Inquadramento Fisiopatologico delle Demenze Extrapiramidali

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1 SIGG 2004 Inquadramento Fisiopatologico delle Demenze Extrapiramidali Alessandro Padovani Università Studi di Brescia Clinica Neurologica

2 Dementia Type Total Population Overall, Alzheimer s disease accounts for just over half of all dementia significantly more than any other form. About two fifths of all patients are in each of the mild and moderate stages, and the remaining fifth are in the severe stage Distribution of Dementia Types 13% 14% 2% 1% 55% 22% 22% Mild cognitive impairment Dementia with Lewy bodies Vascular Mixed Other Alzheimer s disease 15% 11% Alzheimer s mild Alzheimer s moderate Alzheimer s severe Source: Icon and Landis, Fall 2000

3 Cause di demenza organica Diagnosi neuropatologica in 400 pazienti Studio longitudinale di Lund (1992) - DAT: demenza tipo Alzheimer 26% 12% 9% 3% 8% 42% DAT Miste (DAT + demenza vascolare) Demenza vascolare Degenerazioni fronto- temporali non-dat (incl( incl. morbo di Pick 1%) Encefaliti (incl( incl.. morbo di Creutzfeldt-Jacob Jacob) Altre demenze (incl( incl.. tumori 1%) McKeith et al, Neurology 1996; 47:

4 Extrapyramidal symptoms and signs in Alzheimer's disease: prevalence and correlation with the first symptom. Tsolaki M, Kokarida K, Iakovidou V, Stilopoulos E, Meimaris J, Kazis A. Am J Alzheimers Dis Other Demen 2001 Sep-Oct;16(5): The most common types of EPS presented in the patient group were hypomimia ([facial mask] 60 percent), difficulty in talking (53.66 percent), bradykinesia (51.4 percent), postural instability (47.33 percent), abnormal gait (34.66%), and rigidity (26 percent), respectively. No significant differences were found when examining for the presence of resting tremor, other tremors, dystonias, and dyskinesias. The mean duration of the disease in patients appearing with EPS is found to be / years. The presence of EPS increases proportionally with the progression of the disease and cognitive and functional decline Patients who presented EPS at initial examination appeared to deteriorate faster, mainly cognitively, but also functionally. The mean decrease in MMSE scores in patients with EPS was found to be /- 3.46; while in patients without EPS at initial visit, MMSE scores were /

5 Risk of Dementia in PD patients 43 out of 130 PD patients developed dementia during a 4.2 years follow-up period The incidence of dementia was 95.3 per 1000 person years while it was 25.5 per 1000 person years among control subjects Patients with PD had a 5.9-fold higher risk for developing dementia than controls without PD after adjustement for age, gender, and education Baseline Characteristics Mean Age Duration of Disease, >7y MMSE Score <29 UPDRS motor score >20 H-Y stage <2.5 L-Dopa dose <450 mg Dementia N=43 (33%) 73,7 (5,7) 65% 77% 28% 21% 42% No Dementia N=87 (67%) 67,7 (8,3) 45% 41% 61% 54% 63% Aarsland et al., Neurology 2001

6 Lopez et al., Arch Neurol, 2002

7 Costa et al Mov Dis 2003.

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9 Parkinsonismi Neurodegenerativi Sinucleinopatie M. con Corpi di Lewy: M. Parkinson, Demenza con Corpi di Lewy (forma limbica o neocorticale), M. Alzheimer variante a Corpi di Lewy M. con Inclusioni Gliali: Atrofia MultiSistemica (OPCA, SNA) Altre sinucleinopatie: M. Hallervorden Spatz, Atrofia Pallidonigroluysiana Taupatie Paralisi Supranucleare Progressiva Degenerazione Cortico Basale Parkinsonismo Postenecefalitico Complesso SLA-Parkinsonismo (Guam) Demenza Fronto-Temporale con Parkinsonismo (FTDP-17) M. Alzheimer Altro Atassia Spinocerebellare M. Huntington variante rigida DRPLA Distonia Parkinsonismo X-linked (Lubac)

10 Parkinsonismi Sintomatici Parkinsonismo Vascolare Parkinsonismo da Esposizione a Tossici M.Metaboliche (M. Wilson) Parkinsonismo infettivo: CJD Encefalopatia HIV Altre Infezioni Idrocefalo Normoteso Tumori Cerebrali Parkinsonismo Post- Traumatico

11 Cause di Parkinsonismo Cause frequenti M. Parkinson Parkinsonismo Iatrogeno Demenza a Corpi di Lewy Atrofia Multisistemica M. Alzheimer Paralisi Supranucleare Progressiva Degenerazione CorticoBasale Cause Infrequenti Degenerazione Fronto- Temporale Encefalopatia Vascolare M. Wilson M. Huntington Tumori Cerebrali Idrocefalo Normoteso Esposizione Tossici Trauma Cranico

12 Tauopathies Alzheimer Disease Pick s Disease Fronto-temporal dementia (frontal variant and temporal variant) FTD-Motor Neuron Disease Slowly Progressive Aphasia Semantic Dementia Dementia Pugilistica Progressive Subcortical Gliosis Progressive Sopranuclear Palsy Cortico-Basal Degeneration

13 Parkinson Disease (sporadic, familial with alphas mutations, familial without alphas mutations) Dementia with Lewy bodies (Pure Lewy body dementia, Lewy Body variant of AD, Familial AD with APP mutations, Familial AD with PS1 mutations, Familial AD with PS2 mutations) Multiple System Atrophy (Shy- Drager syndrome, Striatonigral degeneration, OPCA) Neurodegeneration with brain iron accumulation, type 1 (Hallervorden Spatz syndrome, Neuroaxonal Dystrophy) Other Disease (Traumatic brain injury, Pick Disease, ALS) Sinucleinopathies

14 Pathology Gross loss of pigmented neurons in substantia nigra (zona compacta) ) and locus ceruleus Histology Lewy bodies (eosinophilic core with clear halo) in neuronal cytoplasm - highly characteristic for PD; cell loss in basal nucleus of Meynert (PD dementia??)

15 α-synuclein in human brain Substantia Nigra, Basal Ganglia nuclei, deep layers of neocortex, hippocampus, entorhinal cortex, thalamic intralaminar nuclei, basis pontis, granular layer of cerebellar cortex (in conjunction with parkin) nucleus basalis of Meynert, locus coeruleus, medial geniculate body, amygdala, anterodorsal and ventral lateral nucleus of thalamus de-waxed section of human brain temporal cortex showing a-synuclein immunoreactivity in Lewy bodies. Diffuse Lewy body disease. ABC-peroxidase method. Nissl counterstain.

16 Comparison of PD, DLB, and AD: Neuroimaging and neuropathology PD DLB AD Global brain atrophy Medial temporal lobe atrophy Occipital hypoperfusion Impaired Dopaminergic Activity SP density Tangle density Subcortical LB Cortical LB

17 Wirdefeldt et al., 2001

18 Reperti Patologici in Pazienti con Diagnosi Clinica di Parkinsonismo (n=720, ) NEUROPATOLOGIA TOTALE % M. Parkinson Idiopatico (MPI) MPI+ Stato Lacunare/Infarti (113/19) MPI+ M.Alzheimer/DAT MPI+ con variante a Corpi di Lewy M. a Corpi Diffusi di Lewy MPI+ altre lesioni patologiche ,8 18,3 13,3 3,7 6,8 8,3 MALATTIA DA CORPI DI LEWY PRIMARIA 589/720 81,8

19 Reperti Patologici in Pazienti con Diagnosi Clinica di Parkinsonismo (n=720, ) NEUROPATOLOGIA M.Alzheimer/DAT (22/16) Encefalopatia Vascolare Paralisi Supranucleare Progressiva Atrofia Multi Sistemica Degenerazione Cortico Basale Lesioni del SNC non classificate Altro Nessuna Anomalia (TE?) TOTALE % 5,3 4,2 2,9 2,8 0,7 0,8 1,0 0,5 SINDROMI PARKINSONIANE SECONDARIE ,2

20 Discordanza diagnostica in una serie di autopsie di pazienti con diagnosi clinica di M. Parkinson (con/senza demenza) Hughes et al., 1992 Rajput et al., 1992 Jellinger, 1988 Jellinger, 2003 N=100 N=41 N=380 N=275 Demenza con Corpi di Lewy 1 0 3,6 4,7 M. Alzheimer 6 2 2,6 1,9 Encefalopatia Vascolare 0 2 3,5 1,2 PSP 8 0 1,8 1,2 MSA ,2 1,2 Atrofia S. Nigra 2 2 0,5 0,3 MA+EV 0 0 0,5 0,3 Deg. Cortico Basale 0 0 0,2 0,3 Normale 1 0 0,3 0,3 Totale ,3 12

21 Analisi anatomo-patologica di 255 pazienti con diagnosi clinica di parkinsonismo (Vienna, ) NEUROPATOLOGIA TOTALI DEMENTI % M. Parkinson ,1 MPI+ Stato Lacunare/Infarti MPI+ M. Alzheimer MPI+ Encefalopatia Multiinfartuale MPI+ Demenza Mista (MID-DAT) M. Alzheimer variante Corpi di Lewy Demenza a Corpi Diffusi di Lewy MPI con altra patologia MALATTIE CON CORPI DI LEWY ,6

22 Analisi anatomo-patologica di 255 pazienti con diagnosi clinica di parkinsonismo (Vienna, ) NEUROPATOLOGIA TOTALI DEMENTI % M. Alzheimer MA+ Stato Lacunare/Infarti Encefalopatia Vascolari PSP (+MA) 8 (2) 2 25 MSA (+MA) 7 (2) 2 29 Degenerazione Cortico Basale Altre Sindromi PARKINSONISMI SECONDARI

23 Analisi anatomo-patologica di 107 pazienti con diagnosi clinica di Demenza Parkinsoniana (Vienna, ) NEUROPATOLOGIA DEMENTI % Malattia di Parkinson Idiopatico (MPI) MPI+ M. Alzheimer M. Alzheimer M. Alzheimer variante Corpi di Lewy MA+ Stato Lacunare/Infarti ,8 17,7 14,9 16,0 3,7 PSP+MSA+CBD 7 6,5 Demenza a Corpi Diffusi di Lewy 25 23,4 Encefalopatia Vascolare (+MPI) 11 (+2) 12,1 PARKINSONISMI DEMENTI/TOTALI 107/255 41,9

24 The continuum of LBD and AD DLBD LBD + AD AD+LBV AD

25 The relationship between pathologies: in Alzheimer's disease the Aß pathology is upstream of, and can potentiate, the Lewy body pathology. This latter can be activated directly by -synuclein mutations (or other genetic lesions). If an individual close to the threshold for developing Lewy bodies starts to develop Aß pathology, this can initiate the cortical Lewy body formation (see Ref. 20 ). Abbreviations: AD = Alzheimer's disease; PD = Parkinson's disease; DLB = dementia with Lewy bodies.

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