Mircea Balasa’s research while affiliated with University of Barcelona and other places

INTRODUCTION We aimed to determine whether cognitively unimpaired (CU) amyloid‐ beta‐positive (Aβ+) individuals display decreased practice effects on serial neuropsychological testing. METHODS We included 209 CU participants from three research centers, 157 Aβ− controls and 52 Aβ+ individuals. Participants underwent neuropsychological assessment at baseline and annually during a 2‐year follow‐up. We used linear mixed‐effects models to analyze cognitive change over time between the two groups, including time from baseline, amyloid status, their interaction, age, sex, and years of education as fixed effects and the intercept and time as random effects. RESULTS The Aβ+ group showed reduced practice effects in verbal learning (β = −1.14, SE = 0.40, p = 0.0046) and memory function (β = −0.56, SE = 0.19, p = 0.0035), as well as in language tasks (β = −0.59, SE = 0.19, p = 0.0027). DISCUSSION Individuals with normal cognition who are in the Alzheimer's continuum show decreased practice effects over annual neuropsychological testing. Our findings could have implications for the design and interpretation of primary prevention trials. Highlights This was a multicenter study on practice effects in asymptomatic Aβ+ individuals. We used LME models to analyze cognitive trajectories across multiple domains. Practice‐effects reductions might be an indicator of subtle cognitive decline. Implications on clinical and research settings within the AD field are discussed.

Background/Objectives: We aimed at evaluating the prevalence of cognitive impairment before cardiac surgery, its associated risk factors, and the diagnostic performance of cognitive tests. Methods: This prospective, single-center observational study included patients aged 50 years or older with coronary artery and/or valvular heart disease waiting for cardiac surgery. Patients underwent a cognitive and physical assessment before cardiac surgery. The cognitive assessment included eight tests exploring different cognitive domains and two questions exploring subjective cognitive complaints. Physical assessment included functional capacity and physical activity level. Cognitive tests with adjusted scores below 1.5 or more standard deviations from cognitively unimpaired subjects were considered abnormal. Cognitive impairment was defined as two or more abnormal cognitive tests. Results: We identified objective cognitive impairment in 41 out of 134 patients (31%). Interestingly, 66% of patients with objective cognitive impairment did not report any complaints. Moreover, similar complaints were reported among patients with and without objective cognitive impairment. The combination of Phonetic Fluency Test, Trail Making Test B, Digit Modalities Test, and the digit span forwards from the Wechsler Adult Intelligence Scale yielded the best diagnostic accuracy (AUC: 0.88; 95 CI: 0.82–0.93). Finally, cognitive impairment was associated with a worse Sit-To-Stand performance. Conclusions: Objective cognitive impairment before cardiac surgery is prevalent but subjective cognitive complaints are unreliable. We propose a combination of four cognitive tests with an efficient diagnostic profile to enhance its clinical applicability.

Discrepancies in results between cerebrospinal fluid (CSF) 14-3-3 protein and prion protein detection using real-time quaking-induced conversion (RT-QuIC) might limit the confidence in ante-mortem clinical diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD). We aimed to evaluate the concordance and diagnostic performance of 14-3-3 protein and RT-QuIC in a real clinical practice cohort, and to analyze neuronal/glial damage biomarkers in sCJD patients based on their diagnostic assay results. A retrospective multicentre study was conducted on 157 suspected sCJD patients from 38 Spanish hospitals in a 4-year period. CSF 14-3-3 protein and RT-QuIC were simultaneously evaluated in a single laboratory. A diagnosis of probable sCJD was established in 63 patients (40.1%), of which 12 (19.0%) were ultimately diagnosed with definite sCJD. Forty-one sCJD patients (65.1%) were positive for both 14-3-3 protein and RT-QuIC, 17 (27.0%) isolated positive for RT-QuIC, and 5 (7.9%) isolated positive for 14-3-3 protein. RT-QuIC demonstrated higher sensitivity (92.1%) and specificity (98.9%) compared to 14-3-3 (73.0% and 62.8%) for the diagnosis of sCJD. Isolated RT-QuIC positivity was associated with longer disease duration (median: 10.5 months, IQR: 8.8–15.7), higher frequency of Met/Val cases (75.0%), lower prevalence of periodic sharp-wave complexes (5.9%), and lower levels of GFAP (3967.4 pg/mL), UCH-L1 (2218.1 pg/mL), and t-Tau (228.8 pg/mL) compared to double-positive and isolated 14-3-3-positive patients. In conclusion, CSF RT-QuIC is a highly specific and sensitive biomarker for ante-mortem sCJD diagnosis and should be considered as the preferred CSF ancillary test. Isolated RT-QuIC positivity indicates a less aggressive biological disease in sCJD patients.

Objectives Frontotemporal dementia (FTD) usually shows more asymmetric atrophy patterns than Alzheimer’s disease (AD). We aim to quantify this asymmetry to differentiate FTD, AD, and FTD subtypes. Methods We studied T1-MRI scans, including FTD (different phenotypes), AD, and healthy controls (CTR). We defined the Cortical Asymmetry Index (CAI) using measures based on a metric derived from information theory with the cortical thickness measures. Some participants had additional follow-up MRIs, cerebrospinal fluid (CSF), or plasma measures. We analysed differences at cross-sectional and longitudinal levels. We then clustered FTD and AD participants based on the CAI values and studied the patients’ fluid biomarker characteristics within each cluster. Results A total of 101 FTD patients (64 ± 8 years, 53 men), 230 AD patients (65 ± 10 years, 84 men), and 173 CTR (59 ± 15 years, 67 men) were studied. CAI differentiated FTD, AD, and CTR. It also distinguished the semantic variant primary progressive aphasia (svPPA) from the other FTD phenotypes. In FTD, the CAI increased over time. The cluster analysis identified two subgroups within FTD, characterised by different neurofilament-light (NfL) levels, and two subgroups within AD, with different plasma glial fibrillary acidic protein (GFAP) levels. In AD, CAI correlated with GFAP and Mini-Mental State Examination (MMSE); in FTD, the CAI was associated with NfL levels. Conclusions The proposed method quantifies asymmetries previously described visually. The CAI could define clinically and biologically meaningful disease subgroups in the differential diagnosis of AD and FTD and its subtypes. CAI could also be of interest in tracking disease progression in FTD. Key Points Question There is a need to find quantitative metrics from MRI that can identify disease subgroups, and that could be useful for diagnosis and tracking. Findings We propose a Cortical Asymmetry Index that differentiates Alzheimer’s disease (AD) from Frontotemporal dementia (FTD), distinguishes FTD subtypes, correlates with NFL and GFAP levels, and monitors FTD progression. Clinical relevance Our proposed index holds the potential to support clinical applications for diagnosis and disease tracking in AD and FTD, using a quantitative summary metric from MRI data. It also contributes to the understanding of these diseases.

PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer’s disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p < 0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p < 0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease.

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72 , 38 GRN , and 25 MAPT ) and 55 symptomatic (27 C9orf72 , 17 GRN , and 11 MAPT ) mutation carriers as well as 76 mutation-negative controls (“noncarriers”). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer’s disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

Plasma tau phosphorylated at threonine 181 (p-tau181) and 217 (p-tau217) have demonstrated high accuracy for Alzheimer’s disease (AD) diagnosis, defined by CSF/PET amyloid beta (Aβ) positivity, but most studies have been performed in research cohorts, limiting their generalizability. We studied plasma p-tau217 and p-tau181 for CSF Aβ status discrimination in a cohort of consecutive patients attending an academic memory clinic in Spain (July 2019–June 2024). All patients had CSF AD biomarkers performed as part of their routine clinical assessment. Aβ positivity was defined with a local cut-off of CSF Aβ1–42 < 600 pg/mL; in patients with borderline Aβ1–42 values or when there was a mismatch between the Aβ and the T status (T + if CSF p-tau181 ≥ 65 pg/mL), a ratio Aβ1–42/Aβ1–40 < 0.07 was used. Plasma p-tau217 and p-tau181 were measured retrospectively, from blood samples collected at first visit, with Fujirebio Lumipulse and Quanterix Simoa assays, respectively. We included 468 patients (mean age 67 years, 50% female, 61% Aβ positive). Plasma p-tau217 outperformed plasma p-tau181 in discriminating CSF Aβ status (AUC 0.95 vs 0.90, p = 0.005). A 97.5% sensitivity and specificity plasma p-tau217 algorithm, classifying patients into three groups of Aβ probability (Low, Intermediate and High), resulted in 67% of patients in the Low and High groups, having their Aβ status predicted (as negative and positive, respectively) with 96% accuracy. The remaining 33% in the Intermediate group were candidates to undergo CSF/PET testing. A model with a 10% variation in p-tau217 levels yielded small changes in accuracy (95%). In conclusion, plasma p-tau217 could have discriminated CSF Aβ status in two-thirds of patients with very high accuracy in a memory clinic cohort. These results support the implementation of plasma p-tau217 as an initial diagnostic tool in memory clinics for AD diagnosis, reducing the need for more invasive/expensive testing.

Background Brain Health (BH) perspectives and practices among health care professionals constitute a crucial piece of information for developing tailored initiatives to foster BH at the regional level. We aim to characterize knowledge and clinical practices associated with BH in Spanish neurologists by a cross‐sectional survey. Method An original online survey was distributed by email among all members of the Spanish Society of Neurology. The survey included four sections: BH knowledge; BH‐related clinical practices; perspectives about the importance of BH in neurology practice; and limiting factors for BH promotion in daily practice. Result 400 neurologists participated in the survey, and 75.8% fully completed it. Participants were 61.7% females, mainly workers in tertiary (71.0%) and public hospitals (85.7%), and 74.2% had a sub‐specialization. Many participants considered to be familiar (41.7%) or somehow familiar (43.6%) with the concept and recommendations of BH, but 48.7% did not know any supporting scientific study. A substantial percentage of respondents considered that BH cannot be improved in aging (19.2%) or dementia (21.1%). Clinical interview was the main tool to evaluate BH (81.3%), but 22.1% of neurologists did not routinely explore BH. A higher percentage of females than males declared to regularly ask patients about their familiar situation (68.9% vs 53.0%, p 0.018) and social activities (62.9% vs 47.8%, p 0.019) and recommended more frequently healthy diet (75.7% vs 64.9%, p 0.0080). Also, more females considered that it is important to develop BH plans (98.9% vs 89.4% males), even adjusting by age (p <0.0001). The main limiting factor for BH evaluation and promotion during clinical visits were time constraints (in 76.8% of cases), followed by scarcity of support resources (61.3%), but a significant number of neurologists with <10 years of experience considered lack of education about official BH recommendations as a limitation (26.5% vs 14.0% in >20 years, p 0.047). Conclusion This survey was conducted as a situational analysis to guide next steps of the BH roadmap in Spain. While time constraints and scarcity of resources should be approached from a health policy perspective, we identify poor BH knowledge as an opportunity to improve BH related practices, especially among young neurologists.

Background Alzheimer's disease (AD) features a complex interplay of factors influencing cognitive decline. While CSF and plasma biomarkers have widely demonstrated their diagnostic utility, whether they may add prognostic value remains unrevealed. With this longitudinal study we aim to address this knowledge gap by evaluating the predictive value of several fluid biomarkers over cognitive decline in a cohort of biomarker‐confirmed AD individuals. Method We included 139 participants with biologically‐confirmed AD (A+T+N+). Four cerebrospinal fluid (CSF) biomarkers (Amyloid‐Beta1‐42 [Aβ1‐42], tau phosphorylated at threonine 181 [p‐tau181], total tau [t‐tau], and neurofilament light chain [NfL]) were determined with enzyme immunoassay, and three plasma biomarkers (p‐tau181, NfL and glial fibrillary acidic protein [GFAP]) were determined with single‐molecule array. Biomarkers were stratified into tertiles. Comprehensive neuropsychological assessments were administered at baseline (n=139) and annually (Year 1 n=108, Year 2 n=78, Year 3 n=25, Year 4 n=3 and Year 5 n=3; mean follow‐up time 1.7 years [SD 0.3]). Mixed Models for Repeated Measures explored the effectof CSF and blood biomarkers on Mini‐Mental State Examination (MMSE) score progression. Result Participants had a mean age at onset of 65.7 (SD 6.4) years, 17% were non‐amnestic, 58% were APOEε4 carriers. Higher baseline plasma p‐tau181 and GFAP concentrations correlated with MMSE score decline (p=0.009 and p=0.002, respectively) (Table 1, Table 2, Figure 1). Conversely, no significant associations were observed between plasma NfL or CSF biomarkers concentrations and MMSE decline. Conclusion This longitudinal study highlights the potential prognostic value of baseline plasma p‐tau181 and GFAP concentrations for cognitive decline progression in AD.

Background Although Alzheimer’s disease (AD) is a common cause of dementia, whether patients and caregivers have notions of its risk factors, behavioral aspects or care considerations is unclear. Therefore, our study aims to evaluate caregiver’s knowledge of AD by using the Alzheimer’s Disease Knowledge Scale (ADKS). Method The ADKS is a comprehensive 25‐item true/false assessment tool that explores the understanding of AD. Comprising four subscales (Causes and characteristics, Communication and behavior, Considerations of care, and Risk factors and health promotion), it provides a nuanced evaluation of knowledge levels. In this prospective consecutive observational study conducted between February 2021 and December 2023, we recruited 132 participants with clinically diagnosed MCI/dementia. Their caregivers completed the Spanish version of the ADKS. Scores for the entire test, its subscales, and the individual questions were normalized on a scale from 0 to 10, to facilitate result interpretation. Result The mean ADKS test score was 21.7 [SD 0.7], equivalent to 4.3/10 [SD 1.4]. Most of the subscales scored below 5, indicating a poor familiarity with aspects related to “Risk factors and health promotion” (4.3/10 [SD 1.8]), “Causes and characteristics” (4.2/10 [SD 1.9]), and “Communication and behavior” (2.0/10 [SD 1.6]) (Table 1). The only subscale with an average score over 5 was “Considerations of care,” (6.7/10 [SD 2.3]). Conclusion The findings underscore the limited knowledge of AD‐related aspects among caregivers of individuals suffering from cognitive impairment. It highlights the need to implement educational interventions in both the general population and diagnosed patients and their support networks.