Francesco Motolese

Objectives Limbic-predominant age-related TDP-43 encephalopathy (LATE) often presents in older adults with a hippocampal-type amnestic syndrome that is clinically indistinguishable from Alzheimer’s disease (AD). In the era of anti-amyloid therapies, misdiagnosis carries therapeutic consequences. Methods Single-patient case report. The patient provided written informed consent and all data included in this paper are de-identified. Results A 71-year-old with isolated episodic memory impairment underwent neuropsychological testing, cerebrospinal fluid (CSF) AD biomarkers, and ¹⁸F-FDG PET in 2021. Baseline findings showed preserved global cognition, negative AD biomarkers, and mild bilateral medial temporal hypometabolism. Over the subsequent years, episodic memory declined, while daily function and other cognitive domains remained intact. MRI demonstrated bilateral medial temporal atrophy. Repeat CSF examination showed negative AD biomarkers, whereas NfL levels were markedly elevated. On repeat ¹⁸F-FDG PET, bilateral medial temporal hypometabolism progressed, while inferolateral temporal metabolism—usually reduced in AD—remained preserved. Discussion The slowly progressing isolated amnestic profile, medial temporal–predominant neurodegeneration, high CSF NfL level, and persistently negative AD biomarkers supported the diagnosis of LATE. LATE should be actively considered in elderly patients with a hippocampal-type amnestic syndrome and negative AD biomarkers. This requires a high index of suspicion, but it is increasingly critical to avoid ineffective therapies and to refine clinical trial selection.

Background: Amyloid-targeting therapies (ATTs) such as donanemab may change the management of Alzheimer's disease (AD). However, ATTs require meticulous eligibility assessment to optimize the benefit-to-risk ratio. Objective: To quantify the proportion of patients eligible for donanemab in a real-world Italian memory clinic, and to assess how this proportion changes under stricter biological criteria. Methods: In this real-world study, we retrospectively evaluated consecutive patients with new-onset cognitive symptoms at the Fondazione Policlinico Campus Bio-Medico between October 2024 and March 2026. Amyloid status was determined by cerebrospinal fluid (CSF) examination or PET-imaging. Eligibility was determined using European Medicines Agency and Appropriate Use Recommendations (AUR). Results: We included 179 consecutive patients (mean age 72.3 ± 7.2 years, 77 [44.0%] female) with mean Mini-Mental State Examination score 26.4 ± 3.3. A clinical diagnosis of AD was made in 78 (43.6%), and 46 (25.7%) were amyloid-positive. Overall, 21 patients (11.7% of the total cohort and 45.6% of amyloid-positive individuals) fulfilled all AUR criteria for donanemab. Requiring concomitant CSF p-tau positivity further reduced eligibility to 13 patients, accounting for 7.3% of the total cohort. Conclusions: Although ATTs represent a novel therapeutic option that targets the underlying AD pathology, their real-world applicability remains limited to a small patient fraction, narrowing further under strict biological stratification. Concerns regarding cost-effectiveness and practical implementation persist. Early-stage AD diagnosis and precise stratification are paramount to ensure that the promise of disease-modifying therapies can be translated into tangible clinical impact.

Objectives: To investigate clinical and imaging predictors of short- and long-term outcomes in patients with posterior circulation stroke (PCS), with particular focus on infarct topography and ischemic burden. Methods: We conducted a retrospective multicenter observational study including 251 consecutive patients with acute PCS. All patients underwent CT angiography within 24 h and follow-up CT/MRI at 48–72 h. Clinical data, vascular risk factors, stroke severity (NIHSS), and functional outcome assessed by modified Rankin Scale (mRS), were collected. Short-term outcome was defined as mRS at discharge and long-term outcome as mRS at 3 months. Favorable outcome was defined as independence, graded as mRS 0–1. Imaging analysis included pc-ASPECTS, collateral scores, and quantitative ischemic volume assessment. Multivariable logistic regression was performed to identify independent predictors of outcome. Results: Among 251 patients, 105 (41.8%) had LVO. Patients with LVO presented with higher NIHSS scores, larger infarct volumes, and more frequent multiregional involvement. Basilar artery occlusion was associated with the most severe clinical and radiological profile. Infarct location, ischemic volume, baseline NIHSS, and pre-stroke mRS were independently associated with short-term outcome. For long-term outcome, age, infarct location, diabetes, and pre-stroke mRS remained significant predictors. LVO status and treatment variables were not independently associated with outcome. Conclusions: In PCS, outcome is primarily influenced by infarct topography and clinical factors rather than LVO status alone. Multiregional involvement and baseline disability are key determinants of prognosis. These findings underscore the need for PCS-specific prognostic models and highlight the importance of detailed imaging assessment beyond vessel occlusion.

Objective: To investigate the integrated relationship between Cerebral Small Vessel Disease (CSVD) markers and quantitative facial soft-tissue measurements in Alzheimer’s disease (AD) continuum, utilizing peripheral muscle health as a potential biomarker for systemic frailty and neurodegeneration. Methods: Retrospective analysis of 3T brain MRI data from 67 patients (AD, N = 45; Mild Cognitive Impairment [MCI], N = 22). CSVD markers were assessed using STRIVE and standardized scales (Fazekas, Potter). Facial soft-tissue metrics, including masseter and tongue volume, temporal muscle thickness (TMT), and fat infiltration (Mercuri Scale), were quantified via semi-automatic segmentation on T1-weighted sequences. Group comparisons (AD vs. MCI) used regression models adjusted for age and sex. The overall central–peripheral relationship was explored via Canonical Correlation Analysis (CCA). Results: The AD group showed a highly significant cognitive decline (MMSE: 23.2 ± 4.1 vs. 28.2 ± 1.4, p < 0.0001). Centrally, the presence of PVSs in the mesencephalic region was the most robust predictor for AD (p = 0.003). Peripherally, average masseter muscle volume was significantly lower in the AD group (p = 0.0273), and masseter fat infiltration was significantly higher (p = 0.025), supporting localized sarcopenia. The CCA demonstrated a statistically significant positive multivariate relationship (r = 0.51, Roy’s Largest Root p = 0.015) between a higher combined CSVD burden and a worse soft tissue profile across the cohort. Conclusions: Quantitative indices of facial soft tissues, particularly masseter muscle volume and quality, reflect systemic frailty and cognitive deterioration along the AD continuum. The strong central–peripheral correlation suggests that sarcopenia and CSVD are interconnected manifestations of a shared pathobiological process. These easily measurable facial markers could serve as valuable, non-invasive peripheral biomarkers, complementing traditional neuroimaging risk stratification in AD.

Background: Multiple Sclerosis (MS) is a chronic disease with a high prevalence of neuropsychiatric symptoms. Mindfulness is a practice that encourages individuals to cultivate a present-focused, acceptance-based approach for managing neuropsychiatric symptoms. Its positive effect on MS has been demonstrated, but learning such technique is expensive and time-consuming. In this study, we investigated the feasibility and efficacy of an 8-week, at-home, technology-supported mindfulness program in a cohort of MS patients. Methods: The study included two visits, one at baseline and another after the mindfulness program. We measured adherence to the proposed mindfulness treatment and its effect on different neuropsychological scales and in terms of quantitative EEG parameters. All participants received a smart biofeedback device to be used during the therapeutic program consisting of daily meditative exercises. Results: Twenty-nine patients were recruited for the present study. Among them, 27 (93%) completed the entire program and 17 (63%) completed more than 80% of the scheduled sessions. We observed a statistically significant reduction of the Ruminative Response Scale score and a significant increase in the Digit Span Backward. Regarding neurophysiological data, we found a significant reduction of the whole-scalp beta and parieto-occipital theta power post intervention. Conclusion: Our results show that an at-home, technology-supported mindfulness program is feasible for people with MS. The efficacy in terms of reappraisals of stress, cognitive and emotional coping responses is also supported by our neurophysiological data. Further studies are warranted to better explore the role of such approaches in managing the psychological impact of MS diagnosis.