#10
Barbara Segura 

Glymphatic Dysfunction in Synucleinopathies: MRI Proxies and Clinical and Neurodegenerative Correlates 

Glymphatic system dysfunction has been proposed as a contributing mechanism in neurodegenerative disorders, potentially promoting the accumulation of pathological proteins. Noninvasive MRI proxies offer a novel approach to assess glymphatic activity in vivo.

In this symposium, we will present evidence from studies in synucleinopathies. Patients consistently show glymphatic impairment based on MRI proxies. Importantly, these alterations are associated with nonmotor symptoms, including cognitive deficits and olfactory dysfunction, as well as with circadian and sleep–wake disturbances. Moreover, glymphatic dysfunction correlates with brain atrophy and reduced dopaminergic uptake, linking it to established markers of neurodegeneration.

These findings support glymphatic dysfunction as an early feature of synucleinopathies and highlight its relevance to clinical and imaging markers. While promising, MRI-based proxies remain research tools, and further longitudinal studies are needed to establish their role in disease progression and therapeutic targeting.

#11
Rosaleena Mohanty 

Imaging correlates of polypathology in Alzheimer’s disease 

Alzheimer’s disease (AD) rarely occurs in isolation. Most older adults harbor multiple coexisting neuropathologies such as alpha-synuclein, TDP-43, hippocampal sclerosis, and cerebrovascular pathology. Beyond the AD hallmarks of amyloid and tau pathologies, these non-AD pathologies may contribute to neurodegeneration and eventual cognitive decline. Not all non-AD pathologies, however, cannot yet be reliably identified by antemortem imaging. This talk will link evidence from antemortem neuroimaging and postmortem neuropathology to: (1) delineate the interaction of AD and non-AD pathologies in explaining neurodegeneration and cognitive status, (2) discuss the role of coexisting neuropathologies to better understand disease heterogeneity or subtypes in AD and (3) highlight the need to account for etiological and biological heterogeneity within individual neuropathologies. Thus, reliable neuroimaging correlates of polypathology can help identify otherwise hidden biological pathways to cognitive impairment.

#13
Amanda Annettesdotter 

Neuropathological correlates of amygdala subregional volumes

Background: The amygdala is a hotspot for neuropathologies and neurodegeneration, but whether local or distal pathology in connected regions leads to neurodegeneration and in what amygdala subregions is still unknown. We investigated associations between whole and subregional amygdala volumes and measures of tau, amyloid-β (Aβ), β-synuclein, and transactive response DNA-binding protein 43 (TDP-43) pathology in the amygdala and other medial temporal lobe (MTL) regions in individuals with and without neurodegenerative diseases.

Methods: Postmortem data from 78 individuals (78±11 [44–101] years; 38% females; 73% cognitively impaired) was included. Volumes of the whole amygdala and amygdala subregions (lateral, basolateral, basomedial, cortical, and centralmedial; for n=69 individuals) were manually segmented on 0.2×0.2×0.2 mm3 postmortem magnetic resonance images (Fig.1). Contralateral semi-quantitative ratings of Aβ, tau, β-synuclein, and TDP-43 in the amygdala, dentate gyrus, Cornu Ammonis 1/subiculum, and entorhinal cortex, and a separate ipsilateral quantitative measure of amygdala tau burden were obtained.

Results: Higher tau ratings in MTL regions, and higher TDP-43 ratings in the amygdala and MTL, were associated with smaller whole amygdala volumes (partial Spearman correlations adjusting for age, sex, other pathologies; Fig.2a–b). The association between MTL TDP-43 and amygdala volume was not significant after adjusting for amygdala TDP-43. Average MTL and amygdala tau ratings correlated with lateral, basolateral, basomedial, and centralmedial subregional volumes, whereas TDP-43 was associated with all subregional volumes (Fig.2c). No associations were observed for Aβ and β-synuclein. Subregional mapping of tau pathology showed tau tangles primarily in the lateral and tau threads in the basal subregion (Fig.3a). Linear regression models (adjusting for age, sex, other pathologies) showed that higher quantitative amygdala tau burden was associated with smaller whole amygdala volume (Fig.3b), and higher lateral tau burden with smaller lateral volume (Fig.3c). No associations were found for the other subregions.

Conclusions: These findings suggest that tau pathology may contribute to amygdala neurodegeneration both directly, through its effects within the amygdala, and indirectly through other MTL regions via retrograde transsynaptic degeneration. In contrast, TDP-43 associates to amygdala volume only directly. Subregional analyses further indicate that MTL tau and TDP-43 pathology are associated with neurodegeneration across multiple amygdala subregions.

#14
Celia Cruz Escalera

Phenotype-specific white-matter degeneration in FTD using longitudinal diffusion MRI

Background: Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous neurodegenerative disorder. Diffusion MRI (dMRI), particularly diffusion tensor imaging (DTI), has shown strong potential for detecting microstructural white matter alterations through fractional anisotropy (FA) and mean diffusivity (MD). This study aims to explore cross-sectional and longitudinal differences in regional FA and MD values between healthy control (CTR), behavioral variant FTD (bvFTD), semantic variant of primary progressive aphasia (svPPA), and nonfluent variant of primary progressive aphasia (nfvPPA).

Methods: Longitudinal dMRI data was obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI), a multicentric study. We selected a homogeneous subset including only data from the University of California San Francisco, with 64 diffusion directions. We focused on bvFTD, svPPA, nfvPPA, and CTR (Table 1). We included all visits (1–6 visits) with the inclusion criteria at baseline: CTR: CDR=0; FTD: CTR>0. Images were preprocessed to estimate DTI maps, and regional FA and MD values were extracted using the JHU ICBM-DTI-81 atlas (1mm). Cross-sectional group differences at baseline were assessed using ANCOVA with age and sex as covariates. Longitudinal differences were evaluated using linear mixed-effects models with age at baseline and sex as fixed effects. Bonferroni correction was applied across regions (threshold: p<0.0013).

Results: At baseline, FA values are lower in CTR than FTD, and MD values are higher in CTR than FTD. MD consistently shows larger and more widespread group differences than FA. Longitudinal analyses revealed significant differences in whole-brain FA and MD change rates across diagnostic groups, except between svPPA and nfvPPA. Regionally, we found different patterns of alterations across groups, with FA having greater sensitivity for disease-CTR comparisons, whereas MD better distinguished among FTD variants.

Conclusions: FA and MD reveal distinct cross-sectional and longitudinal white-matter alterations across FTD, with complementary sensitivity to phenotype. This may support differential diagnosis and monitoring disease progression.