Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia.

Background: Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy.

Methods: We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included patients with FTD ( = 189), Alzheimer’s Disease dementia (AD;  = 232), and cognitively unimpaired individuals ( = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 67).

Regional associations between cerebrovascular disease and cholinergic white matter pathways in the Lewy body continuum.

Cerebrovascular disease is common in patients on the Lewy body (LB) continuum (dementia with Lewy bodies (DLB) and prodromal-DLB). White matter signal abnormality (WMSA) volume is higher in patients with LB than controls, both globally and in cholinergic white matter. However, it remains unknown if the higher WMSA in cholinergic white matter reflects selective cholinergic vulnerability or results from higher global WMSA.

Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer's disease and involves APOE4.

In the central nervous system, apolipoprotein (APO)E-containing lipoprotein particles mediate the transport of glial-derived cholesterol to neurons, which is essential for neuronal membrane remodeling and maintenance of the myelin sheath. We aimed to examine cholesterol transport via lipoprotein particles in cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients compared to control individuals. Additionally, we explored the ability of reconstituted HDL containing different APOE isoforms to regulate cholesterol transport.

CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer's disease patients.

Background: Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL), APOE E4 carriership (APOE4), and extremely low CSF Aβ42 concentrations (A). We hypothesize that studying the CSF proteome of Alzheimer's disease (AD) dementia patients from a high-risk group (MBLAPOE4A) can inform on the biological underpinnings of ARIA risk and aid the progress of ARIA risk biomarkers.

Prospective evaluation of plasma pTau stability for the detection of Alzheimer's disease in a tertiary memory clinic.

Background: Knowledge on the effect of analytical variability and storage conditions are essential for the successful implementation of plasma pTau in prospective settings.

Aims: To investigate the performance of plasma pTau, measured in consecutive samples with LUMIPULSE, for detecting Alzheimer's disease in a prospective memory clinic setting, along with evaluating its pre-analytical and analytical stability.

Methods: We prospectively measured pTau using the LUMIPULSE automated platform in consecutive patient plasma samples collected between May and November 2024 at the Sant Pau Memory Unit (Barcelona).

Impact of Alzheimer's disease on sleep in adults with Down syndrome.

Introduction: Down syndrome (DS) is a genetic form of Alzheimer's disease (AD), with a high prevalence of sleep disorders, but data in adults with DS and dementia are lacking. We aim to assess sleep in adults with DS across the AD continuum.

Methods: We studied 78 healthy controls and 229 adults with DS (154 asymptomatic, 25 with prodromal AD, and 75 with AD) with subjective sleep measures and objective nocturnal polysomnography.

Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease.

Almost all individuals with Down Syndrome (DS) develop Alzheimer's disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n = 229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD pathophysiology from asymptomatic to dementia stages and compared the proteomic biomarker changes in DS to those observed in LOAD and ADAD.

Serum level changes of the synaptic marker beta-synuclein in Alzheimer's disease continuum and other dementias.

Background: Beta-synuclein is an emerging blood biomarker for detecting synaptic damage in Alzheimer's disease (AD) but its role in early AD as well as in other dementias is unclear.

Methods: We measured with immunoprecipitation mass-spectrometry serum beta-synuclein levels in an exploratory cohort of 80 patients recruited at the University of Perugia (Perugia, Italy) (n=56 AD; n=24 controls) and in a validation cohort of 269 patients recruited at the University of Barcelona (Barcelona, Spain) (n=108 AD; n=53 frontotemporal lobar degeneration (FTLD); n=73 dementia with Lewy bodies and mild cognitive impairment (MCI) with Lewy bodies, together Lewy body disease (LBD); n=27 controls). We tested associations with diagnostic groups, cognitive decline and other cerebrospinal fluid (CSF) and blood markers (phosphorylated tau protein in position 181 (pTau181), neurofilament light chain protein (NfL), glial fibrillar acidic protein (GFAP)).

Clinical use and reporting of neurofilament quantification in neurological disorders: A global overview.

Introduction: Neurofilament light chain (NfL) quantification aids in diagnosing and predicting neurological disorders, but clinical and laboratory practices vary across centers. Differences in result interpretation and reporting further challenge test commutability. This study aimed to review the global analytical and post-analytical methods used for NfL measurement in routine clinical practice across different contexts.

Diagnostic performance of plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL along the continuum of Alzheimer's disease and non-AD dementias: An international multi-center study.

Introduction: Plasma phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and amyloid beta ratio (Aβ42/40) may have diagnostic and prognostic value in Alzheimer's disease (AD). Here we assess which markers can best identify AD from controls and other non-AD dementias in a large international multi-center study.

Methods: Plasma samples (n = 1298) were collected from six international centers.

Alpha-synuclein co-pathology in Down syndrome-associated Alzheimer's disease.

Introduction: Alpha-synuclein (αSyn) seed amplification assay (SAA) enables in vivo study of αSyn but remains underexplored in Down syndrome-associated Alzheimer's disease (DSAD).

Methods: We analyzed αSyn-SAA in cerebrospinal fluid (CSF) from 270 adults with Down syndrome, from the Down Alzheimer Barcelona Neuroimaging Initiative and from the AD21 cohort from the Department of Neurology at the University Hospital, Ludwig Maximilian University of Munich, Germany. Neuropathological examinations were conducted in 19 brain donors (five with ante mortem CSF).

The Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) and its contributions to understanding Alzheimer's disease in Down syndrome: A decade of discovery.

Down syndrome (DS) is a genetic form of Alzheimer's disease (AD) that offers crucial insights into AD pathogenesis. The Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) is a population-based multimodal biomarker cohort studying AD's natural history and clinical trials in DS. DABNI included 1135 participants (mean age 42.

Cargo of small extracellular vesicles from neuronal origin shows progression of dementia in individuals with Down syndrome.

Introduction: Individuals with Down syndrome (DS) are at an ultra-high risk of developing Alzheimer's disease (AD). Diagnosis of AD onset in people with DS can be challenging due to the variable degrees of intellectual disability and cognitive impairment among individuals.

Methods: Plasma samples from individuals with DS diagnosed with AD dementia (n = 33), prodromal AD (n = 31), or cognitively stable (n = 43) were enriched for neuron-derived extracellular vesicles (NDEV) using immunocapture with the L1CAM antibody.

Development and validation of a novel Simoa assay for NPTX2 in Alzheimer's disease and Down syndrome.

Introduction: Synaptic dysfunction and loss are pathological hallmarks of neurodegenerative diseases. Neuronal pentraxin 2 (NPTX2), a presynaptic protein involved in synaptic plasticity, has been linked to cognitive decline in Alzheimer's disease (AD) and other neurodegenerative disorders.

Methods: We developed and validated a novel single molecule array (Simoa) for NPTX2 in cerebrospinal fluid, which was evaluated in two independent cohorts.

Association of Plasma Phosphorylated Tau 217 With Clinical Deterioration Across Alzheimer Disease Stages.

Background And Objectives: Phosphorylated tau at threonine 217 (p-tau217) is a highly sensitive blood-based biomarker for Alzheimer disease (AD) pathology, showing high diagnostic accuracy. However, its prognostic value across different clinical stages of AD remains unclear. The aim of this study was to assess the prognostic utility of plasma p-tau217, measured using a commercially available immunoassay, regarding clinical and functional decline across the clinical stages of AD in a cohort with up to 10 years of follow-up.

Cerebrovascular co-pathology and cholinergic white matter pathways along the Lewy body continuum.

Dementia with Lewy bodies often presents with cholinergic degeneration and varying degrees of cerebrovascular disease. There is a lack of radiological methods for evaluating cholinergic degeneration in dementia with Lewy bodies. We investigated the potential of the Cholinergic Pathway Hyperintensities Scale (CHIPS) in identifying cerebrovascular disease-related disruptions in cholinergic white matter pathways, offering a practical and accessible method for assessing cholinergic integrity in neurodegenerative diseases.

Sex differences in the executive and behavioral reserve of autosomal dominant frontotemporal dementia.

Introduction: Self-reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear.

Methods: We analyzed 394 genetic-FTD patients and 279 controls from the ALLFTD consortium, assessing annual neuropsychological performance and MRI-based cortical thickness. Clinical characteristics and cortical thickness were compared between sexes.

Plasma p-tau212 as a biomarker of sporadic and Down syndrome Alzheimer's disease.

Background: All individuals with Down syndrome (DS) will develop full-blown Alzheimer´s disease (AD) pathology by age 40. Several genes encoded in chromosome 21, including dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), have been proven to contribute to the pathology. Phosphorylation of tau at threonine-212 (p-tau212) is very sensitive to DYRK1A phosphorylation and is increased in DSAD brain lysates.

Nerve growth factor precursor alterations in neuron-derived extracellular vesicles from individuals with Down syndrome along the Alzheimer's disease continuum.

Background: In Down syndrome (DS) and Alzheimer's disease (AD), nerve growth factor precursor protein (proNGF) accumulates in the brain. However, its non-invasive detection using neuron-derived extracellular vesicles (NDEVs) from plasma remains unexplored.

Methods: We included 139 adults with DS (45 asymptomatic [aDS], 94 symptomatic for AD [sDS]) and 37 healthy controls.

A Novel CHMP2B Splicing Variant in Atypical Presentation of Familial Frontotemporal Lobar Degeneration.

C-truncating variants in the charged multivesicular body protein 2B (CHMP2B) gene are a rare cause of frontotemporal lobar degeneration (FTLD), previously identified only in Denmark, Belgium, and China. We report a novel CHMP2B splice-site variant (c.35-1G>A) associated with familial FTLD in Spain.

Advancing Personalized Medicine in Alzheimer's Disease: Liquid Biopsy Epigenomics Unveil ε4-Linked Methylation Signatures.

Recent studies show that patients with Alzheimer's disease (AD) harbor specific methylation marks in the brain that, if accessible, could be used as epigenetic biomarkers. Liquid biopsy enables the study of circulating cell-free DNA (cfDNA) fragments originated from dead cells, including neurons affected by neurodegenerative processes. Here, we isolated and epigenetically characterized plasma cfDNA from 35 patients with AD and 35 cognitively healthy controls by using the Infinium MethylationEPIC BeadChip array.

Medial temporal lobe atrophy in Down syndrome along the Alzheimer's disease continuum.

Medial temporal lobe structures are among the first areas impacted by neurofibrillary tangle pathology, making volumetric changes of these areas promising biomarkers for Alzheimer's disease. To date, little is known about the integrity of these regions in individuals with Down syndrome, a population that almost invariably develops Alzheimer's disease and thus offers a unique opportunity to determine the earliest structural changes related to the disease. We aimed to characterize the sequential involvement of medial temporal lobe structures with Alzheimer's disease progression, explore associations with fluid biomarkers of Alzheimer's pathology and assess the utility of regional volumes and cortical thickness in distinguishing Alzheimer's disease clinical stages in Down's syndrome.

Regional Brain Metabolism across the Alzheimer's Disease Continuum in Down Syndrome.

Objective: The goal was to examine the effect of sociodemographic variables, Alzheimer's disease (AD) clinical stages and pathology on brain metabolism in Down syndrome (DS).

Methods: We included 71 euploid healthy controls (HC) and 105 adults with DS (67 asymptomatic, 12 prodromal, and 26 with dementia) from the Down-Alzheimer Barcelona Neuroimaging Initiative. Participants underwent [18F]fluorodeoxyglucose positron emission tomography, 3 Tmagnetic resonance imaging, and lumbar puncture to measure cerebrospinal fluid (CSF) biomarkers (ratio beween amyloid β peptide 42 and 40, phosphorylated tau 181, and neurofilament light chain [NfL]).

Relationship of cognitive decline with glucocerebrosidase activity and amyloid-beta 42 in DLB and PD.

Objective: Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) share clinical, pathological, and genetic risk factors, including GBA1 and APOEε4 mutations. Biomarkers associated with the pathways of these mutations, such as glucocerebrosidase enzyme (GCase) activity and amyloid-beta 42 (Aβ42) levels, may hold potential as predictive indicators, providing valuable insights into the likelihood of cognitive decline within these diagnoses. Our objective was to determine their association with cognitive decline in DLB and PD.

Evaluation of cerebrospinal fluid levels of VAMP-2 and SNAP-25 in a dementia with Lewy bodies clinical cohort stratified by Alzheimer's pathophysiological biomarkers.

Background: Synaptic protein levels in cerebrospinal fluid (CSF) may represent much-needed objective biomarkers of cognitive impairment, disease progression and drug efficacy in patients with dementia with Lewy bodies (DLB). Soluble N-ethylmaleimide-sensitive factor attachment proteins receptors (SNARE) proteins, such as VAMP-2 and SNAP-25, are implicated in α-synuclein pathophysiology and CSF levels of these proteins are associated with pathophysiological biomarkers and cognitive decline in Alzheimer's disease (AD). The aim of the study was to compare CSF levels of VAMP-2 and SNAP-25 in patients with DLB to cognitively unimpaired controls and AD patients and study their association with cognitive performance and AD and neurodegeneration biomarkers.