German Center for Neurodegenerative Diseases

Cerebral small vessel disease (CSVD) is a common incidental MRI finding in patients with transient ischemic attack (TIA) and stroke and has been linked to cognitive decline. This study investigated the prevalence of CSVD imaging biomarkers in TIA patients and their association with cognitive performance over 3 years. We included 246 TIA patients from the INSPiRE-TMS study (ClinicalTrials.gov: NCT01586702). CSVD was assessed on baseline 3 T MRI using a composite score (0-4) including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVS). Cognitive performance was evaluated using the Montreal Cognitive Assessment (MoCA) at baseline and annually for 3 years. At least one CSVD imaging biomarker was present in 58.5% of patients. Lacunes (36.6%) were the most common, followed by PVS (28.1%), WMH (19.5%), and CMBs (17.9%). Higher CSVD-score was independently associated with greater cognitive decline over 3 years (β = -0.52, 95% CI -0.95- -0.08, p = 0.020), along with older age (β = -0.08, 95% CI -0.13 to -0.03, p = 0.001). CMB burden was the strongest predictive component of the CSVD-score (β = 0.42, 95% CI -0.63 to -0.22, p < 0.001). CSVD-score was particularly associated with decline in the memory domain (adjusted β of -0.18, 95% CI -0.32 to -0.04, p = 0.015). CSVD imaging markers are present in over half of TIA patients and are independently associated with cognitive decline up to 3 years, with the strongest effect on memory. Whether the presence of CMBs is the strongest predictive imaging biomarker of cognitive decline in TIA patients requires confirmation in further studies.

Transactive response DNA binding protein 43 kDa (TDP-43) pathology, is a central molecular hallmark of amyotrophic lateral sclerosis (ALS). However, the underlying triggers are incompletely understood. Here, we show that infection with herpes simplex virus (HSV) induces molecular hallmarks of ALS in various in vitro and in vivo models and is associated with an increased risk of ALS in human population data. German healthcare provider data (n = 238,440) and herpesvirus serology of an ALS patient and control cohort (n = 1,100) showed that HSV infection elevated the ALS risk by 210% and odds by ~65%, respectively. On a molecular level, HSV infection promoted TDP-43 pathology in neuronal cell models, human iPSC-derived motoneurons and cerebral organoids, mice, and human tissue sections. This effect was triggered by HSV-1 or 2, but not by several other related herpesviruses. Mechanistically, the infected cell protein 0 (ICP0) of HSV-1/2 drives TDP-43 pathology by disturbance of promyelocytic leukemia nuclear bodies (PML-NBs), thereby abrogating TDP-43 SUMO2/3ylation. Taken together, we reveal a previously unrecognized association between HSV infection and ALS and clarify the underlying molecular mechanism that drives TDP-43 pathology. Our data may guide future studies into therapeutic and prophylactic interventions against ALS.

The Dementia Leaders programme aims to enhance active public involvement in dementia research by developing a programme for potential coresearchers that includes the perspectives of individuals who experience the disease directly, such as people living with dementia, their informal caregivers and healthcare professionals. The planned study will evaluate this programme (which includes workshops, webinars and online meetings) with a focus on, for example, the content and structure of the programme as well as the experience of the participants regarding their active involvement. A mixed-methods design will be used to evaluate the Dementia Leaders programme. For this purpose, we will conduct semistructured interviews with the participants in the programme. Additionally, we will conduct an online survey after each webinar associated with the programme. The data will be analysed using qualitative content analysis (for the interview data and the open-ended questions included in the online survey) and by employing descriptive statistical methods (for the closed-ended questions of the online survey). Finally, the results obtained via both analytical methods will be synthesised, interpreted and discussed. This study received approval from the ethics committee of the German Society of Nursing Science (Number 25-014). The results will be presented and published alongside the coresearchers at (inter)national conferences and in journals targeting practitioners, caregivers and people living with dementia as well as in peer-reviewed journals.

Positron emission tomography (PET) of the brain using [18F]fluorodeoxyglucose (FDG) is becoming increasingly important for the diagnosis and differential diagnosis of atypical parkinsonian syndrome such as multiple system atrophy (MSA), which is characterized by hypometabolism of the putamen, pons, and cerebellum. We report on a patient with clinically established MSA based on a rapidly progressive, poorly levodopa-responsive parkinsonian syndrome, multidomain autonomic failure, and imaging findings where hereditary spastic paraplegia was discussed as a differential diagnosis. PET images revealed a well-preserved glucose metabolism in the striatum, specifically in the putamen, while metabolism in the cerebellum was significantly reduced. This pattern of glucose metabolism might indicate a distinct subtype of synucleinopathy as proven by seed-amplification assay and should be taken into account when diagnosing patients with MSA.

Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and juxtaneuronal microglia are derived from embryonic yolk sac precursors, long-living and maintain their populations through self-renewal. Following depletion, microglia autonomously repopulate from single surviving cells. In contrast, the course of sdCAM repopulation remains poorly understood. Here, by combining multilineage fate mapping, multiomic profiling and high-resolution imaging, we demonstrate divergent repopulation dynamics between sdCAMs and microglia. Unlike microglia, sdCAMs do not renew cell-autonomously, but become transiently accessible to CCR2+Ly6C+ monocyte engraftment after niche induction in an integrin-dependent manner. Moreover, replenished monocyte-derived sdCAMs remain transcriptomically, epigenetically and functionally distinct from their embryo-derived counterparts. Finally, we present a protocol enabling selective exchange of sdCAMs, modulating disease response without functionally affecting microglia. These new insights into CNS immune biology suggest new therapeutic avenues for neuroinflammatory and neurodegenerative diseases.

Rupture of an intracranial aneurysm (IA) can result in aneurysmal subarachnoid hemorrhage (ASAH), a severe and often fatal form of stroke. The configuration of the intracranial arteries - collectively known as the circle of Willis (CoW) - influences the risk of IA development and rupture. Although CoW variation is known to be heritable, its genetic underpinnings and contribution to IA remain poorly understood. Here, we aimed to investigate the genetic architecture of CoW variation and its potential link with IA. Using a semi-automated detection tool, we characterized the diameters, bifurcation angles, and presence of arterial segments of the CoW in 1078 participants from a population-based cohort and 682 IA patients. Composite traits capturing variation in all CoW characteristics were generated through principal component analysis. We conducted a genome-wide association study (GWAS) on these composite traits and identified four loci with suggestively significant associations. Lead single-nucleotide polymorphisms (SNPs) were located in or near the genes DPYSL2, CSMD3, TRPC6, and PKD1L2. Notably, PKD1L2 is closely related to PKD1, a gene implicated in autosomal dominant polycystic kidney disease, a connective tissue disorder that increases IA susceptibility. We observed statistically significant SNP-based heritability for the second principal component of CoW variation (heritability estimate = 0.95, standard error = 0.25). All lead SNPs demonstrated nominal association (p < 0.05) with multiple CoW characteristics and other vascular traits. Our findings highlight a substantial genetic contribution to CoW morphology and offer new insights into the molecular mechanisms underlying CoW variation and its role in IA pathogenesis.