BackgroundA growing body of literature has documented emotional disorders in patients with dementia with Lewy bodies (DLB). While emotional symptoms have been well studied in Alzheimer's disease (AD) and Parkinson's disease (PD), no study to date has provided a comprehensive overview of emotional disturbances specifically associated with DLB.ObjectiveThis study aimed to investigate the emotional profile of patients with prodromal or mild DLB compared to healthy controls.MethodsBehavioral data were collected from 24 prodromal or mild DLB patients, and 24 healthy participants, matched for age, gender and educational level. Statistics, including group comparisons and correlation analyses, were conducted using the following measures: the Florida Affect Battery (FAB), the 20-item Toronto Alexithymia Scale (TAS-20), the Echelle d'Humeur Depressive (EHD), and the Generalized Anxiety Disorder 7-item (GAD-7) scale.ResultsPatients with DLB demonstrated significantly impaired performance on the FAB alongside elevated scores on the TAS-20, the EHD, and the GAD-7 compared to controls.ConclusionsThese findings highlight profound disruptions in internal emotional experience among patients with prodromal or mild DLB, notably marked by elevated alexithymic traits, altered emotional expression, emotional dyscontrol, anxiety, and impairments in automatic and implicit recognition of facial emotions. Our study supports the critical need for early detection, systematic evaluation, and personalized management of emotional symptoms through targeted interventions.

Background:The well-documented bidirectional relationship between Alzheimer's disease (AD) and epilepsy suggests that seizures are not merely a complication of AD but may also contribute to disease progression. Emerging evidence indicates that antiseizure medications (ASMs) could potentially slow the disease course and act as disease-modifying agents if initiated early. Objectives:We investigated the long-term cognitive and functional effects of ASMs when introduced at the prodromal stage of AD. Methods:Twenty-two sporadic epileptic prodromal AD patients (epADs) and 21 matched subjects without epilepsy (nepADs) were followed for a median of 7 years. Baseline cognition, daily functioning, clinical/paraclinical features, and pharmacological profiles were compared. Annual assessments included cognition, pharmacological burden, and functional impairment. Results:At the final follow-up, epADs evidenced more preserved cognition than nepADs, reflecting a significantly slower annual rate of cognitive decline (-1.2 ± 0.9 vs. -2.7 ± 2.4 points/year on the MMSE score, respectively; p = 0.01). They were also less likely to require neuroleptics (9.1% vs. 47.6%, p < 0.01) or memantine (0% vs. 28.6%, p < 0.01). However, epADs and nepADs had the same proportion of Alzheimer's dementia at the final follow-up visit (90.9% vs. 90.5%, p = 0.96). Despite being significant, these results had low statistical power due to our small sample size and should be considered exploratory. Conclusion:Our findings support the idea that early ASM treatment may attenuate cognitive decline in sporadic prodromal AD patients with comorbid epilepsy. However, these benefits were not accompanied by a lower dementia rate at the final follow-up visit, suggesting that ASMs alone are insufficient for sustained disease modification. Combinatorial therapeutic strategies may be needed to achieve long-term neuroprotection in AD.

BACKGROUND AND OBJECTIVES:The α-synuclein (α-syn) seed amplification assay (SAA) has shown promising results for diagnosing dementia with Lewy bodies (DLB) using CSF samples. A barrier to implementing α-syn SAA clinically is the use of different protocols for the assay. It is unknown how different protocols perform in comparison with each other. We compared the performance of α-syn SAA across 4 laboratories using CSF samples of patients with DLB. METHODS:This was a retrospective cross-sectional study that included data from 4 different European laboratories. We included probable patients with DLB with a positive dopamine transporter (DaT)-SCAN and known amyloid-β status who had mild-to-moderate dementia, along with age-matched and sex-matched controls. The α-syn SAA was run across 4 laboratories using different protocols varying α-syn concentration and plate reader settings. CSF samples were provided by a fifth independent laboratory, which also performed statistical and result analyses. RESULTS:We included 20 patients with DLB (mean age 67 ± 6 years, 60% male) and 10 controls (mean age 67 ± 2 years, 70% male). Neuropathologic confirmation was available for 2 patients with DLB. On average, the 4 laboratories achieved 78.8% sensitivity (minimum 55%, maximum 100%), 77.5% specificity (minimum 60%, maximum 100%), and 78.5% accuracy (minimum 57%, maximum 100%) for discriminating DLB from controls, but our findings show that diagnostic performance of SAA varied across laboratories: Lab A achieved 100% sensitivity (CI 84%-100%) and 100% specificity (CI 72%-100%); Lab B achieved 85% sensitivity (CI 64%-95%) and 90% specificity (CI 59%-99%); Lab C achieved 55% sensitivity (CI 34%-74%) and 60% specificity (CI 31%-83%); and Lab D achieved 75% sensitivity (CI 53%-89%) and 60% specificity (CI 31%-83%). In general, SAA results showed numerically lower sensitivity in β-amyloid (Aβ)-positive patients with DLB (70%) compared with Aβ-negative patients with DLB (87.5%) (nonstatistically significant). A fair agreement of SAA results was obtained across the 4 laboratories (average κ = 0.246). DISCUSSION:This study highlights challenges for the reproducibility of α-syn SAA results across different protocols applied by different laboratories. This finding, together with the methodological variability reported across laboratories, may challenge the clinical implementation of the α-syn SAA. This study provides relevant support for initiating harmonization and standardization of SAA protocols to move the field toward the clinical implementation of SAAs for the biomarker-based diagnosis of DLB. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence of variations in the accuracy of CSF α-syn SAA across 4 separate laboratories in distinguishing patients with DLB from healthy controls.

Background Language and communication disorders in dementia with Lewy bodies (DLB) remain understudied and have rarely been explored from the caregiver's perspective. Comparative studies with Alzheimer's disease (AD) are also limited. Objective To provide an initial overview of language and communication profiles in DLB, compared to AD and healthy elderly controls (HC); to assess subjective complaints reported by patients, caregivers and healthcare professionals; and to explore their relationships with rapid language screening. A further aim was to aid non-specialist professionals in identifying patients needing speech therapy referral. Methods Seventeen DLB patients, 15 AD patients, and 11 HC completed the Diagnostic Tool for Language Assessment and the alpha version of the Communication Support Needs Assessment Tool for Dementia (CoSNAT-D), alongside a semi-directed interview (SDI). Proxy-ratings were also collected from caregivers and healthcare professionals (HP) for the CoSNAT-D and SDI. Results Compared to HC, DLB patients showed significantly poorer performance in repetition, verbal working memory, sentence comprehension and dictation, and reported more communication difficulties. Compared to AD patients, DLB patients had greater impairments in phonemic fluency, and more frequent reports of discomfort, vocal changes, and difficulties with writing and handwriting execution. Perceptions of communicative difficulties and their functional impact varied across patients, caregivers, and HP. Conclusions This study has identified distinct language and communication deficits in DLB versus AD and HC. Discrepancies between patient and caregiver perceptions were frequent in both groups and may contribute to increased caregiver burden. Findings highlight the potential value of rapid screening tools to better support patients and their caregivers.

INTRODUCTION:Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are neurocognitive disorders characterized by distinct but often overlapping pathological processes. These include α-synuclein, amyloid-beta 42 (Aβ42), and tau protein aggregation. While cerebrospinal fluid (CSF) biomarkers provide in vivo insight into these pathologies, their relationship with large-scale brain network dysfunction remains poorly understood. This study aimed to investigate the associations between CSF biomarker concentrations and resting-state functional connectivity in patients with DLB, AD, and mixed AD/DLB. METHODS:Sixty-nine DLB patients, 17 AD patients, and 24 patients with mixed AD/DLB underwent clinical and neuropsychological evaluations, lumbar puncture for CSF biomarker analysis (total α-synuclein, Aβ42, pTau181, and tTau), and resting-state functional MRI. Patients were stratified by disease stage for subgroup analyses. Besides CSF total α-synuclein levels, α-synuclein seeding activity was assessed using real-time quaking-induced conversion (RT-QuIC) assays. ROI-to-ROI analyses were conducted using the CONN toolbox to explore associations between CSF biomarker levels and functional connectivity within and between major brain networks. RESULTS:In DLB patients, lower CSF α-synuclein levels correlated with increased connectivity within the default mode network (DMN) (p FDR < 0.05). In dementia-stage DLB (d-DLB), lower Aβ42 levels correlated with reduced connectivity within the salience network (SN) (p FDR < 0.05). In AD, higher tTau levels correlated with decreased connectivity between the DMN and the SN (p FDR < 0.05). No significant associations were observed for CSF pTau181 or any RT-QuIC metric in any group, and the mixed AD/DLB group showed no biomarker-connectivity correlations at all. DISCUSSION:We identified distinct patterns of DMN and SN connectivity changes associated with CSF α-synuclein and Aβ42 levels, respectively. These findings reflect key functional disruptions that may contribute to core clinical symptoms. They underscore the value of combining CSF biomarkers with functional MRI to elucidate DLB pathophysiology.

Background and ObjectivesThe alpha-synuclein (alpha-syn) seed amplification assay (SAA) has shown promising results for diagnosing dementia with Lewy bodies (DLB) using CSF samples. A barrier to implementing alpha-syn SAA clinically is the use of different protocols for the assay. It is unknown how different protocols perform in comparison with each other. We compared the performance of alpha-syn SAA across 4 laboratories using CSF samples of patients with DLB.MethodsThis was a retrospective cross-sectional study that included data from 4 different European laboratories. We included probable patients with DLB with a positive dopamine transporter (DaT)-SCAN and known amyloid-beta status who had mild-to-moderate dementia, along with age-matched and sex-matched controls. The alpha-syn SAA was run across 4 laboratories using different protocols varying alpha-syn concentration and plate reader settings. CSF samples were provided by a fifth independent laboratory, which also performed statistical and result analyses.ResultsWe included 20 patients with DLB (mean age 67 +/- 6 years, 60% male) and 10 controls (mean age 67 +/- 2 years, 70% male). Neuropathologic confirmation was available for 2 patients with DLB. On average, the 4 laboratories achieved 78.8% sensitivity (minimum 55%, maximum 100%), 77.5% specificity (minimum 60%, maximum 100%), and 78.5% accuracy (minimum 57%, maximum 100%) for discriminating DLB from controls, but our findings show that diagnostic performance of SAA varied across laboratories: Lab A achieved 100% sensitivity (CI 84%-100%) and 100% specificity (CI 72%-100%); Lab B achieved 85% sensitivity (CI 64%-95%) and 90% specificity (CI 59%-99%); Lab C achieved 55% sensitivity (CI 34%-74%) and 60% specificity (CI 31%-83%); and Lab D achieved 75% sensitivity (CI 53%-89%) and 60% specificity (CI 31%-83%). In general, SAA results showed numerically lower sensitivity in beta-amyloid (A beta)-positive patients with DLB (70%) compared with A beta-negative patients with DLB (87.5%) (nonstatistically significant). A fair agreement of SAA results was obtained across the 4 laboratories (average kappa = 0.246).DiscussionThis study highlights challenges for the reproducibility of alpha-syn SAA results across different protocols applied by different laboratories. This finding, together with the methodological variability reported across laboratories, may challenge the clinical implementation of the alpha-syn SAA. This study provides relevant support for initiating harmonization and standardization of SAA protocols to move the field toward the clinical implementation of SAAs for the biomarker-based diagnosis of DLB.Classification of EvidenceThis study provides Class III evidence of variations in the accuracy of CSF alpha-syn SAA across 4 separate laboratories in distinguishing patients with DLB from healthy controls.

Regional brain atrophy has been observed in dementia with Lewy bodies (DLB), yet determinants of regional vulnerability remain unclear. Using imaging transcriptomics, we examined whether normative gene expression patterns relate to regional atrophy in DLB. We included 164 DLB patients (49 women) and 164 age- and sex-matched healthy controls from three European centres and the Mayo Clinic, USA. Volumetric atrophy was quantified from T1-weighted MRI across 58 left-hemispheric regions using w-scores. Normative expression of twelve genes implicated in alpha-synuclein, beta-amyloid, and tau pathology was extracted from the Allen Human Brain Atlas. DLB patients showed diffuse atrophy across most regions. In the full cohort, normative expression of MAPT, PINK1, and PSEN2 predicted regional atrophy after correction for spatial autocorrelation, although none survived multiple-testing correction. In the Mayo Clinic sub-cohort, expression of APP, BIN1, GBA, MAPT, PINK1, SNCA, and TMEM175 significantly predicted atrophy and survived multiple-testing correction. Random forest models did not outperform spatial null models in the full cohort, but PARK7, PINK1, and PSEN2 consistently emerged as important predictors. A significant global model was observed in the Mayo Clinic sub-cohort, driven by GBA, LRP1, and PINK1. These findings suggest that normative gene expression partially contributes to regional brain atrophy in DLB.

BACKGROUND:Frailty is a prevalent condition among older adults with neurocognitive disorders. OBJECTIVES:To ascertain whether frailty contributes to the severity of cognitive impairment and neuropsychiatric symptoms, and its association with cerebral pathology measured in vivo by fluid and imaging biomarkers. DESIGN:We conducted cross-sectional and longitudinal analyses based on CLEM Study, a multicentre memory-clinic cohort that recruited participants between 2014 and 2018. SETTING:CLEM Study occurred in eight memory centres in France (Lyon, Paris, Strasbourg, Poitiers, Tours, Grenoble) and Monaco. PARTICIPANTS:A total of 168 participants (mean age 80.5 ± 4.8 years) with mild to moderate dementia due to at least one aetiological diagnosis between Alzheimer's disease, dementia with Lewy bodies or vascular dementia were included in the study. MEASUREMENTS:The participants were evaluated at baseline and followed up for two years. The concept of frailty was operationalised using a 45-item Frailty Index. Cognition was assessed using the ADAS-cog scale, while neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory. The cerebral pathological score, a proxy for brain pathologies, was a composite score based on the presence of several in vivo biomarkers: presynaptic dopaminergic denervation on 123I-FP-CIT SPECT (DaTscan®), vascular lesions on MRI, elevated blood-based pTau181, neurofilaments light-chain or glial fibrillary acid protein. Linear and mixed regression analyses were conducted to model the relationships between cognitive or neuropsychiatric symptoms, frailty and cerebral pathologic score, adjusted for age, sex and education. RESULTS:The findings indicate an impact of both frailty (β = 0.28, 95 % CI [0.14-0.43], p < 0.001) and cerebral pathological score (β = 0.30, 95 % CI [0.13-0.47], p = 0.002) on cognitive impairment. However, only frailty was associated with neuropsychiatric symptoms (β = 0.28, 95 % CI [0.14-0.43], p < 0.001), particularly with apathy (β = 0.40, 95 % CI [0.26-0.53], p < 0.001). We found an association between cerebral pathological score and longitudinal cognitive decline (β = 0.36, 95 % CI [0.19-0.53], p < 0.001) in exploratory analyses with available longitudinal data at 24 months (n = 74). CONCLUSIONS:Neurocognitive disorders are complex entities, where cognitive and neuropsychiatric symptoms are not fully influenced by the same factors. When cognitive symptoms seem more driven by cerebral pathology than frailty, neuropsychiatric symptoms appear to be more influenced by general state of frailty. Measuring and treating frailty might be a key factor in dealing with neuropsychiatric symptoms and their consequences.

Some cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker profiles are difficult to interpret. We investigated one such case: normal Aβ42 and pathologically increased levels of Tau and P-Tau (Tau PTau profile). We first extracted details of 184 patients with a Tau PTau profile who had been followed up in Strasbourg, France (cohort 1) and whose diagnosis has been reviewed. Secondly, we recovered and analyzed the AD biomarker results and clinical diagnoses of a cohort of 1199 patients also followed up in Strasbourg (cohort 2). In cohort 1, 57

Accurate prediction of which patients with mild cognitive impairment (MCI) will progress to dementia remains a major challenge. Current biomarkers detect amyloid pathology with high accuracy but offer limited prognostic value for disease progression. We conducted a prospective analysis in the multicentre BALTAZAR cohort, all diagnosed with MCI at baseline and followed for 3 years. Paired cerebrospinal fluid (CSF) and plasma samples were analysed with the NULISA ultrasensitive multiplex platform quantifying more than 120 central nervous system biomarkers. Prognostic performance was assessed using area under the curve (AUC) and hazard ratios (HRs), both for individual markers and for elastic-net-derived biomarker combinations validated by bootstrap and survival analyses. During the 3-year follow-up, 36% of participants converted to dementia. Plasma p-tau biomarkers showed strong accuracy for detecting amyloid positivity (AUC > 0.90) but limited prognostic value for conversion (AUC < 0.75). In CSF, markers of neurodegeneration (tau, NfL) and synaptic dysfunction (NPTX2 encoding the Neuronal Pentraxin 2) predicted conversion with higher accuracy, exceeding p-tau217 performance. The best-performing CSF combination (IL-16, tau, NPTX2) achieved an AUC of 0.86 (95%CI 0.80-0.91) and an HR of 39.8 (95%CI 9.6-165.2). Plasma combinations (p-tau181 or p-tau217 with YWHAG encoding for 14-3-3 protein gamma, a member of the 14-3-3 protein family) provided only modest improvement, likely reflecting the absence of robust synaptic markers in blood. Prognostic assessment of MCI progression to dementia is best achieved through CSF biomarker combinations reflecting neurodegeneration and synaptic dysfunction, complemented by inflammatory markers. These findings emphasize the clinical and pathophysiological relevance of downstream processes beyond amyloid and tau, and support the implementation of multimarker panels for prognosis and therapeutic monitoring.

Abnormal brain accumulation of amyloid-β peptides, represents one of the earliest biological indicators of Alzheimer’s disease (AD) risk. Estimation on amyloid positivity (A+) prevalence among older adults without dementia are needed to assess the epidemiological impact of AD diagnosis solely through biological markers. We combined data from the French MEMENTO clinical cohort, where amyloid status was assessed through reference procedures, with the nationally representative SHARE-HCAP survey. Using stabilized inverse odds of selection weights, we adjusted the MEMENTO sample to estimate the prevalence of A+ in the French population aged 65–85 without dementia and their five-year risk of developing AD dementia. A+ prevalence was 21.4% (95% CI: 18.4–24.7) in French adults aged 65–85 without dementia i.e. approximately 2.5 million individuals, reaching 27.5% in the 80–85 age group. Over five years of follow-up, the cumulative incidence of AD dementia was 22.7% among A+ individuals, 8.0% among cognitively normal A+ adults and 62.3% among those with mild cognitive impairment. While A+ is common in older adults without dementia, most do not develop dementia within five years. Defining AD by A+ could substantially increase diagnoses, raising major public health, ethical, and health system challenges, especially as new anti-amyloid therapies emerge.

BackgroundWhile language impairments are well-documented in Alzheimer's disease (AD), their longitudinal progression in dementia with Lewy bodies (DLB) remains poorly understood.ObjectiveTo compare four-year trajectories of naming and verbal fluency in DLB, AD, and healthy controls (HC), and to identify the cognitive correlates underlying naming performance over time.MethodsThis study included 111 participants (62 DLB, 26 AD, 23 HC) followed at baseline, 12, 24, and 48 months. Primary outcomes were naming (DO-80) and verbal fluency (letter/semantic) scores. Secondary assessments included verbal memory, executive, and visuospatial functions. Linear Mixed Models compared longitudinal trajectories, and Spearman correlations explored cognitive associations.ResultsA significant Visit x Group interaction (p < 0.001) revealed that naming remained stable in DLB (-1.15 points) and HC, whereas AD patients showed a steep decline (-7.77 points). In DLB, letter fluency remained stable over 48 months, while semantic fluency significantly decreased (p = 0.002). Conversely, AD patients deteriorated across all tasks. By month 48, DLB patients significantly outperformed AD patients in naming (p = 0.002) and semantic fluency (p = 0.015). Naming in DLB was positively and increasingly correlated with executive functions (Frontal Assessment Battery: rho 0.416 to 0.578) and Mini-Mental State Examination, whereas in AD, it was tied to episodic memory. No correlation was found with attentional fluctuations in DLB.ConclusionsThese findings highlight distinct language trajectories: naming abilities are relatively preserved in DLB compared to the global collapse in AD. This preservation in DLB appears increasingly dependent on executive control, underscoring the need for tailored, domain-specific interventions.

BACKGROUND: In dementia with Lewy bodies (DLB), autonomic and neurosensory disorders can precede neurocognitive symptoms by several years. Improving knowledge of these symptoms is essential to avoid associated complications and could reveal potential diagnostic biomarkers and shed light on the pathophysiological mechanisms involved in the early stages of the disease. METHODS: Within the AlphaLewyMA cohort, 142 probable DLB patients at the mild cognitive impairment or dementia stages were screened for 10 autonomic and three neurosensory disorders, at 0, 6, 12, 18, 24, 36, 48, 60, 72, 84 and 96 months of follow-up, using a standardized questionnaire and a test for neurogenic orthostatic hypotension. We described the prevalence and evolution over time of these disorders. To explore their neuroanatomical correlates, we performed whole-brain voxel-based morphometry (VBM) analyses on grey matter volumes in a subsample of 116 patients with MRI data. RESULTS: The mean age was 71, and 51% were men. Reports of autonomic and neurosensory disorders were very common in our main sample. As some fluctuated during follow-up, repeated screening had a major impact on their prevalence, with 95.7% of the patients declaring an autonomic disorder at least once during the follow-up and 76.8% a neurosensory disorder. The six most frequent symptoms over the follow-up were rhinorrhoea (79.3%), dry mouth (73.3%), sexual dysfunction (70.6%), neurogenic orthostatic hypotension (68.9%), urinary dysfunction (68.0%) and constipation (67.2%). In VBM analysis, dryness (whether ocular, nasal or oral) and severe taste disorders were associated with lower grey matter volumes in the left insula and in the left putamen and caudate nucleus, respectively. CONCLUSION: Reports of autonomic and neurosensory disorders were very common and some seemed to fluctuate, highlighting the need for regular, systematic screening. Among these disorders, several symptoms little studied so far in DLB turned out to be the most frequently reported by our patients (rhinorrhoea, dry mouth and sexual dysfunction) and could provide interesting clues for diagnosis. VBM analysis may support an involvement of the insula and certain basal ganglia in dryness-type symptoms and taste disorders. Further prospective studies combining self-reporting and objective measures are needed to refine our results.

OBJECTIVES:Depressive symptoms are frequent in the early stages of dementia with Lewy bodies (DLB), and more than half of DLB patients would have a history of depression. Our study sought to investigate the functional connectivity (FC) changes associated with depressive symptoms in prodromal to mild DLB patients compared with controls. METHODS:MRI data were collected from 66 DLB patients and 18 controls. Depression was evaluated with the Mini International Neuropsychiatric Interview. Resting-state FC (rsFC) was investigated with the CONN toolbox using a seed-based approach and both regression and comparison analyses. RESULTS:Correlations were found between the depression scores and the rsFC between fronto-temporal and primary visual areas in DLB patients (p < 0.05, FDR corrected). Depressed DLB patients also showed decreased rsFC within the salience network (SN), increased rsFC between the default mode network (DMN) and the language network (LN) and decreased rsFC between the cerebellar network (CN) and the fronto-parietal network (FPN) compared to non-depressed DLB patients (p < 0.05, uncorrected). Comparison analyses between antidepressant-treated and non-treated DLB patients highlighted FC changes in treated patients involving the SN, the DMN, the FPN and the dorsal attentional network (p < 0.05, uncorrected). CONCLUSIONS:Our findings revealed that depressive symptoms would especially be associated with rsFC changes between fronto-temporal and primary visual areas in DLB patients. Such alterations could contribute to difficulties in regulating emotions, processing biases towards negative stimuli, and self-focused ruminations. TRIAL REGISTRATION:This study is part of the cohort study AlphaLewyMA (https://clinicaltrials.gov/ct2/show/NCT01876459).

BACKGROUND:The use of cerebrospinal (CSF) biomarkers in the diagnosis of Alzheimer's disease (AD) has been gaining interest in clinical practice. Although their usefulness has been demonstrated, their potential value in older patients remains debated. OBJECTIVES:To assess whether knowledge of the results of CSF AD biomarkers was associated with the same gain in diagnostic confidence in older adults > 80 than in younger patients. DESIGN:Prospective multicenter study, including memory clinics physicians who completed a two-part questionnaire for all their patients addressing the requirement for assessment of Alzheimer's disease biomarkers in CSF proposed as part of routine care during the study period. SETTING:30 secondary or tertiary memory clinics in France. MEASUREMENTS:Clinicians indicated their diagnosis hypothesis and an estimate of their diagnostic confidence [scale 1-10]. Receiver operating characteristic (ROC) analysis, including the calculation of the area under the curve (AUC), was conducted using logistic regression to evaluate the diagnostic performance of CSF AD biomarkers. RESULTS:In 813 consecutive patients, median age 70 [interquartile range (IQR) = 63 - 77] including 132 patients over 80 years, we observed a similar confidence gain in CSF biomarkers between older and younger patients, both for AD and non-AD diagnoses. In older patients, the added value of CSF biomarkers was greater when CSF biomarkers indicated AD profile whereas the initial hypothesis was "non-AD", leading to a final diagnosis of AD (2.4 ± 1.6 versus 1.1 ± 2.1, p-value, p = 0.03). ROC analyses showed similar performance of AD CSF biomarkers in older and younger patients. CONCLUSION:CSF AD biomarkers added substantial value to clinical assessment in patients over 80. Their use seems crucial in the diagnostic process for older adults referred to memory clinics.

BackgroundMetabolic biomarkers can potentially be used for early diagnosis, prognostic risk stratification and/or early treatment and prevention of individuals at risk to develop Alzheimer's disease (AD).ObjectiveOur goal was to evaluate changes in metabolite concentration levels associated with AD to identify biomarkers that could support early and accurate diagnosis and therapeutic interventions by using targeted mass spectrometry and machine learning approaches.MethodsSerum samples collected from a total of 107 individuals, including 55 individuals diagnosed with AD and 52 healthy controls (HC) enrolled previously to ADDIA cohort were analyzed using the biocrates AbsoluteIDQ® p400 HR kit metabolite and lipid panel. Several machine learning models including Least Absolute Shrinkage and Selection Operator (LASSO), Partial Least Squares (PLS), Random Forest, and XGBoost were trained to classify AD and HC. Repeated cross-validation was used to ensure performance evaluation.ResultsThe LASSO and PLS models showed the strongest classification performance on the test set, achieving area under the ROC curve (AUC) values of 0.84 and 0.90, respectively. A refined model based on only the top 5 metabolites maintained strong performance, and the inclusion of Apolipoprotein E (APOE) genotype information notably improved classification accuracy, particularly by reducing false negatives in AD cases.ConclusionsThese results highlight important metabolic signatures that could help to reduce misdiagnosis and support the development of metabolomic panels to detect AD. The combination of multiple serum metabolic biomarkers and APOE genotyping can significantly improve classification accuracy and potentially assist in making non-invasive, cost-effective diagnostic approach.

The diagnosis of Dementia with Lewy Bodies (DLB) is primarily based on clinical features. The main driver of DLB is alpha-synuclein-related pathology, but cerebrovascular disease (CVD) and Alzheimer’s Disease (AD) co-pathologies are often found in patients with DLB. Fluid biomarkers and magnetic resonance imaging (MRI) can provide mechanistic and diagnostic information beyond clinical features. Therefore, the aim of this study was to investigate the association of plasma biomarkers (GFAP, NfL, Aβ42/40, pTau231, pTau181) with MRI markers of neurodegeneration and CVD in DLB and in patients with AD as a control group. We also evaluated the ability of biomarkers and clinical features to discriminate between DLB and AD. We included 134 patients from the European DLB consortium (DLB (n = 92) and AD (n = 43)) with plasma biomarkers determined with Simoa and MRI assessed with radiological scales for medial temporal lobe atrophy (MTA), global cortical atrophy scale – frontal subscale (GCA-F), posterior atrophy (PA), and cerebrovascular disease (Fazekas scale). Associations between plasma and MRI biomarkers were assessed with the Mann-Whitney U test, and group differences and the discrimination between DLB and AD were assessed with ANCOVA, Random Forest, and ROC analyses. In DLB, plasma concentrations of GFAP and NfL were associated with MTA, GCA-F, and Fazekas scale; and the Aβ42/40 ratio was associated with PA and Fazekas. Most of these associations were not statistically significant in AD. Individually, plasma and MRI biomarkers had a limited ability to discriminate DLB from AD. Plasma biomarkers helped increase the low specificity of core clinical features from 68