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Bussè, Cinzia (2017) Cognitive and clinical phenotype in dementia with Lewy bodies. [Ph.D. thesis]

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Abstract (italian or english)

This dissertation describes the research studies I have most occupied during my Ph. D course. Due to the limited number of studies addressing which clinical and cognitive features are most useful in diagnosing early dementia with Lewy bodies (DLB) (Jicha et al. 2010; Boeve et al. 2012) I initially focused on the visuo-constructional impairments in prodromal DLB (study 1); afterwards on visual-spatial and visual-perceptual deficits (study 2) in a different sample of prodromal DLB. Later I investigated which cognitive impairments could be predictive of DLB in regards to the memory domain (Study 3 and 4). Here below the abstract for each study.

Study 1. Assessment of visual-constructional deficits in MCI-DLB.
Introduction: Visual-constructional deficits are a prominent feature of dementia with Lewy bodies (DLB) that may contribute to the differential diagnosis with Alzheimer's Disease (AD). The analysis of the pentagon copy included in the MMSE could be a promising tool for the diagnosis of DLB since its early stages (Ala et al. 2001).
Aim: To assess the pentagon copy performance in prodromal stage of DLB with the Qualitative Scoring MMSE Pentagon Test (QSPT) (Caffarra et al., 2013).
Methods: 30 patients with non amnestic-Mild Cognitive Impairment diagnosed as prodromal DLB (MCI-DLB) and 23 patients with amnestic-MCI diagnosed as prodromal AD (MCI-AD) were enrolled. All patients obtained a MMSE score ≥ 26/30. The diagnosis of DLB and AD was confirmed at 3-year follow-up visit according to established criteria. Each MMSE test was examined with the QSPT which is based on the assessment of different parameters of the pentagon drawing. A broad standard neuropsychological assessment was also performed.
Results: The percentage of subjects who were unable to determine the correct number of angles in the pentagon copy test was 45.1% of MCI-DLB and 8.3% of MCI-AD patients (sensitivity 41.1%; specificity 91%). Attentive/executive functions and visual-spatial abilities were worse in the MCI-DLB group, while episodic memory impairment was greater in MCI-AD. Subtle extrapyramidal signs (63%) and RBD symptoms (56%) were the most frequent clinical features supporting the diagnosis of MCI-DLB.
Conclusions: We suggest that a poor performance in determining the number of angles when performing the pentagon copying test, together with the presence of subtle extrapyramidal signs and symptoms of RBD may serve as a predictive tool for early DLB.
Output of the study: This study has been published in parkinsonism and Related Disorders, 21(3), 303–305. (2015). High specificity of MMSE pentagon scoring for diagnosis of prodromal dementia with Lewy bodies. Cagnin, A., Bussè, C., Jelcic, N., Gnoato, F., Mitolo, M., & Caffarra, P.
Study 2. Assessment of visual attention, visual-spatial and visual-constructional deficits in MCI-DLB.
Background: Patients with prodromal dementia with Lewy bodies (DLB) may display a different cognitive pattern from Alzheimer's disease (AD) with more severe impairment of attentive and visuo-spatial abilities (Mc Keith, 2005).
Objective: to investigate which cognitive functions could be predictive of the diagnosis of DLB and AD in patients with mild cognitive impairment (MCI).
Methods: Fifty-three patients with MCI were followed over 3-years until a diagnosis of DLB (MCI-DLB: n=25) and AD (MCI-AD: n=28) were made according to standard criteria. At the first assessment patients underwent a thorough cognitive assessment, including MMSE-QSPT (Caffarra, 2013;), attention, memory, executive functions, constructive apraxia, visuo-perceptual abilities (VOSP battery).
Results: The best clinical predictor of DLB was the presence of soft extrapyramidal signs (mean UPDRS score: 4.04 ± 5.9) detected in 72% of patients, followed by REM sleep behavior disorder (60%) and fluctuations (60%). Wrong performances in the pentagon’s number of angles were obtained in 44% of DLB and 3.7% of AD patients and correlated with speed of visual attention. Executive functions, visual attention and visuospatial abilities were worse in DLB, while verbal episodic memory impairment was greater in AD. Deficits in the visual-perceptual domain were present in both MCI-DLB and AD.
Conclusions: Poor performance in the pentagon’s number of angles is specific of DLB and correlates with speed of visual attention. The dorsal visual stream seems specifically more impaired in MCI-DLB with respect to the ventral visual stream, the latter being involved in both DLB and AD. These cognitive features, associated with subtle extrapyramidal signs, should alert clinicians to a diagnostic hypothesis of DLB.
Output of the study: This study has been published in Dementia and Geriatric Cognitive Disorders Extra 2015. Clinical and Cognitive Phenotype of Mild Cognitive Impairment Evolving to Dementia with Lewy Bodies. Cagnin, A., Bussè, C., Gardini, S., Jelcic, N., Guzzo, C., Gnoato, F., et al. 5 (3), 442–9.

Study 3. Analysis of memory domain: specific verbal memory indices of the Rey’s Auditory Verbal Learning Test.
Introduction: Several neuropsychological tests exploring episodic memory can’t always give a careful contribution to the differential diagnosis of degenerative diseases. The serial position effects, rather than the traditional scores, along with some important learning characteristic measures, could contribute to address towards a specific type of dementia.
Objective: To comprehend if any of the specific measures of verbal memory obtained with the RAVLT, as the verbal learning (VL), verbal forgetting (VF) and the serial position effects, could be of value in distinguishing DLB from AD.
Method: thirty-two AD and twenty-nine DLB patients were enrolled in the study and followed longitudinally for 3 years until the diagnosis was made according standard criteria. Twenty-eight normal elderly subjects served as controls. All subjects underwent baseline neuropsychological assessment including RAVLT. Specific verbal memory measures were evaluated: verbal learning (VL) [immediate recall test: trial 5 minus trial 1], verbal forgetting (VF) [trial 6 of delayed recall minus trial 5 of immediate recall], percentage of verbal forgetting (VF%) [% verbal forgetting/trial 5] and the serial position effects of immediate recall (trial 1).
Results: The performances of DLB and AD were comparable in the immediate and delayed recall of the RAVLT (IC=95%). However, VL was higher in DLB than AD (DLB=0.25±0.1, AD=0.19±0.1; p<0.05) while VF% was greater in AD (AD=65.85%±41.3, DLB=42.97±33.0%; p=0.001). Logistic regression analysis showed that VF% may be considered a predictive marker of disease group allocation (T=-0.02, Wald (1)=4.85, p=0.03). With a VF% cut-off ≥75%, AD and DLB patients were differently distributed (Choerish=5.1), being 58% of AD versus 21% of DLB above this cut-off. Considering the serial position effects, recency effect was significant higher in AD than DLB (AD=2.09±1.1, DLB=1.34±1.2; p<0.05). Number of recalled words in the recency domain correlated positively with scores of the digit span backward test (r=0.54, p=0.005) and digit span forward (r=0.25, p=0.02) only in DLB (digit span backward: AD: r=0.88, p=0.88; NC: r=-0.02, p=0.94; digit span forward: AD: r=0.12, p=0.52; NC: r=0.24; p=0.22).
Discussion: DLB patients showed different memory performances from AD at the RAVLT. In details, DLB had better performances of verbal learning and worse verbal forgetting and recency effect. These specific measures of verbal memory could be used as diagnostic marker in the differential diagnosis between DLB and AD.
Output of the study: This study is in submission.

Study 4. Analysis of memory domain in mild cognitive impairment: investigating the efficacy of the Free and Cued Selective Reminding Test (FCSRT).
Objective: The main goal was to comprehend the efficacy of the Free and Cued Selective and Reminding Test (FCSRT) in differentiating patients with mild cognitive impairment converting to dementia with Lewy bodies (MCI-DLB) from patients with MCI due to Alzheimer’s disease (MCI-AD).
Materials and methods: Thirty-five participants with MMSE≥26 were included in the study. Fifth-teen were diagnosed as probable DLB (MCI-DLB: n=15) and twenty as probable AD (MCI-AD: n=20) according to current criteria (Ferman et al. 2013; Albert et al. 2011). Patients underwent a comprehensive cognitive evaluation including the FCSRT for the episodic memory assessment.
Results: At the FCSRT, MCI-DLB were significantly more spared than MCI-AD regarding the total memory recall (ITR) and the index of sensitivity of cueing (ISC) (ITR: DLB=35.13±1.26, AD=29.95±1.08, p=0.01; ISC: DLB=0.94±0.04, AD=0.76±0.04, p=0.00). Moreover, MCI-DLB performed worse than MCI-AD in digit cancellation task (DLB=45.49±1.43; AD=49.83±1.22; p=0.03), number of angles of Mini Mental (MMSE) pentagons copy (DLB=3.11±0.17; AD=3.72±0.15; p=0.01) and Rey figure copy (DLB=23.77±1.47; AD= 27.90±1.26; p= 0.05).
Discussion: At early stage DLB showed to benefit more than AD from the controlled learning through category cues, exhibiting a greater ISC. MCI-DLB showed poorer performances in attentive and visuo-constructional tasks respect to AD.
Conclusions: The FCSRT has shown its utility in the distinction between DLB and AD at early stage increasing the diagnostic accuracy. Moreover, since the main characteristic of the FCSRT is to assess verbal episodic memory isolating the storage capacities of the patients, we exclude a storage memory impairment in MCI-DLB patients.
Output of the study: This study is in preparation.


Abstract (a different language)

Studio 1. Valutazione dei deficit visuo-costruttivi in MCI-DLB.
Background: I deficit visuo-costruttivi sono caratteristiche prominenti nella demenza a corpi di Lewy (DLB) che possono contribuire a una diagnosi differenziale con la malattia di Alzheimer (AD). L’analisi della copia dei pentagoni crociati del MMSE può essere uno strumento promettente per la diagnosi di DLB sin dalle prime fasi di malattia (Ala et al. 2001).
Obiettivo: valutare le prestazioni di copia dei pentagoni in fase prodromica di DLB con il Qualitative Scoring MMSE Pentagon Test (QSPT) (Caffarra et al., 2013).
Metodi: 30 pazienti con decadimento cognitivo lieve non amnestico diagnosticati come DLB prodromico (MCI-DLB) e 23 pazienti con MCI amnesico diagnosticati come AD prodromico (MCI-AD) sono stati arruolati nello studio. Tutti i pazienti hanno ottenuto un punteggio MMSE ≥ 26/30. La diagnosi di DLB e AD è stata confermata al follow-up a 3 anni sulla base dei criteri clinici stabiliti. Ogni performance al MMSE è stata esaminata con il QSPT che si basa sulla valutazione di diversi parametri del disegno dei pentagoni. Una estesa valutazione neuropsicologica standard è stata inoltre eseguita.
Risultati: La percentuale di soggetti non in grado di determinare il corretto numero di angoli nel test copia dei pentagoni è stato 45,1% di MCI-DLB e il 8,3% dei pazienti MCI-AD (sensibilità 41,1%; la specificità 91%). Le funzioni attentive / esecutive e le abilità visuo-spaziali erano peggiori nel gruppo MCI-DLB, mentre la memoria episodica è stata maggiormente deteriorata in MCI-AD. Segni extrapiramidali sottili (63%) e sintomi RBD (56%) sono state le caratteristiche cliniche più frequenti a supporto della diagnosi di MCI-DLB.
Conclusioni: Suggeriamo che un scarso rendimento nel determinare il numero corretto di angoli durante l'esecuzione del test di copia dei pentagoni, insieme con la presenza di segni extrapiramidali sottili e sintomi di RBD, può servire come strumento predittivo per l'inizio di DLB.
Output: Parkinsonism and Related Disorders, 21(3), 303–305. (2015). High specificity of MMSE pentagon scoring for diagnosis of prodromal dementia with Lewy bodies. Cagnin, A., Bussè, C., Jelcic, N., Gnoato, F., Mitolo, M., & Caffarra, P.
Studio 2. Valutazione di attenzione visiva, deficit visuo-spaziale e visivo-costruttive in MCI-DLB.
Background: Nei pazienti con malattia con corpi di Lewy (DLB) in fase prodromica è possibile visualizzare un modello cognitivo diverso da malattia di Alzheimer (AD) con deterioramento più marcato delle capacità attentive e visuo-spaziali (Mc Keith, 2005).
Obiettivo: indagare quali funzioni cognitive potrebbero essere predittive della diagnosi di DLB e AD in pazienti con decadimento cognitivo lieve (MCI).
Metodi: Cinquanta-tre pazienti con MCI sono stati seguiti nel corso di 3 anni fino a quando le diagnosi di DLB (MCI-DLB: n = 25) e AD (MCI-AD: n = 28) sono state effettuate secondo criteri standard. Ai primi pazienti sono stati sottoposti a una valutazione approfondita cognitiva, tra cui MMSE-QSPT (Caffarra, 2013;), l'attenzione, la memoria, funzioni esecutive, aprassia costruttiva, le abilità visuo-percettivo (VOSP batteria).
Risultati: Il miglior predittore clinico della DLB è stata la presenza di sottili segni extrapiramidali (UPDRS punteggio medio: 4.04 ± 5.9) rilevata nel 72% dei pazienti, seguiti da disturbo del comportamento del sonno REM (60%) e le fluttuazioni (60%). Errate performances nel numero del degli angoli dei pentagoni crociati sono stati ottenute nel 44% dei DLB e il 3,7% dei pazienti affetti da AD e correlati con la velocità di attenzione visiva. Funzioni esecutive, attenzione visiva e le abilità visuo-spaziali erano peggiori in DLB, mentre un deficit della memoria episodica è stata maggiore in AD. I deficit nel dominio visuo-percettivo erano presenti in entrambi MCI-DLB e AD.
Conclusioni: Scarso rendimento nel numero di angoli dei pentagoni è specifico di DLB e correla con la velocità di attenzione visiva. La via visiva dorsale sembra specificamente più ridotta in MCI-DLB rispetto alla visiva ventrale, quest'ultima coinvolta sia in DLB che in AD. Queste caratteristiche cognitive, associate a segni extrapiramidali sottili, devono orientare gli specialisti verso una ipotesi diagnostica di DLB.
Output: Dementia and Geriatric Cognitive Disorders Extra 2015. Clinical and Cognitive Phenotype of Mild Cognitive Impairment Evolving to Dementia with Lewy Bodies. Cagnin, A., Bussè, C., Gardini, S., Jelcic, N., Guzzo, C., Gnoato, F., et al. 5 (3), 442–9.
Studio 3. Analisi del dominio menstico: specifici indici di memoria verbale di Auditory Verbal Learning Test di del Rey.
Introduzione: Diversi test neuropsicologici che esplorano la memoria episodica non possono sempre dare un contributo attento alla diagnosi differenziale delle malattie degenerative. Gli effetti di posizione seraile, piuttosto che i punteggi tradizionali, insieme ad alcune importanti misure di apprendimento, potrebbero contribuire a indirizzare verso un tipo specifico di demenza.
Obiettivo: comprendere se una qualsiasi delle specifiche misure di memoria verbale ottenute con la RAVLT, come l'apprendimento verbale (VL), oblio verbale (VF) e gli effetti di posizione di serie, potrebbe essere di valore nel distinguere DLB da AD.
Metodo: trentadue AD e ventinove pazienti DLB sono stati arruolati nello studio e seguiti longitudinalmente per 3 anni fino a quando la diagnosi è stata fatta secondo criteri standard. Ventotto normali soggetti anziani sono serviti come controlli. Tutti i soggetti sono stati sottoposti valutazione neuropsicologica di base tra cui RAVLT. Sono stati valutati specifiche misure di memoria verbale: apprendimento verbale (VL) [Test immediato richiamo: trial 5 prova meno 1], l'oblio verbale (VF) [studio 6 di richiamo ritardato processo meno 5 di richiamo immediato], percentuale di oblio verbale (VF% ) [% verbale oblio / trial 5] e gli effetti di posizione di serie di richiamo immediato (prova 1).
Risultati: Le prestazioni di DLB e AD erano comparabili nel richiamo immediato e ritardato del RAVLT (IC = 95%). Tuttavia, VL era più alta nel DLB di AD (DLB = 0.25 ± 0.1, AD = 0,19 ± 0,1; p <0.05), mentre VF% era maggiore in AD (AD = 65.85% ± 41.3, DLB = 42.97 ± 33,0%; p = 0,001). L'analisi di regressione logistica ha mostrato che VF% può essere considerato un marker predittivo di allocazione gruppo malattia (T = -0.02, Wald (1) = 4,85, p = 0,03). Con cut-off ≥75% VF%, DLB AD e sono stati diversamente distribuiti (Choerish = 5.1), essendo il 58% di AD contro il 21% di DLB di sopra di questo cut-off. Considerando gli effetti di posizione seriali, un effetto recency era significativamente più alto in AD rispetto a DLB (AD = 2.09 ± 1.1, DLB = 1.34 ± 1.2; p <0.05). Il numero di parole richiamate nel dominio recency correlava positivamente con i punteggi del test all'indietro digit span (r = 0.54, p = 0.005) e digit span avanti (r = 0.25, p = 0.02) solo in DLB (digit span all'indietro: AD: r = 0.88, p = 0.88; NC: r = -0.02, p = 0,94; digit span avanti: AD: r = 0,12, p = 0,52; NC: r = 0.24; p = 0.22).
Discussione: I pazienti DLB hanno mostrato diverse prestazioni di memoria al RAVLT rispetto ai pazienti AD. Nel dettaglio, pazienti conDLB avevano migliori prestazioni di apprendimento verbale, peggiore oblio e scarso effetto recency. Queste misure specifiche di memoria verbale potrebbero quindi essere utilizzate come marker diagnostico nella diagnosi differenziale tra DLB e AD.
Output: Questo studio stato sottomesso.
Studio 4. Analisi del dominio mnestico nel deficit cognitivo lieve: indagare l'efficacia del Free and Cued Selective Reminding Test (FCSRT).
Obiettivo: L'obiettivo principale era quello di capire l'efficacia del Free and Cued Selective and Reminding Test (FCSRT) nel differenziare i pazienti con decadimento cognitivo lieve prodromico per corpi di Lewy (MCI-DLB) da pazienti con MCI prodromico per malattia di Alzheimer (MCI-AD).
Materiali e metodi: Trentacinque partecipanti con MMSE≥26 sono stati inclusi nello studio. Quindici sono stati diagnosticati come probabile DLB (MCI-DLB: n = 15) e venti come probabile AD (MCI-AD: n = 20) secondo i criteri clinici (Ferman et al 2013; Albert et al 2011.). I pazienti sono stati sottoposti a una valutazione cognitiva globale che includeva FCSRT per la valutazione della memoria episodica.
Risultati: Al FCSRT, le prestazioni dei pazienti MCI-DLB erano significativamente più risparmiate di MCI-AD per quanto riguarda il richiamo totale di memoria (ITR) e l'indice di sensibilità ai cues (ISC) (ITR: DLB = 35.13 ± 1.26, AD = 29,95 ± 1,08, p = 0.01; ISC: DLB = 0.94 ± 0.04, AD = 0,76 ± 0,04, p = 0,00). Inoltre, MCI-DLB avevano prestazioni peggiori rispetto a MCI-AD nel task di cancellazione cifre (DLB = 45.49 ± 1.43; dC = 49.83 ± 1.22; p = 0.03), nel numero di angoli dei pentagoni crociati del Mini Mental (MMSE) (DLB = 3.11 ± 0.17 ; dC = 3.72 ± 0.15; p = 0.01) e nella copia di figura Rey (DLB = 23.77 ± 1.47; dC = 27.90 ± 1.26; p = 0.05).
Discussione: In fase precoce, i pazienti con DLB ha dimostrato di beneficiare più dei pazienti MCI-AD dell’apprendimento controllato attraverso i cues semantici, esibendo una performance normalizzante all’indice di sensibilità ISC. MCI-DLB erano inoltre più scarsi nei compiti attentivi e visuo-costruttivi rispetto ad AD.
Conclusioni: Il FCSRT ha dimostrato la sua utilità nella distinzione tra DLB e AD in fase precoce aumentando l'accuratezza diagnostica. Inoltre, dal momento che la caratteristica principale del FCSRT è quella di valutare la memoria episodica verbale a codifica controllata (isolando, pertanto, le capacità di immagazzinamento delle informazioni), è possibile orientarsi ad una comprensione del deficit di memoria dei pazienti MCI-DLB, escludendo pertanto un coinvolgimento a livello delle prime fasi del processo di apprendimento (immagazzinamento).
Output of the study: Questo studio è in fase di preparazione.

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EPrint type:Ph.D. thesis
Tutor:Semenza, Carlo
Ph.D. course:Ciclo 29 > Corsi 29 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI
Data di deposito della tesi:31 January 2017
Anno di Pubblicazione:31 January 2017
Key Words:Lewy Body Disease, Alzheimer Disease, Episodic memory, Visuo-spatial abilities, Cognitive Impairments
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/26 Neurologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Dipartimenti > Dipartimento di Neuroscienze
Codice ID:10264
Depositato il:17 Nov 2017 09:31
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