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INTRODUZIONE: La letteratura internazionale mostra che il 20-40% dei pazienti con deterioramento cognitivo, ricoverati in strutture a lungo termine, può reagire durante l'assistenza infermieristica con comportamenti aggressivi come urla, minacce, calci, pugni e graffi.L'obiettivo di questo studio è quello di validare in italiano la "Care Recipient Behavior Assessment Scale" (CAREBA), uno strumento di valutazione progettato per misurare l'aggressività fisica e verbale della persona con demenza. METODI: La CAREBA è stata ritradotta attraverso uno studio osservazionale. È stato somministrato a un campione di pazienti affetti da demenza con comportamenti aggressivi fisici e/o verbali, in un ospedale del Nord Italia. Sono state valutate l'affidabilità e la validità. RISULTATI: La scala mostra una consistenza interna soddisfacente (Alpha di Cronbach = 0,79) e una validità di contenuto (CVI-S= 90%). CONCLUSIONI: La scala CAREBA è uno strumento valido e affidabile per rilevare l'aggressività nei pazienti con demenza., INTRODUCTION: The international literature shows that 20-40% of patients with cognitive impairment, hospitalized in long-term facilities, may react during nursing care with aggressive behaviors such as screaming, threats, kicks, punches and scratches. The objective of this study is to validate in Italian the "Care Recipient Behavior Assessment Scale" (CAREBA), an assessment tool designed to measure physical and verbal aggression of the person with dementia. METHODS: The CAREBA was back-translated through an observational study. It was administered to a sample of dementia patients with physical and/or verbal aggressive behaviors, conducted in a hospital in Northern Italy . Reliability and validity were assessed. RESULTS: The scale shows satisfactory internal consistency (Cronbach's Alpha = 0.79) and content validity (CVI-S= 90%). CONCLUSIONS: The CAREBA scale is a valid and reliable tool to detect aggression in patients with dementia.

Background: Physical activity in the elderly is recommended by international guidelines to protect against cognitive decline and functional impairment. Objective: This Randomized Controlled Trial (RCT) was set up to verify whether medium-intensity physical activity in elderly people living in the community is effective in improving cognitive performance. Design: RCT with parallel and balanced large groups. Setting: Academic university hospital and Olympic gyms. Subjects: People aged 65 years old and older of both genders living at home holding a medical certificate for suitability in non-competitive physical activity. Methods: Participants were randomized to a 12-week, 3 sessions per week moderate physical activity program or to a control condition focused on cultural and recreational activities in groups of the same size and timing as the active intervention group. The active phase integrated a mixture of aerobic and anaerobic exercises, including drills of “life movements”, strength and balance. The primary outcome was: any change in Addenbrooke's Cognitive Examination Revised (ACE-R) and its subscales. Results: At the end of the trial, 52 people completed the active intervention, and 53 people completed the control condition. People in the active intervention improved on the ACE-R (ANOVA: F(1;102)=4.32, p=0.040), and also showed better performances on the memory (F(1;102)=5.40 p=0.022) and visual-space skills subscales of the ACE-R (F(1;102)=4.09 p=0.046). Conclusion: A moderate-intensity exercise administered for a relatively short period of 12 weeks is capable of improving cognitive performance in a sample of elderly people who live independently in their homes. Clinical Trials Registration No: NCT03858114

INTRODUZIONE: Il bagno è una delle attività più intime durante le quali le persone affette da demenza vengono assistite. La letteratura suggerisce che il 20-40% dei pazienti con deterioramento cognitivo, ricoverati in strutture a lungo termine, può reagire con comportamenti aggressivi. OBIETTIVI: valutare l'efficacia della tecnica del bagno con asciugamano nel ridurre l'agitazione, l'aggressività e il disagio dei pazienti con demenza ricoverati in casa di cura. MATERIALI E METODI: È stato condotto uno studio crossover intenzionale; è stato arruolato un campione di pazienti con demenza. I comportamenti aggressivi sono stati valutati utilizzando la versione italiana del Care Recipient Behavior Assessment (CAREBA- ita). RISULTATI: Sono stati arruolati 71 residenti. La tecnica del bagno con l'asciugamano ha mostrato una riduzione degli episodi di aggressività e del tempo di esecuzione della procedura con una differenza statisticamente significativa (p < 0,05). CONCLUSIONI: La tecnica Towel bath fornisce una valida alternativa al bagno tradizionale per ridurre l'aggressività nei pazienti con demenza., BACKGROUND: Bathing is one of the most intimate activities during which persons with dementia are cared for. The literature suggests that 20-40% of patients with cognitive impairment, hospitalized in long-term facilities, may react with aggressive behaviours. AIM: To evaluate the efficacy of the towel bath technique in reducing agitation, aggression, and discomfort in nursing home residents with dementia. MATERIALS AND METHODS: An Inteentional crossover study was conducted; a convenience sample of patients with dementia, was enrolled. Aggressive behaviors were evaluated using the italian version of the Care Recipient Behavior Assessment (CAREBA- ita). RESULTS: 71 resident were enrolled. Towel Bath technique showed a reduction in episodes of aggression and in the execution time of the procedure with a statistically significant difference (p < 0.05). CONCLUSIONS: The technique Towel bath provides a viable alternative to traditional bath to reduce aggression in patients with dementia.

Neurodegenerative diseases are associated with the accumulation of toxic proteins in the human brain. A growing body of evidence suggests that such proteins can propagate in the brain in a prion-like fashion through the connections between neurons. The most recent evidence suggest that the clinical picture of each neurodegenerative disease might largely depend on the damage of the anatomical pathways connecting the different regions of the brain. Magnetic resonance imaging (MRI) advanced techniques, particularly diffusion tensor (DT) imaging and resting state functional MRI (RS-fMRI), allow exploring the role of network alterations in these disorders. In this dissertation, I explored network connectivity alterations in the wide spectrum of clinical presentations due to frontotemporal lobar degeneration (FTLD), including not only a range of purely cognitive disorders (i.e., frontotemporal dementia [FTD] variants), but also motor neuron disease (MND), such as amyotrophic lateral sclerosis (ALS). The overlap between ALS and FTD has been suggested not only by the presence of mixed clinical presentations, but also by common pathological and genetic determinants. In the studies here reported, volumetric techniques, DT MRI, RS-fMRI and novel connectomic approaches were employed to explore converging and diverging brain network signatures across the ALS/FTD continuum. The analysis of grey matter volumes and white matter DT MRI alterations in patients with MND revealed useful structural MRI markers of motor and cognitive progression, as well as prognostic indicators of a subsequent benign or aggressive disease course, which might be used to predict time to the development of clinical milestones. Moreover, a combined analysis of structural and functional connectomics showed extensive network reorganization both in motor and extra-motor brain regions of MND patients. When examining in detail cognitive FTD phenotypes, for each variant, we showed characteristic volumetric MRI signatures and patterns of functional network reorganization propagating from the corresponding disease epicenter. Finally, we provided further evidence supporting the notion of a continuum across FTD and MND, both in sporadic and in genetic presentations of FTLD. Taken together, our studies suggest that the assessment of network connectivity in the ALS/FTD spectrum is useful in improving our understanding of the mechanisms that link protein deposition and consequent neuronal damage to motor and cognitive symptoms in these patients. A more profound knowledge of such mechanisms will allow a better stratification of patients and an improved prognostic definition that will be vital in future clinical trials with disease modifying drugs. Le malattie neurodegenerative si associano all'accumulo di proteine tossiche nel cervello umano. Un numero sempre maggiore di evidenze suggerisce che tali proteine possano propagarsi nel cervello in maniera simil-prionica tramite connessioni interneuronali. Le evidenze più recenti suggeriscono che il quadro clinico di ciascuna malattia neurodegenerativa dipenda in larga misura dal danno delle vie anatomiche che collegano le diverse regioni cerebrali. Le tecniche avanzate di risonanza magnetica (RM), in particolare l'imaging con tensore di diffusione (DTI) e la RM funzionale in stato di riposo (RS-fMRI), permettono di esplorare il ruolo delle alterazioni dei network in queste malattie. In questa tesi, ho esplorato le alterazioni di connettività dei network nell'ampio spettro di presentazioni cliniche dovute alla degenerazione lobare frontotemporale (FTLD), che include non solo un insieme di condizioni puramente cognitive (varianti della demenza frontotemporale [FTD]), ma anche le malattie del motoneurone (MND), quale la sclerosi laterale amiotrofica (SLA). La sovrapposizione tra SLA e FTD è stata suggerita non solo dalla presenza di presentazioni cliniche miste, ma anche da fattori determinanti comuni a livello patologico e genetico. Negli studi qui riportati, sono state utilizzate tecniche volumetriche, DTI, RS-fMRI, oltre a nuovi approcci di connettomica per esplorare pattern caratteristici nei network cerebrali che convergono e divergono all'interno del continuum SLA/FTD. L'analisi dei volumi di sostanza grigia e delle alterazioni DTI della sostanza bianca in pazienti con MND hanno rivelato l'esistenza di utili marcatori RM di progressione motoria e cognitiva, nonché indicatori prognostici di un conseguente andamento benigno o aggressivo della malattia, che potrebbero essere utilizzati al fine di predire il tempo necessario per lo sviluppo di eventi di interesse clinici. Inoltre, un'analisi combinata della connettomica strutturale e funzionale ha dimostrato un'estesa riorganizzazione dei network nelle regioni sia motorie che extra-motorie dei pazienti con MND. Analizzando nel dettaglio i fenotipi FTD cognitivi, per ciascuna variante, abbiamo dimostrato l'esistenza di pattern caratteristici di RM volumetrica e di riorganizzazione dei network funzionali che si propagano dal corrispondente epicentro di malattia. Infine, abbiamo fornito maggiori evidenze a favore della nozione di un continuum tra FTD e MND, in presentazioni sia sporadiche che genetiche di FTLD. Complessivamente, i nostri studi suggeriscono che la valutazione della connettività dei network nello spettro SLA/FTD è utile al fine di migliorare la nostra comprensione dei meccanismi che mettono in relazione la deposizione proteica e il conseguente danno neuronale con i sintomi motori e cognitivi in questi pazienti. Una conoscenza più approfondita di tali meccanismi permetterà una migliore stratificazione e definizione prognostica dei pazienti che risulterà di vitale importanza in futuri trial clinici effettuati con farmaci in grado di modificare il decorso di malattia.

Parkinson’s disease (PD) is the neurological disease with the fastest growing rate. 1% of the world population over 60 years have a PD diagnosis. PD presents a complex and heterogenous clinical picture during the disease course, and dementia represents the most severe condition. This thesis investigates the neurobiological mechanisms and cognitive features of PD patients with a severe clinical phenotype – developing cognitive deterioration, reaching dementia condition. The studies included in this dissertation contributed to identifying risk factors, biomarkers, cognitive features, and sources of clinical variability of dementia in Lewy Bodies disorders (LBD) with multiple methodological approaches to neuroimaging data. Moreover, the cognitive picture of the LBD clinical spectrum has been explored by combining cross-sectional and longitudinal approaches. This dissertation provides new evidence on modifiable and non-modifiable risk factors that influence the development of severe phenotypes within LBD and those acting on the timing of dementia symptoms onset. Moreover, we identify valuable biomarker and cognitive marker candidates for dementia risk profiling since early preclinical stages. La malattia di Parkinson è la malattia neurologica con il tasso di crescita più rapida. L'1% della popolazione mondiale oltre i 60 anni ha una diagnosi di Parkinson. Il morbo di Parkinson presenta un quadro clinico complesso ed eterogeneo durante il decorso della malattia, di cui la demenza rappresenta la condizione più grave. Questa tesi indaga i meccanismi neurobiologici e le caratteristiche cognitive dei pazienti affetti da Malattia di Parkinson con un grave fenotipo clinico – che sviluppano un deterioramento cognitivo raggiungendo la condizione di demenza. Gli studi inclusi in questo elaborato hanno contribuito a identificare fattori di rischio, biomarcatori, caratteristiche cognitive e fonti di variabilità clinica della demenza nei disturbi a corpi di Lewy (LBD) con molteplici approcci metodologici ai dati di neuroimaging. Inoltre, è stato esplorato il quadro cognitivo dello spettro clinico LBD combinando approcci cross-sectional e longitudinali. Questa tesi fornisce nuove evidenze sui fattori di rischio modificabili e non modificabili che influenzano lo sviluppo di fenotipi gravi all'interno della LBD e sui fattori che agiscono sui tempi di insorgenza dei sintomi della demenza. Identifica inoltre validi candidati biomarcatori e marcatori cognitivi per la profilazione del rischio di demenza sin dalle fasi precliniche.

Nella pagine seguenti sono riportate le istruzioni di somministrazione della versione Italiana della check list RMBPC di Teri et al. (1992). Le proprietà psicometriche della versione italiana sono state descritte da Ottoboni et al. (In press).

Many areas in the cortex are active during reading of narrative material, and these activations in the brain produce significant changes in connectivity. Following previous results showing cognitive benefits in memory domains of a narrative training program in nursing home patients living with dementia, the aim of the present study was to perform a more in depth investigation of the effects of this training on memory domains and other cognitive areas. Methods: An experimental group of eight patients underwent auditory narrative training of 60 hours. At the beginning and end of the training, subjects were tested with a neuropsychological battery to quantify any improvements in individual performance. Results: The results showed a statistically significant improvement in the list learning task (immediate memory) and list learning recognition for single tasks, and a statistically significant improvement in overall cognitive area scores for immediate and delayed memory. Conclusion: Results replicate and expand our previous findings, indicating that this type of intervention can increase performance on memory-related tests. RESUMO Muitas áreas no córtex são ativos durante a leitura do material narrativa, e essas ativações no cérebro podem produzir mudanças significativas na conectividade. Na sequência dos resultados anteriores mostrando os benefícios cognitivos em domínios de memória de um programa de treinamento narrativa em pacientes do lar de idosos que vivem com demência, o objetivo do presente estudo foi realizar uma investigação mais aprofundada dos efeitos desta formação sobre os domínios de memória e outras áreas cognitivas. Métodos: Um grupo experimental de oito pacientes foram submetidos a treinamento narrativa auditivo de 60 horas. No início e no final do treinamento, os participantes foram testados com uma bateria neuropsicológica para quantificar quaisquer melhorias no desempenho individual. Resultados: Os resultados mostraram uma melhoria estatisticamente significativa na tarefa lista de aprendizagem (memória imediata) e reconhecimento lista de aprendizagem para tarefas individuais e uma melhoria estatisticamente significativa na pontuação da área cognitivas gerais para a memória imediata e tardia. Conclusão: Replicar os resultados e expandir nossas descobertas anteriores, indicando que este tipo de intervenção pode aumentar o desempenho em testes relacionados à memória.

The Tower of London (ToL) is a problem-solving task, which is a valuable tool for the neuropsychological examination of a patient with a possible cognitive decline. The aim of the present study was to evaluate the ToL in comparison to the Mini Mental State Examination (MMSE) in a group of older people with or without dementia.Seventy outpatients of both sexes, 30 with low-moderate dementia and 40 with apparently normal cognition were evaluated with the MMSE and the ToL task in the same day. The ToL score was calculated according to the Krikorian method and also the execution time was measured. The differences between groups were assessed with the unpaired t-test, and the relationship between two parameters was assessed with the analysis of the coefficient of linear regression. The results were adjusted for age and education.The evaluation of cognitive impairment by MMSE showed a significant difference in the two groups (p0.001). The mean scores (p0.001) and execution times (p0.05) of the ToL, resulted significantly lower in the patients affected by dementia. However, seven participants with dementia had a normal score in the ToL test, indicating that the executive neuropsychological tasks could be preserved notwithstanding the cognitive decline and nine participants with normal MMSE obtained a low ToL score, suggestive of the higher sensibility of the ToL for the executive task that reveals an unknown cognitive deficit.The correlation between MMSE and ToL is good, but ToL test provides complementary information to the MMSE and vice versa.

Background: Postmarketing surveillance studies (PMS) are an important tool for evaluating a drug’s effectiveness and safety in clinical practice. To our knowledge, no PMS on memantine monotherapy for moderately-severe-to-severe Alzheimer’s disease (AD) according to National Institute of Neurological and Communicative Disorders and Stroke — Alzheimer’s Disease and Related Disorders Association criteria has been conducted to date. Objective: The Lombardy Health Office, Italy, promoted this PMS to evaluate the effectiveness and safety of memantine in the treatment of moderately-severe-to-severe AD in clinical practice. Methods: A total of 451 patients with moderately-severe-to-severe AD (mean age 77 ± 7 years; 72% female), free of cholinergic medication, received memantine (standard titration to 10 mg twice daily). After 6 months of therapy, treatment effectiveness was evaluated according to two definitions of response (‘no deterioration’ and ‘improvement’), as measured by changes in baseline scores on the Clinical Global Impression of Change, Mini-Mental State Examination, Neuropsychiatric Inventory and Activities of Daily Living scales. The safety measure was the frequency of adverse events (AEs). Results: At 6-month assessment, 26.8% of subjects showed no deterioration and 3.8% showed improvement. In those showing no deterioration, response to treatment at the 3-month assessment was associated with a greater probability of a response at 6 months (adjusted odds ratio = 8.54; 95% CI 4.54, 16.05). Seventy patients (15.5%) experienced at least one AE and 39 (8.6%) discontinued treatment prematurely because of an AE. Of those who experienced an AE, 27 (38.6%) manifested behavioural and psychological symptoms of dementia. Conclusion: The proportion of responders to memantine treatment in this PMS was similar to that reported in a previous randomized clinical trial (26.8% vs 29%, respectively). The proportion of patients who discontinued treatment prematurely because of an AE (8.6%) was similar to that reported in two previous randomized clinical trials (10% and 12.4%). This PMS provides additional evidence that both the effectiveness and the tolerability of memantine may be transferred into real world medicine, where AD patients receiving treatment are not selected according to strict criteria.

Background and Aim: To investigate the role of vascular risk factors in different subtypes of mild cognitive impairment (MCI) in a multicentric, clinic-based, cross-sectional study. Methods: Two-hundred and seven subjects with MCI were included in the study: 33 with single non-memory MCI (snmMCI), 42 with multiple-domain amnestic MCI (mdMCI-a) and 132 with amnestic MCI (aMCI). Several clinical vascular risk factors and magnetic resonance imaging (MRI) brain lesions were evaluated. Results: snmMCI showed a higher frequency of ischaemic heart disease and of transient ischaemic attack (TIA)/stroke, a higher Hachinski ischaemic score and a higher frequency of white-matter lesions on MRI compared to aMCI. Subjects with mdMCI-a showed clinical characteristics similar to aMCI, except for a higher frequency of a history of TIA/stroke. Conclusion: Our findings suggest that snmMCI may be considered a vascular cognitive disorder.

Background A new locus for amyotrophic lateral sclerosis – frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p. Methods We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus. Results Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples. Conclusion Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.

Non-verbal pain assessment scales are useful tools for pain evaluation in persons with communication disorders and moderate-severe dementia. The Doloplus (R) was one of the first scales to be developed and validated as a pain assessment tool in older adults with dementia. This study aims at evaluating the translation of the Doloplus (R) scale in five languages, as regards test-retest and inter-rater reliability. Results show that both tests are good or excellent for the English, Italian, Portuguese and Spanish versions and moderate for the Dutch version. These results bring a unique opportunity to include the translated Doloplus (R) scale in daily assessment of elderly persons with communication disorders, and future studies should focus on enriching the validation of the scale in each language.

The objective of this study was to verify the adherence of Italian family physicians and neurologists to the Guidelines on Diagnosis of Dementia of the Italian Society of Neurology. A multicentre survey was carried out, in 72 neurological centres. The centres included at least 15 consecutive subjects suspected of having a dementia. The adherence of family physicians to the guidelines was poor. Neurologists performed a complete neuropsychological evaluation in a minority of the cases. Patients who had a decrease of Mini Mental Status Examination scores after six months higher than or equal to 4 were more represented among those patients for whom one or more recommendations were not respected. In Italy the adherence to the Guidelines on Diagnosis of Dementia and AlzheimerValidation studys Disease of the Italian Society of Neurology is very poor for family physicians (GPs) and satisfactory, albeit improvable, on the part of neurologists. Respect for the guidelines might improve the outcome of patients with dementia.