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Competing Interests: EF was called as a speaker in a course organized by Viatris and for a brief period served as neurological expert for the same company several years ago. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Behavioral and Psychological Symptoms of Dementia (BPSD) are a heterogeneous set of psychological and behavioral abnormalities seen in persons with dementia (PwD), significantly impacting their quality of life and that of their caregivers. Current assessment tools, such as the Neuropsychiatric Inventory (NPI), are limited by recall bias and lack of direct observation. This study aims to overcome this limitation by making caregiver reports more objective through the use of a novel instrument, referred to as the BPSDiary. This randomized controlled trial will involve 300 caregiver-PwD dyads. The objective is to evaluate whether the use of the BPSDiary could significantly reduce caregiver burden, assessed using the Zarit Burden Interview (ZBI), compared to usual care. The study will include adult PwD, caregivers living with or close to the patient, and BPSD related to the HIDA (hyperactivity, impulsivity, irritability, disinhibition, aggression, agitation) domain. Caregivers randomized to the intervention arm will use the BPSDiary to record specific BPSD, including insomnia, agitation/anxiety, aggression, purposeless motor behavior, and delusions/hallucinations, registering time of onset, severity, and potential triggers. The primary outcome will be the change in ZBI scores at 3 months, with secondary outcomes including changes in NPI scores, olanzapine equivalents, NPI-distress scores related to specific BPSD domains, and caregiver and physician satisfaction. The study will be conducted in 9 Italian centers, representing diverse geographic and sociocultural contexts. While potential limitations include the relatively short observation period and the focus on specific BPSD disturbances, the BPSDiary could provide physicians with objective data to tailor appropriate non-pharmacological and pharmacological interventions. Additionally, it may empower caregivers by encouraging reflection on BPSD triggers, with the potential to improve the quality of life for both PwD and their caregivers., Trial Registry: NCT05977855., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Pozzi, Calì, D'Antonio, Altomare, Sepe Monti, Panigutti, Di Crosta, Palumbo, Bonanni, Carlucci, Bussè, Cagning, Urso, Vilella, Logroscino, Alberoni, Bellinvia, Farina, de Rino, Gavazzi, Zuffi, Bruno, Bessi, Cotta Ramusino, Perini, Costa, Ferrarese, Appollonio and Tremolizzo.)

Background: Behavioral and psychological symptoms of dementia (BPSD) have a high prevalence, and their presence is associated with a severe impact in terms of social costs. However, dedicated clinical tools or biomarkers to detect these symptoms are lacking. Thus, BPSD management in clinical settings is challenging. The aim of this study was to investigate the perception and the treatment strategies for BPSD in Italian centers working in the dementia field., Methods: A multicenter, national survey was developed by BPSD Study Group of the Italian Neurological Society for Dementia (SINDEM). The survey consisted of a semi-structured questionnaire that was e-mailed to SINDEM members, dementia centers part of the national network of memory clinics (Centers for Cognitive Deterioration and Dementia [CDCD]), and clinicians working in dementia care settings. The questions were focused on (1) perceived global frequency and relevance of BPSD; (2) tools used to assess BPSD; (3) pharmacological treatment for psychosis, apathy, agitation, aggression, depression, anxiety, sleep, and nutrition disturbances; (4) non-pharmacological treatments; (5) drugs side effects., Results: One-hundred and thirty-six clinicians participated in this study. Seventy-nine participants worked in a CDCD and 57 in other settings. The perceived frequency of BPSD was 74%. BPSD are detected by means of a clinical assessment for 96.3% or a caregiver interview for 97%. For psychosis treatment the first choice was atypical antipsychotics (83.3%), followed by typical antipsychotic (8.9%) and antidepressants (4.8%). For agitation, atypical antipsychotics were the first-choice treatment in 64% of cases and antidepressants in 16.1%. For aggression, the most used drugs were atypical antipsychotics (82.9%). For anxiety, 55.2% use antidepressants, 17.9% use atypical antipsychotics, and 16.9% use benzodiazepines. Interestingly, most of the centers apply non-pharmacological treatments for BPSD. Some differences emerged comparing the responses from CDCD and other care settings., Conclusion: The survey results revealed many differences in BPSD perception, treatment options, and observed side effect according to the clinical setting. This variability can be explained by the absence of clear guidelines, by differences in patients' characteristics, and by clinical practice based on subjective experience. These results suggest that producing guidelines for the pharmacological treatment of BPSD is a major need., Competing Interests: EF was employed by IRCCS Don Gnocchi Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 D'Antonio, Tremolizzo, Zuffi, Pomati, Farina and the Sindem BPSD Study Group.)

AbstractClimate can exert an effect on the strength of sexual selection, but empirical evidence is limited. Here, we tested whether climate predicts the geographic distribution and introgressive spread of sexually selected male color ornamentation across 114 populations of the common wall lizard, Podarcis muralis . Coloration was highly structured across the landscape and did not reflect genetic differentiation. Instead, color ornamentation was consistently exaggerated in hot and dry environments, suggesting that climate-driven selection maintains geographic variation in spite of gene flow. Introgression of color ornamentation into a distantly related lineage appears to be ongoing and was particularly pronounced in warm climates with wet winters and dry summers. Combined, these results suggest that sexual ornamentation is consistently favored in climates that allow a prolonged reproductive season and high and reliable opportunities for lizard activity. This pattern corroborates theoretical predictions that such climatic conditions reduce the temporal clustering of receptive females and increase male-male competition, resulting in strong sexual selection. In summary, we provide compelling evidence for the importance of climate for the evolution of color ornamentation, and we demonstrate that geographic variation in the strength of sexual selection influences introgression of this phenotype.

Conceptual knowledge is supported by multiple semantic systems that are specialized for the analysis of different properties associated with object concepts. Various types of semantic association between concrete concepts-categorical (CA), encyclopedic (EA), functional (FA), and visual-encyclopedic (VEA) associations-were tested through a new picture-to-picture matching task (semantic association task, SAT). Forty individuals with Alzheimer's disease (AD), 13 with behavioral variant of frontotemporal dementia (bv-FTD), 6 with primary progressive aphasia (PPA), and 37 healthy participants were tested with the SAT. Within-group comparisons highlighted a global impairment of all types of semantic association in bv-FTD individuals but a disproportionate impairment of EA and FA, with relative sparing of CA and VEA, in AD individuals. Single-case analyses detected dissociations in all dementia groups. Conceptual knowledge can be selectively impaired in various types of neurodegenerative disease on the basis of the specific cognitive process that is disrupted.

Sixty-nine dyads of patients with Alzheimer's disease and primary caregivers have been followed up for 1 year to evaluate cognitive (Mini-Mental State Examination), functional (Instrumental Activities of Daily Living), and behavioral (Neuropsychiatric Inventory) decline of patient in relation to burden (Caregiver Burden Inventory), stress (Relative Stress Scale), anxiety (State-Trait Anxiety Inventory Y), and depression (Beck Depression Inventory) reported by the caregivers. After 1 year of observation, cognitive and functional scores worsened while behavioral problems remained unchanged and relatively mild in patients. After 1 year, caregivers' scores of scales of anxiety and depression decreased significantly, while stress scores remained unchanged and burden slightly increased. In our opinion, the unexpected improvement in psychological situation of caregivers may be mainly due to educational interventions focused on knowledge of the disease with a particular attention directed toward emotional support and individual needs.

Prion diseases are neurodegenerative disorders which are caused by an accumulation of the abnormal, misfolded prion protein known as scrapie prion protein (PrP Sc ). These disorders are unique as they occur as sporadic, genetic and acquired forms. Sporadic Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease, accounting for approximately 85-90% of cases, whereas autosomal dominant genetic forms, due to mutations in the prion protein gene (PRNP), account for 10-15% of cases. Genetic forms show a striking variability in their clinical and neuropathological picture and can sometimes mimic other neurodegenerative diseases.We report a novel PRNP mutation (V189I) in four CJD patients from three unrelated pedigrees. In three patients, the clinical features were typical for CJD and the diagnosis was pathologically confirmed, while the fourth patient presented with a complex phenotype including rapidly progressive dementia, behavioral abnormalities, ataxia and extrapyramidal features, and the diagnosis was probable CJD by current criteria, on the basis of PrP Sc detection in CSF by Real Time Quaking-Induced Conversion assay. In all the three patients with autopsy findings, the neuropathological analysis revealed diffuse synaptic type deposition of proteinase K-resistant prion protein (PrP res ), and type 1 PrP res was identified in the brain by western blot analysis. So, the histopathological and biochemical profile associated with the V189I mutation was indistinguishable from the MM1/MV1 subtype of sporadic CJD.Our findings support a pathogenic role for the V189I PRNP variant, confirm the heterogeneity of the clinical phenotypes associated to PRNP mutations and highlight the importance of PrP Sc detection assays as diagnostic tools to unveil prion diseases presenting with atypical phenotypes.

Color polymorphism often is associated with alternative reproductive strategies and may reflect different adaptive optima that coexist within populations. The equilibrium among morph frequencies is maintained by the occurrence of opposite selective pressures (disruptive vs. stabilizing), which promote polymorphism while preserving gene flow. Sexual selection may contribute on both sides, particularly when morphs do not mate randomly. Reptiles offer a good model, notably lizards. Nevertheless, previous studies on mate choice in polymorphic lizards have generated contrasting results, with some studies suggesting that female morphs might tune their preference depending on environmental/social conditions such as crowding. We experimentally manipulated the number of individuals a female common wall lizard Podarcis muralis perceives around her, to test if females of different morphs (white or yellow) tune their choice for white and yellow males in order to maximize the probability that hatchlings follow the strategy best adapted to the population density. Results showed that crowding experienced by females did not affect mate choice, arguing against a flexible choice strategy by females. However, white females significantly associated with white males, whereas yellow females did not significantly associate with yellow males. Thus, sexual selection could contribute to the maintenance of color polymorphism in this species by a mix of assortative and non-assortative mating strategies, which could maintain the equilibrium between gene divergence and gene flow among morphs.

Previous studies suggest that genetic variants in CHRNA7, which encodes for the major subunit of the acetylcholine receptor (α7-nAChR), are associated with the clinical response to cholinesterase inhibitors (ChEI) in Alzheimer's disease (AD) patients. We sought to replicate the association of two SNPs in the CHRNA7 gene, rs6494223 and rs8024987, with response to ChEI treatment in an Italian cohort of 169 AD patients, further extending the study to gene-level analysis. None of the tested variants was associated with clinical response. However, rs6494223 showed a consistent effect direction (OR = 1.4; p = 0.17), which after meta-analysis with previous study yielded a significant result (OR = 1.57, p = 0.02, I2 = 0%).

The early differentiation between Alzheimer's disease (AD) and frontal variant of frontotemporal dementia (fvFTD) is frequently difficult, albeit critical for the adequate management of patients and their caregivers. In order to assess the accuracy of CSF levels of beta-amyloid 1-42 (Aβ), tau (τ) and Thr 181-phosphorilated tau (Pτ) in the early differentiation of AD from fvFTD, we designed a prospective study in which patients have been followed up for at least 2 years. Seventy-two patients with AD and 42 patients with fvFTD showed significantly different CSF levels of Pτ (increased in AD, p = 0.0001), Aβ (reduced in AD, p = 0.03), and ratios of Pτ to Aβ (p = 0.003). ROC analyses showed that the ratio Pτ/Αβ is able to predict diagnosis with an AUC of 0.73 (optimal level being 0.16) corresponding to a sensitivity of 80% and a specificity of 68%. Our findings suggest that CSF metabolites may be the important tools in the early differential diagnosis between AD and fvFTD, albeit to be correlated with clinical, neuropsychological and bio imaging features.

Verbal confabulation (VC) has been described in several pathological conditions characterized by amnesia and has been defined as 'statements that involve distortion of memories'. Here we describe another kind of confabulation (graphic confabulation, GC), evident at the recall of the Rey-Osterrieth complex figure (ROCF). In a retrospective study of 267 patients with mild-to-moderate dementia, 14 patients (4.9 %) recalled the abstract ROCF as drawings with recognizable semantic meaning. VC was evident at the story recall test in 19.8% of the study participants. VC and GC were homogeneously distributed among the different types of dementia. VC has been proposed to originate from complex interactions of amnesia, motivational deficit and dysfunction of monitoring systems. On the contrary, GC seems to be the result of a deficit in visual memory replaced by the semantic translation of isolated parts of the ROCF along with a source monitoring deficit.

Background: The latest developments in Lewy Body Dementia (DLB) raise some controversies on clinical features, neuroimaging and therapy. The aim of our study is to determine clinical, neuropsychological, neuroimaging and EEG profile of DLB through retrospective and prospective data of 102 patients., Methods: data were collected with an analytical form that was developed by an expertise of neurologists., Results: DLB represented 4.8% of the dementia population, with no sex difference. Family history of dementia was common (24.5%), while familiarity for parkinsonism was rare (4.9%). Cognitive disturbances were the predominant clinical presentation at onset (49%), followed by behavioral symptoms (29.4%) and parkinsonism (21.6%). Clinical features at consultation were: memory disturbances (almost all cases), symmetrical (68.6%) or asymmetrical (18.6%) parkinsonism, cognitive fluctuations (49%), visuospatial deficits (53.9%), and visual hallucinations (44.1%). Autonomic signs were present in a third of the cases, while sleep disorders were present in 44.1%. Some clinical response to antiparkinsonian drugs was evident in half of the cases. MRI, SPET, EEG and Neuropsychiatric Inventory data were available in a subgroup of patients., Conclusions: Most of our data were in accordance with the previous literature. However, some data underline the relationship between DLB, Alzheimer's and Parkinson's disease.

Background: An early differentiation of Alzheimer's disease (AD) from frontotemporal dementia (FTD) is important, since these conditions are essentially different regarding prognosis and therapeutical approach. Until now, no single test is available which allows a reliable differentiation. The Frontal Assessment Battery (FAB) has been found to have good reliability in identifying an executive deficit in frontal syndromes and in extrapyramidal disorders. The ability of the FAB to distinguish AD from FTD in mildly demented patients is less clearly assessed., Methods: We compared FAB scores in a consecutive series of 33 FTD (frontal variant) and 85 AD patients., Results: FAB global scores in the two groups were very similar, also when considering only mildly demented subgroups [Mini Mental State Examination (MMSE) score > or = 20; 20 FTD and 38 AD patients]. Considering FAB subscores, only the 'go-no go' subtest showed a significant difference, reflecting a poorer inhibitory motor control in AD patients. FAB scores in the two groups of patients correlated with global cognitive decline (MMSE), and with executive and visuospatial test scores, showing good concurrent validity., Conclusion: The FAB does not differentiate patients with AD from those with FTD, like all other executive tests. However, it may be useful in the examination of executive function in AD, FTD and several other pathological conditions., (Copyright (c) 2006 S. Karger AG, Basel.)

In patients with the frontal variant of frontotemporal lobar degeneration (fv-FTLD), behavioral abnormalities may vary from apathy with motor slowness (apathetic form) to disinhibition with agitation (disinhibited form). These clinical presentations may be related to specific regional cerebral dysfunction and to deficit in the serotoninergic system. We studied cerebral glucose uptake using (18)F-fluorodeoxyglucose and positron emission tomography in 18 patients fulfilling clinical criteria for fv-FTLD and showing, respectively, an apathetic or disinhibited behavioral syndrome. In eight of these patients, we also evaluated the 5-hydroxytryptamine-2A receptor cerebral receptor distribution with [(11)C]MDL and positron emission tomography. We found a reduction of frontal glucose metabolism in the whole group of fv-FTLD patients. Apathetic syndrome was associated with a prevalent dorsolateral and frontal medial hypometabolism, whereas the disinhibited syndrome demonstrated a selective hypometabolism in interconnected limbic structures (the cingulate cortex, hippocampus/amygdala, and accumbens nucleus). The in vivo measurements of [(11)C]MDL indicated a significant reduction of 5-hydroxytryptamine-2A receptors in orbitofrontal, frontal medial, and cingulate cortices. These (18)F-fluorodeoxyglucose positron emission tomography changes can be considered as specific functional markers of the different behavioral presentations in fv-FTLD. The serotoninergic system dysfunction provides a rationale for therapeutic trials with selective serotonin reuptake inhibitors.

Objective: To investigate the extent and the nature of white matter tissue damage of patients with Alzheimer's disease using diffusion tensor magnetic resonance imaging (DT-MRI)., Background: Although Alzheimer's disease pathology mainly affects cortical grey matter, previous pathological and MRI studies showed that also the brain white matter of patients is damaged. However, the nature of Alzheimer's disease associated white matter damage is still unclear., Methods: Conventional and DT-MRI scans were obtained from 16 patients with Alzheimer's disease and 10 sex and age matched healthy volunteers. The mean diffusivity (D), fractional anisotropy (FA), and inter-voxel coherence (C) of several white matter regions were measured., Results: D was higher and FA lower in the corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimer's disease than in the corresponding regions from healthy controls. D and FA of the white matter of the occipital lobe and internal capsule were not different between patients and controls. C values were also not different between patients and controls for any of the regions studied. Strong correlations were found between the mini mental state examination score and the average overall white matter D (r=0.92, p<0.001) and FA (r=0.78; p<0.001)., Conclusions: White matter changes in patients with Alzheimer's disease are likely to be secondary to wallerian degeneration of fibre tracts due to neuronal loss in cortical associative areas.

Surface dyslexia is a pattern of reading impairment which has been seldom described in Italian native speakers. We report the case of a female Italian patient, RM, suffering from primary progressive aphasia (PPA) of the fluent type, who presented stress assignment errors in reading aloud. In Italian these errors are considered to be strongly suggestive of surface dyslexia. We studied RM's reading performance in light of existing cognitive models on reading. Since the first assessment, she presented multi-level impairment involving pre-semantic, lexical-semantic and post-semantic stages. Her stress assignment errors have been interpreted as a generalisation of the most frequent tendency in Italian language: namely to assign stress to the penultimate syllable. In agreement with previous studies, our case suggests that surface dyslexia in PPA is not a monolithic entity but, on the contrary, that it may arise from impairment at various stages of the reading process.

The retrospective neurological, neuroradiological and neuropsychological observation of 9 cases of dementia with frontal symptoms is reported. Aim of this paper is to contribute to the clinical corpus of data related to the frontal features of the frontotemporal dementia (FTD) syndrome, so as to support clinicians' awareness and widen the information available for the diagnostic approach to the dementias. FTD is a clinical diagnosis which does not imply a single underlying pathology, since more than one condition can induce the syndrome. Inertia and behavioural symptoms were the traits characterizing both the onset and the progression of the disease in our patients. Progression brought to the surface behavioural and neuropsychological patterns generically traced back to frontal dysfunction. Social inadequacy was the most salient trait. From a clinical point of view frontal dementias may be regarded as a conceptually different type of dementia with respect to Alzheimer's disease, i.e., a 'behavioural' as opposed to a 'cognitive' progressive disorder.

This is a prospective neuropsychological study on face processing in Alzheimer's disease (AD). The aim was to assess the prevalence and the nature of face processing disorders in AD, and at investigating possible inter-test dissociations within the framework of currently used face processing models. A standardized four-test battery of unknown face discrimination and familiar face recognition was given to 30 mildly deteriorated patients with AD. Half of the patients performed below the cut-off in at least one of the tests. Deficits in familiar face recognition tests were more frequently observed than deficits in unknown face discrimination tests. There was no correlation between impairment of face processing and overall cognitive impairment or visual disorders. A multiple single case approach allowed us to elicit statistically warranted double dissociations between tasks assessing unknown face discrimination and tasks assessing familiar face recognition. Moreover, the ability to decide whether or not a stimulus is a face or a non-face has proven to be a non-mandatory step to further process the face stimuli. All together, these findings support the hypothesis that distinct pathways are involved in the processing of unknown and familiar faces, as posited by Bruce and Young [Br. J. Psychol. 77, 305-327, 1986].

A new, short, neuropsychologically oriented test for dementia assessment--the Milan Overall Dementia Assessment (MODA)--is described. Age and education adjusted norms based on 217 healthy controls are given. A validation study on 312 outpatients suspected of dementia (121 with probable Alzheimer's disease) showed that the MODA differentiated patients with cognitive impairment from normal subjects more effectively than did the DSM III-R. The correlation between the MODA and the mini mental state examination was 0.63 in controls and 0.84 in patients with Alzheimer's dementia. The MODA test-retest reliability was 0.83. The test proved to be well suited to longitudinal studies.