APP - Gencat.cat

Línies d’investigació actuals en
les demències degeneratives
d’inici precoç.
Dr Rafael Blesa
Servei de Neurologia
Hospital de la Sta. Creu i St. Pau
[email protected]
Epidemiología
50
41,2
40
30
23
EA (%)
20
14,7
10
1,3
3,8
6,1
0
65 - 69 70 - 74 75 - 79 80 - 84 85 - 89
> 90
Edad
Launer, LJ et al: Rates and risk factors for Dementia
and Alzheimer’s disease. Results from EURODEM
pooled analysis. Neurology, 1999; 52: 78-84
Demencias neurodegenerativas = PROTEINOPATÍAS
DEMENCIA LOBULAR
FRONTEMPORAL
ALZHEIMER
Inicio tempr ano 1-2%
(Años 90s, hasta el 2006)
Inicio tar dío 98-99 %
PS1, PS2, APP
ApoEε4
3R
Ab1–42
TAUPATÍAS
AGD
FTDP-17
CBD
PiD
PSP
4R
Ubicuitina +
Amiloide
Tau
SINUCLEINOPATÍAS
PD, DLB, MSA
SIN HISTOLOGÍA
ESPECÍFICA
Ubicuitina -
MUERTE NEURONAL
FTDP-17: frontotemporal dementia and parkinsonism linked to chromosome 17 associated with Tau gene mutations,
CBD:Corticobasal degeneration. PiD: Pick´s disease. AGD: Argyrophilic grain disease. PSP: Progressive supranuclear palsy
PD: Parkinson´s disease, DLB: Dementia with Lewy bodies. MSA: Multiple system atrophy
Criterios NINCDS-ARDRA
de Enfermedad de Alzheimer probable, 1984
• Demencia establecida por examen clínico y documentada por el
Mini-Mental test, la escala de demencia Blessed u otra
exploración similar y confirmada por test neuropsicológicos.
• Defectos en dos o más áreas cognitivas
• Empeoramiento progresivo de la memoria y otras funciones
cognitivas
• Ausencia de alteraciones de la conciencia
• Inicio entre los 40 y 90 años de edad, más frecuentemente
después de los 65
• Ausencia de alteraciones sistémicas u otras enfermedades
cerebrales que por ellas mismas puedan explicar los trastornos
progresivos de la memoria y la cognición
AD pathology: brain atrophy and distribution
of plaques and neurofibrillary tangles
Plaques (yellow)
Shadow of
‘healthy’
brain
Angiopatía amiloide
Neurofibrillary tangles (pink)
A presenilin 1 mutation (Ser169Pro) associated with early-onset AD
and myoclonic seizures.
Ezquerra M, Carnero C, Blesa R, Gelpi, J, Ballesta F, Oliva R.
Neurology. 52(3):566-570, February 1999.
.DNA sequence of exon 6 of the presenilin 1 gene
showing the T to C substitution leading to the Ser169Pro
mutation. wt = wild type sequence.
Copyright © 2009 Wolters Kluwer.
. PS1 helices 2 and 3 modeling in the wild-type
(WT) and mutated (Ser168Pro) proteins.
2
A Novel Presenilin 1 Mutation (Leu166Arg)
Associated With Early-Onset Alzheimer Disease
Arch Neurol. 2000;57:485-488
Ezquerra M,Carnero C, Blesa R,Oliva R.
The disease follows an autosomal inheritance pattern with
early onset (range, 32-44 years)
7
A Novel Mutation in the PSEN2 Gene (T430M) Associated
With Variable Expression in a Family With Early-Onset Alzheimer Disease
Arch Neurol. 2003;60:1149-1151
Ezquerra M, Lleo A, Castellvı, Queralt R, Santacruz P, Pastor P, Molinuevo JL, Blesa
R, Oliva R
The studied family originated from
Barcelona, Spain. The proband was a 49year-old (III-3) because of a 4-year history
of cognitive decline. The family complained
of frequent oversights, problems
remembering recent events, word-finding
difficulty, and paranoid thinking about the
neighbors, difficulty performing home tasks
such as cleaning and using the washing
machine. A history of facial motor tics. 1
parent and 1 grandpar-ent (I-2 and II-2,
respectively) had AD. One of the proband’s
siblings (III-1) had memory problems but no
functional impairment. Some family
members also had a history of Tourette
Syndrome.
8
Whole genome analysis in a consanguineous family with early onset
Alzheimer’s disease
Clarimon J, et al. Neurobiology of Aging (2008)
This is the first study describing a family with a segregation pattern of
EOAD suggesting a recessive mode of inheritance.
We have narrowed the
homozygosity region shared by
both siblings to 250 MB, thus
discarding 92% of the genome
to contain any hypothetical
recessive gene (at least in the
present family)
The present data contributes as a significant start for subsequent studies in which large scale
genotyping and sequencing will be performed in both familial and sporadic EOAD patients not
carrying mutations in any of the known Mendelian genes linked to the disease
PSEN1: Ex3-12
PSEN2: Ex3-12
APP: Ex 16-17
7612 Secuencias
121 Controles
148 MUESTRAS
Media edad inicio: 53.7a
Rango: 31a-64a
Sexos M: 80 (54%)
Ha Familiar:
64 con Ha Familiar (43.2%) / 7 Autos.Dom.
72 esporádicos (48.6%)
12 desconocido (8.1%)
GEN APP
- I716F (g.275338A>T;c.2146A>T) (H.Clínic)
HOMBRE
31a inicio *
36a fallecimiento
* EDAD DE INICIO MÁS TEMPRANA JAMÁS
DESCRITA PARA APP.
Ha familiar:
Padre inicio : 36a
Padre fallece : 41a (1975)
CONFIRMACIÓN EN MUESTRA DE BIOPSIA CEREB.
*I716V (Florida) Y *I716T HAN SIDO DESCRITAS
EDADES DE INICIO 55a.
PARA ENTENDER LA ENFERMEDAD,
DEBEMOS ENTENDER LA NORMALIDAD
¿CUÁNTA VARIACIÓN HAY EN
PRESENILINAS Y APP?
¿DÓNDE LA ENCONTRAMOS?
ÁFRICA…
Nat Genet. 2003 33; Suppl:266-275
Mozabite
n=24
PSENs Y
APP
EN MUESTRA
AFRICANA
“HUMAN
GENOME
DIVERSITY
PANEL”
N = 130
Mandenka
n=23
Yoruba n=22
Biaka
n=29
San
n=2
Mbuti
n=13
Bantu
n=17
Genetic screening of Alzheimer’s disease genes in Iberian and African samples yields novel mutations in presenilins and APP
Guerreiro RJ,, et al. Neurobiol Aging. 2008 Jul 28.
231 patients from the Iberian peninsular with a clinical diagnosis of early-onset AD (mean age at onset of 52.9 years; range 31–64).
APP
Secuencia
APP
Secuencia DNA
paciente
Secuencia
mutagénesis
-Elisa Aβ40 y 42
-Elisa Aβ total
-APP C terminales (CTF)
-Actividad γ-secretasa
-APP soluble α
CHOk1
Clinical, neuropathological and biochemical profile
of the Amyloid Precursor Protein I716F mutation
Guardia-Laguarta C, et al. Journal of Neuropathology and Experimental Neurology 2009
(en prensa JNEN 09-203R1)
Diffuse amyloid plaques, mainly composed of
A• 42, and widespread neurofibrillary pathology.
Chinese Hamster Ovary (CHO) cells transfected
with this mutation showed a marked increase in
the A• 42/40 ratio and APP Cterminal fragments
and a decrease in APP intracellular domain
production, suggesting reduced APP proteolysis
by γ -secretase
The aggressive APP I716F mutation is associated with the youngest age of onset for
this locus. These findings strengthen the inverse association between A• 42/40 ratio
and age at onset. The mutation leads to a protein that is poorly processed by γ -secretase. This
loss-of-function may be an additional mechanism by which some mutations around the γ -secretase
17
cleavage site lead to AD.
Guerreiro RJ, et al. 2008 Jul 28.
Yes
Yes
Confirmed Genetic Variants Associated With Alzheimer’s Disease
chromosome
gene
age-at-onset
pattern
variants
ch21q21.3
APP
30 to 60
AD
23 mutations
ch14q24.13
PSEN1
30 to 50
AD
>180 mutations
ch1q31.42
PSEN2
50 to 70
AD
17 mutations
ch19q13.2
APOE
50 to 80+ familial/sporadic
3 isoforms
19
Apolipoprotein E–Dependent Accumulation of Alzheimer
Disease–Related Lesions Begins in Middle Age
Kok E, et al. Ann Neurol 2009;65:650–657
Appeared at around 30 years of age,
reaching almost 100% in the oldest.
Interpretation: The brain changes associated with AD may already begin developing
early in middle age, especially among APOE ε 4 carriers.
Transcriptomic and genetic studies identify IL-33 as a candidate
gene for Alzheimer's disease.
Chapuis J, et al Molecular Psychiatry (2009) 14, 1004–1016
-Transcriptomic analysis of 2741 genes ( AD cases and controls).
-From 82 differentially expressed genes, 1156 polymorphisms (n=945).
-17 genes exhibited at least one polymorphism associated with AD risk, and following
correction for multiple testing, we retained the interleukin (IL)-33 gene:
- decreased in the brain of AD cases
- Three polymorphisms associated with AD risk in non-APOE 4 carriers.
- associated with less cerebral amyloid angiopathy (CAA) in non-APOE 4 AD
- restricted to vascular capillaries
- overexpression in cellular models led to a specific decrease in
secretion of the A β40 peptides, the main CAA component.
In conclusion, our data suggest that genetic variants in IL-33 gene may
be associated with a decrease in AD risk potentially in modulating CAA
formation.
21
The dichotomy of AD genetics
Late-onset (>65 years):
Decrease
in AD risk
IL-33
From: Bertram & Tanzi (2003) ISN Neuropath Press (Basel), p.40-46
“Simplex AD” (<5%)
“Complex AD” (>95%)
Lennart Mucke, NATURE Vol 461|15 October 2009
23
Factors de risc, patogènia
Factores genéticos y ambientales que pueden influir en la forma senil
de la enfermedad de Alzheimer: estudio de casos y controles anidado
Bufill E et al. Neurología 2009;24(2):108-112
La edad es el principal factor asociado a la EA. Otros factores: sexo femenino, haber estado expuestos a anestesia general y ApoE4
Conclusiones. Los resultados concuerdan con la hipótesis de que la EA senil es una
enfermedad compleja, multifactorial, en la que intervienen diversos factores
genéticos y ambientales entre los que el recibir anestesia general puede
desempeñar un papel a considerar en investigaciones futuras.
Highly pathogenic H5N1 influenza virus can enter
the central nervous system and induce
neuroinflammation and neurodegeneration
Janga H, et al. PNAS August 18, 2009 vol. 106 no. 33 14063–14068
Localization of A/Vietnam/1203/04 (H5N1) influenza virus in the nervous system.
Activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after
resolution of the infection. Loss of dopaminergic neurons in the substantia nigra pars compacta 60
days after infection. Our results suggest that a pandemic H5N1 pathogen, or other neurotropic
influenza virus, could initiate CNS disorders of protein aggregation including Parkinson’s and
Alzheimer’s diseases.
NEURODEGENERATIVE DISEASE. Proving the link
Katherine Whalley NATURE rev | Neuroscience vol 10 | October 2009
This study shows that — as predicted by the prion hypothesis — a mutation in PrP can result in
the generation of an infectious agent capable of causing a distinct neurodegenerative disease.
Propagation of Tau Misfolding from the Outside
to the Inside of a Cell
Bess Frost B, et al. THE JOURNAL OF BIOLOGICAL CHEMISTRY
VOL. 284, NO. 19, pp. 12845–12852, May 8, 2009
0.3 and 0.25% of cells are dual positive when cells are treated with
buffer (B) or monomer (M), versus 1% when treated with
Tau aggregates (A), indicating transfer of aggregated full-length TauYFP between cells.
Direct visualization indicates a Tau-YFP inclusion (white
arrowhead) within an mCherry-expressing cell
Tau aggregates can propagate a fibrillar, misfolded state from the outside to the inside of a cell.
This may have important implications for understanding how protein misfolding spreads
through the brains of tauopathy patients, and it is potentially relevant to myriad
neurodegenerative diseases associated with protein misfolding.
Richard J. Perrin et al. NATURE |Vol 461|15 October 2009|
New research diagnostic criteria for AD
1 major criterion
A. An episodic memory disorder
Progressive change in memory function (patient or informant)
Evidence of a recall deficit that does not normalize with cueing
Deficit isolated or associated with other cognitive changes
+1 or more minor criteria
B. Structural: atrophy of medial temporal lobe (MRI)
or
C. Biochemical: changes in biomarkers (CSF)
or
D. Functional: neuroimaging pattern on PET or SPECT
or
E. Genetic: autosomal dominant mutation in immediate family
Dubois B, et al. Lancet Neurol 2007;6:734–46
MRIs: Hippocampal Atrophy in AD
Normal
Good correlation with
neurofibrillary pathology
in aging and dementia
Mild Atrophy
Alzheimer’s
Disease
Richard J. Perrin et al. NATURE |Vol 461|15 October 2009|
33
PET imaging of amyloid deposition in
patients with mild cognitive impairment
Forsberg A et al. Neurobiology of Aging 29 (2008) 1456–1465
Conversion of amyloid positive and negative MCI to AD
over 3 years. An 11C-PIB PET study
Okello, A, et al. Neurology 2009 early ed
31 MCI with 11C-PIB PET, MRI, and neuropsychometry have been
clinically followed up for 1 to 3 years.
1.
2.
3.
55% with MCI had increased 11C-PIB retention at baseline and 82% clinically converted to
AD during follow-up.
Only one PIB negative MCI cases converted to AD.
PIB-positive MCI, 47% converted to AD within 1 year of baseline PIB PET,
PIB-positive subjects with mild cognitive impairment (MCI) are significantly more
likely to convert to AD than PIB-negative patients, faster converters having higher
PIB retention levels at baseline than slower converters.
Frequent Amyloid Deposition Without
Significant Cognitive Impairment Among the Elderly
Aizenstein HJ et al. Arch Neurol. 2008;65(11):1509-1517
Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed
evidence of early amyloid deposition in at least 1 brain area
Amyloid can be identified among cognitively normal elderly and the prevalence of
asymptomatic amyloid may be similar to that of symptomatic amyloid deposition.
Disruption of Functional Connectivity in
Clinically Normal Older Adults Harboring Amyloid Burden
Hedden T, et al. The Journal of Neuroscience, October 7, 2009 • 29(40):12686 –12694
Clinically normal participants with high amyloid burden displayed significantly
reduced functional correlations within the default network relative to participants
with low amyloid burden.
Whole-brain analyses revealed significant disruption in the default network
including functional disconnection of the hippocampal formation.
Tractament
ChEI + Memantine:
Can they be associated?
ChEI Memantine
NICE 2006
MMSE
30
20
10
¿?
3
Disease’s modifying strategies
• Non specific
Hormone replacement
Nonsteroidal anti-inflammatory drugs
Diet/cholesterol/statins
Vitamine and antioxidantes
PPAR-g agonist
•
Specific
antiamyloid
anti- microtubule-associated protein tau
Metal protein attenuating compounds
ONGOING CLINICAL TRIALS FOR TREATING ALZHEIMER’S DISEASE
41
Lennart Mucke, NATURE Vol 461|15 October 2009
Altres demències
Dementia with Lewy bodies (DLB)
Substantia nigra
Hans Förstl for Neuronet, Novartis
Dementia with Lewy Bodies
Criteria for the diagnosis of probable DLB
Cognitive decline sufficient to interfere with social / occupational function
CORE features:
– Fluctuation
– Recurrent visual hallucinations
– Spontaneous parkinsonism
Suggestive features:
– REM sleep behaviour disorder
– Neuroleptic sensitivity
– Dopaminergic abnormalities in basal ganglia on SPECT / PET
Two features (one must be core) for probable DLB
One feature (core or suggestive) for possible DLB
McKeith IG, et al. Neurology 2005;65:1863–72
Early-Onset Familial Lewy-Body Dementia with Extensive Tauopathy:
A Clinical, Genetic and Neuropathological Study.
Clarimon J, et al. Journal of Neuropathology and Experimental Neurology
Vol. 68, No. 1 January 2009 pp.73-82
Double-labelling immuno fluorescence and confocal
microscopy with α-synuclein (green) and phospho-tau (red)
antibodies in brain sections of patient II-1
We report a unique family with pathologically confirmed early-onset DLB with widespread tau and
α -synuclein deposition. The absence of mutations in genes known to cause LBD suggests that a
novel locus or loci are implicated in this neurodegenerative disease.
Frontotemporal lobar degeneration (FTLD)
Slowly progressive,
non-fluent aphasia
(green)
Frontotemporal
dementia
(yellow)
Semantic dementia
(orange)
Hans Förstl for Neuronet, Novartis
Frontotemporal Degeneration
Criteria for the diagnosis of
frontotemporal lobar degeneration (FTLD)
FTLD is a group of neurodegenerative diseases that share the common
feature of focal, lobar progressive degeneration and atrophy
Three main clinical syndromes:
– Behavioural variant, frontal lobe syndrome, frontal lobe dementia
– Language syndromes
– Progressive non-fluent aphasia
– Semantic dementia
– Motor syndromes
– Progressive apraxia
– Corticobasal degeneration / progressive supranuclear palsy
All syndromes may present with or without motor neuron disease (MND)
All syndromes may present with or without parkinsonism
All syndromes may be sporadic or familial
Brun A, et al. J Neurol Neurosurg Psychiatry 1994;57:416–18
Clinical manifestations of FTLD:
Behavioural variant
Insidious onset of progressive changes in personality and behavioural
abnormalities
– Loss of personal/social awareness, lack of empathy, self-centeredness,
emotional coldness, decreased concern
– Poor insight
– Disinhibition, impulsivity, antisocial behaviour
– Distractibility, restlessness, pressured speech, irritability, aggressiveness,
violent outbursts
– Verbal inappropriateness, sexual comments/gestures
– Stereotyped perseverative behaviours and language, compulsions
– Euphoria, jocularity, exaggerated self-esteem
– Apathy, emotional withdrawal, mutism
– Dietary changes, craving for sweets
– Executive dysfunction
Structural neuroimaging (MRI) in FTLD:
Behavioral variant
MRI image provided by, and used with the kind permission of, Dr Pablo
Martínez-Lage
Structural/functional neuroimaging of FTLD:
Progressive non-fluent aphasia
Afasia Progresiva no fluente
Lalas
paciente:
A
pacientes se les presentó una lámina en la que se
veían unos niños jugando con sus padres en la playa y la
“……….E…llos
jugar………madre.…pa..dre..
en la
………plata..
madre
lavando
la ropa en un barreño en
orilla y se les
(playa)”
pidió que describieran lo que estaba ocurriendo, todos
ellos tuvieron algún problema de comprensión teniendo
que repetir algunas frase, cambiar alguna palabra por otra
presenta
esfuerzo
en la salida desintácticamente
la voz y
yLa
enpaciente
otros casos
hubo
que simplificarlas
dificultades articulatorias (apraxia), presenta un severo
agramatismo presentando supresión casi constante de los
morfemas gramaticales y la reducción de las frases apenas a
una secuencia de morfemas léxicos, presenta parafasias
MRI and PET images provided by, and used with
fonéticas
, anomia
sin
compensación
the kind
permission
of, Dr
Pablo Martínez-Lagey omisiones.
Structural/functional neuroimaging of
Demencia Semántica
FTLD : Semantic dementia
La paciente :
“al lado de ellos (por los niños)... se encuentra su..., es una persona
(por madre), una señora (por madre) ella se ve que está lavando en
un cacharro (por barreño)…así grande..de estos donde se pone la
ropa y le das y la sacas limpia (circunloquio)”.
El lenguaje se presenta fluente y correcto gramaticalmente, sin embargo, la paciente
presenta circunloquios, parafasias semánticas….el lenguaje presenta pérdida de contenido
y las palabras han iniciado un deterioro en el gradiente del sistema semántico pasando a
ser palabras cada vez más generales dentro de la categoría semántica (persona en lugar de
madre)..hecho que irá evolucionando hacia la pérdida de las mismas desarrollando un
lenguaje vacío de contenido.
MRI and PET images provided by, and used with
the kind permission of, Dr Pablo Martínez-Lage
Clinical and Pathological Heterogeneity of Neuronal
Intermediate Filament Inclusion Disease
Molina-Porcel L, Blesa R, et al. Arch Neurol. 2008;65(2):272-275
inclusions are
immunoreactive to
α-internexin.
Frontotemporal lobar degeneration with FUS pathology
Neumann M, et al. Brain Advance Access published August 11, 2009
fused in sarcoma (FUS)
In patients with aFTLD-U, neurons with inclusions
(arrow) retained at least some of the normal nuclear
and cytoplasmic staining
Subgroup of FTD patients (10%) characterized by frontotemporal lobar
degeneration with severe progressive behavioural and personality changes
in the absence of aphasia or significant motor features with neuronal
inclusions composed of an unidentified ubiquitinated protein
All cases were sporadic and had early-onset.
All aFTLD-U cases, FUS immunohistochemistry labelled all the neuronal
inclusions and also demonstrated previously unrecognized glial pathology.
No mutations in the FUS gene were identified in any of our patients
FUS is the pathological protein in a significant subgroup of sporadic FTD
and reinforce the concept that FTD and amyotrophic lateral sclerosis are
closely related conditions
Biochemical classification of degenerative dementias
1.Tauopathies (examples):
- Tangle-dominant dementia (3+4R tau, no/few amyloid deposits)
- Argyrophilic grain disease (4R tau) (+/¡ Alzheimer lesions)
- Progressive supranuclear palsy, Corticobasal degeneration (4R tau)
- Frontotemporal dementia linked to chromosome 17 (FTDP-17)
- Pick’s disease (3R tau doublet, no Exon 10)
1a. Alzheimer disease (3+4R tau triplet + amyloid) – probably a specific entity
2. -Synucleinopathies
- Dementia with Lewy bodies
- Parkinson’s disease with dementia (PDD)
3. TDP-43 proteinopathies
- ALS-dementia (uibiquitin/TDP-43 + inclusions)
- Familial FTLD with Ubi + , Tau-negative inclusions FTD + MND)
4. Polyglutamine repeat (CAG) disorders
- Huntington’s disease (CAG triplet repeat)
5. Neuro Filmentopathies
- Intermediate filament inclusion disease (NIFID)
6. Neuroserpinopathies
-Dementia + myoclonus epilepsy (neuroserpin gene mutation)
7. Prion diseases
8. Lysosomal disorders
- Niemann-Pick type C disease. Ceroid lipofuscinosis, etc.
54
[progranulin]
Classificació anatomopatològica
Degeneració lobular
frontotemporal
Tau +
Ubiquitina + (Tau -)
TDP 43 +
Pick
FTLD
amb
mutació
MAPT
CBD
PSP
AGD
MSTD
TDP 43 -
Demència
amb cabdells
neurofibrilars
Altres tauopaties
FTLD-U Tipus 1-4
FTLD-U Tipus 5
Ubiq -
FUS
Brain
August 2007,
11, 2009
Acta Neuropathol
114:5-22
No disease in the brain of a 115-year-old woman
Wilfred F.A. den Dunnena et al Neurobiology of Aging 29 (2008) 1127–1132
The Nun Study
Clinically silent AD, neuronal hypertrophy, and linguistic skills in early life
Iacono D, et al.Neurology 2009;73:665–673
Linguistic ability in early life in 2
groups of subjects with an autopsyconfirmed diagnosis 5 decades later
1) Neuronal hypertrophy may constitute an early cellular response to AD pathology or
reflect compensatory mechanisms that prevent cognitive impairment despite
substantial AD lesions
2) higher idea density scores in early life are associated with intact cognition in late
life despite the presence of AD lesions.
CONCLUSIONS
•
LES DEMÈNCIES NEURODEGENERATIVES SON CONSEQUENCIA
DEL DIPÒSIT DE PROTEÏNES ANORMALS EN EL CERVELL.
•
L’APARICIÓ DE LA SIMPTOMATOLOGIA SEMBLA ESTAR
RELACIONADA PER LA QUANTITAT I LOCALITZACIÓ DEL
DIPÒSIT DE PROTEÏNES
•
ELS FACTOR GENÈTICS AVANÇEN L’APARICIÓ DELS
SÍMPTOMES (MUTACIONS CAUSALS).
•
ELS FACTORS DE RISC GENÈTICS FACILITEN L’ACUMULACIÓ
DE LES PROTEÏNES I JUNTAMENT AMB ALTRES FACTORS
DETERMINEN EL COMENÇAMENT DE LA CLÍNICA.
•
LA RECERCA VA DIRIGIDA A COMPRENDRE EL MECANISMES
DE PRODUCCIÓ DE LES PROTEÏNES ANORMALS I A EVITAR LA
SEVA CREACIÓ I ACUMULACIÓ
Pascual Maragall
declaró en Octubre
del 2007, en el salón
de actos del Hospital
de St Pau, que le
habían diagnosticado
un “principio” de la
enfermedad de
Alzheimer.
Ha creado la
Fundación Pascual
Maragall para la
investigación de la
enfermedad de
Alzheimer
Hospital de la Santa Creu i Sant Pau
2009
1904