Malattia di Parkinson

Malattia di Parkinson - Storia
•
1897 James Parkinson “An Essay
on shaking palsy”: patologia
caratterizzata da tremore a riposo
e riduzione progressiva della
motricità ad andamento
lentamente progressivo, con
caratteristiche turbe della marcia
e dell’eloquio
•
1875 Trousseau e Charcot
aggiunsero la rigidità
•
1929 Wilson completò il quadro
con l’aggiunta dell’acinesia
Malattia di Parkinson
Shaking palsy
Paralysis
agitans
Parkinson`s
disease
Parkinsonsyndrom
Morbus
Parkinson
4.2
Malattia di Parkinson -Epidemiologia
•
La MP è la più frequente delle malattie
degenerative del SNC dopo la Malattia di Alzheimer
•
La prevalenza è di 1 su 400 su tutta la popolazione
e di 1 su 200 per i soggetti che abbiano superato i
40 anni di età
•
Rare forme monogeniche prima dei 40 anni
•
Le forme sporadiche sono più frequenti ed
insorgono dopo i 60 anni
Malattia di Parkinson – Anatomia patologica
• la MP può essere definita come un’affezione
degenerativa del sistema extrapiramidale ed
autonomico; degenera la parte compatta della
sostanza nera
• L’elemento istologico caratteristico è costituito dai
corpi di Lewy, inclusioni neuronali
intracitoplasmatiche, di forma ovalare, acidofile
• Degenerazione anche a carico del locus
coeruleus, del nucleo dorsale del vago, della
formazione reticolare; alterazioni anche
nell’ipotalamo e nel midollo spinale (tratto intermedio
laterale)
Location of the problem
Parkinson’s Disease
Normal
Substantia nigra
4.16
Neurotransmitter interactions
Cortex
Glutamic acid (+)
GABA
(–)
GABA
(–)
Globus
pallidus
GABA
(–)
Glu(-)
GABA
(–)
Thalamus
Dopamine
Serotonin
SN
S. nigra
N. raphe
4.19
disturbed !!
Striate
body
Acetylcholine
Neuropathological lesions involving
deposition of abnormal proteins in
major neurodegenerative diseases
a) HD: intranuclear inclusions =
ubiquitin (cerebral cortex)
b) HD: intranuclear inclusions =
huntingtin (cerebral cortex)
c) AD: neuritic plaque = A (cerebral
cortex)
d) AD: neuritic plaque = silver stain
(cerebral cortex)
e) PD: Lewy body = α-synuclein
(substantia nigra)
f) PD: Lewy body = phosphorylated
α-synuclein
g) ALS: cytoplasmic inclusions =
ubiquitin (medulla oblongata)
h) ALS: cytoplasmic inclusions =
neurofilament (medulla
oblongata)
Malattia di Parkinson – Eziologia
• Fattori genetici (alpha-sinucleina, parkina,
DJ1)
• Fattori tossici (MPTP, rotenone ed altri
pesticidi)
• Fattori infettivi (parkinsonismo post-infettivo)
• Ipotesi più probabile: eterogeneità eziologica
Relations between the PARK genes
There are five clearly defined genetic causes of Parkinson's disease (PD) and/or parkinsonism.
The diagram is color-coded with dominant genes in red, recessive genes in green, protein
functions in blue, and the pathological outputs of cell loss and Lewy body formation as a
black box and a circle, respectively (Hardy et al., Annals of Neurology 2006).
Malattia di Parkinson – Patogenesi
MtDNA
mutation
Exogenous toxins
MPP
L-Dopa
Complex I
deficiency in nigral
neurons
ATP
Endogenous toxins
dopamine
NO
Free radicals
Apoptotic
cell death
Simplified cortical-basal ganglia circuit
cortex
glutamate
striatum
dopamine
GABA
substantia
nigra
output
structures
• Motor activity
• Motor learning
• Reward
Clinical symptoms after degeneration
of 70-80% of the substantia nigra
Rigidity
Tremor at rest
Vegetative disorders
(hypersteatosis,
hypersalivation)
4.28
Akinesia
Psychiatric
changes
Malattia di Parkinson – Clinica dei disturbi motori
• Tremore a riposo (8-12 c/s), “far pillole”,
“contar monete”
• Rigidità (plastica, a tubo di piombo,
fenomeno della troclea dentata), assiale, degli
arti, atteggiamento camptocormico
• Bradicinesia: facies figèe = amimia facciale,
raro ammiccamento, marcia a piccoli passi,
calpestio preparatorio, festinazione (rapida
accellerazione), parola flebile, micrografia,
acatisia
Malattia di Parkinson – Disturbi vegetativi
• Scialorrea
• Seborrea
• Stipsi
• Disfagia
• Impotenza
• Alterazioni della termoregolazione
• Alterazioni della vasomotricità periferica
• Alterazione della regolazione pressoria
• Disfunzioni vescico-sfinteriche
Malattia di Parkinson – Disturbi delle funzioni
superiori e dell’umore
• Sebbene nella classica descrizione di Parkinson si dichiarava
espressamente che l’intelletto non era compromesso, un’ accurata analisi
neuropsicologica ha rivelato la presenza di alterazioni cognitive nella MP
• Base anatomica: degenerazione della proiezione dopaminergica
mesocorticale e mesolimbica
• Alterazione delle funzioni visuospaziali e percettivo motorie
• Demenza sottorticale
• Depressione
• Insistenza nelle domande nelle lamentele, petulanti (acairia)
• Disturbi nel sonno
Malattia di Parkinson – Evoluzione
Classificazione in 5 stadi proposta da Hoen e Yahr 1967
• I STADIO. La sintomatologia è in genere unilaterale, il malato conserva la
propria autonomia nella vita familiare, nell’attività lavorativa e nelle relazioni
sociali.
• II STADIO. I sintomi della malattia sono bilaterali, pur mantenendo una
prevalenza di lato, e si possono associare a segni meno frequenti di
carattere vegetativo.
• III STADIO. La sintomatologia bilaterale è ingravescente, ma il p. è ancora
autosufficiente. Si iniziano a sviluppare le fluttuazioni motorie.
• IV STADIO. Dopo 10-15 anni di malattia il quadro clinico motorio è
dominato dalle fluttuazioni delle prestazioni motorie, non sempre correlabili
con l’assunzione della malattia e dalla perdita dell’autosufficienza.
• V STADIO. Il paziente è costretto a letto o sulla sedia a rotelle e necessita
a tempo pieno dell’assistenza in tutte le funzioni del vivere quotidiano.
Malattia di Parkinson – Diagnosi
• Bradicinesia
• ed almeno uno di questi segni
- rigidità muscolare
- tremore a riposo
- instabilità posturale non causata da disfunzioni del
sistema visivo, cerebellare, propriocettivo
Imaging nella MP:
TC, MR
SPECT
PET
Imaging nella MP: PET
Malattia di Parkinson – Criteri di esclusione
• Storia di ictus ripetuti con progressione a scalini
• Storia di ripetuti traumi cranici
• Storia di encefalite definita
• Crisi oculogire
• Trattamento con neurolettici all’esordio dei sintomi
• Più di un familiare affetto
• Paralisi sopranucleare dello sguardo
• Remissione prolungata
• Segni cerebellari
• Interessamento autonomico precoce e severo
• Demenza severa e precoce con disturbi della memoria
• Risposta scarsa o assente alla L-DOPA
• Tumore cerebrale o idrocefalo
Malattia di Parkinson – Terapia
La L-DOPA è un precursore della dopamina che viene
trasformato in dopamina dalla DOPA-decarbossilasi
(+Benserazide or +Carbidopa)
.
La L-DOPA viene somministrata in associazione con un
inibitore periferico della DOPA-decarbossilasi per aumentarne
la disponibilità cerebrale e per evitare disturbi periferici.
• Fase iniziale = risposta positiva
• Fase finale = discinesia indotta da L-DOPA
Malattia di Parkinson – Terapia
Dopamino-agonisti : pramipexolo, ropinololo,
rotigotina (cerotto transdermico)
Inibitori della COMT
Amantadina
Rasagilina (Inibitore MAO B)
(Anticolinergici)
Stimolazione profonda del subtalamo
Motor and behavioral effects
Motor
activation
Mechanisms of action
Increase of
DA release
Cognitive
activity
Synaptic plasticity
NMDAR subunit
changes
L-DOPA
Dyskinesia
Motor fluctuations
Impulse control disorders
Increase in
BDNF
Sprouting of
5-HT fibers
Structural plasticity
Duodopa è un'associazione a dosi fisse di levodopa e carbidopa (in rapporto 4:1)
sotto forma di gel per somministrazione intestinale. Il gel viene infuso nel duodeno
con pompa portatile tramite un sondino permanente posizionato con gastrostomia
endoscopica percutanea (PEG)1. L'obiettivo è quello di mantenere costanti le
concentrazioni plasmatiche di levodopa, in modo da ridurre le fluttuazioni motorie di
fine dose (fasi "off") che si verificano nei pazienti con Parkinson avanzato trattati con
la stessa associazione per via orale
Drug-induced parkinsonism
• Drug-induced parkinsonism usually arises after
exposure to neuroleptics.
• Antiemetic and promotility agents (promethazine,
prochlorperazine, and metoclopramide),
reserpine, tetrabenazine, and some calciumchannel blockers (flunarizine and cinnarizine) can
also cause parkinsonism.
• Symptoms are symmetric, and drug-induced
parkinsonism resolves when the drug is stopped,
although resolution can take weeks to months.
Essential tremor
• Essential tremor is characterised by action tremor that typically
interferes with drinking from a cup rather than resting tremor.
• It tends to be bilateral but frequently asymmetric, and in half of
patients there is a family history.
• The frequency of essential tremor is higher (8 Hz) than that of
Parkinson's disease, but it falls with age.
• In severe cases, essential tremor can be present at rest, making its
differentiation from parkinsonian tremor quite difficult.
• Presence of rigidity, bradykinesia, and response to dopaminergic
treatment help to differentiate Parkinson's disease from essential
tremor. However, to complicate matters, some patients with
Parkinson's disease have a postural rather than a rest tremor, or
both postural and rest tremor, and some individuals with
longstanding essential tremor can develop parkinsonism.
Multiple system atrophy
• Multiple system atrophy is the current term for grouping the previously
separate entities olivopontocerebellar atrophy, Shy-Drager syndrome,
and striatonigral degeneration.
• It presents with parkinsonism, cerebellar, autonomic (orthostatic
hypotension, bladder and bowel dysfunction, temperature dysregulation),
and pyramidal dysfunction in various combinations.
•
Multiple system atrophy-P (formerly striatonigral degeneration) is
characterised by symmetric parkinsonism without tremor and early,
pronounced postural instability.
• Multiple system atrophy-C (formerly olivopontocerebellar atrophy)
manifests with cerebellar signs and parkinsonism.
•
Corticospinal tract signs and respiratory stridor can be recorded in all
categories of multiple system atrophy. A poor response to dopaminergic
treatment is seen.
Progressive supranuclear palsy
• Progressive supranuclear palsy, oculomotor
disturbance, speech and swallowing difficulties,
imbalance with falls, and frontal dementia are
predominant.
• Patients have symmetric onset of parkinsonism,
early postural instability, severe axial rigidity,
absence of tremor, and a poor response to
dopaminergic treatment.
• Supranuclear gaze palsy, especially of downgaze,
is the defining characteristic. Blepharospasm and
eyelid opening apraxia are also typical.
Corticobasal degeneration
• Corticobasal degeneration manifests with
pronounced asymmetric parkinsonism and cortical
signs.
• Asymmetric limb dystonia and limb apraxia occur,
and corticospinal tract signs are noted.
• Cortical myoclonus, early oculomotor and eyelid
abnormalities, cortical sensory signs (eg,
extinguishing to double simultaneous stimulation),
and the alien limb phenomenon can be present.
• Patients respond poorly to dopaminergic drugs.
Dementia with Lewy bodies
• Dementia with Lewy bodies is characterised by progressive
parkinsonism and early dementia.
• Little or no resting tremor is reported. Early cognitive and
psychiatric features are noted.
• Hallucinations, REM sleep behaviour disorder, and psychosis
can be present, even before dopaminergic treatment. Motor
symptoms do not improve, and psychiatric symptoms are
exacerbated by small doses of these drugs.
• These patients also strikingly deteriorate with neuroleptics,
even those people whose parkinsonism has a low propensity
to worsen.
• Cognitive function can improve with central cholinesterase
inhibitors.
Vascular parkinsonism normal pressure hydrocephalus
• Vascular parkinsonism is attributable to multiple infarcts in
the basal ganglia and the subcortical white matter.
• Gait difficulty is a typical presentation. A wide-based
shuffling gait is very suggestive of this entity. Tremor is
usually absent.
• Brain imaging shows extensive small-vessel disease.
• Dementia, pseudobulbar affect, urinary symptoms, and
pyramidal signs frequently accompany vascular
parkinsonism.
• No therapeutic response is seen to dopaminergic treatment.
• Normal pressure hydrocephalus can produce a similar
picture.
Huntington´s chorea
Also known as … Huntington´s chorea.
• The disease was named after a young
physician, George Huntington, who in 1872
described the spasmodic and uncoordinated
limb movement (chorea) afflicting a handful of
families of English descent living in a region of
Long Island, New York.
• He had first encountered these patients when he
was just 8 years old, accompanying his father
and grandfather on medical rounds.
Clinical and pathological features
of Huntington’s disease
l
Progressive, autosomal dominant degenerative disease
l
Cognitive decline and chorea
l
Death occurs within 10-20 years from the onset of symptoms
l
Chromosome 4: mutation containing expanded polyglutamine
(CAG) repeats
l
Onset and severity of symptoms influenced by n of CAG repeats
l
Typical striatal degeneration mainly involving GABAergic spiny
neurons while interneurons are spared
l
Impaired activity of mitochondrial complex II in the striatum
Huntington´s chorea
What are the symptoms?
• The disease is characterized by
involuntarymovements, severe emotional
disturbance and cognitive decline.
• It usually strikes in mid-adulthood and
progresses inexorably until death occurs ten to
twenty years later.
• The disease, which affects about 1 in 10,000
people, is a dominantly inherited trait.
Huntington´s chorea
Has the gene been mapped?
• With the realization in the early 1980s that
inherited disease genes could be mapped in
large families, Wexler´s Venezuelan samples
became a precious commodity.
• In 1983, James Gusella started linkage studies
with a random collection of polymorphic markers
on different chromosomes. Incredibly, one of the
first dozen tested, called G8, from chromosome
4, tracked with the disease gene.
Huntington´s chorea
Who found the gene?
• A consortium of almost 60 researchers, including
Gusella and Wexler, from six teams working in
Boston, London, Cardiff, Michigan and California
finally identified the disease gene in 1993.
• The lab name for the gene was `IT15´, for
`interesting transcript 15´; the protein was
subsequently dubbed `huntingtin´.
Huntington´s chorea
What causes the disease?
• In common with genes involved in a number of
neurodegenerative diseases, the Huntington´s disease
gene contains a triplet repeat sequence (CAG) that
encodes a run of glutamine residues in the
corresponding protein.
• Healthy people have about 35 CAG repeats in this gene
but expansions above this limit, sometimes to more than
100, are invariably associated with the disease.
• In general, the longer the repeat, the earlier the age of
onset.
Huntington´s chorea
What is known about huntingtin?
• Not much, other than that it is a large protein (about 350
kDa), widely expressed and essential for mouse embryonic
development.
• The recent identification of proteins that interact with
huntingtin specifically and in a glutamine-dependent manner
should shed some light on this. What is clear is that the
increased run of glutamines causes the mutant huntingtin
protein to form aggregates in and around the nucleus in
certain neurons.
• The pathological significance of this is borne out by similar
observations in other triplet repeat diseases, including
spinocerebellar ataxia.
A hypothesis on the pathogenesis
of Huntington’s disease
Genetic
alteration
Abnormal
glutamate release
from cortex
Complex II
deficiency in
striatal neurons
ATP
Endogenous toxins
dopamine
NO
Free radicals
Apoptotic
cell death
Huntington´s chorea
Is any of the research looking promising?
• The transgenic mouse models that have recently
been developed.
• On the clinical front, there is a trial under way in
the US of two drugs, Remacemide and
Coenzyme Q10, which may be able to slow the
pace of nerve damage.
• Inhibitors of transglutaminases and apoptosis
could also prove effective therapeutics down the
line.
Altre malattie ipercinetiche
•
•
•
•
•
•
•
•
Malattia di Sydenam
Corea Gravidica
Ballismo (Emiballismo)
Atetosi
Malattia di Hallervorden Spatz
Discinesie tardive
Malattia di Wilson
Distonia di torsione (Focale Segmentaria, Generalizzata) :
Torcicollo, blefarospasmo, crampo dello scrivano
• Tics
• Sindrome di Gilles de La Tourette (Tics ed ecolalia)