Istituto di Gerontologia e Geriatria Università degli Studi di Perugia

Presentazione sul tema: "Istituto di Gerontologia e Geriatria Università degli Studi di Perugia"— Transcript della presentazione:

1 Istituto di Gerontologia e Geriatria Università degli Studi di Perugia
La Demenza con corpi di Lewy: diagnosi e trattamento Patrizia Mecocci Istituto di Gerontologia e Geriatria Università degli Studi di Perugia Ferrara, 26 ottobre 2012

2 La DLB rappresenta la seconda causa più comune di demenza degenerativa nella popolazione anziana dopo la demenza di Alzheimer William Utermohlen Jim Dine

3 AD DLB Prevalenza nella popolazione: 0-5%
Prevalenza nei soggetti affetti da demenza: % Secondo la review condotta da Zaccai e coll. (2005), dove sono stati presi in considerazione solo gli studi in cui erano pienamente soddisfatti i criteri di inclusione per la diagnosi di DLB elaborati nel 1996 da McKeith e coll., la prevalenza della DLB oscilla tra lo 0 ed il 5% nella popolazione generale e dallo 0 al 30.5% all’interno dei pazienti affetti da demenza. The Cache County Study di Meich e coll., ha dimostrato che il tasso d’incidenza annuale della DLB è pari allo 0.15% nella popolazione generale e al 3.2% di tutti i nuovi casi di demenza (2002). Secondo McKeith e coll., il 7% della popolazione generale sopra i 65 anni è affetta da DLB fino ad arrivare al 30% dei soggetti con età superiore agli 80 anni. Nello studio di popolazione finlandese condotto da Rahkonen e coll. (2003), la prevalenza della DLB nei soggetti sopra i 75 anni è pari al 5% e rappresenta il 22% di tutti i casi si demenza. The Islington Study condotto nel Regno Unito nel 2002 da Stevens e coll. ha dimostrato che la DLB rappresenta l’11% di tutti i casi di demenza nei soggetti con età superiore ai 65 anni. Nonostante i numerosi sforzi di identificare criteri diagnostici sempre più accurati e specifici per porre una corretta diagnosi di DLB, i tassi di prevalenza della DLB risultano esser inferiori fino al 50% rispetto ai tassi di DLB identificati post-mortem nel corso di autopsia. Secondo alcuni dati riportati in letteratura, la prevalenza di DLB stimata nel corso di autopsia oscilla tra il 15 ed il 25% (Heidebrink 2002), confermando che la DLB rappresenta la seconda causa più frequente di demenza degenerativa nella popolazione anziana Incidenza nella popolazione: 0.1% l’anno Incidenza nei soggetti affetti da demenza: 3.2% l’anno Zaccai et al., A systematic review of prevalence and incidence studies of dementia with Lewy bodies, Age and Ageing 2005; 34: 561–566

4 I corpi di Lewy Dr. Friederich Lewy, 1912
La DLB si caratterizza da un punto di vista istopatologico dall’accumulo all’interno delle cellule neuronali e gliali di aggregati insolubili di alfa-sinucleina denominati corpi di Lewy e neuriti di Lewy. L’alfa-sinucleina è una proteina sinaptica implicata nel produzione delle vescicole.

5 La formazione dei corpi di Lewy: possibili meccanismi
La DLB si caratterizza da un punto di vista eziopatogenetico dall’accumulo all’interno delle cellule neuronali e gliali di aggregati insolubili di alfa-sinucleina denominati corpi di Lewy e neuriti di Lewy. L’alfa-sinucleina è una proteina sinaptica implicata nel produzione delle vescicole. Analogamente al PDD, dove l’accumulo di aggregati insolubili di tale proteina è riconducibile alla triplicazione del gene SCNA (gene dell’alfa sinucleina), nella DLB la raccolta anomala dell’alfa sinucleina si realizza anche per l’incremento dell’espressione dell’mRNA del gene SCNA. Un altro possibile meccanismo eziopatogenetico alla base dell’accumulo dell’alfa sinucleina è rappresentato da un anomalo catabolismo dovuto alla disfunzione del sistema dei proteosomi, con la produzione finale di “protofibrille” ad azione neurotossica. Il sequestro di tali protofibrille e la conseguente formazione dei corpi di Lewy potrebbe esser il meccanismo mediante il quale le cellule neuronali tentano di arginare lo stress biologico esercitato da tali accumuli. Erikersen et al., Caught in the act: alfa sinuclein is the culprit in Parkinson’s Disease. Neuron., vol. 40, , 2003

6 La formazione dei corpi di Lewy: possibili meccanismi
proposed aggresome-related model underlying the formation of Lewy bodies. Under normal physiological conditions, there is a dynamic balance between the production of unwanted proteins and their degradation by the ubiquitin–proteasome system (UPS) in conjunction with heat shock proteins (HSPs). In PD, proteolytic stress is induced as a result of impaired degradation or excess production of unwanted proteins (mutant, misfolded, denatured, and damaged proteins). These proteins begin to accumulate and aggregate and are actively transported along microtubules to the perinuclear centrosome, which contains tubulin and pericentrin. Other factors, such as ubiquitin (Ub), are also recruited to the centrosome to facilitate degradation of sequestered proteins. Sequestered components are encased by cytoskeletal elements such as neurofilaments to form an aggresome with a distinct core and a peripheral halo. If sequestered proteins are successfully degraded, proteolytic equilibrium is restored. However, if the proteolysis in aggresomes fails as a result of defects in the protein degradation machinery or the overwhelming production of abnormal proteins, the aggresome continues to expand and form an insoluble mass of proteins—a Lewy body Olanow et al., Lewy-body formation is an aggresome-related process: a hypothesis; The Lancet, Neurology Vol

7 Demenza con corpi di Lewy Complesso Parkinson-Demenza
Le sinucleinopatie Malattia di Parkinson Demenza con corpi di Lewy Complesso Parkinson-Demenza

8 McKeith IG et al. 2005

9 Segni Extrapiramidali
La Sequenza Temporale Segni Extrapiramidali Demenza «The 1-year Rule»

10 Demenza «Central feature»
- fluttuazione delle performance cognitive, soprattutto dell’attenzione - ricorrenti allucinazioni visive - segni di parkinsonismo «Core features» DLB PROBABILE: demenza + 2 delle «core features» oppure demenza +1 «core features» e almeno 1 «suggestive criteria» Demenza «Central feature» DLB POSSIBILE: Demenza + 1 delle «core features» o demenza + 1 dei «suggestive criteria» -cadute frequenti -sincopi -disautonomia -allucinazioni in altre modalità sensoriali, -depressione, -neuroimaging «Supportive Criteria» - disturbi del sonno REM severa ipersensibilità ai neurolettici tipici ed atipici, basso uptake della dopamina a livello dei nuclei della base (DAT-SCAN) «Suggestive criteria» L’età di insorgenza della DLB oscilla dai 50 agli 85 anni, con un media di 68 anni. I criteri diagnostici per identificare la DLB sono stati formulati per la prima volta nel corso del First International Workshop del Consortium sulla Demenza a corpi di Lewy (Ian McKeith, Galasko, Kosaka) tenutosi nel 1996 e comprendono la presenza di demenza (definita come progressivo declino cognitivo con compromissione della memoria, delle abilità visuo-spaziali, dell’attenzione e delle funzioni esecutive con conseguente riduzione dell’autonomia funzionale), fluttuazione delle performance cognitive, soprattutto dell’attenzione, ricorrenti allucinazioni visive strutturate e segni di parkinsonismo. La diagnosi di demenza rappresenta la caratteristica centrale essenziale per la diagnosi di DLB probabile o possibile. La fluttuazione dell’attenzione, le allucinazioni visive ed il parkinsonismo appartengono al nucleo delle caratteristiche sufficienti per la diagnosi di DLB; se, oltre alla demenza, sono presenti due caratteristiche su tre è legittimo porre la diagnosi di DLB probabile, mentre se è presente una sola caratteristica si pone il sospetto di DLB possibile. In relazione al riscontro di un accettabile specificità ma di una sensibilità subottimale di tali criteri per la diagnosi di DLB probabile, nel 2003 è stato organizzato il terzo International Workshop del Consortium sulla DLB nel corso del quale sono stati rielaborati nuovi criteri diagnostici della DLB mediante l’introduzione di nuovi segni clinici. Alla caratteristica centrale della demenza ed al nucleo delle manifestazioni sufficienti per la diagnosi di DLB (parkinsonismo, fluttuazione ed allucinazioni) sono state aggiunte diverse caratteristiche cliniche distinte in due macro-categorie: le manifestazioni cliniche suggestive di DLB (disturbi del sonno REM, severa ipersensibilità ai neurolettici tipici ed atipici, basso uptake della dopamina a livello dei nuclei della base documentato mediante DAT-SCAN) le quali contribuiscono alla diagnosi di DLB probabile solo in presenza della demenza e del nucleo centrale delle manifestazioni cliniche sopra citate, e le manifestazioni cliniche che supportano una diagnosi di DLB, comunemente presenti ma senza un’elevata specificità diagnostica (cadute frequenti, ricorrenti transitorie perdita di coscienza e sincopi, disautonomia, allucinazioni in altre modalità sensoriali, depressione, relativa conservazione delle strutture del lobo temporale valutata mediante TC o RMN encefalo, basso uptake del metabolita attivo alla SPECT/PET-TC con riduzione dell’attività occipitale, basso uptake del radiometabolita alla scintigrafia miocaridica MIBG, anomalo EEG con predominante attività ad onda lenta e transitori complessi punte-onda nel lobo temporale, deliri). Qualora la presentazione clinica comprenda, oltre alla demenza, esclusivamente una o più caratteristiche cliniche suggestive in assenza di allucinazioni, fluttuazione e parkinsonismo può esser posta una diagnosi di DLB possibile. Nel corso della revisione dei criteri diagnostici, particolare enfasi è stata posta alla sequenza temporale tra la manifestazione clinica dei disturbi extrapiramidali e la demenza. La diagnosi di DLB dovrebbe esser posta qualora i segni di parkinsonismo si manifestino prima, contemporaneamente o entro un anno dalla diagnosi di demenza; se invece la demenza si instaura nel contesto di una PD con disturbi extrapiramidali stabilizzati da più di 12 mesi, dovrebbe esser posta la diagnosi di PDD. Tuttavia, la distinzione tra PDD e DLB esclusivamente basata sul criterio temporale di “1 anno” risulta esser utile prevalentemente sul piano clinico, poiché PDD e DLB, da un punto di vista genetico e molecolare, si collocano entrambe all’interno dello spettro continuo delle sinucleopatie accomunate dal medesimo meccanismo eziopatogentico, ossia l’accumulo di corpi di Lewy. Secondo i criteri rivisitati di McKeith, una diagnosi di DLB è meno probabile qualora si verifichino le seguenti condizioni: 1) presenza di deficit neurologici focali all’esame obiettivo o lesioni cerebrovascolari documentate mediante neuromaging; 2) presenza di qualsiasi altra condizione morbosa od encefalopatia che possa giustificare in parte o totalmente il quadro clinico; 3) insorgenza dei segni di parkinsonismo nei stati avanzati di demenza. Tuttavia, è opportuno ricordare che fino al 30% dei casi di pazienti con DLB confermata in sede autoptica presentano segni di encefalopatia ischemica cronica lacunare a carico della sostanza bianca documentata tramite neuroimaging.

11 Applicando ai 167 soggetti inclusi nello studio i criteri diagnostici del 1996, è stata diagnosticata una DLB probabile in 25 casi (12.8%) e una DLB possibile in 13 soggetti (6.6%) mentre utilizzando i nuovi criteri di McKeith del pazienti (15.8%) presentavano una DLB probabile e 8 (4,1%) una DLB possibile con un incremento del 24% della proporzione di DLB probabile (95%, CI 18-30) ed un decremento corrispondente del numero di soggetti con DLB possibile. La transizione da DLB possibile a probabile è avvenuta grazie al riscontro di disordini del comportamento nel corso del sonno REM in quattro casi ed alla positività della SPECT in due casi. DLB POSSIBILE incremento del 24% della proporzione di DLB probabile (95%, CI 18-30) ed un decremento corrispondente del numero di soggetti con DLB possibile DLB PROBABILE Aarsland et al., Dement Geriatr Cogn 448 Disord 2008;26:445–452

12 Il profilo neuropsicologico nella DLB
Disfunzioni visuo-spaziali ed aprassia visuo-percettiva Agnosia e prosopoagnosia Atassia ideo-motoria ed alterazioni delle funzioni esecutive Compromissione dell’attenzione selettiva Relativa preservazione della memoria Fluttuazione delle funzioni cognitive Nella DLB la compromissione della sfera cognitiva si caratterizza tipicamente per la presenza di ricorrenti episodi di stato confusionale inseriti in un contesto di progressivo deterioramento. I pazienti affetti da DLB mostrano tipicamente una compromissione simultanea sia delle funzioni neuropsicologiche corticali che sottocorticali con relativa conservazione delle capacità mnesiche, spiccati deficit attentivi, agnosia e prosopoagnosia, atassia ideomotoria e prevalenti disfunzioni visuo-spaziali e fronto-subcorticali. I disturbi del linguaggio comprendono la confabulazione, la perseverazione e la riduzione della fluenza verbale. Tale profilo neuro-psicologico di presentazione della DLB, può consentire, soprattutto nelle fasi iniziali, una corretta diagnosi differenziale rispetto alle altre forme di demenza, tuttavia, con la progressione dei deficit ed il concomitante peggioramento della memoria, si realizza una compromissione globale delle funzioni cognitive che rende ardua la diagnosi differenziale. La fluttuazione delle performance cognitive, la cui manifestazione può variare da alcuni minuti a ore o giorni, si verifica nel 50-75% de soggetti affetti da DLB. Il riconoscimento della fluttuazione rappresenta un subdolo ostacolo nella pratica clinica non solo a causa dell’assenza di scale o strumenti facilmente utilizzabili per una corretta diagnosi ma soprattutto in relazione alla attuale inesistenza di scale che consentano di effettuare una corretta diagnosi differenziale tra la fluttuazione presente nella DLB, nella PDD, nella demenza a genesi vascolare e negli stati di agitazione psicomotoria su base organica. I disturbi psichiatrici quali allucinazioni visive strutturate, deliri, apatia e stato ansioso sono estremamente comuni nella DLB e si presentano sin dalle fasi iniziali del decorso della patologia, tendendo a persistere. FOTO: ■ Abstract Parkinson’s disease (PD) is characterized by its motor impairment. However, non-motor symptoms such as psychiatric disorders, autonomic disturbances and sleep disorders frequently complicate the course of the disease. In particular, psychiatric disturbances including cognitive impairment, depression and psychosis impact these patients considerably. Approximately 31 % of PD patients suffer from cognitive impairment and dementia. Currently, two different clinical presentations are distinguished in PD patients, who present with dementia: Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), which are two different presentations of a single underlying disease process leading to the deposition of α-synuclein. Clinically, PDD is distinguished from DLB alone by the different temporal manifestations of extrapyramidal motor symptoms. Dementia is characterized by a subtle onset and progressive cognitive decline with a predominant dysexecutive syndrome, which can be accompanied by different behavioral symptoms such as hallucinations, depression, anxiety and sleep disorders. Dysregulation of different neurotransmitters has been associated with cognitive decline, but reduced cholinergic transmission is currently thought to be the pivotal mechanism in the development of cognitive dysfunction. Therefore, cholinesterase inhibitors are used in the treatment of dementia and accompanying behavioral symptoms in PDD and DLB. The occurrence of dementia impacts not only the patients themselves but also their care- givers and family. ACh

13 Le allucinazioni visive
13-80% dei pazienti affetti da DLB Zooptiche Tridimensionali, spiccatamente colorate Spiccata e diffusa riduzione della acetilcolina a livello delle aree corticali, presenza di un maggior numero di corpi di Lewy a livello della porzione anteriore ed inferiore del lobo temporale e ridotta perfusione delle corteccia occipitale a livello delle aree visive primitive e secondarie

14 Segni extrapiramidali
Fino al 70% dei soggetti affetti da DLB sviluppano una sindrome extrapiramidale prevalentemente acinetico-rigida caratterizzata da spiccata instabilità posturale, cadute ricorrenti e minor prevalenza di tremore a riposo asimmetrico rispetto ai pazienti affetti da PD. Fino al 25% dei casi di DLB confermata mediante riscontro autoptico non manifestano segni di extrapiramidalismo

15 I disturbi del sonno REM
I disordini del comportamento nel corso del sonno REM si manifestano clinicamente come sogni vividi e spaventosi accompagnati da movimenti motori complessi (i pazienti si muovono violentemente poiché sembrano “recitare” i propri sogni) in relazione alla mancata inibizione motoria ed atonia tipica del sonno REM. Tali disturbi spesso precedono di diversi anni l’instaurazione della demenza e dei segni extrapiramidali e posso rappresentare una precoce manifestazione clinica del gruppo di patologie incluse nelle sinucleinopatie, quindi non solo tipiche del PD o DLB ma anche della PDD e della atrofia multisistemica (MSA).

16 La diagnosi differenziale

17 AD o DLB? AD e DLB presentano una differente progressione del declino cognitivo, utile come criterio ex-adjuvantibus per la diagnosi differenziale? ABSTRACT Objectives: Dementia with Lewy bodies (DLB) accounts for 10%e15% of dementia cases at autopsy and has distinct clinical features associated with earlier institutionalisation and a higher level of carer distress than are seen in Alzheimer’s disease (AD). At present, there is on-going debate as to whether DLB is associated with a more rapid cognitive decline than AD. An understanding of the rate of decline of cognitive and non-cognitive symptoms in DLB may help patients and carers to plan for the future. Design: In this cohort study, the authors compared 100 AD and 58 DLB subjects at baseline and at 12-month follow-up on cognitive and neuropsychiatric measures. Setting: Patients were recruited from 40 European centres. Participants: Subjects with mildemoderate dementia. Diagnosis of DLB or AD required agreement between consensus panel clinical diagnosis and visual rating of 123I-FP-CIT (dopamine transporter) single photon emission computed tomography neuroimaging. Outcome measures: The Cambridge Cognitive Examination including Mini-Mental State Examination and Neuropsychiatric Inventory (NPI). Results: The AD and DLB groups did not differ at baseline in terms of age, gender, Clinical Dementia Rating score and use of cholinesterase inhibitors or memantine. NPI and NPI carer distress scores were statistically significantly higher for DLB subjects at baseline and at follow-up, and there were no differences between AD and DLB in cognitive scores at baseline or at follow-up. There was no significant difference in rate of progression of any of the variables analysed. Conclusions: DLB subjects had more neuropsychiatric features at baseline and at follow-up than AD, but the authors did not find any statistically significant difference in rate of progression between the mildemoderate AD and DLB groups on cognitive or neuropsychiatric measures over a 12-month follow-up period. Walker Z, McKeith I, Rodda J, et al. BMJ Open 2012

18 Article focus - Dementia with Lewy bodies (DLB) has distinct neuropsychiatric features - At present, we do not know whether the poorer prognosis of DLB is due to a more rapid cognitive decline compared with Alzheimer’s disease (AD) Key messages - In this fairly large cohort of patients with DLB and AD, while there was no difference in level of cognitive impairment (Cambridge Cognitive Examination (CAMCOG) score) at baseline and at 12-month follow-up, DLB patients had significantly higher Neuropsychiatric Inventory (NPI) and NPI carer distress scores both at baseline and at 12-month follow-up. - Therefore, the worse prognosis of DLB is likely to be mediated by neuropsychiatric or other symptoms and not only by cognitive decline Strengths and limitations of this study - Inclusion of high number of subjects from 40 European clinical centres - Well-characterised cases with both consensus panel clinical diagnosis (three clinical experts) and dopaminergic transporter single photon emission computed tomography imaging - No autopsy data were available and therefore it is possible that more rapid cognitive decline may be present in pure DLB - Only 1 year of follow-up - There was higher attrition rate (no-follow-up assessment) in the DLB group, and DLB patients that did not return for follow-up were more impaired than AD patients.

19 DLB o PDD? Disturbi della sfera cognitiva PDD e DLB presentano profili neuropsicologici sovrapponibili; nella DLB maggior compromissione delle funzioni esecutive Sintomi psichiatrici Allucinazioni e deliri molto più frequenti nella DLB rispetto a PDD Segni extrapiramidali Severità e progressione della sindrome extrapiramidale simile nella DLB e nel PDD, con prevalente simmetria dei disturbi, minor tremore ed instabilità posturale rispetto al PD ABSTRACT The diagnosis of Parkinson's disease with dementia (PDD) or dementia with Lewy bodies (DLB) is based on an arbitary distinction between the time of onset of motor and cognitive symptoms. These syndromes share many neurobiological similarities, but there are also differences. Deposition of beta-amyloid protein is more marked and more closely related to cognitive impairment in DLB than PDD, possibly contributing to dementia at onset. The relatively more severe executive impairment in DLB than PDD may relate to the loss of frontohippocampal projections in DLB.Visual hallucinations and delusions associate with more abundant Lewy body pathology in temporal cortex in DLB. The differential involvement of pathology in the striatum may account for the differences in parkinsonism. Longitudinal studies with neuropathological and neurochemical evaluations will be essential to enable more robust comparisons and determine pathological substrates contributing to the differences in cognitive, motor, and psychiatric symptoms. (J Geriatr Psychiatry Neurol 2004; 17: ) Cognitive Deficits The cognitive profile of both PDD and DLB has been characterized as featuring visuospatial, attentional, and executive impairment with relatively less memory impairment.1,47 This is based on studies comparing DLB and PDD patients with patients with Alzheimer’s disease. The overall profile of cognitive deficits is quite similar in the 2 syndromes (details of studies in Table 1), with both PDD and DLB patients exhibiting significantly more marked executive and less severe memory deficits than did those with Alzheimer’s disease. Interestingly, fluctuating attention, a key feature of DLB, was found in both DLB and PDD patients but not in patients with Alzheimer’s disease or PD without dementia, and less marked fluctuation of attention was also found in DLB patients without parkinsonism.48 An additional study comparing pentagon copying in patients with DLB and PDD suggested a similar severity of impairment in the 2 conditions and a pattern of errors indicating executive dysfunction.49 A further study, although suggesting marked executive dysfunction in both PDD and DLB, showed that in the context of mild dementia, patients with DLB had a significantly lower score on the Dementia Rating Scale Conceptualization subscale than did PD patients, suggesting that executive impairment is more pronounced in DLB than in PD patients with mild dementia. Overall, however, the profile of cognitive impairments in DLB and PDD appears to be similar and distinct from Alzheimer’s disease but with some subtle differences, including more marked executive dysfunction in DLB. Psychiatric Symptoms Psychiatric symptoms are common in all dementia syndromes, but a characteristic psychiatric profile has been reported in patients with DLB and PDD (Table 2).Visual hallucinations and delusions are much more common in DLB than in Alzheimer’s disease, occurring in 60% to 70% of patients with DLB,50,51 whereas in PDD, hallucinations (45%-50%) but not delusions (15%-24%) were more common than in Alzheimer’s disease.51,52 Another distinguishing feature of these syndromes is the high frequency of REM sleep disorders, which are also much more common in DLB and PDD than in other dementias (see Boeve, this issue).53 Other symptoms commonly reported, such as depression, apathy, and anxiety, are common in other dementias, although several studies suggest a higher frequency of depression in DLB,50,51 consistent with the high frequency of depression in PD.54 Comparisons of the phenomenology of psychotic symptoms in DLB and PDD show that the content of the hallucinations and delusions was indistinguishable.51,52 However, the frequency of hallucinations51,52 and delusions52 was significantly higher in DLB patients than in PDD patients. Parkinsonism It has frequently been suggested, based largely on anecdote, that parkinsonism is less severe in DLB than in PD. However, comparative studies have usually not supported this view, finding similar or even more severe symptoms in DLB than in PD (Table 3). A similar profile of parkinsonism has also been reported,55 although in one study DLB patients had more symmetrical parkinsonism and relatively higher rigidity and lower resting tremor scores than did PD patients.56 Importantly, these studies usually included subjects with and without dementia. In the most detailed comparative study of parkinsonism to date, Burn et al found that DLB patients had less severe parkinsonism than did PDD patients but a similar severity of motor deficits to PD patients without dementia.57 Postural instability and gait difficulties, predominantly mediated by nondopaminergic deficits, were more pronounced in DLB and PDD patients than in PD patients without dementia, whereas the opposite was found for tremor. Although there are no direct comparative studies, the rate of progression of rating scales of parkinsonism appears to be about 9% per annum in DLB and PD.58,59 Overall, therefore, severity of parkinsonism is similar in DLB and PD and progresses at the same rate, although there appears to be relatively more nondopaminergic symptoms and less asymmetry in DLB, consistent with neurochemical findings. Treatment Studies Frequently, DLB patients experience severe sensitivity reactions in response to neuroleptic drugs (NSR),60 and preliminary evidence suggests similar reactions in a considerable proportion of PDD patients, although occurring less commonly than in DLB patients.61 The symptoms of severe NSR experienced by the respective groups of patients are very similar, although it appears that PDD patients are less likely to die within a few months of neuroleptic exposure. Two randomized placebo-controlled studies support the use of clozapine for PD patients with psychosis (with no or mild dementia), but undertaking such trials in DLB is problematic because of the high frequency of severe NSR and the high related mortality rates. Recent reports of higher mortality rates and risk of cerebrovascular incidents in elderly patients with dementia associated with risperidone and olanzapine underline the potential high risk of these agents. Favorable symptomatic improvement is seen in both DLB and PDD following cholinesterase inhibitor therapy (see articles in this issue). We are aware of only one open-label study comparing the treatment effects in PDD and DLB. Minett et al62 showed a similar improvement on cognition and psychiatric symptoms on donepezil in DLB and PDD patients and no change in parkinsonism in both groups, although PDD patients showed a greater worsening of psychiatric symptoms after withdrawal of the drug. Unfortunately, there are no systematic reports of the response to levodopa treatment in DLB patients, and no published comparisons exist. Theoretically, the high proportion of DLB patients with predominantly nondopaminergic motor deficits suggests that such therapy would be less effective in DLB patients than in PD patients. Preliminary evidence from ongoing studies supports this hypothesis Aarsland et al., 2004

20 Clinical Overlap DLB o PDD? CLINICO NEURO- PSICOLOGICO ISTO-
PATOLOGICO They could be considered as distinct conditions. (2) They could be considered as part of a spectrum of dementia related to cortical Lewy body disease. (3) Both DLB with parkinsonism and PDD could be considered as a distinct condition but separate from DLB without parkinsonism and PD without dementia. (4) They could be considered as part of a spectrum of Lewy body– and Alzheimer-type pathology. The commonality of the presenting symptoms, treatment response, and many neuropathological/neurochemical substrates would seem to best support a spectrum model, although the additional cortical Aβ deposition in DLB suggests important differences subserving dementia at onset. The paucity of direct comparisons, however, makes conclusions speculative, and further comparative studies are a high priority. Longitudinal studies with neuropathological and neurochemical evaluations are essential to enable more robust comparisons and to determine the impact on presentation of the individual pathological substrates that may contribute to cognitive, motor, and psychiatric symptoms

21 Segni Extrapiramidali: diagnosi differenziali
Chadwick W et al. 2004 Segni Extrapiramidali: diagnosi differenziali Lento Decorso Terapia con dopamino-antagonisi Decorso rapidamente progressivo (settimane/mesi) Parkinsonismi iatrogeni Parkinsonismi Atipici PD verosimile Risposta L-Dopa Buona Scarsa Malattia Parkinson Precoce Demenza Cadute precoci Disautonomia Segni cerebellari o corticospinali Fattori di rischio cardiovascolari o pregressi ictus DLB PD vascolare PSP CBD AD MSA NEUROIMAGING

22 Segni Extrapiramidali: diagnosi differenziale
PSP CBD PD MSA DLB Motilità oculare ridotta / Instabilità posturale/cadute / / Rigidità Bradicinesia / Simmetria / Tremore / / /- Disautonomia Atassia / Risposta L-DOPA / / /+ + = generalmente presenti +/− = occasionalmente presenti − = assenti Rampello L et al. 2005

23 Sensibilità 78% Specificità 98%
NEUROIMAGING Atrofia ippocampale alla RM molto più spiccata nell’AD rispetto alla DLB FLUROPROPIL CT-SPECT: ridotto uptake dopaminergico a carico di PUTAMEN e CAUDATO Sensibilità 78% Specificità 98%

24 nella DLB c’è un prevalente interessamento delle seguenti regioni:
NEUROIMAGING Pattern di relativa diminuzione dell’attività metabolica patologia-relata: nella DLB c’è un prevalente interessamento delle seguenti regioni: OCCIPITALE PARIETO-TEMPORALE Abstract: The differential diagnosis of neurodegenerative brain diseases on clinical grounds is difficult, especially at an early disease stage. Several studies have found specific regional differences of brain metabolism applying [18F]-fluoro-deoxyglucose positron emission tomography (FDG-PET), suggesting that this method can assist in early differential diagnosis of neurodegenerative brain diseases.We have studied patients who had an FDGPET scan on clinical grounds at an early disease stage and included those with a retrospectively confirmed diagnosis according to strictly defined clinical research criteria. Ninetysix patients could be included of which 20 patients with Parkinson’s disease (PD), 21 multiple system atrophy (MSA), 17 progressive supranuclear palsy (PSP), 10 corticobasal degeneration (CBD), 6 dementia with Lewy bodies (DLB), 15 Alzheimer’s disease (AD), and 7 frontotemporal dementia (FTD). FDG PET images of each patient group were analyzed and compared to18 healthy controls using Statistical Parametric Mapping (SPM5). Disease-specific patterns of relatively decreased metabolic activity were found in PD (contralateral parietooccipital and frontal regions), MSA (bilateral putamen and cerebellar hemispheres), PSP (prefrontal cortex and caudate nucleus, thalamus, and mesencephalon), CBD (contralateral cortical regions), DLB (occipital and parietotemporal regions), AD (parietotemporal regions), and FTD (frontotemporal regions). The integrated method addressing a spectrum of various neurodegenerative brain diseases provided means to discriminate patient groups also at early disease stages. Clinical follow-up enabled appropriate patient inclusion. This implies that an early diagnosis in individual patients can be made by comparing each subject’s metabolic findings with a complete database of specific disease related patterns Movement Disorder Society Tenue et al., Mov Dis 2010

25 LA TERAPIA

26 Uno sguardo panoramico…
Despite the frequency and importance of dementia associated with Parkinson’s disease (PDD) and dementia with Lewy bodies (DLB), there is relatively little evidence on which to base treatment. Evidence from meta-analysis suggests that rivastigmine can improve cognition and functioning in PDD and also reduce risk of falling. There is also evidence supporting its use in DLB. Recent evidence suggests that memantine may also be effective, particularly for PDD, although evidence is more conflicting. Memantine may also improve parkinsonism and dyskinesias. Few clinical trials of cognition in PD without dementia exist, but there is preliminary evidence for atomoxetine, memantine, and piribedil. There is a lack of systematic evidence for the treatment of visual hallucinations and depression in PDD and DLB. In addition, there is a need for studies of whether potentially disease-modifying agents can prevent or delay the progression to dementia in PD.

27 7 studi (2 donepezil, 4 rivastigmina, 1 galantamina)
This article reviews the cholinergic changes in Parkinson’s disease and dementia (PDD) and dementia with Lewy bodies (DLB), their potential clinical implications, and the available evidence for cholinesterase inhibitors in the treatment of PDD and DLB. Marked neuronal loss of cholinergic nuclei, reduced cholinergic markers in the neocortex, hippocampus, and selected thalamic nuclei, and receptor changes have been reported. One large and 2 small placebo-controlled trials and nearly 20 open-label studies suggest that cholinesterase inhibitors have a positive effect on cognition, psychiatric symptoms, and global function in patients with DLB and PDD. The treatment is well tolerated in most patients without any apparent worsening of extrapyramidal motor features. Given the high risk of severe sensitivity reactions and increased risk of cerebrovascular incidents during treatment with neuroleptics, more clinical trials of cholinesterase inhibitors are encouraged to establish their precise role in DLB and PDD. 7 studi (2 donepezil, 4 rivastigmina, 1 galantamina) Pazienti totali 250 Punteggio medio MMSE al baseline: 19 (SD 17-20) Durata media del trattamento: 16 settimane (SD 12-26) Miglioramento statisticamente significativo del punteggio MMSE in 5 studi (miglioramento medio 2.7) Miglioramento dei disturbi psichiatrici Aarsland et al., 2004

28 Background Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement. Objectives To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and cognitive impairment in Parkinson’s disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease). Search methods The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly. Reference lists of relevant studies were searched for additional trials. Selection criteria Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson’s disease (CIND-PD). Data collection and analysis Data were extracted from published reports by one review author (MR). The data for each ’condition’ (that is DLB, PDD or CINDPD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0. Main results Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson’s disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson’s disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000). For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer’sDisease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI to -0.24, P < ). For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI to -0.23, P < ). There was evidence of a positive effect of cholinesterase inhibitors on theMini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = ) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial. For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI to -0.04, P = 0.01). For activities of daily living, combined data for the ADCS and the Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI to -0.02, P = 0.03). For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/ 842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = ) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = ). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < ) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03). Authors’ conclusions The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD «Le attuali evidenze in letteratura supportano l’utilizzo degli AchEI nei pazienti affetti da PDD in termini di miglioramento dei deficit cognitivi, dei disturbi comportamentali e dell’autonomia funzionale. Nei pazienti con DLB l’utilizzo e l’efficacia degli AchEI non è attualmente supportato da sufficienti studi clinici.»

29 Edwards K, Farlow M, Hake A, et al.
Objective To compare efficacy of different cholinesterase inhibitors (ChEIs) for treating patients with dementia with Lewy bodies (DLB). Design Retrospective comparison of three independent clinical studies of ChEI treatment using donepezil, galantamine or rivastigmine in patients with DLB. Method Data was obtained from open label trials of donepezil and galantamine and a placebo controlled randomized trial of rivastigmine in DLB. Changes in Mini Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI) and United Parkinson’s Disease Rating Scale (UPDRS-III) scores were compared between the three treatments at 12 and 20 weeks. Results All ChEIs significantly improved cognitive and neuropsychiatric measures. Reduction in the total NPI score appeared significantly greater after donepezil treatment. There was no significant increase in UPDRS-III scores. Conclusions It is unclear to what extent these findings reflect true differences between ChEIs or are due to methodological artefacts of comparing different studies. There is so far no compelling evidence that any one ChEI is better than the other in treating DLB but head to head comparative studies of different ChEIs are warranted to clarify this. Copyright#2007 John Wiley & Sons, Ltd. Edwards K, Farlow M, Hake A, et al. An open label, 24-week, flexible dose trial to assess the safety and efficacy of galantamine in patients with dementia Lewy bodies. NeuroBiology of Aging 2004; 25(S2): 21. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356: 2031–2036. Thomas AJ, Burn DJ, Rowan EN, et al. A comparison of the efficacy of donepezil in Parkinson’s disease with dementia and dementia with Lewy bodies. Int J Geriatric Psychiatr 2005; 20: Bhasin et al., 2007

30

31 memantine and placebo treatments in patients with DLB
Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial Aarsland D. et al., Lancet Neurol, 2009 “In a preliminary descriptive subgroup analysis, there were no differences in the mean CGIC LOCF between the memantine and placebo treatments in patients with DLB The mean score in the PDD group was 4.3 in the placebo group and 2.9 in the memantine group suggesting a more pronounced global response in patients with PDD.”

32

33 Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial Emre M. et al., Lancet Neurol, 2010 DLB

34 Changes since baseline
Efficacy of Memantine in PDD and DLB: an extension study including washout and open-label treatment Johansson C. et al., Int J Geriatr Psychiatry, 2011 Memantine Open-label treatment Placebo Blinded treatment Washout 1 0,8 0,6 Improvement 0,4 0,2 Changes since baseline in CGIC score -0,2 Deterioration -0,4 -0,6 Recurrence of symptoms. Text citations such as ‘Increased confusion, disorientation and hallucinations’ exemplify what was interpreted as a recurrence of symptoms. In the memantine group, 14 out of 24 patients (58%) experienced a recurrence of symptoms upon drug withdrawal (Figure 2). This was significantly more common (x2 test, p¼0.04,) than in patients randomized to placebo (five out of 20, 25%). The proportions of DLB and PDD patients were similar in the patients that exhibited recurrence of symptoms (53 vs. 47%, DLB and PDD) as in those that did not exhibit recurrence of symptoms (52 vs. 48%, DLB and PDD). -0,8 12 24 28 54 Week No pts Placebo No pts Memantine Results from Clinical Global Impression of Change (CGIC) efficacy analysis. The data are mean change (SEM) from baseline in the doubleblind randomized controlled trial (RCT) in CGIC scores during washout and the open-label memantine treatment, based on an observed-cases analysis. Weeks are cumulative from the start of the RCT.

35 The effect of memantine on sleep behaviour in dementia with Lewy bodies and Parkinson's disease dementia Larsson V. et al., Int J Geriatr Psychiatry, 2010 “Probable RBD (REM sleep behaviour disorder), expressed as a physically active behaviour during sleep, decreased significantly within the memantine group during treatment. The number of patients with no or mild probable RBD increased over time (40 to 57% and 16 to 30%, respectively), whilst patients with moderate probable RBD decreased (44 to 13%). The same pattern was not seen in the placebo group. Separate statistical analysis of DLB and PDD patients concerning these results showed that both groups contributed equally to the significant outcome.” Physical activity during sleep Physical activity during sleep Memantine group Placebo group 100 OBJECTIVE: Two common and characteristic sleep disturbances have been described in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD); excessive daytime sleepiness and REM sleep behaviour disorder (RBD). This study is an analysis of a secondary outcome measure of a larger study already reported, aimed to determine whether memantine has an effect on the sleep disturbances in DLB and PDD patients. METHODS: Patients with DLB or PDD were included in a placebo-controlled, randomised controlled study of memantine (20 mg per day) for 24 weeks. The Stavanger Sleep Questionnaire and the Epworth Sleepiness Scale were used to evaluate the effect on sleep disturbances. RESULTS: Forty two patients started treatment; 20 with memantine and 22 with placebo. The primary analysis was the comparison of change between the two groups during a 24-week period, using the modified ITT population (last observation carried forward). At 24 weeks, patients treated with memantine were less physically active during sleep while patients in the placebo group worsened. Mean difference between the groups (0.5 [ ]) was significant (p = 0.006). No significant change was observed in severity of excessive daytime sleepiness. CONCLUSIONS: Memantine decreases probable REM sleep behaviour disorder in patients with DLB and PDD. Both diagnostic groups contributed equally to the outcome. 100 80 80 60 60 40 40 20 20 Baseline (n=26) 12 weeks (n=26) 24 weeks (n=26) Baseline (n=29) 12 weeks (n=29) 24 weeks (n=29) Frequency (%) of probable RBD in memantine group and placebo group over time.

36 Antipsicotici e DLB

37 Specifica riduzione dei deliri e delle allucinazioni visive al dosaggio di 5 mg
Nessuna esacerbazione dei segni di extrapiramidalismo statisticamente significativa tra placebo ed i pazienti trattati Cummings et al., 2002

38 Scarsa Efficacia ABSTRACT Objective: To assess the efficacy and tolerability of quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Methods: Multicenter randomized, double-blind, placebocontrolled parallel groups clinical trial involving 40 patients with dementia with Lewy bodies (n 23), Parkinson disease (PD) with dementia (n 9), or Alzheimer disease with parkinsonian features (n 8). The main outcome measure for efficacy was change in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of therapy. For tolerability it was change in the Unified PD Rating Scale (UPDRS) motor section over the same time period. The trial was confounded by the need for a design change and incomplete recruitment. Results: No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning. Conclusions: Quetiapine was well-tolerated and did not worsen parkinsonism. Although conclusions about efficacy may be limited, the drug in the dosages used did not show demonstrable benefit for treating agitation or psychosis in patients with dementia and parkinsonism. These findings are in keeping with prior studies reporting limited efficacy of various medications for reducing behavioral problems in demented patients.

39 Levodopa e DLB

40 A 14 pazienti su 27 affetti da DLB è stata somministrata Levodopa 100 mg;
il 36% di questi soggetti ha presentato un miglioramento >20% del punteggio UPDRS III, del test della deambulazione e dei movimenti fini delle mani (classificati come «RESPONDER») Background: One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson’s disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms. Aim: To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD). Method: EPS assessment consisted of the Unified Parkinson’s Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the ‘‘off’’ state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa. Results: Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p,0.0001) and 23% in PDD (n = 30, p,0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as ‘‘responders’’ on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion. Conclusion: L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment. The L-dopa response of each patient was assessed, with ‘‘response’’ defined as a greater than 20% improvement over baseline on two of the three motor assessments. When the data were analysed in this way, only 36% of the DLB group was classified as L-dopa responsive, compared with 70% of the PDD group and 57% of the PD. group (table 4). Conversely, 29% of the DLB were classified as unresponsive, compared with 10% PDD and 21% PD patients Chronic L-dopa use (tolerability) Of the 27 patients with DLB, one did not commence L-dopa at the request of the physician owing to fear of neurobehavioural sequelae (UPDRS=38) and one had severe symptomatic orthostatic hypotension. Thus, 25 of the 27 DLB patients were chronically treated with L-dopa. Six of these were already taking this medication at study entry. Of the 25 DLB patients, 82% (n=21) warranted and tolerated long term L-dopa therapy. Nineteen patients with DLB were therefore commenced de novo on L-dopa for the purposes of this study, with a view to chronic dosing over at least 6 months. The six patients already taking L-dopa did not differ significantly in age, disease duration, MMSE, or baseline UPDRS from those not taking L-dopa at baseline assessment (data not shown). Of the 19 patients, two were unable to tolerate L-dopa within the first 2 weeks due to worsening confusion (n=1) and severe exacerbation of hallucinations (n=1). A further two patients withdrew before the 3 month assessment, owing to gastrointestinal intolerance, nausea, abdominal pain, and bloating. All side effects resolved once the dopaminergic medication was stopped. Fifteen DLB patients (84%) were therefore able to tolerate L-dopa for the 6 month study duration. The mean daily L-dopa dose achieved was 323 (182) mg. None of the DLB patients either previously receiving or those commenced de novo on L-dopa developed dyskinesias during the study period. (table 4). Comparison between L-dopa responding and non-responding DLB patients revealed no difference in sex, disease duration, MMSE, UPDRS, five item UPDRS, or dose of L-dopa achieved. L-dopa responders were, however, younger (68.5 v 77.1 years, p=0.014). 19 pazienti su 27 hanno assunto Levodopa 323 mg per sei mesi consecutivi e solo 1 soggetto ha interrotto la terapia per esacerbazione dello stato confusionale e delle allucinazioni visive Molloy et al., 2005

41 Levodopa e DLB Purpose: To evaluate levodopa responsiveness in patients with probable dementia with Lewy bodies (DLB) compared to early Parkinson’s disease (PD) patients. Methods: Twenty four cases with DLB and 21 with PD underwent a baseline assessment with UPDRS (sub-item II and III) and an acute levodopa challenge test. Positive response to acute levodopa test was defined as an improvement of at least 15% in the tapping test, and at least 25% in the walking test and rigidity or tremor score. Subsequently, all patients were treated continuously with levodopa and evaluated after 6 and 12 months by means of UPDRS II/III. Results: Positive response to the acute levodopa test was observed in 55% of DLB patients (acute DLB responders), and in 90% of PD patients (acute PD responders). Acute DLB responders showed increased latency, and reduction of both duration and amplitude of response to acute levodopa in comparison with acute PD responders. At the 6-month follow-up visit, acute DLB responders showed a greater motor benefit compared with acute DLB non-responders. This improvement was similar to that observed in PD patients. However, at 1-year follow-up acute DLB responders showed a faster worsening of UPDRS III scores compared with acute PD responders, implying a reduction of levodopa efficacy. Conclusions: Positive response to acute levodopa test can occur in DLB patients and may be predictive of long-term benefit of chronic levodopa therapy, although the motor improvement is less impressive than in PD patients.

42 L’iniziale miglioramento del punteggio UDPRS II e III nei pazienti affetti da DLB «acute responders» si è marcatamente ridotto dopo un anno di follow-up rispetto ai pazienti con PD trattati con L-dopa, indicando una minor risposta alla terapia cronica Fig. 2. Change (%) in UPDRS II (A) and UPDRS III (B) scores at the 6-month and 1-year follow-up in 3 subgroups of patients (acute PD levodopa non-responders were not included). The negative scores indicate motor improvemen

43 Curcumin reduces α-synuclein induced cytotoxicity in Parkinson's disease cell model
Wang M.S., et al., BMC Neurosci, 2010 Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro Ono K., Yamada M., J Neurochem, 2006 Statins reduce neuronal α-synuclein aggregation in in vitro model of in Parkinson's disease model Bar-On P. et al., J Neurochem, 2010 Inhibition of FK506 binding proteins reduces α-synuclein aggregation and Parkinson’s disease-like pathology Gerard M. et al., J Neurosci, 2010

44 CONCLUSIONS As with the disagreement between the islanders of Lilliput and Blefuscu over which end of the egg to break, there can ultimately be no right or wrong about what one calls Parkinson’s disease with dementia or dementia with Lewy bodies. It is a matter of opinion and without stretching the analogy too far, the egg will taste pretty much the same wherever it is cracked, much as patient management should follow the same general principles, whatever the diagnostic label. However, patients and their families will expect us to be consistent in our approach and this is where the importance of this issue lies.

45 Grazie per l’attenzione