RESUMO
PURPOSE: To examine and compare longitudinal changes of cortical glucose metabolism in amnestic and non-amnestic sporadic forms of early-onset Alzheimer's disease and assess potential associations with neuropsychological performance over a 3-year period time. METHODS: Eighty-two participants meeting criteria for early-onset (< 65 years) sporadic form of probable Alzheimer's disease and presenting with a variety of clinical phenotypes (47 amnestic and 35 non-amnestic forms) were included at baseline and followed up for 1.44 ± 1.23 years. All of the participants underwent a work-up at baseline and every year during the follow-up period, which includes clinical examination, neuropsychological testing, genotyping, cerebrospinal fluid biomarker assays, and structural MRI and 18F-FDG PET. Vertex-wise partial volume-corrected glucose metabolic maps across the entire cortical surface were generated and longitudinally assessed together with the neuropsychological scores using linear mixed-effects modeling as a function of amnestic and non-amnestic sporadic forms of early-onset Alzheimer's disease. RESULTS: Similar evolution patterns of glucose metabolic decline between amnestic and non-amnestic forms were observed in widespread neocortical cortices. However, only non-amnestic forms appeared to have a greater reduction of glucose metabolism in lateral orbitofrontal and bilateral medial temporal cortices associated with more severe declines of neuropsychological performance compared with amnestic forms. Furthermore, results suggest that glucose metabolic decline in amnestic forms would progress along an anterior-to-posterior axis, whereas glucose metabolic decline in non-amnestic forms would progress along a posterior-to-anterior axis. CONCLUSIONS: We found differences in spatial distribution and temporal trajectory of glucose metabolic decline between amnestic and non-amnestic early-onset Alzheimer's disease groups, suggesting that one might want to consider treating the two forms of the disease as two separate entities.
Assuntos
Doença de Alzheimer , Fluordesoxiglucose F18 , Doença de Alzheimer/diagnóstico por imagem , Encéfalo , Humanos , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. METHODS: Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. RESULTS: Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aß42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. DISCUSSION: Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.
Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/complicações , Amiloide/genética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/complicações , Hemorragia Cerebral/complicações , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Imageamento por Ressonância Magnética , Fenótipo , Estudos RetrospectivosRESUMO
Objective: Predicted age difference (PAD) is a score computed by subtracting chronological age from "brain" age, which is estimated using neuroimaging data. The goal of this study was to evaluate the PAD as a marker of phenotypic heterogeneity and severity among early-onset Alzheimer's disease (EOAD) patients. Methods: We first used 3D T1-weighted (3D-T1) magnetic resonance images (MRI) of 3,227 healthy subjects aged between 18 and 85 years to train, optimize, and evaluate the brain age model. A total of 123 participants who met the criteria for early-onset (<65 years) sporadic form of probable Alzheimer's disease (AD) and presented with two distinctive clinical presentations [an amnestic form (n = 74) and a non-amnestic form (n = 49)] were included at baseline and followed-up for a maximum period of 4 years. All the participants underwent a work-up at baseline and every year during the follow-up period, which included clinical examination, neuropsychological testing and genotyping, and structural MRI. In addition, cerebrospinal fluid biomarker assay was recorded at baseline. PAD score was calculated by applying brain age model to 3D-T1 images of the EOAD patients and healthy controls, who were matched based on age and sex. At baseline, between-group differences for neuropsychological and PAD scores were assessed using linear models. Regarding longitudinal analysis of neuropsychological and PAD scores, differences between amnestic and non-amnestic participants were analyzed using linear mixed-effects modeling. Results: PAD score was significantly higher for non-amnestic patients (2.35 ± 0.91) when compared to amnestic patients (2.09 ± 0.74) and controls (0.00 ± 1). Moreover, PAD score was linearly correlated with the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating Sum of Boxes (CDR-SB), for both amnestic and non-amnestic sporadic forms. Longitudinal analyses showed that the gradual development of the disease in patients was accompanied by a significant increase in PAD score over time, for both amnestic and non-amnestic patients. Conclusion: PAD score was able to separate amnestic and non-amnestic sporadic forms. Regardless of the clinical presentation, as PAD score was a way of quantifying an early brain age acceleration, it was an appropriate method to detect the development of AD and follow the evolution of the disease as a marker of severity as MMSE and CDR-SB.
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BACKGROUND: Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator. METHODS: Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE). RESULTS: Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients. CONCLUSIONS: FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.
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Doença de Alzheimer , Demência Frontotemporal , Pré-Escolar , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/epidemiologia , Humanos , Memória , Testes NeuropsicológicosRESUMO
BACKGROUND: Determinants of early-onset Alzheimer's disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation. OBJECTIVE: The objective of this study was to assess the putative association between VRFs and EOAD. METHODS: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in multivariable logistic regression analyses. RESULTS: We studied 102 participants with dementia (mean±standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; pâ<â0.0001), were less likely to be regular alcohol consumers (pâ<â0.0001), had a lower body mass index (-2âkg/m2; pâ<â0.0004), and a lower mean systolic blood pressure (-6.2 mmHg; pâ=â0.0036). The prevalence of APOE É4 allele was higher in participants with dementia than in controls (50% versus 29.4%; pâ=â0.0002), as was the prevalence of depression (48% versus 32%; pâ<â0.001). Similar results were observed in multivariable analysis. Compared with EOAD participants lacking VRFs, EOAD participants with at least one VRF had a higher prevalence of depression (29.6% versus 53.3%, respectively; pâ=â0.03). CONCLUSION: The prevalence of VRFs is not elevated in EOAD patients (in contrast to older AD patients). Extensive genetic testing should be considered more frequently in the context of EOAD.