Dopaminergic signalling is critical for regulating large-scale brain network dynamics and is implicated in the pathophysiology of psychotic disorders. 22q11.2 deletion syndrome (22q11DS), a high-penetrance genetic risk factor for schizophrenia, is associated with both dopaminergic alterations and disruptions in functional connectivity (FC), yet the degree to which these separate people with 22q11DS from healthy controls and their inter-relationship remains unclear. Eighteen individuals with 22q11DS (no history of psychosis or antipsychotic use) and 22 controls underwent [18F]-DOPA PET imaging to assess striatal dopamine synthesis (indexed by Kicer values) and resting-state fMRI to examine FC. Classification performance using FC, dopamine measures, and their combination was assessed via repeated 10-fold cross-validation. Associations between Kicer, connectivity, and psychotic symptoms were evaluated using linear regression. FC alone classified 22q11DS with 68% balanced accuracy (p = 0.004), Kicer alone with 77% (p < 0.001), and combined measures with 85% balanced accuracy (p < 0.001), indicating additive value. The somatomotor and auditory networks contributed most to group discrimination. Across individuals, higher Kicer was significantly associated with more control-like connectivity profiles (p = 0.011), with significant effects in all striatal subdivisions. No association was found between FC and subclinical psychotic symptoms. This multimodal study demonstrates a significant association between striatal dopamine synthesis capacity and functional brain network architecture in 22q11DS. Higher dopamine synthesis was linked to more normative FC, potentially suggesting FC differences reflect a compensatory, rather than pathogenic role. These findings bridge genetic risk at the 22q11.2 locus with dopamine dysfunction and large-scale networks, offering novel insights into the neurobiology of 22q11DS and related neuropsychiatric risk.
V. Mancini, M. Rogdaki, S. Jauhar et al.· Molecular Psychiatry· 0 citations
BackgroundThe choroid plexus (CP) is involved in cerebrospinal fluid production, immune surveillance, and brain fluid homeostasis. CP enlargement has been linked to neuroinflammation, glymphatic dysfunction, and white matter lesion (WML) burden, but the mechanisms underlying these associations remain uncertain.ObjectiveTo investigate the relationships among CP volume, glymphatic function estimated using diffusion tensor imaging along the perivascular space (DTI-ALPS), WML burden, and global cognitive performance in individuals with suspected neurodegenerative conditions, and to assess whether DTI-ALPS mediates the association between CP enlargement and white matter damage.MethodsWe retrospectively analyzed 104 participants, including 63 individuals with neurodegenerative conditions and 41 without neurodegeneration, who underwent multimodal MRI with 3D-T1-weighted, 3D-FLAIR, and diffusion-weighted sequences. CP volume was segmented using ASCHOPLEX and normalized to total intracranial volume. DTI-ALPS indices were derived from diffusion imaging, WML burden was quantified by automated segmentation, and global cognition was assessed using the Mini-Mental State Examination. Associations were tested using linear and quantile regression models. Mediation analysis evaluated indirect effects through DTI-ALPS.ResultsGreater CP volume was associated with lower DTI-ALPS values and higher WML burden. DTI-ALPS partially mediated the relationship between CP volume and WML burden, although the magnitude of mediation was modest. No significant mediation effect was observed for global cognitive performance. DTI-ALPS also showed strong associations with white matter integrity metrics, suggesting possible sensitivity to non-glymphatic microstructural changes.ConclusionsCP enlargement is associated with reduced DTI-ALPS and greater WML burden, but the contribution of glymphatic impairment remains uncertain. Alternative mechanisms, including neuroinflammation, blood-brain barrier dysfunction, and white matter microstructural damage, may contribute to these findings.
L. Sacchi, Valentina Veronesi, Giorgio Bocca et al.· Journal of Alzheimer's Disea...· 0 citations
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