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BACKGROUND AND PURPOSE: Our objective was to define phenotypes of non-lesional late-onset epilepsy (NLLOE) depending on its presumed aetiology and to determine their seizure and cognitive outcomes at 12 months. METHODS: In all, 146 newly diagnosed NLLOE patients, >50 years old, were prospectively included and categorized by four presumed aetiological subtypes: neurodegenerative subtype (patients with a diagnosis of neurodegenerative disease) (n = 31), microvascular subtype (patients with three or more cardiovascular risk factors and two or more vascular lesions on MRI) (n = 39), inflammatory subtype (patient meeting international criteria for encephalitis) (n = 9) and unlabelled subtype (all individuals who did not meet the criteria for other subtypes) (n = 67). Cognitive outcome was determined by comparing for each patient the proportion of preserved/altered scores between initial and second neuropsychological assessment. RESULTS: The neurodegenerative subtype had the most severe cognitive profile at diagnosis with cognitive complaint dating back several years. The microvascular subtype was mainly evaluated through the neurovascular emergency pathway. Their seizures were characterized by transient phasic disorders. Inflammatory subtype patients were the youngest. They presented an acute epilepsy onset with high rate of focal status epilepticus. The unlabelled subtype presented fewer comorbidities with fewer lesions on brain imaging. The neurodegenerative subtype had the worst seizure and cognitive outcomes. In other groups, seizure control was good under antiseizure medication (94.7% seizure-free) and cognitive performance was stabilized or even improved. CONCLUSION: This new characterization of NLLOE phenotypes raises questions regarding the current International League Against Epilepsy aetiological classification which does not individualize neurodegenerative and microvascular aetiology per se.
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INTRODUCTION: This study aims to examine whether physical activity moderates the association between biomarkers of brain pathologies and dementia risk. METHODS: From the Memento cohort, we analyzed 1044 patients with mild cognitive impairment, aged 60 and older. Self-reported physical activity was assessed using the International Physical Activity Questionnaire. Biomarkers of brain pathologies comprised medial temporal lobe atrophy (MTA), white matter lesions, and plasma amyloid beta (Aß)42/40 and phosphorylated tau181. Association between physical activity and risk of developing dementia over 5 years of follow-up, and interactions with biomarkers of brain pathologies were tested. RESULTS: Physical activity moderated the association between MTA and plasma Aß42/40 level and increased dementia risk. Compared to participants with low physical activity, associations of both MTA and plasma Aß42/40 on dementia risk were attenuated in participants with high physical activity. DISCUSSION: Although reverse causality cannot be excluded, this work suggests that physical activity may contribute to cognitive reserve. HIGHLIGHTS: Physical activity is an interesting modifiable target for dementia prevention. Physical activity may moderate the impact of brain pathology on dementia risk. Medial temporal lobe atrophy and plasma amyloid beta 42/40 ratio were associated with increased dementia risk especially in those with low level of physical activity.
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Doença de Alzheimer , Disfunção Cognitiva , Demência , Humanos , Pessoa de Meia-Idade , Idoso , Demência/complicações , Peptídeos beta-Amiloides , Imageamento por Ressonância Magnética , Progressão da Doença , Disfunção Cognitiva/patologia , Biomarcadores , Encéfalo/patologia , Atrofia/patologia , Doença de Alzheimer/patologia , Proteínas tauRESUMO
Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.
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Encéfalo/patologia , Tauopatias/patologia , Proteínas tau/metabolismo , Adulto , Idade de Início , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Heterozigoto , Humanos , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Tauopatias/metabolismo , Proteínas tau/genéticaRESUMO
INTRODUCTION: Although some studies have previously addressed the clinical impact of amyloid positron emission tomography (PET), none has specifically addressed its selective and hierarchical implementation in relation to cerebrospinal fluid analysis in a naturalistic setting. METHODS: This multicenter study was performed at French tertiary memory clinics in patients presenting with most complex clinical situations (i.e., early-onset, atypical clinical profiles, suspected mixed etiological conditions, unexpected rate of progression), for whom cerebrospinal fluid analysis was indicated but either not feasible or considered as noncontributory (ClinicalTrials.gov: NCT02681172). RESULTS: Two hundred five patients were enrolled with evaluable florbetaben PET scans; 64.4% of scans were amyloid positive. PET results led to changed diagnosis and improved confidence in 66.8% and 81.5% of patients, respectively, and altered management in 80.0% of cases. DISCUSSION: High-level improvement of diagnostic certainty and management is provided by selective and hierarchical implementation of florbetaben PET into current standard practices for the most complex dementia cases.
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Amiloide/metabolismo , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Demência/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Estilbenos , Idoso , Encéfalo/metabolismo , Demência/metabolismo , Diagnóstico Diferencial , Feminino , França , Humanos , MasculinoRESUMO
BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. METHODS AND FINDINGS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid ß (Aß)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. CONCLUSIONS: Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.
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Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Presenilina-2/genética , Adulto , Idade de Início , Feminino , França , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
Cognitive-behaviour units are specialised units within follow-up and rehabilitation care services for people suffering from Alzheimer's disease. These units were created in response to measure 17 of the 3rd Alzheimer's Plan. To stabilise behavioural disorders, as part of a non pharmacological care plan, the therapeutic garden is a useful care tool. This article presents an original initiative in Nancy.
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Doença de Alzheimer/terapia , Terapia Cognitivo-Comportamental/métodos , Jardinagem , Idoso , Doença de Alzheimer/psicologia , HumanosRESUMO
OBJECTIVES: Terminally ill patients may require sedation to relieve refractory suffering. The prevalence and modalities of this practice in palliative care services remain unclear. This study estimated the prevalence of all sedation leading to a deep unconsciousness, whether transitory, with an undetermined duration, or maintained until death, for terminally ill patients referred to a home-based or hospital-based palliative care service. METHODS: We conducted a national, multicentre, observational, prospective, cross-sectional study. In total, 331 centres participated, including academic/non-academic and public/private institutions. The participating institutions provided hospital-based or home-based palliative care for 5714 terminally ill patients during the study. RESULTS: In total, 156 patients received sedation (prevalence of 2.7%; 95% CI, 2.3 to 3.2); these patients were equally distributed between 'transitory', 'undetermined duration' and 'maintained until death' sedation types. The prevalence was 0.7% at home and 8.0% in palliative care units. The median age of the patients was 70 years (Q1-Q3: 61-83 years); 51% were women and 78.8% had cancers. Almost all sedation events occurred at a hospital (90.4%), mostly in specialised beds (74.4%). In total, 39.1% of patients were unable to provide consent; only two had written advance directives. A collegial procedure was implemented in 80.4% of sedations intended to be maintained until death. Midazolam was widely used (85.9%), regardless of the sedation type. CONCLUSIONS: This nationwide study provides insight into sedation practices in palliative care institutions. We found a low prevalence for all practices, with the highest prevalence among most reinforced palliative care providers, and an equal frequency of all practices.
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Sedação Profunda , Assistência Terminal , Idoso , Feminino , Humanos , Masculino , Estudos Transversais , França/epidemiologia , Hipnóticos e Sedativos/uso terapêutico , Cuidados Paliativos/métodos , Prevalência , Estudos Prospectivos , Assistência Terminal/métodos , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Precisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [18F] fluoro-2-deoxy-2-D-glucose (18F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain 18F-FDG PET scans. Here, we aimed to estimate the value of brain 18F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology. METHODS: Longitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain 18F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer's Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777-88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain 18F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels. RESULTS: Among the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a 18F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers. CONCLUSION: A normal brain 18F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term. TRIAL REGISTRATION: Clinical Trials database (NCT04804722). March 18, 2021. Retrospectively registered.
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Biomarcadores , Demência , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Humanos , Tomografia por Emissão de Pósitrons/métodos , Feminino , Masculino , Idoso , Demência/diagnóstico por imagem , Demência/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos Longitudinais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Pessoa de Meia-Idade , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Progressão da Doença , Idoso de 80 Anos ou mais , Diagnóstico Precoce , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Estudos de CoortesRESUMO
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.
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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
BACKGROUND: Epilepsy seems to be an important comorbidity in patients with early onset Alzheimer's disease (EOAD). Currently, seizures are still underestimated in this population. However, seizures may interact with AD evolution with possible acceleration of cognitive decline. OBJECTIVE: To better define the epileptic disorders observed in patients with EOAD. METHODS: All patients diagnosed as EOAD in our hospital between 2013 and 2019 with positive CSF biomarkers for AD were selected. The usual follow-up was extended with a 3-h EEG and a consultation with an epilepsy expert. Information on epilepsy and AD were collected and analyzed. RESULTS: Among the 25 included patients, 10 (40%) were classified as epileptic. Seizure types were tonic-clonic (25%), typical temporal seizures (25%), myoclonus (25%), focal extra-temporal seizures (8%), and other seizure types (17%). AD-E patients had a significant lower MMSE (15.3±8.4 AD-E versus 22.1±5.1 AD-NE, pâ=â0.036) and a lower autonomy (IADL 4.1±2.7 AD-E versus 6.4±1.9 AD-NE, pâ=â0.046) at AD diagnosis with comparable ages between AD-E and AD-NE. Epileptic patients seemed to present a faster cognitive decline ([ΔMMSE per year 1.7±1.3 AD-E versus 0.9±1.4 AD-NE; pâ=â0.09). All patients with severe cognitive impairment (MMSE ≤ 10) had an epileptic comorbidity. CONCLUSION: Epilepsy is a frequent comorbidity in EOAD patients, with a percentage of 40%in our study. This comorbidity may be associated with a severe form of EOAD. The role of epilepsy in the acceleration of cognitive decline and the positive impact of antiepileptic drugs on cognition need further research.
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Doença de Alzheimer/fisiopatologia , Epilepsia/diagnóstico , Convulsões/classificação , Idade de Início , Idoso , Doença de Alzheimer/complicações , Anticonvulsivantes/uso terapêutico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Comorbidade , Eletroencefalografia , Epilepsia/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos ProspectivosRESUMO
Progressive neurocognitive pathologies frequently alter the architecture of sleep with: advanced sleep phase or phase delay, sleep fragmentation, decrease of slow-wave sleep, REM sleep, nocturnal agitation and wandering or even complete reversal of the nycthemeral rhythm. This has a clear impact on the health and quality of life of the patient. Hospitalization increases the risk of sleep disturbances due to inactivity, some sensory deprivation and daytime hypovigilance. The therapeutic gardens offer in an attractive, sensorially stimulating setting and exposed to natural light, the possibility of an adapted physical exercise. Their impact on the quality and quantity of sleep in cognitive-behavioral units has been evaluated in an exploratory manner. The hypnogram of two groups of 30 patients was compared depending on whether they used the garden (weather permitting, in summer) or not (in winter). The results show that the patients who use the garden are significantly more active during the day, have a longer nighttime sleep duration and are less restless at night. In addition, patients who use and walk longer in the garden benefit from an increase in their sleep time. In view of their multiple interests, therapeutic gardens, if they meet validated design criteria, should be integrated more widely into establishments welcoming people with neurocognitive diseases.
Les pathologies neurocognitives évolutives altèrent fréquemment l'architecture du sommeil avec : avance ou retard de phase, fragmentation du sommeil, diminution du sommeil lent profond et du sommeil paradoxal, agitation et déambulation nocturnes voire inversion complète du rythme nycthéméral. Cela retentit nettement sur la santé et la qualité de vie du patient. L'hospitalisation accroît le risque de perturbations du sommeil du fait de l'inactivité, d'une certaine privation sensorielle et de l'hypovigilance diurne. Les jardins thérapeutiques offrent, dans un cadre attractif, stimulant sensoriellement et exposé à la lumière naturelle, la possibilité d'un exercice physique adapté. Leur impact sur la qualité et la quantité de sommeil en Unité cognitivo-comportementale a été évalué de manière exploratoire. L'hypnogramme de deux groupes de 30 patients a été comparé selon qu'ils utilisaient le jardin (lorsque la météo le permettait, en été) ou non (en hiver). Les résultats montrent que les patients qui utilisent le jardin sont significativement plus actifs la journée, ont une durée supérieure de sommeil nocturne et sont moins agités la nuit. De plus, les patients utilisant et marchant plus longtemps dans le jardin bénéficient d'une augmentation de leur durée de sommeil. Au vu de leurs intérêts multiples, les jardins thérapeutiques, pour peu qu'ils répondent à des critères de conception validés, devraient être intégrés plus largement dans les établissements accueillants des personnes atteintes de maladies neurocognitives.
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Qualidade de Vida , Transtornos do Sono-Vigília , Humanos , Sono , Transtornos do Sono-Vigília/terapia , Jardinagem , Agitação PsicomotoraRESUMO
BACKGROUND: This work aimed to investigate the potential pathways involved in the association between social and lifestyle factors, biomarkers of Alzheimer's disease and related dementia (ADRD), and cognition. METHODS: The authors studied 2323 participants from the Memento study, a French nationwide clinical cohort. Social and lifestyle factors were education level, current household incomes, physical activity, leisure activities, and social network from which two continuous latent variables were computed: an early to midlife (EML) and a latelife (LL) indicator. Brain magnetic resonance imaging (MRI), lumbar puncture, and amyloid-positron emission tomography (PET) were used to define three latent variables: neurodegeneration, small vessel disease (SVD), and AD pathology. Cognitive function was defined as the underlying factor of a latent variable with four cognitive tests. Structural equation models were used to evaluate cross-sectional pathways between social and lifestyle factors and cognition. RESULTS: Participants' mean age was 70.9 years old, 62% were women, 28% were apolipoprotein-ε4 carriers, and 59% had a Clinical Dementia Rating (CDR) score of 0.5. Higher early to midlife social indicator was only directly associated with better cognitive function (direct ß = 0.364 (0.322; 0.405), with no indirect pathway through ADRD biomarkers (total ß = 0.392 (0.351; 0.429)). In addition to a direct effect on cognition (direct ß = 0.076 (0.033; 0.118)), the association between latelife lifestyle indicator and cognition was also mostly mediated by an indirect effect through lower neurodegeneration (indirect ß = 0.066 (0.042; 0.090) and direct ß = - 0.116 (- 0.153; - 0.079)), but not through AD pathology nor SVD. CONCLUSIONS: Early to midlife social factors are directly associated with higher cognitive functions. Latelife lifestyle factors may help preserve cognitive functions through lower neurodegeneration.
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Doença de Alzheimer , Disfunção Cognitiva , Doenças Vasculares , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Biomarcadores , Cognição , Disfunção Cognitiva/metabolismo , Estudos Transversais , Feminino , Humanos , Estilo de Vida , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de PósitronsRESUMO
This longitudinal study evaluates the prognostic impact of amyloid PET in patients suspected of Alzheimer's disease and presenting with isolated cerebrospinal fluid (CSF) increases in P-Tau proteins (NCT02556502). The rate of conversion, based on the DSM-5 criteria and all collected data (average follow-up of 39.2±13.2 months), was determined by a panel of experts blinded to the PET results and was 75%(6/8) for positive and 35%(6/17) for negative baseline amyloid PET. In this population with isolated CSF increases in P-Tau, a positive baseline amyloid PET was associated with greater than twice the proportion of dementia conversions within the following three years.
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Doença de Alzheimer/diagnóstico por imagem , Proteínas Amiloidogênicas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Biomarcadores/líquido cefalorraquidiano , Feminino , Radioisótopos de Flúor , França , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Prognóstico , EstilbenosRESUMO
BACKGROUND: The environment of patients with Alzheimer's disease and related disorders (ADRD) intensifies the consequences of cognitive impairment and exacerbates behavioral problems if inappropriate or, conversely, mitigate these problems if its design is tailored to the needs of these persons. OBJECTIVE: We evaluate the impacts of hospitalization and of a specific healing garden on self-consciousness which represent a central impairment in ADRD. The self-consciousness questionnaire (SCQ), validated for its assessment at mild to moderate phases of the disease, explores the dimensions of personal identity, awareness of cognitive deficiencies, self-assessment of affective state, awareness of body representation, prospective memory, capacity for introspection, and moral judgments. METHODS: After having verified, by means of a preliminary study, its feasibility to the more advanced stages of the disease, this questionnaire allowed assessment of the impact of the environment by comparing, in routine care, patients hospitalized in a cognitive-behavioral unit who solely remain indoors with others who use the Art, Memory and Life healing garden. RESULTS: A significant decrease in SCQ due to an increase in anosognosia during hospitalization was observed in the group that remained indoors. For the group using the garden, a positive effect on overall SCQ score was observed, as a result of a significant improvement in body representation as the driving parameter. CONCLUSION: Factors that are grounded in the hypotheses that spearheaded its conception, such as sensory enrichment, familiarity, contact with nature, scaffolding role for cognitive functions, supportive effect for social interactions, and the "Nancy hypotheses of beauty", thus contribute to their validation.
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Doença de Alzheimer/psicologia , Doença de Alzheimer/terapia , Terapia Cognitivo-Comportamental/métodos , Jardinagem , Autoimagem , Idoso , Idoso de 80 Anos ou mais , Agnosia/complicações , Doença de Alzheimer/complicações , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Inquéritos e QuestionáriosRESUMO
PURPOSE: Digital PET cameras markedly improve sensitivity and spatial resolution of brain 18F-FDG PET images compared to conventional cameras. Our study aimed to assess whether specific control databases are required to improve the diagnostic performance of these recent advances. METHODS: We retrospectively selected two groups of subjects, twenty-seven Alzheimer's Disease (AD) patients and twenty-two healthy control (HC) subjects. All subjects underwent a brain 18F-FDG PET on a digital camera (Vereos, Philips®). These two group (AD and HC) are compared, using a Semi-Quantitative Analysis (SQA), to two age and sex matched controls acquired with a digital PET/CT (Vereos, Philips®) or a conventional PET/CT (Biograph 6, Siemens®) camera, at group and individual levels. Moreover, individual visual interpretation of SPM T-maps was provided for the positive diagnosis of AD by 3 experienced raters. RESULTS: At group level, SQA using digital controls detected more marked hypometabolic areas in AD (+ 116 cm3 at p < 0.001 uncorrected for the voxel, corrected for the cluster) than SQA using conventional controls. At the individual level, the accuracy of SQA for discriminating AD using digital controls was higher than SQA using conventional controls (86% vs. 80%, p < 0.01, at p < 0.005 uncorrected for the voxel, corrected for the cluster), with higher sensitivity (89% vs. 78%) and similar specificity (82% vs. 82%). These results were confirmed by visual analysis (accuracies of 84% and 82% for digital and conventional controls respectively, p = 0.01). CONCLUSION: There is an urgent need to establish specific digital PET control databases for SQA of brain 18F-FDG PET images as such databases improve the accuracy of AD diagnosis.
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OBJECTIVE: To assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)-specific neurodegeneration using longitudinal multimodal neuroimaging measures. METHODS: Change in verbal fluency was analyzed among 2261 non-demented individuals with a follow-up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non-amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow-up, and relations with magnetic resonance imaging (MRI; n = 1536) and 18F-fluorodeoxyglucose brain positron emission tomography (18F-FDG-PET) imaging (n = 756) using linear regression models across 2 years of follow-up. RESULTS: Semantic fluency declined-fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)-while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced 18F-FDG-PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus-posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole-brain neurodegeneration over time was associated with faster decline in both fluencies, while AD-specific regions were associated with a faster rate of decline in semantic but not letter fluency. INTERPRETATION: This study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD-specific neurodegeneration.
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INTRODUCTION: Subjective cognitive complaints may be a signature of preclinical stage Alzheimer's disease. However, the link between subjective cognitive and non-cognitive complaints and brain alterations remains unclear. METHODS: The relationship between cognitive and non-cognitive complaints and brain biomarkers, measured by structural magnetic resonance imaging, was investigated in 2056 participants of the MEMENTO cohort of outpatients, who were dementia-free at baseline. We assessed whether the cognitive status at inclusion or the presence of the apolipoprotein E gene variant (APOE) ε4 could modulate the association between the intensity of complaints and brain lesions. RESULTS: Smaller hippocampal volume was associated with higher memory complaints and discomfort in daily life. In APOE ε4 carriers, smaller whole-brain white matter and gray matter volumes and gyrification indices in several regions of interest of the parietal and temporal lobes, in the entorhinal and the para-hippocampal gyrus, were associated with higher memory complaint score. CONCLUSIONS: The intensity of subjective complaints in not only memory but discomfort in daily life was associated with brain degeneration markers. The presence of APOE ε4 modulated the relationships between subjective memory complaints and brain alterations.
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BACKGROUND: Atypical cerebrospinal fluid (CSF) patterns, involving an increase in the concentration of phosphorylated-tau (P-tau) proteins but normal amyloid-ß concentration, are not uncommon in patients with mild neurocognitive disorders and suspected Alzheimer's disease (AD). In these conditions, however, AD diagnosis may be ruled out in the absence of any amyloid deposition at positron-emission tomography (PET). This pilot cross-sectional study was aimed to determine whether this negativity of amyloid PET can be predicted by CSF profiles in such patients. METHODS: Twenty-five patients (73 [68-80] years, 10 women) with mild neurocognitive disorders, suspected AD and an increase in the CSF concentration of P-tau proteins but normal Aß42 concentration and Aß42/Aß40 ratio were prospectively included and referred to a 18F-florbetaben PET. The latter was considered as definitively negative with the conjunction of both visual (brain amyloid plaque load score) and quantified (standard uptake value ratios) criteria. Predictors of a negative PET were searched among current CSF biomarkers (Aß42, Aß40, T-tau, P-tau, Aß42/Aß40, Aß42/p-tau). RESULTS: Amyloid PET was negative in 15 patients (60%) with a CSF Aß42 concentration being the sole independent predictor of this negativity. The criterion of an Aß42 concentration in the very high range (> 843 pg/mL), observed in 60% (15/25) of the study patients, was associated with a negative amyloid PET in 93% (14/15) of cases. CONCLUSIONS: In mild neurocognitive disorders patients with suspected AD and showing an increase in CSF P-tau protein level, amyloid PETs are commonly negative, when Aß42 concentration is in the very high range. In such case, AD diagnosis based on biomarkers can be ruled out with reasonable certainty, without the need for additional CSF second-line assays or results from amyloid PET.
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Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Feminino , Humanos , Masculino , Fragmentos de Peptídeos/metabolismo , Fosforilação/fisiologia , Projetos Piloto , Estudos Prospectivos , Proteínas tau/metabolismoRESUMO
BACKGROUND/OBJECTIVE: The aim of this study was to assess, in routine, the rates with which an amyloid deposition was documented by 18F-florbetaben PET in patients with suspected Alzheimer's disease (AD) but with isolated increases in cerebrospinal fluid (CSF) tau-protein concentrations, and the subsequent impact of these PET results on medical management. METHODS: This prospective study included 34 patients with mild neurocognitive disorders (MND) and suspected AD (73±9 years, 16 women) and with abnormal CSF concentrations in total-tau (T-tau) and/or phosphorylated-tau (P-tau) proteins but normal Aß42 concentration and Aß42/Aß40 ratio. These patients were referred to 8F-florbetaben PET from which the PET-related changes in the confidence for AD diagnosis (low, intermediate, or high) and treatments were reported. RESULTS: The PET examinations were positive for amyloid deposition (brain amyloid plaque load, BAPL score >1) in none of the 9 patients with an increase in only T-tau proteins and in 8 among the 25 (32%) with an increase in P-tau proteins (one BAPL score of 2 and seven BAPL scores of 3). Knowledge of the PET results was associated with subsequent changes in diagnostic confidence in 44% of patients (15/34) and in the intention-to-treat with a cholinesterase inhibitor drug in 18% (6/34). CONCLUSION: In patients with suspected AD and isolated increase in CSF tau protein concentrations, an amyloid deposition is documented by 18F-florbetaben PET in as much as one third of cases when the concentration of P-tau is abnormal, and PET results are associated with significant further changes in medical management.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Proteínas Amiloidogênicas/metabolismo , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Neuroimagem , Fragmentos de Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , EstilbenosRESUMO
OBJECTIVE: We aimed to study the epidemiology of the prodromal and mild stages of Alzheimer's disease (AD) patients who are eligible for clinical trials with disease-modifying therapies. SETTINGS: We analysed two large complementary databases to study the incidence and characteristics of this population on a nationwide scope in France from 2014 to 2018. The National Alzheimer Database contains data from 357 memory centres and 90 private neurologists. Data from 2014 to 2018 have been analysed. PARTICIPANTS: Patients, 50-85 years old, diagnosed with AD who had an Mini-Mental State Exam (MMSE) score of ≥20 were included. We excluded patients with mixed and non-AD neurocognitive disorders. PRIMARY OUTCOME MEASURE: Descriptive statistics of the population of interest was the primary measure. RESULTS: In the National Alzheimer Database, 550 198 patients were assessed. Among them, 72 174 (13.1%) were diagnosed with AD and had an MMSE ≥20. Using corrections for specificity of clinical diagnosis of AD, we estimated that about 50 000 (9.1%) had a prodromal or mild AD. In the combined electronic clinical records database of 11 French expert memory centres, a diagnosis of prodromal or mild AD, certified by the use of cerebrospinal fluid AD biomarkers, could be established in 195 (1.3%) out of 14 596 patients. CONCLUSIONS: AD was not frequently diagnosed at a prodromal or mild dementia stage in France in 2014 to 2018. Diagnosis rarely relied on a pathophysiological marker even in expert memory centres. National databases will be valuable to monitor early stage AD diagnosis efficacy in memory centres when a disease-modifying treatment becomes available.