BackgroundMild Cognitive Impairment (MCI) and Mild Behavioral Impairment (MBI) can be prodromal stages of neurodegenerative disease associated with plasma biomarkers of tau pathology and neuroaxonal damage. However, in psychiatric populations, the relationship between MCI, MBI and these plasma biomarkers remains unclear.ObjectiveThis study examined the association of MCI with plasma biomarkers of neurodegeneration (phosphorylated tau217 [p-tau217] and neurofilament light chain [NfL]), metabolic alterations, psychiatric disorder features, and MBI in older adults receiving psychiatric treatment.MethodsFifty-one non-demented patients ≥60 years, referred for mood or anxiety disorders, were enrolled and classified based on cognitive performance as MCI (n = 20) or non-MCI (n = 31). Assessments included psychiatric, cognitive, functional, and plasma biomarker measures.ResultsMCI patients exhibited higher p-tau217 (P = .003) and NfL (P = .042) levels, lower cognitive scores (P < .001), and a trend toward reduced functioning (P = .074). MCI was also associated with later onset of psychiatric symptoms (P = .033) and greater prevalence of MBI (P < .001). Logistic regression identified plasma NfL as a marker of MCI (P < .05) in this sample.ConclusionOur findings suggest that integrating cognitive, psychiatric, and biomarker assessments may improve early detection of dementia risk.

INTRODUCTION:Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive decline in older adults. Current diagnosis relies mainly on neuroimaging, which lacks pathophysiological specificity. AREAS COVERED:This narrative review summarizes evidence on cerebrospinal fluid (CSF) and plasma biomarkers in sporadic CAA. In CSF, CAA is typically associated with reduced Aβ42 and Aβ42/Aβ40 ratio, although similar alterations are observed in Alzheimer's disease (AD), limiting diagnostic specificity. Lower Aβ40 levels may reflect vascular amyloid deposition and appear more characteristic of CAA, but alone provide insufficient discrimination. Plasma biomarker studies have yielded inconsistent findings due to methodological and population heterogeneity. Nevertheless, amyloid isoforms, phosphorylated tau species, and neurofilament light chain (NfL) show potential, with NfL correlating with imaging markers and disease burden. The increasing need to distinguish CAA from AD and other cerebral small vessel diseases has driven growing interest in fluid biomarkers. EXPERT OPINION:Despite promising findings, no fluid biomarker currently demonstrates sufficient specificity or validation for routine clinical use in CAA. Significant overlap with AD pathology remains a major limitation. Large longitudinal real-world studies are needed to determine the diagnostic, prognostic, and incremental clinical value of fluid biomarkers in CAA.

Dependent older patients show high risk of adverse health outcomes when admitted to the emergency department (ED). The prompt identification of ED use risk factors in such population is hence needed. While frailty and cognitive impairment are a known clinical risk factors, biomarkers of most prevalent dementias have been scarcely investigated as possible ED use predictors. Within this framework, this prospective study explored whether plasma phospho-tau181 (ptau181) and cerebrovascular burden provide additional predictive value for 6-month ED use in elderly dependent patients, beyond frailty and age. We collected baseline clinical and laboratory data to validate a 32-item frailty index, while assessing cognitive impairment through the Mini-Mental State Examination. Biomarkers of cognitive impairment included plasma ptau181 and cerebrovascular burden, i.e., the Fazekas Scale. Binomial and Cox regression models tested the biomarkers of cognitive impairment as predictors of ED use, adjusting for frailty and age. The interaction between cognitive impairment biomarkers was explored. Of the 102 recruited patients, 38 visited the ED. In the binomial models, the frailty index (OR = 1.69, p = 0.011) and the Fazekas Scale (OR = 3.57, p = 0.007) predicted ED use. At lower p-tau181 levels, ED admission risk increased only with higher cerebrovascular burden. Conversely, higher p-tau181 levels predicted ED use (OR = 4.90, p = 0.037) irrespective of cerebrovascular burden. No significant predictors of time to ED use emerged. Beyond measures of clinical frailty, the routinary employment of cognitive impairment biomarkers may contribute identifying dependent older patients at short-term high risk of ED use, possibly reducing adverse health outcomes in such population. ● Plasma phosho-tau181 and cerebrovascular burden predict emergency department use in dependent older patients. ● Cognitive impairment biomarkers predict emergency department use irrespective of multidimensional frailty. ● The assessment of cognitive impairment biomarkers may reduce adverse health outcomes in dependent older patients.

Obstructive sleep apnoea syndrome (OSAS) is a breathing disorder frequently associated with mild cognitive impairment (MCI), a potential prodromal stage of Alzheimer’s disease (AD). However, the mechanisms underlying MCI in OSAS remain unclear, making the identification of early biomarkers crucial. This pilot study investigates biochemical parameters related to oxygen disturbance and AD in OSAS patients with and without MCI (OSAS + MCI and OSAS-MCI, respectively) and explores their interplay through a network-based analysis. A total of 45 subjects (30 OSAS patients; 15 healthy controls) were enrolled, undergoing clinical assessment, polygraphy, and blood sampling. Compared to controls, OSAS patients exhibited increased apnoea-hypopnea index, oxygen desaturation index, and the percentage of cumulative time with oxygen saturation below 90

ABSTRACT:Frontotemporal dementia (FTD) encompasses a group of clinically, neuropathologically, and genetically heterogeneous disorders characterized by atrophy in the frontal and anterior temporal lobes. Psychiatric and behavioral symptoms are common throughout the course of FTD, and pharmacological treatments show limited efficacy. In this review, we analyzed literature on the use of electroconvulsive therapy (ECT) in patients with FTD to assess its effectiveness and predictors of response in this population. A systematic review was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines, with searches in the MEDLINE, Scopus, and Web of Science databases. Eligibility criteria included original studies and case reports on FTD patients treated with ECT. Of 88 screened abstracts, 25 studies were included, documenting 37 patients with FTD or Pick disease who were treated with ECT. ECT was primarily administered for catatonia (37.84%) and depressive episodes (35.14%). Most patients had not responded to at least 1 prior medication, primarily antipsychotics. Following the initial ECT course, 40.54% of patients experienced symptom remission, 21.62% showed partial or transient improvement, and 32.43% saw little to no benefit. Continuation and maintenance ECT appeared to be valid treatment options following a response to acute ECT. Notably, patients with the C9orf72 mutation showed a poor response to ECT. For many FTD patients with behavioral, mood, and catatonic symptoms, ECT appears to be more effective than pharmacological treatments; however, its impact on cognition and long-term outcomes requires further investigation. Systematic clinical studies on larger samples are necessary to confirm the efficacy and tolerability of ECT for psychiatric disorders in FTD.

Background: An increased risk of cognitive decline has been reported in patients with older age bipolar disorder (OABD); however, the underlying factors contributing to this association remain unclear. This cross-sectional study aims to identify the clinical features associated with cognitive impairment in OABD. Methods: A total of 152 participants, aged at least 50 years and diagnosed with bipolar disorder (BD) and related disorders in agreement with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria, were included in the study and divided into two subgroups based on the presence/absence of cognitive impairment, defined as a diagnosis of Mild Neurocognitive Disorder or Major Neurocognitive Disorder. Univariate comparisons and multivariate logistic regression models were performed to investigate the associations between clinical variables and cognitive impairment. Results: Cognitively impaired patients had a higher prevalence of otherwise specified BD/cyclothymic disorder, while BD type 2 was more common in the cognitively unimpaired group. Additionally, the cognitively impaired group had a later onset of major mood episodes (p < 0.05), fewer lifetime depressive episodes (p = 0.006), a higher prevalence of vascular leukoencephalopathy (p = 0.022) and dyslipidemia (p = 0.043), a lower prevalence of agoraphobia (p = 0.040), worse global functioning (p < 0.001), and higher psychopathology severity (p < 0.001). Late onset, vascular leukoencephalopathy, and dyslipidemia were all independently associated with cognitive impairment. Conclusions: Atypical BD, late onset of mood episodes, and somatic comorbidities like vascular leukoencephalopathy and dyslipidemia are associated with a higher risk of developing cognitive impairment and neurodegenerative disorders in OABD patients.

We describe a 63-year-old man diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD), specifically sporadic fatal insomnia, confirmed through real-time quaking-induced conversion (RT-QuIC) analysis of cerebrospinal fluid and polysomnography. He presented with rapid cognitive decline, behavioural changes, sleep disturbances and dysautonomic symptoms. Initial MR imaging, electroencephalogram and cerebrospinal fluid analyses were inconclusive, highlighting the difficulty in diagnosing this rare subtype of CJD. Clinical evaluation is fundamental in defining the diagnosis of sCJD. When clinical suspicion is strong, the diagnostic work-up should be continued. In this case, the combination of comprehensive clinical evaluations and advanced diagnostic tools, including RT-QuIC and polysomnography, proved essential in making a definitive diagnosis.

BackgroundMild Behavioral Impairment (MBI) has been increasingly recognized as a potential early clinical marker of neurodegenerative disease, while blood-based biomarkers such as phosphorylated tau 217 (p-tau217) and neurofilament light chain (NfL) are associated with Alzheimer's disease and axonal damage, respectively.ObjectiveTo investigate the role of MBI and blood-based biomarkers of neurodegeneration in the early detection of dementia.MethodsFifty-one individuals without dementia aged 60 or older with mood or anxiety disorders underwent psychiatric, neuropsychiatric, and cognitive evaluations, as well as assessment of plasma p-tau217 and NfL at baseline and at one-year follow-up.ResultsA higher proportion of males was observed in the MBI group compared to the non-MBI group (P = 0.076). MBI was significantly associated with a higher risk of conversion to dementia (P = 0.006). MBI patients showed a trend toward higher baseline p-tau217 (P = 0.096) and significantly higher NfL at follow-up (P = 0.025), suggesting active neurodegeneration. Individuals who converted to dementia had marginally higher baseline p-tau217 (P = 0.053) and NfL (P = 0.091).ConclusionMBI and blood-based biomarkers of neurodegeneration appear to be promising clinical tools for identifying dementia risk in its early stages.

The study aimed to evaluate the effects of monoclonal antibodies (mAbs) acting on the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP/R mAbs) on migraine comorbidities of depression, anxiety, and fatigue in patients resistant to traditional therapies. The issue addressed in this study is pivotal to unveiling the role of this neurotransmitter beyond pain processing. We conducted an open-label prospective study assessing comorbidities in patients with high frequency (HFEM) and chronic migraine (CM), medication overuse headache (MOH), and resistance to traditional prophylaxis. All patients were treated with anti-CGRP/R mAbs for 3 months. Seventy-seven patients were enrolled with either HFEM (21%) or CM (79%) with or without MOH (56% and 44%, respectively). We identified 21 non-responders (27%) and 56 responders (73%), defined on the reduction ≥50% of headache frequency. The two groups were highly homogeneous for the investigated comorbidities. Disease severity in terms of headache frequency, migraine-related disability, and affective comorbid symptoms was reduced in both groups with different thresholds; allodynia and fatigue were ameliorated only in responders. We found that anti-CGRP/R antibodies improved pain together with affection, fatigue, and sensory sensitization in a cohort of migraine patients resistant to traditional prophylaxis. Our results offer novel perspectives on the early efficacy of anti-CGRP/R mAbs in difficult-to-treat patients focusing on clinical features other than pain relief.

Objective: The study aimed to evaluate the effects of monoclonal antibodies (mAbs) acting on the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP/R mAbs) on comorbid symptoms of depression, anxiety, and fatigue in migraine patients resistant to traditional prophylaxis. Methods: The study was an open-label prospective study assessing comorbidities in patients with high frequency (HFEM) and chronic migraine (CM), medication overuse headache (MOH), and resistance to traditional prophylaxis treated with anti-CGRP/R mAbs for 3 months. Results: 77 patients were enrolled with either HFEM (21%) or CM (79%) with or without MOH (56% and 44% respectively). We identified 21 non-responders (27%) and 56 responders (73%), defined on the reduction ≥ 50% of headache frequency. The two groups were highly homogeneous for investigated comorbidities. Disease severity in terms of headache frequency, migraine-related disability, and affective comorbid symptoms were reduced in both groups with different thresholds; allodynia and fatigue were ameliorated only in responders. Conclusion: anti-CGRP/R antibodies improve pain together with affection, fatigue, and sensory sensitization in migraine patients.

The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks of AD, including amyloid β-protein (Aβ) deposits and abnormal tau protein isoforms, in the retinas of AD patients and animal models. Moreover, structural and functional vascular abnormalities such as reduced blood flow, vascular Aβ deposition, and blood-retinal barrier damage, along with inflammation and neurodegeneration, have been described in retinas of patients with mild cognitive impairment and AD dementia. Histological, biochemical, and clinical studies have demonstrated that the nature and severity of AD pathologies in the retina and brain correspond. Proteomics analysis revealed a similar pattern of dysregulated proteins and biological pathways in the retina and brain of AD patients, with enhanced inflammatory and neurodegenerative processes, impaired oxidative-phosphorylation, and mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific amyloid deposits, as well as vasculopathy and neurodegeneration in the retina of living AD patients, suggesting alterations at different disease stages and links to brain pathology. Current and exploratory ophthalmic imaging modalities, such as optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, and hyperspectral imaging, may offer promise in the clinical assessment of AD. However, further research is needed to deepen our understanding of AD's impact on the retina and its progression. To advance this field, future studies require replication in larger and diverse cohorts with confirmed AD biomarkers and standardized retinal imaging techniques. This will validate potential retinal biomarkers for AD, aiding in early screening and monitoring.

BackgroundChimeric Antigen Receptor (CAR) T cell therapies are innovative treatments against hematological malignancies, with increasing therapeutic indications. Despite their great efficacy, these therapies are hampered by high rates of neurotoxicity (immune effector cell-associated neurotoxicity (ICANS)). In the past few years, several risk factors have been associated with ICANS and grouped together in the attempt to build validated models able to predict neurologic complications. However, little is known about pre-existing neurologic conditions possibly related to the development of neurotoxicity.Methods and resultsIn our case series, including sixteen consecutive patients treated with CAR T cells, we observed that (i) neurotoxicity only occurred in the two patients who presented subtle clinical signs of frontal lobe impairment at baseline and (ii) neurologic manifestations of ICANS consisted of language disturbances and cortical frontal myoclonus, which were both manifestations of a frontal predominant dysfunction.DiscussionBased on our experience, we suggest that a pre-existing frontal lobe impairment, even if at a subclinical level, may eventually drive to ICANS, which in turn shows symptoms compatible with a frontal encephalopathy. It is remarkable that this focal neurotoxicity involved the same CNS regions that were responsible of subtle neurological signs at baseline. Future studies on larger numbers of patients are needed to confirm the possible role of baseline frontal lobe dysfunction as a predictor of ICANS, in order to enhance efforts to safely deliver CAR T cell therapy.

The Mild Behavioral Impairment (MBI) concept was developed to determine whether late-onset persistent neuropsychiatric symptoms (NPSs) may be early manifestations of cognitive decline. Our study aims to investigate the prevalence and differentiating features of MBI with respect to major neurocognitive disorders (MNDs) and primary psychiatric disorders (PPDs). A total of 144 elderly patients who were referred to our psychogeriatric outpatient service were recruited. The severity of mental illness was evaluated by means of the Clinical Global Impression Severity scale, the severity of psychopathology was evaluated by means of the Brief Psychiatric Rating Scale (BPRS), and overall functioning was evaluated by means of the Global Assessment of Functioning scale. The sample included 73 (50.6%) patients with PPDs, 40 (27.8%) patients with MBI, and 31 (21.5%) patients with MNDs. Patients with MNDs reported the greatest severity of mental illness, the highest BPRS Total, Psychosis, Activation, and Negative Symptom scores, and the lowest functioning. Patients with MBI and PPDs had comparable levels of severity of mental illness and overall functioning, but MBI patients reported higher BPRS Total and Negative Symptom scores than PPD patients. Patients with MBI frequently reported specific clinical features, including a higher severity of apathy and motor retardation. These features merit further investigation since they may help the differential diagnosis between MBI and PPDs.

Mild Behavioral Impairment (MBI) refers to a late-onset neurobehavioral syndrome in which neuropsychiatric symptoms (NPS) represent early markers of dementia. Though being a promising diagnostic category for neurobiological research, in daily clinical practice, the boundaries and relationships between MBI and late-life psychiatric disorders are yet to be established. Particularly, no studies have been conducted so far on the prognostic implications of an MBI diagnosis in the psychogeriatric context. For these reasons, since June 2020, we are conducting a prospective longitudinal study on MBI in psychogeriatric patients. On June 2022, 144 elderly patients (≥50 years) referred to the outpatient clinic of the 2nd Psychiatric Unit of the University of Pisa had been recruited. Patients had been diagnosed with a primary psychiatric disorder (N=73, 50.6%), MBI (N=40, 27.8%) or dementia (N=31, 21.5%). Patients with MBI showed a significantly higher age at onset of psychiatric disorders and depressive episodes than patients diagnosed with primary psychiatric disorders. MCI and vascular leukoencephalopathy were also more common in patients with MBI. Moreover, compared to primary psychiatric disorders, MBI was associated with a significantly higher psychopathology severity, especially in the apathy and negative symptoms domain. Preliminary longitudinal analyses were also performed on a subsample of 83 patients followed-up for at least 3 months (on average for one year): at baseline 44 patients had been diagnosed with primary mood disorders including 23 patients in remission and 21 patients with current mood episodes; 22 patients had MBI and 17 were diagnosed with dementia. While at follow-up patients with mood episodes showed a significant decrease in psychopathology severity and increase in global functioning, those with MBI had no significant improvements. In conclusion, MBI is a common condition in psychogeriatric settings and shows distinctive clinical features that may help differential diagnosis. Moreover, the presence of MBI in patients with late-life psychiatric disorders may affect both clinical and functional outcomes. The recognition of patients with MBI symptoms, including apathy, might be useful for the early detection of individuals with poor prognosis.

Locus Coeruleus (LC) degeneration occurs early in Alzheimer's disease (AD) and this could affect several brain regions innervated by LC noradrenergic axon terminals, as these bear neuroprotective effects and modulate neurovascular coupling/neuronal activity. We used LC-sensitive Magnetic Resonance imaging (MRI) sequences enabling LC integrity quantification, and [18F]Fluorodeoxyglucose (FDG) PET, to investigate the association of LC-MRI changes with brain glucose metabolism in cognitively impaired patients (30 amnesticMCI and 13 demented ones). Fifteen cognitively intact age-matched controls (HCs) were submitted only to LC-MRI for comparison with patients. Voxel-wise regression analyses of [18F]FDG images were conducted using the LC-MRI parameters signal intensity (LCCR) and LC-belonging voxels (LCVOX). Both LCCR and LCVOX were significantly lower in patients compared to HCs, and were directly associated with [18F]FDG uptake in fronto-parietal cortical areas, mainly involving the left hemisphere (p < 0.001, kE > 100). These results suggest a possible association between LC degeneration and cortical hypometabolism in degenerative cognitive impairment with a prevalent left-hemispheric vulnerability, and that LC degeneration might be linked to large-scale functional network alteration in AD pathology.