Günter U. Höglinger

[Multiple system atrophy].

Health-related factors and their impact on blood-based biomarkers of Alzheimer's disease

Background Health-related factors may influence blood-based biomarkers (BBBM) of Alzheimer's disease (AD). In this analysis, associations between modifiable factors and plasma biomarkers of neurodegeneration were investigated across the Alzheimer's disease spectrum and in cognitively healthy controls in a cerebrospinal fluid–confirmed (CSF) cohort. Methods Plasma biomarkers included the Aβ1–42/1–40 ratio, pTau181, GFAP, NFL and ApoE4. Multiple linear regression was used to test associations with lifestyle factors (physical activity and sleep), physiological factors (including renal and lipid metabolism markers), genetic factors (APOE ε4), age and sex. Percentage effect sizes and confidence intervals were calculated. Results The study included CSF-characterized individuals with AD (mild cognitive impairment due to AD and AD dementia) and cognitively healthy controls (n = 116; mean age 71.2 years). Overall, the associations were modest, with wide confidence intervals reflecting variability in the outcomes and the limited range of predictors in this relatively healthy sample. In CSF-confirmed participants, age emerged as the most consistent predictor of plasma biomarker levels, particularly NFL and pTau181. APOE ε3/ε4 genotype was additionally associated with higher pTau181 levels. Other demographic, metabolic and lifestyle-related variables showed only weak or inconsistent associations. Conclusion To implement BBBM in broader populations, a systematic evaluation of confounders is required. As aging cohorts present with mixed pathologies, strategies to address heterogeneity will be essential. The limited number of robust associations observed suggests that plasma biomarkers are influenced primarily by age and genetic background rather than by metabolic factors in this cohort. Validation in more diverse populations remains warranted.

Molecular Disease Stages of Oligodendrocytic and Neuronal Tau Burden in Progressive Supranuclear Palsy

Background Progressive supranuclear palsy (PSP) is a primary tauopathy defined by the accumulation of 4R tau isoforms in neurons, oligodendrocytes and astrocytes. Despite evidence of genetic susceptibility operating through glial cell types, it remains poorly understood how cell type-specific epigenetic-transcriptional programs evolve with progression of tau pathology. Methods We conducted single-nucleus chromatin accessibility (snATACseq) and RNA sequencing (snRNAseq) on postmortem frontal cortex samples from PSP patients (n = 8) and matched controls (n = 8), yielding over 144,000 nuclei passing quality control. Tau pathology burden, including neurofibrillary tangles, coiled bodies, and tufted astrocytes, was quantified on AT8-immunostained sections from the same individuals. We integrated differential gene expression analysis, transcription factor motif enrichment, weighted gene co-expression network analysis, and pseudotime modeling anchored to cell type-specific tau pathology burden to delineate molecular pseudo-progression trajectories. Results In eight cell types, 20 subclasses, and 70 subclusters, PSP brains displayed a selective depletion of certain excitatory deep-layer neurons and oligodendrocyte subclusters, with relative preservation of inhibitory neurons and vascular cells. Genetic risk enrichment was localized to astrocytes and oligodendrocytes, whereas excitatory neurons exhibited the greatest transcriptional dysregulation. Oligodendrocyte pseudo-progression indicated a transition from homeostatic myelination programs (MBP, MOBP) through glucocorticoid-responsive stress (FKBP5, ZBTB16), to compensatory myelination (PLP1, CNP) and proteostasis stress (UCHL1, CYRAB, CLU). Neuronal pseudo- progression revealed early dysregulation of synaptic (RORB2, NRG3, NPTX1), microtubule dynamics (KIF2C, RAB27B, TUBA/B), and survival (MEG3, FTX) pathways, alongside a transient increase in neuron-glia interactions (GRIP, CNTNAP4, ERBB4), converging late on ribosomal translation and vesicular trafficking modules across all neuronal subtypes. Cross-modal integration with independent cerebrospinal fluid proteomics identified a concordant subset of glial reactivity, axonal injury, and synaptic markers jointly dysregulated in inhibitory neurons, oligodendrocytes, and excitatory deep-layer neurons. Conclusion PSP pathogenesis reflects a combination of glial genetic susceptibility and staged, cell type-specific transcriptional dysfunction. Oligodendrocytes transition from myelination-competent states to FKBP5-mediated stress states, while neurons show variably timed loss of synaptic excitability and survival programs, preceded by neuron-glia interactions and followed by convergent ribosomal-proteostatic failure. These cytopathology-anchored trajectories outline a potential pathophysiological sequence and may inform candidate selection for stage-specific therapeutic interventions in PSP.

Multiple system atrophy: cure and care.

Bridging advances in pathophysiology with patient-centred care will be essential for improving outcomes in MSA, and advances in fluid biomarkers and multimodal imaging are expected to facilitate earlier detection, improve diagnostic accuracy, and provide more robust tools for monitoring disease progression.

Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies

It is shown that early complement associated pruning of inhibitory synapses precedes overt α-synuclein aggregation and neuronal loss in prodromal synucleinopathy, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration.