Vincent Malotaux

Cerebral glucose metabolism is distinctly disrupted in Alzheimer's disease (AD), though its role in downstream cognitive decline remains unclear. Ueda et al. leverage Mendelian Randomization by integrating genetics, imaging and cognitive data to demonstrate that cerebral glucose metabolism is causally linked to cognitive performance. This approach lays the groundwork for novel therapeutic strategies by suggesting that metabolism-focused interventions may mitigate cognitive impairment in AD. Future studies should further integrate single-cell and multi-omics strategies to elucidate cellular and molecular pathways related to causal effects and explore the influence of co-pathologies and epigenetics on metabolic and cognitive performance.

INTRODUCTION: Plasma phosphorylated tau (p‐tau)‐231 is a promising biomarker for Alzheimer's disease (AD), particularly in preclinical stages. We evaluated its diagnostic value in presenilin 1 ( PSEN1 ) E280A mutation carriers versus non‐carriers and compared it to p‐tau217 and neurofilament light chain (NfL). METHODS: We analyzed plasma p‐tau231 in 722 carriers and 640 non‐carriers (ages 18–75). Longitudinal data from 164 carriers and 132 non‐carriers were available, with 137 carriers and 109 non‐carriers having p‐tau231, p‐tau217, and NfL levels. Analyses used linear mixed effects models and restricted cubic splines. RESULTS: E280A carriers had higher p‐tau231 levels than non‐carriers (9.0 ± 7.4 vs. 5.2 ± 3.4 pg/mL, P < 0.001). Baseline p‐tau231 levels correlated with age, distinguishing carriers at age 23. Rates of change differed at age 19, ≈ 25 years before cognitive impairment. In a subset, p‐tau231 changes differentiated carriers by age 20, earlier than p‐tau217 and NfL. DISCUSSION: Plasma p‐tau231 is a sensitive biomarker for early AD detection and progression monitoring. Highlights: Plasma phosphorylated tau (p‐tau)231 levels are associated with age in presenilin 1 carriers and non‐carriers. Baseline p‐tau231 levels diverged between carriers and non‐carriers at age 23. Plasma p‐tau231 changes distinguished carriers by age 19, at very early stages. P‐tau231 longitudinal changes differentiate carriers earlier than p‐tau217 or neurofilament light chain.

Background: Cortico-basal degeneration (CBD) is a neurodegenerative disease typically responsible for cortico-basal syndrome (CBS) or progressive limb apraxia. Half of CBD patients, however, present atypical symptoms, making the diagnosis difficult. Objective: We reported the case of a woman in her late sixties (BM208), an unusual case of autopsy-proven CBD, showing early signs of Benson's syndrome or posterior cortical atrophy. In addition, we compared cognitive performance and atrophy in different brain regions of BM208 with other neurodegenerative diseases patients to highlight clinical signs that could have guided the diagnosis earlier. Methods: We retrospectively compared BM208 to patients with typical amnestic Alzheimer's disease (AD) (n = 18, Mini-Mental State Exam (MMSE) scores between 18 and 24), Benson's syndrome due to AD (n = 3), CBS/progressive supranuclear palsy (PSP) syndrome (n = 5), and Lewy body dementia (LBD) patients (n = 3) and a control group (n = 24). All these participants underwent an MMSE, a complete neuropsychological examination and 3DT1 MRI. Results: Although BM208 was more severely cognitively impaired overall, her cognitive performance was more similar to Benson's syndrome patients’ cognitive profile compared to CBS patients or any other degenerative pathology (typical AD/LBD). Consistently, although BM208 was more atrophic than all other groups, she showed cortical atrophy that matched a Benson's syndrome pattern more than typical AD or CBS. However, the analysis of subcortical atrophy revealed atrophy of the basal ganglia corresponding CBS cases. Furthermore, visual analyses on sagittal T1 images showed atrophy of the midbrain, characteristic of CBS/PSP syndrome. Conclusions: These results highlight the additive value of fine-grained MRI subcortical quantification to diagnose non-AD rare neurodegenerative disorders.

Introduction: Second‐generation tau‐PET tracers like [¹⁸F]MK‐6240 are increasingly used both for diagnosing and quantifying Alzheimer's Disease (AD) tauopathy. However, while [¹⁸F]MK‐6240 tau‐PET has demonstrated excellent sensitivity for AD tauopathy, data assessing its specificity and binding in non‐AD tauopathies are still scarce.Methods: Participants were assigned to exclusive categorical diagnoses based on their amyloid (Aβ) and cognitive status. We quantified mesiotemporal (MTL) and neocortical [¹⁸F]MK‐6240 tau‐PET signal in 28 Aβ− cognitively impaired (CI) patients presenting various non‐AD neurodegenerative disorders. Tau‐PET quantifications were compared with Aβ− cognitively unimpaired (CU) subjects (n = 51) and Aβ+ CI patients (n = 77).Results: Among the 28 Aβ− impaired subjects, only five presented significant and isolated mesiotemporal signal, most of them being suspected of primary age‐related tauopathy (PART). Only two Aβ− impaired patients (7%) presented positive neocortical signal, both being diagnosed with fronto‐temporal degeneration (FTD). The Tau‐PET results of all the remaining Aβ− patients were comparable to the CU population, including eight other FTD patients. Importantly, 4R‐only tauopathies (CBD and PSP) and sv‐PPA were negative.Conclusion: [¹⁸F]MK‐6240 tau‐PET has a special affinity for tauopathies involving 3R/4R paired helical filaments: AD, PART (Aβ− subjects with MTL‐restricted tau‐PET signal) and some forms of FTD while most primary tauopathies do not exhibit significant cortical signal. Positive neocortical scans are therefore highly specific for AD tauopathy. Based on those and previous results, we propose a diagnostic flowchart for MCI subjects suspected of AD or another tauopathy which may significantly reduce the need for amyloid PET or CSF measurement.

INTRODUCTION: Magnetic resonance imaging (MRI) segmentation algorithms make it possible to study detailed medial temporal lobe (MTL) substructures as hippocampal subfields and amygdala subnuclei, offering opportunities to develop biomarkers for preclinical Alzheimer's disease (AD).METHODS: We identified the MTL substructures significantly associated with tau‐positron emission tomography (PET) signal in 581 non‐demented individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI‐3). We confirmed our results in our UCLouvain cohort including 110 non‐demented individuals by comparing volumes between individuals with different visual Braak's stages and clinical diagnosis.RESULTS: Four amygdala subnuclei (cortical, central, medial, and accessory basal) were associated with tau in amyloid beta‐positive (Aβ+) clinically normal (CN) individuals, while the global amygdala and hippocampal volumes were not. Using UCLouvain data, we observed that both Braak I‐II and Aβ+ CN individuals had smaller volumes in these subnuclei, while no significant difference was observed in the global structure volumes or other subfields.CONCLUSION: Measuring specific amygdala subnuclei, early atrophy may serve as a marker of temporal tauopathy in preclinical AD, identifying individuals at risk of progression.Highlights: Amygdala atrophy is not homogeneous in preclinical Alzheimer's disease (AD). Tau pathology is associated with atrophy of specific amygdala subnuclei, specifically, the central, medial, cortical, and accessory basal subnuclei. Hippocampal and amygdala volume is not associated with tau in preclinical AD. Hippocampus and CA1‐3 volume is reduced in preclinical AD, regardless of tau.

Purpose: [¹⁸F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer’s disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr). Methods: [¹⁸F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values. Results: The EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R² + 0.08–0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R² = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values. Conclusions: Quantifying [¹⁸F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.