Perspectives terapèutiques a la malaltia d Alzheimer · Perspectives terapèutiques a la malaltia...

1

Perspectives terapèutiques a la

malaltia d’Alzheimer

Barcelona 18 de Febrer 2017

Dr. Alberto Lleó

Unitat de Memòria

Servei de Neurologia

Hospital de Sant Pau

Barcelona

1906 Dr. Alois Alzheimer primera descripción de enfermedad

Auguste D. Alois Alzheimer

La demencia es el problema de salud más importante

en el siglo XXI

OECD (2014), Life expectancy (indicator). doi:

10.1787/27e0fc9d-en (Accessed on 04 December 2014)

Esperanza de vida al nacer, población total

Cada vez somos más longevos

Lesiones en la enfermedad de Alzheimer

Placas amiloides Ovillos neurofibrilares

Nat Neurosci 2017

“El diagnóstico no se puede realizar por test de laboratorio”

“Tests son importantes para identificar otras causas de

demencia”

EA se conceptualiza como demencia

1984 Criterios Alzheimer NINCDS-ADRDA

McKhann, Neurology 1984;34:939-44

2011 – Criterios NIA-AAS

Sd. amnésico característico

(tipo hipocampal)

Memoria episódica

(recuerdo diferido)

Reconocimiento

No mejora con claves

CUADRO CLÍNICO

Test de recuerdo libre y con pistas de Buschke

(FCSRT, Buschke, 1984).

Nuevos criterios de Alzheimer permiten

diagnosticar antes de la demencia

Albert M, Alzheimer & Dementia 2011

Pérdida de memoria objetiva +

marcador característico

Análisis de líquido cefalorraquídeo

PET: tomografía por emisión de positrones

Biomarcadores

Líquido cefalorraquídeo

-amiloide

tau

PET

(18F-Florbetapir)

PET

(18F-Fluorodeoxiglucosa)

Resonancia magnética

70 años (médico jubilado)

Memoria (olvida nombres, algún

hecho reciente y más reiterativo).

Le cuesta visualizar rutas.

Vida normal.

MMSE: 30/30. FCSRT: Normal. Lista

CERAD: alterada.

Padre con Alzheimer a 79 años.

CASO CLÍNICO

A42 : 529 pg/ml (>550)

T-tau: 781 pg/ml (<350)

P-tau: 107 (<61)

Resultado LCR

Sant Pau

LCR característico de E. de Alzheimer

PET

puede medir proteína Tau

(Investigación)

Ovillos neurofibrilares

(proteína tau hiperfosforilada)

Cómo se informa del diagnóstico

Fuente: Alzheimer Association 2015

1976

Hipótesis colinérgica de la enfermedad de Alzheimer

disease1403

Letters to the Editor

SELECTIVE LOSS OF CENTRAL CHOLINERGIC

NEURONS IN ALZHEIMER’S DISEASE

SIR,-Alzheimer’s disease is a progressive cerebral degener-ation which continues without remission until death, usuallyin profound dementia. Morphologically, the disease is charac-terised by large numbers of senile plaques and neurofibrillarytangles in the brain, these tangles being especially abundant inthe cerebral cortex. Neurochemical studies are still in their in-

fancy, and we know nothing of the molecular basis of the dis-ease.

We have studied the enzymes associated with the putativeneurotransmitters acetylcholine, y-aminobutyric acid, dopa-mine, noradrenaline and 5-hydroxytryptamine in twenty re-

gions of brains obtained at necropsy from three patients withAlzheimer’s disease and from ten individuals who died without

evidence of neurological or psychiatric disorder. The brains

were removed 24-36 h after death, and each brain was

divided in half down the mid-line. The right half was used forbiochemical analyses, whilst the left half was fixed in formalinfor neuropathological examination. Alzheimer’s disease wasconfirmed histologically. There was no evidence of cerebrovas-cular disease in any of the thirteen cases. The ten controls

ranged in age from 46 to 74; the Alzheimer patients were aged61, 70, and 75. Tissues from the right half of the brain werestored at -190°C. Choline acetyltransferase (C.A.T.) and ace-

tylcholinesterase (A.C.E.) activities were measured by the

methods of Fonnum, and glutamic acid decarboxylase (G.A.D.)activity by the method of Roberts and Simonsen.2

C.A.T. activity in the Alzheimer’s disease brains was muchreduced in the amygdala, hippocampus, and cortex (table I).Only three Alzheimer brains have been studied but the extentof the reduction in these areas strongly suggests this is not achance occurrence. The activity of A.C.E. is dramaticallyreduced in the same areas of the cerebral cortex that show

reductions in C.A.T. activity (table II), and is below the levelsfound in the normal brains in all the other areas. The areas

of the cerebral cortex which show the maximum reductions in

c.A.T. and A.C.E. activity are those which contain the greatestdensity of neurofibrillary tangles.The reductions in the activity of the enzymes involved in the

metabolism of acetylcholine are not a result of non-specificdegenerative process. The activity of G.A.D. in all the areas ofthe Alzheimer’s disease brains studied appears to be well

within the normal range, means ranging from 74% to 121% ofcontrol activities. That this is the case in the cortical areas

which show large losses of c.A.T. and A.C.E. supports the notionthat a selective degenerative process has occurred. The normalvalues obtained for G.A.D. are of special significance because this

enzyme is particularly sensitive to ante-mortem hypoxia.3 It

seems unlikely, therefore, that the decreased activity of

enzymes associated with cholinergic transmission can be

ascribed to this cause; none of the patients with Alzheimer’sdisease had prolonged terminal hypoxic episodes.

Preliminary studies of tyrosine hydroxylase, aromatic amino-acid decarboxylase, dopamine-&bgr;-hydroxylase, and monoamineoxidase indicate no loss of these enzyme activities in Alz-

heimer’s disease and lend weight to the notion that a selectivedestruction of the cortical cholinergic system is an importantfeature of this condition.

We considered the possibility that selective loss of choliner-

gic system components could be due to prolonged drugregimens used in the patients with Alzheimer’s disease. How-

ever, there is no standard drug therapy for Alzheimer’s, and

1. Fonnum, F. Biochem. J. 1969, 115, 465.2. Roberts, E., Simonsen, D. E. Biochem. Pharmac. 1963, 12, 113.3. Bowen, D. M., Davison, A. N. in Biochemistry and Neurological Disease

edited by A. N. Davison); p. 2. Oxford, 1976.

TABLE I--CHOLINE ACETYLASE ([L mol/h/g WET WEIGHT)

TABLE II-ACETYLCHOLINESTERASE (MMOWG WET WEIGHT)

treatment is symptomatic. All three patients were given nitra-

zepam, but this drug was also given to five of the ten control

patients during their terminal illness. Opiates were adminis-tered to two of the Alzheimer patients and five of the con-trols, and phenothiazines were given to one and two patients,respectively. Thus no drug treatment was exclusive to the Alz-heimer’s disease patients, and it seems improbable that thedeficit in C.A.T. and A.C.E. activity in the cortex of these indi-viduals is drug induced.

Expression of results relative to protein, D.N.A., or R.N.A.

content does not alter the pattern of the results significantly.If these data can be confirmed in a larger series of cases the

concept of Alzheimer’s disease as a cholinergic system failure

may have important consequences for research on this condi-tion.

M.R.C. Brain Metabolism Unit,

University Department of Pharmacology,1 George Square,Edinburgh EH8 9JZ

University Department of Pathology,Royal Infirmary of Edinburgh, and

Department of Neuropathology,Western General Hospital,

Edinburgh

P. DAVIES

A. J. F. MALONEY

HEADACHE AFTER LUMBAR PUNCTURE

SiR,—The frequency of headache after lumbar puncture inthe four large series cited by Wolff was 25%.’ The headacheis thought to be due to continued leakage of cerebrospinal fluid

(c.s.F.) through the hole in the theca, the subsequent low pres-sure in the c.s.F. pathways inducing pain by traction on the

pain-sensitive neural endings in the dura and intracranial

venous sinuses and arteries. Aqueous vasopressin injection(’Pitressin’) as a prophylactic measure was popular some years

1. Wolff, H. G. Headache and Head Pain; p. 112. New York, 1963.

N=3

1995 Tacrina aprobada

Tratamientos actualmente aprobados para el Alzheimer

Lleo A, Grennberg S, Growdon JH. Ann Rev Med 2016

10 Aug 2005 21:13 AR ANRV262-ME57-07.tex XMLPublishSM(2004/02/24)P1: OKZ /OAH P2:OJO

AR REVIEWS IN ADVANCE10.1146/annurev.med.57.121304.131442

PHARMACOTHERAPY FOR ALZHEIMER’S 7.3

Figure1 Acetylcholine (ACh) biosynthesis, synaptic transmission, and metabolism.

ACh is synthesized from acetyl coenzyme A and choline through the action of the en-

zyme choline acetyltransferase. ACh is concentrated in vesicles and released into the

synaptic cleft where it acts on presynaptic receptors regulating further release of ACh,

and on postsynaptic receptors regulating neurotransmission. Acetylcholinesterase hy-

drolyzes ACh into acetate and choline; choline is then taken up into the presynaptic

neuron for ACh resynthesis. Acetylcholinesterase inhibitors reduce degradation of ACh

and therefore increase its synaptic concentration and postsynaptic neurotransmission

effects.

choline acetyltransferase (see Figure 1), concentrated in vesicles, and released from

the presynaptic cell following depolarization. ACh interacts with muscarinic and

nicotinic cholinergic receptors on pre- and postsynaptic cells. In the case of postsy-

naptic cells, this interaction leads to an activation of biochemical pathways within

the cell. Once released into the synaptic cleft, ACh is rapidly hydrolyzed by local

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Tratamiento actual para el Alzheimer

Lleó A, Ann Rev Med 2006; 57:513-33

• IACEs muestran beneficios modestos en pacientes

con enfermedad leve, moderada o grave en medidas

de cognición, funcionales, y conductuales.

• El tratamiento estándar es iniciar con IACE y añadir

memantina cuando progresa enfermedad (MMSE <20).

• La combinación se mantiene hasta la fase avanzada a

no ser que aparezcan efectos adversos o se observe

falta de eficacia (GDS 7B).

Resumen tratamiento actual del Alzheimer

Lleó A, Ann Rev Med 2006; 57:513-33

Rivastigmina: parche 13,3 mg

Estudio OPTIMA

Novedades “recientes”

Efectos a largo plazo de IACEs

Long-term observational controlled studies (LTOCs)

Roundtree SD, Alz & Dem 2013;9:1-8

30 10 320

NICE 2006

Memantina

Combinado

MMSE

IACE

14

0

10.000

20.000

30.000

40.000

50.000

60.000

70.000

80.000

90.000

100.000

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DONEPEZILO

MEMANTINA

RIVASTIGMINA

GALANTAMINA

* GENERICS

MERCADO “ANTI- ALZHEIMER” en ESPAÑA

IMS mat Apr 2013

Rivastigmina

parcheGenéricos

* GENERICS. Donepezil, Galantamine,

Rivastigmine oral

Rivastigmina

Parche 98,5%

Oral 1,5%

• En Cataluña se registraron

60.645 EA durante el año 2014,

• Un 68,6% (41.576) tratamiento

específico (32,3% hombres,

67,7% mujeres, edat media de

80 años) 0,55% de la población

total.

• El consumo de fármacos

aumenta en función de la edad,

del 0,1% a los 55-59 años al

máximo a los 85-89 años,

• El 67% de los tratados tenían

80 o más años

PAUTES PER A L’HARMONITZACIÓ DEL TRACTAMENT

FARMACOLÒGIC DE LA MALALTIA D’ALZHEIMER - 2016

Patrón de uso de medicamentos para la EA

- 86,1% monoterapia - (65% un IACE y 21,1% memantina) - 13,9% IACE asociado a memantina, como mínimo dos

trimestres consecutivos.

- Monoteràpia en función del principio activo:- rivastigmina 34% (12.950)- donepezil 30% (11.447).

Donepezil; 11.447 (30%)

Rivastigmina; 12.950 (34%)

Galantamina; 4.607 (12%)

Memantina; 9.423 (24%) Donepezil+

memantina; 2.502(40%)

Rivastigmin+memantina2.520(41%)

Galantamina+

memantina 1.192 (19%)

Monoterapia Combinación

Fortasyn Connect

Souvenaid 125ml, contiene Fortasyn® Connect

combinación de ácidos grasos omega3, colina, uridina

monofosfato, fosfolípidos, antioxidantes y vitaminas B.

Food for Special Medical Purpose (FSMP).

1976

Hipótesis colinérgica de la enfermedad de Alzheimer

disease1403

Letters to the Editor

SELECTIVE LOSS OF CENTRAL CHOLINERGIC

NEURONS IN ALZHEIMER’S DISEASE

SIR,-Alzheimer’s disease is a progressive cerebral degener-ation which continues without remission until death, usuallyin profound dementia. Morphologically, the disease is charac-terised by large numbers of senile plaques and neurofibrillarytangles in the brain, these tangles being especially abundant inthe cerebral cortex. Neurochemical studies are still in their in-

fancy, and we know nothing of the molecular basis of the dis-ease.

We have studied the enzymes associated with the putativeneurotransmitters acetylcholine, y-aminobutyric acid, dopa-mine, noradrenaline and 5-hydroxytryptamine in twenty re-

gions of brains obtained at necropsy from three patients withAlzheimer’s disease and from ten individuals who died without

evidence of neurological or psychiatric disorder. The brains

were removed 24-36 h after death, and each brain was

divided in half down the mid-line. The right half was used forbiochemical analyses, whilst the left half was fixed in formalinfor neuropathological examination. Alzheimer’s disease wasconfirmed histologically. There was no evidence of cerebrovas-cular disease in any of the thirteen cases. The ten controls

ranged in age from 46 to 74; the Alzheimer patients were aged61, 70, and 75. Tissues from the right half of the brain werestored at -190°C. Choline acetyltransferase (C.A.T.) and ace-

tylcholinesterase (A.C.E.) activities were measured by the

methods of Fonnum, and glutamic acid decarboxylase (G.A.D.)activity by the method of Roberts and Simonsen.2

C.A.T. activity in the Alzheimer’s disease brains was muchreduced in the amygdala, hippocampus, and cortex (table I).Only three Alzheimer brains have been studied but the extentof the reduction in these areas strongly suggests this is not achance occurrence. The activity of A.C.E. is dramaticallyreduced in the same areas of the cerebral cortex that show

reductions in C.A.T. activity (table II), and is below the levelsfound in the normal brains in all the other areas. The areas

of the cerebral cortex which show the maximum reductions in

c.A.T. and A.C.E. activity are those which contain the greatestdensity of neurofibrillary tangles.The reductions in the activity of the enzymes involved in the

metabolism of acetylcholine are not a result of non-specificdegenerative process. The activity of G.A.D. in all the areas ofthe Alzheimer’s disease brains studied appears to be well

within the normal range, means ranging from 74% to 121% ofcontrol activities. That this is the case in the cortical areas

which show large losses of c.A.T. and A.C.E. supports the notionthat a selective degenerative process has occurred. The normalvalues obtained for G.A.D. are of special significance because this

enzyme is particularly sensitive to ante-mortem hypoxia.3 It

seems unlikely, therefore, that the decreased activity of

enzymes associated with cholinergic transmission can be

ascribed to this cause; none of the patients with Alzheimer’sdisease had prolonged terminal hypoxic episodes.

Preliminary studies of tyrosine hydroxylase, aromatic amino-acid decarboxylase, dopamine-&bgr;-hydroxylase, and monoamineoxidase indicate no loss of these enzyme activities in Alz-

heimer’s disease and lend weight to the notion that a selectivedestruction of the cortical cholinergic system is an importantfeature of this condition.

We considered the possibility that selective loss of choliner-

gic system components could be due to prolonged drugregimens used in the patients with Alzheimer’s disease. How-

ever, there is no standard drug therapy for Alzheimer’s, and

1. Fonnum, F. Biochem. J. 1969, 115, 465.2. Roberts, E., Simonsen, D. E. Biochem. Pharmac. 1963, 12, 113.3. Bowen, D. M., Davison, A. N. in Biochemistry and Neurological Disease

edited by A. N. Davison); p. 2. Oxford, 1976.

TABLE I--CHOLINE ACETYLASE ([L mol/h/g WET WEIGHT)

TABLE II-ACETYLCHOLINESTERASE (MMOWG WET WEIGHT)

treatment is symptomatic. All three patients were given nitra-

zepam, but this drug was also given to five of the ten control

patients during their terminal illness. Opiates were adminis-tered to two of the Alzheimer patients and five of the con-trols, and phenothiazines were given to one and two patients,respectively. Thus no drug treatment was exclusive to the Alz-heimer’s disease patients, and it seems improbable that thedeficit in C.A.T. and A.C.E. activity in the cortex of these indi-viduals is drug induced.

Expression of results relative to protein, D.N.A., or R.N.A.

content does not alter the pattern of the results significantly.If these data can be confirmed in a larger series of cases the

concept of Alzheimer’s disease as a cholinergic system failure

may have important consequences for research on this condi-tion.

M.R.C. Brain Metabolism Unit,

University Department of Pharmacology,1 George Square,Edinburgh EH8 9JZ

University Department of Pathology,Royal Infirmary of Edinburgh, and

Department of Neuropathology,Western General Hospital,

Edinburgh

P. DAVIES

A. J. F. MALONEY

HEADACHE AFTER LUMBAR PUNCTURE

SiR,—The frequency of headache after lumbar puncture inthe four large series cited by Wolff was 25%.’ The headacheis thought to be due to continued leakage of cerebrospinal fluid

(c.s.F.) through the hole in the theca, the subsequent low pres-sure in the c.s.F. pathways inducing pain by traction on the

pain-sensitive neural endings in the dura and intracranial

venous sinuses and arteries. Aqueous vasopressin injection(’Pitressin’) as a prophylactic measure was popular some years

1. Wolff, H. G. Headache and Head Pain; p. 112. New York, 1963.

N=3

1995 Tacrina aprobada

Chartier-Harlin, Nature. 1991;353:844-6

Glenner GG, Wong CW. Biochem Biophys Res Commun. 1984;120:885-90

Sherrington R. Nature 1995; 375: 754-760.

β-amiloide y enf. de Alzheimer

1991

Primera mutación gen

Proteína Precursora

de Amiloide en

Alzheimer

1995

Mutaciones en

Presenilinas causan

Alzheimer

1986

Tau identificada en cerebros de pacientes

con Alzheimer

Wolozin, Science Science. 1986;232(4750):648-50.

Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI.

Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7.

Ihara Y, Nukina N, Miura R, Ogawara M.

J Biochem. 1986 Jun;99(6):1807-10.

Kosik KS, Joachim CL, Selkoe DJ.

Proc Natl Acad Sci U S A. 1986 Jun;83(11):4044-8.

Wood JG, Mirra SS, Pollock NJ, Binder LI.

Proc Natl Acad Sci U S A. 1986 Jun;83(11):4040-3.

1992 Hipótesis amiloide marca avance

conceptual clave

Selkoe & Hardy, EMBO Mol Med 2016;8:595-608

< 1% 99%?

Nicoll, Nat Med 2003

Ferrer, Brain Pathol 2004

2000 – Primeros estudios con inmunización

“activa” anti-amiloide en Alzheimer

Paciente

inmunizado

Paciente con

placebo

NATURE REVIEWS | NEUROLOGY VOLUME 11 | JANUARY 2015 | 47

Nonetheless, a small group of patients underwent CSF

analyses, and their data indicated that AN1792 reduced

levels of tau, but not Aβ1–42

, in antibody responders.97 The

lack of change in CSF Aβ1–42

contrasts with the reductions

in brain Aβ plaque load observed on postmortem assess-

ment.98 This result suggests that that removal of aggre-

gated Aβ does not necessarily affect the pool of soluble Aβ

in CSF, or that clearance of cortical Aβ can occur through

pathways other than CSF.

In agreement with these data, active immunization

with CAD-106, a small Aβ peptide fragment (Aβ1–6

),

had no effect on CSF Aβ1–42

in a phase I trial.99 The

reduction in CSF tau levels by AN1792 might indicate

downstream effects of the treatment on pathology, such

that the intensity of neuronal degeneration is reduced

by Aβ immunization. This notion is supported by post-

mortem neuropathology studies that show amelioration of

neurite abnormalities in patients treated with AN1792.100

In addition, it is possible that the reduction in CSF tau

levels is partly attributable to a mild effect of AN1792

on tau pathology, as has been observed in transgenic

mouse models of AD.101,102 However, autopsy studies of

AN1792-treated patients with AD have reported mild or

no changes in the density of neurofibrillary tangles and

neuropil threads compared with non-treated patients,

suggesting that the effects of Aβ immunization on tau

pathology, at least in patients with dementia, are small.100

Taken together, the data from the AN1792 trial suggest

that removal of cortical Aβ probably ameliorated abnor-

malities in neuronal morphology, which in turn, though

not sufficient to change the clinical course of the disease,

reduced the levels of CSF tau. Other immunization trials

with CAD-106 or ACC-001 in patients with MCI due to

AD, or with mild to moderate AD, are ongoing; these trials

include CSF biomarkers as secondary outcomes (Table 1).

In light of the adverse events observed with active

immunization, most immunotherapy studies in AD now

use passive immunization, which is based on the admin-

istration of monoclonal antibodies directed towards

different regions of Aβ. Bapineuzumab is a human-

ized version of the monoclonal antibody 3D6, which is

directed against the N-terminal region of Aβ and binds to

monomeric, oligomeric and fibrillar forms of Aβ.103 Trials

of bapineuzumab have included CSF biomarkers as sec-

ondary outcome measures of neurodegeneration. In two

phase II trials, bapineuzumab decreased CSF t-tau and

p-tau, but not Aβ1–42

or AβX–42

levels compared with base-

line.104 These data are in general agreement with recent

data from two phase III trials,105 in which bapineuzumab

at two different doses reduced CSF p-tau levels at 71 weeks

relative to placebo in Apo-E ε4 allele (APOE*ε4) carriers.

In noncarriers, however, the antibody only reduced CSF

p-tau levels at the highest dose. Bapineuzumab did not

change CSF Aβ1–42

or Aβ1–40

levels in either the carriers

or the noncarriers, mirroring the results of the active Aβ

immunization trials.

In the phase III trials, bapineuzumab was shown to

modestly decrease the rate of Aβ accumulation in the

brain in APOE*ε4 carriers, suggesting that the concen-

tration of Aβ1–42

in CSF does not always reflect changes

in fibrillar Aβ deposits. Together with the data from

active Aβ immunization trials, these results support a

model in which deposition of fibrillar Aβ decreases CSF

Aβ1–42

, presumably by sequestering Aβ1–42

into plaques,

but removal of fibrillar Aβ does not necessarily have an

effect on the CSF pool of soluble Aβ. The reduction in

CSF p-tau levels in both the phase II and phase III trials

suggests that bapineuzumab reduces tau phosphoryla-

tion in the brain, although this change was not associated

with any clinical benefit. This observation is supported

by data from experiments in rat hippocampal neurons,

which showed that treatment with the 3D6 antibody

prevented tau hyperphosphorylation.103

Clinical development of bapineuzumab was discon-

tinued owing to the lack of clinical benefit. The dose

of bapineuzumab used in these studies, however, was

limited by the emergence of amyloid-related imaging

abnormalities at higher doses. Therefore, it is possible

that despite some target engagement, too little Aβ was

removed to test whether changes in neurodegeneration

markers occur after bapineuzumab treatment.

Solanezumab is a humanized version of the anti-Aβ

monoclonal antibody m266, which has selective affinity

for soluble Aβ. Two large phase III trials (EXPEDITION 1

and 2) have evaluated the efficacy of solanezumab.

Primary end points were not reached, but a pooled analy-

sis showed that solanezumab slowed cognitive decline in

patients with mild AD.106 In a subset of 121 patients who

underwent CSF analyses, total Aβ1–40

and Aβ1–42

levels

were increased after solanezumab treatment, whereas

free (unbound) Aβ1–40

was reduced. These results rep-

licated those observed in phase I and II trials,107,108 and

suggest positive target engagement with mobilization of

the central soluble Aβ pool. Solanezumab is not expected

to bind to fibrillar Aβ109 and, therefore, the observed

increase in total CSF Aβ is unlikely to have come from

interactions with the fibrillar Aβ component. Whether

the effects reflect mobilization within the central soluble

Aβ pool and/or promotion of Aβ efflux from the CNS to

the peripheral circulation remains unclear.110

In addition to Aβ, t-tau and p-tau levels were meas-

ured in CSF after solanezumab treatment, and no

changes were detected.106 This result indicates that mobi-

lization of the Aβ pool did not affect any of the markers

of neurodegeneration. These data seem to support the

Figure 2 | Monoclonal antibodies that target Aβ pathology. One of the main

pathological hallmarks of AD is Aβ plaques, which are formed by progressive

accumulation of Aβ peptides. Solanezumab was designed to bind to monomeric Aβ,

thereby preventing oligomerization and deposition. Bapineuzumab is a humanized

N-terminus-specific monoclonal antibody that binds to Aβ. In animal models of AD,

3D6—the murine form of the antibody—binds to monomeric, oligomeric and fibrillar

forms of Aβ.117 Only the two most investigated antibodies with available cerebrospinal

fluid data have been included. Abbreviations: Aβ, amyloid-β; AD, Alzheimer disease.

Solanezumab

Monomeric Aβ Oligomeric Aβ Protof bril Aβ

Bapineuzumab

Amyloid plaque

Nature Reviews | Neurology

REVIEWS

© 2015 Macmillan Publishers Limited. All rights reserved

Terapias modificadoras de la enfermedad

Terapias anti-amiloide

Lleo A, Nat Rev Neurol 2015; 11:45-55


aid clinical trials of β-secretase inhibitors in patients

with AD, as this peptide can reliably reveal drug target

engagement. Apolipoprotein E (Apo-E) levels in CSF have

also been investigated. Although levels are comparable

between patients with AD and controls, they correlate

positively with CSF tau, and lower levels of Apo-E are

associated with cognitive decline and brain atrophy.59,60

A number of tau-independent markers of neuro-

degeneration have also been investigated in patients

with AD, including heart fatty acid-binding protein and

visinin-like protein 1,61,62 which might be useful markers

of neuronal injury in clinical trials. CSF biomarkers of

microglial activation include chitotriosidase, YKL-40

(also known as chitinase-3-like protein 1) and C–C motif

chemokine 2.63,64 Levels of these markers are elevated in

the CSF in patients with AD and other neurodegenera-

tive dementias, but longitudinal studies are required to

determine whether they correlate with disease sever-

ity or clinical progression. CSF biomarkers that reflect

early synaptic damage would be a useful addition to the

current arsenal, as they are likely to correlate with clinical

symptoms or disease progression. A series of presynap-

tic and postsynaptic proteins have been detected in CSF,

and increased levels of the dendritic protein neurogra-

nin have been found in the CSF of patients with AD.65,66

Finally, markers that can detect common copathologies

usually observed in the brain in AD may be of interest.

For example, α-synuclein in CSF is a potential marker for

Lewy body pathology in AD,67 and TAR DNA-binding

protein 43 (TDP-43) in CSF has been explored to detect

TDP-43 pathology.68

Clinicobiological correlations

Clinicopathological studies have shown that low CSF Aβ1–42

levels are associated with fibrillar Aβ deposits and cerebral

amyloid angiopathy postmortem,3,5,69 and with fibrillar Aβ

deposits in cortical biopsies.70 In agreement with these data,

low CSF Aβ1–42

levels are associated with increased cortical

amyloid burden, as assessed by amyloid PET imaging in

patients with AD dementia or MCI and cognitively normal

individuals.71–76 Importantly, the concordance between

CSF Aβ1–42

and amyloid PET is usually ≥90%, regardless

of whether CSF Aβ1–42

is analysed under ideal research

conditions or as part of the clinical routine.77 Exceptions

to this rule, however, are seen in carriers of some rare APP

mutations associated with autosomal dominant AD.78

Together, these data suggest that in the vast majority of

patients, a high correlation exists between soluble CSF

Aβ1–42

and amyloid pathology, and soluble CSF Aβ1–42

levels

decrease as amyloid pathology builds up, presumably due

to sequestration of Aβ1–42

in the brain parenchyma.

Increases in CSF t-tau5 and p-tau79 levels have been

linked to neurofibrillary tangle burden at autopsy. The

majority of studies in patients with AD evaluated the

levels of p-tau181

, although the levels of p-tau231

have been

reported to correlate better with postmortem tangle load

than do p-tau181 levels.

79,80 These data suggest that in AD,

CSF p-tau levels probably reflect neurofibrillary tangle

pathology, whereas CSF t-tau levels are a reflection of

the overall cytoskeletal derangement, and of neuronal

cell damage or death.

In summary, most of the current literature supports the

notion that CSF Aβ1–42

and p-tau levels reflect the main

pathological hallmarks of AD, while t-tau levels are a

measure of the degree of neuronal cell damage. An impor-

tant caveat is that although clinicopathological studies

indicate that tau pathology precedes amyloid pathology

in the disease course of AD, t-tau and p-tau levels become

abnormal in CSF later than does Aβ1–42

, indicating that

a substantial degree of neurofibrillary tangle pathology

and neuronal damage must occur before evidence is seen

in CSF.81 These correlates need further investigation to

facilitate interpretation of the changes in CSF biomarkers

in clinical trials.

Clinical trials in Alzheimer disease

Many of the current clinical trials in patients with AD

include CSF biomarkers as a measure of target engage-

ment. Less frequently, CSF biomarkers are used as second-

ary outcome measures to monitor disease modification,

or for sample enrichment or stratification of patients in

different stages of the pathophysiological process of AD

(Tables 1 and 2). Despite the growing use of these bio-

markers in clinical trials, however, interpretation of the

data is not always straightforward. Whereas the data from

Figure 1 | Main CSF biomarkers used in trials of anti-amyloid drugs in AD. Amyloid

precursor protein is processed sequentially by β-secretase and γ-secretase, and

subsequently aggregates into amyloid plaques in patients with AD. The main CSF

biomarkers used in trials with BACE and γ-secretase inhibitors are shown.

Abbreviations: Aβ, amyloid-β; AD, Alzheimer disease; APP, amyloid precursor protein;

BSI, β-secretase inhibitors; CSF, cerebrospinal fluid; GSI, γ-secretase inhibitors;

sAPPβ, soluble APPβ.

sAPPβ

Aβ peptideβ-Secretase

N-terminus

APP

C-terminus

γ-Secretase

BSI

BSI

BSI

GSI

BSI

GSI

GSI

Aβ5–40

Aβ1–40

Aβ1–42

Aβ1–15/ 16


REVIEWS


Inmunización pasiva

Tratamientos activos en ensayo clínico en Alzheimer

Otros tratamientos en investigación:

inhibidores de producción de amiloide

Nat Neurosci 2017

Avagacestat (inhibidor γ-secretasa) fase 2

Coric V et al, JAMA Neurol 2015;85:626-33

Otros tratamientos en investigación:

inhibidores de producción de amiloide

Buenas noticias en 2016

La Vanguardia 2016

3 de noviembre de 2016

Inmunización: Bapineuzumab y solanezumab















),






































or AβX–42









or Aβ1–40












Aβ1–42


into plaques,


























and Aβ1–42

levels


























Solanezumab


Bapineuzumab

Amyloid plaque


REVIEWS


Salloway S, 2014

Bapineuzumab fase 3

Niveles de p-tau en LCR

Salloway S, N Engl J Med 2014;370:322-33.

Doody R, N Engl J Med 2014;370:311-21.

Buenas noticias en 2016

La Vanguardia 2016

1 de septiembre de 2016

Otros medicamentos en investigación:

anticuerpos anti-amiloide

Lleo A, Nat Rev Neurol 2015















),






































or AβX–42









or Aβ1–40












Aβ1–42


into plaques,


























and Aβ1–42

levels


























Solanezumab


Bapineuzumab

Amyloid plaque


REVIEWS


Aducanumab (BIIB037)

Tau como diana en el Alzheimer

Holtzman D, Alzheimers Dement. 2016 May 4. pii: S1552-5260(16)30019-X.

AADvac1

Fase II

LMTX®

Medicamentos en investigación para el Alzheimer

Cortesía: Roser Ribosa

Estudios activos según enfermedad

(2017)

Cortesía: Roser Ribosa

12.409 Cáncer

5.498 Enf. cardiovasculares

369 Alzheimer

Otras demencias: demencia con cuerpos de Lewy

Se puede prevenir el Alzheimer?

Avance en prevención en 2016

22-44% reducción de casos

nuevos de demencia en 3

décadas

The Lancet 2015 385, 2255-2263DOI: (10.1016/S0140-6736(15)60461-5) Copyright © 2015 Elsevier Ltd Terms and Conditions

Estudio FINGER - Finlandia

1260 personas 60-77 años

2 años

Intervención intensiva

- Dieta

- Ejercicio físico (2-5 veces por semana)

- Estimulación cognitiva

- Control factores de riesgo: diabetes, colesterol, etc

http://www.elsevier.com/termsandconditions

Programa mejora 25-150% las funciones intelectuales

The Lancet 2015 385, 2255-2263DOI: (10.1016/S0140-6736(15)60461-5)

Copyright © 2015 Elsevier Ltd Terms and Conditions

http://www.elsevier.com/termsandconditions

Es importante tener un plan nacional sobre Alzheimer

Mensajes finales

√ Biomarcadores han abierto una nueva era

√ Diagnóstico precoz e información son clave

√ Terapias anti-amiloide en el horizonte

√ Otras estrategias todavía en su infancia

√ El Alzheimer merece un diagnóstico y

tratamiento agresivo como hacemos en otras

enfermedades (ictus o cáncer)

Perspectives terapèutiques a la malaltia d Alzheimer · Perspectives terapèutiques a la malaltia...

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