Irena Rektorova

Alzheimer’s disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050¹. AD is highly heritable, with twin-based heritability estimates of 60–80%². Although 1,200 causal loci are predicted to exist for AD³, approximately 80 loci have been associated with AD in two recent studies^4,5. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found⁶. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.

Substantia nigra hyperechogenicity (SN+) detected by transcranial sonography (TCS) has been proposed as a risk marker for synucleinopathies, particularly Parkinson’s disease. Its role in prodromal dementia with Lewy bodies (DLB) remains insufficiently explored. To examine clinical, cognitive, genetic, EEG, and plasma biomarker differences between SN+ and normal echogenicity (SN−) individuals in a well-characterized at-risk-of-DLB cohort, with additional sex-stratified analyses. A total of 121 participants aged 55–70 years from an at-risk-of-DLB cohort underwent TCS, neurological and neuropsychological assessment, nighttime wrist actigraphy, high-density EEG, genetic testing for APOE allelic variants, and plasma biomarker analysis (NfL, GFAP, pTau181). SN status was defined using laboratory-specific cut-offs. Group differences were assessed using non-parametric statistics with relevant corrections for multiple comparisons and adjustment for age. SN+ status as compared to SN− status was associated with poorer verbal memory performance and altered visuo-constructive performance (driven mostly by males), and significant differences in distinct actigraphy-derived sleep parameters. SN+ participants showed higher plasma NfL levels (particularly in males) and a higher prevalence of DLB-specific EEG patterns (driven by females). No significant associations were observed for global cognition, motor parkinsonism, cognitive fluctuations, hallucinations, REM sleep behavior disorder, depressive symptoms, olfactory function, plasma biomarkers of degeneration, neuroinflammation, β-amyloid deposition, or APOE status. In individuals at risk of DLB, SN hyperechogenicity is linked to early markers of neurodegeneration and cholinergic dysfunction, including elevated NfL and DLB-specific EEG abnormalities, as well as selective posterior cortical cognitive impairment and sleep disturbances. The observed sex-specific effects require further investigation.

Aims: This study employed diffusion kurtosis imaging (DKI) and proton magnetic resonance spectroscopy ( ¹ H‐MRS) on an MPTP‐induced mouse model of Parkinson's disease (PD) to examine microstructural changes linked to neuroinflammation and neurodegeneration. Methods: MPTP (20 mg/kg, i.p.) was given for 4 days, and behavioral assessment, MRI imaging, and immunohistochemistry were performed at 24 h and 72 h after last MPTP treatment. Results: At 24 h, DKI showed higher diffusivity metrics in the hippocampus and thalamus, while ¹ H‐MRS identified reduced Glu/tCr and Glx/tCr ratios in the striatum of MPTP‐treated mice compared to saline‐treated mice. Behavioral tests at 72 h revealed motor impairment and DKI showed increased diffusivity in the somatosensory cortex, thalamus, and striatum in MPTP‐treated mice. Notably, at 72 h, the hippocampus showed partial recovery in diffusivity, suggesting adaptive changes or partial restoration. Higher diffusivity was observed in the cortex, striatum, and thalamus in MPTP‐treated mice. Furthermore, ¹ H‐MRS detected a higher Tau/tCr in the striatum, while in the hippocampus, lower Gln/tCr and NAA/tCr and higher Cho/NAA were observed at 72 h in MPTP‐treated mice, indicating persistent neuronal death and membrane deterioration. Immunofluorescence staining at 72 h confirmed these findings, showing a decrease in NeuN+ neurons and an increase in GFAP+ glial cells in the striatum and hippocampus, indicating neurodegeneration and gliosis. Additionally, MPTP caused a loss of dopaminergic neurons in the substantia nigra and striatum, which likely explains the higher diffusivity shown by DKI. Conclusion: These findings demonstrate DKI and ¹ H‐MRS are sensitive, non‐invasive modalities for detecting and monitoring neurodegenerative microstructural and neurochemical changes, enhancing the understanding of PD‐related pathology and progression.

Brain connectivity dynamics in mild cognitive impairment with Lewy bodies (MCI-LB) is largely unknown. We aimed to identify brain connectivity dynamics related to cognitive performance in drug naïve MCI-LB. Healthy (55 participants, age 67.7 ± 6.4, 33 females) and MCI-LB subjects (30 participants, age 68.5 ± 6.0, 16 females) underwent cognitive testing and fMRI. The fast eigenvector centrality dynamic functional connectivity was employed to detect connectivity states. Mean state duration and occurrence were correlated to cognitive measures. In the MCI-LB group only, the occurrence and mean duration of the state characterized by between-network connectivity of the dorsal attention, sensorimotor, and visual networks correlated with visuospatial function (VSF) domain z-scores ( r = 0.68, p = 0.003, and r = -0.68, p = 0.003, respectively). The VSF also correlated with the occurrence of the state characterized by intra-network connectivity of the frontoparietal control network ( r = -0.55, p = 0.041). We identified specific mechanisms that seem to facilitate visuospatial performance in MCI-LB.

Lewy body diseases, including Parkinson’s disease and dementia with Lewy bodies, are marked by neuronal α‑synuclein aggregation, motor parkinsonism, cognitive impairment and diverse non‑motor symptoms including communication impairments. Compared to other symptoms, non‑motor communication impairments remain under-explored, especially outside English‑speaking cohorts. The aim of this study was to elucidate the neural underpinnings of linguistic deficits as assessed by fMRI in Czech-speaking patients diagnosed with neuronal Lewy body disease and mild cognitive impairment (LBD-MCI). Scores from the Short Neuropsychological Battery and resting‑state functional MRI data were analyzed in 26 Czech‑speaking patients with LBD‑MCI and 24 healthy controls. Analyses targeted regions of interest within the dorsal and ventral language networks. We applied graph theory metrics, within‑network connectivity and seed‑based functional connectivity analysis. Graph analysis revealed dorsal‑stream disruption in LBD‑MCI: reduced clustering coefficient, increased path length, and diminished node strength, each correlating with language functions; ventral‑stream topology remained intact. Within‑network analyses showed impaired connectivity across both pathways, but weaker coupling between the opercular inferior frontal gyrus and posterior superior temporal gyrus predicted behavioral scores in language functioning, further highlighting dorsal vulnerability. Seed‑based analysis identified reduced frontotemporal connectivity in the dorsal stream and decreased fronto‑occipital and temporo-cerebellar connections in the ventral stream. LBD‑MCI is characterized particularly by network‑specific reductions in dorsal language stream efficiency and functional connectivity, underpinning syntactic and phonological processing deficits. These findings offer novel insights in the neural basis of language impairment in LBD-MCI.

This work investigates aperiodic bursts of neuronal activity, referred to as neuronal avalanches, which are thought to support flexible information processing in Lewy body (LB) disease. We compared avalanche-derived features across LB disease phenotypes (prodromal dementia with LB and Parkinson's disease, PD), with healthy controls (HC). Based on the premise that focal neurodegeneration alters whole-brain dynamics, we examined whether the "richness" of brain dynamics was associated with clinical symptoms and with the microstructural integrity of catecholaminergic nuclei - the right caudal locus coeruleus (rcLC) and the substantia nigra pars compacta (SNpc). The sample comprised 30 HC, 56 cognitively normal individuals with core clinical features of dementia with LB (CN-CCF), 34 individuals with mild cognitive impairment with LB (MCI-LB), and 30 advanced PD patients. Neuronal avalanches were extracted from source-reconstructed resting-state EEG and described by their count, the number of unique spatial patterns (flexibility), hemispheric symmetry of flexibility, and avalanche transition matrices. LC and SNpc integrity were assessed using neuromelanin-sensitive MRI and free-water diffusion imaging, respectively. Lewy body disease groups exhibited increased flexibility relative to HC, which was, in prodromal groups, associated with cognitive fluctuations and REM sleep behavior disorder symptoms, but not parkinsonism. Flexibility was negatively related to rcLC integrity, which was lowest in MCI-LB. These findings suggest that elevated flexibility reflects dysregulated brain dynamics linked to malignant non-motor features of LB diseases and to the caudal LC involvement.

To tackle the disease-related process in early pre-dementia Lewy Body Dementia, we investigated the changes of functional brain networks and their cognitive relevance. A cohort of 38 Mild Cognitive Impairment with Lewy Bodies (MCI-LB) subjects and one of 24 healthy controls (HC) underwent neuropsychological assessment and resting state (RS) functional and structural MRI. Functional connectivity (FC) between ROIs belonging to a set of RS networks, including the Salience Network (SN), Fronto-Parietal (FPN), Default Mode (DMN), Dorsal and Ventral Attention (DAN and VAN), Somato-Motor (SMN), Visual (VN) and Language (LN) was estimated and compared between cohorts. Finally, neuropsychological scores were correlated with FC of MCI-LB and HC separately. Compared to HC, MCI-LB exhibited lower FC between DAN, FPN and LN. Higher inter-network FC was found between FPN and SN, FPN and DMN, SN and SMN and DAN and SMN. In MCI-LB the correlational analysis revealed significant positive and negative associations between cognitive performance and FC values between nodes. In conclusion, we found a possible compensation mechanism between nodes in SN and FPN, and FPN and DMN following disconnection between the control system of the FPN and the top down attention system. The complex compensatory mechanisms involving multiple networks may not be efficient to counteract the cognitive impairment in MCI-LB. Overall, in MCI-LB we found an aberrant engagement of the networks that are not primarily involved in the performance of specific tasks.

The “Neuroimaging and Pathology Biomarkers in Parkinson’s Disease” course held on 12–13 September 2025 in Milan, Italy, convened an international faculty to review state-of-the-art biomarkers spanning neurotransmitter dysfunction, protein pathology and clinical translation. Here, we synthesize the four themed sessions and highlights convergent messages for diagnosis, stratification and trial design. The first session focused on neuroimaging markers of neurotransmitter dysfunction, highlighting how positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) provided complementary insights into dopaminergic, noradrenergic, cholinergic and serotonergic dysfunction. The second session addressed in vivo imaging of protein pathology, presenting recent advances in PET ligands targeting α-synuclein, progress in four-repeat tau imaging for progressive supranuclear palsy and corticobasal syndromes, and the prognostic relevance of amyloid imaging in the context of mixed pathologies. Imaging of neuroinflammation captures inflammatory processes in vivo and helps study pathophysiological effects. The third session bridged pathology and disease mechanisms, covering the biology of α-synuclein and emerging therapeutic strategies, the clinical potential of seed amplification assays and skin biopsy, the impact of co-pathologies on disease expression, and the “brain-first” versus “body-first” model of pathological spread. Finally, the fourth session addressed disease progression and clinical translation, focusing on imaging predictors of phenoconversion from prodromal to clinically overt stages of synucleinopathies, concepts of neural reserve and compensation, imaging correlates of cognitive impairment, and MRI approaches for atypical parkinsonism. Biomarker-informed pharmacological, infusion-based, and surgical strategies, including network-guided and adaptive deep brain stimulation, were discussed as examples of how multimodal biomarkers may inform personalized management. Across all sessions, the need for harmonization, longitudinal validation, and pathology-confirmed outcome measures was consistently emphasized as essential for advancing biomarker qualification in multicentre research and clinical practice.