Cerebrospinal Fluid Biomarkers Profiling in Cerebral Amyloid Angiopathy and Relationship With Disease Phenotypes Mattia Losa, Matteo Cotta Ramusino, Isabella Cama, Lorenzo Gualco, Ilaria Gandoglia, et al. 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.
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, et al. 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.
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, et al. 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, et al. 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, et al. 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, et al. 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 < 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.
