Neurología Cognitiva

Characterization of individuals fulfilling clinical criteria for limbic-predominant age-related TDP43 encephalopathy (LATE) in a tertiary memory clinic

2026-01-07T00:00:00Z

Characterization of individuals fulfilling clinical criteria for limbic-predominant age-related TDP43 encephalopathy (LATE) in a tertiary memory clinic Groot, Colin; Calandri, Ismael Luis; Bader, Ilse; Bocancea, Diana I.; de Bruin, Hannah; Carrigan, Maria; Kamps, Suzie; de Koning, Lotte A.; Mastenbroek, Sophie E.; Rikken, Roos M.; van Tol, Bastiaan G. J.; Vermeiren, Marie R.; Wesseling, Alex; Xia, Ye; Teunissen, Charlotte E.; van de Giessen, Elsmarieke; Barkhof, Frederik; Jonkman, Laura E.; van der Lee, Sven J.; de Boer, Casper Background Limbic-predominant age-related TDP-43 encephalopathy (LATE) clinically mimics and often co-occurs with Alzheimer's disease (AD). Expert consensus criteria have been proposed for the LATE clinical diagnosis, integrating clinical and radiological features, and AD biomarkers. Here, we applied the newly proposed criteria in a tertiary memory clinic population. Method We included participants from the Amsterdam Dementia Cohort aged >50 years who received a diagnosis of MCI or dementia between 1997-2024. Following the LATE consensus criteria scheme (Figure 1), we categorized participants as “Probable LATE”, “Possible LATE” or “Possible LATE-AD” (i.e. LATE clinical and radiological profile with AD biomarker profile). Participants not fulfilling criteria for LATE but fulfilling NIA-AA criteria for AD were categorized as AD. We compared the LATE groups with AD on cognitive decline (N = 1046, N Mean time=2.7[1.8] years) and atrophy (N = 208, Mean time=2.1[1.6]) using linear-mixed effects models, and on mortality rates using Cox proportional hazard models. Result Of the 3367 individuals, 1920 were classified into one of the four groups. Fifty-one (1.5%) were classified as Probable LATE, 102 (3.0%) as Possible LATE, 122 (3.6%) as Possible LATE-AD, and 1645 (48.8%) as AD (Table 1). Compared to AD, Probable LATE showed an attenuated cognitive decline (b[SE] for MMSE=0.12[0.05], p = 0.02) and lower mortality rates (HR[95% CI]=0.75[0.58-0.95], p = 0.02), while individuals with Possible LATE-AD had faster cognitive decline (b for MMSE=-0.12[0.05], p = 0.01) and higher mortality rates (HR=1.55[1.25-1.92], p <0.001, Figure 2). Compared to AD, Probable LATE had, at baseline, lower hippocampal volumes (b=-0.83[0.27], p <0.01), and higher inferior-temporal to hippocampal volume ratios (b=0.81[0.27], p <0.01). Furthermore, in Probable LATE, atrophy in a whole-brain region-of-interest was slower compared to AD (b=0.14[0.08], p = 0.04). Possible LATE-AD had, at baseline, thinner whole-brain cortex (b=-0.69[0.30], p = 0.02), lower hippocampal volumes (b=-1.54[0.31], p <0.01), and higher inferior-temporal to hippocampal volume ratios (b=1.73[0.30], p <0.01) than AD, but there was no difference in atrophy rates between Possible LATE-AD and the other groups (Figure 3). Conclusion In a tertiary memory clinic population, the newly proposed clinical LATE criteria reveal clinical and atrophy trajectories that are distinct from AD, especially for Probable LATE and Possible LATE-AD. Differential clinical and biological disease trajectories highlight the relevance of the LATE classification for diagnostic and prognostic purposes

Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial

2025-07-01T00:00:00Z

Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial McCullough, Austin; Chen, Charles D.; Gordon, Brian A.; Joseph-Mathurin, Nelly; Jack Jr, Clifford R; Koeppe, Robert; Hornbeck, Russ; Koudelis, Deborah; McKay, Nicole S.; Hobbs, Diana A.; Flores, Shaney; Keefe, Sarah J.; Aggarwal, Neelum T.; Allegri, Ricardo Francisco; Berman, Sarah B.; Bird, Thomas; Black, Sandra E.; Brooks, William S.; Chhatwal, Jasmeer P.; Day, Gregory S.; DIAN‐TU Study Team Introduction: Monoclonal anti-amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). Methods: In the DIAN-TU-001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [11C]-Pittsburgh compound-B (PiB) positron emission tomography (PET), [18F]-fluoro-2-deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). Results: Gantenerumab significantly reduced PiB-PET uptake overall and in most regions and showed no changes in FDG-PET or MRI measures. Drug effects were associated with baseline PiB-PET uptake, and the largest effects occurred in medial regions. Discussion: Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB-PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. Highlights: Gantenerumab unevenly decreased Aβ burden as measured by PiB-PET across brain regions. The strongest decrease in PiB-PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG-PET metabolism or MRI volumetrics after 4 years.

Effect of Cognitive Reserve on Age at Symptom Onset and Cognitive Decline in Individuals With Dominantly Inherited Alzheimer Disease

2026-04-28T00:00:00Z

Effect of Cognitive Reserve on Age at Symptom Onset and Cognitive Decline in Individuals With Dominantly Inherited Alzheimer Disease Llibre Guerra, Jorge J.; Lu, Ruijin; Clarens, María Florencia; Liu, Ian; Renton, Alan E.; Ryan, Natalie S.; Goate, Alison M.; Aguillón, David; Allegri, Ricardo Francisco; Benzinger, Tammie L.S.; Berman, Sarah B.; Chhatwal, Jasmeer P.; Chrem Méndez, Patricio Alexis; Vigo, Gabriela; Cruchaga, Carlos; Day, Gregory S.; Farlow, Martin R.; Fox, Nick C.; Gordon, Brian A.; Hassenstab, Jason Background and objectives: Cognitive reserve has been shown to modulate the onset and progression of Alzheimer disease (AD) symptoms. Although its role in sporadic AD is well-studied, how cognitive reserve influences the timing and progression of symptoms in dominantly inherited AD (DIAD) remains unclear. This study aimed to quantify cognitive reserve in DIAD carriers and test whether higher cognitive reserve is associated with later symptom onset and slower functional decline. Methods: We analyzed data from the Dominantly Inherited Alzheimer's Network study. Cognitive reserve was modeled using a residual-based latent variable approach, decomposing cognitive performance into demographic (CogD), biomarker (CogB), and reserve or residual (CogR) components. Primary outcomes were age at clinical symptom onset (CDR >0) and longitudinal change in the Clinical Dementia Rating-Sum of Boxes (CDR-SBs). Data were analyzed using Cox proportional hazards models and linear mixed-effects models, adjusting for estimated years from onset (EYO). Result: A total of 710 Dominantly Inherited Alzheimer Network (DIAN) participants were included in the analysis, comprising 271 non-DIAD carriers (nMC), 284 asymptomatic DIAD carriers (aMC), and 155 symptomatic DIAD carriers. In asymptomatic carriers, using a zero-inflation model adjusted for EYO showed that a 1 SD increase in the reserve component (CogR) was associated with a 4.06-fold increase in the odds of being clinically unimpaired (CDR-SB = 0; 95% CI 1.84-8.95). Similarly, a 1 SD increase in the demographic (CogD) and biomarker (CogB) components increased the odds of being CDR-SB = 0 by 2.60 (95% CI 1.10-6.16) and 5.16 (95% CI 2.00-13.33), respectively. Among symptomatic carriers, only the reserve and the biomarker components were significant. A 1 SD increase in CogR was associated with a 0.81-fold reduction in baseline CDR-SB score (95% CI 0.72-0.92), and a 1 SD increase in CogB was associated with a 0.60-fold reduction in CDR-SB (95% CI 0.50-0.71). Discussion: Our findings indicate that higher cognitive reserve values are associated with delayed conversion to mild cognitive impairment and slower progression on clinical dementia rating scales. These findings suggest that cognitive reserve plays a protective role in modifying the clinical trajectory of genetically determined AD.

Characterizing Individuals Fulfilling Clinical Criteria for Limbic-Predominant Age-Related TDP-43 Encephalopathy in a Tertiary Memory Clinic

2026-05-12T00:00:00Z

Characterizing Individuals Fulfilling Clinical Criteria for Limbic-Predominant Age-Related TDP-43 Encephalopathy in a Tertiary Memory Clinic Groot, Colin; Calandri, Ismael Luis; Bader, Ilse; Bocancea, Diana I.; de Bruin, Hannah; Carrigan, Maria; Collij, Lyduine E.; Duits, Flora H.; Kamps, Suzie; de Koning, Lotte A.; Lemstra, Afina W.; Mastenbroek, Sophie E.; Rikken, Roos M.; van Tol, Bastiaan G. J.; Vermeiren, Marie R.; Wesseling, Alex; Xia, Ye; Teunissen, Charlotte E.; van de Giessen, Elsmarieke; Barkhof, Frederik Background and objectives: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by an amnestic- and limbic-predominant phenotype, which can mimic Alzheimer disease (AD). In a memory clinic cohort, we tested whether clinical criteria for LATE can detect a clinical profile of LATE that is distinct from AD. Methods: In this retrospective examination of a longitudinal memory clinic cohort from the Alzheimer Center Amsterdam, we included individuals with mild cognitive impairment (MCI) and dementia (aged >50 years). We classified individuals based on baseline data on cognition, atrophy, amyloid-status, and tau-status into Probable- and Possible-LATE, co-occurring LATE and AD (LATE-AD), and AD (without LATE). Next, we compared these groups on demographics, clinical features, cognition, and atrophy. Results: Of 3,606 individuals (mean age at baseline 66 [SD 6], 49.2% female) available for classification, we classified 56 (1.6%) as Probable-LATE, 115 (3.2%) as Possible-LATE, 127 (3.5%) as LATE-AD, and 1,675 (46.5%) as AD. Individuals with Probable-LATE progressed slower than AD on mini-mental state examination (MMSE) (sβ [SE] = 0.12 [0.05], p = 0.02), memory (sβ [SE] = 0.11 [0.5], p = 0.01), attention (sβ [SE] = 0.12 [0.16], p = 0.05), executive functioning (sβ [SE] = 0.09 [0.04], p = 0.03), and visuospatial functioning (sβ [SE] = 0.10 [0.05], p = 0.05). Individuals with LATE-AD progressed faster than AD on MMSE (sβ [SE] = -0.12 [0.05], p = 0.01), attention (sβ [SE] = -0.13 [0.06], p = 0.04), and executive functioning (sβ [SE] = -0.10 [0.05], p = 0.03). Mortality risk, compared to AD, was lower in individuals with Probable-LATE (hazard ratio [HR] 0.70 [0.49-0.99], p = 0.04) and higher in Possible LATE-AD (HR 1.25 [1.01-1.53], p = 0.04). Compared to AD, at baseline, individuals with Probable-LATE and Possible-LATE had higher inferior temporal-to-hippocampus ratios (indicating limbic-predominant atrophy; sβ [SE] = 0.59 [0.16], p < 0.01; sβ [SE] = 0.40 [0.13], p < 0.01), and Probable-LATE, Possible-LATE, and LATE-AD all showed smaller amygdalar volumes at baseline than AD (sβ [SE] = -0.55 [0.15], p < 0.01; sβ [SE] = -0.43 [0.12], p < 0.01; sβ [SE] = -0.62 [0.11], p < 0.01). Individuals with LATE-AD had thinner cortex at baseline in an "AD-signature" composite region compared to AD (sβ [SE] = -0.73 [0.11], p < 0.01). Discussion: Using an operationalization of clinical criteria for LATE, 8.2% of participants with MCI or dementia from our tertiary memory clinic were classified as Possible-LATE, Probable-LATE, or LATE-AD. Probable-LATE was characterized by a milder disease course than AD, whereas LATE-AD was characterized by a more aggressive disease course. This underscores the value of the proposed clinical criteria in identifying individuals with suspected LATE, who have distinct clinical trajectories from AD. Our findings, therefore, support the use of these criteria to improve diagnostic and prognostic accuracy in the memory clinic.