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Multifactorial models integrating brain variables at multiple scales are warranted to investigate aging and its relationship with neurodegeneration. Our aim was to evaluate how aging affects functional connectivity of pivotal regions of the human brain connectome (i.e., hubs), which represent potential vulnerability 'stations' to aging, and whether such effects influence the functional and structural changes of the whole brain. We combined the information of the functional connectome vulnerability, studied through an innovative graph-analysis approach (stepwise functional connectivity), with brain cortical thinning in aging. Using data from 128 cognitively normal participants (aged 20-85 years), we firstly investigated the topological functional network organization in the optimal healthy condition (i.e., young adults) and observed that fronto-temporo-parietal hubs showed a highly direct functional connectivity with themselves and among each other, while occipital hubs showed a direct functional connectivity within occipital regions and sensorimotor areas. Subsequently, we modeled cortical thickness changes over lifespan, revealing that fronto-temporo-parietal hubs were among the brain regions that changed the most, whereas occipital hubs showed a quite spared cortical thickness across ages. Finally, we found that cortical regions highly functionally linked to the fronto-temporo-parietal hubs in healthy adults were characterized by the greatest cortical thinning along the lifespan, demonstrating that the topology and geometry of hub functional connectome govern the region-specific structural alterations of the brain regions., (© 2023. The Author(s).)

Objective: To assess longitudinal patterns of brain functional MRI (fMRI) activity in a case of prodromal semantic variant of a primary progressive aphasia (svPPA)., Methods: Clinical, cognitive and neuroimaging data (T1-weighted and task-based fMRI during silent naming [SN] and object knowledge [OK]) were obtained at baseline, month 8 and month 16 from a 49-year-old lady presenting with anomias and evolving to overt svPPA in 8 months., Results: At baseline, the patient showed isolated anomias and mild left anterior temporal pole atrophy. During SN-fMRI, she showed bilateral temporal and left inferior frontal gyri (iFG) activations. During OK-fMRI, we observed normal performance and the recruitment of bilateral posterior hippocampi, iFG and left middle orbitofrontal gyrus (mOFG). At month 8, the patient received a diagnosis of svPPA and showed isolated right iFG activity during SN-fMRI, and a borderline performance during OK-fMRI together with a disappearance of mOFG recruitment. At the last visit (after 7-month language therapy), the patient showed a stabilization of naming disturbances, and, compared to previous visits, an increased left iFG recruitment during SN-fMRI. During OK-fMRI, she performed abnormally and did not show the activity of mOFG and iFG. Across all visits, brain atrophy remained stable., Conclusions: This case report showed longitudinal fMRI patterns during semantic-related tasks from prodromal to overt svPPA. Frontal brain recruitment may represent a compensatory mechanism in patients with early svPPA, which is likely to be reinforced by language-therapy. Brain fMRI is more sensitive compared with structural MRI to detect progressive brain changes associated with disease and treatment.

Objectives: To characterize patterns of language lateralization in a right-handed woman with nonfluent/agrammatic primary progressive aphasia (nfvPPA) clinical picture despite showing a prevalent right-sided brain damage., Methods: We report a case of a 58-year-old woman with nfvPPA diagnosis (age at onset = 55) previously described as a crossed aphasia case with progranulin mutation. At 2 years from the first visit, patient underwent 3DT1-weighted and a task-based functional MRI (fMRI). During the fMRI task, she was asked to perform a letter fluency test as the task of interest and to count forward as the control condition. Image processing and data analysis were performed using SPM12 and the effect of each task was tested at p < 0.05 FWE corrected., Results: The structural MRI confirmed a widespread right fronto-temporal atrophy mainly involving the right inferior frontal gyrus. During the letter fluency task, we observed an increased activation centered at the right inferior orbitofrontal gyrus and right middle frontal gyrus. By reducing the threshold, the pattern of functional activation was still dramatically prevalent at the right side., Conclusions: We provided evidence of the right language lateralization in a previously suspected crossed nfvPPA. Despite the long disease duration and the large amount of atrophy at the right side, there was no fMRI evidence of a left-hemisphere contribution to language function. We might speculate that compensatory effects do not appear when the premorbid language lateralization is purely right. The investigation of the underlying functional brain substrates in crossed nfvPPA cases may help understanding disease vulnerability in these neurodegenerative conditions.