Cerebrospinal Fluid Biomarkers Profiling in Cerebral Amyloid Angiopathy and Relationship With Disease Phenotypes Mattia Losa, Matteo Cotta Ramusino, Isabella Cama, Lorenzo Gualco, Ilaria Gandoglia, Federico Massa, Andrea Donniaquio, Pierumberto Mortola, Lucia Argenti, Lorenzo Lombardo, Wendy Kreshpa, Virginia Pelagotti, Giulia Bozzo, Beatrice Orso, Pietro Mattioli, Dario Arnaldi, Alessio Cirone, Shahzad Ali, Mehrnaz Hamedani, Martina Pulze, Domenico Plantone, Luigi Lorenzini, Laura Falcitano, Federico Mazzacane, Giulia Perini, Alfredo Costa, Michele Piana, Lucio Castellan, Antonio Uccelli, Angelo Schenone, Mariel Kozberg, Fabrizio Piazza, Massimo Del Sette, Sara Garbarino, Luca Roccatagliata, Lisa Maria Farina, Matteo Pardini Journal of the American Heart Association, 2025 Background Cerebral amyloid angiopathy (CAA) is a heterogeneous small vessel disease that can occur independently or alongside Alzheimer disease (AD). CAA is diagnosed using the Boston Criteria 2.0, integrating clinical and neuroimaging features, whereas the Cerebrospinal Fluid (CSF) role in clinical practice remains under investigation. This study explores whether CSF biomarkers can identify distinct disease phenotypes, supporting hemorrhagic risk stratification. Methods We enrolled probable patients with CAA retrospectively (Boston Criteria 2.0) from 2 institutions, collecting clinical, neuroimaging, and follow‐up data alongside core CSF biomarkers (Aβ40 [amyloid β 1–40], Aβ42 [amyloid β 1–42], p‐Tau181 [phosphorylated Tau], total‐Tau). Patients with CAA were stratified applying the Amyloid Tau Neurodegeneration (ATN) research framework, according to the presence of CSF amyloidosis (A + CAA versus A − CAA) and tauopathy (A + T + CAA versus A + T − CAA), and using unsupervised clustering, which defined CAA subgroups based on CSF biomarker levels only. Kaplan‐Meier and Cox regression analyses assessed the predictive value of CSF‐based subgroups for symptomatic hemorrhages during follow‐up. Results Seventy‐one probable CAA patients (aged 71.77±8.45 years, 66% men, median follow‐up 1.15 years [0.50–2.44]) were enrolled. A + CAA showed a higher prevalence of cortical superficial siderosis than A − CAA (67% versus 25%, P =0.016). A + T − CAA had a greater hemorrhagic risk than A + T + CAA during follow‐up (29 versus 7 events per 100 patient‐years, P =0.010; log‐rank test: P =0.013). Unsupervised clustering identified 2 subgroups, which we defined as pure CAA and CAA‐ADA, with pure CAA presenting more symptomatic hemorrhages during follow‐up (22 versus 0 events per 100 patient‐years, P =0.017; log‐rank test, P =0.011). Conclusions CSF‐based profiling effectively stratifies CAA phenotypes, offering a promising prognostic tool alongside neuroimaging markers. Further validation is needed to confirm its role in identifying patients with CAA with different natural histories.
BIOmarkers in NEuropsychiatric SYmptoms (BIONESY): A multicenter nation survey and a systematic review Giulia Perini, Matteo Cotta Ramusino, Marco Vergani, Alberto Gatti, Camillo Imbimbo, et al. Journal of Alzheimer S Disease, 2025 Background Behavioral and psychological symptoms of dementia (BPSD) have poorly understood pathological/morphological correlates. Objective We aimed to (1) investigate the perception of the utility of different biomarkers in the assessment of BPSD among Italian Memory Clinics and (2) review current literature in this regard. Methods A multicenter, national survey was launched by the BPSD Study Group of the Italian Neurological Society for Dementia (SINdem). Participants completed a semi-structured questionnaire on their perception of possible associations between the occurrence/severity of different BPSD and different biomarkers, based on their individual knowledge and clinical experience, regarding any type and severity of cognitive impairment. Then, we performed a systematic review according to PRISMA guidelines. Only papers reporting biomarkers correlates of BPSD in neurocognitive disorders were included. Results Among the 53 responders, 94%, 68%, 68%, and 45% perceived neuropsychological testing, MRI, FDG-PET, and EEG, respectively, associated with the total amount of BPSD. EEG alterations were perceived selectively associated with nighttime behavior disturbances and psychosis cluster (p < 0.01). Hallucinations, apathy and delusions were perceived as more correlated with biomarkers. Years of experience using biomarkers for diagnosis were associated with a more selective use of topographical biomarkers (p < 0.01). 91% of participants consider useful increasing the use of biomarkers to predict the occurrence/severity of BPSD. The literature review identified 99 eligible studies. Brain MRI (60 articles) and FDG-PET (12 studies) alterations are the most associated with BPSD. Conclusions In clinical practice, topographical biomarkers related to regional consequences of the pathology are perceived as potentially informative in the BPSD's assessment.
APOE 5’UTR Methylation Pattern Analysis in Blood and Brain Tissue from Alzheimer’s Disease Affected Patients R. Di Gerlando, F. Dragoni, Bartolo Rizzo, Riccardo Rocco Ferrari, E. Zardini, M. C. Ramusino, G. Perini, Alfredo Costa, T. E. Poloni, O. Pansarasa, Annalisa Davin, Stella Gagliardi Aging and Disease, 2025 APOE ɛ4 allele is the major genetic risk factor for Alzheimer’s Disease (AD). Furthermore, APOE methylation pattern has been described to be associated with the disease and to follow a bimodal pattern, with a hypermethylated CpG island and a hypomethylated promoter region. However, little is known about the methylation levels in the APOE 5’UTR region. Here, the methylation of two regions (R1 and R2) within APOE 5’UTR was investigated in both peripheral blood mononuclear cells (PBMCs) and hippocampus (HIC) samples to identify differentially methylated CpG sites and to associate clinical, genetic features and cerebrospinal fluid (CSF) biomarkers levels. DNA was extracted from PBMCs of 20 AD and 20 healthy controls (HC) and from 6 AD and 3 HC HIC samples. The methylation analysis was carried out by means of pyrosequencing. In AD PBMCs we found that R1 region displayed a higher methylation level, while the opposite trend was observed in R2. The presence of ɛ4 allele highlighted a marked increase in R1 methylation level and a decrease in R2. In AD PBMCs and HIC, age progression resulted to be associated with an increase in the methylation level of R1. Lastly, the methylation of a CpG site in R2 was found to be related to CSF biomarkers. Despite the lack of a statistical significance, the outcome from this exploratory analysis highlighted the presence of a difference in methylation in APOE 5’UTR in PBMCs of AD patients which seemed to be associated also with APOE genotype, age and CSF biomarkers level.
Emerging Pharmacological Approaches for Psychosis and Agitation in Alzheimer’s Disease Camillo Imbimbo, Matteo Cotta Ramusino, Silvia Leone, Federico Mazzacane, Valentino De Franco, Alberto Gatti, Giulia Perini, Alfredo Costa CNS Drugs, 2025 Psychosis and agitation are among the most distressing neuropsychiatric symptoms (NPSs) of Alzheimer's disease (AD), linked to faster disease progression and earlier admission to nursing homes. While nonpharmacological treatments may alleviate mild behavioral symptoms, more severe syndromes often require pharmacological intervention. Brexpiprazole is the only medication approved for agitation in AD, although its limited clinical efficacy has raised criticism. No drugs have been approved for treating psychosis in AD, highlighting the critical need for new, effective, and safe treatments. Recent studies have elucidated part of the neurobiological basis of NPSs in the AD brain, offering insights for testing repurposed and novel drugs. We conducted a comprehensive nonsystematic literature review, aiming to provide a critical overview of both current treatments and emerging pharmacological interventions under clinical development for treating psychosis and agitation in AD. Additionally, we present strategies to optimize the clinical development of new drug candidates. We identify three promising compounds that are currently in phase 3 trials: xanomeline-trospium for AD psychosis, and dextromethorphan-bupropion and dexmedetomidine for agitation in AD. We propose that biomarkers linked to the neuropsychiatric traits of AD patients should be identified in dedicated studies and then included in phase 2 dose-range-finding studies with novel compounds to establish biological engagement. Furthermore, phase 3 placebo-controlled studies should be carried out in AD biomarker-confirmed subjects with narrower cognitive impairment ranges and precise NPS severity at screening. Alternative study designs, such as sequential phase approaches, may also be adopted.
Arterial hypertension in the chronic evolution of migraine: bystander or risk factor? An overview Federico Mazzacane, G. Vaghi, M. Cotta Ramusino, G. Perini, Alfredo Costa Journal of Headache and Pain, 2024 BACKGROUND: Several risk factors are associated with the chronic evolution of migraine. Clinical and preclinical studies have provided data about the role of hypertension (HT) as one of the potential modifiable risk factors of chronic migraine (CM). This review is focused on the biological and clinical evidence supporting common mechanisms underlying HT and migraine and the potential role of HT in the transition from episodic to chronic migraine. METHODS: We conducted a narrative review from a literature search covering the available evidence from studies investigating: i) the role of HT in the transition to CM in clinical practice; ii) the biological mechanisms potentially underpinning the association between HT and evolution to CM; iii) the role of antihypertensive medications in migraine prophylaxis. RESULTS: HT proved to be at the base of multiple mechanisms underlying migraine and migraine chronicization. Endothelial dysfunction, blood-brain barrier alterations, calcitonin gene-related peptide signaling, and renin-angiotensin-aldosterone system dysregulation are involved in the worsening effect of HT on migraine frequency, and the role of HT in the transition to CM is supported by clinical observations. CONCLUSIONS: The observed evidence supports HT contribution to CM evolution due to shared pathophysiologic mechanisms. While a bidirectional influence appears to be ascertained, data are still lacking about the one-way role of HT as direct risk factor for CM transition. Further research is needed to confirm a causal role of HT in this process.
Exploring the anti-inflammatory effects of curcumin encapsulated within ferritin nanocages: a comprehensive in vivo and in vitro study in Alzheimer’s disease Carlo Morasso, Marta Truffi, Veronica Tinelli, Polychronis Stivaktakis, Rosalinda Di Gerlando, Dragoni Francesca, Giulia Perini, Mahvish Faisal, Jana Aid, Bekzod Noridov, Benjamin Lee, Linda Barbieri, Sara Negri, Dragana Nikitovic, Lydia-Nefeli Thrapsanioti, Aristides Tsatsakis, Cristina Cereda, Arianna Bonizzi, Serena Mazzucchelli, Davide Prosperi, Miriam A. Hickey, Fabio Corsi, Stella Gagliardi Journal of Nanobiotechnology, 2024 BACKGROUND: The global demographic shift towards an aging population is generating a rise in neurodegenerative conditions, with Alzheimer's disease (AD) as the most prominent problem. In this landscape, the use of natural supplements has garnered attention for their potential in dementia prevention. Curcumin (Cur), derived from Curcuma longa, has demonstrated promising pharmacological effects against AD by reducing the levels of inflammatory mediators. However, its clinical efficacy is hindered by poor solubility and bioavailability. Our study introduces the use of H-Ferritin nanocages (HFn) as a nanoformulation vehicle for Cur, aiming to enhance its therapeutic potential for AD. In this work, we characterized a nanoformulation of Cur in HFn (HFn-CUR) by evaluating its safety, stability, and its transport across the blood-brain barrier (BBB) in vitro. Moreover, we evaluated the efficacy of HFn-CUR by transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from both AD patients and healthy controls (HC), and by using the well-established 5xFAD mouse model of AD. RESULTS: Our data show that HFn-CUR exhibits improved water dispersibility, is non-toxic, and can traverse the BBB. Regarding its activity on PBMCs from AD patients, HFn-CUR enhances cellular responses to inflammation and reduces RAGE-mediated stress. Studies on an AD mouse model demonstrate that HFn-CUR exhibits mild beneficial effects on cognitive performance. Moreover, it effectively reduces microgliosis and astrogliosis and in vivo in mouse, suggesting potential neuroprotective benefits. CONCLUSIONS: Our data suggest that HFn-CUR is safe and effective in reducing inflammation in both in vitro and in vivo models of AD, supporting the need for further experiments to define its optimal use.
Neurophysiological Alterations of the Visual Pathway in Posterior Cortical Atrophy: Systematic Review and a Case Series Matteo Cotta Ramusino, Lucia Scanu, Linda Gritti, Camillo Imbimbo, Lisa Maria Farina, Giuseppe Cosentino, Giulia Perini, Alfredo Costa Journal of Alzheimer S Disease, 2024 Background: The clinical features of posterior cortical atrophy (PCA), a rare condition often caused by Alzheimer’s disease, have been recently defined, while little is known about its neurophysiological correlates. Objective: To describe neurophysiological alterations of the visual pathway as assessed using visual field test (VF), visual evoked potentials (VEP), and electroretinogram (ERG) in PCA patients. Methods: Studies reporting VF, VEPs, and ERG in PCA patients were selected according PRISMA method. Of the 323 articles that emerged from the literature, 17 included the outcomes of interest. To these data, we added those derived from a patient cohort enrolled at our clinic. Results: The literature review included 140 patients, half of them (50%) presented with homonymous hemianopia or quadrantanopia. VEPs were available in 4 patients (2 normal findings, 1 decreased amplitude, and 1 increased latency) and ERG in 3 patients (substantially normal findings). Our case series included 6 patients, presenting with homonymous lateral hemianopia in 50% and contralateral cortical atrophy. VEPs showed normal amplitude in 66–83% according to the stimulation check, and increased latency in 67% in absence of myelin damage on MRI. Latency was increased in both eyes in 50% and only on one side in the other 50%. Such alterations were observed in patients with more severe and symmetric atrophy. ERG showed normal findings. Conclusions: Neurophysiological investigations of the visual pathway in PCA are almost absent in literature. Alterations involve both amplitude and latency and can be also monocular. A multiple-point involvement of the optical pathway can be hypothesized.
Retinal and Cortical Visual Processing Dysfunction in a Case of Mild Cognitive Impairment with Lewy Bodies: A Case Report Giulia Perini, Matteo Cotta Ramusino, Francesca Conca, Giuseppe Cosentino, Lisa Maria Farina, Alfredo Costa, Elisabetta Farina Journal of Alzheimer S Disease Reports, 2024 The prodromal stage of Lewy body dementia includes a mild cognitive impairment with visual processing and/or attention-executive deficits. A clinical presentation with progressive visual loss is indeed seldom reported and can be misleading with a posterior cortical atrophy disease. While the neurodegeneration at the occipital cortex can only partially explain the visual disturbances of Lewy body dementia, more recently a retinal dysfunction has been suggested by preliminary optical coherence tomography and autoptic findings. Herein, we present a case of a mild cognitive impairment with Lewy bodies, who presented initially with visual disturbances and signs of both retinal and cortical visual processing dysfunction. A complete neuropsychological, neurophysiological and brain imaging assessment highlighted a prominent ventral visual pathway involvement. This report provides first that the prodromal stage of Lewy body dementia can manifest as a primarily progressive visual loss, second that the involvement of visual pathway, particularly the ventral stream, can be detectable from the retinal to the cortical level.
Role of fronto-limbic circuit in neuropsychiatric symptoms of dementia: clinical evidence from an exploratory study Matteo Cotta Ramusino, Camillo Imbimbo, Marco Capelli, Raffaella Fiamma Cabini, Sara Bernini, Francesca Paola Lombardo, Laura Mazzocchi, Lisa Maria Farina, Anna Pichiecchio, Giulia Perini, Alfredo Costa Frontiers in Psychiatry, 2024 BackgroundNeuropsychiatric symptoms (NPSs) are a distressful aspect of dementia and the knowledge of structural correlates of NPSs is limited. We aimed to identify associations of fronto-limbic circuit with specific NPSs in patients with various types of cognitive impairment.MethodsOf 84 participants, 27 were diagnosed with mild cognitive impairment (MCI), 41 with Alzheimer’s disease (AD) dementia and 16 with non-AD dementia. In all patients we assessed regional brain morphometry using a region of interest (ROI)-based analysis. The mean cortical thickness (CT) of 20 cortical regions and the volume (V) of 4 subcortical areas of the fronto-limbic system were extracted. NPSs were rated with the Neuropsychiatric Inventory (NPI). We used multiple linear regression models adjusted for age and disease duration to identify significant associations between scores of NPI sub-domains and MRI measures of brain morphometry.ResultsAll significant associations found were negative, except those between irritability and the fronto-opercular regions in MCI patients (corresponding to a 40-50% increase in CT) and between delusions and hippocampus and anterior cingulate gyrus (with a 40-60% increase). Apathy showed predominant involvement of the inferior frontal regions in AD group (a 30% decrease in CT) and of the cingulate cortex in non-AD group (a 50-60% decrease in CT). Anxiety correlated in MCI patients with the cingulate gyrus and caudate, with a CT and V decrease of about 40%, while hallucinations were associated with left enthorinal gyrus and right amygdala and temporal pole. Agitation showed associations in the AD group with the frontal regions and the temporal pole, corresponding to a 30-40% decrease in CT. Euphoria, disinhibition and eating abnormalities were associated in the MCI group with the entorhinal, para-hippocampal and fusiform gyri, the temporal pole and the amygdala (with a 40-70% decrease in CT and V). Finally, aberrant motor behavior reported a significant association with frontal and cingulate regions with a 50% decrease in CT.ConclusionOur findings indicate that specific NPSs are associated with the structural involvement of the fronto-limbic circuit across different types of neurocognitive disorders. Factors, such as age and disease duration, can partly account for the variability of the associations observed.
Italian standardization of the BPSD-SINDEM scale for the assessment of neuropsychiatric symptoms in persons with dementia Federico Emanuele Pozzi, Fabrizia D'Antonio, Marta Zuffi, Oriana Pelati, Davide Vernè, Massimiliano Panigutti, Margherita Alberoni, Maria Grazia Di Maggio, Alfredo Costa, , Lucio Tremolizzo, Elisabetta Farina Frontiers in Neurology, 2024 IntroductionBehavioral and Psychological Symptoms of Dementia (BPSD) are a heterogeneous set of psychological reactions and abnormal behaviors in people with dementia (PwD). Current assessment tools, like the Neuropsychiatric Inventory (NPI), only rely on caregiver assessment of BPSD and are therefore prone to bias.Materials and methodsA multidisciplinary team developed the BPSD-SINDEM scale as a three-part instrument, with two questionnaires administered to the caregiver (evaluating BPSD extent and caregiver distress) and a clinician-rated observational scale. This first instrument was tested on a sample of 33 dyads of PwD and their caregivers, and the results were qualitatively appraised in order to revise the tool through a modified Delphi method. During this phase, the wording of the questions was slightly changed, and the distress scale was changed into a coping scale based on the high correlation between extent and distress (r = 0.94). The final version consisted of three 17-item subscales, evaluating BPSD extent and caregiver coping, and the unchanged clinician-rated observational scale.ResultsThis tool was quantitatively validated in a sample of 208 dyads. It demonstrated good concurrent validity, with the extent subscale correlating positively with NPI scores (r = 0.64, p &lt; 0.001) and the coping subscale inversely correlating with NPI distress (r = −0.20, p = 0.004). Diagnosis (Lewy body dementia and frontotemporal dementia), medication (antidepressants and antipsychotics), caregiver, and PwD age predicted BPSD burden on the BPSD-SINDEM scale. Caregiver coping was influenced by diagnosis (Alzheimer’s and Lewy body dementia) and benzodiazepine.DiscussionThe BPSD-SINDEM scale offers a more comprehensive approach compared to NPI, by combining caregiver ratings with clinician observations. The design of the scale allows for rapid administration in diverse clinical contexts, with the potential to enhance the understanding and management of BPSD.
A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia (MAINSTREAM): A Study Protocol Maria Cotelli, Francesca Baglio, Rosa Manenti, Valeria Blasi, Daniela Galimberti, Elena Gobbi, Ilaria Pagnoni, Federica Rossetto, Emanuela Rotondo, Valentina Esposito, Roberto De Icco, Carla Giudice, Cristina Tassorelli, Eleonora Catricalà, Giulia Perini, Cristina Alaimo, Elena Campana, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Tiziana Carandini, Stefano Francesco Cappa Brain Sciences, 2023
BPSDiary study protocol: a multi-center randomized controlled trial to compare the efficacy of a BPSD diary vs. standard care in reducing caregiver’s burden Federico Emanuele Pozzi, Luisa Calì, Fabrizia D'Antonio, Arianna Ida Altomare, Micaela Sepe Monti, Massimiliano Panigutti, Adolfo Di Crosta, Rocco Palumbo, Laura Bonanni, Valentina Carlucci, Cinzia Bussè, Annachiara Cagning, Daniele Urso, Davide Vilella, Giancarlo Logroscino, Margherita Alberoni, Angelo Bellinvia, Elisabetta Farina, Francesca de Rino, Armando Gavazzi, Marta Zuffi, Giuseppe Bruno, Valentina Bessi, Matteo Cotta Ramusino, Giulia Perini, Alfredo Costa, Carlo Ferrarese, Ildebrando Appollonio, Lucio Tremolizzo Frontiers in Dementia, 2023
THE DIAGNOSIS OF ALZHEIMER’S DISEASE: AN UPDATE AND CURRENT CONTROVERSIES Confinia Cephalalgica Et Neurologica, 2022
Outcomes of clinical utility in amyloid-PET studies: state of art and future perspectives Matteo Cotta Ramusino, Giulia Perini, Daniele Altomare, Paola Barbarino, Wendy Weidner, Gabriella Salvini Porro, Frederik Barkhof, Gil D. Rabinovici, Wiesje M. van der Flier, Giovanni B. Frisoni, Valentina Garibotto, Stefan Teipel, Marina Boccardi European Journal of Nuclear Medicine and Molecular Imaging, 2021
Being the Family Caregiver of a Patient With Dementia During the Coronavirus Disease 2019 Lockdown Milena Zucca, Valeria Isella, Raffaele Di Lorenzo, Camillo Marra, Annachiara Cagnin, Chiara Cupidi, Laura Bonanni, Valentina Laganà, Elisa Rubino, Nicola Vanacore, Federica Agosta, Paolo Caffarra, Renato Sambati, Davide Quaranta, Valeria Guglielmi, Ildebrando M. Appollonio, Giancarlo Logroscino, Massimo Filippi, Gioacchino Tedeschi, Carlo Ferrarese, Innocenzo Rainero, Amalia C. Bruni, and Frontiers in Aging Neuroscience, 2021
Different mirna profiles in plasma derived small and large extracellular vesicles from patients with neurodegenerative diseases Daisy Sproviero, Stella Gagliardi, Susanna Zucca, Maddalena Arigoni, Marta Giannini, Maria Garofalo, Martina Olivero, Michela Dell’Orco, Orietta Pansarasa, Stefano Bernuzzi, Micol Avenali, Matteo Cotta Ramusino, Luca Diamanti, Brigida Minafra, Giulia Perini, Roberta Zangaglia, Alfredo Costa, Mauro Ceroni, Nora I. Perrone-Bizzozero, Raffaele A. Calogero, Cristina Cereda International Journal of Molecular Sciences, 2021
