Weight loss and hypermetabolism are early and prognostically significant features of amyotrophic lateral sclerosis (ALS) and are associated with hypothalamic atrophy and degeneration of melanin-concentrating hormone (MCH) neurons that regulate energy balance. To investigate whether MCH vulnerability arises from upstream network dysfunction, we performed whole-brain retrograde rabies tracing in SOD1G93A mice. We identified an early, selective loss of monosynaptic inputs from the zona incerta (ZI), a dopaminergic (DA)/gamma-aminobutyric acid (GABA)ergic nucleus that preceded MCH neuron degeneration. Neurochemical profiling confirmed the DA/GABAergic identity of these ZI input neurons, and ZI/DAergic neurons later degenerated. ALS-related pathology emerged early in the ZI, paralleling pathology in the motor cortex, while anterograde mapping revealed that motor cortical projections preferentially targeted the ZI, linking vulnerable motor and metabolic networks. Loss of ZI/DAergic neurons was observed in conjunction with weight loss in non-SOD1 ALS models. These findings identify the ZI as an early-affected node within hypothalamic networks and suggest that disruption of DA/GABAergic inputs to MCH neurons is associated with subsequent MCH and DA neuronal vulnerability, degeneration and metabolic imbalance in ALS.The online version contains supplementary material available at 10.1186/s40478-026-02231-z. Scekic-Zahirovic, Jelena; Antonucci, Stefano; Wiesner, Diana; Ebner, Chiara; El Hajj, Hussein; Aousji, Oumayma; Halablab, Kareen; Fan, Yiting; Zelaya, Anneka; Yartas, Gizem; Baskar, Karthik; Çakmak, E. Anastasia; Bayer, David; Sung, Hoon-Ki; Dupuis, Luc; Park, Jeehye; Roselli, Francesco
Digital speech-based assessments provide scalable tools for detecting subtle cognitive decline. Here, we investigated whether digitally derived speech-based composite score of cognition and individual speech features were associated with alterations in functional connectivity (FC) within task-related brain networks in the Alzheimer's disease spectrum, which are known to reflect cognitive performance and disease-related changes.Data were analyzed from 129 participants of the German PROSPECT-AD study, ranging from cognitively healthy individuals to those with mild cognitive impairment. Speech-based cognitive scores and speech features were derived from automated phone-administered semantic verbal fluency (SVF) and verbal learning tasks (VLT). Resting-state fMRI assessed FC, with intrinsic connectivity networks identified via independent component analysis and dual regression. Associations were examined using permutation-based voxel-wise regression, controlling for demographic and clinical covariates. Seed-to-voxel analyses were conducted to support network identification and complement findings.Greater language network connectivity in the left middle temporal gyrus was associated with increased SVF temporal cluster switching (FWE < .05, cluster size = 12 voxels, mean T = 3.86). Exploratory analyses (uncorrected p < .01) demonstrated no significant associations between cognitive composite scores and FC. However, individual SVF and VLT speech features exhibited network-specific associations across executive, language, and default mode networks, indicating exploratory yet spatially distinct connectivity patterns.Digital speech-based assessments may have limited current utility for detecting FC alterations in at-risk individuals. Further validation using complementary methodological approaches, shorter intervals between fMRI and speech assessments, and testing in independent cohorts, are essential to establish their reliability and clinical relevance for monitoring brain network changes. Li, Qingyue; Alexopoulou, Zampeta-Sofia; Dyrba, Martin; Mallick, Elisa; Tröger, Johannes; Spruth, Eike; Altenstein, Slawek; Bartels, Claudia; Glanz, Wenzel; Incesoy, Enise I; Butryn, Michaela; Kilimann, Ingo; Sodenkamp, Sebastian; Maier, Franziska; Rostamzadeh, Ayda; Osterrath, Antje; Priller, Josef; Schneider, Anja; Wiltfang, Jens; Laske, Christoph; Falkenburger, Björn; Wagner, Michael; Duezel, Emrah; Spottke, Annika; Petzold, Gabor C; Jessen, Frank; König, Alexandra; Köhler, Stefanie; Teipel, Stefan; DELCODE, DESCRIBE study groups
Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists. Feiten, Astrid Feentje; Dahm, Kilian; Schlepckow, Kai; van Lengerich, Bettina; Suh, Jung H; Reifschneider, Anika; Wefers, Benedikt; Bartos, Laura M; Wind, Karin; de Weerd, Lis; Ulas, Thomas; De-Domenico, Elena; Grundschöttel, Pia; Paulusch, Stefan; Tast, Benjamin; Honda, Tamisa; Müller, Stephan A; Becker, Matthias; Khalin, Igor; Ricci, Alessio; Liesz, Arthur; Brunner, Bettina; Krenner, Claudia; Buschmann, Katrin; Nuscher, Brigitte; Spieth, Lena; Junker, Niklas; Berghoff, Stefan A; Davis, Sonnet S; Neher, Jonas J; Wurst, Wolfgang; Plesnila, Nikolaus; Lewcock, Joseph W; Simons, Mikael; Lichtenthaler, Stefan F; Di Paolo, Gilbert; Brendel, Matthias; Capell, Anja; Monroe, Kathryn M; Schultze, Joachim L; Haass, Christian
Recent evidence suggests glial dysfunction, particularly involving oligodendrocytes and myelin, as an important part of the primary disease mechanism of sporadic Creutzfeldt–Jakob disease. To the best of our knowledge, cerebrospinal fluid (CSF) biomarkers reflecting oligodendrocyte or myelin damage have not yet been systematically investigated in this context. CSF samples from patients with sporadic Creutzfeldt–Jakob disease (CJD), Alzheimer's disease (AD) and non-neurodegenerative controls (n = 18, respectively) were included in the study, and levels of myelin basic protein (MBP), neural/glial antigen 2 (NG2) and cyclic nucleotide 3′-phosphodiesterase (CNPase) were quantified. Additionally, p25-positive cells were quantified in autopsy tissue from the frontal and parietal cortical regions of five patients with CJD and four controls. In the primary cohort, MBP quantification revealed significantly higher CSF levels in CJD compared to AD (p = 0.004) and controls (p = 0.0001) and this difference remained significant after adjustment for age and neurofilament light chain (NfL), indicating that MBP elevations cannot be explained solely by neuroaxonal degeneration. Significant differences were also found for CNPase in CJD compared to AD (p = 0.0011) and controls (p = 0.0004). There were no differences in NG2 levels (p > 0.05) among the groups. However, no significant differences were observed in the total number of p25-positive mature oligodendrocytes between CJD and controls in cortical brain tissue (p > 0.05). Additionally, MBP and NfL were quantified in a second cohort of 28 CJD and 20 biomarker-defined AD patients. In this cohort, characterized by more advanced AD pathology, MBP strongly covaried with NfL and no longer differed between diagnostic groups, suggesting a greater influence of neuroaxonal injury on MBP levels in advanced disease stages. In conclusion, in CJD, MBP elevations appear to be only partly related to neuroaxonal degeneration and may reflect disease-related myelin involvement.The online version contains supplementary material available at 10.1186/s40478-026-02247-5. Maass, Fabian; Thomas, Carolina; Kurvits, Lille; Hermann, Peter; Schmitz, Matthias; Bähr, Mathias; Stadelmann, Christine; Zechel, Sabrina; Canaslan, Sezgi; Zerr, Inga
Resistance to age-related pathological changes (brain maintenance), including Alzheimer’s disease, cerebrovascular disease, and neurodegeneration may promote cognitive resilience in aging. However, how lifestyle and health profiles relate to successful cognitive and brain aging remains poorly understood. In a novel, deeply phenotyped cohort of 211 cognitively unimpaired older adults (age = 71.0 ± 7.4 years, 46% female), we characterized principal components of lifestyle and health using questionnaire, fitness, and blood data. We estimated cognitive age gap (CAG) based on comprehensive neuropsychological data and brain age gap (BAG) based on brain-pathology markers, including plasma biomarkers of Alzheimer’s pathology (pTau217 and Aβ1-42/Aβ1-40), MRI-based measures of white matter hyperintensities, perivascular spaces, and brain atrophy. Regression analyses tested how the observed lifestyle-health profiles were related to CAG and BAG. Seven principal components explained 49% of the variance in health and lifestyle. The second component, characterized by a mentally and physically active life and low cardiovascular risk, was associated with lower CAG (β = − 0.66, p < 0.001) and BAG (β = − 0.52, p = 0.003), reflecting a younger-than-expected brain and cognitive age, respectively. The association of an active lifestyle and lower CAG was partially mediated by BAG. Higher CAG was also associated with other lifestyle components characterized by low mental stimulation. APOE-ε4 carriers exhibited higher BAG. In conclusion, a lifestyle combining low cardiovascular risk, high mental engagement throughout life and high physical activity/fitness is jointly associated with less-than-expected brain pathology and better-than-expected cognitive performance, supporting its involvement in brain maintenance and cognitive resilience to aging. Behrenbruch, Niklas; Schwarck, Svenja; Schumann-Werner, Beate; Molloy, Eóin N.; Garcia Garcia, Berta; Hochkeppler, Anne; Fischer, Larissa; Büchel, Anna-Therese; Incesoy, Enise I.; Bernal, Jose; Vockert, Niklas; Müller, Patrick; Behnisch, Gusalija; Morgado, Bárbara; Esselmann, Hermann; Seidenbecher, Constanze I.; Schott, Björn H.; Barthel, Henryk; Sabri, Osama; Wiltfang, Jens; Kreissl, Michael C.; Düzel, Emrah; Maass, Anne
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