Real-life management of patients with mild cognitive impairment: an Italian survey.

BACKGROUND: Mild cognitive impairment (MCI) is a syndrome with heterogeneous underlying causes and different rates of disease progression, whose clinical heterogeneity leads to a wide variation in diagnostic and therapeutic approaches in clinical practice. The lack of uniform practical recommendations on diagnostic workup and treatment for MCI patients hinders optimal management of these patients, worsening their prognosis. Standardized guidelines for the investigation and follow-up of MCI are therefore urgently required. AIM: Aim of our study was to assess the diagnostic and therapeutic approach to MCI patients in the setting of Italian Memory Clinics. METHODS: A survey was delivered to a sample of Italian neurologists through two different phases: a first exploratory phase recording general information about the usual clinical management of patients with MCI, and a subsequent operative phase assessing the practical diagnostic and therapeutic decisions taken in a real life setting to manage subjects with MCI. RESULTS: A total of 121 neurologists participated to the first phase of the survey and 203 patients were enrolled in the second phase. Information gathered in the first phase of the survey highlighted a non-uniform use of diagnostic criteria and procedures for MCI, as well as a very heterogeneous therapeutic strategy among Italian neurologists. In the second phase, recorded data on diagnostic and therapeutic approach confirmed the large variability observed in the first phase of the survey. CONCLUSIONS: The results of our study reflect a suboptimal management of MCI patients in Italy and highlight the need of standardized diagnostic and therapeutic approaches for this condition.

Phantom limb syndrome: from pathogenesis to treatment. A narrative review.

Phantom Limb Syndrome (PLS) can be defined as the disabling or painful sensation of the presence of a body part that is no longer present after its amputation. Anatomical changes involved in Phantom Limb Syndrome, occurring at peripheral, spinal and brain levels and include the formation of neuromas and scars, dorsal horn sensitization and plasticity, short-term and long-term modifications at molecular and topographical levels. The molecular reorganization processes of Phantom Limb Syndrome include NMDA receptors hyperactivation in the dorsal horn of the spinal column leading to inflammatory mechanisms both at a peripheral and central level. At the brain level, a central role has been recognized for sodium channels, BDNF and adenosine triphosphate receptors. In the paper we discuss current available pharmacological options with a final overview on non-pharmacological options in the pipeline.

Cognitive resilience/reserve: Myth or reality? A review of definitions and measurement methods.

INTRODUCTION: This review examines the concept of cognitive reserve (CR) in relation to brain aging, particularly in the context of dementia and its early stages. CR refers to an individual's ability to maintain or regain cognitive function despite brain aging, damage, or disease. Various factors, including education, occupation complexity, leisure activities, and genetics are believed to influence CR. METHODS: We revised the literature in the context of CR. A total of 842 articles were identified, then we rigorously assessed the relevance of articles based on titles and abstracts, employing a systematic approach to eliminate studies that did not align with our research objectives. RESULTS: We evaluate-also in a critical way-the methods commonly used to define and measure CR, including sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures. The challenges and limitations of these measures are discussed, emphasizing the need for more targeted research to improve the understanding, definition, and measurement of CR. CONCLUSIONS: The review underscores the significance of comprehending CR in the context of both normal and pathological brain aging and emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation in both healthy and neurologically impaired older individuals. HIGHLIGHTS: This review examines the concept of cognitive reserve in brain aging, in the context of dementia and its early stages. We have evaluated the methods commonly used to define and measure cognitive reserve. Sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures are discussed. The review emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation.

Research diagnostic criteria for mild cognitive impairment with Lewy bodies: A systematic review and meta-analysis.

INTRODUCTION: Operationalized research criteria for mild cognitive impairment with Lewy bodies (MCI-LB) were published in 2020. The aim of this systematic review and meta-analysis was to review the evidence for the diagnostic clinical features and biomarkers in MCI-LB set out in the criteria. METHODS: MEDLINE, PubMed, and Embase were searched on 9/28/22 for relevant articles. Articles were included if they presented original data reporting the rates of diagnostic features in MCI-LB. RESULTS: Fifty-seven articles were included. The meta-analysis supported the inclusion of the current clinical features in the diagnostic criteria. Evidence for striatal dopaminergic imaging and meta-iodobenzylguanidine cardiac scintigraphy, though limited, supports their inclusion. Quantitative electroencephalogram (EEG) and fluorodeoxyglucose positron emission tomography (PET) show promise as diagnostic biomarkers. DISCUSSION: The available evidence largely supports the current diagnostic criteria for MCI-LB. Further evidence will help refine the diagnostic criteria and understand how best to apply them in clinical practice and research. HIGHLIGHTS: A meta-analysis of the diagnostic features of MCI-LB was carried out. The four core clinical features were more common in MCI-LB than MCI-AD/stable MCI. Neuropsychiatric and autonomic features were also more common in MCI-LB. More evidence is needed for the proposed biomarkers. FDG-PET and quantitative EEG show promise as diagnostic biomarkers in MCI-LB.

Hyperconnectivity in Dementia Is Early and Focal and Wanes with Progression.

We investigated in a longitudinal multicenter cohort study functional cortical connectivity changes along the course of frontotemporal dementia (FTD) and Alzheimer's disease (AD) from the prodromal stage of the diseases. Electroencephalography (EEG) was recorded in 18 FTD and 18 AD patients at the prodromal stage of dementia, at dementia onset, and 3 years after dementia onset. Twenty healthy controls (HC) underwent EEG recordings at the same time interval as the patients. Mutual information (MI) analysis measured the strength of functional network connectivity. FTD and AD patients showed greater MI at the prodromal stage of dementia (FTD vs. HC P = 2 × 10-8; AD vs. HC P = 4 × 10-3). Local connectivity was higher in left and right frontal areas of FTD (P = 7 × 10-5 and 0.03) and in left and right posterior areas in AD (P = 3 × 10-5 and 5 × 10-5) versus HC. We showed cortical hyperconnectivity at the prodromal stage of dementia in areas involved in the specific pathological process of FTD (frontal regions) and AD (posterior regions). Hyperconnectivity disappeared during follow-up, thus suggesting that it is an early electrophysiological feature of dementia, potentially useful to identify prodromal FTD and AD.

Accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) among the Italian Dementia Centers: a study by the Italian DLB study group (DLB-SINdem).

INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.

Preexisting Bipolar Disorder Influences the Subsequent Phenotype of Parkinson's Disease.

BACKGROUND: Patients with bipolar spectrum disorders (BSDs) exhibit an increased risk of Parkinson's disease (PD). OBJECTIVE: The aim is to investigate whether a previous diagnosis of BSDs influences the phenotype of PD. METHODS: Of 2660 PD patients followed for at least 6 years (6-27), 250 (BSD-PD) had BSDs, 6-20 years before PD diagnosis; 48%-43% had a PD or BSD family history, and 34 carried glucocerebrosidase (GBA) and Parkin (PRKN) mutations. The cohort was split into a subset of 213 BSD-PD patients, compared with 426 matched PD patients without BSDs, and a subset of 34 BSD-PD and 79 PD patients carrying GBA or PRKN mutations. Carriers of mutations absent in BSD-PD patients and of synuclein triplication were excluded. Structured clinical interviews and mood disorder questionnaires assessed BSDs. Linear mixed models evaluated the assessment scales over time. Thirteen BSD-PD patients underwent subthalamic nucleus deep brain stimulation (STN-DBS) and were compared with 27 matched STN-DBS-treated PD patients. RESULTS: Compared to PD patients, BSD-PD showed (1) higher frequency of family history of PD (odds ratio [OR] 3.31; 2.32-4.71) and BSDs (OR 6.20; 4.11-9.35) 5); (2) higher incidence of impulse control disorders (hazard ratio [HR] 5.95, 3.89-9.09); (3) higher frequency of functional disorders occurring before PD therapy (HR, 5.67, 3.95-8.15); (4) earlier occurrence of delusions or mild dementia (HR, 7.70, 5.55-10.69; HR, 1.43, 1.16-1.75); and (5) earlier mortality (1.48; 1.11-1.97). Genetic BSD-PD subjects exhibited clinical features indistinguishable from nongenetic BSD-PD subjects. STN-DBS-treated BSD-PD patients showed no improvements in quality of life compared to the control group. CONCLUSIONS: BSDs as a prodrome to PD unfavorably shape their course and are associated with detrimental neuropsychiatric features and treatment outcomes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.

The 2019 new coronavirus (SARS-CoV-2) is a novel respiratory virus which has increasingly spread all over the world. Although the predominant clinical presentation is represented by respiratory symptoms, neurological manifestation of SARS-CoV-2 is being increasingly recognized. In the present report, we present a case of post SARS-CoV-2 autoimmune encephalitis associated with a new-onset refractory status epilepticus (NORSE).

The factitious/malingering continuum and its burden on public health costs: a review and experience in an Italian neurology setting.

Factitious disorder is classified as one of the five aspects of somatic symptom disorders. The fundamental element of factitious disorder is deception, i.e., pretending to have a medical or psychiatric disorder, but the enactment of deception is considered unconscious. Indeed, volition, i.e., the perception of deliberate deception, is blurred in patients presenting with factitious disorder. In the USA and the UK, factitious disorder has received constant media attention because of its forensic implications and outrageous costs for the National Health Systems. Unfortunately, a comparable level of attention is not present in Italian National Health System or the Italian mass media. The review analyzes the classifications, disorder mechanisms, costs, and medico-legal implications in the hope of raising awareness on this disturbing issue. Moreover, the review depicts 13 exemplification cases, anonymized and fictionalized by expert writers. Finally, our paper also evaluates the National Health System's expenditures for each patient, outlandish costs in the range between 50,000 and 1 million euros.

Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

BACKGROUND AND AIM: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. CONCLUSIONS: To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

Clinical presentation of strokes confined to the insula: a systematic review of literature.

BACKGROUND AND PURPOSE: The insular cortex serves a wide variety of functions in humans, ranging from sensory and affective processing to high-level cognition. Hence, insular dysfunction may result in several different presentations. Ischemic strokes limited to the insular territory are rare and deserve a better characterization, to be quickly recognized and to receive the appropriate treatment (e.g. thrombolysis). METHODS: We reviewed studies on patients with a first-ever acute stroke restricted to the insula. We searched in the Medline database the keywords "insular stroke" and "insular infarction", to identify previously published cases. Afterwards, the results were divided depending on the specific insular region affected by the stroke: anterior insular cortex (AIC), posterior insular cortex (PIC) or total insula cortex (TIC). Finally, a review of the clinical correlates associated with each region was performed. RESULTS: We identified 25 reports including a total of 49 patients (59.7 ± 15.5 years, 48% male) from systematic review of the literature. The most common clinical phenotypes were motor and somatosensory deficits, dysarthria, aphasia and a vestibular-like syndrome. Atypical presentations were also common and included dysphagia, awareness deficits, gustatory disturbances, dysautonomia, neuropsychiatric or auditory disturbances and headache. CONCLUSIONS: The clinical presentation of insular strokes is heterogeneous; however, an insular stroke should be suspected when vestibular-like, somatosensory, speech or language disturbances are combined in the same patient. Further studies are needed to improve our understanding of more atypical presentations.

Low molecular weight heparin in COVID-19 patients prevents delirium and shortens hospitalization.

BACKGROUND: COVID-19 patients present with delirium during their hospitalization. AIMS: To assess the incidence of delirium in hospitalized COVID-19 patients and analyze the possible association with demographic, clinical, laboratory, and pharmacological factors. METHODS: COVID-19 patients were assessed for clinical signs of delirium and administered the assessment test for delirium and cognitive impairment (4AT) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scales. RESULTS: Out of the 56 patients of our cohort, 14 (25.0%) experienced delirium. The use of low molecular weight heparin (LMWH) (enoxaparin 1 mg/kg/daily) was less frequent in patients with delirium (p = 0.004) and was accompanied by lower C reactive protein (CRP) levels (p = 0.006). DISCUSSION: The use of LMWH was associated with absence of delirium, independently of comorbidities and age. CONCLUSIONS: The use of LMWH may help preventing the occurrence of delirium in COVID-19 patients, with possible reduction of length of stay in the hospital and sequelae.

New daily persistent headache after SARS-CoV-2 infection: a report of two cases.

BACKGROUND: The 2019 Coronavirus (SARS-CoV-2) is a novel respiratory virus which causes Coronavirus Disease19 (COVID-19). Although the predominant clinical picture of COVID-19 is represented by respiratory symptoms, neurological manifestations are being increasingly recognized. Headache, in particular migraine-like and tension types, has been largely reported in patients suffering from COVID-19 both in the acute and the healing phase of the infection. New daily persistent headache (NDPH) is a primary headache characterized by persistent and daily painful symptoms, with pain becoming continuous and non-remitting within 24 h, and lasting more than 3 months. Even though an increasing number of reports describe patients who develop a persistent headache, diagnosis of NPDH has been rarely explored in the context of COVID-19. METHODS: Two patients with persistent headache and Sars-CoV-2 infection were identified. Both underwent a full clinical and neuroradiological evaluation. Blood sample with inflammatory biomarkers search was also performed. RESULTS: According to International Classifications of Headache Disorders diagnosis of probable new daily persistent headache was made. The treatment with high doses of steroids was associated with relief of symptoms. CONCLUSIONS: Our report described two cases of probable NDPH due to SARS-CoV-2 infection. Clinical evaluation of COVID-19 patients presenting with persistent headache should take into consideration NDPH. Given the supposed major role for neuroinflammation in the genesis of Sars-CoV-2-driven NDPH, immunomodulatory therapy should be promptly started. In line with this hypothesis, we obtained a good therapeutic response to short-term high dose of corticosteroids.

Delirium in COVID-19 patients: a multicentric observational study in Italy.

INTRODUCTION: Although recent data show that SARS-CoV-2 infection seems to affect the central nervous system (CNS), little is known about the neuropsychiatric effects resulting from this condition. In addition to the well-known neurotrophism of coronaviruses, recent evidence shows also that the "cytokine storm" induced by the infection is at the basis of the neuroinflammation of the CNS. Furthermore, prolonged hospitalization, polypharmacotherapy, and isolation could be at the basis of the onset of delirium in hospitalized COVID patients. This multicentric observational study explores the incidence of the onset of delirium in an Italian cohort of SARS-CoV-2 positive inpatients. METHODS: Data were collected in the COVIDhospitals of Brescia, Bergamo, Chieti, and Genova. Different socio-demographic, medical, neurological, and pharmacological parameters were collected. As a rapid screening for delirium, the 4AT scale was used. Eighty COVID-19 inpatients (mean age 74.7 ± 14.5 years) met the inclusion criteria (confirmed positivity to the SARS-CoV-2 virus; the presence of delirium and/or psychomotor agitation and/or new onset of other neuropsychiatric symptoms during hospitalization). RESULTS: The majority of these patients (68.8%) had "hyperactive delirium" subtype. Polypharmacotherapy, current treatment with corticosteroids, and higher age were associated with delirium severity. CONCLUSION: These data provide an insight into the onset of delirium among COVID-19 patients underlining the need for monitoring, especially in elderly patients, the neuropsychiatric symptoms, and the therapy in order to have shorter hospitalization times and better outcomes.

Diaphragmatic myoclonus due to SARS-CoV-2 infection.

A wide range of neurological signs and symptoms have been associated with SARS-CoV-2 infection. In the present report, we described two Italian patients diagnosed with diaphragmatic myoclonus after COVID-19. In both cases, mild lymphocytosis at cerebrospinal fluid analysis and no structural brain changes were reported. The pathophysiological origin of the myoclonus in the two cases was different. In case 1, electroencephalogram did not reveal any cortical correlates and brain imaging of the spine was unremarkable, while in case 2, cortical origin of myoclonus was demonstrated. With the present two cases, we confirm and extend the neurological manifestations of SARS-CoV-2 infection.

Neuropsychological and electrophysiological measurements for diagnosis and prediction of dementia: a review on Machine Learning approach.

INTRODUCTION: Emerging and advanced technologies in the field of Artificial Intelligence (AI) represent promising methods to predict and diagnose neurodegenerative diseases, such as dementia. By using multimodal approaches, Machine Learning (ML) seems to provide a better understanding of the pathological mechanisms underlying the onset of dementia. The purpose of this review was to discuss the current ML application in the field of neuropsychology and electrophysiology, exploring its results in both prediction and diagnosis for different forms of dementia, such as Alzheimer's disease (AD), Vascular Dementia (VaD), Dementia with Lewy bodies (DLB), and Frontotemporal Dementia (FTD). METHODS: Main ML-based papers focusing on neuropsychological assessments and electroencephalogram (EEG) studies were analyzed for each type of dementia. RESULTS: An accuracy ranging between 70-90% or even more was observed in all neurophysiological and electrophysiological results trained by ML. Among all forms of dementia, the most significant findings were observed for AD. Relevant results were mostly related to diagnosis rather than prediction, because of the lack of longitudinal studies with appropriate follow-up duration. However, it remains unclear which ML algorithm performs better in diagnosing or predicting dementia. CONCLUSIONS: Neuropsychological and electrophysiological measurements, together with ML analysis, may be considered as reliable instruments for early detection of dementia.

Search in the Periphery for Potential Inflammatory Biomarkers of Dementia with Lewy Bodies and Alzheimer's Disease.

Background: Neuroinflammation, with altered peripheral proinflammatory cytokine production, plays a major role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), while the role of inflammation in dementia with Lewy bodies (DLB) is less known and the results of different studies are often in disagreement. Objective: The present study aimed to investigate the levels of TNFα and IL-6 in serum and supernatants, and the related DNA methylation in patients affected by DLB and AD compared to healthy controls (HCs), to clarify the role of epigenetic mechanisms of DNA promoter methylation on of pro-inflammatory cytokines overproduction. Methods: Twenty-one patients with DLB and fourteen with AD were frequency-matched for age and sex with eleven HCs. Clinical evaluation, TNFα and IL-6 gene methylation status, cytokine gene expression levels and production in serum and peripheral blood mononuclear cell (PBMC) supernatants were performed. Results: In AD and DLB patients, higher serum levels of IL-6 and TNFα were detected than in HCs. Differences in LPS-stimulated versus spontaneous PBMCs were observed between DLB, AD, and HC in the levels of TNFα (p = 0.027) and IL-6 (p < 0.001). Higher levels were also revealed for sIL-6R in DLB (p < 0.001) and AD (p < 0.001) in comparison with HC.DNA hypomethylation in IL-6 and TNFα CpG promoter sites was detected for DLB and AD patients compared to the corresponding site in HCs. Conclusions: Our preliminary study documented increased levels of IL-6 and TNFα in DLB and AD patients to HCs. This overproduction can be due to epigenetic mechanisms regarding the hypomethylation of DNA promoters.