“Real-world” eligibility for anti-amyloid treatment in a tertiary memory clinic setting

INTRODUCTION: The societal impact of anti-amyloid treatment (AAT) for Alzheimer's disease (AD) depends largely on patient eligibility. Estimates suggest that 1% to 18% of individuals with AD may qualify for AAT; however, data from everyday clinical practice remain limited. This study assessed AAT eligibility in patients at a tertiary memory clinic. METHODS: We included 1309 new patients (63 ± 8 years, 45% women, Mini-Mental State Examination [MMSE] 25 ± 5) who presented to the Alzheimer Center Amsterdam (2020–2022) for standardized diagnostic workup. Eligibility for AAT was based on lecanemab's approved label guidelines. RESULTS: Of 1309 new patients, 514 (39% of new patients) had clinical mild cognitive impairment (MCI) or AD. Of these, 108 (8% new patients/21% clinical MCI/AD) met Clinical Dementia Rating/MMSE criteria, were amyloid positive, and had < 4 microbleeds/superficial siderosis. After further excluding apolipoprotein E ε4/ε4 homozygotes and anticoagulant users, 79 patients (6% new patients/15% clinical MCI/AD) remained eligible. DISCUSSION: Findings indicate limited eligibility for AAT in tertiary memory clinics. Highlights: Initial eligibility for lecanemab was 8% of all patients and 21% of those with clinical mild cognitive impairment (MCI) or Alzheimer's disease (AD) based on approved guidelines in a tertiary memory clinic population. After strict exclusions (such as apolipoprotein E ε4/ε4 homozygosity and anticoagulant use), eligibility dropped to 6% of all patients and 15% of those with clinical MCI or AD. The study highlights the limited real-world applicability of anti-amyloid treatment under current guidelines

The natural history of primary progressive aphasia: beyond aphasia

Introduction: Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes. Methods: In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1–6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed. Results: Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4). Discussion: Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration

Tau PET and relative cerebral blood flow in Dementia with Lewy bodies: A PET study

Purpose: Alpha-synuclein often co-occurs with Alzheimer’s disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. / Methods: Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology(DLB-AD+). Receptor parametric mapping(cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. / Results: Regional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p>0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p<0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p<0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stβ=0.72) and category fluency (stβ=0.69) tests. Lower parietal R1 was related to lower delayed (stβ=0.50) and immediate (stβ=0.48) recall, VOSP number location (stβ=0.70) and fragmented letters (stβ=0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stβ=0.61), all p<0.05. / Conclusion: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET

Computerized decision support to optimally funnel patients through the diagnostic pathway for dementia

Background: The increasing prevalence of dementia and the introduction of disease-modifying therapies (DMTs) highlight the need for efficient diagnostic pathways in memory clinics. We present a data-driven approach to efficiently guide stepwise diagnostic testing for three clinical scenarios: 1) syndrome diagnosis, 2) etiological diagnosis, and 3) eligibility for DMT. Methods: We used data from two memory clinic cohorts (ADC, PredictND), including 504 patients with dementia (302 Alzheimer’s disease, 107 frontotemporal dementia, 35 vascular dementia, 60 dementia with Lewy bodies), 191 patients with mild cognitive impairment, and 188 cognitively normal controls (CN). Tests included digital cognitive screening (cCOG), neuropsychological and functional assessment (NP), MRI with automated quantification, and CSF biomarkers. Sequential testing followed a predetermined order, guided by diagnostic certainty. Diagnostic certainty was determined using a clinical decision support system (CDSS) that generates a disease state index (DSI, 0–1), indicating the probability of the syndrome diagnosis or underlying etiology. Diagnosis was confirmed if the DSI exceeded a predefined threshold based on sensitivity/specificity cutoffs relevant to each clinical scenario. Diagnostic accuracy and the need for additional testing were assessed at each step. Results: Using cCOG as a prescreener for 1) syndrome diagnosis has the potential to accurately reduce the need for extensive NP (42%), resulting in syndrome diagnosis in all patients, with a diagnostic accuracy of 0.71, which was comparable to using NP alone. For 2) etiological diagnosis, stepwise testing resulted in an etiological diagnosis in 80% of patients with a diagnostic accuracy of 0.77, with MRI needed in 77%, and CSF in 37%. When 3) determining DMT eligibility, stepwise testing (100% cCOG, 83% NP, 75% MRI) selected 60% of the patients for confirmatory CSF testing and eventually identified 90% of the potentially eligible patients with AD dementia. Conclusions: Different diagnostic pathways are accurate and efficient depending on the setting. As such, a data-driven tool holds promise for assisting clinicians in selecting tests of added value across different clinical contexts. This becomes especially important with DMT availability, where the need for more efficient diagnostic pathways is crucial to maintain the accessibility and affordability of dementia diagnoses

Protein disulfide isomerases as CSF biomarkers for the neuronal response to tau pathology

Introduction: Cerebrospinal fluid (CSF) biomarkers for specific cellular disease processes are lacking for tauopathies. In this translational study we aimed to identify CSF biomarkers reflecting early tau pathology-associated unfolded protein response (UPR) activation. Methods: We employed mass spectrometry proteomics and targeted immunoanalysis in a combination of biomarker discovery in primary mouse neurons in vitro and validation in patient CSF from two independent large multicentre cohorts (EMIF-AD MBD, n = 310; PRIDE, n = 771). Results: First, we identify members of the protein disulfide isomerase (PDI) family in the neuronal UPR-activated secretome and validate secretion upon tau aggregation in vitro. Next, we demonstrate that PDIA1 and PDIA3 levels correlate with total- and phosphorylated-tau levels in CSF. PDIA1 levels are increased in CSF from AD patients compared to controls and patients with tau-unrelated frontotemporal and Lewy body dementia (LBD). Highlights: Neuronal unfolded protein response (UPR) activation induces the secretion of protein disulfide isomerases (PDIs) in vitro. PDIA1 is secreted upon tau aggregation in neurons in vitro. PDIA1 and PDIA3 levels correlate with total and phosphorylated tau levels in CSF. PDIA1 levels are increased in CSF from Alzheimer's disease (AD) patients compared to controls. PDIA1 levels are not increased in CSF from tau-unrelated frontotemporal dementia (FTD) and Lewy body dementia (LBD) patients

Visual associative learning to detect early episodic memory deficits and distinguish Alzheimer's disease from other types of dementia

Objective: We investigated how well a visual associative learning task discriminates Alzheimer's disease (AD) dementia from other types of dementia and how it relates to AD pathology. Methods: 3,599 patients (63.9 ± 8.9 years old, 41% female) from the Amsterdam Dementia Cohort completed two sets of the Visual Association Test (VAT) in a single test session and underwent magnetic resonance imaging. We performed receiver operating curve analysis to investigate the VAT's discriminatory ability between AD dementia and other diagnoses and compared it to that of other episodic memory tests. We tested associations between VAT performance and medial temporal lobe atrophy (MTA), and amyloid status (n = 2,769, 77%). Results: Patients with AD dementia performed worse on the VAT than all other patients. The VAT discriminated well between AD and other types of dementia (area under the curve range 0.70-0.86), better than other episodic memory tests. Six-hundred forty patients (17.8%) learned all associations on VAT-A, but not on VAT-B, and they were more likely to have higher MTA scores (odds ratios range 1.63 (MTA 0.5) through 5.13 for MTA ≥ 3, all p <.001) and to be amyloid positive (odds ratio = 3.38, 95%CI = [2.71, 4.22], p <.001) than patients who learned all associations on both sets. Conclusions: Performance on the VAT, especially on a second set administered immediately after the first, discriminates AD from other types of dementia and is associated with MTA and amyloid positivity. The VAT might be a useful, simple tool to assess early episodic memory deficits in the presence of AD pathology

Implications and opportunities regarding biological frameworks in overt and prodromal dementia with Lewy bodies

\ua9 2025 Lewy Body Dementia Association and The Author(s). Alzheimer\u27s &amp; Dementia published by Wiley Periodicals LLC on behalf of Alzheimer\u27s Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.Dementia with Lewy bodies (DLB), a progressive neurodegenerative disease with heterogeneous clinical presentations, greatly impacts patients, caregivers, and society. Despite its frequency, diagnosing and treating DLB remains challenging. Advances in in vivo biomarker assays reflecting underlying pathology are improving disease identification, diagnostic accuracy, and therapeutic development for biologically targeted, disease-modifying agents. Consequently, definitions of Alzheimer\u27s disease and Parkinson\u27s disease (PD) have shifted to focus on pathological changes occurring before clinical features, with proposed frameworks for detecting pathological amyloid and tau, neurodegeneration, and other markers (National Institute on Aging-Alzheimer\u27s Association) and alpha-synucleinopathy and dopaminergic degeneration (Neuronal α-synuclein Disease Integrated Staging System, SynNeurGe). The biological frameworks, particularly those related to alpha-synuclein (α-synuclein), have sparked debate about unifying DLB and PD under a single pathobiologic disease. This paper discusses the implications of these biological frameworks for the DLB community, addressing topics regarding multiple pathologies and neurochemical systems, clinical heterogeneity, and functional impairment, and exploring the potential impact on clinical trials and care. Highlights: DLB is a progressive neurodegenerative disease with varied clinical presentations. Diagnosing and treating DLB remains challenging despite its frequency. Biological frameworks are reshaping Alzheimer\u27s and Parkinson\u27s definitions. In vivo biomarkers are improving DLB identification and diagnostic accuracy. Debate exists regarding unifying DLB and Parkinson\u27s under one pathobiology

Sex differences in brain atrophy in dementia with Lewy bodies

\ua9 2023 The Authors. Alzheimer\u27s &amp; Dementia published by Wiley Periodicals LLC on behalf of Alzheimer\u27s Association.INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 \ub1 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 \ub1 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Highlights: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age

Five-class differential diagnostics of neurodegenerative diseases using random undersampling boosting

Differentiating between different types of neurodegenerative diseases is not only crucial in clinical practice when treatment decisions have to be made, but also has a significant potential for the enrichment of clinical trials. The purpose of this study is to develop a classification framework for distinguishing the four most common neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobe degeneration, Dementia with Lewy bodies and vascular dementia, as well as patients with subjective memory complaints. Different biomarkers including features from images (volume features, region-wise grading features) and non-imaging features (CSF measures) were extracted for each subject. In clinical practice, the prevalence of different dementia types is imbalanced, posing challenges for learning an effective classification model. Therefore, we propose the use of the RUSBoost algorithm in order to train classifiers and to handle the class imbalance training problem. Furthermore, a multi-class feature selection method based on sparsity is integrated into the proposed framework to improve the classification performance. It also provides a way for investigating the importance of different features and regions. Using a dataset of 500 subjects, the proposed framework achieved a high accuracy of 75.2% with a balanced accuracy of 69.3% for the five-class classification using ten-fold cross validation, which is significantly better than the results using support vector machine or random forest, demonstrating the feasibility of the proposed framework to support clinical decision making

Evaluating combinations of diagnostic tests to discriminate different dementia types

INTRODUCTION: We studied, using a data-driven approach, how different combinations of diagnostic tests contribute to the differential diagnosis of dementia. METHODS: In this multicenter study, we included 356 patients with Alzheimer's disease, 87 frontotemporal dementia, 61 dementia with Lewy bodies, 38 vascular dementia, and 302 controls. We used a classifier to assess accuracy for individual performance and combinations of cognitive tests, cerebrospinal fluid biomarkers, and automated magnetic resonance imaging features for pairwise differentiation between dementia types. RESULTS: Cognitive tests had good performance in separating any type of dementia from controls. Cerebrospinal fluid optimally contributed to identifying Alzheimer's disease, whereas magnetic resonance imaging features aided in separating vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. Combining diagnostic tests increased the accuracy, with balanced accuracies ranging from 78% to 97%. DISCUSSION: Different diagnostic tests have their distinct roles in differential diagnostics of dementias. Our results indicate that combining different diagnostic tests may increase the accuracy further