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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.

In the last few decades, brain functional connectivity (FC) has been extensively assessed using resting-state functional magnetic resonance imaging (RS-fMRI), which is able to identify temporally correlated brain regions known as RS functional networks. Fundamental insights into the pathophysiology of several neurodegenerative conditions have been provided by studies in this field. However, most of these studies are based on the assumption of temporal stationarity of RS functional networks, despite recent evidence suggests that the spatial patterns of RS networks may change periodically over the time of an fMRI scan acquisition. For this reason, dynamic functional connectivity (dFC) analysis has been recently implemented and proposed in order to consider the temporal fluctuations of FC. These approaches hold promise to provide fundamental information for the identification of pathophysiological and diagnostic markers in the vast field of neurodegenerative diseases. This review summarizes the main currently available approaches for dFC analysis and reports their recent applications for the assessment of the most common neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and frontotemporal dementia. Critical state-of-the-art findings, limitations, and future perspectives regarding the analysis of dFC in these diseases are provided from both a clinical and a technical point of view.

BackgroundWe performed an observational study of laughter during seminaturalistic conversations between patients with dementia and familial caregivers. Patients were diagnosed with (1) behavioural variant frontotemporal dementia (bvFTD), (2) right temporal variant frontotemporal dementia (rtFTD), (3) semantic variant of primary progressive aphasia (svPPA), (4) non-fluent variant primary progressive aphasia (nfvPPA) or (5) early onset Alzheimer’s disease (eoAD). We hypothesised that those with bvFTD would laugh less in response to their own speech than other dementia groups or controls, while those with rtFTD would laugh less regardless of who was speaking.MethodsPatients with bvFTD (n=39), svPPA (n=19), rtFTD (n=14), nfvPPA (n=16), eoAD (n=17) and healthy controls (n=156) were recorded (video and audio) while discussing a problem in their relationship with a healthy control companion. Using the audio track only, laughs were identified by trained coders and then further classed by an automated algorithm as occurring during or shortly after the participant’s own vocalisation ('self' context) or during or shortly after the partner’s vocalisation ('partner' context).ResultsIndividuals with bvFTD, eoAD or rtFTD laughed less across both contexts of self and partner than the other groups. Those with bvFTD laughed less relative to their own speech comparedwith healthy controls. Those with nfvPPA laughed more in the partner context compared with healthy controls.ConclusionsLaughter in response to one’s own vocalisations or those of a conversational partner may be a clinically useful measure in dementia diagnosis.

Crossed aphasia has been reported mainly as post-stroke aphasia resulting from brain damage ipsilateral to the dominant right hand. Here, we described a case of a crossed nonfluent/agrammatic primary progressive aphasia (nfvPPA), who developed a corticobasal syndrome (CBS). We collected clinical, cognitive, and neuroimaging data for four consecutive years from a 55-year-old right-handed lady (JV) presenting with speech disturbances. 18-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) and DaT-scan with 123 I-Ioflupane were obtained. Functional MRI (fMRI) during a verb naming task was acquired to characterize patterns of language lateralization. Diffusion tensor MRI was used to evaluate white matter damage within the language network. At onset, JV presented with prominent speech output impairment and right frontal atrophy. After 3 years, language deficits worsened, with the occurrence of a mild agrammatism. The patient also developed a left-sided mild extrapyramidal bradykinetic-rigid syndrome. The clinical picture was suggestive of nfvPPA with mild left-sided extrapyramidal syndrome. At this time, voxel-wise SPM analyses of 18 F-FDG PET and structural MRI showed right greater than left frontal hypometabolism and damage, which included the Broca’s area. DaT-scan showed a reduced uptake in the right striatum. FMRI during naming task demonstrated bilateral language activations, and tractography showed right superior longitudinal fasciculus (SLF) involvement. Over the following year, JV became mute and developed frank left-sided motor signs and symptoms, evolving into a CBS clinical picture. Brain atrophy worsened in frontal areas bilaterally, and extended to temporo-parietal regions, still with a right-sided asymmetry. Tractography showed an extension of damage to the left SLF and right inferior longitudinal fasciculus. We report a case of crossed nfvPPA followed longitudinally and studied with advanced neuroimaging techniques. The results highlight a complex interaction between individual premorbid developmental differences and the clinical phenotype.

Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and the accumulation of beta‐amyloid and tau proteins. Optical coherence tomography (OCT) is a non‐invasive imaging method that evaluates retinal layers, which may serve as biomarkers for AD. Plasma biomarkers, including beta‐amyloid ratios, phosphorylated tau (p‐tau), and neurofilament light chain (NfL), provide minimally invasive diagnostic and monitoring tools. This study evaluates how retinal thickness changes in relation to different plasma biomarkers. Method This cross‐sectional study included 145 consecutive patients with cognitive disturbances due to heterogeneous conditions from the tertiary Memory Clinic at San Raffaele Hospital, Milan, Italy. They all underwent OCT imaging and blood sampling for plasma biomarker assessment. Linear regression analyses were performed to assess associations between the average retinal layer thicknesses of both eyes and plasma biomarkers, adjusting for age, sex, and disease duration. Patients were stratified into three groups based on dual pTau217 cutoffs, calculated on a sample of 184 individuals to achieve 97% sensitivity and specificity for identifying pathological CSF pTau181/Aβ42 ratios: Group 1 (p217 < 0.1325; no amyloid pathology), Group 2 (0.1325 ≤ p217 < 0.356; gray zone), and Group 3 (p217 ≥ 0.356; amyloid pathology). Subgroup‐specific regressions were performed, and intergroup comparisons were analyzed. Result A positive correlation was identified between the temporal retinal nerve fiber layer (T_RNFL) and the beta‐amyloid 42/40 ratio (Ab42/40) in the overall cohort. In Group 1, a negative correlation was found between the inferior RNFL (I_RNFL) and Ab42/40. Group 2 exhibited a positive correlation between I_RNFL and NfL levels. In Group 3, negative correlations were observed between plasma phosphorylated tau 181 (p181) and the global RNFL (G_RNFL), superior RNFL (S_RNFL), and global ganglion cell and inner plexiform layers (GCL‐IPL). No significant differences were observed in intergroup comparisons. Conclusion This study highlights the potential of OCT‐derived retinal measurements as complementary biomarkers for AD. The findings suggest complex, stage‐specific associations between retinal thickness and plasma biomarkers, underscoring the importance of stratifying patients by amyloid status. These results contribute to understanding neurodegenerative processes and may inform diagnostic and monitoring strategies for AD. Funding: Fujirebio Italia

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and the accumulation of beta-amyloid and tau proteins. Optical coherence tomography (OCT) is a non-invasive imaging method that evaluates retinal layers, which may serve as biomarkers for AD. Plasma biomarkers, including beta-amyloid ratios, phosphorylated tau (p-tau), and neurofilament light chain (NfL), provide minimally invasive diagnostic and monitoring tools. This study evaluates how retinal thickness changes in relation to different plasma biomarkers. This cross-sectional study included 145 consecutive patients with cognitive disturbances due to heterogeneous conditions from the tertiary Memory Clinic at San Raffaele Hospital, Milan, Italy. They all underwent OCT imaging and blood sampling for plasma biomarker assessment. Linear regression analyses were performed to assess associations between the average retinal layer thicknesses of both eyes and plasma biomarkers, adjusting for age, sex, and disease duration. Patients were stratified into three groups based on dual pTau217 cutoffs, calculated on a sample of 184 individuals to achieve 97% sensitivity and specificity for identifying pathological CSF pTau181/Aβ42 ratios: Group 1 (p217 < 0.1325; no amyloid pathology), Group 2 (0.1325 ≤ p217 < 0.356; gray zone), and Group 3 (p217 ≥ 0.356; amyloid pathology). Subgroup-specific regressions were performed, and intergroup comparisons were analyzed. A positive correlation was identified between the temporal retinal nerve fiber layer (T_RNFL) and the beta-amyloid 42/40 ratio (Ab42/40) in the overall cohort. In Group 1, a negative correlation was found between the inferior RNFL (I_RNFL) and Ab42/40. Group 2 exhibited a positive correlation between I_RNFL and NfL levels. In Group 3, negative correlations were observed between plasma phosphorylated tau 181 (p181) and the global RNFL (G_RNFL), superior RNFL (S_RNFL), and global ganglion cell and inner plexiform layers (GCL-IPL). No significant differences were observed in intergroup comparisons. This study highlights the potential of OCT-derived retinal measurements as complementary biomarkers for AD. The findings suggest complex, stage-specific associations between retinal thickness and plasma biomarkers, underscoring the importance of stratifying patients by amyloid status. These results contribute to understanding neurodegenerative processes and may inform diagnostic and monitoring strategies for AD. Fujirebio Italia.

Background and Purpose Precise and timely diagnosis is crucial for the optimal use of emerging disease‐modifying treatments for Alzheimer disease (AD). Electroencephalography (EEG), which is noninvasive and cost‐effective, can capture neural abnormalities linked to various dementias. This study explores the use of individual alpha frequency (IAF) derived from EEG as a diagnostic and prognostic tool in cognitively impaired patients. Methods This retrospective study included 375 patients from the tertiary Memory Clinic of IRCCS San Raffaele Hospital, Milan, Italy. Participants underwent clinical and neuropsychological assessments, brain imaging, cerebrospinal fluid biomarker analysis, and resting‐state EEG. Patients were categorized by amyloid status, the AT(N) classification system, clinical diagnosis, and mild cognitive impairment (MCI) progression to AD dementia. IAF was calculated and compared among study groups. Receiver operating characteristic (ROC) analysis was used to calculate its discriminative performance. Results IAF was higher in amyloid‐negative subjects and varied significantly across AT(N) groups. ROC analysis confirmed IAF's ability to distinguish A–T–N– from the A+T+N+ and A+T–N+ groups. IAF was lower in AD and Lewy body dementia patients compared to MCI and other dementia types, with moderate discriminatory capability. Among A+ MCI patients, IAF was significantly lower in those who converted to AD within 2 years compared to stable MCI patients and predicted time to conversion (p < 0.001, R = 0.38). Conclusions IAF is a valuable tool for dementia diagnosis and prognosis, correlating with amyloid status and neurodegeneration. It effectively predicts MCI progression to AD, supporting its use in early, targeted interventions in the context of disease‐modifying treatments.

Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and cortical dysfunction. Resting‐state EEG provides insights into AD‐related neurophysiological changes. This study investigates the associations between 32‐channel resting‐state EEG and AD plasma biomarkers in patients from a Memory Clinic population. Method This cross‐sectional study consecutively included 193 patients with cognitive disturbances due to heterogeneous conditions from the tertiary Memory Clinic at San Raffaele Hospital, Milan, Italy. Resting‐state 32‐channel EEG and Lumipulse plasma biomarkers (pTau217, pTau181, NfL, Ab42/40 ratio) were collected. Patients were stratified into three groups based on dual pTau217 cutoffs, calculated on a sample of 184 individuals to achieve 97% sensitivity and specificity for identifying pathological CSF pTau181/Aβ42 ratios. Linear regression models, adjusted for age, sex, and disease duration, assessed associations between plasma biomarkers and EEG parameters, including alpha amplitude, alpha frequency, and relative power in delta, theta, alpha, beta, and gamma bands. ANCOVA compared EEG parameters across the three pTau217‐defined groups. Result In the full sample, pTau217, pTau181, and the pTau217/Ab42 ratio were positively associated with theta power (+0.34 to +0.45) and delta power (+0.24), and negatively with alpha amplitude, alpha power (‐0.20 to ‐0.32), and beta power (‐0.20). In group 1 (low pTau217), the pTau217/Abeta42 ratio was negatively associated with beta, gamma, and alpha power (‐0.27 to ‐0.32). In group 2 (intermediate pTau217), NfL was positively associated with theta power (+0.47) and negatively with beta power (‐0.35). In group 3 (high pTau217), pTau217, pTau181, and the pTau217/Abeta42 ratio were positively associated with theta (+0.39) and delta power (+0.30), and negatively with alpha amplitude and alpha power. ANCOVA showed reduced alpha amplitude and alpha power together with higher theta in groups 2 and 3 versus group 1. Conclusion This study demonstrates that resting‐state EEG parameters, particularly theta and alpha power, are closely linked to AD plasma biomarkers. Stratification based on pTau217 revealed distinct EEG patterns across biomarker‐defined groups, emphasizing EEG's utility as a non‐invasive tool for capturing disease‐specific neurophysiological alterations. These findings underline the potential of EEG as an accessible, non‐invasive, and scalable method to support the diagnosis and monitoring of AD. Funding: Fujirebio Italia

In multiple sclerosis (MS), physical and cognitive deficits not only reflect structural damage, but also functional imbalance in and between brain networks. Resting-state functional magnetic resonance imaging (fMRI) allows one to investigate intrinsic, synchronized brain activity across the whole brain, and to measure the degree of functional correlation between different cortical regions. This review describes the major findings obtained in MS patients at different clinical stages using resting state fMRI, and discusses how the use of fMRI techniques may improve our ability to identify novel biomarkers useful in the context of the diagnostic work-up, establishing prognosis and monitoring treatment.

Introduction The large-scale approval of anti-amyloid monoclonal antibodies for treating Alzheimer’s disease (AD) has raised concerns about their safety due to treatment-emergent amyloid-related imaging abnormalities (ARIA). Methods We present two cases of patients diagnosed with mild cognitive impairment due to AD who were enrolled in the GRADUATE I clinical trial. They received subcutaneous gantenerumab every two weeks during the study period. Results Both patients experienced recurrent ARIA-Effusion/Edema type (ARIA-E). One developed symptomatic and severe ARIA, leading to hospitalization and study withdrawal. We report a long follow-up post-randomization (65 and 54 months), during which the adverse events did not appear to have a negative impact on disease progression. Additionally, one patient had a negative amyloid-PET over a year after treatment cessation. Discussion These cases suggest that recurrent ARIA-E do not inevitably lead to accelerated progression, instead, may relate to possible long-term benefits. The mechanisms underlying these findings warrant further real-life evidence.