < .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%]; P < .001; MCI: 45/108 [42%] vs 9/102 [9%]; P < .001; dementia: 39/80 [49%] vs 16/80 [20%]; P < .001). Conclusion and Relevance: In this study, early amyloid PET allowed memory clinic patients to receive an etiological diagnosis with very high confidence after only 3 months compared with patients who had not undergone amyloid PET. These findings support the implementation of amyloid PET early in the diagnostic workup of memory clinic patients. Trial Registration: EudraCT Number: 2017-002527-21.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Masculino , Feminino , Idoso , Doença de Alzheimer/psicologia , Encéfalo/metabolismo , Estudos Prospectivos , Tomografia por Emissão de Pósitrons , Amiloide/metabolismo , Proteínas Amiloidogênicas , Peptídeos beta-Amiloides/metabolismoRESUMO
BACKGROUND: The Multidomain Alzheimer Preventive Trial (MAPT) was designed to assess the efficacy of omega-3 fatty acid supplementation, multidomain intervention (MI), or a combination of both on cognition. Although the MAPT study was negative, an effect of MI in maintaining cognitive functions compared to placebo group was showed in positive amyloid subjects. A FDG PET study (MAPT-NI) was implemented to test the impact of MI on brain glucose metabolism. METHODS: MAPT-NI was a randomized, controlled parallel-group single-center study, exploring the effect of MI on brain glucose metabolism. Participants were non-demented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. Participants were randomly assigned (1:1) to "MI group" or "No MI group." The MI consisted of group sessions focusing on 3 domains: cognitive stimulation, physical activity, nutrition, and a preventive consultation. [18F]FDG PET scans were performed at baseline, 6 months, and 12 months, and cerebral magnetic resonance imaging scans at baseline. The primary objective was to evaluate the MI effect on brain glucose metabolism assessed by [18F]FDG PET imaging at 6 months. The primary outcome was the quantification of regional metabolism rate for glucose in cerebral regions involved early in Alzheimer disease by relative semi-quantitative SUVr (FDG-based AD biomarker). An exploratory voxel-wise analysis was performed to assess the effect of MI on brain glucose metabolism without anatomical hypothesis. RESULTS: The intention-to-treat population included 67 subjects (34 in the MI group and 33 in the No MI group. No significant MI effect was observed on primary outcome at 6 months. In the exploratory voxel-wise analysis, we observed a difference in favor of MI group on the change of cerebral glucose metabolism in limbic lobe (right hippocampus, right posterior cingulate, left posterior parahippocampal gyrus) at 6 months. CONCLUSIONS: MI failed to show an effect on metabolism in FDG-based AD biomarker, but exploratory analysis suggested positive effect on limbic system metabolism. This finding could suggest a delay effect of MI on AD progression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT01513252 .
Assuntos
Doença de Alzheimer , Ácidos Graxos Ômega-3 , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/terapia , Encéfalo/diagnóstico por imagem , Fluordesoxiglucose F18 , Glucose , Humanos , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: Sporadic cerebral amyloid angiopathy shows progressive amyloid-ß deposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. OBJECTIVE: To investigate whether amyloid load and distribution, assessed by florbetapir positron emission tomography (PET), differs between patients with probable CAA-related intracerebral hemorrhage (CAA-ICH) and mild cognitive impairment due to Alzheimer's disease (MCI-AD). METHODS: We assessed [18F]florbetapir uptake in 15 patients with probable CAA-ICH and 20 patients with MCI-AD patients. Global and regional florbetapir retention were assessed using standard uptake values ratio (SUVr) in region-based and voxel-wise approaches. Visual reading of florbetapir scans was performed for all participants. Group comparisons were performed using univariate and multivariate analysis. RESULTS: Global florbetapir retention was lower in patients with CAA-ICH than MCI-AD (median SUVr, 1.33 [1.21-1.41] versus 1.44 [1.35-1.66]; pâ=â0.032). In the region-based analysis, regional florbetapir distribution was similar between the two groups. There was a trend for an increased occipital/global ratio in CAA-ICH patients compared to MCI-AD (pâ=â0.060). In the voxel-wise approach, two clusters, one in parietal regions and the other in temporal regions, had higher uptake in MCI-AD relative to CAA patients. CONCLUSIONS: Patients with CAA-ICH had a lower global florbetapir PET burden than patients with MCI-AD. Relative florbetapir retention in the posterior regions tended to be higher in CAA patients in region-based analysis but was not statistically different between groups. Investigation on differences in amyloid deposits distribution between groups required a fine-grained voxel-wise analysis. In future studies, selective amyloid tracers are needed to differentiate vascular from parenchymal amyloid.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina/farmacocinética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Etilenoglicóis/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Carga Corporal (Radioterapia) , Angiopatia Amiloide Cerebral/complicações , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Hemorragias Intracranianas/etiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Observational and interventional studies addressing the link between amyloid (Aß) burden and cognitive decline are increasing, but a clear definition of amyloid positivity is still lacking. This may represent a great stake for therapeutic studies enrolling Aß + patients only. The main objective of this study was to define a population with "equivocal" amyloid status, and evaluate their cognitive changes. METHODS: Sixty-five participants over 75 years old, from the Control group of the interventional MAPT study, at risk to develop Alzheimer's disease, were included. Participants were classified into three groups in terms of amyloid load: Aß +, Aß - and Equivocal participants (according to visual reading, global standardized uptake (SUVR) cut-offs, or a k-mean clustering method). The cognitive changes over time (memory, executive functions, attention and processing speed) of this Equivocal group were then compared to Aß + and Aß - participants. RESULTS: When classified by visual read, Equivocal participants' memory scores were comparable to the Aß- participants, and greater than in Aß + participants over time. Secondary analyses, using SUVR cut-offs classification, showed different trajectories with Equivocal participants being comparable to the Aß + participants, and lower than Aß-, on executive performance over time. CONCLUSIONS: This original work pointed out a population that may be of great interest for interventional studies, raising the question of how amyloid status should be defined and integrated in such studies. These findings should be replicated in future studies on larger datasets, to confirm what methodological approach would be the most suitable to highlight this specific neuroimaging entity.
Assuntos
Amiloide/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Cognição , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Idoso , Envelhecimento/metabolismo , Envelhecimento/psicologia , Compostos de Anilina , Cognição/fisiologia , Disfunção Cognitiva/terapia , Etilenoglicóis , Função Executiva/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Memória/fisiologia , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Compostos RadiofarmacêuticosRESUMO
Objective: Posterior Cortical Atrophy (PCA) is a neurodegenerative disease characterized predominantly by visual impairment. However, diagnosis of PCA remains complicated with an interval of several years between initial reporting of symptoms and diagnosis. The aim of the present study is to define if patients' visual and gestural complaints are consistent with their clinical profile. Method: An evaluation of daily visual problems as well as a full neuropsychological assessment and FDG-PET were performed in 15 PCA patients. We compared glucose metabolism between these PCA patients and 18 healthy controls. Correlation analyses were conducted in PCA patients between visual and gestural complaint, clinical impairments, and brain glucose metabolism. Results: Major impairment of cognitive functions was detected in PCA patients specifically in visual domains. Positive correlations were found between visual impairments and hypometabolism in the right temporo-parieto-occipital cortices. However, no correlation was found between complaint and visual impairment in PCA patients. Discussion: Our main results suggest a consistent relationship between clinical impairment and brain metabolism. However, the patient's complaint and visual performance are not linked. Combining the literature and our results, it seems that patients are generally aware of difficulties but misinterpret them. This misinterpretation may be responsible for the delayed diagnosis.
RESUMO
BACKGROUND: The range of onset ages within some PSEN1 families is wide, and a few cases of reduced penetrance of PSEN1 mutations have been reported. However, published data on reduced penetrance have been limited to clinical histories, often collected retrospectively and lacking biomarker information. We present a case of reduced penetrance of the PSEN1 H163Y mutation in a carrier prospectively followed for 22 years. METHODS: Two brothers (A and B), both carriers of the H163Y mutation, were followed between 1995 and 2017. They underwent repeated clinical evaluations, neuropsychological assessments, and cerebrospinal fluid analyses, as well as brain imaging examinations with structural magnetic resonance, [18F]fluorodeoxyglucose positron emission tomography, and [11C]Pittsburgh compound B positron emission tomography. RESULTS: Brother A was followed between 44 and 64 years of age. Cognitive symptoms due to Alzheimer's disease set in at the age of 54. Gradual worsening of symptoms resulted in admittance to a nursing home owing to dependence on others for all activities of daily living. He showed a curvilinear decline in cognitive function on neuropsychological tests, and changes on magnetic resonance imaging, positron emission tomography, and biomarkers in the cerebrospinal fluid supported a clinical diagnosis of Alzheimer's disease. Brother A died at the age of 64 and fulfilled the criteria for definitive Alzheimer's disease according to neuropathological examination results. Brother B was followed between the ages of 43 and 65 and showed no cognitive deterioration on repeated neuropsychological test occasions. In addition, no biomarker evidence of Alzheimer's disease pathology was detected, either on imaging examinations or in cerebrospinal fluid. CONCLUSIONS: The average (SD) age of symptom onset for PSEN1 H163Y is 51 ± 7 years according to previous studies. However, we present a case of a biomarker-verified reduction in penetrance in a mutation carrier who was still symptom-free at the age of 65. This suggests that other genetic, epigenetic, and/or environmental factors modify the onset age.