Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup.

The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.

Time-encoded ASL reveals lower cerebral blood flow in the early AD continuum.

INTRODUCTION: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time-encoded arterial spin labeling (te-ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. METHODS: We compared te-ASL with single-postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aß) negative (-), CU Aß positive (+), and CI Aß+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. RESULTS: te-ASL was more sensitive at detecting CBF reduction in the CU Aß+ and CI Aß+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aß, tau, synaptic dysfunction, and neurodegeneration. DISCUSSION: CBF reduction occurs early in the AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF changes in AD. HIGHLIGHTS: Lower CBF can be detected in CU subjects in the early AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF alterations in AD. CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration.

Neuroimaging Methods for MRI Analysis in CSF Biomarkers Studies.

Among others, the existence of pathophysiological biomarkers such as cerebrospinal fluid (CSF) Aß-42, t-tau, and p-tau preceding the onset of Alzheimer's disease (AD) symptomatology has shifted the conceptualization of AD as a continuum. In addition, magnetic resonance imaging (MRI) enables the study of structural and functional cross-sectional correlates and longitudinal changes in vivo, and therefore, the combination of CSF data and imaging analyses emerges as a synergistic approach to understand the structural correlates related with specific AD-related biomarkers. In this chapter, we describe the methods used in neuroimaging that will allow researchers to combine data on CSF metabolites with imaging analyses.

Omega-3 blood biomarkers relate to brain glucose uptake in individuals at risk of Alzheimer's disease dementia.

INTRODUCTION: Brain glucose hypometabolism is a preclinical feature of Alzheimer's disease (AD). Dietary omega-3 fatty acids promote brain glucose metabolism, but clinical research is incipient. Circulating omega-3s objectively reflect their dietary intake. METHODS: This was a cross-sectional study in 320 cognitively unimpaired participants at increased risk of AD dementia. Using lipidomics, we determined blood docosahexaenoic (DHA) and alpha-linolenic (ALA) acid levels (omega-3s from marine and plant origin, respectively). We assessed brain glucose metabolism using [18-F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). RESULTS: Blood ALA directly related to FDG uptake in brain areas known to be affected in AD. Stronger associations were observed in apolipoprotein E ε4 carriers and homozygotes. For DHA, significant direct associations were restricted to amyloid beta-positive tau-positive participants. DISCUSSION: Blood omega-3 directly relate to preserved glucose metabolism in AD-vulnerable brain regions in individuals at increased risk of AD dementia. This adds to the benefits of omega-3 supplementation in the preclinical stage of AD dementia. Highlights: Blood omega-3s were related to brain glucose uptake in participants at risk of Alzheimer's disease (AD) dementia.Complementary associations were observed for omega-3 from marine and plant sources.Foods rich in omega-3 might be useful in early features of AD.

Association between telomere length and cognitive function among cognitively unimpaired individuals at risk of Alzheimer's disease.

INTRODUCTION: Leukocyte telomere length (LTL) is an objective biomarker of biological aging, and it is proposed to play a crucial role in Alzheimer's disease (AD) risk. We aimed at evaluating the cross-sectional association between LTL and cognitive performance in middle-aged cognitively unimpaired individuals at increased risk of AD. METHODS: A total of 1520 participants from the ALFA cohort were included. Relative telomere length was measured in leukocytes through qPCR. LTL was residualized against age and sex, and associations with cognitive performance were assessed in short and long groups based on residualized LTL (rLTL). Interactions with sex and genetic risk of AD were tested. RESULTS: Non-linear associations were found between LTL and episodic memory (EM). Better EM was associated with longer rLTL among women in the short rLTL group. DISCUSSION: Results suggest a potential role of telomeres in the cognitive aging process with sex-specific patterns.

The mediating role of neuroimaging-derived biological brain age in the association between risk factors for dementia and cognitive decline in middle-aged and older individuals without cognitive impairment: a cohort study.

BACKGROUND: Neuroimaging-based brain-age delta has been shown to be a mediator linking cardiovascular risk factors to cognitive function. We aimed to assess the mediating role of brain-age delta in the association between modifiable risk factors of dementia and longitudinal cognitive decline in middle-aged and older individuals who are asymptomatic, stratified by Alzheimer's disease pathology. We also explored whether the mediation effect is specific to cognitive domain. METHODS: In this cohort study, we included participants from the ALFA+ cohort aged between 45 years and 65 years who were cognitively unimpaired and who had available structural MRI, cerebrospinal fluid ß-amyloid (Aß)42 and Aß40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaßeta Brain Research Center (Barcelona, Spain). Included individuals underwent a first assessment between Oct 25, 2016, and Jan 28, 2020, and a follow-up cognitive assessment 3·28 (SD 0·27) years later. We computed brain-age delta and composites of different cognitive function domains (preclinical Alzheimer's cognitive composite [PACC], attention, executive function, episodic memory, visual processing, and language). We used partial least squares path modelling to explore mediation effects in the associations between modifiable risk factors (including cardiovascular, mental health, mood, metabolic or endocrine history, and alcohol use) and changes in cognitive composites. To assess the role of Alzheimer's disease pathology, we computed separate models for Aß-negative and Aß-positive individuals. FINDINGS: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aß-positive and 194 as Aß-negative. In Aß-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22-16·66]) the association between modifiable risk factors and decline in overall cognition (across cognitive domains). Brain-age delta fully mediated (mediation proportion 28·03% [26·25-29·21]) the effect of modifiable risk factors on the PACC, wherein increased values for risk factors correlated with an older brain-age delta, and, consequently, an older brain-age delta was linked to greater PACC decline. This effect appears to be primarily driven by memory decline. Mediation was not significant in Aß-negative individuals (3·52% [0·072-4·17]) on PACC, although path coefficients were not significantly different from those in the Aß-positive group. INTERPRETATION: Our findings suggest that brain-age delta captures the association between modifiable risk factors and longitudinal cognitive decline in middle-aged and older people. In asymptomatic middle-aged and older individuals who are Aß-positive, the pathology might be the strongest driver of cognitive decline, whereas the effect of risk factors is smaller. Our results highlight the potential of brain-age delta as an objective outcome measure for preventive lifestyle interventions targeting cognitive decline. FUNDING: La Caixa Foundation, the TriBEKa Imaging Platform, and the Universities and Research Secretariat of the Catalan Government. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Association Between Years of Education and Amyloid Burden in Patients With Subjective Cognitive Decline, MCI, and Alzheimer Disease.

OBJECTIVES: Higher-educated patients with Alzheimer disease (AD) can harbor greater neuropathologic burden than those with less education despite similar symptom severity. In this study, we assessed whether this observation is also present in potential preclinical AD stages, namely in individuals with subjective cognitive decline and clinical features increasing AD likelihood (SCD+). METHODS: Amyloid-PET information ([18F]Flutemetamol or [18F]Florbetaben) of individuals with SCD+, mild cognitive impairment (MCI), and AD were retrieved from the AMYPAD-DPMS cohort, a multicenter randomized controlled study. Group classification was based on the recommendations by the SCD-I and NIA-AA working groups. Amyloid PET images were acquired within 8 months after initial screening and processed with AMYPYPE. Amyloid load was based on global Centiloid (CL) values. Educational level was indexed by formal schooling and subsequent higher education in years. Using linear regression analysis, the main effect of education on CL values was tested across the entire cohort, followed by the assessment of an education-by-diagnostic-group interaction (covariates: age, sex, and recruiting memory clinic). To account for influences of non-AD pathology and comorbidities concerning the tested amyloid-education association, we compared white matter hyperintensity (WMH) severity, cardiovascular events, depression, and anxiety history between lower-educated and higher-educated groups within each diagnostic category using the Fisher exact test or χ2 test. Education groups were defined using a median split on education (Md = 13 years) in a subsample of the initial cohort, for whom this information was available. RESULTS: Across the cohort of 212 individuals with SCD+ (M(Age) = 69.17 years, F 42.45%), 258 individuals with MCI (M(Age) = 72.93, F 43.80%), and 195 individuals with dementia (M(Age) = 74.07, F 48.72%), no main effect of education (ß = 0.52, 95% CI -0.30 to 1.58), but a significant education-by-group interaction on CL values, was found (p = 0.024) using linear regression modeling. This interaction was driven by a negative association of education and CL values in the SCD+ group (ß = -0.11, 95% CI -4.85 to -0.21) and a positive association in the MCI group (ß = 0.15, 95% CI 0.79-5.22). No education-dependent differences in terms of WMH severity and comorbidities were found in the subsample (100 cases with SCD+, 97 cases with MCI, 72 cases with dementia). DISCUSSION: Education may represent a factor oppositely modulating subjective awareness in preclinical stages and objective severity of ongoing neuropathologic processes in clinical stages.

Where is VALDO? VAscular Lesions Detection and segmentatiOn challenge at MICCAI 2021.

Imaging markers of cerebral small vessel disease provide valuable information on brain health, but their manual assessment is time-consuming and hampered by substantial intra- and interrater variability. Automated rating may benefit biomedical research, as well as clinical assessment, but diagnostic reliability of existing algorithms is unknown. Here, we present the results of the VAscular Lesions DetectiOn and Segmentation (Where is VALDO?) challenge that was run as a satellite event at the international conference on Medical Image Computing and Computer Aided Intervention (MICCAI) 2021. This challenge aimed to promote the development of methods for automated detection and segmentation of small and sparse imaging markers of cerebral small vessel disease, namely enlarged perivascular spaces (EPVS) (Task 1), cerebral microbleeds (Task 2) and lacunes of presumed vascular origin (Task 3) while leveraging weak and noisy labels. Overall, 12 teams participated in the challenge proposing solutions for one or more tasks (4 for Task 1-EPVS, 9 for Task 2-Microbleeds and 6 for Task 3-Lacunes). Multi-cohort data was used in both training and evaluation. Results showed a large variability in performance both across teams and across tasks, with promising results notably for Task 1-EPVS and Task 2-Microbleeds and not practically useful results yet for Task 3-Lacunes. It also highlighted the performance inconsistency across cases that may deter use at an individual level, while still proving useful at a population level.

Reaprendizaje de vocabulario. Análisis comparativo entre un caso de demencia semántica y enfermedad de Alzheimer con afectación predominante del lenguaje / Relearning vocabulary. A comparative analysis between a case of dementia and Alzheimer’s disease with predominant compromise of language

Introducción. La demencia semántica se caracteriza por una pérdida progresiva del contenido semántico que afecta inicialmente la capacidad para nominar, asociándose a atrofia temporal anterior asimétrica. En la enfermedad de Alzheimer (EA) con afectación predominante del lenguaje, la anomia es también el síntoma principal. Se estudió la capacidad de reaprendizaje de vocabulario en un paciente de cada una de estas dos formas de anomia degenerativa. Casos clínicos. Ambos casos presentaban edad, género, escolarización y grado de afectación similares. La capacidad de nominar una lista de 40 imágenes se evaluó basalmente, tras 20 sesiones de reaprendizaje, al mes y a los seis meses. La paciente con demencia semántica basalmente nominaba 25/40 objetos, tras el reaprendizaje 40/40, al mes 35/40 y a los 6 meses 27/40. La paciente con EA basalmente nominaba 29/40, tras el reaprendizaje 30/40, al mes 29/40, a los 6 meses 32/40. No se objetivaron intrusiones tras el reaprendizaje.Conclusiones. La paciente con demencia semántica fue capaz de reaprender todo el vocabulario presentado, si bien tras interrumpir el tratamiento perdió lo adquirido. La EA no mejoró su capacidad de nominación con la terapia. Estas diferencias sugieren una afectación diferencial en los circuitos de aprendizaje y consolidación. Los sujetos con demencia semántica, pero no los sujetos con EA, podrían beneficiarse de estrategias de reaprendizaje de palabras con esta metodología (AU)

Introduction. Semantic dementia is characterised by a progressive loss of semantic content that initially affects the capacity to name things, and is associated with asymmetric atrophy of the anterior temporal lobes. In Alzheimer’s disease (AD) with predominant compromise of language, anomia is also the main symptom. The study examined the capacity to relearn vocabulary of two patients, each exhibiting one of these two forms of degenerative anomia. Case reports. The two cases presented similar ages, gender, levels of schooling and degree of compromise. Their capacity to name a list of 40 pictures was evaluated at baseline, following 20 sessions of relearning, at one month and at six months. The patient with semantic dementia named 25/40 objects at baseline, 40/40 after relearning, 35/40 at one month and 27/40 at six months. The patient with AD named 29/40 at baseline, 30/40 after relearning, 29/40 at one month and 2/40 at six months. No intrusions were observed following relearning. Conclusions. The patient with semantic dementia was able to relearn all the vocabulary she was shown, even though she lost everything she had acquired after treatment was interrupted. The AD patient did not improve her naming capacity with therapy. These differences suggest that the learning and consolidation circuits are affected in different ways. Subjects with semantic dementia, but not those with AD, could benefit from word relearning strategies with this method (AU)

Eficacia y seguridad de la palidotomía posteroventral en el tratamiento de la enfermedad de Parkinson avanzada / Efficacy and safety of posteroventral pallidotomy for the treatment of advanced Parkinson's disease

Fundamento: Analizar la efectividad y seguridad de la palidotomía unilateral guiada por microrregistro en el tratamiento de la enfermedad de Parkinson (EP) avanzada después de 3 meses y al año de la intervención. Pacientes y métodos: Se intervinieron 23 pacientes con EP avanzada (edad media, 58,9 años; duración media de la enfermedad, 14,4 años). La evaluación clínica, a los 3 meses (n = 23) y al año (n = 16) de la intervención, se efectuó por la mañana 12 h después de la última dosis de medicación (off) y tras la administración de un 100-150 por ciento de la dosis habitual (on). En cada una de las evaluaciones se administraron escalas para valoración de las actividades de la vida diaria, evaluación motora y discinesias, así como pruebas cronometradas de la actividad motora. Resultados: Las discinesias contralaterales al hemisferio intervenido se redujeron un 92 por ciento a los 3 meses y un 89 por ciento al año. Los síntomas motores de la enfermedad mejoraron un 36,5 por ciento a los 3 meses y un 26,7 por ciento al año de la intervención. En el análisis anual apareció una mejoría en el temblor contralateral del 48 por ciento, en la rigidez del 36,2 por ciento y en la bradicinesia del 37,4 por ciento Todos los cambios observados fueron estadísticamente significativos (p < 0,01). Los efectos adversos fueron leves o transitorios. La dosis de medicación antiparkinsoniana no se modificó durante el tiempo de seguimiento. Conclusiones: La palidotomía unilateral guiada por microrregistro es un método seguro y eficaz para mejorar los síntomas de la EP contralaterales, siendo especialmente eficaz en el tratamiento de las discinesias inducidas por L-dopa. (AU)

Características clínicas de una familia con enfermedad de Alzheimer de inicio temprano asociada a una mutación (M139T) en el gen de la presenilina 1 / Clinical characteristics of a family with early-onset Alzheimer's disease associated with a presenilin 1 mutation (M139T)

FUNDAMENTO: Describir las características clínicas y el estudio genético de una familia con enfermedad de Alzheimer familiar con patrón autosómico dominante. PACIENTES Y MÉTODO: Se estudiaron las características clínicas y las exploraciones complementarias de los individuos de esta familia. Se realizó un estudio genético del caso índice en busca de mutaciones de los genes de la proteína precursora de amiloide, presenilina 1 y presenilina 2 mediante estudio de polimorfismos de cadena sencilla y posterior secuenciación. Se determinó el genotipo APOE. RESULTADOS: El caso índice era un paciente de 52 años con enfermedad de Alzheimer de inicio a los 49 años. Como antecedentes familiares destacaba la presencia de varios miembros de la familia con demencia. El cuadro clínico en todos ellos se caracterizaba por alteraciones cognitivas y conductuales de inicio entre los 40 y 50 años. Se observó una variabilidad importante en la edad de inicio entre los miembros de la familia (intervalo 39-51 años). El estudio genético del caso índice detectó una mutación en el gen de la presenilina 1, que predecía un cambio de metionina por treonina en el codón 139 (M139T). El genotipo APOE fue 3/3. CONCLUSIONES: El cuadro clínico de esta familia con la mutación M139T en el gen de la presenilina 1 es similar a la forma esporádica de enfermedad de Alzheimer. La variabilidad observada en la edad de inicio de la demencia indica que, a pesar de ser una enfermedad determinada genéticamente, otros factores genéticos o ambientales modifican la expresión clínica (AU)