A Systematic Review on Drugs Acting as Nicotinic Acetylcholine Receptor Agonists in the Treatment of Dementia.

Acetylcholine signaling is attenuated in early Alzheimer's disease (AD) and other dementias. A significant reduction in the expression of nicotinic acetylcholine receptors (nAChRs) in the brain of AD patients has also been reported in several molecular biological and in situ labeling studies. The modulation of the functional deficit of the cholinergic system as a pharmacological target could therefore have a clinical benefit, which is not to be neglected. This systematic review was conducted to identify clinical trials, which evaluated the safety and efficacy of nicotinic acetylcholine receptor agonists using Clinicaltrial (CT) and EudraCT databases. Structured searches identified 39 trials, which used 15 different drugs designed to increase the function of the nAChRs. Most of the identified clinical trials were phase II trials, with some of them classified as ongoing for several years. The systematic screening of the literature led to the selection of 14 studies out of the 8261 bibliographic records retrieved. Six trials reported detailed data on adverse events associated with the intervention, while twelve trials reported data on efficacy measures, such as attention, behavior and cognition. Overall, smost of the physical side effects of cholinergic agonists were reported to be well tolerated. Some trials also reported improvements in attention. However, the efficacy of these drugs in other cognitive and behavioral outcomes remains highly controversial.

Neuropathological hints from CSF and serum biomarkers in corticobasal syndrome (CBS): a systematic review.

Corticobasal syndrome (CBS) is a clinical syndrome determined by various underlying neurodegenerative disorders requiring a pathological assessment for a definitive diagnosis. A literature review was performed following the methodology described in the Cochrane Handbook for Systematic Reviews to investigate the additional value of traditional and cutting-edge cerebrospinal fluid (CSF) and serum/plasma biomarkers in profiling CBS. Four databases were screened applying predefined inclusion criteria: (1) recruiting patients with CBS; (2) analyzing CSF/plasma biomarkers in CBS. The review highlights the potential role of the association of fluid biomarkers in diagnostic workup of CBS, since they may contribute to a more accurate diagnosis and patient selection for future disease-modifying agent; for example, future trial designs should consider baseline CSF Neurofilament Light Chains (NfL) or progranulin dosage to stratify treatment arms according to neuropathological substrates, and serum NfL dosage might be used to monitor the evolution of CBS. In this scenario, prospective cohort studies, starting with neurological examination and neuropsychological tests, should be considered to assess the correlations of clinical profiles and various biomarkers.

Normative data beyond the total scores: a process score analysis of the Rey's 15 word test in healthy aging and Alzheimer's Disease.

BACKGROUND: The Rey's 15 words test is currently the most frequently used task in Italy to detect memory deficits in AD. The current standardised version is however quite outdated and lacks some cognitive indexes which may highlight problems in recall or encoding processes. The aim of the study was to update the normative data of the test and to consider some variables which were not accounted for in the original study, that is, recognition, learning rate and forgetfulness. We also adopted the process scores approach to ascertain the effects of serial position (primacy and recency). METHODS: Three hundred ninety-six healthy participants were recruited. To detect any variables useful for intercepting the early stages of dementia, a group of 208 patients in the very early stage of AD was also recruited. Linear models were used to calculate the corrections scores for age, education, and gender, and ROCs were used to calculate cut-offs based on the maximum sum of sensitivity and specificity and the positive and negative predictive values. RESULTS: All main indexes showed excellent Area Under the Curve (0.90-1), strong sensitivity and PPVs for distinguishing between the HCs and AD participants. However, the Intrusions index performed poorly in all parameters. CONCLUSION: The study provides updated, normative data which may be reliably used as a cognitive marker to detect early AD. The strength of the study is the large sample size and the number of indexes which make it possible to explore the utility of memory test process scores.

A new national survey of centers for cognitive disorders and dementias in Italy.

INTRODUCTION: A new national survey has been carried out by the Italian Centers for Cognitive Disorders and Dementias (CCDDs). The aim of this new national survey is to provide a comprehensive description of the characteristics, organizational aspects of the CCDDs, and experiences during the COVID-19 pandemic. METHODS: A list of all national CCDDs was requested from the delegates of each Italian region. The online questionnaire is divided in two main sections: a profile section, containing information on location and accessibility, and a data collection form covering organization, services, treatments, activities, and any service interruptions caused by the COVID-19 outbreak. RESULTS: In total, 511 out of 534 (96%) facilities completed the profile section, while 450 out of 534 (84%) CCDDs also completed the data collection form. Almost half of the CCDDs (55.1%) operated for 3 or fewer days a week. About one-third of the facilities had at least two professional figures among neurologists, geriatricians and psychiatrists. In 2020, only a third of facilities were open all the time, but in 2021, two-thirds of the facilities were open. CONCLUSION: This paper provides an update on the current status of CCDDs in Italy, which still shows considerable heterogeneity. The survey revealed a modest improvement in the functioning of CCDDs, although substantial efforts are still required to ensure the diagnosis and care of patients with dementia.

A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.

Advances in amyloid-targeting monoclonal antibodies for Alzheimer's disease: clinical and public health issues.

INTRODUCTION: Alzheimer's disease (AD) is a major global public health challenge. To date, no treatments have been shown to stop the underlying pathological processes. The cerebral accumulation of amyloid-beta (Ab) is still considered as the primum movens of AD and disease-modifying treatments targeting Ab are reaching - or have already reached - clinical practice. AREAS COVERED: The authors explore the main advancements from Aß-targeting monoclonal antibodies (mAbs) for the treatment of AD. From a public health perspective, they address ethically relevant issues such as the benevolence and non-maleficence principles. They report on the potential biological and clinical benefits of these drugs, discussing minimal clinically important differences (MCID) and other relevant outcomes. They examine the short- and long-term effects of amyloid-related imaging abnormalities (ARIA), and explore the differences between eligibility criteria in clinical trials, appropriate use recommendations, and prescribing information content. In doing so, they contextualize the discussion on the disagreements among different regulatory authorities. EXPERT OPINION: Although anti-ß-amyloid monoclonal antibodies may be effective in selected scenarios, non-negligible knowledge gaps and implementation limits persist. Overcoming these gaps can no longer be postponed if we are to ensure the principles of Quality of Care for patients with cognitive impairment who would be eligible for this class of drugs.

Guillain-Barré syndrome in patients dying with COVID-19 in Italy: a retrospective study.

INTRODUCTION: We presented a four-case series of COVID-19 related deaths occurred in patients with Guillain-Barré syndrome (GBS) between February 2020 and January 2022 in Italy. METHODS: They were extracted from 8,436 medical charts of COVID-19 patients dying. All cases, ranged 48-73 years, showed classical GBS clinical onset - limb weakness, sensory deficits, hypoareflexia - and three of them were admitted in intensive care unit (ICU) for ventilator support. RESULTS: The cerebrospinal fluid showing albumin-cytological dissociation was performed in two cases. Nerve conduction studies supported the diagnosis in all cases. Interstitial pneumonia was documented by chest X-rays or CT scans in all cases: they were treated with intravenous immunoglobulin (IVIg) and the drugs used for COVID-19 infection. CONCLUSIONS: Although the mechanism of GBS onset is still unclear in COVID-19, fatal cases may be more frequent than other virus-related GBS, so that strictly monitoring in high-risk patients could dramatically decrease the mortality of GBS.

Raw Water and ALS: A Unifying Hypothesis for the Environmental Agents Involved in ALS.

Different studies identified the presence of several altered genes in familial and sporadic amyotrophic lateral sclerosis (ALS) forms. The experimental data, together with the epidemiological data, would seem to suggest the existence of molecular mechanisms (e.g., axonal transport) related to these genes, together with a susceptibility of the same genes to certain environmental factors that would therefore suggest an impact of the environment on the etiopathogenesis of ALS. In our review, we considered the most relevant environmental clusters around the world, collecting different hypotheses and underlining common environmental factors among the different clusters. Moreover, further epidemiological data identified a higher risk of ALS in professional athletes and, in particular, in soccer and football players. Despite this increased risk of ALS highlighted by the epidemiological evidence in aforementioned sports, the mechanisms remain unclear. At last, the use of raw water has been associated with ALS risk. The aim of the present review is to characterize a possible relationship between these clusters, to be explored in the context of the interaction between genetic and environmental factors on the etiopathogenesis of ALS.

Children under 6 years with acute headache in Pediatric Emergency Departments. A 2-year retrospective exploratory multicenter Italian study.

BACKGROUND: Preschool age (i.e. children under six years of age) represents a red flag for requiring neuroimaging to exclude secondary potentially urgent intracranial conditions (PUIC) in patients with acute headache. We investigated the clinical characteristics of preschoolers with headache to identify the features associated with a greater risk of secondary "dangerous" headache. METHODS: We performed a multicenter exploratory retrospective study in Italy from January 2017 to December 2018. Preschoolers with new-onset non-traumatic headache admitted to emergency department were included and were subsequently divided into two groups: hospitalized and discharged. Among hospitalized patients, we investigated the characteristics linked to potentially urgent intracranial conditions. RESULTS: We included 1455 preschoolers with acute headache. Vomiting, ocular motility disorders, ataxia, presence of neurological symptoms and signs, torticollis and nocturnal awakening were significantly associated to hospitalization. Among the 95 hospitalized patients, 34 (2.3%) had potentially urgent intracranial conditions and more frequently they had neurological symptoms and signs, papilledema, ataxia, cranial nerves paralysis, nocturnal awakening and vomiting. Nevertheless, on multivariable logistic regression analysis, we found that only ataxia and vomiting were associated with potentially urgent intracranial conditions. CONCLUSION: Our study identified clinical features that should be carefully evaluated in the emergency department in order to obtain a prompt diagnosis and treatment of potentially urgent intracranial conditions. The prevalence of potentially urgent intracranial conditions was low in the emergency department, which may suggest that age under six should not be considered an important risk factor for malignant causes as previously thought.

Frequency and characterization of cognitive impairments in patients diagnosed with paediatric central nervous system tumours: a systematic review.

Background: This systematic review has been conducted with the aim of characterizing cognitive deficits and analyzing their frequency in survivors of paediatric Central Nervous System tumours. Materials and methods: All literature published up to January 2023 was retrieved searching the databases "PubMed", "Cochrane", "APA PsycInfo" and "CINAHL". The following set of pre-defined inclusion criteria were then individually applied to the selected articles in their full-text version: i) Retrospective/prospective longitudinal observational studies including only patients diagnosed with primary cerebral tumours at ≤ 21 years (range 0-21); ii) Studies including patients evaluated for neuro-cognitive and neuro-psychological deficits from their diagnosis and/or from anti-tumoral therapies; iii) Studies reporting standardized tests evaluating patients' neuro-cognitive and neuro-psychological performances; iv) Patients with follow-ups ≥ 2 years from the end of their anti-tumoral therapies; v) Studies reporting frequencies of cognitive deficits. Results: 39 studies were included in the analysis. Of these, 35 assessed intellectual functioning, 30 examined memory domains, 24 assessed executive functions, 22 assessed attention, 16 examined visuo-spatial skills, and 15 explored language. A total of 34 studies assessed more than one cognitive function, only 5 studies limited their analysis on a single cognitive domain. Attention impairments were the most recurrent in this population, with a mean frequency of 52.3% after a median period post-treatment of 11.5 years. The other cognitive functions investigated in the studies showed a similar frequency of impairments, with executive functions, language, visuospatial skills and memory deficits occurring in about 40% of survivors after a similar post-treatment period. Longitudinal studies included in the systematic review showed a frequent decline over time of intellectual functioning. Conclusions: Survivors of paediatric Central Nervous System tumours experience cognitive sequelae characterized by significant impairments in the attention domain (52.3%), but also in the other cognitive functions. Future studies in this research field need to implement more cognitive interventions and effective, but less neurotoxic, tumour therapies to preserve or improve neurocognitive functioning and quality of life of this population.

Hospital admission and mortality rates for non-Covid diseases among residents of the long-term care facilities before and during the pandemic: a cohort study in two Italian regions.

Aim: Long-term-care facility residents are a vulnerable population who experienced reduced healthcare access during the pandemic. This study aimed to assess the indirect impact of the COVID-19 pandemic, in terms of hospitalisation and mortality rates, among this population in two Italian Regions, Tuscany and Apulia, during 2020 in comparison with the pre-pandemic period. Subject and methods: We conducted a retrospective cohort study on people residing in long-term-care facilities from 1 January 2018 to 31 December 2020 (baseline period: 1 January 2018-8 March 2020; pandemic period: and 9 March-31 December 2020). Hospitalisation rates were stratified by sex and major disease groups. Standardised weekly rates were estimated with a Poisson regression model. Only for Tuscany, mortality risk at 30 days after hospitalisation was calculated with the Kaplan-Meier estimator. Mortality risk ratios were calculated using Cox proportional regression models. Results: Nineteen thousand two hundred and fifty individuals spent at least 7 days in a long-term-care facility during the study period. The overall mean non-Covid hospital admission rate per 100 000 residents/week was 144.1 and 116.2 during the baseline and pandemic periods, with a decrease to 99.7 and 77.3 during the first (March-May) and second lockdown (November-December). Hospitalisation rates decreased for all major disease groups. Thirty-day mortality risk ratios for non-Covid conditions increased during the pandemic period (1.2, 1.1 to 1.4) compared with baseline. Conclusion: The pandemic resulted in worse non-COVID-related health outcomes for long-term-care facilities' residents. There is a need to prioritise these facilities in national pandemic preparedness plans and to ensure their full integration in national surveillance systems. Supplementary information: The online version contains supplementary material available at 10.1007/s10389-023-01925-1.

An updated overview of recent and ongoing deep brain stimulation (DBS) trials in patients with dementia: a systematic review.

BACKGROUND: Dementia affects more than 55 million people worldwide. Several technologies have been developed to slow cognitive decline: deep brain stimulation (DBS) of network targets in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have been recently investigated. OBJECTIVE: This study aimed to review the characteristics of the populations, protocols, and outcomes of patients with dementia enrolled in clinical trials investigating the feasibility and efficacy of DBS. MATERIALS AND METHODS: A systematic search of all registered RCTs was performed on Clinicaltrials.gov and EudraCT, while a systematic literature review was conducted on PubMed, Scopus, Cochrane, and APA PsycInfo to identify published trials. RESULTS: The literature search yielded 2122 records, and the clinical trial search 15 records. Overall, 17 studies were included. Two of 17 studies were open-label studies reporting no NCT/EUCT code and were analysed separately. Of 12 studies investigating the role of DBS in AD, we included 5 published RCTs, 2 unregistered open-label (OL) studies, 3 recruiting studies, and 2 unpublished trials with no evidence of completion. The overall risk of bias was assessed as moderate-high. Our review showed significant heterogeneity in the recruited populations regarding age, disease severity, informed consent availability, inclusion, and exclusion criteria. Notably, the standard mean of overall severe adverse events was moderately high (SAEs: 9.10 ± 7.10%). CONCLUSION: The population investigated is small and heterogeneous, published results from clinical trials are under-represented, severe adverse events not negligible, and cognitive outcomes uncertain. Overall, the validity of these studies requires confirmation based on forthcoming higher-quality clinical trials.

Case Identification and Characterization of Migrants with Dementia in the Lazio Region Using Health Administrative Data.

BACKGROUND: A crucial step for planning effective public health policies for migrants with dementia is the collection of data on the local dimensions of the phenomenon and patients' characteristics. OBJECTIVE: This study aimed to identify and characterize migrants with dementia in the Lazio region using health administrative databases. METHODS: Residents with dementia aged 50 years or older, living in the Lazio region as of December 31, 2018, were identified using a validated algorithm based on hospital discharge(s), claims for antidementia drugs, and co-payment exemption for dementia. Migrants were defined as people born abroad and grouped in migrants from High Migratory Pressure Countries (HMPCs) and Highly Developed Countries (HDCs). Overall and age-specific prevalence rates were estimated in native- and foreign-born patients. RESULTS: Dementia was ascertained in 38,460 residents. Among them, 37,280 (96.9%) were born in Italy, 337 (0.9%) were migrants from HDCs, and 843 (2.2%) from HMPCs. Dementia prevalence was higher among natives (1.15%, 95% CI 1.14-1.16) relative to migrants from HDCs (0.60%, 95% CI 0.54-0.67) and HMPCs (0.29%, 95% CI 0.27-0.31). The prevalence of comorbidities did not differ between groups. Migrants with dementia had a lower likelihood of receiving antidementia treatments compared with natives (51.6% in migrants from HDCs, 49.3% in migrants from HMPCs, and 53.5% among Italians). CONCLUSION: Routinely collected data in healthcare administrative databases can support the identification of migrants with dementia. Migrants exhibited a lower age-standardized prevalence of registered dementia and lower access to dedicated treatments than Italians. These findings are suggestive of underdiagnosis and undertreatment of dementia in migrants.

Anti-dementia drugs: a descriptive study of the prescription pattern in Italy.

INTRODUCTION: Acetylcholinesterase inhibitors (AChEIs) and memantine are currently the only anti-dementia drugs (ADDs) approved for treating Alzheimer's disease (AD) in Italy. This nationwide study aims to characterize dementia drug utilization in a population > 65 years, during 2018-2020. METHODS: Different administrative healthcare databases were queried to collect both aggregate and individual data. RESULTS: ADD consumption remained stable throughout the study period (~ 9 DDD/1000 inhabitants per day). AChEI consumption was over 5 DDD/1000 inhabitants per day. Memantine consumption was nearly 4 DDD/1000 inhabitants per day, representing 40% of ADD consumption. The prevalence of use of memantine represented nearly half of ADD consumption, substantially unchanged over the 3 years. Comparing the AD prevalence with the prevalence of ADDs use, the gap becomes wider as age increases. In 2019, the proportion of private purchases of ADDs was 38%, mostly represented by donepezil and rivastigmine. In 2020, memantine was the only ADD with an increase in consumption (Δ% 19-20, 1.3%). DISCUSSION: To our knowledge, this study represents the first attempt to investigate the ADD prescription pattern in Italy with a Public Health approach. In 2019, the proportion of ADD private purchases point out several issues concerning the reimbursability of ADDs. From a regulatory perspective, ADDs can be reimbursed by the National Health System only to patients diagnosed with AD; therefore, the off-label use of ADDs in patients with mild cognitive impairment may partially explain this phenomenon. The study extends knowledge on the use of ADDs, providing comparisons with studies from other countries that investigate the prescription pattern of ADDs.

States of Mind with Respect to Attachment: a comparative study between women who killed their children and mothers diagnosed with post-partum depression.

INTRODUCTION: Attachment theory has been linked with the caregiving system, acting as a drive for a mother's behavior towards her offspring. The most dramatic consequence of distress following maternity is filicide. Despite this, only few studies addressed the attachment models of women who committed filicide, and very little provided comparisons with mothers diagnosed with post-partum depression. OBJECTIVE: We described the socio-demographic and psychopathological characteristics of mothers who committed filicide. Our aim was to detect differences in the attachment models between mothers who committed filicide, mothers with post-partum depression and control mothers. Participants and setting: We recruited 19 women who committed filicide (group F) along with 52 women with post-partum depression (group D), and 23 control mothers (group C). METHODS: We administered a semi-structured interview on socio-demographic aspects and psychiatric history along with the Adult Attachment Interview. We performed an ANOVA, a post-hoc analysis and a logistic regression. RESULTS: The logistic regression showed a higher prevalence of Dismissing and Disorganized attachments in women of group F compared with group C (p = 0.002, p = 0.007). Dismissing attachment was also overrepresented in group D vs group C (p = 0.012). Interestingly, women of group F showed a Preoccupied/entangled attachment to a lesser extent than those of group D, reaching a borderline significance (p = 0.056). CONCLUSIONS: Disorganized and Dismissing models of attachment are prevalent in women who committed filicide compared with mothers with post-partum depression and controls, while other models of attachment are less frequent. Therefore, attachment could be taken into consideration to define the risk for committing filicide.

Identification of dementia and MCI cases in health information systems: An Italian validation study.

Introduction: The identification of dementia cases through routinely collected health data represents an easily accessible and inexpensive method to estimate the prevalence of dementia. In Italy, a project aimed at the validation of an algorithm was conducted. Methods: The project included cases (patients with dementia or mild cognitive impairment [MCI]) recruited in centers for cognitive disorders and dementias and controls recruited in outpatient units of geriatrics and neurology. The algorithm based on pharmaceutical prescriptions, hospital discharge records, residential long-term care records, and information on exemption from health-care co-payment, was applied to the validation population. Results: The main analysis was conducted on 1110 cases and 1114 controls. The sensitivity, specificity, and positive and negative predictive values in discerning cases of dementia were 74.5%, 96.0%, 94.9%, and 79.1%, respectively, whereas in detecting cases of MCI these values were 29.7%, 97.5%, 92.2%, and 58.1%, respectively. The variables associated with misclassification of cases were also identified. Discussion: This study provided a validated algorithm, based on administrative data, which can be used to identify cases with dementia and, with lower sensitivity, also early onset dementia but not cases with MCI.